TW201630907A - TGFβR拮抗劑 - Google Patents
TGFβR拮抗劑 Download PDFInfo
- Publication number
- TW201630907A TW201630907A TW104142991A TW104142991A TW201630907A TW 201630907 A TW201630907 A TW 201630907A TW 104142991 A TW104142991 A TW 104142991A TW 104142991 A TW104142991 A TW 104142991A TW 201630907 A TW201630907 A TW 201630907A
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- TW
- Taiwan
- Prior art keywords
- alkyl
- hydrogen
- pyridin
- halogen
- independently
- Prior art date
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- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
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- 229950005972 urelumab Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
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Abstract
本發明一般係關於調節TGFβR-1及TGFβR-2活性之化合物、含有該等化合物之醫藥組合物及採用本發明化合物治療增殖性病症及細胞凋亡失調性病症(諸如癌症)之方法。
Description
本申請案主張2014年12月22日申請之美國臨時申請案第62/095,328號之優先權,該案全文係以引用之方式併入本文中。
本發明一般係關於調節TGFβR-1及TGFβR-2活性之化合物、含有該化合物之醫藥組合物及採用本發明化合物治療增殖性病症及細胞凋亡失調性病症(諸如癌症)之方法。
TGFβ係多功能細胞激素,其調節包括細胞增殖及分化、遷移及黏附、胞外基質修飾(包括腫瘤基質及免疫抑制)、血管生成及結締組織生成在內的眾多生物過程(Ling and Lee,Current Pharmaceutical Biotech.2011,12:2190-2202)、支持腫瘤進程及晚期疾病之程序。
TGFβ活化型係通過形成分別由絲胺酸蘇胺酸1型及2型受體、TGFβR-1(ALK5)及TGFβR-2構成的膜結合異源四聚體來傳遞信號的二聚體。在兩1型及兩2型受體結合時,2型組成型活化受體使1型受體之富含甘胺酸及絲胺酸之「GS區域」磷酸化,從而通過胞內信號傳遞效應分子(Smad2或Smad3)活化信號級聯。TGFβR-1磷酸化受體Smad2及/或Smad3(RSmads),其與Smad4形成複合物(Shi and Massague,Cell 2003,113:685-700)。此等複合物隨後移動至細胞核,其中其誘發導致基因表現改變的多種轉錄反應(Weiss and Attisano,WIREs
Developmental Biology,2013,2:47-63)。該等TGFβ蛋白質係哺乳動物中相關因子大家族之原型成員,其中此等蛋白中有若干种亦在其他門類中被識別。一般而言,已表徵兩個群組,類TGFβ及類BMP配體。此外,在脊椎動物中,已識別七種1型受體及五種2型受體。配體/受體結合之又一層面複雜性係促進配體結合至1型及2型受體複合物的稱為3型之輔助受體之潛能。此等3型受體(亦稱為β聚糖及內皮糖蛋白)係由大型胞外結構域與短細胞質尾構成且結合不同TGFβ家族成員(Bernabeu等人,Biochem Biophys Acta 2009,1792:954-73)。儘管3型受體促進信號傳遞,但胞外結構域之裂解可產生隔離配體之可溶性蛋白質及可潛在抑制信號傳遞(Bernabeu等人,Biochem Biophys Acta 2009,1792:954-73)。儘管此大家族之多重冗餘性對識別選擇性抑制劑造成挑戰,但TGFβR-1及-2分別係TGFβ配體接合之選擇標靶。
TGFβ信號傳遞之改變與多種人類病症(包括纖維化、發炎、骨骼、肌肉及心血管病症以及癌症)有關(Harradine等人,2006,Annals of Medicine 38:403-14)。在人類癌症中,TGFβ信號傳遞改變可發生在生殖系中或在各種癌症類型中自發產生。TGFβ亦係血管生成之強有力誘導物,其提供實體腫瘤之關鍵支持系統以及用於腫瘤細胞傳播之機制(Buijs等人,2011,Curr Pharmaceutical Biotech,12:2121-37)。因此,已在多種疾病狀態中採用多種抑制TGFβ信號傳遞之策略。
在本發明之第一態樣中,提供一種式(I)化合物:
其中:
R係或經0至4個R2取代之雜環或雜雙環基團;
X1、X2、X3及X4獨立地係-CR4或-N-,其中至少一者係-N-;R1係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C6)烷基、(C2至C6)烯基、(C1至C6)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C6)烷胺基-、(C1至C6)烷胺基(C1至C6)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;
R4係氫或(C1-C6)烷基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;或R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1、2、3、或4。
n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在另一態樣中,提供一種包含本發明化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受載劑、稀釋劑或賦形劑的醫藥組合物。
在另一態樣中,提供一種用於治療之本發明化合物或其醫藥上可接受之鹽。特定言之,用於治療TGFβR拮抗劑適用之疾病或病狀。
在另一態樣中,提供一種治療癌症、纖維化、發炎、骨骼、肌肉及心血管病症之方法,其包括向有此需要之個體投與治療有效量之TGFβR拮抗劑。
在本發明之第一態樣中,提供一種式(I)化合物:
其中:
R係或經0至4個R2取代之雜環或雜雙環基團;
X1、X2、X3及X4獨立地係-CR4或-N-,其中至少一者係-N-;R1係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C6)烷基、(C2至C6)烯基、(C1至C6)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C6)烷胺基-、(C1至C6)烷胺基(C1至C6)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或(C1-C6)烷基;
R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;或R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1、2、3、或4;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明第一態樣範圍內之第二態樣中,提供一種式(II)化合物
其中:X1、X2、X3及X4獨立地係-CR4或-N-,其中至少一者係-N-;R1係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-
CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C6)烷基、(C2至C6)烯基、(C1至C6)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C6)烷胺基-、(C1至C6)烷胺基(C1至C6)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或(C1-C6)烷基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;或R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1、2、3、或4;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明第一與第二態樣範圍內之第三態樣中,提供一種式(II)化合物
其中:X1、X2、X3及X4獨立地係-CR4或-N-,其中至少一者係-N-;R1係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C3)烷基、(C1至C3)烷氧基或-SO2(C1至C3)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C3)烷基、(C2至C6)烯基、(C1至C3)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C3)烷胺基-、(C1至C3)烷胺基(C1至C3)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或(C1-C6)烷基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;或
R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1、2、3、或4;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明第一、第二與第三態樣範圍內之第四態樣中,提供一種式(II)化合物
其中:X1及X2獨立地係-CH或-N-;R1係氫、(C1至C3)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-
CN、(C1至C3)烷基、(C1至C3)烷氧基或-SO2(C1至C3)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C3)烷基、(C2至C6)烯基、(C1至C3)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C3)烷胺基-、(C1至C3)烷胺基(C1至C3)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或(C1-C3)烷基;R5及R6獨立地係氫、-C(O)烷基或(C1至C3)烷基;或R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C3)烷基或-CN;R8係氫、(C1至C3)烷基、(C3至C6)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C3)烷基、(C3至C6)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1、2、3、或4;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之第五態樣中,提供一種式(II)化合物
其中:X1及X2獨立地係-CH或-N-;R1係氫、(C1至C3)烷基、(C4至C6)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C3)烷基、(C1至C3)烷氧基或-SO2(C1至C3)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C3)烷基、(C2至C6)烯基、(C1至C3)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C3)烷胺基-、(C1至C3)烷胺基(C1至C3)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或甲基;R5及R6獨立地係氫、-C(O)烷基或(C1至C3)烷基;或
R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C3)烷基或-CN;R8係氫、(C1至C3)烷基或-COR9;R9係氫、(C1至C3)烷基、(C3至C6)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;m係0、1或2。
及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之第六態樣中,提供一種式(III)化合物。
其中:R係經0至4個R2取代之雜環或雜雙環基團;R1係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C6)烷基、(C2至C6)烯基、(C1至C6)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C6)烷胺基-、(C1至C6)烷胺基(C1至C6)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-
SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或(C1-C6)烷基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;或R5及R6可與其連接之氮原子一起以形成5至7員雜環;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之另一態樣中,提供一種式(III)化合物。
其中:R係經0至4個R2取代之雜環或雜雙環基團;R1係氫、(C1至C3)烷基、(C3至C6)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-
胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C3)烷基、(C2至C6)烯基、(C1至C3)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C3)烷胺基-、(C1至C3)烷胺基(C1至C3)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或甲基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;R7獨立地係一或多個氫、鹵素、鹵代(C1至C6)烷基或-CN;R8係氫、(C1至C6)烷基、(C3至C8)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C6)烷基、(C3至C8)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之另一態樣中,提供一種式(III)化合物
其中:R係經0至4個R2取代之噻唑、噻二唑、噻吩、吡唑、異喹啉、吲哚或喹啉;R1係氫、(C1至C3)烷基、(C3至C6)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9,除氫外其中任一者係經0至3個Rx取代;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C6)烷基、(C1至C6)烷氧基或-SO2(C1至C6)烷基;R3獨立地係一或多個氫、CD3、OCD3、鹵素、-CN、(C1至C3)烷基、(C2至C6)烯基、(C1至C3)烷氧基、(C3至C8)環烷基、羥基(C1至C3)烷基、(C1至C3)烷胺基-、(C1至C3)烷胺基(C1至C3)烷基、5至6員雜芳基、雜環基、O-雜環基、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、-CHCF2COOCH2OH或-CHCF2CONH2,除氫外其中任一者係經0至4個Ry取代;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;R4係氫或甲基;R5及R6獨立地係氫、-C(O)烷基或(C1至C3)烷基;R7獨立地係一或多個氫、鹵素、鹵代(C1至C3)烷基或-CN;
R8係氫、(C1至C3)烷基、(C3至C6)環烷基、-CONHR9、-COOR9、-COR9或-SO2R9;R9係氫、(C1至C3)烷基、(C3至C6)環烷基、雜環基烷基-、雜環基(C1至C3)烷胺基(C1至C3)烷基-或(C1至C3)烷胺基(C1至C3)烷基;n係0、1、2或3;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之另一態樣中,提供一種式(III)之化合物。
其中:R係經0至4個R2取代之噻唑、吡唑、異喹啉、吲哚或喹啉;R1係經0至2個Rx取代之-COR9;Rx係氫、鹵素、-OH、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基或-CN;R2獨立地係一或多個氫、-CD3、OCD3、鹵素、-CF3、-CHF2、-CN、(C1至C3)烷基、(C1至C3)烷氧基或-SO2(C1至C3)烷基;R3獨立地係一或多個氫、鹵素、-CN、(C1至C3)烷基、(C1至C3)烷氧基、(C3至C6)環烷基、5至6員雜芳基、雜環、-NR5R6、-CONR5R6、-COOR4、-COR4、-SO2R4、或經0至2個Ry取代之(C1至C3)烷胺基;Ry係氫、鹵素、-OH、(C1至C3)烷基、鹵代(C1至C3)烷基、羥基(C1至C3)烷基、-胺基(C1至C3)烷基、-NHCOOH、或-CN;
R4係氫或甲基;R5及R6獨立地係氫、-C(O)烷基或(C1至C6)烷基;R7獨立地係一或多個氫、鹵素、鹵代(C1至C3)烷基或-CN;R8係-COR9;R9係氫、(C1至C3)烷基或(C3至C6)環烷基;n為0、1或2;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在本發明之另一態樣中,提供一種式(III)之化合物
其中:R係經0至4個R2取代之噻唑、異喹啉、吲哚或喹啉;R1係-COR9;R2獨立地係一或多個氫、鹵素、-CF3、-CN、(C1至C3)烷基、(C1至C3)烷氧基或-SO2(C1至C3)烷基;R3獨立地係一或多個氫、鹵素、-CN或(C1至C3)烷基;R7獨立地係一或多個氫、鹵素、鹵代(C1至C3)烷基或-CN;R8係氫;R9係氫或(C1至C3)烷基;n為0、1或2。
及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在另一態樣中,提供一種選自在第一態樣範圍內之例示實例之
化合物,或其醫藥上可接受之鹽、互變異構體或立體異構體。
在另一態樣中,本提供一種選自在任何上述態樣範圍內之化合物之任何子列表的化合物。
在另一態樣中,本發明提供一種選自下列列表之如技術方案1之化合物:N-{4-[6-氟-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-{[3-(嗎啉-4-基)丙基]胺基}乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-(甲氧基-d3)-1H-吡啶并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)1吡啶-2-基)-6-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(二甲胺基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1R)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1S)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(甲胺基)甲基]-1H-吡咯并
[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(2-羥基丙-2-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-(7-(1-羥乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,或N-(4-(6-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺;及/或其醫藥上可接受之鹽、互變異構體或立體異構體。
在另一態樣中,本發明提供一種選自下列列表之如技術方案1之化合物:N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-{4-[6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-(4-(3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-氯-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-氟-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-甲氧基-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,或
N-(4-(6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺及/其醫藥上可接受之鹽、互變異構體或立體異構體。
本發明之其他實施例
在另一實施例中,本發明提供一種醫藥組合物,其包括醫藥上可接受載劑及治療有效量之至少一本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、或溶劑合物。
在另一實施例中,本發明提供一種製備本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、或溶劑合物之方法。
在另一實施例中,本發明提供一種治療及/或預防多種類型癌症之方法,其包括向有此治療及/或預防需要之患者單獨投與治療有效量之一或多種本發明化合物或視情況其與另一本發明化合物及/或至少一其他類型治療劑之組合。
在另一實施例中,本發明提供一種治療及/或預防多種類型癌症之方法,該癌症包括但不限於小細胞肺癌、非小細胞肺癌、結腸直腸癌、多發性骨髓瘤、急性骨髓性白血病(AML)、急性淋巴母細胞白血病(ALL)、胰臟癌、肝癌、肝細胞癌、神經母細胞瘤、其他實體腫瘤或其他血液癌。
在另一實施例中,本發明提供一種治療及/或預防多種類型癌症之方法,該癌症包括但不限於小細胞肺癌、非小細胞肺癌、三陰性乳癌、結腸直腸癌、前列腺癌、黑色素瘤、胰臟癌、多發性骨髓瘤、T-急性淋巴母細胞白血病或AML。
在另一實施例中,本發明提供一種治療及/或預防與TGF-β表現異常有關之馬凡氏(Marfan's)症侯群及相關疾病、病症及病狀之方法。
在另一實施例中,本發明提供一種治療及/或預防纖維化諸如肝
或肺纖維化之方法。
在另一實施例中,本發明提供一種用於治療之本發明化合物。
在另一實施例中,本發明提供一種同時、單獨或連續用於治療之本發明化合物與額外治療劑的組合製劑。
治療應用
本發明式(I)化合物係TGFβR拮抗劑及在治療TGFβR拮抗劑適用之疾病及症狀方面具有潛在效用。
在一實施例中,提供一種治療有此需要之個體中之TGFβR拮抗劑適用之疾病或病狀之方法,其包括投與治療有效量之式(I)化合物或其醫藥上可接受之鹽。
在另一實施例中,提供一種治療有此需要之個體中之慢性自體免疫及/或發炎病狀之方法,其包括投與治療有效量之一或多種式(I)化合物或其醫藥上可接受之鹽。
在又一實施例中,提供一種治療有此需要之個體中之癌症之方法,其包括投與治療有效量之一或多種式(I)化合物或其醫藥上可接受之鹽。
在一實施例中,有此需要之個體係哺乳動物,特定言之人類。
據信TGFβR拮抗劑可用於治療與系統或組織發炎、對感染或缺氧之發炎反應、細胞活化及增殖、脂類新陳代謝、纖維化有關的各種疾病或病狀及預防與治療病毒感染。
TGFβR拮抗劑可用於治療纖維化病狀,諸如特發性肺纖維化、腎纖維化、術後狹窄、瘢瘤生成、硬皮症及心臟纖維化。
TGFβR拮抗劑可用於治療癌症,包括血液、上皮(包括肺、乳腺之及結腸)癌、中線癌、間葉、肝、腎及神經系統腫瘤。
術語「TGFβR適用之疾病或病狀」意在包括任何或全部上文疾病狀態。
當可用於治療時,式(I)化合物以及其醫藥上可接受之鹽可作為該化合物本身投與,其更通常係作為醫藥組合物存在。
醫藥組合物可以每單位劑量含有預定量活性成分之單位劑型存在。較佳單位劑量組合物係含有日劑量或子劑量或其適當部分之活性成分之彼等。因此,可一天超過一次地投與此等單位劑量。較佳單位劑量組合物係含有如本文上文指出之日劑量或子劑量(用於一天投與超過一次)或其適當部分之活性成分之彼等。
可由本發明化合物治療之癌症類型包括但不限於腦癌、皮膚癌、膀胱癌、卵巢癌、乳癌、胃癌、胰臟癌、前列腺癌、結腸癌、血癌、肺癌及骨癌。此等癌症類型之實例包括神經母細胞瘤、腸癌(諸如直腸癌、結腸癌、家族性腺瘤性息肉癌及遺傳性非息肉結腸直腸癌)、食道癌、唇癌、喉癌、下咽癌、舌癌、唾腺癌、胃癌、腺癌、甲狀腺髓質癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、卵巢癌、子宮頸癌、子宮體癌、子宮內膜癌、絨毛膜癌、胰腺癌、前列腺癌、睪丸癌、乳癌、泌尿系統癌、黑色素瘤、腦腫瘤(諸如神經膠質母細胞瘤、星形細胞瘤、腦脊髓膜瘤、神經管胚細胞瘤及周圍神經外胚層母細胞瘤)、霍奇金(Hodgkin)淋巴瘤、非霍奇金淋巴瘤、伯基特(Burkitt)淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(DLBCL)、肝細胞癌、膽囊癌、支氣管癌、小細胞肺癌、非小細胞肺癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、視網膜母細胞瘤、脈絡膜黑色素瘤、精細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肉瘤、纖維肉瘤、尤因(Ewing)肉瘤及漿細胞瘤。
除在腫瘤中發現之細胞凋亡缺陷外,吾人認為在消除由於抗細胞凋亡引起之免疫系統之自身反應細胞能力方面之缺陷在自體免疫疾
病之發病機制方面具有重要作用。自體免疫疾病之特徵在於免疫系統細胞產生對抗其自身器官及分子之抗體或直接攻擊組織,導致後者受破壞。彼等自身反應細胞未能經歷細胞凋亡導致表現出疾病。在自體免疫疾病(諸如系統性紅斑狼瘡或類風濕性關節炎)中已確定細胞凋亡調節方面之缺陷。
本發明化合物本身或與其他治療劑或放射治療組合或共同投與以用於治療特定類型癌症。由此,在一實施例中,本發明化合物係與放射治療或具有抑制細胞生長或抗贅生活性之第二治療劑共同投與。適宜抑制細胞生長化療化合物包括但不限於(i)抗代謝物;(ii)DNA-斷裂劑,(iii)DNA-交聯劑,(iv)嵌入劑,(v)蛋白質合成抑制劑,(vi)拓樸異構酶I毒物,諸如喜樹鹼或拓撲替康(topotecan);(vii)拓樸異構酶II毒物,(viii)微管定向劑,(ix)激酶抑制劑,(x)混雜研究劑,(xi)激素及(xii)激素拮抗劑。考慮本發明化合物可與任何落在以上12類中之已知試劑以及任何當前在發展中之未來試劑結合使用。特定言之,考慮本發明化合物可與當前護理標準以及在可預見之未來形成之任一者結合使用。特定劑量及給藥方案應基於醫師之進化知識及此項技術之一般技藝。
本文進一步提供治療方法,其中本發明化合物連同一或多種免疫-腫瘤劑投與。本文使用之免疫-腫瘤劑(亦稱為癌症免疫治療)有效增強、刺激、及/或向上調控在個體中免疫反應。在一態樣中,連同免疫-腫瘤劑投與本發明化合物在抑制腫瘤生長方面具有協同功效。
在一態樣中,在投與免疫-腫瘤劑前連續投與本發明化合物。在另一態樣中,與免疫-腫瘤劑同時投與本發明化合物。在又一態樣中,在投與免疫-腫瘤劑後連續投與本發明化合物。
在另一態樣中,本發明化合物可經由免疫-腫瘤劑共同調配。
免疫-腫瘤劑包括(例如)小分子藥物、抗體、或其他生物或小分
子。生物製劑免疫-腫瘤劑之實例包括但不限於癌症疫苗、抗體、及細胞激素。在一態樣中,該抗體係單株抗體。在另一態樣中,該單株抗體係人源化或人類抗體。
在一態樣中,該免疫-腫瘤劑係(i)刺激(包括輔助刺激)受體之促效劑或(ii)T細胞上抑制(包括輔助抑制)信號之拮抗劑,其二者均導致放大抗原特異性T細胞反應(通常稱為免疫檢查點調節器)。
某些刺激及抑制分子係免疫球蛋白超家族(IgSF)之成員。結合至輔助刺激或輔助抑制受體之膜結合配體之一重要家族係B7家族,其包括B7-1、B7-2、B7-H1(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)、及B7-H6。另一結合至輔助刺激或輔助抑制受體之膜結合配體家族係結合至同源THF受體家族成員之THF分子家族,包括CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α 1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
在另一態樣中,該免疫-腫瘤劑係抑制T細胞活化之細胞激素(例如,IL-6、IL-10、TGF-ß、VEGF、或其他免疫抑制細胞激素)或刺激T細胞活化以刺激免疫反應之細胞激素。
在一態樣中,T細胞反應可藉由本發明化合物與以下一或多者之組合來刺激:(i)抑制T細胞活化之蛋白質拮抗劑(例如,免疫檢查點抑制劑),諸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、
CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1、及TIM-4,及(ii)刺激T細胞活化之蛋白質促效劑,諸如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3及CD28H。
可與本發明化合物結合用於治療癌症之其他試劑包括NK細胞上抑制受體之拮抗劑或NK細胞上活化受體之促效劑。例如,本發明化合物可與KIR拮抗劑結合,諸如利利單抗(lirilumab)。
用於組合治療之其他試劑包括抑制或減少巨噬細胞或單核細胞之試劑,包括但不限於CSF-1R拮抗劑,諸如CSF-1R拮抗劑抗體,包括RG7155(WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008(WO11/140249;WO13169264;WO14/036357)。
在又一態樣中,本發明化合物可連同以下一或多者結合使用:拼接正向共同刺激受體之促效劑,通過抑制受體、拮抗劑減弱信號傳遞之封端劑,及一或多種系統增加抗腫瘤T細胞頻率之試劑,在腫瘤微環境中克服獨特免疫抑制路徑之試劑(例如,阻斷抑制受體接合(例如,OD-L1/PD-1相互作用)、減少或抑制Tregs(例如,使用抗CD25單株抗體(例如,達利珠單抗(daclizumab))或藉由體外抗CD-25珠粒減少)、抑制新陳代謝酶諸如IDO、或逆轉/阻止T細胞無反應性或衰竭)及在腫瘤部位引發先天免疫活化及/或發炎之試劑。
在一態樣中,該免疫-腫瘤劑係CTLA-4拮抗劑,諸如拮抗CTLA-4抗體。適宜CTLA-4抗體包括(例如)YERVOY(依匹裏木馬(ipilimumab))或曲美木單抗(tremelimumab)。
在另一態樣中,該免疫-腫瘤劑係PD-1拮抗劑,諸如拮抗PD-1抗體。適宜PD-1抗體包括(例如)OPDIVO(尼沃單抗(nivolumab))、KEYTRUDA(派姆單抗(pembrolizumab))、或MEDI-0680(AMP-514;
WO2012/145493)。該腫瘤免疫劑亦可包括皮地珠單抗(pidilizumab)(CT-011),但其對PD-1結合之特異性已受到質疑。另一標靶PD-1受體之途徑係由融合至IgG1之Fc部分之PD-L2(B7-DC)細胞外結構域構成的重組蛋白質,稱為AMP-224。
在另一態樣中,該免疫-腫瘤劑係PD-L1拮抗劑,諸如拮抗PD-L1抗體。適宜PD-L1抗體包括(例如)MPDL3280A(RG7446;WO2010/077634)、杜拉魯單抗(durvalumab)(MEDI4736)、BMS-936559(WO2007/005874)、及MSB0010718C(WO2013/79174)。
在另一態樣中,該免疫-腫瘤劑係LAG-3拮抗劑,諸如拮抗LAG-3抗體。適宜LAG3抗體包括(例如)BMS-986016(WO10/19570、WO14/08218)、或IMP-731或IMP-321(WO08/132601、WO09/44273)。
在另一態樣中,該免疫-腫瘤劑係CD137(4-1BB)促效劑,諸如促效CD137抗體。適宜CD137抗體包括(例如)烏瑞魯單抗(urelumab)及PF-05082566(WO12/32433)。
在另一態樣中,該免疫-腫瘤劑係CITR促效劑,諸如促效CITR抗體。適宜GITR抗體包括(例如)BMS-986153、BMS-986156、TRX-518(WO06/105021、WO09/009116)及MK-4166(WO11/028683)。
在另一態樣中,該免疫-腫瘤劑係IDO拮抗劑。適宜IDO拮抗劑包括(例如)INCB-024360(WO2006/122150、WO07/75598、WO08/36653、WO08/36642)、吲哚西莫(indoximod)、或NLG-919(WO09/73620、WO09/1156652、WO11/56652、WO12/142237)。
在另一態樣中,該免疫-腫瘤劑係OX40促效劑,諸如促效OX-40抗體。適宜OX40抗體包括(例如)MEDI-6383或MEDI-6469。
在另一態樣中,該免疫-腫瘤劑係OX40L拮抗劑,諸如拮抗OX40抗體。適宜OX40L拮抗劑包括(例如)RG-7888(WO06/029879)。
在另一態樣中,該免疫-腫瘤劑係CD40促效劑,諸如促效CD40
抗體。在又一實施例中,該免疫-腫瘤劑係CD-40拮抗劑,諸如拮抗CD40抗體。適宜CD40抗體包括(例如)魯卡木單抗(lucatumumab)或達西珠單抗(dacetuzumab)。
在另一態樣中,該免疫-腫瘤劑係CD27促效劑,諸如促效CD27抗體。適宜CD27抗體包括(例如)瓦利路單抗(varlilumab)。
在另一態樣中,該免疫-腫瘤劑係MGA271(結合至B7H3)(WO11/109400)。
該組合治療係意在包括以連續方式投與此等治療劑,即,其中各個治療劑係於不同時間投與,以及以大體上同時之方式投與此等治療劑,或該等治療試劑中之至少二者。可(例如)藉由向個體投與具有固定比例之各個治療劑之單一劑型或多個各個治療試劑之單一劑型達成大體上同時給藥。可藉由包括但不限於口服途徑、靜脈內途徑、肌肉內途徑、及通過黏膜組織直接吸收之任何適當途徑實現連續或大體上同時投與各個治療試劑。可藉由相同途徑或藉由不同途徑投與該等治療劑。例如,可藉由靜脈注射投與經選擇之組合之第一治療劑,而該組合之其他治療劑可口服投與。或者,例如,全部治療試劑均可口服投與或可藉由靜脈注射投與全部治療劑。組合治療亦可包括與其他生物活性成分及非藥物治療(例如,手術或輻射治療)進一步組合投與如上文描述之治療劑。當該組合治療進一步包括非藥物治療,只要達成獲自該治療劑與非藥物治療組合之共同作用的有利功效,可於任何適宜時間進行該非藥物治療。例如,在適當情形下,當從投與該治療劑暫時除移該非藥物治療(或許數日或甚至數週)時仍可達成該有利功效。
可以其他特殊形式進行本發明而不脫離其範圍或主要屬性。本發明包含本文指出之全部本發明較佳態樣之組合。應瞭解本發明之任何及全部實施例可與任何其他實施例結合以描述額外實施例。亦應瞭
解實施例之各個獨立元素係其本身獨立實施例。此外,實施例之任何元素係意在與獲自任何實施例之任何及全部其他元素結合以描述額外實施例。
醫藥組合物及給藥
本發明亦提供包括與一或多種醫藥上可接受載劑(添加劑)及/或稀釋劑,及視情況,一或多個種上文描述之其他治療劑一起調配之治療有效量之一或多種式I化合物之醫藥上可接受組合物。如下文詳細描述,可特別調配本發明之醫藥組合物用於以固體或液體形式投與,包括適用於下列投與方式之彼等:(1)口服投與,例如,灌劑(水性或非水性溶液或懸浮液)、錠劑(例如,用於口腔、舌下、及系統吸收之彼等)、丸劑、粉劑、粒劑、應用於舌之糊狀物;(2)非經腸投與,例如,作為例如無菌溶液或懸浮液,或持續釋放調配物藉由皮下、肌肉內、靜脈內或硬膜外注射;(3)局部應用,例如作為應用於皮膚之乳霜、軟膏、或控制釋放貼片或噴霧;(4)經陰道或直腸,例如,作為子宮托、乳霜或發泡體;(5)經舌下;(6)經眼;(7)經皮;或(8)經鼻。
本文採用之片語「醫藥上可接受」係指在合理範圍的醫藥判斷下適於用於與人體及動物組織接觸而無過度毒性、刺激性、過敏反應、或其他問題或併發症,且符合合理效益/風險比值之彼等化合物、材料、組合物、及/或劑型。
如本文所使用之片語「醫藥上可接受載劑」意指醫藥上可接受材料、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、製造助劑(例如,潤滑劑、滑石鎂、硬脂酸鈣或硬脂酸鋅、或空間酸)、或參與將主體化合物從一人體之器官或部分攜帶或運輸至人體之另一器官或部分之溶劑密封材料。各載劑必須在與該調配物之其他成分相容且對患者不會造成傷害之意義上是「可接受」。可充當醫藥上可接受載劑之材料之一些實例包括:(1)糖,諸如乳糖、葡萄糖及蔗糖;
(2)澱粉,諸如玉米澱粉及馬鈴薯澱粉;(3)纖維素,及其衍生物,諸如羧基甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)黃蓍膠粉;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,諸如可可脂及栓劑蠟;(9)油,諸如花生油、棉籽油、紅花子油、麻油、橄欖油、玉米油及黃豆油;(10)二醇,諸如丙二醇;(11)多元醇,諸如甘油、山梨糖醇、甘露醇及聚乙二醇;(12)酯,諸如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,諸如氫氧化鎂及氫氧化鋁;(15)海藻酸;(16)無熱原水;(17)等滲鹽水;(18)林格氏(Ringer's)溶液;(19)乙醇;(20)pH緩衝溶液;(21)聚酯、聚碳酸酯及/或聚酐;及(22)其他用於醫藥調配物之無毒相容物質。
濕潤劑、乳化劑及潤滑劑,諸如月桂基硫酸鈉及硬脂酸鎂,以及著色劑、脫模劑、塗佈劑、甜味劑、矯味劑及芳香劑、防腐劑及抗氧化劑亦可存在於該組合物中。
醫藥上可接受抗氧化劑之實例包括:(1)水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及類似物;(2)油溶性抗氧化劑,諸如抗壞血酸棕櫚酸酯、丁基化的羥基苯甲醚(BHA)、二丁基羥基甲苯(BHT)、卵磷脂、棓酸丙酯、α-維生素E、及類似物;及(3)金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及類似物。
本發明之調配物包括適宜口服、經鼻、局部(包括口腔及舌下)、直腸、陰道及/或非經腸投與之彼等。調配物可便利地以單位劑型存在及可藉由藥物技術中已知的任何方法製備。可與載劑材料組合以製造單一劑型之活性成分之用量將根據所治療之患者及特殊投與模式而變化。可與載劑材料結合來製備單一劑型之活性成分之用量一般應係產生治療功效之化合物用量。一般而言,就百分比而言,此用量可介於約0.1%至約99%之活性成分,較佳地約5%至約70%,更佳地約10%
至約30%變化。
在某些實施例中,本發明之調配物包括選自由以下組成之群的賦形劑:環糊精、纖維素、脂質體、成膠束劑(例如,膽汁酸)及可聚合載劑(例如,聚酯及聚酐);及本發明化合物。在某些實施例中,先前提及之調配物得到具有口服生物可利用性之本發明化合物。
製備此等調配物或組合物之方法包括使本發明化合物與載劑,及視情況一或多種輔助成分結合之步驟。一般而言,可藉由使本發明化合物與液體載劑,或經細分散之固體載劑,或二者均勻且緊密結合,及隨後(若需要)使該產物成型來製備該調配物。
本發明適宜口服之調配物可係呈膠囊、藥丸、丸劑、錠劑、含片(使用調味基質,一般蔗糖及阿拉伯膠或黃蓍膠)、粉劑、粒劑之形式或作為在水性或非水性液體中之溶液或懸浮液、或作為水包油或油包水液體乳液,或作為酏劑或糖漿,或作為片劑(使用惰性基質,諸如明膠或甘油,或蔗糖及阿拉伯膠)及/或作為漱口劑及類似物,各者含有預定量之本發明化合物作為活性成分。本發明之化合物亦可作為大丸劑、舐劑或糊狀物投與。
在用於口服之本發明固體劑型(膠囊、錠劑、丸劑、糖衣錠、粉劑、粒劑、口含錠及類似物)中,活性成分係與一或多種醫藥上可接受載劑(諸如檸檬酸鈉或磷酸氫鈣)、及/或下列任一者混合:(1)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇、及/或矽酸;(2)黏結劑,諸如,例如,羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及/或阿拉伯膠;(3)保濕劑,諸如甘油;(4)崩解劑,諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;(5)溶液阻滯劑,諸如石蠟;(6)吸收促進劑,諸如四級銨化合物及表面活性劑,諸如聚羥亞烴及月桂基硫酸鈉;(7)濕潤劑,諸如,例如,十六烷醇、單硬脂酸甘油酯,及非離子表面活性
劑;(8)吸收劑,諸如高嶺土及膨潤土黏土;(9)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉、硬脂酸鋅、硬脂酸鈉、硬脂酸、及其混合物;(10)著色劑;及(11)控制釋放劑諸如交聚維酮或乙基纖維素。在膠囊、錠劑及丸劑之情形下,該醫藥組合物亦可包括緩衝劑。相似類型固體組合物亦可在使用諸如乳糖或乳糖,以及高分子量聚乙二醇及類似物之賦形劑的軟及硬殼明膠膠囊中用作填充劑。
可藉由壓制或模壓,視情況使用一或多種輔助成分來製備錠劑。可使用黏結劑(例如,明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如,澱粉羥乙酸鈉或交聯之羧基甲基纖維素鈉)、表面活性劑或分散劑製備壓製錠劑。可藉由在適宜機器中模壓經惰性液體稀釋劑潤濕之化合物粉末的混合物來製造模壓錠劑。
本發明醫藥組合物之錠劑及其他固體劑型,諸如糖衣錠、膠囊、丸劑及顆粒,可視情況加刻痕或製備有包衣及外殼(諸如腸溶包衣或醫藥調配技術中熟知之其他包衣)。其亦可經調配來使用(例如)羥丙基甲基纖維素提供以變化比例緩慢或控制釋放其中之活性成分,以提供期望釋放曲線,其他聚合物基質、脂質體及/或微球體。其可經調配以用於快速釋放,例如,冷凍乾燥。其可藉由(例如)通過細菌截留過濾器過濾、或藉由在使用前立即併入呈可溶於無菌水或一些其他無菌可注射介質中之無菌固體組合物形式之滅菌劑來滅菌。此等組合物亦可視情況含有乳濁劑及可係僅或優先在胃腸道特定位置視情況以延遲之方式釋放活性成分的組合物。可使用之包埋組合物的實例包括可聚合物質及蠟。該活性成分亦可呈(若適當)具有一或多種上文描述之賦形劑之微囊封形式。
用於口服投與本發明化合物之液體劑型包括醫藥上可接受乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性成分外,液體劑型
可含有通常用於此項技術之惰性稀釋劑,諸如,例如,水或其他溶劑、增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、油(特定言之,棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫呋喃醇、聚乙二醇及山梨糖醇脂肪酸酯,及其混合物。
除惰性稀釋劑外,該口服組合物亦可包括佐劑諸如濕潤劑、乳化劑及懸浮劑、甜味劑、矯味劑、著色劑、芳香劑及防腐劑。
除活性化合物外,懸浮液可含有懸浮劑,例如,乙氧基化之異硬脂醇、聚氧乙烯山梨醇及山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨土、瓊脂-瓊脂及黃蓍膠,及其混合物。
用於直腸或陰道投與之本發明醫藥組合物之調配物可作為栓劑存在,其可藉由混合一或多種本發明化合物與一或多種適宜無刺激賦形劑或載劑來製備,適宜無刺激賦形劑或載劑包括(例如)可可脂、聚乙二醇、栓劑蠟或水楊酸酯,及其於室溫時係固體,但於人體溫度時係液體及,由此,可在直腸或陰道內融化並釋放活性化合物。
適合陰道投與之本發明調配物亦包括含有此等在此項技術中熟知係適當之載劑的子宮托、棉塞、乳霜、凝膠、糊狀物、發泡體或噴霧調配物。
用於局部或經皮投與本發明化合物之劑型包括粉末、噴霧、軟膏、糊狀物、乳霜、洗劑、凝膠、溶液、貼片及吸入物。活性化合物可在滅菌條件下與醫藥上可接受載劑、及與任何需要之防腐劑、緩衝劑、或推進劑混合。
軟膏、貼片、乳霜及凝膠除本發明活性化合物外可含有賦形劑,諸如動物及植物脂肪、油、蠟、石蠟、澱粉、黃蓍膠、纖維素衍生物、聚乙二醇、聚矽氧、膨潤土、矽酸、滑石及氧化鋅、或其混合物。
粉末及噴霧除本發明化合物外可含有賦形劑,諸如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺粉末、或此等物質之混合物。噴霧可額外含有常規推進劑,諸如含氯氟烴及揮發性未經取代之烴,諸如丁烷及丙烷。
經皮貼片具有提供本發明化合物至人體之可控遞送的額外優點。此等劑型可藉由在適當介質中溶解或分散該化合物來製備。吸收促進劑亦可用於增加穿過皮膚之化合物通量。此通量之速率可藉由提供速率控制膜或將該化合物分散在聚合物基質或凝膠中來控制。
經眼調配物、眼膏、粉末、溶液及類似物,亦可考慮在本發明範圍內。
適宜非經腸投與之本發明醫藥組合物包括與一或多種醫藥上可接受滅菌等滲水性或非水性溶液、分散液、懸浮液或乳液,或可在使用前復水得到無菌可注射溶液或分散液之無菌粉末結合之一或多種本發明化合物,其可含有糖、醇、抗氧化劑、緩衝劑、抑菌劑、使得該調配物與預定接受者之血液等滲的溶質或懸浮劑或增稠劑。
可用於本發明醫藥組合物之適宜水性或非水性載劑之實例包括水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇、及類似物),及其適宜混合物、植物油(諸如橄欖油)、及可注射有機酯(諸如油酸乙酯)。適度流動性之維持方法為(例如)藉由使用諸如卵磷脂之包衣材料、若為分散液則藉由維持所需之粒徑、及藉由使用表面活性劑。
此等組合物亦可含有佐劑,諸如防腐劑、濕潤劑、乳化劑及分散劑。預防微生物作用於主題化合物可藉由包含多種抗細菌及抗真菌劑,例如對羥基苯甲酸酯、氯丁醇、苯酚山梨酸及類似物確保。亦期望在組合物中包括等滲劑,諸如糖、氯化鈉及類似物。此外,延長吸收該可注射醫藥形式可藉由包括延遲吸收之試劑諸如單硬脂酸鋁及明膠達成。
在一些情形下,為延長藥物功效,期望減緩從皮下或肌肉注射劑吸收該藥物。此可藉由使用具有不良水溶性之結晶或非晶材料的液體懸浮液達成。吸收該藥物之速率則取決於其溶解速率,繼而可取決於晶體尺寸及結晶形式。或者,延遲吸收非經腸投與之藥物形式係藉由將該藥物溶解或分散在油性媒劑中達成。
可注射儲積物形式可藉由在生物可降解聚合物諸如聚丙交酯-聚乙交酯中形成該主題化合物之微囊封基質來製備。根據藥物與聚合物之比例、採用之特定聚合物之特性,可控制藥物釋放速率。其他可生物降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。儲積可注射調配物亦藉由將該藥物密封在與人體組織相容之脂質體或微乳液中製備。
當將本發明化合物作為藥品投與至人類及動物時,其本身可給予或作為含有與醫藥上可接受載劑結合之(例如)0.1至99%(更佳地,10至30%)活性成分的醫藥組合物給予。
與選擇之給藥途徑無關,藉由為一般技術者熟知之習知方法將可以適宜水合物形式使用之本發明化合物及/或本發明醫藥組合物調配為醫藥上可接受劑型。
可改變本發明醫藥組合物中活性成分之實際劑量水平以獲得活性成分有效達到針對特定患者、組合物及投藥模式之期望治療反應,但對患者無毒性之量。
選擇之劑量水平將取決於各種因素,包括採用之本發明特定化合物、或其酯、鹽或醯胺之活性,及投與途徑、投與時間,採用之特定化合物的排洩或新陳代謝速率,吸收速率及程度,治療持續時間、與採用之特定組合物結合使用的其他藥物、化合物及/或材料、待治療患者之年齡、性別、體重、條件、一般健康及先前醫學病史,及醫藥領域中熟知之類似因素。
一般技術之醫師或獸醫可輕易決定及規定需要之醫藥組合物之
有效量。例如,醫師或獸醫可以低於達成期望治療功效需要之水平開始用於該醫藥組合物中的本發明化合物劑量,並逐漸增加劑量直至達成期望功效。
一般而言,本發明化合物之適宜每日劑量可係有效產生治療效果之最低劑量的化合物含量。此有效劑量一般將取決於上文描述之因素。一般而言,用於患者之本發明化合物之口服、靜脈內、腦室內及皮下劑量可從約0.01至約50mg/千克體重/日變化。
若期望,該活性化合物之有效每日劑量可作為以適宜間隔分開投與之二、三、四、五、六或更多個子劑量投與,視情況,呈單位劑型。在本發明之特定態樣中,劑量係每天投與一次。
雖然可單獨投與本發明化合物,但較佳作為醫藥調配物(組合物)投與該等化合物。
除非本文另作特殊說明,否則單數之參考亦可包括複數。例如,「一(a)」及「一(an)」可指一、或者一或多個。
除非另作說明,否則假設任何具有不飽和價數之雜原子具有足夠使價數飽和之氫原子。
在本說明書及隨附申請專利範圍中,給出之化學式或名稱應包含其全部立體及光學異構體及外消旋體,只要此等異構體存在。除非另作說明,否則全部對掌性(對映異構體及非對映異構體)及外消旋形式係在本發明範圍內。C=C雙鍵、C=N雙鍵、環系統,及類似物之眾多幾何異構體亦可存在於該化合物中,且本發明中涵蓋全部此等穩定異構體。描述本發明化合物之順及反(或E-及Z-)幾何異構體及可作為異構體混合物或獨立異構形式分離。本發明化合物可以光學活性或外消旋形式分離。光學活性形式可藉由解析外消旋形式或藉由自光學活性初始材料合成製備。用於製備本發明化合物之全部方法及其中產生
之中間物均視為本發明之一部分。當製備對映異構或非對映異構產物時,其可藉由習知方法分離,例如,藉由層析或分段結晶。根據方法條件,可獲得呈游離(中性)或鹽形式之本發明最終產物。此等最終產物之游離形式及鹽均係在本發明範圍內。若期望,可將化合物之一形式轉化為另一形式。游離鹼或酸可轉化為鹽;鹽可轉化為游離化合物或另一鹽;本發明異構化合物之混合物可分為獨立異構體。本發明之化合物、其游離形式或鹽可以多種互變異構形式存在,其中將氫原子轉移至分子其他部分及分子原子間之化學鍵由此重排。應瞭解全部互變異構形式(在其可存在之範圍內)係包含於本發明中。
除非另作定義,否則當取代基註明為「視情況取代」時,取代基係選自,例如,取代基諸如烷基、環烷基、芳基、雜環、鹵基、羥基、烷氧基、側氧基、醯基、芳氧基、醯氧基、胺基、烷胺基、芳胺基、芳基烷胺基、經二取代之胺(其中該等2個胺基取代基選自烷基、芳基或芳烷基);醯胺基、芳醯胺基、芳烷醯胺基、經取代之醯胺基、經取代之芳胺基、經取代之芳烷醯胺基、硫醇、烷硫基、芳硫基、芳基烷硫基、烷基硫羰基、芳基硫羰基、芳烷基硫羰基、烷基磺醯基、芳基磺醯基、芳烷基磺醯基、磺醯胺基(例如-SO2NH2)、經取代之磺醯胺基、硝基、氰基、羧基、胺甲醯基(例如-CONH2)、經取代之胺甲醯基(例如-CONH烷基、-CONH芳基、-CONH芳烷基)或其中氮上具有兩個選自烷基、芳基或芳烷基之取代基的情形;烷氧基羰基、芳基、經取代之芳基、胍基、雜環基(例如,吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯啶基、哌啶基、嗎啉基、哌嗪基、高哌嗪基及類似物)、及取代之雜環基。
出於明確之目的並依照在此項技術中標準慣例,符號用
於式及表中來顯示部分或取代基連接至結構核/核心之點的鍵。
此外,出於明確之目的,其中取代基具有未在兩個字母或符號間之破折號(-);此係用於表明取代基之連接點。例如,-CONH2係通過碳原子連接。
此外,出於明確之目的,當在實線末端未顯示取代基時,此表明具有連接至該鍵之甲基(CH3)。
如本文所使用,術語「烷基」或「伸烷基」意在包括具有特定數量碳原子之分支鏈及直鏈飽和脂肪族烴基。例如,「C1至C6烷基」指具有1至6個碳原子之烷基。實例烷基包括但不限於甲基(Me)、乙基(Et)、丙基(例如,正丙基及異丙基)、丁基(例如,正丁基、異丁基、第三丁基)、及戊基(例如,正戊基、異戊基、新戊基)。
術語「烯基」指含有一或多個雙鍵及通常長度為2至20個碳原子的直鏈或分支鏈烴基。例如,「C2至C8烯基」含有二至八個碳原子。烯基包括但不限於(例如)乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、庚烯基、辛烯基及類似物。
術語「炔基」指含有一或多個三鍵及通常長度為2至20個碳原子的直鏈或分支鏈烴基。例如,「C2至C8炔基」含有二至八個碳原子。代表性炔基包括(但不限於)例如乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等等。
術語「烷氧基」或「烷基氧基」指-O-烷基。「C1-6烷氧基」(或烷基氧基)係意在包括C1、C2、C3、C4、C5、及C6烷氧基。實例烷氧基包括但不限於甲氧基、乙氧基、丙氧基(例如,正丙氧基及異丙氧基)、及第三丁氧基。相似地,「烷硫基」或「硫代烷基」代表通過硫橋連接之如上文定義之具有指定數量碳原子的烷基,例如甲基-S-及乙基-S-。
術語「芳基」,單獨或作為較大部分諸如「芳烷基」、「芳基烷氧基」、或「芳氧基烷基」之一部分,指總共具有五至15個環成員的單
環、雙環及三環系統,其中該系統中至少一個環係芳族及其中該系統中各個環含有三至七個環成員。在本發明之某些實施例中,「芳基」指芳族環系統(包括但不限於苯基、聯苯、二氫茚基、1-萘基、2-萘基及四氫萘基)。術語「芳烷基」或「芳基烷基」指連接至芳環的烷基殘基。非限制性實例包括苄基、苯乙基等等。稠合芳基可於環烷基環或芳族環上適宜位置連接至另一基團。例如:
從該環系統畫出之帶箭頭線表明該鍵可連接至任何適宜環原子。
術語「環烷基」指環化烷基。C3-6環烷基意在包括C3、C4、C5、及C6環烷基。實例環烷基包括但不限於環丙基、環丁基、環戊基、環己基、及降莰烷基。分支鏈環烷基諸如1-甲基環丙基及2-甲基環丙基係包括於「環烷基」之定義中。術語「環烯基」指環化烯基。C4-6環烯基意在包括C4、C5、及C6環烯基。實例環烯基包括但不限於環丁烯基、環戊烯基、及環己烯基。
術語「環烷基烷基」指鍵接至連接至該化合物核心之烷基的環烷基或經取代之環烷基。
「鹵基」或「鹵素」包括氟、氯、溴及碘。「鹵代烷基」係意在包括經1或多個鹵素取代之具有特定數量碳原子的分支鏈及直鏈飽和脂肪族烴基。鹵代烷基實例包括但不限於氟代甲基、二氟甲基、三氟
甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基、及七氯丙基。鹵代烷基之實例亦包括「氟代烷基」,其意在包括經1或多個氟原子取代之具有特定數量碳原子之分支鏈及直鏈飽和脂肪族烴基。
「鹵代烷氧基」或「鹵代烷基氧基」表示如上文定義之具有指定數量通過氧橋連接之碳原子的鹵代烷基。例如,「C1-6鹵代烷氧基」,意在包括C1、C2、C3、C4、C5、及C6鹵代烷氧基。鹵代烷氧基實例包括但不限於三氟甲氧基、2,2,2-三氟乙氧基及五氟乙氧基。相似地,「鹵代烷硫基」或「硫代鹵代烷氧基」表示如上文定義之具有指定數量通過硫橋連接之碳原子的鹵代烷基,例如三氟甲基-S-,及五氟乙基-S-。
如本文所使用,術語「苄基」指其上一氫原子由苯基置換的甲基。
如本文所使用,術語「雜環」、「雜環基」、或「雜環基團」意在意指穩定3-、4-、5-、6-、或7-員單環或雙環或7-、8-、9-、10-、11-、12-、13-、或14-員多環雜環,其係飽和、部分不飽和、或全部不飽和,及其含有碳原子及1、2、3或4個獨立地選自由N、O及S組成之群的雜原子;及包括其中上文定義之任何雜環稠合至苯環之任何多環基團。可視情況氧化氮及硫雜原子(即,N→O及S(O)p,其中p係0、1或2)。氮原子可係經取代或未經取代(即,N或NR,其中R係H或另一取代基(若確定))。該雜環於可產生穩定結構之任何雜原子或碳原子連接至其側基。若所得化合物係穩定,則本文描述之雜環之碳或氮原子可經取代。可視情況季鹼化在該雜環中之氮。較佳地,當在該雜環中S及O原子之總數超過1時,則此等雜原子不彼此相鄰。較佳地,該雜環中S及O原子之總數不超過1。當使用術語「雜環」時,其意在包括雜芳基。
雜環之實例包括但不限於吖啶基、氮雜環丁基、吖辛因基(azocinyl)、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異噁唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、色滿基、烯基、啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃并[2,3-b]四氫呋喃、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑基、1H-吲唑基、咪唑并吡啶基、吲哚烯基、吲哚啉基、吲嗪基、吲哚基、3H-吲哚基、靛紅基、異苯并呋喃基、異色滿基、異吲唑基、異吲哚啉基、異吲哚基、異喹啉基、異噻唑基、異噻唑并吡啶基、異噁唑基、異噁唑并吡啶基、亞甲基二氧苯基、嗎啉基、萘啶基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑并吡啶基、噁唑烷基啶基、羥吲哚基、嘧啶基、菲啶基、菲啉基、吩嗪基、吩噻嗪基、氧硫雜蒽基、吩噁基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、哌喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑并吡啶基、吡唑基、噠嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯啶酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹噁啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑并吡啶基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、硫代苯基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、及呫吨基。亦包括含有(例如)上文雜環之稠合環及螺化合物。
如本文所使用,術語「雙環雜環」或「雙環雜環基團」意在指
含有兩個稠合環且由碳原子及1、2、3或4個獨立地選自由N、O及S組成之群的雜原子組成的穩定9-或10-員雜環系統。在兩個稠合環中,一個環係5-或6-員單環芳族環,包括5-員雜芳族環,6-員雜芳族環或苯環,各者稠合至第二個環。該第二個環係5-或6-員單環,其係飽和、部分不飽和、或不飽和,且包括5-員雜環,6-員雜環或碳環(只要當該第二個環係碳環時,第一個環不係苯環)。
該雙環雜環基團於可產生穩定結構的任何雜原子或碳原子連接至其側基。若所得化合物係穩定,本文描述之雙環雜環基團之碳或氮原子可經取代。較佳地,當該雜環中S與O原子之總數超過1時,則此等雜原子不彼此相鄰。較佳地,該雜環中S與O原子之總數不超過1。
雙環雜環基團之實例係但不限於喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、吲哚啉基、1H-吲唑基、苯并咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫-喹啉基、2,3-二氫-苯并呋喃基、色滿基、1,2,3,4-四氫-喹噁啉基及1,2,3,4-四氫-喹唑啉基。
如本文所使用,術語「芳族雜環基團」或「雜芳基」係意在指包括至少一個雜原子環成員諸如硫、氧、或氮的穩定單環及多環芳族烴。雜芳基包括但不限於吡啶基、嘧啶基、吡嗪基、噠嗪基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、異噻唑基、嘌呤基、咔唑基、苯并咪唑基、吲哚啉基、苯并二氧戊環基及苯并二噁烷。雜芳基係經取代或未經取代。該氮原子係經取代或未經取代(即,N或NR,其中R係H或另一取代基(若確定))。可視情況氧化該氮及硫雜原子(即,N→O及S(O)p,其中p係0、1或2)。
橋接環亦包括於雜環之定義中。當一或多個(較佳地一至三個)原
子(即,C、O、N、或S)連接兩個不相鄰碳或氮原子時出現橋接環。橋接環實例包括但不限於一個碳原子、兩個碳原子、一個氮原子、兩個氮原子、及碳-氮基團。應注意橋總是將單環轉化為三環。當環係橋接時,針對該環引述之取代基可存在於橋上。
術語「雜環基烷基」指鍵接至連接至該化合物核心之烷基的雜環基或經取代之雜環基。
術語「抗衡離子」用於表示帶負電物質諸如氯離子、溴離子、氫氧根離子、乙酸根離子及硫酸根離子或帶正電物質諸如鈉(Na+)、鉀(K+)、銨(RnNHm +,其中n=0至4及m=0至4)及類似物。
術語「吸電子基團」(EWG)指極化鍵之取代基,向自身吸引電子密度並遠離其他相連原子。EWG實例包括但不限於CF3、CF2CF3、CN、鹵素、鹵代烷基、NO2、碸、亞碸、酯、磺醯胺、甲醯胺、烷氧基、烷氧基醚、烯基、炔基、OH、C(O)烷基、CO2H、苯基、雜芳基、-O-苯基及-O-雜芳基。EWG之較佳實例包括但不限於CF3、CF2CF3、CN、鹵素、SO2(C1-4烷基)、CONH(C1-4烷基)、CON(C1-4烷基)2、及雜芳基。EWG之更佳實例包括但不限於CF3及CN。
如本文所使用,術語「胺保護基」意指在有機合成技術中已知用於保護胺基且對酯還原劑、雙取代肼、R4-M及R7-M、親核劑、肼還原劑、活化劑、強鹼、受阻胺鹼及環化劑穩定之任何基團。符合此等標準之此等胺保護基包括在Wuts,P.G.M.與Greene,T.W.Protecting Groups in Organic Synthesis,第四版,Wiley(2007)及The Peptides:Analysis,Synthesis,Biology,第三卷,Academic Press,New York(1981)(其揭示內容以引用的方式併入本文中)中列出之彼等。胺保護基團實例包括但不限於下列:(1)醯基類諸如甲醯基、三氟乙醯基、鄰苯二甲醯基、及對甲苯磺醯基;(2)芳族胺基甲酸酯類諸如苄氧羰基(Cbz)及經取代之苄氧羰基、1-(對聯苯)-1-甲基乙氧基羰基、9-茀基
甲氧基羰基(Fmoc);(3)脂族胺基甲酸酯類諸如第三丁氧基羰基(Boc)、乙氧基羰基、二異丙基甲氧基羰基、及烯丙氧基羰基;(4)環烷基胺基甲酸酯類諸如環戊氧基羰基及金剛烷氧基羰基;(5)烷基類諸如三苯基甲基及苄基;(6)三烷基矽烷諸如三甲基矽烷;(7)含硫醇類諸如苯基硫代羰基及二硫雜丁二醯基;及(8)烷基類諸如三苯基甲基、甲基及苄基;及經取代烷基類諸如2,2,2-三氯乙基、2-苯基乙基、及第三丁基;及三烷基矽烷類諸如三甲基矽烷。
如本文指出,術語「經取代」意指至少一氫原子經由非氫基團置換,只要維持標準價數及取代產生穩定化合物。如本文所使用,環雙鍵係在兩個相鄰環原子間形成之雙鍵(例如,C=C、C=N、或N=N)。
在本發明化合物上具有氮原子(例如,胺)之情形下,可藉由經氧化劑(例如,mCPBA及/或過氧化氫)處理將此等轉化為N-氧化物,以獲得本發明其他化合物。由此,顯示及主張之氮原子被視為涵蓋顯示之氮及其N-氧化物(N→O)衍生物。
當任何可變化在任何化合物組分或式中出現超過一次時,其在每次出現時之定義係與其在每次其他出現時之定義無關。由此,例如,若顯示基團經0至3個R取代,則該基團可視情況經多達三個R基團取代,及在每次出現時,R係獨立地選自R之定義。此外,只要此等組合產生穩定化合物,可允許取代基及/或變化之組合。
當顯示至取代基之鍵穿過連接環中兩個原子之鍵時,則此取代基可鍵接至環上任何原子。當列出取代基而未指明其中此取代基鍵接至所給出式之化合物之其餘部分之原子時,則此取代基可通過在此取代基中任何原子連接。只要此組合產生穩定化合物,則可允許取代基及/或變化之組合。
如本文所使用,「醫藥上可接受鹽」指揭示化合物之衍生物,其
中母體化合物藉由製備其酸或鹼鹽修飾。醫藥上可接受鹽實例包括但不限於鹼性基團諸如胺之無機或有機酸鹽;及酸性基團諸如羧酸之鹼或有機鹽。醫藥可接受之鹽包括(例如)由非毒性無機或有機酸形成之母體化合物的習知非毒性鹽或四級銨鹽。例如,此等習知非毒性鹽包括衍生自無機酸諸如氯化氫、溴化氫、硫酸、胺基磺酸、磷酸、及硝酸之彼等;及由無機酸諸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、雙羥萘酸、馬來酸、羥基馬來酸、苯基乙酸、麩胺酸、苯甲酸、水楊酸、磺胺酸、2-乙醯氧基苯甲酸、富馬酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸、及羥乙磺酸、等等製備之鹽。
可藉由習知化學方法由含有鹼性或酸性部分之母體化合物合成本發明之醫藥上可接受之鹽。一般而言,可藉由使此等化合物之游離酸或鹼形式與化學計量適當鹼或酸在水中或在有機溶劑中,或在二者之混合物中反應來製備此等鹽;一般而言,非水性介質如醚、乙酸乙酯、乙醇、異丙醇、或乙腈係較佳。適宜鹽之列表可見於Remington:The Science and Practice of Pharmacy,第22版,Allen,L.V.Jr.編;Pharmaceutical Press,London,UK(2012),其揭示內容以引用的方式併入本文中。
此外,式I化合物可具有前藥形式。可在活體內轉化以提供生物活性劑(即,式I化合物)之任何化合物係在本發明範圍及精髓內之前藥。此項技術中已知各種形式前藥。就此等前藥衍生物之實例而言,參見:a)Bundgaard,H.編,Design of Prodrugs,Elsevier(1985),及Widder,K.等人編,Methods in Enzymology,112:309-396,Academic Press(1985);b)Bundgaard,H.,第5章,「Design and Application of Prodrugs,」
A Textbook of Drug Design and Development,第113至191頁,Krosgaard-Larsen,P.等人編,Harwood Academic Publishers(1991);c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992);d)Bundgaard,H.等人,J.Pharm.Sci.,77:285(1988);e)Kakeya,N.等人,Chem.Pharm.Bull.,32:692(1984);及f)Rautio,J(編者).Prodrugs and Targeted Delivery(Methods and Principles in Medicinal Chemistry),第47卷,Wiley-VCH,2011。
含有羧基之化合物可形成充當前藥之生理上可水解之酯,其藉由在體內水解產生式I化合物本身。由於眾多實例中在消化酶影響下大部分出現水解,此等前藥較佳係口服投與。當該酯本身具有活性,或在彼等其中在血液中出現水解之實例中,可使用非經腸給藥。式I化合物之生理上可水解之酯的實例包括C1-6烷基、C1-6烷基苄基,4-甲氧基苄基、二氫茚基、鄰苯二甲醯基、甲氧基甲基、C1-6醯氧基-C1-6烷基(例如,乙醯氧甲基、特戊醯氧甲基或丙醯氧基甲基)、C1-6烷氧基羰氧基-C1-6烷基(例如,甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基、甘胺醯氧基甲基、苯基甘胺醯氧基甲基、(5-甲基-2-側氧基-1,3-二氧雜環戊烯-4-基)-甲基)、及其他用於(例如)青黴素及頭孢菌素技術中之熟知生理上可水解之酯。此等酯可藉由在此項技術中已知之習知技術製備。前藥製法係此項技術中所熟知,及描述於例如,King,F.D.,編,Medicinal Chemistry:Principles and Practice,The Royal Society of Chemistry,Cambridge,UK(第2版,再版,2006);Testa,B.等人,Hydrolysis in Drug and Prodrug Metabolism.Chemistry,Biochemistry and Enzymology,VCHA and Wiley-VCH,Zurich,Switzerland(2003);Wermuth,C.G.,編,The Practice of Medicinal Chemistry,第3版,Academic Press,San Diego,CA(2008)。
本發明意欲包括本發明化合物上出現的原子之所有同位素。同
位素包括彼等具有相同原子序數但具有不同質量數之原子。作為一般實例且無限制地,氫之同位素包括氚及氘。氫之同位素可表示為1H(氫)、2H(氘)及3H(氚)。亦通常將其表示為D(氘)及T(氚)。在本申請案中,CD3表示其中全部氫原子係氘之甲基。碳同位素包括13C及14C。一般而言,可藉由熟習此項技術者已知的習知技術或與本文中所述者類似的方法使用適當同位素標記試劑代替另外使用的非標記試劑來製備本發明之同位素標記化合物。
術語「溶劑合物」意指本發明化合物與一或多種有機或無機溶劑分子物理締合。此物理締合包括氫鍵結。在某些實例中,該溶劑合物可單離,例如,當將一或多種溶劑分子併至結晶固體之晶格中時。在溶劑合物中,溶劑分子可以規則排列及/或無序排列存在。溶劑合物可包括化學計量或非化學計量之溶劑分子。「溶劑合物」涵蓋溶液-相及可單離溶劑合物。例示性溶劑合物包括但不限於水合物、乙醇合物、甲醇合物、及異丙醇合物。於相關技術中已熟知溶劑化作用之方法。
如本文所使用,術語「患者」指待藉由本發明方法治療之生物。此等生物較佳地包括但不限於哺乳動物(例如,鼠類、猴、馬、牛、豬、犬、貓等等),且最佳地指人類。
如本文所使用,術語「有效量」意指可引發(例如)由研究者或醫師尋求之組織、系統、動物或人類的生物或醫學反應之藥物或醫藥試劑(即,本發明化合物)之含量。此外,術語「治療有效量」意指與未接受此量之對應個體相比產生改良之治療、治癒、預防、或改善疾病、病症、或副作用、或降低疾病或病症之進展速率的任何量。可以一或多次投與、施加或給藥投與有效量及無意限制於特定調配或投與途徑。該術語之範圍內亦包括有效增強正常生理功能之量。
如本文所使用,術語「治療」包括任何功效,例如減輕、降
低、調節、改善或消除,其導致改良病狀、疾病、病症等等,或改善其症狀。
如本文所使用,術語「醫藥組合物」指活性劑與使該組合物特別適宜活體內或活體外診斷或治療用途的惰性或活性載劑之組合。
鹼之實例包括但不限於鹼金屬(例如,鈉)氫氧化物、鹼土金屬(例如,鎂)氫氧化物、氨、及式NW4 +化合物,其中W係C1-4烷基,等等。
對於治療用途,考慮本發明化合物之鹽係醫藥上可接受。然而,亦發現非醫藥上可接受之酸及鹼之鹽可用於(例如)製備或純化醫藥上可接受化合物。
可藉由若干種熟習有機合成技術者熟知的方法來製備本發明化合物。可使用下文描述之方法,連同合成有機化學技術中熟知之合成方法或由熟習此項技術者據此知曉之變異形式合成本發明化合物。較佳方法包括但不限於下文描述之彼等。本文中所引用之全部參考文獻之全文係以引用之方式併入本文中。
可使用在此部分中描述之反應及技術製備本發明化合物。在對採用之試劑及材料而言適當之溶劑中進行該等反應,且該等反應適合所涉及之轉化。此外,在下文描述之合成方法之描述中,應瞭解全部提出之反應條件(包括溶劑選擇、反應氣氛、反應溫度、實驗持續時間及處理步驟)係經選擇為該反應之標準條件,其當輕易為熟習此項技術者所暸解。熟習有機合成技術者應瞭解,分子各部分存在之官能度必須與提出之試劑及反應相容。熟習此項技術者應輕易知曉對與反應條件相容之取代基之此等限制,及必須隨後使用替代方法。此有時將需要判斷以修改合成步驟順序或選擇優於另一者之一特定方法流程以獲得期望之本發明化合物。亦應瞭解,在此領域中設計任何合成途
徑時另一主要考慮因素係明智選擇用於保護在本發明描述之化合物中存在之反應性官能團的保護基。為受訓醫師描述眾多選擇之權威說明係Greene and Wuts(Protective Groups In Organic Synthesis,第三版,Wiley and Sons,1999)。
可參考以下流程闡明之方法製備式(I)化合物。如其中所顯示,最終產物係具有與式(I)相同結構式之化合物。應瞭解可藉由流程由適宜選擇具有適當取代基之試劑製備任何式(I)化合物。一般技術者可容易選擇溶劑、溫度、壓力及其他反應條件。初始材料係市售或容易由一般技術者製備。化合物組分係如本文或在此說明書中其他處所定義。
可使用在流程1至4中總結之方法合成式(I)化合物。
可由經適宜取代之2-胺基吡啶i(X=鹵素或其他適當官能度)藉由在存在鹼諸如DMAP時,使用適宜溶劑諸如二甲基甲醯胺於適當溫度下經醯化劑諸如乙酸酐(LG=-OAc)處理來製備通式ii化合物。使用經
保護之乙炔諸如三甲矽烷基乙炔在存在觸媒諸如Pd(PPh3)2Cl2與添加劑諸如CuI且存在鹼諸如三乙胺於高溫下處理化合物ii可用於實現轉化為式iii化合物。可藉由經由四丁基氟化銨在溶劑諸如THF中處理或其他熟習此項技術者已知之途徑達成去保護以獲得式iv化合物。式iv化合物與經適宜取代之3-胺基吡啶(v,X=鹵素)在存在觸媒諸如Pd(PPh3)2Cl2與添加劑諸如CuI且存在鹼諸如三乙胺在適當溶劑諸如二甲基甲醯胺中於高溫下反應可用於製備式vi化合物。此外,使用三氟乙酸酐或其他適當醯化試劑在溶劑諸如二氯甲烷中且存在鹼諸如三乙胺時於適當溫度處理式vi化合物可用於獲得式vii化合物。在存在經適當取代之雜芳基鹵化物(R-X)在存在適當觸媒諸如Pd(PPh3)4及鹼諸如Cs2CO3在適當溶劑諸如乙腈中於高溫諸如100℃下環化式vii化合物可獲得式viii化合物。藉由使用適當官能化劑(R8-X)(其中X係離去基團,例如鹵素)在存在鹼諸如三乙胺在適當溶劑諸如二甲基甲醯胺中處理可將式viii化合物進一步加工為通式ix化合物。
或者,如在流程2中描述,可通過經適當試劑諸如CuI於適當溶劑諸如DMF中於高溫處理來直接環化式vi化合物以獲得式x化合物。此外,可藉由使用觸媒諸如Pd(PPh3)4在存在鹼諸如Cs2CO3在適當溶劑諸如乙腈中於高溫諸如100℃下處理式vii化合物來製備式x化合物。
可使用鹵化試劑諸如N-溴代丁二醯亞胺在溶劑諸如二甲基甲醯胺中處理式x化合物以提供式xi化合物。可藉由使用有機金屬試劑諸如硼酸(M=B(OH)2)或硼酸酯在存在觸媒PdCl2(dppf)諸如與鹼諸如K2CO3時在適當溶劑諸如1,4-二噁烷中處理進一步加工式xi化合物以獲得式viii化合物。
亦可如流程3中描述進一步處理式viii化合物。使用鹼諸如氫氧化鈉在溶劑諸如水或水與甲醇之混合物中於高溫處理式viii化合物可提供式xii之游離胺。式xii化合物與含有離去基團(例如鹵素(LG=Hal))之經適當取代試劑在存在鹼時於適當溶劑諸如二甲基甲醯胺中反應可提供式xiii化合物。或者,可使用羧酸(LG=OH)及肽偶合試劑諸如EDC處理式xiii化合物以獲得通式xiii化合物。
或者,可由若干種熟習此項技術者已知之方法選擇性保護式viii化合物。例如,使用磺醯氯(PG-LG=pTsCl)在存在鹼諸如三乙胺時在
適當溶劑諸如二甲基甲醯胺中處理可用於獲得通式xiv化合物。式xiv化合物與含有離去基團(例如鹵素(LG=Hal))之經適當取代之試劑在存在鹼時在適當溶劑諸如二甲基甲醯胺中反應可提供式xv化合物。可以熟習此項技術者已知之眾多方式實現移除保護基團,例如,藉由在溶劑或溶劑混合物諸如甲醇水溶液中使用鹼諸如氫氧化鈉處理以提供通式xiii化合物。
利用以下實例進一步定義本發明。應瞭解實例僅以闡明之方式給出。熟習此項技藝者自前述討論及實例可確定本發明之基本特徵,且可在不脫離其精髓及範圍下進行各種改變及修改以使本發明適用於各種用途及情況。因此,本發明並不限於下文列出之闡明性實例,而係由本文隨附之申請專利範圍定義。
N-{4-[3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
1A):N-(4-溴代吡啶-2-基)乙醯胺
向4-溴代吡啶-2-胺(3.8g,22mmol)含於Ac2O(20mL)之混合物中添加DMAP(0.054g,0.44mmol)。在密封壓力反應器中於140℃加熱該混合物1h,及隨後冷卻至室溫。將該反應混合物倒入冰水中,並使用NH4OH將所得混合物調節至pH=8.4。藉由過濾收集所得沉澱物,使用水清洗並乾燥以獲得實例1A(4.2g,88%)。HPLC:RT=0.587min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=217[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 10.71(br.s.,1H),8.32(d,J.=.1.8Hz,1H),8.22(d,J=5.5Hz,1H),7.35(dd,J=5.3,1.8Hz,1H),2.11(s,3H)。
1B):N-(4-乙炔基吡啶-2-基)乙醯胺
使用氮沖洗實例1A(4.2g,19.3mmol)、乙炔基三甲基矽烷(2.28g,23.2mmol)、雙(三苯基膦)二氯化鈀(II)(0.27g,0.39mmol)及碘化銅(I)(0.15g,0.77mmol)含於TRA(20mL,143mmol)之混合物並加熱至76℃持續2.5h,隨後冷卻至室溫。通過短矽膠柱過濾該混合物,使用EtOAc洗脫。濃縮該濾液以獲得N-(4-((三甲基矽烷基)乙炔基)吡啶-2-基)乙醯胺(5.10g,114%)。將上文固體溶於THF(60mL),且用一份TBAF(12.6g,48.2mmol)處理。於室溫下攪拌該反應混合物2h且接
著濃縮至乾燥。使用水處理該殘留物並使用EtOAc萃取(3x)。使用鹽水清洗合併之萃取物、乾燥(MgSO4)並隨後濃縮。使用矽膠急驟層析法(12g管柱,EtOAc/DCM=0至100%)純化該殘留物以獲得淺黃色固體之實例1B(2.89g,94%)。HPLC:RT=0.43min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=161[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 8.32(s,1H),8.24(dd,J=5.1,0.7Hz,1H),8.05(br.s.,1H),7.11(dd,J=5.1,1.5Hz,1H),3.30(s,1H),2.23(s,3H)。
1C):N-(4-((3-胺基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
使用N2沖洗2-溴代吡啶-3-胺(3.40g,19.7mmol)、實例1B(3g,18.7mmol)、雙(三苯基膦)二氯化鈀(II)(0.13g,0.19mmol)及碘化銅(I)(0.11g,0.56mmol)含於TEA(24mL)及DMF(8mL)之混合物,並隨後於76℃加熱1h。將該反應混合物冷卻至室溫,隨後濃縮及藉由矽膠急驟層析法(40g管柱,MeOH/DCM=0至12%)純化該殘留物以獲得黃色固體之實例1C(5.5g)。HPLC:RT=0.953min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=253[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 8.38(s,1H),8.28(dd,J=5.1,0.9Hz,1H),8.08(dd,J=4.5,1.4Hz,1H),7.96(br.s.,1H),7.23(dd,J=5.2,1.4Hz,1H),7.16-7.10(m,1H),7.09-7.04(m,1H),4.34(br.s.,2H),2.25(s,3H)。
ID):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)吡啶-3-基)-2,2,2-三氟乙醯胺
向實例1C(335mg,1.33mmol)含於CH2Cl2(15mL)之懸浮液中添加TEA,並將該混合物冷卻至0℃。緩慢添加三氟乙酸酐(0.28mL,1.99mmol)。於0℃攪拌該反應混合物30min並隨後使用DCM稀釋。使用飽和NaHCO3水溶液及鹽水清洗該溶液,乾燥(MgSO4)並隨後濃縮。使用DCM/己烷進行超音波處理該殘留物,及藉由過濾收集所得固體以獲得黃色固體之實例1D(412mg,71%)。HPLC:RT=1.530min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=349[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 8.86-8.69(m,2H),8.54(dd,J=4.8,1.5Hz,1H),8.45(s,1H),8.35(dd,J=5.1,0.9Hz,1H),7.99(br.s.,1H),7.44(dd,J=8.5,4.7Hz,1H),7.21(dd,J=5.1,1.3Hz,1H),2.26(s,3H)。
實例1):N-{4-[3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用N2沖洗實例1D(40mg,0.12mmol)、2-溴-6-甲基吡啶(23.7mg,0.14mmol)、Pd(Ph3P)4(6.6mg,5.7μmol)及Cs2CO3(112mg,0.35mmol)含於乙腈(1mL)之混合物。隨後於100℃在密封瓶中加熱該
混合物2h,並隨後冷卻至室溫。過濾掉固體,並使用10% MeOH/DCM沖洗,及濃縮該濾液。將該殘留物溶於DMF,及藉由製備型HPLC(YMC-Pack C-18 30x100mm,使用含有5mmol NH4OAc之10%至70% CH3CN水溶液在20min內洗脫,30mL/min,波長=254nm)純化以獲得白色固體之實例1E(12.5mg,31%)。HPLC:RT=1.040min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=344[M+H]+;1H NMR=(400MHz,甲醇-d4)δ ppm 8.39(dd,J=4.6,1.3Hz,1H),8.31-8.21(m,2H),7.97(dd,J=8.1,1.3Hz,1H),7.83(t,J=7.7Hz,1H),7.50(d,J=7.7Hz,1H),7.32(dt,J=8.4,4.2Hz,2H),7.13(dd,J=5.2,1.7Hz,1H),2.53(s,3H),2.17(s,3H)。
N-{4-[3-(6-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基)乙醯胺
由實例1D及2-溴-6-甲氧基吡啶藉由針對實例1顯示之一般方法製備實例2。HPLC:RT=0.72min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1 x 50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=360[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.73(s,1H),8.67(d,J=5.0Hz,1H),8.57-8.30(m,3H),7.96(s,1H),7.81-7.65(m,2H),7.35-7.20(m,2H),6.81(d,J=8.4Hz,
1H),2.51(br.s.,3H),2.11(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D、及2-溴-6-氯代吡啶藉由針對實例1顯示之一般方法製備實例3。HPLC:RT=0.77min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=364[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.69(s,1H),8.63(d,J=5.0Hz,1H),8.42(d,J=5.0Hz,1H),8.38-8.27(m,2H),7.94-7.86(m,1H),7.80(d,J=7.1Hz,1H),7.59(dd,J=7.9,5.6Hz,1H),7.46(d,J=8.1Hz,1H),7.26(d,J=4.4Hz,1H),2.10(s,3H)。
N-{4-[3-(6-氟代吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D及2-氟-5-碘代吡啶藉由針對實例1顯示之一般方法製備實例4。HPLC:RT=0.58min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=348[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.18(s,1H),10.61(s,1H),8.44(d,J=4.4Hz,1H),8.36(d,J=5.0Hz,1H),8.29(s,2H),8.16-8.05(m,1H),7.91(d,J=8.1Hz,1H),7.34-7.21(m,2H),7.17(d,J=5.0Hz,1H),2.09(s,3H)。
N-{4-[3-(5-氯代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D及5-氯-2-碘代吡啶藉由針對實例1顯示之一般方法製備實例5。HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=364[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.77(s,1H),8.75-8.62(m,2H),8.55-8.43(m,2H),8.37(s,1H),8.00-7.91(m,1H),7.75-7.58(m,2H),7.30(d,J=4.4Hz,1H),2.12(s,3H)。
N-{4-[3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D及2-溴-5-氟代吡啶藉由針對實例1顯示之一般方法製備實例6。HPLC:RT=0.70min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=348[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.77(s,1H),8.75-8.63(m,2H),8.57(d,J=8.4Hz,1H),8.48(d,J=5.4Hz,1H),8.34(s,1H),7.84-7.70(m,2H),7.56(dd,J=8.1,3.7Hz,1H),7.31(d,J=5.0Hz,1H),2.11(s,3H)。
N-(4-{3-[6-(三氟甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
由實例1D及2-溴-6-(三氟甲基)吡啶藉由針對實例1顯示之一般方法製備實例7。HPLC:RT=0.87min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=398[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.63(s,1H),8.62(d,J=4.4Hz,1H),8.41-8.30(m,2H),
8.29-8.20(m,2H),8.17(t,J=7.7Hz,1H),7.84-7.78(m,1H),7.53(dd,J=8.1,5.0Hz,1H),7.26(d,J=4.4Hz,1H),2.08(s,3H)。
N-{4-[3-(嘧啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D及2-溴代嘧啶藉由針對實例1顯示之一般方法製備實例8。HPLC:RT=0.54min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=331[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.77(s,1H),8.86(d,J=5.0Hz,2H),8.78(d,J=5.7Hz,1H),8.71(d,J=8.4Hz,1H),8.54-8.45(m,2H),7.85(dd,J=8.1,6.1Hz,1H),7.50-7.41(m,2H),2.13(s,3H)。
N-{4-[3-(6-氯代吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
由實例1D及5-溴-2-氯代吡啶藉由針對實例1顯示之一般方法製備
實例9。HPLC:RT=0.64min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=364[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.24(s,1H),10.63(s,1H),8.52-8.40(m,2H),8.36(d,J=5.0Hz,1H),8.30(s,1H),8.00(dd,J=8.4,2.4Hz,1H),7.91(d,J=8.1Hz,1H),7.55(d,J=8.1Hz,1H),7.29(dd,J=8.2,4.5Hz,1H),7.16(d,J=4.4Hz,1H),2.09(s,3H)。
N-{4-[3-(5,6-二氟吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2,3-二氟-5-碘代吡啶製備實例10。HPLC:RT=0.70min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=366[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.28(s,1H),10.61(s,1H),8.46(d,J=4.4Hz,1H),8.38(d,J=5.0Hz,1H),8.27(br.s.,1H),8.17(t,J=9.8Hz,1H),8.08(s,1H),7.92(d,J=8.4Hz,1H),7.30(dd,J=8.1,4.4Hz,1H),7.25(d,J=4.7Hz,1H),2.08(s,3H)。
N-{4-[3-(6-氟-5-甲基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶
-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及5-溴-2-氟-3-甲基吡啶製備實例11。HPLC:RT=0.70min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=362[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.60(s,1H),8.43(d,J=3.7Hz,1H),8.37-8.25(m,2H),8.10-7.94(m,2H),7.90(d,J=7.7Hz,1H),7.28(dd,J=8.1,4.7Hz,1H),7.16(d,J=4.4Hz,1H),2.28(s,3H),2.09(s,3H)。
N-{4-[3-(6-氰基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及5-溴代氰基吡啶製備實例12。HPLC:RT=0.58min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=355[M+H]+;1H NMR(500MHz,DMSO-d6)δ
ppm 10.70(br.s.,1H),8.84(s,1H),8.58(br.s.,1H),8.41(br.s.,1H),8.29-8.16(m,3H),8.11(d,J=8.1Hz,1H),7.95(s,1H),7.53(br.s.,1H),7.20(d,J=4.0Hz,1H),2.09(s,3H)。
N-(4-{3-[6-(三氟甲基)吡啶-3-基]-1H-吡咯并[3,2-b]1吡啶-2-基}吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例1D及5-溴-2-(三氟甲基)吡啶製備實例13。HPLC:RT=0.78min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=398[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.36(s,1H),10.64(s,1H),8.84(s,1H),8.47(d,J=4.4Hz,1H),8.37(d,J=5.0Hz,1H),8.30(s,1H),8.23(d,J=8.1Hz,1H),7.94(m,2H),7.32(dd,J=8.2,4.5Hz,1H),7.18(d,J=4.7Hz,1H),2.08(s,3H)。
N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
方法A:
藉由針對實例1顯示之一般方法由實例1D及5-溴-2-甲氧基吡啶製備實例14。HPLC:RT=0.62min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=360[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.01(s,1H),10.58(s,1H),8.41(dd,J=4.5,1.4Hz,1H),8.37-8.29(m,2H),8.26(d,J=2.0Hz,1H),7.87(dd,J=8.1,1.3Hz,1H),7.80(dd,J=8.5,2.3Hz,1H),7.25(dd,J=8.3,4.5Hz,1H),7.13(dd,J=5.1,1.5Hz,1H),6.87(d,J=8.6Hz,1H),2.10(s,3H)。
亦可藉由替代方法B製備實例14:
14A):N-(4-(1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用N2沖洗實例1D(5g,14.36mmol)、Pd(Ph3P)4(0.829g,0.718mmol)及Cs2CO3(9.36g,28.7mmol)含於乙腈(60mL)之混合物。隨後於100℃在密封壓力反應器中加熱該混合物過夜,及隨後冷卻至室溫。使用MeOH/DCM稀釋該反應混合物,及直接負載於矽藻土上,並隨後藉由矽膠急驟層析法(80g管柱,MeOH/DCM=0至10%)純化以獲得實例14A(2.37g,65%)。HPLC:RT=0.850min(H2O/MeOH及
0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=25[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.03(s,1H),10.57(s,1H),8.53(s,1H),8.39(ddd,J=6.8,5.0,1.0Hz,2H),7.82(dt,J=8.0,1.2Hz,1H),7.61(dd,J=5.3,1.5Hz,1H),7.21-7.11(m,2H),2.15(s,3H)。
14B):N-(4-(3-溴-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例14A(6.55g,26.0mmol)含於DMF(70mL)之懸浮液中於0℃添加NBS(4.62g,26.0mmol)。隨後於室溫攪拌該反應30min,使用MeOH淬冷,並隨後濃縮。使用MeOH處理該殘留物,及藉由過濾收集該固體沉澱物並乾燥以獲得淺黃色固體之實例14B(7.7g,90%)。HPLC:RT=0.953min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=332[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.31(s,1H),10.67(s,1H),8.76(s,1H),8.58-8.33(m,2H),7.88(dd,J=8.4,1.3Hz,1H),7.60(dd,J=5.3,1.8Hz,1H),7.30(dd,J=8.3,4.5Hz,1H),2.15(s,3H)。
實例14):N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用N2沖洗實例14B(7.5g,22.65mmol)、(6-甲氧基吡啶-3-基)硼酸(8.66g,56.6mmol)、PdCl2(dppf)-CH2Cl2加合物(0.555g,0.679mmol)及2M K2CO3(34.0mL,67.9mmol)含於1,4-二噁烷(200mL)之混合物。將該混合物加熱至回流5h,隨後冷卻至室溫。隨後使用EtOAc稀釋該反應混合物,使用鹽水清洗,乾燥並濃縮。藉由矽膠急驟層析法(120g管柱,MeOH/DCM=0至10%)純化該殘留物以獲得灰白色固體之實例14(3.85g,47%)。
N-{4-[3-(6-氰基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及6-溴代氰基吡啶製備實例15。HPLC:RT=0.74min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=355[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.55(s,1H),8.54(d,J=8.1Hz,1H),8.49(d,J=4.0Hz,1H),8.36
(d,J=5.0Hz,1H),8.25(s,1H),8.10(t,J=7.9Hz,1H),7.98-7.90(m,1H),7.85(d,J=7.4Hz,1H),7.32(dd,J=8.2,4.5Hz,1H),7.25(d,J=5.0Hz,1H),2.08(s,3H)。
N-{4-[3-(6-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-6-氟代吡啶製備實例16。HPLC:RT=0.73min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=348[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.75(s,1H),8.67(d,J=5.0Hz,1H),8.52-8.41(m,2H),8.33(s,1H),8.03(q,J=8.1Hz,1H),7.68(dd,J=7.9,5.6Hz,1H),7.58(d,J=7.1Hz,1H),7.30(d,J=4.0Hz,1H),7.16(d,J=9.8Hz,1H),2.11(s,3H)。
N-{4-[3-(異喹啉-6-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及6-溴代異喹啉製備實例17。HPLC:RT=0.55min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.62(s,1H),9.30(s,1H),8.53-8.43(m,2H),8.38(s,1H),8.29(d,J=5.4Hz,1H),8.24(s,1H),8.08(d,J=8.4Hz,1H),7.93(d,J=8.1Hz,1H),7.82(d,J=5.7Hz,1H),7.71(d,J=8.4Hz,1H),7.30(dd,J=8.1,4.4Hz,1H),7.09(d,J=5.0Hz,1H),2.07(s,3H)。
N-{4-[3-(5-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-5-甲基吡啶製備實例18。HPLC:RT=0.72min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220
nm);MS(ES):m/z=344[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.80(s,1H),8.73-8.64(m,2H),8.49(d,J=5.0Hz,1H),8.45(d,J=8.1Hz,1H),8.36(s,1H),7.91(d,J=7.7Hz,1H),7.67(dd,J=8.1,5.4Hz,1H),7.52(d,J=8.4Hz,1H),7.32(d,J=4.0Hz,1H),2.42(s,3H),2.12(s,3H)。
N-{4-[3-(異喹啉-8-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及8-溴代異喹啉製備實例19。HPLC:RT=0.56min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.46(s,1H),8.88(s,1H),8.46(d,J=5.7Hz,1H),8.31(d,J=3.7Hz,1H),8.25(s,1H),8.13(d,J=5.4Hz,1H),8.02(d,J=8.4Hz,1H),7.96(s,1H),7.91(d,J=5.7Hz,1H),7.82(t,J=7.6Hz,1H),7.57(d,J=6.7Hz,1H),7.28(dd,J=8.2,4.5Hz,1H),6.90(d,J=4.4Hz,1H),2.02(s,3H)。
N-[4-[3-(1H-吲哚-5-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基]乙醯胺
藉由針對實例1顯示之一般方法由實例1D及5-溴-1H-吲哚製備實例20。HPLC:RT=0.81min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=368[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.33(br.s.,1H),10.69(s,1H),8.62(d,J=8.1Hz,1H),8.55(d,J=5.7Hz,1H),8.45(s,1H),8.26(d,J=5.4Hz,1H),7.77-7.67(m,2H),7.53-7.41(m,2H),7.06(d,J=8.1Hz,1H),6.98(d,J=4.7Hz,1H),6.50(br.s.,1H),2.10(s,3H)。
N-{4-[3-(喹啉-8-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及8-溴代喹啉製備實例21。HPLC:RT=0.64min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm
10.37(s,1H),8.58(d,J=2.7Hz,1H),8.41(d,J=8.1Hz,1H),8.26(d,J=4.4Hz,1H),8.20(br.s.,1H),8.08-7.99(m,2H),7.93(d,J=8.1Hz,1H),7.81(d,J=6.7Hz,1H),7.70(t,J=7.6Hz,1H),7.46(dd,J=8.4,4.0Hz,1H),7.23(dd,J=8.1,4.4Hz,1H),6.83(d,J=5.0Hz,1H),2.01(s,3H)。
N-{4-[3-(喹啉-6-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及6-溴代喹啉製備實例22。HPLC:RT=0.54min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.15(s,1H),10.61(s,1H),8.89(d,J=2.7Hz,1H),8.46(d,J=3.7Hz,1H),8.42-8.32(m,2H),8.27(d,J=5.4Hz,1H),8.22(s,1H),7.99(d,J=8.8Hz,1H),7.93(d,J=8.1Hz,1H),7.79(dd,J=8.8,1.3Hz,1H),7.53(dd,J=8.2,4.2Hz,1H),7.30(dd,J=8.2,4.5Hz,1H),7.09(d,J=4.4Hz,1H),2.07(s,3H)。
N-{4-[3-(5-氟-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及6-溴-3-氟-2-甲基吡啶製備實例23。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=362[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.56(s,1H),8.49(d,J=4.4Hz,1H),8.38-8.28(m,2H),8.05-7.89(m,2H),7.68(t,J=9.1Hz,1H),7.35(dd,J=8.1,4.7Hz,1H),7.25(d,J=5.4Hz,1H),2.33(d,J=2.4Hz,3H),2.10(s,3H)。
N-{4-[3-(5-氟-4-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-5-氟-4-甲基吡啶製備實例24。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=362[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.74(s,1H),8.65(d,J=5.0Hz,1H),8.59-8.49(m,2H),
8.46(d,J=5.4Hz,1H),8.35(s,1H),7.71(dd,J=8.1,5.7Hz,1H),7.54(d,J=5.7Hz,1H),7.29(d,J=4.7Hz,1H),2.26(s,3H),2.11(s,3H)。
N-{4-[3-(5-甲磺醯基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-5-(甲磺醯基)吡啶製備實例25。HPLC:RT=0.63min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.61(s,1H),8.84(d,J=2.0Hz,1H),8.61(d,J=8.4Hz,1H),8.53(d,J=4.7Hz,1H),8.43-8.32(m,2H),8.29(s,1H),7.94(d,J=8.1Hz,1H),7.33(dd,J=8.1,4.7Hz,1H),7.25(d,J=5.0Hz,1H),3.45-3.35(m,3H),2.10(s,3H)。
N-{4-[3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-5-甲氧基吡啶製備實例26。HPLC:RT=0.70min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=360[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 13.40(br.s.,1H),10.77(s,1H),8.68(d,J=5.7Hz,1H),8.58(d,J=8.4Hz,1H),8.53-8.46(m,2H),8.39(s,1H),7.75(dd,J=8.1,5.7Hz,1H),7.53(dd,J=8.8,3.1Hz,1H),7.41(d,J=8.8Hz,1H),7.30(dd,J=5.1,1.5Hz,1H),3.91(s,3H),2.12(s,3H)。
N-{4-[3-(2-甲氧基嘧啶-5-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及5-溴-2-甲氧基嘧啶製備實例27。HPLC:RT=0.55min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=361[M+H]+;1H NMR(500MHz,DMSO-
d6)δ ppm 10.63(s,1H),8.68(s,1H),8.47(d,J=4.0Hz,1H),8.37(d,J=5.0Hz,1H),8.32(s,1H),8.03(d,J=8.1Hz,1H),7.37(dd,J=8.1,4.7Hz,1H),7.21(d,J=4.0Hz,1H),3.97(s,3H),2.09(s,3H)。
N-{4-[3-(4-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-4-甲氧基吡啶製備實例28。HPLC:RT=0.58min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=360[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.57(s,1H),8.48(d,J=4.0Hz,1H),8.38-8.19(m,3H),7.90(d,J=8.4Hz,1H),7.72(d,J=2.0Hz,1H),7.28(dd,J=8.1,4.4Hz,1H),7.18(d,J=5.0Hz,1H),6.91(d,J=3.4Hz,1H),3.89(s,3H),2.10(s,3H)。
N-{4-[3-(4-乙基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-4-乙基吡啶製備實例29。HPLC:RT=0.93min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=358[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.57(s,1H),8.49(d,J=4.0Hz,1H),8.38(d,J=5.0Hz,1H),8.35-8.26(m,2H),7.98-7.87(m,2H),7.31(dd,J=7.9,4.5Hz,1H),7.17(dd,J=16.7,4.5Hz,2H),2.70(q,J=7.5Hz,2H),2.10(s,3H),1.23(t,J=7.6Hz,3H)。
N-{4-[3-(6-氯-4-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-6-氯-4-甲基吡啶製備實例30。HPLC:RT=0.88min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.67(s,1H),8.62(d,J=4.7Hz,1H),8.40(d,J=5.0Hz,1H),
8.36-8.21(m,2H),7.72(br.s.,1H),7.62-7.48(m,1H),7.33(s,1H),7.24(d,J=4.0Hz,1H),2.36(s,3H),2.11(s,3H)。
N-{4-[3-(4-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-4-甲基吡啶製備實例31。HPLC:RT=0.57min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=344[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.54(s,1H),8.47(d,J=4.0Hz,1H),8.35-8.21(m,3H),7.94(s,1H),7.89(d,J=7.7Hz,1H),7.27(dd,J=8.2,4.5Hz,1H),7.12(dd,J=10.3,5.2Hz,2H),2.40(s,3H),2.10(s,3H)。
N-{4-[3-(4-氯代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-4-氯代吡啶製備
實例32。HPLC:RT=1.02min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=364[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.74(s,1H),8.71-8.54(m,2H),8.46(d,J=5.0Hz,1H),8.37(br.s.,2H),7.86(br.s.,1H),7.69-7.57(m,1H),7.51(d,J=3.7Hz,1H),7.31(d,J=4.0Hz,1H),2.12(s,3H)。
N-{4-[3-(5-氯-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例1D及6-溴-3-氯-2-甲基吡啶製備實例33。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.73(s,1H),8.67(d,J=5.0Hz,1H),8.54-8.40(m,2H),8.36(s,1H),7.88(d,J=8.4Hz,1H),7.73-7.63(m,1H),7.46(d,J=7.7Hz,1H),7.30(d,J=4.4Hz,1H),2.61(s,3H),2.11(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-5-氟-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
34A):N-(4-((3-胺基-6-氟代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由針對實例1C顯示之相似方法由實例1B及2-溴-6-氟代吡啶-3-胺製備實例34A。HPLC:RT=1.27min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=271[M+H]+。
34B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-6-氟代吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由實例34A製備實例34B。HPLC:RT=1.69min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=367[M+H]+,1H NMR(400MHz,氯仿-d)δ ppm 8.82(br.s.,1H),8.58(dd,J=9.5,2.6Hz,1H),8.49-8.30(m,3H),8.05(br.s.,1H),7.20
(dd,J=5.2,1.4Hz,1H),2.26(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-5-氟-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例34B及2-溴-6-氯代吡啶製備實例34。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.39(s,1H),10.57(s,1H),8.50(s,1H),8.34(d,J=5.0Hz,1H),8.28(s,1H),8.16(d,J=7.4Hz,1H),7.92(t,J=7.7Hz,1H),7.80(dd,J=9.3,2.2Hz,1H),7.36(d,J=7.7Hz,1H),7.21(d,J=5.0Hz,1H),2.09(s,3H)。
N-{4-[5-氟-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例34B及2-溴-5-氟代吡啶製備實例35。HPLC:RT=0.91min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=366[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.37(s,1H),10.54(s,1H),8.46(d,J=3.0Hz,1H),8.31(d,J=5.0Hz,1H),8.23(s,1H),8.06(t,J=7.9Hz,1H),7.98(dd,J=8.6,4.5Hz,1H),7.83(td,J=8.8,3.0Hz,1H),7.15(d,J=4.4Hz,1H),7.02(d,J=8.8Hz,1H),2.08(s,3H)。
N-{4-[5-氟-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例34B及5-碘-2-甲氧基吡啶製備實例36。HPLC:RT=0.96min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.28(s,1H),10.60(s,1H),8.40-8.25(m,2H),8.19(d,J=1.7Hz,1H),8.04(t,J=7.9Hz,1H),7.72(dd,J=8.6,2.2Hz,1H),7.10(d,J=5.4Hz,1H),7.00(d,J=8.8Hz,1H),6.88(d,J=8.4Hz,1H),3.88(s,3H),2.09(s,3H)。
N-{4-[5-氟-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例34B及2-溴-5-甲氧基吡啶製備實例37。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.24(s,1H),10.55(s,1H),8.28(d,J=5.4Hz,2H),8.21(d,J=2.7Hz,1H),8.04(t,J=8.1Hz,1H),7.85(d,J=8.4Hz,1H),7.52(dd,J=8.6,2.9Hz,1H),7.11(d,J=4.0Hz,1H),6.99(d,J=8.4Hz,1H),3.86(s,3H),2.09(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-6-氟-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
38A):N-(4-((3-胺基-5-氟代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由針對實例1C顯示之方法由實例1B及2-溴-5-氟代吡啶-3-胺製備實例38A。HPLC:RT=1.25min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=271[M+H]+,1H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),8.36(d,J=5.3Hz,1H),8.23(s,1H),7.79(d,J=2.6Hz,1H),7.35(dd,J=5.1,1.3Hz,1H),6.95(dd,J=11.1,2.5Hz,1H),6.17(s,2H),2.12(s,3H)。
38B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-氟代吡啶-3-基)-2,2,2-三氟乙醯胺
藉由針對實例1D顯示之方法由實例38A製備實例38B。HPLC:RT=1.69min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=367[M+H]+,1H NMR(400MHz,DMSO-d6)δ ppm 11.74(s,1H),10.67(s,1H),8.70(d,J=2.9Hz,1H),8.41(dd,J=5.1,0.7Hz,1H),8.24(s,1H),8.09(dd,J=9.1,2.8Hz,1H),7.19(dd,J=5.1,1.3Hz,1H),2.12(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-6-氟-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例38B及2-溴-6-氯代吡啶製備實例38。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.57(s,1H),8.50(s,1H),8.34(d,J=5.4Hz,1H),8.28(s,1H),8.16(d,J=7.7Hz,1H),7.93(t,J=7.7Hz,1H),7.80(dd,J=9.3,2.5Hz,1H),7.36(d,J=7.7Hz,1H),7.21(d,J=5.4Hz,1H),2.09(s,3H)。
N-{3-[6-氟-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例38B及2-溴-5-甲氧基吡啶製備實例39。HPLC:RT=0.77min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-
d6)δ ppm 12.15(s,1H),10.54(s,1H),8.45(s,1H),8.35-8.24(m,2H),8.21(d,J=2.7Hz,1H),7.95(d,J=8.4Hz,1H),7.74(dd,J=9.4,2.4Hz,1H),7.50(dd,J=8.6,2.9Hz,1H),7.12(d,J=4.4Hz,1H),3.86(s,3H),2.10(s,3H)。
N-{4-[6-氟-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例38B及5-溴-2-甲氧基吡啶製備實例40。HPLC:RT=0.88min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.24(s,1H),10.67(s,1H),8.43(s,1H),8.33(d,J=5.0Hz,1H),8.29(s,1H),8.24(d,J=2.0Hz,1H),7.81-7.72(m,2H),7.13(d,J=5.0Hz,1H),6.88(d,J=8.8Hz,1H),3.88(s,1H),2.10(s,1H)。
N-{4-[3-(6-氯代吡啶-2-基)-6-氯-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
41A):N-(4-((3-胺基-5-氯代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由與針對實例1C顯示之彼等相似之方法由實例1B及2-溴-5-氯代吡啶-3-胺製備實例41A。HPLC:RT=1.53min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=287[M+H]+,1H NMR(400MHz,DMSO-d6)δ 10.61(s,1H),8.36(d,J=5.1Hz,1H),8.24(s,1H),7.80(d,J=2.0Hz,1H),7.36(dd,J=5.1,1.5Hz,1H),7.20(d,J=2.2Hz,1H),6.14(s,2H),2.12(s,3H)。
41B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-氯代吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由實例41A製備實例41B。HPLC:RT=1.93min(H2O/MeOH及0.1% TFA,Chromolith
SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=383[M+H]+,1H NMR(400MHz,DMSO-d)δ ppm 11.73(s,1H),10.68(s,1H),8.72(d,J=2.2Hz,1H),8.41(dd,J=5.1,0.7Hz,1H),8.25(d,J=2.2Hz,2H),7.20(dd,J=5.2,1.4Hz,1H),2.12(s,3H)。
實例41):N-{4-[3-(6-氯代吡啶-2-基)-6-氯-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-氯代吡啶製備實例41。HPLC:RT=1.14min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=398[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.45(s,1H),10.59(s,1H),8.49(d,J=2.0Hz,1H),8.35(d,J=5.4Hz,1H),8.30(s,1H),8.16(d,J=7.7Hz,1H),8.00(d,J=2.0Hz,1H),7.93(t,J=7.7Hz,1H),7.37(d,J=7.7Hz,1H),7.22(d,J=4.0Hz,1H),2.10(s,1H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-氟代吡啶製備實例42。HPLC:RT=0.95min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.34(s,1H),10.57(s,1H),8.47(dd,J=4.9,2.5Hz,2H),8.33(d,J=5.0Hz,1H),8.27(s,1H),8.10(dd,J=8.6,4.5Hz,1H),7.98(d,J=2.0Hz,1H),7.83(td,J=8.8,2.7Hz,1H),7.17(d,J=4.7Hz,1H),2.09(s,1H)。
N-{4-[6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及5-溴-2-甲氧基吡啶製備實例43。HPLC:RT=1.03min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394[M+H]+;1H NMR(500MHz,DMSO-
d6)δ ppm 12.29(s,1H),10.68(s,1H),8.42(s,1H),8.34(d,J=5.4Hz,1H),8.30(s,1H),8.24(s,1H),7.98(s,1H),7.77(d,J=8.4Hz,1H),7.14(d,J=4.7Hz,1H),6.88(d,J=8.4Hz,1H),3.88(s,3H),2.10(s,3H)。
N-{4-[6-氯-3-(5-氟-4-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-氟-4-甲基吡啶製備實例44。HPLC:RT=1.03min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=396[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.32(s,1H),10.56(s,1H),8.46(br.s.,1H),8.34(s,1H),8.31(d,J=5.0Hz,1H),8.26(br.s.,1H),7.98(d,J=1.7Hz,1H),7.94(d,J=6.1Hz,1H),7.14(d,J=4.4Hz,1H),2.36(s,1H),2.09(s,1H)。
N-{4-[6-氯-3-(6-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-氟代吡啶製備實例45。HPLC:RT=1.03min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.44(s,1H),10.59(s,1H),8.48(s,1H),8.36(d,J=5.0Hz,1H),8.26(s,1H),8.07(d,J=4.4Hz,2H),8.00(d,J=1.7Hz,1H),7.22(d,J=4.7Hz,1H),7.03(d,J=7.1Hz,1H),2.09(s,3H)。
N-{4-[6-氯-3-(5-氯代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-氯代吡啶製備實例46。HPLC:RT=1.15min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=398[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.61(s,1H),8.47(br.s.,2H),8.33(d,J=5.4Hz,1H),8.25
(br.s.,1H),8.11(d,J=8.4Hz,1H),8.04-7.97(m,2H),7.18(d,J=5.0Hz,1H),2.09(s,3H)。
N-{4-[6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-甲氧基吡啶製備實例47。HPLC:RT=0.89min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.22(s,1H),10.55(s,1H),8.43(d,J=2.0Hz,1H),8.35-8.24(m,2H),8.20(d,J=2.7Hz,1H),8.01-7.86(m,2H),7.50(dd,J=8.8,3.0Hz,1H),7.12(d,J=6.1Hz,1H),3.86(s,3H),2.09(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
48A):N-(4-((3-胺基-5-甲氧基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由與針對實例1C顯示之彼等相似之方法由實例1B及2-溴-5-甲氧基吡啶-3-胺製備實例48A。HPLC:RT=1.22min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=283[M+H]+,1H NMR(400MHz,氯仿-d)δ 8.34(s,1H),8.25(dd,J=5.2,0.8Hz,1H),7.93(br.s.,1H),7.82(d,J=2.4Hz,1H),7.20(dd,J=5.1,1.3Hz,1H),6.56(d,J=2.6Hz,1H),4.36(br.s.,2H),3.87(s,3H),2.24(s,3H)。
48B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-甲氧基吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由實例48A製備實例48B。HPLC:RT=1.73min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=379[M+H]+,1H NMR(400MHz,氯仿-d)δ ppm 8.78(br.s.,1H),8.41(s,1H),8.36-8.27(m,2H),8.24(d,J=2.6Hz,1H),7.94(br.s.,1H),7.18(dd,J=5.1,1.3Hz,1H),3.97(s,3H),2.26(s,3H)。
N-{4-[3-(6-氯代吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基]
吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例48B及2-溴-6-氯代吡啶製備實例48。HPLC:RT=0.81min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.07(s,1H),10.50(s,1H),8.31(d,J=5.2Hz,1H),8.23(d,J=2.4Hz,2H),8.14(d,J=7.3Hz,1H),7.90(t,J=7.8Hz,1H),7.42(s,1H),7.33(d,J=7.9Hz,1H),7.19(d,J=3.7Hz,1H),3.89(s,3H),2.08(s,3H)。
N-{4-[3-(5-氟代吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例48B及2-溴-5-氟代吡啶製備實例49。HPLC:RT=0.84min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波
長=220nm);MS(ES):m/z=378[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.95(s,1H),10.50(s,1H),8.44(d,J=2.4Hz,1H),8.28(d,J=5.0Hz,1H),8.23(d,J=6.7Hz,2H),8.10(dd,J=8.6,4.5Hz,1H),7.85-7.77(m,1H),7.39(s,1H),7.15(d,J=5.0Hz,1H),3.89(s,3H),2.08(s,3H)。
N-{4-[3-(5-氯代吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例48B及2-溴-5-氯代吡啶製備實例50。HPLC:RT=0.95min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.67(s,1H),8.56(d,J=2.0Hz,1H),8.36(d,J=5.0Hz,1H),8.31(d,J=2.4Hz,1H),8.26(br.s.,1H),8.00-7.95(m,1H),7.94-7.89(m,1H),7.66(br.s.,1H),7.22(d,J=5.0Hz,1H),3.94(s,3H),2.10(s,3H)。
N-{4-[3-(5-氟-6-甲基吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例48B及6-溴-3-氟-2-甲基吡啶製備實例51。HPLC:RT=0.91min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=392[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.94(s,1H),10.47(s,1H),8.33-8.23(m,2H),8.21(d,J=2.0Hz,1H),7.90(dd,J=8.2,3.2Hz,1H),7.66(t,J=9.1Hz,1H),7.40(s,1H),7.20(d,J=5.0Hz,1H),3.89(s,3H),2.29(d,J=2.4Hz,3H),2.08(s,3H)。
4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-胺
向實例14(38mg,0.106mmol)含於MeOH(8mL)之溶液中添加1N NaOH(1.057mL,1.057mmol)。隨後將該混合物於80℃加熱1.5h,並隨後濃縮。將該固體殘留物懸浮於水中,藉由過濾收集,及乾燥以獲得白色固體之標題產物(27.4mg,80%)。HPLC:RT=0.87min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50
mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=318[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.85(s,1H),8.39(dd,J=4.5,1.4Hz,1H),8.30(d,J=2.0Hz,1H),7.95(d,J=5.3Hz,1H),7.82(ddd,J=8.4,3.9,1.9Hz,2H),7.22(dd,J=8.3,4.5Hz,1H),6.87(dd,J=8.5,0.6Hz,1H),6.63-6.51(m,2H),6.06(s,2H),3.89(s,3H)。
N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}環丙烷甲醯胺
向實例52(12.1mg,0.038mmol)及TEA(10.6μl,0.076mmol)含於THF(0.6mL)之溶液中添加環丙烷羰醯氯(6.8mg,0.065mmol)含於THF(70μl)中之溶液。攪拌該反應2h,並隨後添加濃縮之NH4OH(1滴)。於室溫下攪拌該所得反應混合物過夜。使用DMF稀釋該混合物並藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10mM乙酸銨;流動相B:95:5乙腈:水及10mM乙酸銨;梯度:10至55% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min)純化以獲得實例53(4.0mg,23%)。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=386[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.06(br.s.,1H),10.93(s,1H),8.41(d,J=3.7Hz,1H),8.38(s,1H),
8.31(d,J=5.1Hz,1H),8.24(d,J=1.9Hz,1H),7.88(d,J=8.1Hz,1H),7.80(dd,J=8.5,2.2Hz,1H),7.26(dd,J=8.2,4.6Hz,1H),7.08(d,J=4.1Hz,1H),6.87(d,J=8.6Hz,1H),3.88(s,3H),2.03(br.s.,1H),0.88-0.75(m,4H)。
N-{4-[3-(6-甲氧基吡啶-3-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例14(12mg,0.033mmol)含於DMF(0.5mL)之溶液中添加Cs2CO3(21.76mg,0.067mmol),接著添加碘甲烷(2.088μl,0.033mmol)含於DMF(0.5mL)中之溶液。於室溫攪拌該反應混合物30min並隨後過濾並藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10mM乙酸銨;流動相B:95:5乙腈:水及10mM乙酸銨;梯度:5至65% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min)純化以獲得標題化合物(8.2mg,66%)。HPLC:RT=0.61min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.73(s,1H),8.46(dd,J=15.4,4.7Hz,2H),8.22-8.12(m,2H),8.08(d,J=8.2Hz,1H),7.79(dd,J=8.6,2.2Hz,1H),7.34(dd,J=8.3,4.6Hz,1H),7.18(d,J=5.0Hz,1H),6.81(d,J=8.6Hz,1H),3.83
(s,3H),3.70(s,3H),2.10(s,3H)。
N-{4-[7-(6-氯代吡啶-2-基)-5H-吡咯并[2,3-b]吡嗪-6-基]吡啶-2-基}乙醯胺
55A)N-(4-((3-胺基吡嗪-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由與針對實例1C顯示之彼等相似之方法由實例1B及3-氯代吡嗪-2-胺製備實例55A。HPLC:RT=0.906min(H2O/乙腈及0.1% TFA,Waters Aquity BEH C18,1.7μm粒子,2.0x50mm,梯度=1.5min,波長=220nm);MS(ES):m/z=254[M+H]+。
55B)N-(3-((2-乙醯胺基吡啶-2-基)乙炔基)吡嗪-2-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由55A製備實例55B。
HPLC:RT=0.998min(H2O/乙腈及0.1% TFA,Waters Aquity BEH C18,1.7-μm粒子,2.0x50mm,梯度=1.5min,波長=220nm);MS(ES):m/z=350[M+H]+。
N-{4-[7-(6-氯代吡啶-2-基)-5H-吡咯并[2,3-b]吡嗪-6-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例55B及2-溴-6-氯代吡啶製備實例55。HPLC:RT=0.89min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES);m/z=365[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.56(s,1H),8.56(d,J=2.4Hz,1H),8.42(d,J=2.4Hz,1H),8.37(d,J=5.1Hz,1H),8.27(s,1H),8.11(d,J=7.7Hz,1H),7.93(t,J=7.8Hz,1H),7.37(d,J=7.9Hz,1H),7.28(d,J=5.1Hz,1H),2.08(s,3H)。
5-氯-2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
56A):5-胺基-氯代異煙鹼酸乙酯
於室溫下向3-胺基異煙鹼酸乙酯(4.0g,24.07mmol)含於DMF(25mL)之溶液中添加NCS(3.54g,26.5mmol)。隨後在氮氣下於50℃加熱該反應混合物18h。將該反應混合物冷卻至室溫並經飽和NaHCO3水溶液及乙酸乙酯處理。分離有機層並使用鹽水清洗,乾燥(MgSO4)並過濾。在真空中濃縮該濾液。將該殘留物溶於DCM及藉由矽膠急驟層析法純化,使用30%乙酸乙酯之己烷溶液洗脫以獲得淺黃色固體之期望產物(2.0g,41%);HPLC:RT=0.84min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=200.9[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.98(d,J=0.4Hz,1H),7.66(d,J=0.4Hz,1H),4.38(q,J=7.3Hz,2H),1.42(t,J=7.2Hz,3H)。
56B):3-胺基-2-溴-6-氯代異煙鹼酸乙酯
向實例56A(2.0g,9.97mmol)含於DMF(15mL)之溶液中添加NBS(1.95g,10.97mmol)。於室溫攪拌反應混合物20h。在該反應混合物中添加飽和NaHCO3水溶液及乙酸乙酯。分離有機層並使用飽和NaHCO3溶液清洗,乾燥(MgSO4)並過濾。在真空中濃縮該濾液。將粗產物溶於DCM中及藉由矽膠急驟層析法純化,使用10%乙酸乙酯之己烷溶液洗脫以獲得淺黃色固體之期望產物(2.4g,86%);HPLC:RT=1.01min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=278.9,280.9[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.68(s,1H),6.24(br.s.,2H),4.40(q,J=7.0Hz,2H),1.42(t,J=7.2Hz,3H)。
56C):2-((2-乙醯胺基吡啶-4-基)乙炔基)-3-胺基-6-氯代異煙鹼酸乙酯
向實例56B(2.45g,8.77mmol)及實例1B(1.544g,9.64mmol)含於DMF(18mL)之溶液中添加CuI(0.134g,0.701mmol)及TEA(12.2mL,88mmol)。使用氮氣沖洗該反應混合物,接著添加PdCl2(PPh3)2(0.369g,0.526mmol)。在氮氣下於78℃加熱所得混合物2h。隨後將反應混合物冷卻至室溫並使用乙酸乙酯及飽和NaHCO3水溶液稀釋。使用EtOAc萃取水層(3X)及使用飽和NaHCO3溶液清洗合併之萃取物,並經MgSO4乾燥。過濾該混合物並隨後在真空中濃縮。在該殘留物中添加乙酸乙酯及DCM並收集該沉澱以獲得作為期望產物之黃色固體。進一步在真空中濃縮該濾液及藉由矽膠急驟層析法純
化該殘留物,使用30%乙酸乙酯之DCM溶液洗脫以獲得黃色固體之額外期望產物(2.65g,84%);MS(ES):m/z=359.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.65(s,1H),8.40(dd,J=5.1,0.7Hz,1H),8.30(s,1H),7.67(s,1H),7.40(dd,J=5.1,1.3Hz,1H),6.99(s,2H),4.35(q,J=7.0Hz,2H),2.12(s,3H),1.34(t,J=7.2Hz,3H)。
56D):2-(2-乙醯胺基吡啶-4-基)-5-氯-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
實例56C(160mg,0.446mmol)含於乙腈(6.0mL)之懸浮液經超音波處理並隨後使用Cs2CO3(436mg,1.338mmol)處理。使用氮氣沖洗所得混合物及添加Pd(PPh3)4(51.5mg,0.045mmol)。在氮氣下於100℃加熱該反應混合物2h。將該反應混合物冷卻至室溫並過濾該混合物。使用乙酸乙酯清洗該固體及在真空中濃縮該濾液以獲得期望產物;MS(ES):m/z=345.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.76(s,1H),10.64(s,1H),8.53(s,1H),8.44(d,J=5.1Hz,1H),7.67(dd,J=5.2,1.4Hz,1H),7.60(s,1H),7.23(d,J=2.0Hz,1H),4.02(s,3H),2.15(s,3H)。
56E):2-(2-乙醯胺基吡啶-4-基)-5-氯-1H-吡咯并[3,2-b]吡啶-7-羧酸
向實例56D(0.24g,0.696mmol)含於MeOH(1mL)及1,4-二噁烷(6mL)之懸浮液中逐滴添加1M NaOH溶液(3.48mL,3.48mmol)。於室溫攪拌該反應混合物1h。在該反應混合物中添加水並使用1N HCl溶液將pH調節至1到2。過濾該反應混合物以獲得作為期望產物之固體(0.12g,52%);MS(ES):m/z=331.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.31(br.s.,1H),10.60(s,1H),8.46(s,1H),8.37(d,J=5.3Hz,1H),7.61(dd,J=5.3,1.5Hz,1H),7.33(s,1H),7.11(s,1H),2.14(s,3H)。
56F):2-(2-乙醯胺基吡啶-4-基)-5-氯-N-甲基-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
向實例56E(90mg,0.272mmol)含於DMF(3mL)之懸浮液中添加HATU(124mg,0.327mmol)。於室溫攪拌該反應混合物5min,接著藉由添加甲胺鹽酸鹽(0.049mL,0.544mmol)及4-甲基嗎啉(0.06mL,0.544mmol)。於室溫攪拌所得混合物30min。隨後在真空中濃縮該反應混合物及殘留物與MeOH混合及藉由製備型HPLC(YMC-Pack C-18 30x100mm,使用含0.1% TFA之5%至70%CH3CN水溶液在12min內洗脫,25mL/min,波長=254nm)純化。合併、濃縮、及凍乾含有期望產物之溶離份以獲得產物(83mg,53%);MS(ES):m/z=344.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.74(d,J=1.5Hz,1H),10.66(s,1H),8.93(d,J=4.6Hz,1H),8.50(s,1H),8.40(d,J=5.3Hz,1H),7.71(dd,J=5.4,1.7Hz,1H),7.55(s,1H),7.20(d,J=2.2Hz,1H),2.89(d,J=4.6Hz,3H),2.15(s,3H)。
56G):2-(2-乙醯胺基吡啶-4-基)-3-溴-5-氯-N-甲基-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
向實例56F(80mg,0.140mmol)含於DMF(1.5mL)之溶液中添加NBS(29.9mg,0.168mmol)。於室溫攪拌該反應混合物30min。隨後使用飽和NaHCO3溶液及乙酸乙酯稀釋該反應混合物。分離有機層及經MgSO4乾燥。過濾該混合物及在真空中濃縮該濾液。在該殘留物中添加DCM及MeOH並過濾該殘留物以獲得淺黃色固體之期望產物(42mg,71%);MS(ES):m/z=422.0,424.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.22(s,1H),10.66(s,1H),8.94(d,J=4.4Hz,1H),8.61(s,1H),8.47(dd,J=5.3,0.7Hz,1H),7.64(s,1H),7.52(dd,J=5.1,1.5Hz,1H),2.87(d,J=4.4Hz,3H),2.14(s,3H)。
實例56):5-氯-2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
使用氮氣沖洗實例56G(42mg,0.099mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)吡啶(28.0mg,0.119mmol)及Na2CO3(0.248mL,0.248mmol)含於二噁烷(2mL)之懸浮液,並經
PdCl2(dppf)(7.27mg,9.94μmol)處理。於90℃加熱所得混合物2h。在真空中濃縮該反應混合物。在該殘留物中添加MeOH及DMF,及藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之5%至100% CH3CN水溶液在12min內洗脫,20mL/min,波長=254nm)純化該混合物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之產物(15mg,33%);HPLC:RT=1.02min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)MS(ES):m/z=451.3[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.32(dd,J=5.3,0.7Hz,1H),8.28(s,1H),8.20(d,J=1.8Hz,1H),7.80(dd,J=8.6,2.4Hz,1H),7.56(s,1H),7.21(dd,J=5.2,1.7Hz,1H),6.89-6.84(m,1H),3.94(s,3H),3.01(s,3H),2.16(s,3H)。
2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-N-甲基-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
向實例56(8mg,0.018mmol)含於甲醇(3mL)及乙酸乙酯(1mL)之懸浮液中添加Pd(OH)2(3.74mg,5.32μmol)。在氮氣氛圍下攪拌該反應混合物過夜。隨後使用MeOH及乙酸乙酯稀釋該反應混合物並過濾。在真空中濃縮該濾液。藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之5%至100%CH3CN水溶液在12min內洗
脫,20mL/min,波長=220nm)純化該殘留物。合併、濃縮及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(3mg,40%);HPLC:RT=0.95min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)MS(ES):m/z=417.4[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.47(d,J=4.8Hz,1H),8.31(dd,J=5.3,0.7Hz,1H),8.28(s,1H),8.18(dd,J=2.4,0.7Hz,1H),7.80(dd,J=8.5,2.3Hz,1H),7.54(d,J=4.8Hz,1H),7.24-7.18(m,1H),6.89(dd,J=8.6,0.7Hz,1H),3.95(s,3H),3.03(s,3H),2.16(s,3H)。
5-氯-N-(1,3-二羥基丙-2-基)-2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
58A):2-(2-乙醯胺基吡啶-4-基)-5-氯-N-(1,3-二羥基丙-2-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
藉由與針對實例56F顯示之相似方法由實例56E及2-胺基丙烷-1,3-二醇製備實例58A。HPLC:RT=0.54min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=404.1[M+H]+。
58B):2-(2-乙醯胺基吡啶-4-基)-3-溴-5-氯-N-(1,3-二羥基丙-2-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
使用與針對實例56G顯示之彼等相似之方法製備實例58B。HPLC:RT=0.61min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm)。MS(ES):m/z=482.0,484.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ ppm 12.16(s,1H),10.69(s,1H),8.68-8.57(m,2H),8.46(d,J=5.1Hz,1H),7.81(s,1H),7.52(dd,J=5.3,1.5Hz,1H),4.11-4.00(m,1H),3.64-3.51(m,4H),2.14(s,3H)。
實例58):5-氯-N-(1,3-二羥基丙-2-基)-2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
藉由針對實例56H顯示之一般方法由實例58B製備實例58。HPLC:RT=0.64min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=511.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ ppm 11.85(s,1H),10.58(s,1H),8.59(d,J=8.4Hz,1H),8.31(d,J=5.3Hz,1H),8.28(s,1H),8.19(d,J=1.8Hz,1H),7.76(s,1H),7.72-7.66(m,1H),7.11(dd,J=5.3,1.5Hz,1H),6.87(d,J=8.6Hz,1H),4.11-4.03(m,1H),3.88(s,3H),3.64-3.56(m,4H),2.09(s,3H)。
N-(1,3-二羥基丙-2-基)-2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
藉由針對實例57顯示之相似方法由實例58C製備實例59。
HPLC:RT=0.97min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=477.3[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.48(d,J=5.1Hz,1H),8.30(d,J=5.7Hz,1H),8.27(s,1H),8.18(d,J=2.0Hz,1H),7.79(dd,J=8.6,2.4Hz,1H),7.64(d,J=5.1Hz,1H),7.21(dd,J=5.3,1.5Hz,1H),6.89(dd,J=8.6,0.7Hz,1H),4.42-4.27(m,1H),3.95(s,3H),3.86-3.75(m,4H),2.16(s,3H)。
5-氯-N-(1,3-二羥基丙-2-基)-2-(2-乙醯胺基吡啶-4-基)-3-(吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-甲醯胺
藉由與針對實例56顯示之相似方法由實例58B製備實例60。HPLC:RT=0.92min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=481.3[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.60(s,1H),8.46(d,J=4.0Hz,1H),8.34-8.28(m,1H),8.25(s,1H),8.00(dt,J=8.0,1.8Hz,1H),7.68(s,1H),7.46(dd,J=7.8,5.0Hz,1H),7.16(dd,J=5.2,1.7Hz,1H),4.29(t,J=5.7Hz,1H),3.90-3.73(m,4H),2.15(s,3H)。
N-{4-[7-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶
-2-基}乙醯胺
61A):2-溴-4-氯代吡啶-3-胺
於冰浴溫度攪拌4-氯代吡啶-3-胺(2.0g,15.56mmol)含於TFA(17.98ml,233mmol)之溶液並隨後經NBS(3.05g,17.11mmol)緩慢處理。
於室溫攪拌該反應混合物5h。隨後在真空中濃縮該反應混合物至小體積。在該反應混合物中添加1N NaOH溶液及乙酸乙酯。分離有機層及使用飽和NaHCO3溶液清洗,經MgSO4乾燥,及隨後過濾。在真空中濃縮該濾液。藉由矽膠急驟層析法純化該殘留物,使用15%乙酸乙酯之己烷溶液洗脫以獲得白色固體之期望產物(1.65g,51%)。HPLC:1.03min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=207.1,209.1[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.70(d,J=5.1Hz,1H),7.17(d,J=5.1Hz,1H),4.52(br.s.,2H)。
61B):N-(4-((3-胺基-4-氯代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
向實例61A(1.55g,7.47mmol)及實例1B(1.257g,7.85mmol)含於DME(6mL)之溶液中添加CuI(0.142g,0.747mmol)及TEA(10.41ml,74.7mmol)。使用氮氣沖洗該反應混合物,並使用PdCl2(PPh3)2(0.367g,0.523mmol)處理。在氮氣下於78℃加熱該反應混合物1.5h。隨後將該反應混合物冷卻至室溫,使用乙酸乙酯稀釋並過濾。使用乙酸乙酯及飽和NaHCO3溶液稀釋該棕色濾液。使用乙酸乙酯萃取水層(2X)及使用飽和NaHCO3溶液清洗合併之萃取物,經MgSO4乾燥。過濾該混合物及在真空中濃縮該濾液。使用DCM研磨該殘留物並過濾以獲得作為期望產物之黃色固體。藉由矽膠急驟層析法進一步純化該濾液,使用10% MeOH之DCM溶液洗脫以獲得黃色固體之期望產物(1.55g,72%);HPLC:RT=0.61min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=287.0[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 8.37(s,1H),8.28(d,J=5.1Hz,1H),7.95(d,J=5.1Hz,2H),7.24-7.19(m,2H),4.71(br.s.,2H),2.24(s,3H)。
61C):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-氯代吡啶-3-基)-2,2,2-三氟乙醯胺
於冰浴溫度下向實例61B(0.95g,3.31mmol)含於DCE(12mL)之懸浮液中添加TEA(1.62mL,11.60mmol),接著緩慢添加三氟乙酸酐(0.74mL,5.30mmol)。於0℃攪拌該反應混合物20min。在該混合物中添加更多TEA(1.0mL)及三氟乙酸酐(0.45mL)及於0℃攪拌該反應混合物又40min。使用冷飽和NaHCO 3 溶液淬冷該反應混合物及使用乙酸乙酯萃取所得混合物(2x)。分離有機層並使用飽和NaHCO3溶液清洗,經MgSO4乾燥。過濾該混合物及在真空中濃縮該濾液以獲得棕黃色固體。藉由矽膠急驟層析法純化該粗產物,使用70%乙酸乙酯之DCM溶液洗脫以獲得黃色固體之期望產物(0.4g,32%);HPLC:RT=1.04min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=383.0[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 8.54(d,J=5.3Hz,1H),8.34(s,1H),8.28(d,J=5.1Hz,1H),8.17(br.s.,1H),7.93(br.s.,1H),7.50(d,J=5.3Hz,1H),7.13(dd,J=5.1,1.5Hz,1H),2.24(s,3H)。
實例61):N-{4-[7-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
在密封管中使用氮氣沖洗實例61C(30mg,0.078mmol)、Cs2CO3(77mg,0.235mmol)及2-溴-5-氟代吡啶(17.93mg,0.102mmol)含於乙腈(2mL)之混合物,並經Pd(PPh3)4(9.06mg,7.84μmol)
處理。於100℃加熱該反應混合物1.5h及隨後冷卻至室溫。使用MeOH及乙酸乙酯稀釋該反應混合物並過濾。在真空中濃縮該濾液。藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10mM乙酸銨;流動相B:95:5乙腈:水及10mM乙酸銨;梯度:5至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min)純化該殘留物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(1.6mg,5.3%);HPLC:RT=0.72min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.53(br.s.,1H),10.55(s,1H),8.47-8.38(m,2H),8.31(d,J=5.1Hz,1H),8.22(br.s.,1H),8.12(dd,J=8.7,4.5Hz,1H),7.81(td,J=8.8,2.8Hz,1H),7.44(d,J=5.0Hz,1H),7.19(d,J=4.3Hz,1H),2.07(s,3H)。
N-{4-[7-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例61顯示之一般方法由實例61C及2-溴-5-甲氧基吡啶製備實例62。HPLC:RT=0.73min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.0[M+H]+;1H NMR(500MHz,
DMSO-d6)δ ppm 12.80-12.08(m,1H),10.53(s,1H),8.38(d,J=5.0Hz,1H),8.28(d,J=5.1Hz,1H),8.26(br.s.,1H),8.16(d,J=2.7Hz,1H),7.95(d,J=8.7Hz,1H),7.48(dd,J=8.7,2.8Hz,1H),7.41(d,J=5.0Hz,1H),7.14(d,J=4.9Hz,1H),3.90-3.79(m,3H),2.08(s,3H)。
N-{4-[7-氯-3-(5-氯代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例61顯示之一般方法由實例61C及2-溴-5-氯代吡啶製備實例63。HPLC:RT=0.97min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=398.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.59(s,1H),10.56(s,1H),8.50-8.40(m,2H),8.33(d,J=5.3Hz,1H),8.27(s,1H),8.20(d,J=8.6Hz,1H),8.00(dd,J=8.6,2.6Hz,1H),7.46(d,J=5.1Hz,1H),7.20(dd,J=5.2,1.4Hz,1H),2.13-2.07(m,3H)。
N-{4-[7-氯-3-(6-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例61顯示之一般方法由實例61C及2-溴-6-氟代吡啶製備實例64。HPLC:RT=0.71min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=382.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.56(s,1H),8.41(d,J=5.0Hz,1H),8.34(d,J=5.0Hz,1H),8.21(s,1H),8.12(d,J=5.4Hz,1H),8.03(q,J=8.1Hz,1H),7.43(d,J=5.0Hz,1H),7.23(d,J=5.0Hz,1H),6.99(d,J=6.2Hz,1H),2.07(s,3H)。
N-{4-[6-氯-3-(6-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-甲氧基吡啶製備實例65。HPLC:RT=0.73min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.1[M+H]+;1H NMR(500MHz,
DMSO-d6)δ ppm 10.57(s,1H),8.48(d,J=2.0Hz,1H),8.35(d,J=5.1Hz,1H),8.27(br.s.,1H),8.02-7.90(m,2H),7.76(t,J=7.8Hz,1H),7.19(d,J=5.0Hz,1H),6.62(d,J=8.2Hz,1H),3.48(br.s.,3H),2.08(s,3H)。
N-{4-[6-氯-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-甲基吡啶製備實例66。HPLC:RT=0.91min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.26(s,1H),10.51(s,1H),8.42(d,J=1.9Hz,1H),8.35-8.23(m,2H),7.96(d,J=1.9Hz,1H),7.85-7.77(m,1H),7.75-7.67(m,1H),7.19(d,J=4.0Hz,1H),7.13(d,J=7.6Hz,1H),2.29(s,3H),2.07(s,3H)。
N-(4-{6-氯-3-[6-(羥甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及(6-溴代吡啶-2-基)甲醇製備實例67。HPLC:RT=0.78min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.65(s,1H),8.50(d,J=1.9Hz,1H),8.37(d,J=5.1Hz,1H),8.27(s,1H),8.11(t,J=7.8Hz,1H),8.07(d,J=1.7Hz,1H),7.87(d,J=7.9Hz,1H),7.57(d,J=7.7Hz,1H),7.25(d,J=3.2Hz,1H),4.59(s,2H),2.08(s,3H)。
N-[4-(6-氯-3-{6-[(2-羥乙基)胺基]吡啶-2-基}-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基]乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-((6-溴代吡啶-2-基)胺基)乙醇製備實例68。HPLC:RT=0.90min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=423.0[M+H]+;1H NMR
(500MHz,DMSO-d6)δ ppm 10.71(s,1H),8.54(d,J=1.8Hz,1H),8.45(d,J=5.0Hz,1H),8.31(s,1H),8.11(s,1H),7.82(br.s.,1H),7.31(d,J=4.5Hz,1H),6.96(br.s.,1H),6.87(br.s.,1H),2.54(s,4H),2.09(s,3H)。
5-氯-2-(2-乙醯胺基吡啶-4-基)-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
69A):2-((3-乙醯胺基吡啶-4-基)乙炔基)-6-氯-3-(2,2,2-三氟乙醯胺基)異煙鹼酸乙酯
於冰浴溫度下向實例56C(0.2g,0.557mmol)含於DCE(4mL)及二乙醚(10mL)之懸浮液中添加CaCO3(0.223g,2.230mmol)。在該反應混合物中緩慢添加TFAA(0.17mL,1.226mmol)及於冰浴溫度下攪拌該反應混合物2h。在該反應混合物中添加冷水及乙酸乙酯。分離有機層及使用鹽水清洗並經MgSO4乾燥。過濾該混合物及在真空中濃縮該濾液。在該殘留物中添加DCM及過濾所得固體以獲得黃色固體之期望產物(0.15g,60%)。HPLC:RT=0.90min(H2O/ACN及0.05%
TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=455.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.90(s,1H),10.70(s,1H),8.48-8.39(m,1H),8.26(s,1H),7.99(s,1H),7.22(dd,J=5.1,1.5Hz,1H),4.32(q,J=7.1Hz,2H),2.12(s,3H),1.29(t,J=7.0Hz,3H)。
實例69):5-氯-2-(2-乙醯胺基吡啶-4-基)-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
藉由針對實例1顯示之一般方法由實例69A及2-溴-5-氟代吡啶製備實例69。HPLC:RT=1.13min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=440.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.07(s,1H),10.59(s,1H),8.45(d,J=3.1Hz,1H),8.34(d,J=5.1Hz,1H),8.20(s,1H),8.01(dd,J=8.8,4.6Hz,1H),7.84(td,J=8.7,3.0Hz,1H),7.70(s,1H),7.17(dd,J=5.1,1.5Hz,1H),4.02(s,3H),2.09(s,3H)。
5-氯-3-(5-氯代吡啶-2-基)-2-(2-乙醯胺基吡啶-4-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
藉由針對實例1顯示之一般方法由實例69A及2-溴-5-氯代吡啶製備實例70。HPLC:RT=0.92min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=456.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.14(s,1H),10.59(s,1H),8.46(s,1H),8.34(d,J=5.1Hz,1H),8.23(s,1H),8.04(s,2H),7.70(s,1H),7.15(d,J=3.8Hz,1H),4.01(s,3H),2.09(s,3H)。
2-(2-乙醯胺基吡啶-4-基)-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
藉由針對實例57顯示之一般方法由實例69B製備實例71。HPLC:RT=0.96min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=406.3[M+H]+;1H NMR(400MHz,CDCl3+MeOH-d4)δ ppm
8.15(br.s.,1H),8.03(br.s.,1H),7.87(d,J=5.3Hz,1H),7.83(s,1H),7.39(br.s.,2H),7.25-7.17(m,1H),6.82-6.72(m,1H),3.68(s,3H),1.76(s,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-羥基乙醯胺
72A):4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
藉由與針對實例52顯示之彼等相似之方法由實例42製備實例72A。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=340.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.15(br.s.,1H),8.51(d,J=3.1Hz,1H),8.41(d,J=2.2Hz,1H),8.02(dd,J=9.0,4.4Hz,1H),7.94-7.89(m,2H),7.80(td,J=8.8,3.1Hz,1H),6.57(s,1H),6.53(dd,J=5.3,1.5Hz,1H),6.00(s,2H)。
72B)2-((4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)胺基)-2-氧代乙酸乙酯
向實例72A(60mg,0.177mmol)含於DCE(3mL)之懸浮液中添加乙醯氧基乙醯氯(0.06mL,0.54mmol)及TEA(0.1mL,0.71mmol)。於室溫攪拌該反應2h。在該反應混合物中添加0.5mL氫氧化銨溶液及於室溫攪拌該混合物1h。在真空中濃縮所得反應混合物。藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之10%至100% CH3CN水溶液在18min內洗脫,20mL/min,波長=220nm)純化該殘留物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(46mg,58%);HPLC:RT=1.04min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=440.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.74(s,1H),8.45(dd,J=4.6,2.6Hz,2H),8.33(d,J=5.3Hz,1H),8.25(br.s.,1H),8.12(dd,J=8.8,4.6Hz,1H),7.97(d,J=2.2Hz,1H),7.82(td,J=8.8,3.1Hz,1H),7.18(dd,J=5.3,1.5Hz,1H),4.72(s,2H),2.11(s,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-羥基乙醯胺
使用NaOH水溶液(0.8mL,0.80mmol)處理實例72B(35mg,0.08mmol)含於甲醇(2mL)之溶液。於室溫攪拌該反應混合物30min。隨後在真空中濃縮該反應混合物。藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之5%至70%CH3CN水溶液在14min內洗脫,20mL/min,波長=220nm)純化該殘留物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(22mg,69%);HPLC:RT=1.0min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=398.2[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.34(br.s.,1H),9.72(s,1H),8.46(d,J=2.2Hz,2H),8.35(dd,J=5.3,0.7Hz,1H),8.29(s,1H),8.12(dd,J=8.8,4.6Hz,1H),7.98(d,J=2.2Hz,1H),7.83(td,J=8.8,3.1Hz,1H),7.23(dd,J=5.3,1.5Hz,1H),5.73(t,J=6.1Hz,1H),4.03(d,J=5.9Hz,2H)。
2S)-N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-羥基丙醯胺
藉由針對實例72顯示之一般方法由實例72A及(S)-1-氯-氧代丙-2-基乙酸酯製備實例73。HPLC:RT=1.11min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3.0min,波長=220nm);MS(ES):m/z=412.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 9.68(s,1H),8.45(br.s.,2H),8.33(d,J=5.1Hz,1H),8.30(s,1H),8.10(dd,J=8.5,4.5Hz,1H),7.98(d,J=1.7Hz,1H),7.87-7.78(m,1H),7.20(d,J=4.5Hz,1H),5.96(d,J=5.2Hz,1H),4.27-4.16(m,1H),3.45(s,1H),1.29(d,J=6.7Hz,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-(嗎啉-4-基)乙醯胺
74A):2-氯-N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例72A(115mg,0.338mmol)含於DCE(7mL)之懸浮液中緩慢添加氯代乙醯氯(0.14mL,1.70mmol)及TEA(0.25mL,1.70mmol)。於室溫攪拌該反應1h。在該反應混合物中添加1mL氫氧化銨溶液及於室溫攪拌該混合物0.5h。隨後使用CHCl3:2-丙醇(2.5:1)及飽和NaHCO3溶液稀釋該反應混合物。分離有機層並經MgSO4乾燥。過濾該混合物及在真空中濃縮該濾液。在該殘留物中添加DCM及過濾該混合物以獲得期望產物(75mg,53%)。HPLC:RT=1.09min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=416.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.90(br.s.,1H),8.45(d,J=3.1Hz,2H),8.35(d,J=5.1Hz,1H),8.26(s,1H),8.12(dd,J=8.6,4.6Hz,1H),7.98(d,J=1.5Hz,1H),7.82(td,J=8.7,2.6Hz,1H),7.24(d,J=4.6Hz,1H),4.34(s,2H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-(嗎啉-4-基)乙醯胺
向實例74A(35mg,0.084mmol)含於乙腈(2mL)之混合物中添加嗎啉(0.074mL,0.841mmol)及Ag2O(39.0mg,0.168mmol)。於室溫攪拌該反應混合物22h。隨後使用MeOH稀釋該反應混合物並過濾。在真空中濃縮該濾液。藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10mM乙酸銨;流動相B:95:5乙腈:水及10mM乙酸銨;梯度:15至100%B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min)純化該殘留物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(9.1mg,23%);HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=467.3[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.37(s,1H),8.44(br.s.,2H),8.33(d,J=5.1Hz,1H),8.25(s,1H),8.07(dd,J=8.7,4.5Hz,1H),7.99(s,1H),7.81(td,J=8.7,2.8Hz,1H),7.21(d,J=4.8Hz,1H),3.63(br.s.,2H),3.57-3.36(m,4H),2.54(br.s.,4H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-[(2-羥乙基)胺基]乙醯胺
藉由針對實例74顯示之一般方法由實例74A及2-胺基乙醇製備實例75。HPLC:RT=1.00min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=441.1[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.46(d,J=2.9Hz,1H),8.37(d,J=2.0Hz,1H),8.33-8.26(m,2H),7.95(d,J=2.0Hz,1H),7.84(dd,J=8.6,4.6Hz,1H),7.72(td,J=8.5,3.0Hz,1H),7.20(dd,J=5.3,1.5Hz,1H),3.69(t,J=5.4Hz,2H),3.48(s,2H),2.80(t,J=5.4Hz,2H)。
N-(4-(5-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
76A):N-(4-((3-胺基-6-甲氧基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
根據針對實例1C之一般過程由實例1B及2-溴-6-甲氧基吡啶-3-胺製備實例76A。HPLC:RT=0.63min(H2O/乙腈及0.1% TFA,Waters Aquity BEH C18,1.7-μm粒子,2.0x50mm,梯度=1.5min,波長=220nm);MS(ES):m/z=283[M+H]+。
76B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-6-甲氧基吡啶-3-基)-2,2,2-三氟乙醯胺
於-10℃下向實例76A(80mg,0.283mmol)含於醚:DCM(1:1)(4mL)之懸浮液中逐滴添加2,2,2-三氟乙酸酐(0.039mL,0.283mmol)含於DCM(1mL)之溶液。於-10℃至0℃攪拌該反應混合物30min。隨後使用EtOAc稀釋該反應混合物,先後使用水及飽和NaCl水溶液清洗,經MgSO4乾燥並濃縮以產生灰白色固體之實例76B(90mg,0.238mmol,84%產率),其無需進一步純化即可用於下一步驟。HPLC:RT=0.69min(H2O/乙腈及0.1% TFA,Waters Aquity BEH C18,1.7-μm粒子,2.0x50mm,梯度=1.5min,波長=220nm);m/z=379[M+H]+。
N-(4-(5-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
根據針對實例1之一般方法由實例76B及5-溴-2-甲氧基吡啶製備實例76。HPLC:RT=1.05min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.89(s,1H),10.60(s,1H),8.34(d,J=2.0Hz,1H),8.31-8.23(m,2H),7.95(s,1H),7.80(d,J=8.8Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),7.07(d,J=4.4Hz,1H),6.84(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),3.90-3.86(m,3H),3.85(s,3H),2.09(s,3H)。
N-(4-(5-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
根據針對實例1之一般方法由實例76B及2-溴-6-氯代吡啶製備實例77。HPLC:RT=1.21min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220
nm);MS(ES):m/z=394[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.14(s,1H),10.66(s,1H),8.34(d,J=7.7Hz,1H),8.31(d,J=5.4Hz,1H),8.20(s,1H),7.91(t,J=7.7Hz,1H),7.83(d,J=8.8Hz,1H),7.29(d,J=7.7Hz,1H),7.23(d,J=4.4Hz,1H),6.75(d,J=8.8Hz,1H),3.92(s,3H),2.10(s,3H)。
N-(4-(6-氰基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
78A):N-(4-((3-胺基-5-溴代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
使用N2沖洗2,5-二溴吡啶-3-胺(2.16g,8.57mmol,獲自Combi-Blocks,Inc.)、N-(4-乙炔基吡啶-2-基)乙醯胺(1.373g,8.57mmol)、碘化銅(I)(0.082g,0.429mmol)含於Et3N(20mL,143mmol)及DMF(30mL)之混合物。所得混合物經雙(三苯基膦)二氯化鈀(II)(0.060g,0.086mmol)處理,使用N2沖洗並於75℃加熱90min。在真空中濃縮該反應混合物。向該殘留物添加20mL iPrOH,該混合物經超音波處理及過濾該固體並使用iPrOH清洗。使用CH2Cl2研磨所得
固體並藉由過濾收集。濃縮該濾液及使用CH2Cl2研磨該殘留物以獲得第二批標題化合物。合併兩批固體以獲得2g黃色固體。在真空中進一步濃縮該濾液及藉由SiO2管柱層析法(梯度己烷/EtOAc)純化該殘留物以獲得640mg黃色固體之標題化合物,共2.64g(93%產率)。MS(ES):m/z=331、333[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.62(s,1H),8.35(d,J=5.0Hz,1H),8.23(s,1H),7.86(d,J=1.7Hz,1H),7.37-7.33(m,2H),6.13(s,1H),2.11(s,3H)。
78B):N-(4-((3-胺基-5-氰基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
使用N2沖洗實例78A(300mg,0.91mmol)及Zn(CN)2(106mg,0.91mmol)含於DMF(10mL)及水(0.5mL)之混合物,並經PdCl2(dppf)(60mg,0.082mmol)及Pd2dba3(80mg,0.087mmol)處理。使用N2再次沖洗該混合物並於85℃加熱6h。在真空中部分濃縮該反應混合物並使該殘留物經過SiO2管柱(梯度CH2Cl2至10% MeOH在CH2Cl2中)以獲得黃色固體之標題化合物(135mg,0.487mmol,54%產率)。MS(ES):m/z=278[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.33(br.s.,1H),8.09(d,J=1.5Hz,1H),8.05(br.s.,1H),7.47(d,J=1.5Hz,1H),7.46-7.43(m,1H),2.24(br.s.,3H)。
78C):N-(4-(6-氰基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用N2沖洗實例78B(530mg,1.911mmol)、Cs2CO3(685mg,2.103mmol)及Pd(Ph3P)4(110mg,0.096mmol)含於12mL DMF之混合物及於150℃加熱該混合物20分鐘,並隨後冷卻至室溫。在真空中部分濃縮該反應混合物,及該殘留物與15mL CH2Cl2及3mL水混合。過濾該固體並乾燥以獲得淺黃色固體之標題化合物(350mg,1.262mmol,66.0%產率)。MS(ES):m/z=278[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.63(d,J=1.8Hz,1H),8.57(s,1H),8.42(d,J=5.3Hz,1H),8.23(s,1H),7.61(m,1H),7.28(s,1H),2.23(s,3H)。
78D):N-(4-(6-氰基-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例78C(600mg,2.164mmol)含於DMF(15mL)之溶液中添加N-碘代琥珀醯亞胺(487mg,2.164mmol)及於室溫攪拌該混合物1h。在真空中部分濃縮該反應混合物,及使用水研磨該殘留物並過濾該固體以獲得淺棕色固體之標題化合物(620mg,1.538mmol,71.1%產率)。MS(ES):m/z=403.9[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.98(s,1H),10.72(s,1H),8.78(d,J=1.8Hz,1H),8.69(s,1H),8.52(d,J=5.1Hz,1H),8.37(d,J=2.0Hz,1H),7.66-7.56(m,1H),2.15(s,3H)。
N-(4-(6-氰基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用N2沖洗實例78D(35mg,0.087mmol)、2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧代硼-2-基)吡啶(30.6mg,0.130mmol)及0.2mL 3M K3PO4含於DMF(2mL)之混合物。使用PdCl2(dppf)(25.4mg,0.035mmol)處理該混合物,使用N2沖洗並於80℃加熱60min。濃縮該反應混合物至體積1mL及添加3mL MeOH。過濾所得固體及藉由製備型HPLC(Sunfire C-18 19x150mm,經由含1% TFA之5%至100%CH3CN水溶液梯度在12min內洗脫,20mL/min,波長=254nm)純化該濾液以獲得標題化合物(27mg,56%)。HPLC:RT=0.68min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm)。MS(ES):m/z=385[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.65(s,1H),8.74(d,J=2.0Hz,1H),8.40(d,J=2.0Hz,1H),8.38-8.34(m,2H),8.23(dd,J=2.4,0.6Hz,1H),7.77(dd,J=8.5,2.4Hz,1H),7.15(dd,J=5.2,1.7Hz,1H),6.88(dd,J=8.5,0.8Hz,1H),3.89(s,3H),2.10(s,3H)。
N-(4-(6-(胺基甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
在1atm H2下於室溫攪拌實例78(50mg,0.130mmol)及20%碳載Pd(OH)2(10mg)含於MeOH(12mL)之混合物。在4h後添加額外20%碳載Pd(OH)2(20mg)並繼續在1atm H2下攪拌。在7h後,過濾該固體及部分濃縮該濾液及藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之10% CH3CN水溶液至60% CH3CN水溶液梯度在8min內洗脫,20mL/min,波長=254nm)純化該殘留物以獲得淺黃色固體之標題化合物(13mg,0.032mmol,24.44%產率)。HPLC:RT=0.49min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=389[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.45(s,1H),8.30(s,1H),8.26(d,J=5.1Hz,1H),8.17(d,J=1.8Hz,1H),8.05(s,1H),7.76(dd,J=8.6,2.2Hz,1H),7.15-7.11(m,1H),6.88(d,J=8.4Hz,1H),4.29(s,2H),3.95(s,3H),2.16(s,3H)。
根據如在實例78及79中描述之相似過程製備實例80及實例81。
N-(4-(7-氰基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
HPLC:RT=0.68min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=385[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.60(d,J=5.1Hz,1H),8.37(d,J=5.9Hz,1H),8.30-8.28(m,1H),7.96-7.91(m,2H),7.71(d,J=5.1Hz,1H),7.47(dd,J=5.7,1.3Hz,1H),7.03(dd,J=8.7,0.6Hz,1H),4.01(s,3H),2.23(s,3H)。
N-(4-(7-(胺基甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
HPLC:RT=0.50min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=389[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.61(s,1H),8.45(d,J=4.7Hz,1H),8.37-8.33(m,2H),8.24(d,J=1.7Hz,1H),7.78(dd,J=8.5,2.3Hz,1H),7.32(d,J=4.7Hz,1H),7.14(dd,J=5.1,1.6Hz,1H),6.86(d,J=8.5Hz,1H),4.39(s,2H),3.87
(s,3H),2.10(s,3H)。
4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]-N-甲基吡啶-2-胺
82A):N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1-甲苯磺醯基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例72A(0.45g,1.18mmol)含於DMF(8mL)之溶液中添加Cs2CO3(0.85g,2.59mmol)及對甲苯磺醯氯(0.22mL,1.18mmol)。於室溫攪拌該反應混合物過夜。向該反應混合物中添加乙酸乙酯及飽和NaHCO3溶液。使用乙酸乙酯萃取有機層(2x)及使用飽和NaHCO3溶液清洗合併之有機層,經MgSO4乾燥並過濾。在真空中濃縮該濾液。藉由矽膠急驟層析法純化該殘留物,使用0至10% MeOH之DCM溶液洗脫以獲得黃色固體之期望產物(0.16g,25.3%);HPLC:RT=1.30min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,
1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=536.3[M+H]+;1H NMR(400MHz,CDCl3)δ ppm δ 8.68(d,J=2.2Hz,1H),8.61(d,J=2.2Hz,1H),8.33(d,J=3.1Hz,1H),8.30(dd,J=5.1,0.7Hz,1H),7.99(s,1H),7.62(dd,J=8.5,4.3Hz,1H),7.45(d,J=8.6Hz,2H),7.36-7.29(m,1H),7.20(d,J=7.9Hz,2H),7.13(dd,J=5.2,1.4Hz,1H),2.37(s,3H),2.20(s,3H)。
82B):N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1-甲苯磺醯基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-N-甲基乙醯胺
向實例82A(50mg,0.093mmol)含於THF(1mL)之懸浮液中添加含於DMF(0.6mL)及Cs2CO3(61mg,0.187mmol)之碘甲烷(0.017mL,0.280mmol)。於室溫攪拌該反應化合物2h。隨後使用乙酸乙酯及飽和NaHCO3溶液稀釋該反應混合物。分離有機層及經MgSO4乾燥並過濾。在真空中濃縮該濾液以獲得期望產物,其無需純化即可用於下一步驟。HPLC:RT=1.43min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=550.3[M+H]+。
實例82):4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]-N-甲基吡啶-2-胺
向粗製實例82B(30mg,0.055mmol)含於MeOH(2mL)之溶液中添加LiOH水溶液(0.55mL,1.10mmol)。隨後於85℃加熱該反應混合物2h。在真空中濃縮該反應混合物及將該殘留物溶於DMF中並藉由製備型HPLC(Sunfire C-18 19x150mm,經由含5mmol NH4OAc之10%至100% CH3CN水溶液在12min內洗脫,20mL/min,波長=220nm)純化。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(11mg,55%);HPLC:RT=0.67min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=354.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 8.51(d,=3.1Hz,1H),8.38(d,J=2.2Hz,1H),8.05-7.95(m,2H),7.90(d,J=2.2Hz,1H),7.79(td,J=8.7,3.0Hz,1H),6.59(s,1H),6.56-6.48(m,2H),2.75(d,J=4.8Hz,3H)。
N-{4-[6-溴-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
83A):N-(4-((3-胺基-5-溴代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由與針對實例1C顯示之彼等相似之方法由實例1B及2,5-二溴吡啶-3-胺製備實例83A。HPLC:RT=1.43min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=331[M+H]+,1H NMR(400MHz,DMSO-d6)δ 10.61(s,1H),8.36(dd,J=5.1,0.7Hz,1H),8.24(s,1H),7.87(d,J=2.0Hz,1H),7.37-7.34(m,2H),3.31(s,2H),2.12(s,3H)。
83B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-溴代吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由實例83A製備實例83B。HPLC:RT=1.85min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=427[M+H]+,1H NMR(400MHz,DMSO-d)δ ppm 11.72(s,1H),10.68(s,1H),8.79(d,J=2.0Hz,1H),8.41(dd,J=5.1,0.9Hz,1H),8.36(d,J=2.2Hz,1H),8.25(s,1H),7.19(dd,J=5.1,1.5Hz,1H),2.12(s,3H)。
實例83):N-{4-[6-溴-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡
啶-2-基]吡啶-2-基}乙醯胺
藉由針對實例1顯示之一般方法由實例83B及2-溴-5-甲氧基吡啶製備實例83。HPLC:RT=0.91min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=438[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.20(s,1H),10.56(s,1H),8.49(s,1H),8.35-8.25(m,2H),8.20(d,J=2.5Hz,1H),8.08(s,1H),7.93(d,J=8.7Hz,1H),7.50(dd,J=8.6,2.7Hz,1H),7.13(d,J=4.9Hz,1H),3.86(s,3H),2.10(s,3H)。
N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}胺基甲酸甲酯
向實例52(28.8mg,0.091mmol)含於CH2Cl2(2mL)之懸浮液中添加TEA(0.038mL,0.272mmol)及氯甲酸甲酯(0.014mL,0.182mmol)。於室溫攪拌該混合物過夜,及隨後添加MeOH(1mL)及濃縮之NH4OH(1滴)。於室溫攪拌所得反應混合物過夜。隨後濃縮該混合
物,使用DMF稀釋,及藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10mM乙酸銨;流動相B:95:5乙腈:水及10mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min)純化以獲得實例84(10.5mg,31%)。HPLC:RT=0.73min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=376[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.07(br.s.,1H),10.33(s,1H),8.42(d,J=4.1Hz,1H),8.34-8.17(m,2H),8.08(s,1H),7.94-7.71(m,2H),7.27(dd,J=8.0,4.5Hz,1H),7.10(d,J=5.0Hz,1H),6.89(d,J=8.4Hz,1H),3.89(s,3H),3.66(s,2H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}胺基甲酸甲酯
向實例72A(68mg,0.20mmol)含於DCE(3mL)之懸浮液中添加氯甲酸甲酯(0.04mL,0.52mmol)及4-甲基嗎啉(0.13mL,1.20mmol)。於室溫攪拌該反應混合物1h。添加額外氯甲酸甲酯(0.04mL,0.52mmol)及4-甲基嗎啉(0.13mL,1.201mmol)至該反應混合物。於室溫攪拌該反應混合物又0.5h。向該混合物中添加氫氧化銨(0.6mL)及MeOH(3mL)。於室溫攪拌所得混合物20h。隨後使用飽和
NaHCO3溶液及CHCl3:2-丙醇(2.5:1)稀釋該反應混合物。進行層分離及使用CHCl3:2-丙醇(2.5:1)萃取水層。藉由MgSO4乾燥合併的有機層及過濾。在真空中濃縮該濾液以獲得黃色固體。向萃取液中添加DCM,該混合物經超音波處理並隨後過濾以獲得黃色固體之期望產物(35mg,42%)。HPLC:RT=0.72min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=397.9[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.31(s,1H),10.25(s,1H),8.46(dd,J=6.2,2.6Hz,2H),8.28(d,J=5.3Hz,1H),8.11(dd,J=8.8,4.6Hz,1H),8.02(s,1H),7.97(d,J=2.2Hz,1H),7.83(td,J=8.8,2.9Hz,1H),7.13(dd,J=5.3,1.3Hz,1H),3.68-3.63(m,3H)。
4-[6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-胺
藉由針對實例52顯示之一般方法由實例47製備實例86。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm);MS(ES):m/z=352.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 8.37(d,J=2.2Hz,1H),8.24(d,J=2.6Hz,1H),7.95-7.78(m,3H),7.47(dd,J=8.8,3.1Hz,1H),6.62(s,1H),6.53(dd,J=5.3,1.5Hz,1H),5.97(s,2H),3.86(s,3H)。
N-{4-[6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}胺基甲酸甲酯
藉由針對實例85顯示之一般方法由實例86製備實例87。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=410.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.25(s,1H),8.42(d,J=1.9Hz,1H),8.24(d,J=5.1Hz,1H),8.21(d,J=2.8Hz,1H),8.04(s,1H),7.95(d,J=1.9Hz,1H),7.92(d,J=8.6Hz,1H),7.50(dd,J=8.7,2.9Hz,1H),7.09(d,J=5.1Hz,1H),3.85(s,3H),3.65(s,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-(4-甲基哌嗪-1-基)乙醯胺
藉由針對實例74顯示之一般方法由74A及1-甲基哌嗪製備實例
88。HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=480.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.06(br.s.,1H),8.45(br.s.,2H),8.34(d,J=5.1Hz,1H),8.28(s,1H),8.10(dd,J=8.8,4.5Hz,1H),7.98(d,J=1.9Hz,1H),7.83(td,J=8.8,2.9Hz,1H),7.22(d,J=5.0Hz,1H),2.63-2.51(m.,10H),2.39(br.s.,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-{[3-(嗎啉-4-基)丙基]胺基}乙醯胺
藉由針對實例74顯示之一般方法由74A及3-嗎啉丙-1-胺製備實例89。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=524.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 8.45(br.s.,2H),8.37-8.26(m,2H),8.11(dd,J=8.5,4.5Hz,1H),7.98(s,1H),7.87-7.76(m,1H),7.20(d,J=5.0Hz,1H),3.54-3.4(br.s.,6H),3.29(br.s.,4H),2.32(t,J=6.8Hz,2H),1.90(s,2H),1.58(t,J=6.9Hz,2H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶
-2-基}-2-{[2-(嗎啉-4-基)乙基]胺基}乙醯胺
藉由針對實例74顯示之一般方法由74A及2-嗎啉乙胺製備實例90。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=510.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.47(s,1H),8.55-8.39(m,3H),8.27-8.12(m,2H),8.01(s,1H),7.89-7.77(m,1H),7.35(d,J=4.9Hz,1H),4.29-3.59(m,2H),3.45-2.80(m,4H),2.54(br.s,8H)。
N-{4-[6-甲磺醯基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
91A):N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-N-((2-(三甲基矽烷基)乙氧基)甲基)乙醯胺
向實例83(200mg,0.456mmol)含於THF(15mL)/DMF(7mL)之懸浮液中添加60% NaH(146mg,3.65mmol),並攪拌該混合物15min。隨後添加SEM-Cl(0.324mL,1.825mmol),及於室溫攪拌所得混合物1.5h。使用水小心淬冷反應及隨後藉由EtOAc萃取混合物。分離有機層及使用10% LiOH及鹽水清洗,乾燥(MgSO4)並濃縮。藉由矽膠急驟層析法(24g,MeOH/DCM=0至5%)純化該殘留物以獲得實例91A(196mg,62%)。HPLC:RT=3.32min(H2O/MeOH及0.1% TFA,Chromolith SpeedROD,4.6x50mm,梯度=4min,波長=220nm);MS(ES):m/z=698[M+H]+。
實例91):N-{4-[6-甲磺醯基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用氮氣沖洗2打蘭小瓶中之實例91A(25mg,0.036mmol)、甲烷亞磺酸鈉(7.30mg,0.072mmol)、碘化銅(I)(10.22mg,0.054
mmol)、L-脯胺酸(8.24mg,0.072mmol)及Cs2CO3(23.31mg,0.072mmol)含於DMSO(0.7mL)之混合物及隨後於100℃加熱過夜。將該混合物冷卻至室溫,及隨後使用MeOH稀釋及藉由製備型HPLC(Luna 5u C18,20x100mm,經由含5mM NH4OAc之20%至100%乙腈水溶液在15內洗脫,20mL/min,監視器254nm)純化。合併並濃縮所需餾份,及隨後經由50% TFA/DCM(2mL)處理該殘留物及於室溫攪拌2h。濃縮該混合物並藉由製備型HPLC(XBridge C18,5u,19x200mm,經由含10mM乙酸銨之5%至50%乙腈水溶液在20分鐘內洗脫,20mL/min,監視器254nm)純化以獲得實例91(3.4mg,21%)。HPLC:RT=0.62min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=438[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.62(s,1H),8.91(s,1H),8.41-8.27(m,3H),8.22(d,J=2.7Hz,1H),7.99(d,J=8.6Hz,1H),7.53(dd,J=8.7,2.8Hz,1H),7.16(d,J=4.5Hz,1H),3.87(s,3H),2.55(s,3H),2.11(s,3H)。
N-{4-[6-氰基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用與針對實例78B描述之彼等相似之條件由實例83製備實例92。HPLC:RT=0.59min(H2O/ACN及0.05% TFA,Waters Acquity
BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=385[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.75(s,1H),10.60(s,1H),8.78(d,J=1.8Hz,1H),8.41(d,J=1.8Hz,1H),8.35-8.30(m,3H),8.26(d,J=2.6Hz,1H),7.95(d,J=8.8Hz,1H),7.17(dd,J=5.2,1.7Hz,1H),3.88(s,3H),2.09,2.07(s,3H)。
N-{4-[6-(二甲基-1,2-噁唑-4-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用N2沖洗實例83(20mg,0.046mmol)、(3,5-二甲基異噁唑-4-基)硼酸(9.65mg,0.068mmol)、PdCl2(dppf)-CH2Cl2加合物(1.863mg,2.282μmol)及2M磷酸三鉀(0.068mL,0.137mmol)含於THF(2mL)之混合物,及隨後在密封瓶中於85℃加熱30min。將該混合物冷卻至室溫,隨後濃縮及藉由製備型HPLC(XBridge C18,5u,19x200mm,經由含10mM乙酸銨之5%至80%乙腈水溶液在20分鐘內洗脫,20mL/min,監視器254nm)純化以獲得實例93(12.3mg,59%)。HPLC:RT=0.97min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=455[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.56(s,1H),8.44(s,1H),8.34(br.s.,1H),8.30(d,J=5.0Hz,1H),8.21(d,J=2.8Hz,1H),8.04(d,J=8.7Hz,1H),7.84(s,1H),7.51(dd,
J=8.7,2.9Hz,1H),7.16(d,J=5.1Hz,1H),3.87(s,3H),2.47(s,3H),2.29(s,3H),2.10(s,3H)。
N-{4-[6-(二甲基-1H-1,2,3-三唑-5-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用N2沖洗實例84(20mg,0.046mmol)、1,4-二甲基-5-(三丁基甲錫烷基)-1H-1,2,3-三唑(35.2mg,0.091mmol)[Seefeld,M.A.等人PCT Int.Appl.,2008,WO2008098104]、Pd(Ph3P)4(5.27mg,4.56μmol)、碘化銅(I)(1.738mg,9.13μmol)及TEA(0.013mL,0.091mmol)含於DMF(1mL)之混合物,及隨後於90℃加熱過夜。將該混合物冷卻至室溫及藉由製備型HPLC(XBridge C18,5u,19x200mm,經由含10mM乙酸銨之10%至50%乙腈水溶液在20分鐘內洗脫,20mL/min,監視器254nm)純化以獲得實例94(1.7mg,8%)。HPLC:RT=0.75min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=455[M+H]+。
N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
95A)N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(實例83,125mg,0.285mmol)及碳酸銫(139mg,0.428mmol)含於DMF(1mL)及THF(1mL)之懸浮液中添加(2-(氯代甲氧基)乙基)三甲基矽烷(57.1mg,0.342mmol)。於室溫攪拌該反應1h,然後經鹽水淬冷,及使用EtOAc萃取(3x)。濃縮合併之有機層及在ISCO(0-10% MeOH/DCM,24g管柱)上純化以獲得N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(143mg,0.252mmol,88%產率)。MS(ES):m/z=569.9[M+H]+。
95B):N-(4-(6-羥基-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向瓶中添加雙(頻哪醇根基)二硼(156mg,0.616mmol)、N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(140mg,0.246mmol)、Pd2(dba)3(4.51mg,4.92μmol)、XPhos(4.70mg,9.85μmol)、及乙酸鉀(72.5mg,0.739mmol)。排空該瓶並使用N2回填。隨後添加二噁烷(3mL)。隨後將該反應加熱至100℃持續2h。隨後將該反應冷卻至室溫,使用EtOAc稀釋,經矽藻土墊過濾,使用10% MeOH/DCM清洗。濃縮合併之濾液及溶於THF(5mL)及水(2mL)中。向該混合物中添加過硼酸鈉(100mg)。於室溫攪拌所得懸浮液過夜,然後經EtOAc稀釋,使用鹽水清洗,乾燥並在真空中濃縮。在ISCO(0-7% MeOH/DCM,24g管柱)上純化該粗產物以獲得N-(4-(6-羥基-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(79mg,0.156mmol,63.4%產率)。MS(ES):m/z=506.0[M+H]+。
95C):N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於0℃下向N-(4-(6-羥基-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(32mg,0.063mmol)、三苯基膦(16.60mg,0.063mmol)、及2-甲氧基乙醇(14.45mg,0.190mmol)含於THF(0.5mL)之溶液中添加DIAD(0.012mL,0.063mmol)。隨後將該反應加熱至50℃持續1h,然後將其冷卻至室溫並在ISCO(0-10% MeOH/DCM,12g管柱)上純化以獲得N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(25mg,0.044mmol,70.1%產率)。MS(ES):m/z=564[M+H]+。
實例95)N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(26mg,0.046mmol)含於DCM(0.2mL)之溶液中添加TFA(0.3mL)。於室溫攪拌所得反應4h,然後將其濃縮。隨後將所得混合物溶於含於20% MeOH/DCM之0.4M NH3(0.5mL)中並於室溫攪拌1h。隨後濃縮該反應及在ISCO(0-10% MeOH/DCM,12g金柱)上純化以獲得N-(4-(6-(2-甲氧基乙氧基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(13.5mg,0.030mmol,64.2%產率)。HPLC:RT=0.59min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,
2.1x50mm,1.7-μm粒子,梯度=1min,波長=220nm);MS(ES):m/z=434[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.28(dd,J=3.0,0.6Hz,1H),8.24-8.20(m,2H),8.18(d,J=2.6Hz,1H),7.63(dd,J=8.6,0.6Hz,1H),7.54(dd,J=8.6,3.0Hz,1H),7.50(d,J=2.6Hz,1H),7.10-7.05(m,1H),4.38-4.22(m,2H),3.97(s,3H),3.88-3.77(m,2H),3.48(s,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在1分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
N-(4-(3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
104A)2-溴-5-(甲氧基-d3)吡啶
於0℃下向6-溴代吡啶-3-醇(10.00g,57.5mmol)、d4-MeOD(12.44g,345mmol)、及三苯基膦(15.83g,60.3mmol)含於二噁烷(80mL)之溶液中逐滴添加DIAD(11.73mL,60.3mmol)。於0℃攪拌該反應10min,然後溫熱至室溫並攪拌過夜。隨後濃縮該反應及隨後使用DCM(60mL)研磨。過濾該混合物以移除氧化膦副產物。濃縮該濾液並在ISCO(0-10% MeOH/DCM,120g管柱)上純化以獲得2-溴-5-(甲氧基-d3)吡啶(7.1g,37.2mmol,64.7%產率)。MS(ES):m/z=191[M+H]+。1H NMR(400MHz,氯仿-d)δ 8.08(dd,J=3.2,0.4Hz,1H),7.39(dd,J=8.7,0.6Hz,1H),7.12(dd,J=8.7,3.2Hz,1H)。
實例104)N-(4-(3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例1D(1.2g,3.45mmol)及碳酸銫(2.245g,6.89mmol)之混合物並使用N2回填。添加MeCN(17.23mL)及2-溴-5-(甲氧基-d3)吡
啶(1.316g,6.89mmol)。在添加肆(三苯基膦)鈀(0)(0.199g,0.172mmol)前使用N2噴射該混合物5min。該反應經N2噴射1min,隨後將其密封並於110℃攪拌2h。將所得混合物冷卻至室溫,使用10% MeOH-CH2Cl2(20mL)稀釋並通過矽藻土過濾(使用10% MeOH-CH2Cl2清洗)。在真空中濃縮該濾液。藉由ISCO(120g管柱,0-8% MeOH/DCM)純化該粗製材料及在真空下乾燥以獲得N-(4-(3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(540mg,1.460mmol,42.4%產率)。HPLC:RT=0.56min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=1min,波長=220nm);MS(ES):m/z=363[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.98(s,1H),10.52(s,1H),8.44(d,J=4.4Hz,1H),8.36-8.25(m,2H),8.19(d,J=2.9Hz,1H),8.03(d,J=8.7Hz,1H),7.87(d,J=8.2Hz,1H),7.50(dd,J=8.7,2.9Hz,1H),7.26(dd,J=8.1,4.6Hz,1H),7.14(d,J=5.1Hz,1H),2.10(s,3H)。
N-(4-(6-氯-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例41B(110mg,0.287mmol)及碳酸銫(187mg,0.575mmol)之混合物並使用N2回填。添加MeCN(2874μl)及2-溴-5-(甲氧基-
d3)吡啶(110mg,0.575mmol)。使用N2噴射該混合物5min,隨後添加肆(三苯基膦)鈀(0)(16.61mg,0.014mmol)。使用N2噴射該反應1min,隨後將其密封並於110℃攪拌2h。隨後將該反應冷卻至室溫,使用10% MeOH-CH2Cl2(20mL)稀釋及經矽藻土(使用10% MeOH-CH2Cl2)清洗)過濾。在真空中濃縮該濾液。藉由ISCO(40g金柱,0-8% MeOH/DCM,在矽藻土上乾燥)純化該粗製材料並在真空下乾燥以獲得期望產物(48mg,0.119mmol,41.2%產率)。HPLC:RT=0.61min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=1min,波長=220nm);MS(ES):m/z=397[M+H]+ 1H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),10.55(s,1H),8.44(d,J=2.2Hz,1H),8.32(s,1H),8.29(d,J=5.3Hz,1H),8.21(d,J=3.1Hz,1H),7.95(dd,J=5.4,3.2Hz,2H),7.50(dd,J=8.7,3.1Hz,1H),7.13(dd,J=5.2,1.5Hz,1H),2.10(s,3H)。
N-(4-(6-氟-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例38B(110mg,0.300mmol)及碳酸銫(196mg,0.601mmol)之混合物並使用N2回填。添加MeCN(3003μl)及2-溴-5-(甲氧基-d3)吡啶(115mg,0.601mmol)。使用N2噴射該混合物5min,隨後添加肆(三苯基膦)鈀(0)(17.35mg,0.015mmol)。使用N2噴射該反應1
min,隨後將其密封並於110℃攪拌2h。隨後將該反應冷卻至室溫,使用10% MeOH-CH2Cl2(20mL)稀釋,及經矽藻土(使用10% MeOH-CH2Cl2清洗)過濾。在真空中濃縮該濾液。藉由ISCO(40g金柱,0-8% MeOH/DCM)純化該粗製材料並乾燥以獲得N-(4-(6-氟-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(50mg,0.125mmol,41.6%產率)。HPLC:RT=0.56min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=1min,波長=220nm);MS(ES):m/z=381[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.33(t,J=2.2Hz,1H),8.28(dd,J=3.1,0.6Hz,1H),8.27-8.22(m,2H),7.71(dd,J=9.1,2.5Hz,1H),7.67(dd,J=8.7,0.6Hz,1H),7.54(dd,J=8.7,3.1Hz,1H),7.15-7.08(m,1H),2.17(s,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
2-(2-(2-乙醯胺基吡啶-4-基)-3-(6-(二氟甲基)吡啶-2-及)-1H-吡咯并[3,2-b]吡啶-1-基)乙醯胺
向實例281(20mg,0.053mmol)含於DMF(0.3mL)之溶液中添加碳酸鉀(14.57mg,0.105mmol)及碘甲烷(6.59μl,0.105mmol)。於室溫攪拌該反應混合物過夜並隨後過濾及使用MeOH稀釋。隨後藉由製備型HPLC純化該粗產物以獲得2-(2-(2-乙醯胺基吡啶-4-基)-3-(6-(二氟
甲基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-1-基)乙醯胺。HPLC:RT=0.83min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=437[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.58(s,1H),8.66(d,J=7.8Hz,1H),8.56(d,J=4.1Hz,1H),8.37(d,J=4.8Hz,1H),8.13(br.s.,1H),8.01-7.93(m,2H),7.56(br.s.,1H),7.41(d,J=7.5Hz,1H),7.35(dd,J=8.0,4.5Hz,1H),7.23(br.s.,1H),7.08(d,J=4.6Hz,1H),6.50-6.17(m,1H),4.76(s,2H),2.07(s,3H)。
2-(二甲胺基)-N-{4-[6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
115A)N-(4-(6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例48B(0.423g,1.118mmol)及碳酸銫(0.729g,2.236mmol)之混合物並使用N2回填,隨後添加MeCN(10.16mL)及2-溴-5-甲氧基吡啶(0.420g,2.236mmol)。使用N2噴射該混合物5min,隨後添加肆(三苯基膦)鈀(0)(0.065g,0.056mmol)。使用N2噴射該反應1min,隨後將其密封及於110℃攪拌2h。將該反應冷卻至室溫,使用10% MeOH-CH2Cl2(10mL)稀釋,並通過矽藻土(使用10% MeOH-CH2Cl2清洗)過濾。在真空中濃縮該濾液。藉由急驟層析法(40g矽膠及25g預填充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)純化該粗製材料以獲得灰白色固體之實例115A(0.216g,50%)。LC-MS m/z 390[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.78(s,1H),10.47(s,1H),8.29(s,1H),8.24(dd,J=5.3,0.7Hz,1H),8.20-8.17(m,2H),7.96(d,J=8.7Hz,1H),7.47(dd,J=8.7,3.1Hz,1H),7.33(d,J=2.6Hz,1H),7.10(dd,J=5.3,1.6Hz,1H),3.89(s,3H),3.85(s,3H),2.09(s,3H)。
115B)4-(6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
向實例115A(215mg,0.552mmol)含於MeOH(5.52mL)之室溫溶液中添加氫氧化鈉(5.52mL,1M溶液在H2O中,5.52mmol)。密封該反應及於80℃攪拌2h,及隨後將其冷卻至室溫,導致固體沉澱,其可藉由真空過濾(使用H2O清洗)收集以提供實例115B(199mg,定量)。LC-MS m/z 348[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.62
(s,1H),8.24-8.22(m,1H),8.16(d,J=2.7Hz,1H),7.88-7.86(m,1H),7.86-7.85(m,1H),7.45(dd,J=8.7,3.1Hz,1H),7.29(d,J=2.6Hz,1H),6.60-6.57(m,1H),6.51(dd,J=5.3,1.5Hz,1H),5.92(s,2H),3.88(s,3H),3.86(s,3H)。
實例115)2-(二甲胺基)-N-{4-[6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例115B(26.2mg,0.075mmol)含於DMF(151μl)之室溫溶液中添加2-(二甲胺基)乙酸(10.89mg,0.106mmol)、N,N-二異丙基乙胺(65.7μl,0.377mmol)及HATU(40.1mg,0.106mmol)。於室溫攪拌該反應5h,及隨後經DMF稀釋,過濾,並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:5至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例115(26.2mg,50%)。HPLC:Rt=0.725min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 433[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.84(s,1H),9.91(s,1H),8.30(s,1H),8.25(d,J=5.2Hz,1H),8.20-8.17(m,2H),7.95(d,J=8.6Hz,1H),7.48
(dd,J=8.7,2.9Hz,1H),7.35(d,J=2.4Hz,1H),7.15(d,J=5.1Hz,1H),3.88(s,3H),3.84(s,3H),3.11(s,2H),2.29(s,6H)。
2-(二甲胺基)-N-{4-[6-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
116A)N-(4-(6-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例48B(0.360g,0.952mmol)及碳酸銫(0.620g,1.903mmol)之混合物並使用N2回填,隨後添加MeCN(9.52mL)及2-溴-6-甲基吡啶(0.327g,1.903mmol)。使用N2噴射該混合物5min,隨後添加肆(三苯基膦)鈀(0)(0.055g,0.048mmol)。使用N2噴射該反應1min,隨後將其密封並於110℃攪拌2h。將該反應冷卻至室溫,使用10% MeOH-CH2Cl2(10mL)稀釋,並通過矽藻土(使用10% MeOH-CH2Cl2清洗)過濾。在真空中濃縮該濾液。藉由急驟層析法(24g矽膠及5g預填
充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)純化該粗製材料以獲得灰白色固體之實例116A(172mg,48%)。LC-MS m/z 374[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.83(s,1H),10.47(s,1H),8.34(s,1H),8.25(dd,J=5.2,0.7Hz,1H),8.21(d,J=2.7Hz,1H),7.88(d,J=7.7Hz,1H),7.71(t,J=7.7Hz,1H),7.34(d,J=2.6Hz,1H),7.19(dd,J=5.3,1.6Hz,1H),7.10(d,J=7.6Hz,1H),3.89(s,3H),2.30(s,3H),2.09(s,3H)。
116B)4-(6-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
向實例116A(171mg,0.458mmol)含於MeOH(4579μl)之室溫溶液中添加氫氧化鈉(4579μL,1M溶液在H2O中,4.58mmol)。密封該反應並於80℃攪拌2h,隨後將其冷卻至室溫及在N2流下部分濃縮以移除大部分MeOH,導致固體沉澱。使用H2O(10mL)稀釋該混合物及藉由真空過濾(使用H2O清洗)收集該固體以提供黃色固體之實例116B(117mg,77%)。LC-MS m/z 332[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),8.17(d,J=2.7Hz,1H),7.86(d,J=5.4Hz,1H),7.79-7.76(m,1H),7.69(t,J=7.7Hz,1H),7.30(d,J=2.6Hz,1H),7.10(d,J=7.2Hz,1H),6.68-6.64(m,1H),6.56(dd,J=5.4,1.5Hz,1H),5.91(s,2H),3.88(s,3H),2.36(s,3H)。
實例116)2-(二甲胺基)-N-{4-[6-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例116B(30.7mg,0.093mmol)及2-(二甲胺基)乙酸(13.37mg,0.130mmol)含於DMF(185μL)之室溫溶液中添加N,N-二異丙基乙胺(81μL,0.463mmol)及HATU(49.3mg,0.130mmol)。於室溫攪拌該反應18h,隨後經DMF稀釋、過濾、及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例116(19.8mg,51%)。HPLC:Rt=0.710min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS 417[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.90(s,1H),9.97(br s,1H),8.34(s,1H),8.27(d,J=5.2Hz,1H),8.20(d,J=2.5Hz,1H),7.87(d,J=7.7Hz,1H),7.71(t,J=7.7Hz,1H),7.36(d,J=2.4Hz,1H),7.24(d,J=4.2Hz,1H),7.10(d,J=7.7Hz,1H),3.88(s,3H),3.18(s,2H),2.33(s,6H),2.29(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)-2-(二甲胺基)乙醯胺
117A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例48B(0.360g,0.952mmol)及碳酸銫(0.620g,1.903mmol)之混合物及使用N2回填,隨後添加MeCN(9.52mL)及2-溴-6-(二氟甲基)吡啶(0.396g,1.903mmol)。使用N2噴射該混合物5min,隨後添加肆(三苯基膦)鈀(O)(0.055g,0.048mmol)。使用N2噴射該反應1min,隨後將其密封及於110℃攪拌2h。將該反應冷卻至室溫,使用10% MeOH-CH2Cl2(10mL)稀釋,並通過矽藻土(經10% MeOH-CH2Cl2稀釋)過濾。在真空中濃縮該濾液。藉由急驟層析法(24g矽膠及5g預填充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)純化該粗製材料以獲得灰白色固體之實例117A(194mg,50%)。LC-MS m/z 410[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.00(s,1H),10.49(s,1H),8.35-8.30(m,2H),8.27(dd,J=5.3,0.6Hz,1H),8.24(d,J=2.7Hz,
1H),8.05(t,J=7.9Hz,1H),7.54(d,J=7.6Hz,1H),7.37(d,J=2.6Hz,1H),7.21(dd,J=5.1,1.6Hz,1H),6.66(t,J=55.4Hz,1H),3.90(s,3H),2.08(s,3H)。
117B)4-(3-(6-(二氟甲基)吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
向實例117A(193mg,0.471mmol)含於MeOH(4714μL)之室溫溶液中添加氫氧化鈉(4714μL,1M溶液在H2O中,4.71mmol)。密封該反應及於80℃攪拌2h,及隨後將其冷卻至室溫,導致固體沉澱。使用H2O(10mL)稀釋該混合物及藉由真空過濾(使用H2O清洗)收集該固體以提供灰白色固體之實例117B(133mg,77%)。LC-MS m/z 368[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.85(s,1H),8.24-8.20(m,2H),8.03(t,J=7.8Hz,1H),7.88-7.86(m,1H),7.54(d,J=7.5Hz,1H),7.33(d,J=2.6Hz,1H),6.70-6.68(m,1H),6.72(t,J=55.1Hz,1H),6.57(dd,J=5.4,1.5Hz,1H),5.93(s,2H),3.89(s,3H)。
實例117)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)-2-(二甲胺基)乙醯胺
向實例117B(33.6mg,0.091mmol)及2-(二甲胺基)乙酸(13.20mg,0.128mmol)含於DMF(183μL)之室溫懸浮液中添加N,N-二異丙基乙胺(80μL,0.457mmol)及HATU(48.7mg,0.128mmol)。於室溫攪拌該反應18h,隨後經DMF稀釋、過濾、及通過具有以下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:15至55% B在25分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥。通過具有如下條件之製備型LC/MS進一步純化該材料:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:20至60% B在20分鐘內,隨後於100% B維持3分鐘;流速:20mL/min。合併含有期望產物之溶離份及藉由離心蒸發乾燥以提供實例117(10.7mg,26%)。HPLC:Rt=0.817min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 453[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.06(s,1H),9.91(br s,1H),8.35(s,1H),8.32(d,J=8.0Hz,1H),8.29(d,J=5.2Hz,1H),8.25(d,J=2.4Hz,1H),8.05(t,J=7.8Hz,1H),7.54(d,J=7.7Hz,1H),7.39(d,J=2.5Hz,1H),7.27(d,J=4.3
Hz,1H),6.66(t,J=55.3Hz,1H),3.90(s,3H),3.10(s,2H),2.29(s,6H)。
a HPLC條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm。
N-{4-[6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}胺基甲酸甲酯
向實例115B(32mg,0.092mmol)含於CH2Cl2(921μL)之0℃懸浮液中逐滴添加三乙胺(51.4μL,0.368mmol),接著添加氯甲酸甲酯(10.68μL,0.138mmol)。於0℃攪拌該反應5min,隨後將其溫熱至室溫並攪拌18h。添加額外氯甲酸甲酯(3.6μL,0.046mmol)及於室溫攪
拌該反應1h。添加額外氯甲酸甲酯(3.6μL,0.046mmol)及於室溫攪拌該反應1h。使用MeOH(920μL)及氫氧化銨(200μL)稀釋該反應,攪拌3h,及隨後在真空中濃縮。使用CH2Cl2研磨該粗製材料以獲得白色固體之實例124(23.3mg,61%)。HPLC:Rt=5.27min(Sunfire C18,3.0x150mm,3.5-μm粒子;5至95% MeCN-H2O及0.05% TFA在12min內;波長=220nm);LC-MS m/z 406[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.77(s,1H),10.16(s,1H),8.22-8.18(m,3H),8.03(s,1H),7.95(d,J=8.7Hz,1H),7.48(dd,J=8.7,3.1Hz,1H),7.33(d,J=2.6Hz,1H),7.08(dd,J=5.2,1.5Hz,1H),3.89(s,3H),3.86(s,3H),3.66(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
125A)N-(4-(7-氯-3-(6-(二氟甲基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例61C(1.273g,3.33mmol)及碳酸銫(2.167g,6.65mmol)之混合物並使用N2回填,隨後添加DMF(13.30mL)及2-溴-6-(二氟甲基)吡啶(1.384g,6.65mmol)。使用N2噴射該混合物5min,隨後添加第二代XPhos預觸媒(0.131g,0.166mmol)。使用N2噴射該反應2min,隨後將其密封並於120℃攪拌2h。將該反應冷卻至室溫,使用THF(20mL)稀釋,經過矽藻土過濾(先後使用60mL THF及100mL 20% MeOH-CH2Cl2清洗),並在真空中濃縮。將殘留物懸浮在CH2Cl2(25mL)中及藉由真空過濾(使用10mL CH2Cl2清洗)收集該固體以獲得粗製實例125A,其無需進一步純化即可使用。LC-MS m/z 414[M+H]+。
125B)N-(4-(7-氯-3-(6-(二氟甲基)吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向粗製實例125A含於THF(26.3mL)及DMF(26.3mL)之室溫溶液中逐滴添加碳酸銫(3.43g,10.53mmol),接著添加2-(三甲基矽烷基)
乙氧基甲基氯(1.400mL,7.89mmol)。於室溫攪拌該反應1h,及隨後其經EtOAc(400mL)稀釋,使用H2O及飽和NaCl水溶液(400mL)清洗,經Na2SO4乾燥、過濾、並在真空中濃縮。藉由急驟層析法(40g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得黃色發泡體之實例125B(620mg,經過兩個步驟為34%)。LC-MS m/z 544[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),8.50(d,J=5.1Hz,1H),8.43(dd,J=8.0,0.8Hz,1H),8.38(dd,J=5.1,0.7Hz,1H),8.22(s,1H),8.03(t,J=7.8Hz,1H),7.52(d,J=5.0Hz,1H),7.49(d,J=7.6Hz,1H),7.16(dd,J=5.1,1.5Hz,1H),6.45(t,J=55.1Hz,1H),5.65(s,2H),3.33-3.27(m,2H),2.07(s,3H),0.75-0.66(m,2H),-0.14(s,9H)。
125C)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-羥基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例125B(20mg,0.037mmol)及碳酸銫(35.9mg,0.110mmol)之混合物並使用N2回填,隨後添加1,4-二噁烷(331μL)及H2O(36.8μL)。使用N2噴射該混合物5min,隨後添加第二代XPhhos預觸媒(1.446mg,1.838μmol)。使用N2噴射該混合物1min,隨後將其密封並於100℃攪拌4h。添加額外Cs2CO3(36mg,0.11mmol)及H2O(74μL)並使用N2噴射該反應5min,隨後添加額外第二代XPhos預
觸媒(3mg,0.038mmol)。使用N2噴射該反應1min,隨後將其密封及於100℃攪拌20h。將該反應冷卻至室溫,使用EtOAc(25mL)稀釋,使用飽和NaCl水溶液(25mL)清洗,經Na2SO4乾燥,過濾,並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至10% EtOAc-CH2Cl2)純化該粗製材料以獲得白色固體之實例125C(5.9mg,31%)。LC-MS m/z 526[M+H]+。
125D)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-乙氧基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例125C(10.6mg,0.020mmol)含於1,4-二噁烷(202μL)之0℃溶液中逐滴添加三苯基膦(6.35mg,0.024mmol)及乙醇(23.55μL,0.403mmol),接著添加偶氮二甲酸二異丙酯(4.76μL,0.024mmol)。於室溫攪拌該反應30min,隨後於50℃攪拌1h。將該反應冷卻至室溫並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得黃色膜之實例125D(8.8mg,79%)。LC-MS m/z 554[M+H]+。
實例125)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例125D(8.8mg,0.016mmol)含於CH2Cl2(79μL)之室溫溶液中添加TFA(79μL)。於室溫攪拌透明黃色溶液1h。添加額外TFA(79μL)並於室溫攪拌該反應5h。在真空中濃縮該反應。將該殘留物溶於含於CH2Cl2(500μL)之10% 7N NH3/MeOH中,於室溫攪拌1h,並隨後在真空中濃縮。藉由急驟層析法(4g矽膠;線性梯度0至20% MeOH-CH2Cl2)純化該粗製材料以獲得白色固體之實例125(3.6mg,53%)。HPLC Rt=6.03min(Sunfire C18,3.0x150mm,3.5-μm粒子;5至95% MeCN-H2O及0.05% TFA在12min內;波長=220nm);LC-MS m/z 424[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.21(s,1H),10.47(s,1H),8.41(d,J=7.9Hz,1H),8.35-8.29(m,2H),8.26(d,J=5.1Hz,1H),8.03(t,J=7.8Hz,1H),7.50(d,J=7.6Hz,1H),7.22(dd,J=5.2,1.5Hz,1H),6.91(d,J=5.4Hz,1H),6.60(t,J=55.4Hz,1H),4.36(q,J=7.0Hz,2H),2.07(s,3H),1.49(t,J=7.0Hz,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[2-(吡咯啶-1-基)乙氧基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
126A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(2-(吡咯啶-1-基)乙氧基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例125C(21.3mg,0.041mmol)含於1,4-二噁烷(405μL)之0℃懸浮液中逐滴添加三苯基膦(13.82mg,0.053mmol)及2-(吡咯啶-1-基)乙醇(9.48μL,0.081mmol),接著添加偶氮二甲酸二異丙酯(10.37μL,0.053mmol)。於室溫攪拌該反應10min,隨後於50℃攪拌50min。將該反應冷卻至室溫並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)純化該粗製材料以獲得白色固體之實例126A(11.0mg,44%)。LC-MS m/z 623[M+H]+。
實例126)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[2-(吡咯啶-1-基)乙氧基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例126A(11.0mg,0.018mmol)含於CH2Cl2(58.9μL)之室溫溶液中添加TFA(118μL)。於室溫下攪拌該反應17h並接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,及隨後在真空中濃縮,溶於DMSO,過濾,並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在19分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得126(15.4mg)。HPLC Rt=0.818min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 493[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.43(s,1H),8.31(d,J=4.9Hz,1H),8.29-8.23(m,3H),8.02(t,J=8.0Hz,1H),7.51(d,J=8.0Hz,1H),7.22(d,J=5.2Hz,1H),6.91(d,J=5.3Hz,1H),6.61(dd,J=55.4,54.8Hz,1H),4.36(br t,J=5.3Hz,2H),2.99-2.94(m,2H),2.62-2.57(m,4H),2.04(s,3H),1.74-1.69(m,4H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙烯基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
127A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-7-乙烯基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例125B(307mg,0.564mmol)、乙烯基三氟硼酸鉀(113mg,0.846mmol)、及碳酸銫(552mg,1.693mmol)之混合物並使用N2回填,隨後添加1,4-二噁烷(5078μL)及H2O(564μL)。使用N2噴射該混合物5min,隨後添加第二代XPhos預觸媒(22.20mg,0.028mmol)。使用N2噴射該混合物1min,隨後將其密封並於80℃攪拌1h。將該反應冷卻至室溫,使用EtOAc(50mL)稀釋,使用飽和NaCl水溶液(50mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟層析法(24g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得黃色發泡體之實例127A(270mg,0.504mmol,89%)。LC-MS m/z 536[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.60(s,1H),8.56-8.50(m,2H),8.37(dd,J=5.0,0.7Hz,1H),8.22(s,1H),8.01(t,J=7.8Hz,1H),7.52(dd,J=17.3,10.9Hz,
1H),7.46(d,J=7.6Hz,1H),7.43(d,J=4.9Hz,1H),7.13(dd,J=5.1,1.5Hz,1H),6.41(t,J=55.4Hz,1H),6.04(dd,J=17.2,1.2Hz,1H),5.70-5.63(m,1H),5.39(s,2H),3.35-3.26(m,2H),2.07(s,3H),0.78-0.73(m,2H),-0.12(s,9H)。
實例127)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙烯基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例127A(17.1mg,0.032mmol)含於CH2Cl2(106μL)之室溫溶液中添加TFA(213μL)。於室溫攪拌該反應7h,並隨後在真空中濃縮。將該殘留物溶於含於CH2Cl2(500μL)之10% 7N NH3/MeOH中,於室溫攪拌1h,並隨後在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至20% MeOH-CH2Cl2)純化該粗製材料。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)再次純化所得材料以獲得白色固體之實例127(7.2mg,55%)。HPLC Rt=6.19min(Sunfire C18,3.0x150mm,3.5-μm粒子;5至95% MeCN-H2O及0.05% TFA在12min內;波長=220nm);LC-MS m/z 406[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.15(s,1H),10.52(s,1H),8.46(d,J=4.9Hz,1H),8.42(d,J=7.9Hz,1H),8.36-8.30(m,2H),8.05(t,J=7.8Hz,1H),7.54-7.50(m,2H),7.46(dd,J=17.6,11.0Hz,1H),7.27(dd,J=5.1,1.6Hz,1H),6.62(t,J=55.1Hz,1H),6.29(d,J=17.7Hz,1H),5.70(d,J=11.6Hz,1H),2.08(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例127A(37.2mg,0.069mmol)含於EtOH(694μL)之室溫溶液中添加10%碳載鈀(7.39mg,6.94μmol)及甲酸銨(43.8mg,0.694mmol)。於室溫攪拌該反應1h,隨後通過矽藻土(使用MeOH清洗)過濾並在真空中濃縮。將該材料溶於CH2Cl2(230μL)及TFA(460μL)之混合物中。於室溫攪拌該反應16h,並隨後在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌1h,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至100% B在19分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例128(28.6mg,定量,在兩步內)。HPLC Rt=1.062min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 408[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.05(s,1H),10.49(s,1H),8.37(d,J=4.7Hz,1H),8.32(d,J=7.9Hz,1H),8.30-8.27(m,2H),8.02(t,J=7.9Hz,1H),7.51(d,J=7.6Hz,1H),7.23(d,J=5.2Hz,1H),7.14(d,
J=4.7Hz,1H),6.61(t,J=55.3Hz,1H),2.99(q,J=7.6Hz,2H),2.06(s,3H),1.30(t,J=7.6Hz,3H)。
a HPLC條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm。
表5使用與用於製備實例127A及實例128之彼等相似之過程由實例125B及適當烯基频哪醇硼酸酯或三氟硼酸鉀製備表5中之實例131至134。交叉偶合反應使用介於60℃至100℃範圍內之溫度。氫化反應使
a HPLC條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(噁烷-4-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
及
N-{4-[3-(6-甲基吡啶-2-基)-7-(噁烷-4-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
135A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(3,6-二氫-2H-哌喃-4-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例125B(40mg,0.074mmol)、2-(3,6-二氫-2H-哌喃-4-基)-
4,4,5,5-四甲基-1,3,2-二氧硼(23.17mg,0.110mmol)、及碳酸銫(71.9mg,0.221mg)之混合物並使用N2回填,隨後添加1,4-二噁烷(662μL)及H2O(73.5μL)。使用N2噴射該混合物5min,隨後添加第二代XPhos預觸媒(2.89mg,3.68μmol)。使用N2噴射該混合物1min,隨後將其密封及於60℃攪拌2h。將該反應冷卻至室溫,使用EtOAc(25mL)稀釋,使用飽和NaCl水溶液(25mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得黃色發泡體之實例135A(40.2mg,92%)。LC-MS m/z 592[M+H]+。
實例135)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(噁烷-4-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺及實例136N-{4-[3-(6-甲基吡啶-2-基)-7-(噁烷-4-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例135A(40.2mg,0.068mmol)含於EtOH(697μL)之室溫懸浮液中添加THF(348μL),接著添加10%碳載鈀(7.23mg,6.79μmol)及甲酸銨(42.8mg,0.679mmol)。於室溫攪拌該反應15h,隨後於60℃持續1h,隨後於70℃持續2h。添加額外甲酸銨(22mg,0.35mmol)並於70℃攪拌該反應4h。將該反應冷卻至室溫,通過矽藻土(使用THF及MeOH清洗)過濾,並在真空中濃縮。將此材料溶於CH2Cl2(227μL)及TFA(453μL)之混合物中。於室溫攪拌該反應13h。添加額外TFA(0.453mL)並於室溫攪拌該反應27h,及隨後在真空中濃縮。將
該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:15至55% B在25分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份及藉由離心蒸發乾燥以獲得實例135(9.0mg,經過兩個步驟為29%)及實例136(7.7mg,經過兩個步驟為27%)。實例135之特徵數據:HPLC Rt=1.079min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 464;1H NMR(500MHz,DMSO-d6)δ 12.08(s,1H),10.52(s,1H),8.42(d,J=4.9Hz,1H),8.37(br d,J=7.7Hz,1H),8.32-8.28(m,2H),8.03(t,J=7.8Hz,1H),7.50(d,J=7.6Hz,1H),7.24(d,J=5.2Hz,1H),7.19(d,J=4.8Hz,1H),6.60(t,J=55.2Hz,1H),4.00(br d,J=10.8Hz,2H),3.64-3.46(m,3H),2.07(s,3H),1.85-1.77(m,4H)。針對實例136之特徵數據:HPLC Rt=0.826min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 428[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.90(br s,1H),10.43(s,1H),8.35(d,J=4.6Hz,1H),8.26(d,J=4.7Hz,1H),8.20(br s,1H),7.77-7.73(m,1H),7.68(t,J=7.7Hz,1H),7.19(br d,J=4.5Hz,1H),7.14(br d,J=4.5Hz,1H),7.08(br d,J=7.6Hz,1H),4.02-3.78(m,2H),3.63-3.45(m,3H),2.25(s,3H),2.06(s,3H),1.84-1.73(m,4H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(1-甲基哌啶-4-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
及
N-{4-[7-(1-甲基哌啶-4-基)-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用與用於製備實例135及實例136之彼等相似之過程由實例125B及1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1,2,3,6-四氫吡啶製備實例137及實例138。實例137之特徵數據:HPLC Rt=0.831min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 477[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.03(br s,1H),10.52(s,1H),8.43-8.37(m,2H),8.32-8.26(m,2H),8.02(t,J=7.9Hz,1H),7.50(d,J=7.7Hz,1H),7.24(d,J=5.0Hz,1H),7.16(d,J=4.7Hz,1H),6.59(t,J=55.3Hz,1H),3.30-3.20(m,1H),2.94(br d,J=11.4Hz,2H),2.25(s,3H),2.14(br t,J=11.0Hz,2H),2.07(s,3H),1.90-1.75(m,4H)。實例138之特徵數據:HPLC Rt=0.614min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 441[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.85(br s,1H),10.50(s,1H),8.37(d,J=4.6Hz,1H),8.31-8.26(m,2H),7.94(br d,J=7.7Hz,1H),7.69(t,J=7.7Hz,
1H),7.21(d,J=5.0Hz,1H),7.12(d,J=4.8Hz,1H),7.06(d,J=7.4Hz,1H),3.28-3.20(m,1H),2.94(br d,J=10.6Hz,2H),2.27-2.23(m,6H),2.13(br t,J=11.1Hz,2H),2.08(s,3H),1.88-1.74(m,4H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(4-甲基哌嗪-1-基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
排空實例125B(40mg,0.074mmol)、三氟((4-甲基哌嗪-1-基)甲基)硼酸鉀(24.27mg,0.110mmol)、及碳酸銫(71.9mg,0.221mmol)之混合物並使用N2回填,隨後添加THF(331μL)及H2O(36.8μL)。使用N2噴射該混合物5min,隨後添加第二代XPhos預觸媒(2.89mg,3.68μL)。使用N2噴射該混合物1min,隨後將其密封並於80℃攪拌1h。將該反應冷卻至室溫,使用EtOAc(25mL)稀釋,使用飽和NaCl水溶液(25mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。將此材料溶於CH2Cl2(247μL)及TFA(493μL)之混合物中。於室溫下攪拌該反應42h,隨後在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至100% B在20
分鐘內,隨後於100% B維持2分鐘;流速:20mL/min。合併含有期望產物之溶離份及藉由離心蒸發乾燥以獲得實例139(29.3mg,81%)。HPLC Rt=0.896min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 492[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.78(br s,1H),10.53(s,1H),8.43(d,J=4.7Hz,1H),8.39(br d,J=8.0Hz,1H),8.33(br s,1H),8.30(d,J=5.1Hz,1H),8.04(t,J=7.9Hz,1H),7.52(d,J=7.8Hz,1H),7.26-7.20(m,2H),6.62(t,J=55.2Hz,1H),3.89(s,2H),3.63-3.35(m,4H),2.46-2.29(m,4H),2.18(s,3H),2.07(s,3H)。
a HPLC條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
142A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-甲醯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例127A(187.8mg,0.351mmol)含於1,4-二噁烷(2805μL)之
室溫溶液中添加水(701μL)、2,6-二甲基吡啶(82μL,0.701mmol)、四氧化鋨(111μL,4重量%水溶液,0.018mmol)、及過碘酸鈉(300mg,1.402mmol)。於室溫攪拌該反應2h,並隨後使用H2O(30mL)稀釋並使用CH2Cl2(2×30mL)萃取。使用Na2SO4乾燥合併之有機層、過濾並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得黃色固體之實例142A(179mg,95%)。LC-MS m/z 538[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.64(s,1H),10.60(s,1H),8.81(d,J=4.6Hz,1H),8.47(dd,J=7.9,0.9Hz,1H),8.40(dd,J=5.1,0.7Hz,1H),8.23(s,1H),8.04(t,J=7.8Hz,1H),7.78(d,J=4.8Hz,1H),7.50(d,J=7.6Hz,1H),7.16(dd,J=5.1,1.5Hz,1H),6.46(t,J=55.3Hz,1H),5.68(s,2H),3.25-3.19(m,2H),2.08(s,3H),0.69-0.60(m,2H),-0.17(s,9H)。
實例142)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(19.3mg,0.036mmol)含於MeOH(359μL)之室溫溶液中添加硼氫化鈉(2.72mg,0.072mmol)。於室溫攪拌該反應30min,及隨後藉由添加H2O(20mL)淬冷並使用CH2Cl2(2×20mL)萃取。使用Na2SO4乾燥已合併之有機層,過濾並在真空中濃縮。將此材料溶於CH2Cl2(98μL)及TFA(196μL)之混合物中。於室溫攪拌該反應16h,並隨後在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10%
7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持4分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例142(8.6mg,71%)。HPLC Rt=0.882min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 410[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.02(br s,1H),10.48(s,1H),8.45(br d,J=4.6Hz,1H),8.29(br d,J=5.2Hz,1H),8.27-8.24(m,2H),8.02(t,J=7.9Hz,1H),7.52(d,J=7.6Hz,1H),7.34(br d,J=4.4Hz,1H),7.22(br d,J=5.2Hz,1H),6.63(t,J=55.5Hz,1H),5.73(br s,1H),4.92(s,2H),2.05(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(21.1mg,0.039mmol)含於THF(392μL)之0℃溶液中添加甲基溴化鎂(26.2μL,3M溶液含於Et2O中,0.078mmol)。於0℃攪拌該反應1h並隨後藉由添加H2O(25mL)淬冷及使用EtOAc(25
mL)萃取。使用飽和NaCl水溶液(25mL)清洗有機層,經Na2SO4乾燥、過濾並在真空中濃縮。將此材料溶於CH2Cl2(130μL)及TFA(260μL)之混合物中。於室溫下攪拌該反應3h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至100% B在20分鐘內,隨後於100% B維持2分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例143(8.3mg,50%)。HPLC Rt=1.007min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 424[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.88(s,1H),10.46(s,1H),8.43(d,J=4.7Hz,1H),8.30-8.24(m,3H),8.02(t,J=7.8Hz,1H),7.51(d,J=7.6Hz,1H),7.33(d,J=4.7Hz,1H),7.22(br d,J=4.9Hz,1H),6.60(t,J=55.2Hz,1H),5.74-5.69(m,1H),5.39-5.33(m,1H),2.05(s,3H),1.45(br d,J=6.4Hz,3H)。
表7使用與用於製備實例143之彼等相似之過程由實例142A及分別之異丙基溴化鎂及甲基-d3-碘化鎂製備表7中之實例144及實例145。
a HPLC條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1R)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
及
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1S)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(82.4mg,0.153mmol)含於THF(1533μL)之0℃溶液中添加甲基溴化鎂(102μL,3M溶液含於Et2O中,0.307mmol)。於0℃攪拌該反應1h,隨後藉由添加H2O(30mL)淬冷並使用EtOAc(30mL)萃取。使用飽和NaCl水溶液(30mL)清洗有機層,經Na2SO4乾燥、過濾並在真空中濃縮。將此材料溶於CH2Cl2(510μL)及TFA(1020μL)之混合物中。於室溫下攪拌該混合物5h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,及在真空中濃縮。通過具有如下條件之製備型SFC純化該粗製材料:管柱:Chiral AD-H 25x3cm ID,5-μm粒子;流動相75:25 CO2/MeOH;流速:85mL/min。合併含有峰1之溶離份並在真空中濃縮以獲得實例146(23.9mg,37%)。合併含有峰2之溶離份及在真空中濃縮以獲得實例147(24.0mg,35%)。隨意指定此等兩種對映異構體之立體化學。實例146之特徵數據:HPLC Rt=5.43min(Sunfire C18,3.0x150mm,3.5-μm粒子;5至95% MeCN-H2O及0.05% TFA在12min內;波長=220nm);LC-MS m/z 424[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.85(br s,1H),10.51(s,1H),8.45(d,J=4.8Hz,1H),8.43(d,J=7.9Hz,1H),8.34(s,1H),8.30(d,J=5.1Hz,1H),8.04(t,J=7.8Hz,1H),7.51(d,J=7.7Hz,1H),7.33(d,J=4.6Hz,1H),7.24(dd,J=5.2,1.5Hz,1H),6.61(t,J=55.0Hz,1H),5.54-5.48(m,1H),5.43-5.34
(m,1H),2.08(s,3H),1.47(d,J=6.5Hz,3H)。實例147之特徵數據:HPLC Rt=5.42min(Sunfire C18,3.0x150mm,3.5-μm粒子;5至95% MeCN-H2O及0.05% TFA在12min內;波長=220nm);LC-MS m/z 424[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.85(s,1H),10.51(s,1H),8.46(d,J=4.8Hz,1H),8.43(d,J=7.2Hz,1H),8.34(s,1H),8.30(d,J=5.1Hz,1H),8.04(t,J=7.8Hz,1H),7.51(d,J=7.6Hz,1H),7.34(d,J=4.8Hz,1H),7.24(dd,J=5.1,1.6Hz,1H),6.61(t,J=55.3Hz,1H),5.51(br d,J=4.2Hz,1H),5.42-5.35(m,1H),2.08(s,3H),1.47(d,J=6.5Hz,3H)。
N-{4-[7-(2,2-二氟-1-羥乙基)-3-[6-(二氟甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
148A)N-(4-(7-(2,2-二氟-1-羥乙基)-3-(6-(二氟甲基)吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例142A(19.9mg,0.037mmol)含於DMF(370μL)之室溫溶液中添加(二氟甲基)三甲基矽烷(9.19mg,0.074mmol),接著添加氟化銫(0.787mg,5.18μmol)。於室溫攪拌該反應21h,及隨後添加四丁基氟化銨(185μL,1M溶液含於THF中)及於室溫攪拌該反應1h。使用EtOAc(25mL)稀釋該反應,使用H2O(25mL)及飽和NaCl水溶液(25mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得白色膜之實例148A(9.5mg,44%)。LC-MS m/z 590[M+H]+。
實例148)N-{4-[7-(2,2-二氟-1-羥乙基)-3-[6-(二氟甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例148A(9.5mg,0.016mmol)含於CH2Cl2(53.7μL)之室溫溶液中添加TFA(107μL)。於室溫攪拌該反應18h並隨後在真空中濃
縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,及隨後在真空中濃縮,溶於DMSO,過濾並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:0至100% B在15分鐘內,隨後於100% B維持3分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例148(7.1mg,95%)。HPLC Rt=1.042min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 460[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.06(s,1H),10.46(s,1H),8.49(d,J=4.6Hz,1H),8.29(br d,J=5.1Hz,1H),8.27-8.23(m,2H),8.03(t,J=7.8Hz,1H),7.53(d,J=7.7Hz,1H),7.39(d,J=4.6Hz,1H),7.22(br d,J=4.5Hz,1H),6.76(br d,J=5.0Hz,1H),6.73-6.47(m,1H),6.32-6.05(m,1H),5.60-5.49(m,1H),2.05(s,3H)。
N-{4-[7-(二氟甲基)-3-[6-(二氟甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
向實例142A(20.9mg,0.039mmol)含於CH2Cl2(389μL)之0℃溶液中添加三氟化二乙胺基硫(7.70μL,0.058mmol)。於0℃攪拌該反應1h,隨後於室溫持續2h。使用飽和NaHCO3水溶液(25mL)稀釋並
經CH2Cl2(25mL)萃取。有機層經Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(130μL)及TFA(260μL)之混合物中。於室溫下攪拌該反應16h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:15至55% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例149(10.3mg,62%)。HPLC Rt=1.086min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 430[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.50(br s,1H),10.56(s,1H),8.63(br d,J=3.9Hz,1H),8.34-8.26(m,3H),8.06(br t,J=7.6Hz,1H),7.66-7.40(m,3H),7.27-7.20(m,1H),6.65(t,J=55.1Hz,1H),2.07(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(氟代甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
150A)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(羥甲基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例142A(20mg,0.037mmol)含於MeOH(372μl)之室溫溶液中添加硼氫化鈉(2.81mg,0.074mmol)。於室溫攪拌該反應15min,並隨後藉由添加H2O(20mL)淬冷並使用CH2Cl2(2×20mL)萃取。已合併之有機層經Na2SO4乾燥,過濾並在真空中濃縮。使用飽和NH4Cl水溶液(20mL)稀釋含水層並使用CH2Cl2(2×20mL)萃取。已合併之有機層經過Na2SO4乾燥,過濾及在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至10% MeOH-CH2Cl2)純化各個粗製單離物。合併獲自各個管柱之含產物溶離份以獲得白色發泡體之實例150A(18mg,90%)。LC-MS m/z 540[M+H]+。
實例150)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(氟代甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例150A(18mg,0.033mmol)含於CH2Cl2(334μl)之-78℃溶液中添加三氟化二乙胺基硫(6.61μL,0.050mmol)。於-78℃攪拌該反應10min,隨後於室溫攪拌該反應35min。使用飽和NaHCO3水溶液(25
mL)稀釋該反應並使用CH2Cl2(25mL)萃取。有機層經過Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(110μL)及TFA(220μL)之混合物中。於室溫下攪拌該混合物16h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,並通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:15至55% B在25分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例150(3.4mg,25%)。HPLC Rt=1.007min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 412[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.28(br s,1H),10.52(s,1H),8.52(d,J=4.5Hz,1H),8.35(br d,J=7.8Hz,1H),8.33-8.29(m,2H),8.05(t,J=7.8Hz,1H),7.54(d,J=7.7Hz,1H),7.34(br d,J=4.5Hz,1H),7.24(br d,J=5.0Hz,1H),6.63(t,J=55.2Hz,1H),5.87(d,J=46.9Hz,2H),2.07(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(甲胺基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(22.1mg,0.041mmol)含於DCE(411μL)之室溫溶液中添加甲基胺(123μL,2.0M溶液含於THF中,0.247mL),接著添加三乙醯氧基硼氫化鈉(13.94mg,0.066mmol)。於室溫攪拌該反應17h。添加額外三乙醯氧基硼氫化鈉(30mg,0.14mmol)及於室溫攪拌該反應3天。使用飽和NaHCO3水溶液(25mL)稀釋該反應並使用CH2Cl2(25mL)萃取。有機層經過Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(137μL)及TFA(273μL)之混合物中。於室溫下攪拌該反應2天且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮、溶於DMSO、過濾、及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:5至45% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥。通過具有如下條件之製備型LC/MS進一步純化該材料:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:5至35% B在25分鐘內,隨後於35% B維持2分鐘;流速:20mL/min合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例151(2.3mg,13%)。HPLC Rt=0.764min(Waters
Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 423[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.50(s,1H),8.43(d,J=4.8Hz,1H),8.36(d,J=8.1Hz,1H),8.30(d,J=4.9Hz,2H),8.04(t,J=7.9Hz,1H),7.52(d,J=7.8Hz,1H),7.28(d,J=4.7Hz,1H),7.24(d,J=5.0Hz,1H),6.75-6.47(m,1H),4.09(s,2H),2.35(s,3H),2.06(s,3H)。
N-(4-{7-[(3,3-二氟氮雜環丁-1-基)甲基]-3-[6-(二氟甲基)吡啶-2-基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(23.0mg,0.043mmol)含於DCE(428μL)之室溫溶液中添加3,3-二氟氮雜環丁烷鹽酸鹽(8.31mg,0.064mmol)及三乙胺(13.42μL,0.096mmol),接著添加三乙醯氧基硼氫化鈉(14.51mg,0.068mmol)。於室溫攪拌該反應16h,並隨後使用飽和NaHCO3水溶液(25mL)稀釋並使用CH2Cl2(25mL)萃取。有機層經過Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(143μL)及TFA(287μL)之混合物中。於室溫下攪拌該反應4天且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流
動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:20至60% B在19分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例152(8.7mg,42%)。HPLC Rt=1.113min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 485[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.03(br s,1H),10.50(s,1H),8.42(d,J=4.7Hz,1H),8.33(br d,J=8.1Hz,1H),8.31-8.27(m,2H),8.03(t,J=7.8Hz,1H),7.51(d,J=7.6Hz,1H),7.27-7.22(m,2H),6.61(t,J=55.2Hz,1H),4.13(s,2H),3.76-3.68(m,4H),2.06(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(3-羥基氮雜環丁-1-基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例142A(19.4mg,0.036mmol)含於DCE(361μL)之室溫溶液中添加氮雜環丁-3-醇鹽酸鹽(5.93mg,0.054mmol),接著添加三乙胺(11.32μL,0.081mmol)及三乙醯氧基硼氫化鈉(12.24mg,0.058mmol)。於室溫攪拌該反應16h,並隨後使用飽和NaHCO3水溶液(25mL)稀釋並使用CH2Cl2(25mL)萃取。有機層經過Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(120μL)及TFA(240μL)之混合
物中。於室溫下攪拌該混合物2天且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:waters xbridge shield rp18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至35% B在25分鐘內,隨後於35% B維持2分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥。通過具有如下條件之製備型LC/MS進一步純化該材料:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:0至45% B在20分鐘內,隨後於100% B維持3分鐘;流速:20mL/min。合併含有期望產物之溶離份及藉由離心蒸發乾燥以獲得實例153(0.7mg,4%)。HPLC Rt=0.944min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 465[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.95(br s,1H),10.54(s,1H),8.44-8.39(m,2H),8.34-8.29(m,2H),8.04(t,J=7.9Hz,1H),7.52(d,J=7.3Hz,1H),7.24(d,J=5.2Hz,1H),7.20(d,J=4.6Hz,1H),6.62(t,J=55.4Hz,1H),5.40(br s,1H),4.30-4.22(m,1H),4.05-3.97(m,2H),3.68-3.57(m,2H),2.97-2.86(m,2H),2.08(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(2-羥基丙-2-基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
154A)N-(4-(7-乙醯基-3-(6-(二氟甲基)吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例142A(50.3mg,0.094mmol)含於THF(936μL)之0℃溶液中逐滴添加甲基溴化鎂(62.4μl,3M溶液含於Et2O中,0.187mmol)。於0℃攪拌該反應30min,隨後藉由添加H2O(30mL)淬冷並使用EtOAc(30mL)萃取。使用飽和NaCl水溶液(30mL)清洗有機層,經Na2SO4乾燥,過濾,並在真空中濃縮。將此材料溶於CH2Cl2(889μL),並添加戴斯-馬丁(Dess-Martin)高碘烷(45.2mg,0.107mmol)。於室溫攪拌該反應30min,隨後使用CH2Cl2(25mL)稀釋,使用飽和NaHCO3水溶液(25mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟層析法(12g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得白色發泡體之實例154A(44.5mg,91%)。LC-MS m/z 552[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.61(s,1H),8.71(d,J=4.9Hz,1H),8.49(d,J=7.9Hz,1H),8.38(d,
J=5.0Hz,1H),8.17(s,1H),8.03(t,J=7.9Hz,1H),7.70(d,J=4.8Hz,1H),7.48(d,J=7.6Hz,1H),7.15(dd,J=5.1,1.4Hz,1H),6.45(t,J=55.1Hz,1H),5.28(s,2H),3.05-2.96(m,2H),2.72(s,3H),2.07(s,3H),0.60-0.53(m,2H),-0.17(s,9H)。
實例154)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(2-羥基丙-2-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例154A(27.2mg,0.049mmol)含於THF(493μL)之0℃溶液中逐滴添加甲基溴化鎂(32.9μL,3M溶液含於Et2O中,0.099mmol)。於0℃攪拌該反應1.25h,隨後添加額外甲基溴化鎂(17μL,0.051mmol)並於0℃攪拌該反應15min。添加額外甲基溴化鎂(17μL,0.051mmol)並於0℃攪拌該反應15min。藉由添加H2O(30mL)淬冷該反應並使用EtOAc(30mL)萃取。使用飽和NaCl水溶液(30mL)清洗有機層,經Na2SO4乾燥、過濾並在真空中濃縮。將此材料溶於CH2Cl2(163μL)及TFA(327μL)之混合物中。於室溫下攪拌該反應15h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge Phenyl,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:20至45% B在
25分鐘內,隨後於45% B維持2分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例154(7.9mg,37%)。HPLC Rt=1.021min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 438[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.07(s,1H),10.48(s,1H),8.40(d,J=4.8Hz,1H),8.30(d,J=7.9Hz,1H),8.28-8.25(m,2H),8.02(t,J=7.8Hz,1H),7.51(d,J=7.7Hz,1H),7.23-7.18(m,2H),6.61(t,J=55.3Hz,1H),5.83(s,1H),2.06(s,3H),1.64(s,6H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(2-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
155A)(E)-N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(2-乙氧基乙烯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
排空實例125B(90.0mg,0.165mmol)及碳酸銫(216mg,0.662mmol)之混合物並使用N2回填,隨後添加1,4-二噁烷(1489μL)及H2O(165μL)。使用N2噴射該混合物5min,隨後添加第二代XPhos預觸媒(6.51mg,8.27μmol)及(E)-2-(2-乙氧基乙烯基)-4,4,5,5-四甲基-1,3,2-二氧硼(98mg,0.496mmol)。使用N2噴射該混合物1min,隨後將其密封並於80℃攪拌1h。將該反應冷卻至室溫,使用EtOAc(30mL)稀釋,使用飽和NaCl水溶液(30mL)清洗,經Na2SO4乾燥、過濾並在真空中濃縮。藉由急驟層析法(24g矽膠及5g預填充加載濾芯;線性梯度0至100% EtOAc-CH2Cl2)純化該粗製材料以獲得淺黃色固體之實例155A(67.2mg,70%)。LC-MS m/z 580[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),8.52(d,J=8.1Hz,1H),8.40(d,J=4.9Hz,1H),8.35(d,J=5.1Hz,1H),8.23(s,1H),8.00(t,J=7.9Hz,1H),7.44(d,J=7.7Hz,1H),7.40(d,J=12.7Hz,1H),7.30(d,J=5.0Hz,1H),7.11(dd,J=5.1,1.5Hz,1H),6.57-6.26(m,2H),5.40(s,2H),4.02(q,J=7.0Hz,2H),3.37-3.32(m,2H),2.07(s,3H),1.31(t,J=7.0Hz,3H),0.85-0.75(m,2H),-0.09(s,9H)。
實例155)N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(2-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
攪拌實例155A(66mg,0.114mmol)含於CH2Cl2(379μL)及TFA(759μL)之混合物的室溫懸浮液6h,隨後添加H2O(5滴)及攪拌該反應16h。在真空中濃縮該反應。將該殘留物溶於CH2Cl2(20mL)並使用飽和NaHCO3水溶液(20mL)清洗。使用CH2Cl2(2×20mL)萃取水層。已合併之有機層經Na2SO4乾燥,過濾並在真空中濃縮。將此材料溶於MeOH(1140μL)中並添加硼氫化鈉(8.63mg,0.228mmol)。於室溫攪拌該反應15min,隨後使用飽和NH4Cl水溶液(25mL)稀釋並使用CH2Cl2(2×20mL)萃取。已合併之有機層經Na2SO4乾燥,過濾及在真空中濃縮。將該粗製材料溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:5至45% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例155(4.9mg,10%)。HPLC Rt=0.929min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及0.1% TFA在3min內;波長=220nm);LC-MS m/z 424[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.04(br s,1H),10.52(s,1H),8.39-8.33(m,2H),8.32-8.28(m,2H),8.03(t,J=7.7Hz,1H),7.52(d,J=7.6Hz,1H),7.24(br d,J=5.0Hz,1H),7.16(br d,J=4.7Hz,
1H),6.63(t,J=55.5Hz,1H),4.86(br s,1H),3.83-3.77(m,2H),3.15(br t,J=6.6Hz,2H),2.07(s,3H)。
N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(吡咯啶-1-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺
向實例125B(20mg,0.037mmol)含於DMF(184μL)之室溫溶液中添加吡咯啶(61.4μL,0.735mmol)。密封該反應並於110℃攪拌6h,並隨後將其冷卻至室溫,使用EtOAc(25mL)稀釋,使用H2O(25mL)及飽和NaCl水溶液(25mL)清洗,經Na2SO4乾燥、過濾,並在真空中濃縮。將此材料溶於CH2Cl2(123μL)及TFA(247μL)之混合物中。於室溫下攪拌該反應22h且接著在真空中濃縮。將該殘留物溶於含於CH2Cl2(2mL)之10% 7N NH3/MeOH中,於室溫攪拌5min,在真空中濃縮,溶於DMSO,過濾,及通過具有如下條件之製備型LC/MS純化:管柱:XBridge Shield RP18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:15至55% B在20分鐘內,隨後於100% B維持4分鐘;流速:20mL/min。合併含有期望產物之溶離份並藉由離心蒸發乾燥以獲得實例156(3.6mg,21%)。HPLC Rt=1.252min(Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;5至95% MeCN-H2O及
0.1% TFA在3min內;波長=220nm);LC-MS m/z 449[M+H]+;1H NMR(500MHz,DMSO-d6)δ 12.00(br s,1H),10.50(br s,1H),8.35-8.26(m,2H),7.91-7.83(m,1H),7.81-7.75(m,1H),7.47-7.32(m,2H),7.26(br d,J=4.7Hz,1H),7.24-6.97(m,1H),6.32(br d,J=6.2Hz,1H),3.49-3.30(m,4H),2.07(s,3H),2.02-1.98(m,4H)。
N-(4-(6-乙醯胺基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
157A)N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌實例83(765mg,1.745mmol)、碳酸銫(1137mg,3.49mmol)及(2-(氯代甲氧基)乙基)三甲基矽烷(437mg,2.62mmol)含於THF(12mL)及DMF(12mL)之混合物30min。向該反應混合物中添加CH2Cl2及水,分離CH2Cl2層,經MgSO4乾燥,在真空中濃縮及藉由
SiO2急驟管柱(梯度100% CH2Cl2至80% EtOAc在CH2Cl2中,產物於含於CH2Cl2之30至40% EtOAc中洗脫)純化該殘留物以獲得玻璃質材料之6(625mg,1.099mmol,63%)。MS(ES):m/z=568,570[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.65(d,J=2.0Hz,1H),8.33(s,1H),8.28-8.24(m,2H),8.05(d,J=2.0Hz,1H),7.80(d,J=8.6Hz,1H),7.30(dd,J=8.7,3.0Hz,1H),7.14(dd,J=5.2,1.4Hz,1H),5.43(s,2H),3.85(s,3H),3.42-3.36(m,2H),2.19(s,3H),0.85-0.80(m,2H),-0.08(s,9H)。
實例157)N-(4-(6-乙醯胺基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(40mg,0.070mmol)含於二噁烷(2mL)之溶液中添加乙醯胺(41.6mg,0.704mmol)、氧雜蒽膦(8.14mg,0.014mmol)、碳酸銫(45.8mg,0.141mmol)及Pd2(dba)3(12.89mg,0.014mmol)。使用氮氣沖洗該懸浮液5分鐘並加熱至110℃持續1小時。將該反應混合物濃縮至乾燥並再次懸浮於1mL EtOAc中及通過小矽膠塞過濾,先後使用EtOAc及Hex:EtOAc(1:1)洗脫。濃縮EtOAc溶離份以獲得粗產物,於60℃用含於二噁烷(1.5mL)之4N HCl處理粗產物30分鐘。將該反應混合物濃縮、經DMF稀釋並藉由製備型HPLC純化以獲得N-(4-(6-乙醯胺基-3-
(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=417[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.50(s,1H),10.27(s,1H),8.42-8.45(m,1H),8.43(s,1H),8.40(s,1H),8.27(br.s.,1H),8.24(d,J=5.05Hz,1H),8.18(d,J=1.60Hz,1H),7.93(d,J=8.58Hz,1H),7.48(dd,J=2.19,8.50Hz,1H),7.10(d,J=4.88Hz,1H),3.85(s,3H),2.10(s,3H),2.08(s,3H)。
N-(4-(6-(4-甲氧基哌啶-1-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例157A(30mg,0.053mmol)含於DMSO(2mL)之溶液中添加(S)-吡咯啶-2-羧酸(6.68mg,0.058mmol)、K2CO3(14.59mg,0.106mmol)、4-甲氧基哌啶(42.5mg,0.369mmol)及碘化銅(I)(5.33mg,0.028mmol)。使用氮氣沖洗該反應混合物2min,並於100℃攪拌3h。在氮氣流下將該反應混合物濃縮至乾燥並於60℃使用含於二噁烷(3mL)之4N HCl處理30分鐘。濃縮該反應混合物並再次溶於DMF及藉由製備型HPLC純化以獲得N-(4-(6-(4-甲氧基哌啶-1-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.92min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):
m/z=473[M+H]+;1H NMR(500MHz,DMSO-d6)d 12.66(br.s.,1H),10.71(br.s.,1H),8.42(s,1H),8.40(d,J=5.55Hz,1H),8.34(br.s.,1H),8.30(br.s.,1H),7.81(br.s.,1H),7.43-7.59(m,2H),7.10-7.31(m,H),3.89(s,3H),3.51-3.67(m,J=5.39Hz,2H),3.42(br.s.,1H),3.11(t,J=9.47Hz,2H),3.10(s,3H)2.10(s,3H),2.00(br.s.,2H),1.55-1.72(m,2H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
N-(4-(3-(5-甲氧基吡啶-2-基)-6-(吡咯啶-1-基)-1H-吡咯并[3,2-b]
吡啶-2-基)吡啶-2-基)乙醯胺
167A)2-(2-乙醯胺基吡啶-4-基)-3-(5-甲氧基吡啶-2-基)-6-(吡咯啶-1-基)-1H-吡咯并[3,2-b]吡啶-1-羧酸第三丁酯
向實例83(100mg,0.228mmol)及DMAP(5.57mg,0.046mmol)含於THF(3mL)之懸浮液中添加二羧酸二第三丁酯(100mg,0.456mmol)。於室溫下攪拌該反應混合物過夜。使用水(10mL)稀釋該反應混合物並使用EtOAc(3x10ml)萃取。合併有機物,經硫酸鈉乾燥,過濾並濃縮以獲得按原樣用於下一反應之透明黃油2-(2-乙醯胺基吡啶-4-基)-3-(5-甲氧基吡啶-2-基)-6-(吡咯啶-1-基)-1H-吡咯并[3,2-b]吡啶-1-羧酸第三丁酯。HPLC:RT=3.11min(MeOH/H2O及0.1% TFA,管柱:Sun-Fire 5u 4.6x30mm,1.7-μm粒子,梯度=4min,波長=220nm);MS(ES):m/z=529[M+H]+。
實例167)N-(4-(3-(5-甲氧基吡啶-2-基)-6-(吡咯啶-1-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向2-(2-乙醯胺基吡啶-4-基)-6-溴-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-1-羧酸第三丁酯(20mg,0.037mmol)含於DMSO(2mL)之溶液中添加(S)-吡咯啶-2-羧酸(4.70mg,0.041mmol)、K2CO3(10.27mg,0.074mmol)、吡咯啶(13.21mg,0.186mmol)及碘化銅(I)(3.75mg,0.020mmol)。使用氮氣沖洗該反應混合物2min,及週末於90℃攪拌。在反應期間,Boc基團脫離以獲得期望產物。過濾該反應混合物並藉由製備型HPLC純化以獲得N-(4-(3-(5-甲氧基吡啶-2-基)-6-(吡咯啶-1-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.01min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=429[M+H]+。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
N-(4-(6-氯-3-(4-(二氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
172A)2-溴-4-(二氟甲基)噻唑
在氮氣氛圍下向2-溴代噻唑-4-甲醛(0.3g,1.562mmol)含於DCM(10mL)之溶液中逐滴添加DAST(0.826mL,6.25mmol)。於室溫攪拌該反應混合物過夜及隨後經EtOAc(10mL)稀釋及經逐滴添加MeOH(1mL)淬冷直至停止起泡。使用K3PO4水溶液清洗該反應混合物。使用鹽水清洗有機相,經硫酸鎂乾燥,過濾並在減壓下濃縮以獲得淺黃色油,其藉由矽膠急驟層析法純化,經0至50%乙酸乙酯之己烷溶液洗脫以獲得黃色油之2-溴-4-(二氟甲基)噻唑(0.2g,0.934mmol,59.8%產率)。1H NMR(400MHz,甲醇-d4)δ ppm 7.92(t,J=1.5Hz,1H),6.75(t,J=54.6Hz,1H),未顯示LCMS下之[M+H]+。
實例172)N-(4-(6-氯-3-(4-(二氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用氮氣沖洗實例41B(54mg,0.141mmol)、2-溴-4-(二氟甲基)噻唑(60.4mg,0.282mmol)及Cs2CO3(69.0mg,0.212mmol)含於乙腈(2mL)之混合物數分鐘。添加XPhos(6.73mg,0.014mmol)及Pd2(dba)3(3.88mg,4.23μmol)及於120℃在密封瓶中加熱該混合物1h。將該反應混合物冷卻、過濾並藉由製備型HPLC純化以獲得N-(4-(6-氯-3-(4-(二氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.42min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=420[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.63(s,1H),8.57(d,J=1.94Hz,1H),8.53(s,1H),8.40(d,J=5.13Hz,1H),8.10(s,1H),8.04(d,J=1.85Hz,1H),7.49(d,J=5.13Hz,1H),6.99(t,J=54.95Hz,1H),6.57(s,1H),2.10(s,3H)。
N-(4-(3-(6-甲氧基吡啶-3-基)-6-甲基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
173A)N-(4-((3-胺基-5-甲基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由針對實例1C顯示之方法由實例1B及2-溴-5-甲基吡啶-3-胺製備N-(4-((3-胺基-5-甲基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺。HPLC:RT=0.49min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=267[M+H]+;1H NMR(400MHz,DMSO-d6)δ 10.58(s,1H),8.33(dd,J=0.77,5.17Hz,1H),8.21(s,1H),7.64-7.71(m,1H),7.32(dd,J=1.54,5.06Hz,1H),6.93(dd,J=0.88,1.76Hz,1H),5.72(s,2H),2.20(s,3H),2.11(s,3H)。
173B)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-甲基吡啶3-基)-2,2,2-三氟乙醯胺
藉由針對實例1D顯示之方法製備N-(2-((2-乙醯胺基吡啶-4-基)乙
炔基)-5-甲基吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.72min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=363[M+H]+。
實例173)N-(4-(3-(6-甲氧基吡啶-3-基)-6-甲基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例172顯示之一般方法由N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-甲基吡啶-3-基)-2,2,2-三氟乙醯胺及5-碘-2-甲氧基吡啶製備N-(4-(3-(6-甲氧基吡啶-3-基)-6-甲基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374;1H NMR(500MHz,DMSO-d6)δ ppm 11.85(s,1H),10.50(s,1H),8.28(d,J=5.19Hz,1H),8.24(s,2H),8.19(d,J=1.83Hz,1H),7.75(dd,J=2.29,8.39Hz,1H),7.65(s,1H),7.09(d,J=5.19Hz,1H),6.84(d,J=8.24Hz,1H),3.85(s,3H),2.42(s,3H),2.06(s,3H)。
N-(4-(3-(6-(二氟甲氧基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例172顯示之方法由實例1D及2-溴-6-(二氟甲氧基)吡啶製備N-(4-(3-(6-(二氟甲氧基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.93min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=396;1H NMR(500MHz,DMSO-d6)δ ppm 12.26(s,1H),10.63(s,1H),8.52(d,J=4.12Hz,1H),8.35-8.45(m,2H),8.25(s,1H),7.99(t,J=7.87Hz,1H),7.91(d,J=7.91Hz,1H),7.31(dd,J=4.59,8.20Hz,1H),7.26(d,J=4.38Hz,1H),6.87(d,J=7.99Hz,1H),6.65(t,J=73.55Hz,1H),2.09(s,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm
N-(4-(3-(5-氯代噻唑-2-基)-6-氟-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用氮氣沖洗實例38B(42mg,0.109mmol)、2-溴-5-氯代噻唑(43.3mg,0.218mmol)及Cs2CO3(53.4mg,0.164mmol)含於乙腈(2mL)之混合物數分鐘。添加Xphos-Pd-G2(4.30mg,5.46μmol)及於120℃在密封瓶中加熱該反應混合物1h。將該反應混合物冷卻、過濾並藉由製備型HPLC純化以獲得N-(4-(3-(5-氯代噻唑-2-基)-6-氟-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.34min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=388[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.64(s,1H),8.57(s,1H),8.45(s,1H),8.41(d,J=4.88Hz,1H),7.84(d,J=9.26Hz,1H),7.71(s,1H),7.48(d,J=4.96Hz,1H),2.11(s,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
N-(4-(7-甲基-3-(4-(三氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
212A)N-(4-((4-甲基-3-硝基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由針對實例1C顯示之方法由實例1B及2-溴-4-甲基-3-硝基吡啶製備N-(4-((4-甲基-3-硝基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺。HPLC:RT=0.65min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=297[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.72(s,1H),8.73(d,J=5.06Hz,1H),8.41(dd,J=0.66,5.06Hz,1H),8.20(s,1H),7.68(dd,J=0.66,5.06Hz,1H),7.22(dd,J=1.54,5.06Hz,1H),2.41(s,3H),2.12(s,3H)。
212B)N-(4-((3-胺基-4-甲基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
向N-(4-((4-甲基-3-硝基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(2g,6.75mmol)含於(10:1)EtOH:H2O(110ml)之溶液中添加鐵(1.885g,
33.8mmol)及氯化銨(3.61g,67.5mmol及於70℃加熱該反應混合物2h。將該反應混合物冷卻、使用矽藻土攪拌30min並隨後過濾。使用10% MeOH之DCM溶液清洗該濾餅並濃縮該濾液以獲得淺棕色固體,在使用10至15% MeOH之DCM溶液洗脫的短矽膠塞上將其純化以產生淺黃色固體之N-(4-((3-胺基-4-甲基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(1.7g,6.38mmol,95%產率)。HPLC:RT=0.48min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=267[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.61(br.s.,1H),8.35(d,J=4.62Hz,1H),8.23(s,1H),7.75(d,J=4.40Hz,1H),7.23(br.s.,1H),7.06(d,J=3.96Hz,1H),5.55(br.s.,2H),2.14-2.26(m,3H),2.17(s,3H),2.12(s,3H)。
212C)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲基吡啶-3-基)-2,2,2-三氟乙醯胺
藉由針對實例1D顯示之方法由N-(4-((3-胺基-4-甲基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺製備N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲基吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.67min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.8min,波長=220nm);MS(ES):m/z=363[M+H]+,1H NMR(400MHz,DMSO-d6)δ ppm 11.52(s,1H),10.66(s,1H),8.51(d,J=4.84Hz,1H),8.39(dd,J=0.88,5.06Hz,1H),8.22(s,1H),7.50(dd,J=0.55,4.95Hz,1H),7.14(dd,J=1.54,5.06Hz,1H),2.26(s,3H),2.12(s,3H)。
實例212)N-(4-(7-甲基-3-(4-(三氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲基吡啶-3-基)-2,2,2-三氟乙醯胺(40mg,110mmol)及2-溴-4-(三氟甲基)噻唑(51.2mg,0.221mmol)含於DMF(2mL)之溶液中添加Cs2CO3(53.4mg,0.164mmol)並使用氮氣沖洗該反應混合物數分鐘。添加Xphos-Pd-G2(4.30mg,5.46μmol)及於120℃在密封瓶中加熱該反應混合物1h。將該反應混合物冷卻、過濾及藉由製備型HPLC純化以獲得N-(4-(7-甲基-3-(4-(三氟甲基)噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.09min(H2O/ACN及0.1% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm)。MS(ES):m/z=418[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.43(s,1H),10.60(s,1H),8.46(br.s.,1H),8.44(d,J=4.71Hz,1H),8.40(d,J=5.05Hz,1H),8.36(s,1H),7.46(d,J=4.96Hz,1H),7.18(d,J=4.63Hz,1H),2.60(s,3H),2.09(s,3H)。
N-(4-(7-(二氟甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
213A)(3-胺基-2-氯代吡啶-4-基)甲醇
在氮氣氛圍下,於-20℃下向3-胺基-2-氯代異煙鹼酸甲酯(0.4g,2.144mmol)含於THF(5mL)之溶液中添加LAH(2.57mL,2.57mmol)。隨後於0℃攪拌該混合物30min。添加氯化銨(200mg)並在攪拌15min後將矽膠(3mL)添加至該反應混合物並在真空中濃縮。以乾燥形式將該粗產物負載於在3mL矽膠塞上及使用10% MeOH之DCM溶液洗脫以獲得白色片狀固體之(3-胺基-2-氯代吡啶-4-基)甲醇(290mg,1.829mmol,85%產率)。HPLC:RT=0.44min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=159[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 7.61(d,J=4.6Hz,1H),7.18(d,J=4.6Hz,1H),5.40(t,J=5.5Hz,1H),5.24(s,2H),4.43(d,J=5.5Hz,2H)。
213B)3-胺基-2-氯代異煙鹼醛
向(3-胺基-2-氯代吡啶-4-基)甲醇(0.5g,3.15mol)含於THF(31.5
ml)、DCM(31.5ml)之溶液中添加戴斯-馬丁高碘烷(2.006g,4.73mmol)。在室溫下攪拌將混合物1小時。使用EtOAc(30mL)稀釋該反應混合物及倒入含有Na2S2O3(0.4g)之飽和NaHCO3水溶液。攪拌該混合物30min並隨後使用EtOAc(10mL)稀釋。分離有機層並使用水清洗,隨後使用鹽水清洗,乾燥並蒸發。藉由矽膠急驟層析法(12g管柱,EtOAc/DCM=0-100%)純化該粗產物以產生黃色固體3-胺基-2-氯代異煙鹼醛(260mg,1.661mmol,52.7%產率)。HPLC:RT=0.61min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=157[M+H]+;1H NMR(400MHz,氯仿-d)δ 9.97(s,1H),7.87(d,J=5.1Hz,1H),7.36(d,J=4.8Hz,1H)。
213C)2-氯-4-(二氟甲基)吡啶-3-胺
根據針對實例173A顯示之方法由3-胺基-2-氯代異煙鹼醛製備2-氯-4-(二氟甲基)吡啶-3-胺。HPLC:RT=0.68min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=179.0,181.0[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 7.87(d,J=4.8Hz,1H),7.15(d,J=4.8Hz,1H),6.63(t,J=54.8Hz,1H),4.58(br.s.,2H)。
213D)N-(4-((3-胺基-4-(二氟甲基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
向2-氯-4-(二氟甲基)吡啶-3-胺(0.1g,0.560mmol)含於MeCN(5.60mL)之溶液中添加K2CO3(0.232g,1.680mmol)。在該混合物中吹入氬氣5分鐘,隨後添加PdCl2(dppf)(0.020g,0.028mmol)。在於室溫攪拌20min後,添加實例1B(0.135g,0.840mmol)及使用氬氣沖洗該反應混合物隨後於80℃加熱5h。濃縮該反應混合物,懸浮在10% MeOH之DCM溶液中並過濾。濃縮該濾液及藉由矽膠急驟層析法(4g管柱,0至100%梯度;溶劑A=DCM;溶劑B:20% MeOH之DCM溶液)純化以獲得N-(4-((3-胺基-4-(二氟甲基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(100mg,0.331mmol,59.1%產率)。HPLC:RT=0.63min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=303.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.62(s,1H),8.37(dd,J=0.88,5.06Hz,1H),8.27(s,1H),7.94(d,J=4.84Hz,1H),7.38(dd,J=1.32,5.06Hz,1H),7.33(d,J=4.84Hz,1H),7.12(t,J=54.40Hz,1H),6.04(s,2H),2.12(s,3H)。
213E)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(二氟甲基)吡啶-3-基)-2,2,2-三氟乙醯胺
使用與實例1D相似之方法由實例213D製備N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(二氟甲基)吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.73min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=399[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 8.76(d,J=5.1Hz,1H),8.58(br.s.,1H),8.36(s,1H),8.30(dd,J=5.2,0.8Hz,1H),7.99(br.s.,1H),7.62(d,J=5.1Hz,1H),7.14(dd,J=5.1,1.3Hz,1H),6.86(t,J=53.9Hz,1H),2.24(s,3H)。
實例213)N-(4-(7-(二氟甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用針對實例212顯示之一般方法由N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(二氟甲基)吡啶-3-基)-2,2,2-三氟乙醯胺基及5-溴-2-甲氧基吡啶製備N-(4-(7-(二氟甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.89min(H2O/ACN及0.1% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度
=3min,波長=220nm)。MS(ES):m/z=410[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.59(s,1H),8.54(d,J=4.46Hz,1H),8.33(d,J=5.13Hz,1H),8.27(s,1H),8.19(s,1H),7.76(d,J=8.50Hz,1H),7.44(d,J=4.38Hz,1H),7.49(t,J=54.40Hz,1H),7.14(d,J=5.05Hz,1H),6.86(d,J=8.58Hz,1H),3.85(s,3H),2.07(s,3H)。
N-(4-(7-(羥甲基)-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
214A)N-(4-((3-胺基-4-(羥甲基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
根據用於實例213D之過程由(3-胺基-2-氯代吡啶-4-基)甲醇及實例1B製備N-(4-((3-胺基-4-(羥甲基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺。HPLC:RT=0.45min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=283[M+H]+;1H NMR(400MHz,甲醇-d4)δ
ppm 8.32(dd,J=0.66,5.06Hz,1H),8.29(s,1H),7.87(d,J=4.84Hz,1H),7.30(dd,J=1.43,5.17Hz,1H),7.27(d,J=4.62Hz,1H),4.62(s,2H),2.19(s,3H)。
214B)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(羥甲基)吡啶-3-基)-2,2,2-三氟乙醯胺
使用與實例1D相似之方法製備N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(羥甲基)吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.58min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=389[M+H]+。
實例214)N-(4-(7-(羥甲基)-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例212顯示之方法由實例214B及2-溴-4-甲基噻唑製備實例214。HPLC:RT=0.80min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.62(s,1H),8.54(d,J=4.80Hz,1H),8.48(s,1H),8.41
(d,J=4.96Hz,1H),7.39-7.49(m,2H),7.21(s,1H),4.95(s,2H),2.32(s,3H),2.11(s,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:UV於220nm。
N-(4-(7-(1-羥乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
230A)1-(3-胺基-2-氯代吡啶-4-基)乙醇
向1-(3-胺基-2-氯代吡啶-4-基)乙酮(0.5g,2.93mmol)含於無水甲醇(20mL)之溶液中添加NaBH4(0.222g,5.86mmol)。於室溫攪拌該混合物2h隨後使用冷水(約1mL)淬冷並濃縮。在用5% MeOH之DCM溶液洗脫之短沖矽膠塞上純化該粗產物以產生黃色油1-(3-胺基-2-氯
代吡啶-4-基)乙醇(0.46g,2.66mmol,91%產率)。HPLC:RT=0.49min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=173[M+H]+;1H NMR(400MHz,甲醇-d4)δ ppm 7.62(d,J=5.1Hz,1H),7.16(d,J=4.8Hz,1H),4.92(q,J=6.5Hz,1H),1.46(d,J=6.6Hz,3H)。
230B)N-(4-((3-胺基-4-(1-羥乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
根據213D中之過程由1-(3-胺基-2-氯代吡啶-4-基)乙醇及實例1B製備N-(4-((3-胺基-4-(1-羥乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺。HPLC:RT=0.48min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.6min,波長=220nm);MS(ES):m/z=297[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.60(s,1H),8.35(dd,J=0.66,5.06Hz,1H),8.24(s,1H),7.85(d,J=4.62Hz,1H),7.34(dd,J=1.32,5.06Hz,1H),7.20(d,J=4.62Hz,1H),5.56(s,2H),5.47(d,J=4.18Hz,1H),4.88(dq,J=4.40,6.38Hz,1H),2.12(s,3H),1.32(d,J=6.38Hz,3H)。
230C)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-羥乙基)吡啶-3-基)-2,2,2-三氟乙醯胺
根據在實例1D中之過程由N-(4-((3-胺基-4-(1-羥乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(230B)製備N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-羥乙基)吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.61min(H2O/ACN及0.05% TFA,Waters Acquity SDS BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.6min,波長=220nm);MS(ES):m/z=393[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.52(s,1H),10.66(s,1H),8.64(d,J=5.1Hz,1H),8.39(dd,J=5.1,0.7Hz,1H),8.21(s,1H),7.69(d,J=4.8Hz,1H),7.13(dd,J=5.1,1.5Hz,1H),4.83(q,J=6.4Hz,1H),2.11(s,3H),1.26(d,J=6.6Hz,3H)。
實例230)N-(4-(7-(1-羥乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
根據用於實例212之過程由N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-羥乙基)吡啶-3-基)-2,2,2-三氟乙醯胺(230C)製備N-(4-(7-(1-羥乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.79min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220
nm)。MS(ES):m/z=404[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.68(s,1H),10.56(s,1H),8.37(d,J=4.63Hz,1H),8.31(d,J=5.05Hz,1H),8.25(s,1H),8.18(s,1H),7.76(dd,J=1.77,8.58Hz,1H),7.28(d,J=4.63Hz,1H),7.13(d,J=5.05Hz,1H),6.84(d,J=8.50z,1H),5.34(br.s.,1H),3.85(s,3H),1.90(s,3H),1.45(d,J=6.40Hz,3H)。
HPLC/LCMS管柱條件:Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;流動相A:5:95乙腈:水及0.1%三氟乙酸;流動相B:95:5乙腈:水及0.1%三氟乙酸;溫度:50℃;梯度:0至100% B在3分鐘內,隨後於100% B維持0.75分鐘;流速:1.0mL/min;檢測:
UV於220nm。
N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(1-氟代乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
233A)N-(4-((3-胺基-4-(1-氟代乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
於-20℃下向N-(4-((3-胺基-4-(1-羥乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(0.1g,0.337mmol)含於CH2Cl2(334μl)之溶液中添加DAST(0.045ml,0.337mmol)。於-20℃攪拌該反應10min隨後攪拌溫熱至室溫持續45min。使用MeOH淬冷該反應並濃縮。藉由矽膠急驟層析法(4g管柱,EtOAc/己烷=0-100%)純化該粗製材料以獲得N-(4-((3-胺基-4-(1-氟代乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺。HPLC:RT=0.57min(H2O/ACN及0.05% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.6min,波長=220nm)。MS(ES):m/z=299[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 8.37(s,1H),8.27(dd,J=0.77,5.17Hz,1H),8.07(dd,J=1.32,4.84Hz,1H),
7.21(dd,J=1.43,5.17Hz,1H),7.03(dd,J=0.66,4.84Hz,1H),5.70(dq,J=6.60,46.97Hz,1H),4.69(br.S.,2H),2.23(s,3H),1.75(dd,J=6.38,17.61Hz,3H)。
233B)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-氟代乙基)吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與用於實例1D之彼等相似之方法由N-(4-((3-胺基-4-(1-氟代乙基)吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(233A)製備N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-氟代乙基)吡啶-3-基)-2,2,2-三氟乙醯胺。HPLC:RT=0.74min(H2O/ACN及0.05% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=1.6min,波長=220nm)。MS(ES):m/z=395[M+H]+。
實例233)N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(1-氟代乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用針對實例212顯示之一般方法由N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-(1-氟代乙基)吡啶-3-基)-2,2,2-三氟乙醯胺(233B)及2-溴-6-(二氟甲基)吡啶製備N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-(1-氟代乙基)-
1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.01min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm)。MS(ES):m/z=426[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.13(s,1H),10.53(s,1H),8.52(d,J=4.63Hz,1H),8.35(d,J=7.91Hz,1H),8.32(br.s.,1H),8.31(d,J=5.22Hz,1H),8.05(t,J=7.83Hz,1H),7.53(d,J=7.66Hz,1H),7.33(d,J=4.71Hz,1H),6.57(t,J=55.29Hz,1H),6.35(dq,J=6.60,46.95Hz,1H),2.07(s,3H),1.73(dd,J=6.65,24.66Hz,3H)。
N-(4-(7-甲氧基-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
根據與針對實例212顯示之相同方法由N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲氧基吡啶-3-基)-2,2,2-三氟乙醯胺及2-溴-4-甲基噻唑製備N-(4-(7-甲氧基-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.90min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm)。MS(ES):m/z=426[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.54(s,1H),8.50(s,1H),8.39(d,J=5.30Hz,1H),8.33(d,J=5.13Hz,1H),7.44(d,J=5.05Hz,1H),7.20(s,1H),6.95(d,J=5.30Hz,1H),4.04(s,3H),2.27(s,3H),2.10(s,3H)。
N-(4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-(2-羥乙基)哌嗪-1-基)乙醯胺
藉由針對實例286顯示之一般方法由實例290A及2-(哌嗪-1-基)乙醇製備實例235。HPLC:RT=1.02min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=522[M+H]+。
N-(4-(3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用氬氣沖洗N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(25mg,0.061mmol)(實例236)及甲酸鈉(25.01mg,0.368mmol)含於MeOH(2mL)之溶液數分鐘。添
加PdOAc2(5.50mg,0.025mmol)及使用氬氣簡單沖洗該反應混合物,隨後於75℃在密封管中加熱2.5h。過濾該反應混合物及藉由製備型HPLC純化以產生N-(4-(3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.70min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm)。MS(ES):m/z=374[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.96(s,1H),10.48(s,1H),8.41(d,J=3.95Hz,1H),8.34(br.s.,1H),8.25(d,J=5.13Hz,1H),7.86(d,J=8.16Hz,2H),7.40(d,J=8.50Hz,1H),7.24(dd,J=4.50,8.12Hz,1H),7.18(d,J=4.96Hz,1H),3.83(s,3H),2.20(s,3H),2.08(s,3H)。
N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
238A)4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
藉由針對實例52顯示之一般方法由N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(實例236)製備4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺。HPLC:RT=0.39min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.75min,波長=220nm);MS(ES):m/z=366[M+H]+。
238B)2-氯-N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例74A顯示之一般方法由4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺製備2-氯-N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=0.56min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.75min,波長=220nm);MS(ES):m/z=442[M+H]+。
實例238)N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
向2-氯-N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(60.6mg,0.137mmol)及1-甲基哌嗪(41.2mg,0.411mmol)含於DMF(0.5mL)之溶液中添加K2CO3(56.8mg,0.411mmol)及於室溫攪拌該反應混合物3h。使用EtOAc(約3mL)稀釋該反應混合物並經過矽藻土過濾。使用10% MeOH/DCM(約3mL)清洗矽藻土。濃縮該濾液,再次溶於DMF(2mL)及藉由製備型HPLC純化以獲得N-(4-(6-氯-3-(5-甲氧基-6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺。HPLC:RT=0.90min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.75min,波長=220nm);MS(ES):m/z=506[M+H]+。1H NMR(500MHz,DMSO-d6)δ ppm 9.97(s,1H),8.41(s,1H),8.36(s,1H),8.30(d,J=5.13Hz,1H),7.94(d,J=1.60Hz,1H),7.81(d,J=8.41Hz,1H),7.41(d,J=8.50Hz,1H),7.23(d,J=4.63Hz,1H),3.84(s,3H),3.16(s,2H),2.54(br.s.,8H),2.20(s,6H)。
N-(4-(6-氯-3-(5-甲氧基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例172顯示之方法由實例41B及2-溴-5-甲氧基噻唑製備N-(4-(6-氯-3-(5-甲氧基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.25min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=400:1H NMR(500MHz,DMSO-d6)δ 10.64(s,1H),8.52(d,J=1.68Hz,1H),8.45(s,1H),8.39(d,J=5.05Hz,1H),7.98(d,J=1.94Hz,1H),7.47(dd,J=1.01,5.13Hz,1H),7.13(s,1H),3.94(s,3H),2.12(s,3H)。
N-(4-(7-氰基-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
240A)N-(4-(5-溴-7-氰基-3-(4-甲基噻唑-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向2-溴-4-甲基噻唑(145mg,0.814mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧硼)(248mg,0.977mmol)含於1,4-二噁烷(5mL)之溶液中添加乙酸鉀(120mg,1.222mmol)。使用氬氣沖洗該反應混合物數分鐘及添加PdCl2(dppf)-CH2Cl2加合物(20.81mg,0.041mmol)。在該反應混合物中吹入氬氣2min及在密封瓶中於90℃加熱2h。在該冷卻之反應混合物中加入N-(4-(5-溴-7-氰基-3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(499mg,0.814mmol)及磷酸三鉀(0.679ml,2.036mmol)。在該反應混合物中吹入氬氣5min及於110℃加熱過夜。冷卻該反應混合物,使用EtOAc稀釋及使用水隨後使用鹽水清洗。有機相經MgSO4乾燥、濃縮並藉由矽膠急驟層析法(12g管柱,EtOAc/hex=0至50%)純化以獲得N-(4-(5-溴-7-氰基-3-(4-甲基噻唑-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.20min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.75min,波長=220nm);MS(ES):m/z=583,585[M+H]+。
實例240)N-(4-(7-氰基-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(5-溴-7-氰基-3-(4-甲基噻唑-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(80mg,0.137mmol)(實例240A)含於甲醇(3mL)之溶液中添加甲酸鈉(55.9mg,0.823mmol)及使用氬氣沖洗該反應混合物數分鐘。添加Pd(OAc)2(18.47mg,0.082mmol)及於70℃在密封瓶中加熱該反應混合物16h。過濾並濃縮該反應混合物隨後經(1:1)DCM:TFA(3mL)處理及於50℃加熱2h。隨後濃縮該反應混合物並溶於DMF及藉由製備型HPLC純化以獲得N-(4-(7-氰基-3-(4-甲基噻唑-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺。HPLC:RT=1.34min(H2O/MeOH及0.05% TFA,Waters Acquity SDS BEH C18 2.1x50mm 1.7u,梯度=1.75min,波長=220nm);MS(ES):m/z=375[M+H]+。1H NMR(500MHz,DMSO-d6)δ ppm 10.64(s,1H),8.58(s,1H),8.44(d,J=5.13Hz,1H),8.24(s,1H),7.71(d,J=4.97Hz,1H),7.42(s,1H),7.40(s,1H),2.45(s,3H),2.15(s,3H)。
N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-{[2-(嗎啉-4-基)乙基]胺基}乙醯胺
藉由針對實例74顯示之一般方法由實例74A及2-嗎啉乙胺製備實例241。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=510.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.47(s,1H),8.55-8.39(m,3H),8.27-8.12(m,2H),8.01(s,1H),7.89-7.77(m,1H),7.35(d,J=4.9Hz,1H),4.29-3.59(m,2H),3.45-2.80(m,4H),2.54(br.s,8H)。
4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)-N-乙基吡啶-2-胺
藉由針對實例82顯示之一般方法製備實例242。HPLC:RT=1.08min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=379.9[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.17(br.s.,1H),
8.41(br.s.,1H),8.26(br.s.,1H),7.93(br.s.,2H),7.87(d,J=7.0Hz,1H),7.50(d,J=7.5Hz,1H),6.75(br.s.,1H),6.59(d,J=4.8Hz,1H),3.86(s,3H),2.54(m,2H),1.13(t,J=7.0Hz,3H)。
4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)-N-異丁基吡啶-2-胺
藉由針對實例82顯示之一般方法製備實例243。HPLC:RT=1.01min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.13(br.s.,1H),8.40(br.s.,1H),8.25(br.s.,1H),7.92(br.s.,2H),7.86(d,J=8.4Hz,1H),7.49(d,J=8.3Hz,1H),6.69(br.s.,1H),6.56(br.s.,1H),3.86(s,3H),3.00(br.s.,2H),1.83-1.71(m,1H),0.88(d,J=6.4Hz,6H。
N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-羥基哌啶-1-基)乙醯胺
藉由針對實例74顯示之一般方法由74A及哌啶-4-醇製備實例244。HPLC:RT=0.84min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=481.1[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 12.48(br.s.,1H),8.46(br.s.,2H),8.42(d,J=4.5Hz,1H),8.23(br.s.,1H),8.12(dd,J=8.6,4.5Hz,1H),8.01(s,1H),7.89-7.75(m,1H),7.33(br.s.,1H),4.23-3.11(m,3H),2.54(s,4H),1.91(br.s.,2H),1.68(br.s.,2H)。
N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-(二甲基胺基)哌啶-1-基)乙醯胺
藉由針對實例74顯示之一般方法由74A及N,N-二甲基哌啶-4-胺製備實例245。HPLC:RT=0.83min(H2O/ACN及0.1% TFA,Waters
Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=508.3[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 12.43(s,1H),8.44(br.s.,2H),8.36(d,J=5.0Hz,1H),8.22(br.s.,1H),8.07(dd,J=8.7,4.5Hz,1H),8.01(s,1H),7.87-7.71(m,1H),7.28(br.s.,1H),3.87-3.52(m,13H),2.04(br.s.,2H),1.76(br.s.,2H)。
N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基-2-(4-(2-羥乙基)哌嗪-1-基)乙醯胺
藉由針對實例74顯示之一般方法由實例74A及2-(哌嗪-1-基)乙醇製備實例246。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=510.2[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 12.44(s,1H),10.34(br.s.,1H),8.46(br.s.,2H),8.36(d,J=5.0Hz,1H),8.27(br.s.,1H),8.16-8.07(m,1H),8.00(s,1H),7.83(t,J=8.6Hz,1H),7.25(d,J=4.9Hz,1H),3.73(br.s.,4H),3.19(br.s.,4H),3.11-2.63(m,4H),2.54(s,2H)。
N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶
-2-基)-2-(哌嗪-1-基)乙醯胺
藉由針對實例74顯示之一般方法由74A及哌嗪-1-羧酸第三丁酯製備實例247。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=466.0[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 10.13(s,1H),8.46(br.s.,2H),8.34(d,J=5.1Hz,1H),8.28(s,1H),8.15-8.07(m,1H),7.99(s,1H),7.88-7.77(m,1H),7.22(d,J=5.0Hz,1H),3.23(s,2H),2.98(br.s.,4H),2.63(br.s.,4H)。
2-(4-乙醯基哌嗪-1-基)-N-(4-(6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例74顯示之一般方法由74A及1-(哌嗪-1-基)乙酮製備實例248。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters
Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=508.2[M+H];1H NMR(500MHz,DMSO-d6)δ 10.12(s,1H),8.46(s,2H),8.34(d,J=5.2Hz,1H),8.29(s,1H),8.10(dd,J=8.5,4.3Hz,1H),7.99(s,1H),7.88-7.79(m,1H),7.21(d,J=4.9Hz,1H),3.47(d,J=4.3Hz,4H),3.41-3.35(m,4H),3.22(s,2H),1.99(s,3H)。
N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
249A)2-氯-N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於冰浴溫度下向4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺(210mg,0.597mmol)(實例86)含於DCE(8mL)之懸浮液(經超音波處理)中緩慢添加氯乙醯氯(0.214mL,2.69mmol)及
TEA(0.42mL,2.98mmol)。於室溫攪拌該反應混合物0.5h。隨後在該反應混合物中添加2mL氫氧化銨水溶液及於室溫攪拌該混合物2h。隨後使用飽和NaHCO3溶液稀釋該反應混合物並過濾該混合物以獲得期望產物(255mg,99%);HPLC:RT=0.69min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=427.9[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.22(s,1H),10.87(s,1H),8.43(d,J=2.2Hz,1H),8.37-8.28(m,2H),8.20(d,J=2.9Hz,1H),7.99-7.91(m,2H),7.50(dd,J=8.8,3.1Hz,1H),7.20(dd,J=5.2,1.4Hz,1H),4.35(s,2H),3.86(s,3H)。
實例249)N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
向實例249A(60mg,0.140mmol)含於乙腈(4mL)之混合物中添加1-甲基哌嗪(168mg,1.681mmol)及氧化銀(64.9mg,0.280mmol)。於室溫攪拌該反應混合物3.5h。在真空中濃縮該反應混合物及該殘留物與TFA/MeOH混合,隨後在真空中濃縮。在該殘留物中添加少量TFA/MeOH。該混合物經針筒過濾器過濾,並藉由製備型HPLC純化。合併含有期望產物之溶離份,並與CHCl3/2-丙醇(3:1)及NaHCO3溶液混合。分離有機層並經MgSO4乾燥。在真空中濃縮該濾液並凍乾以獲得期望產物(43mg,61%);HPLC:RT=0.57min
(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=492.0[M+H];1H NMR(400MHz,MeOH-d4)δ ppm 8.35(d,J=2.2Hz,1H),8.31(d,J=0.7Hz,1H),8.28-8.23(m,2H),7.94(d,J=2.0Hz,1H),7.67(d,J=8.8Hz,1H),7.52(dd,J=8.7,3.0Hz,1H),7.16(dd,J=5.3,1.5Hz,1H),3.94(s,3H),3.20(s,2H),2.83-2.46(m,8H),2.33(s,3H)。
N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-嗎啉乙醯胺
藉由針對實例249顯示之一般方法由實例249A及嗎啉製備實例250。HPLC:RT=0.77min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=479.0[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 10.06(br.s.,1H),8.42(br.s.,1H),8.31(br.s.,2H),8.19(br.s.,1H),7.95(br.s.,1H),7.91(d,J=8.6Hz,1H),7.49(d,J=7.4Hz,1H),7.17(br.s.,1H),3.84(br.s.,3H),3.62(br.s.,2H),2.54(s,8H)。
N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-乙基哌嗪-1-基)乙醯胺
藉由針對實例249顯示之一般方法由實例249A及1-乙基哌嗪製備實例251。HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=506.1[M+H];1H NMR(500MHz,DMSO-d6)δ 12.27(s,1H),10.21(br.s.,1H),8.42(s,1H),8.35-8.27(m,2H),8.18(br.s.,1H),7.97(s,1H),7.91(d,J=8.7Hz,1H),7.50(dd,J=8.7,2.8Hz,1H),7.18(d,J=4.9Hz,1H),3.84(s,3H),3.53(m,10H),3.20-2.92(m,2H),1.20(t,J=7.2Hz,3H)。
N-(4-(6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-(2-羥乙基)哌嗪-1-基)乙醯胺
藉由針對實例249顯示之一般方法由實例249A及2-(哌嗪-1-基)乙醇製備實例252。HPLC:RT=0.85min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x 0mm,1.7-μm粒子,梯度=3min,波
長=220nm);MS(ES):m/z=522.3[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 9.98(s,1H),8.42(br.s.,1H),8.36-8.27(m,2H),8.18(br.s.,1H),8.01-7.84(m,2H),7.50(d,J=8.5Hz,1H),7.17(d,J=5.0Hz,1H),3.85(s,3H),3.16(s,2H),2.54(br.s.,6H),2.43(br.s.,3H),1.90(s,3H)。
N-(4-(6-氯-3-(5-乙氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-乙氧基吡啶製備實例253。HPLC:RT=1.05min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.20(s,1H),10.56(s,1H),8.42(d,J=1.8Hz,1H),8.35-8.24(m,2H),8.18(d,J=2.6Hz,1H),8.01-7.85(m,2H),7.48(dd,J=8.6,2.7Hz,1H),7.11(d,J=4.5Hz,1H),4.13(q,J=6.9Hz,2H),2.09(s,3H),1.36(t,J=6.9Hz,3H)。
N-(4-(6-氯-3-(5-異丙氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-5-異丙氧基吡啶製備實例254。HPLC:RT=1.16min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=422.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.56(br.s.,1H),10.64(s,1H),8.57-8.47(m,1H),8.35(d,J=5.0Hz,2H),8.21(br.s.,1H),8.03(d,J=1.7Hz,1H),7.93(d,J=8.8Hz,1H),7.79(d,J=7.1Hz,1H),7.22(d,J=5.4Hz,1H),4.81(dt,J=11.9,5.8Hz,1H),2.07(s,3H),1.34(d,J=6.0Hz,6H)。
N-(4-(6-氯-3-(6-異丙氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-異丙氧基吡
啶製備實例255。HPLC:RT=1.35min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=422.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.24(br.s.,1H),10.59(br.s.,1H),8.44(s,1H),8.32(d,J=4.7Hz,1H),8.23(br.s.,1H),7.97(d,J=7.3Hz,1H),7.91(s,1H),7.68(t,J=7.7Hz,1H),7.13(d,J=4.7Hz,1H),6.48(d,J=8.1Hz,1H),4.47-4.26(m,1H),2.04(s,3H),0.88(d,J=6.1Hz,6H)。
N-(4-(6-氯-3-(6-乙氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-乙氧基吡啶製備實例256。HPLC:RT=1.23min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.29(br.s.,1H),10.61(s,1H),8.48(s,1H),8.35(d,J=5.0Hz,1H),8.28(br.s.,1H),8.00(d,J=7.4Hz,1H),7.95(s,1H),7.74(t,J=7.8Hz,1H),7.18(d,J=5.0Hz,1H),6.58(d,J=8.2Hz,1H),3.64(q,J=6.9Hz,2H),2.09(s,3H),1.00(t,J=7.0Hz,3H)。
N-(4-(7-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)
吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由2-溴-6-甲基吡啶製備實例257。HPLC:RT=0.66min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.46(s,1H),8.31(d,J=5.0Hz,2H),8.24(d,J=5.2Hz,1H),7.93(d,J=7.7Hz,1H),7.69(t,J=7.7Hz,1H),7.20(d,J=5.0Hz,1H),7.07(d,J=7.6Hz,1H),6.90(d,J=5.4Hz,1H),4.04(s,3H),2.26(s,3H),2.11-2.03(m,3H)。
N-(4-(6-氯-3-(6-乙氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及5-溴-2-乙氧基吡啶製備實例258。HPLC:RT=1.18min(H2O/ACN及0.1% TFA,Waters
Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.23(br.s.,1H),10.60(s,1H),8.39(s,1H),8.35-8.27(m,2H),8.20(s,1H),7.95(br.s.,1H),7.74(d,J=7.2Hz,1H),7.11(d,J=4.7Hz,1H),6.83(d,J=8.5Hz,1H),4.31(q,J=6.8Hz,2H),1.32(t,J=6.9Hz,3H)。
N-(4-(6-氯-3-(3-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-3-甲基吡啶製備實例259。HPLC:RT=1.16min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.61(br.s.,1H),10.51(s,1H),8.54(br.s.,1H),8.34(s,1H),8.26(d,J=5.0Hz,1H),8.10-7.95(m,3H),7.59(br.s.,1H),7.05(d,J=5.1Hz,1H),2.09(s,3H),1.99(s,3H)。
N-(4-(6-氯-3-(6-異丙基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例41B及2-溴-6-異丙基吡啶製備實例260。HPLC:RT=1.06min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=406.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.28(br.s.,1H),10.53(br.s.,1H),8.46(s,1H),8.30(d,J=4.2Hz,1H),8.23(br.s.,1H),8.01(d,J=7.6Hz,1H),7.97(s,1H),7.77(t,J=7.5Hz,1H),7.18(d,J=4.7Hz,1H),7.09(d,J=7.2Hz,1H),2.87-2.73(m,1H),2.06(s,3H),0.94(d,J=6.6Hz,6H)。
N-(4-(3-(6-氟代吡啶-3-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
261A)1-(3-胺基-2,6-二溴吡啶-4-基)乙酮
向1-(3-胺基吡啶-4-基)乙酮(0.9g,6.61mmol)含於DMF(10mL)之溶液中添加NBS(2.53mg,14.21mmol)。在室溫下攪拌該反應混合物2小時。使用乙酸乙酯及飽和NaHCO3溶液稀釋該反應混合物。使用飽和NaHCO3溶液清洗有機層(萃取兩次),經MgSO4乾燥。在真空中濃縮該濾液。藉由急驟層析法純化該殘留物。使用0至20%乙酸乙酯之己烷溶液洗脫該產物以獲得白色固體之期望產物(1.55g,80%);HPLC:RT=0.88min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=292.8,294.8[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.65(s,1H),6.73(br.s.,2H),2.62(s,3H)。
261B)N-(4-((4-乙醯基-3-胺基-6-溴代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
向1-(3-胺基-2,6-二溴吡啶-4-基)乙酮(6.2g,21.09mmol)含於DMF(30mL)之溶液中添加TEA(29.4mL,211mmol)、CuI(0.20g,1.055mmol)及N-(4-乙炔基吡啶-2-基)乙醯胺(3.72g,23.20mmol)。使用氮氣流沖洗該反應混合物3min,接著添加雙(三苯基膦)氯化鈀(II)(0.888g,1.266mmol)。於80℃加熱該反應混合物2h。冷卻該反應混合物並使用乙酸乙酯及飽和NaHCO3溶液稀釋。合併乙酸乙酯萃
取物(兩次),使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液。在該殘留物中添加DCM,並過濾該混合物以獲得淺棕色固體及濾液。藉由急驟層析法純化該濾液。使用DCM至20%之10% MeOH之DCM溶液洗脫該產物以獲得棕色固體之期望產物,總計(3.4g,43.2%);HPLC:RT=0.78min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=372.8,374.8[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.64(s,1H),8.39(dd,J=5.1,0.9Hz,1H),8.29(s,1H),7.94(s,1H),7.44-7.31(m,3H),2.63(s,3H),2.12(s,3H)。
261C)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-乙醯基-6-溴代吡啶-3-基)-2,2,2-三氟乙醯胺
於冰浴溫度向N-(4-((4-乙醯基-3-胺基-6-溴代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(2.0g,5.36mmol)含於DCE(35mL)之懸浮液(經超音波處理)中逐滴添加TEA(3.73mL,26.8mmol)及三氟乙酸酐(1.29mL,9.11mmol)。於0℃攪拌該反應混合物40min。在該反應混合物中添加更多TEA(2.5mL)及三氟乙酸酐(0.7mL)及於0℃攪拌該反應混合物又40min。使用乙酸乙酯及飽和NaHCO3溶液稀釋該反應混合物。分離有機層並使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液。將該殘留物溶於DCM及濾過針筒過濾器,藉由急驟層析法純化。使用DCM至20%之10% MeOH之DCM溶液洗脫該產物以獲得黃色固體之期望產物(0.8g,32%);HPLC:RT=0.82
min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=470.7[M+H]+;1H NMR(400MHz,氯仿-d)δ ppm 9.46(br.s.,1H),8.37(s,1H),8.30(d,J=5.1Hz,1H),7.94(br.s.,1H),7.75(s,1H),7.15(dd,J=5.1,1.3Hz,1H),2.68(s,3H),2.23(s,3H)。
261D)N-(4-(7-乙醯基-5-溴-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用氮氣流沖洗密封管中之N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-乙醯基-6-溴代吡啶-3-基)-2,2,2-三氟乙醯胺(150mg,0.320mmol)、雙(二亞苄基丙酮)鈀(18.4mg,0.032mmol)、2-(二環己基膦)-2',4'.6'-三異丙基聯苯(10.67mg,0.022mmol)及Cs2CO3(208mg,0.639mmol)含於乙腈(5mL)之反應混合物2min,隨後於110℃加熱2h。冷卻該反應混合物並使用乙酸乙酯萃取。將該殘留物溶於MeOH/TFA溶液,藉由製備型HPLC純化。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(31mg,26%);HPLC:RT=0.67min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=373.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.82(s,1H),10.66(s,1H),8.51(s,1H),8.41(d,J=5.3Hz,1H),7.89(s,1H),7.70(dd,J=5.3,1.5Hz,1H),7.23(d,J=2.0Hz,1H),2.76(s,3H),2.15(s,3H)。
261E)N-(4-(7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)
乙醯胺
向N-(4-(7-乙醯基-5-溴-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(90mg,0.241mmol)含於MeOH(6mL)之反應混合物中添加Pd(OH)2-C(16.93mg,0.024mmol)。該混合經超音波處理、抽真空、隨後使用氫氣球氫化2h。使用MeOH稀釋該反應混合物,過濾。在真空中濃縮該濾液以獲得黃色固體之期望產物(60mg,84%);HPLC:RT=0.46min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=297.1[M+H]+。
261F)N-(4-(7-(1-羥乙基)-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(60mg,0.202mmol)含於DMF(2mL)之溶液中添加NIS(54.7mg,0.243mmol)。在室溫下攪拌將反應混合物1小時。使用乙酸乙酯及鹽水萃取該反應混合物。分離有機層並在真空中濃縮。該粗物質無需進一步純化即可用於下一步驟反應中。HPLC:RT=0.50min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=423.1[M+H]+。
實例261)N-(4-(3-(6-氟代吡啶-3-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
N-(4-(7-(1-羥乙基)-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(30mg,0.071mmol)及2-氟代吡啶-5-硼酸(12.0mg,0.085mmol)於二噁烷(2mL)中之溶液在密封管中。添加1.0M Na2CO3溶液(0.18mL,0.18mmol)及使用氮氣流沖洗該混合物3min,接著添加PdCl2(dppf)(5.2mg,7.11μmol)。於90℃加熱所得混合物2h。在真空中濃縮該反應混合物。將該殘留物溶於MeOH+2滴TFA及經針筒過濾器過濾,藉由製備型HPLC純化。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物2 TFA鹽(5.3mg,12%);HPLC:RT=0.69min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=392.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.65(s,1H),8.53(d,J=5.3Hz,1H),8.38(d,J=5.1Hz,1H),8.28(s,1H),8.23(s,1H),8.04(td,J=8.2,2.2Hz,1H),7.57(d,J=5.0Hz,1H),7.27(br.s.,1H),7.20(d,J=5.0Hz,1H),5.49(q,J=6.2Hz,1H),2.07(s,3H),1.50(d,J=6.4Hz,3H)。
N-(4-(3-(6-氟代吡啶-2-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例261顯示之一般方法由2-溴-6-氟代吡啶製備實例262。HPLC:RT=0.79min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=392.1[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 11.88(s,1H),10.57(s,1H),8.46(d,J=4.7Hz,1H),8.34(d,J=5.0Hz,1H),8.28-8.17(m,2H),8.02(q,J=8.2Hz,1H),7.33(d,J=4.7Hz,1H),7.22(d,J=4.1Hz,1H),6.96(dd,J=8.0,2.3Hz,1H),5.55(d,J=4.4Hz,1H),5.43-5.26(m,1H),2.08(s,3H),1.45(d,J=6.4Hz,3H)。
N-(4-(3-(6-氯代吡啶-2-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例261顯示之一般方法由2-溴-6-氯代吡啶製備實例263。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.2[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 10.68(s,1H),8.61(d,J=5.4Hz,1H),8.42(d,J=5.0Hz,1H),8.28(s,1H),7.92-7.84(m,1H),7.74(br.s.,1H),7.64(d,J=5.3Hz,1H),7.43(d,J=7.9Hz,1H),7.26(s,1H),5.49(d,J=6.5Hz,1H),2.09(s,3H),1.49(d,J=6.5Hz,3H)。
N-(4-(3-(6-氯代吡啶-3-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例261顯示之一般方法由5-溴-2-氯代吡啶製備實例264。HPLC:RT=0.77min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=408.2[M+H];1H NMR(500MHz,DMSO-d6)δ ppm 10.67(s,1H),8.53(d,J=5.2Hz,1H),8.46(d,J=2.0Hz,1H),8.39(d,J=5.1Hz,1H),8.26(s,1H),7.94(dd,J=8.2,2.2Hz,1H),7.68-7.51(m,2H),7.18(d,J=4.9Hz,2H),5.47(q,J=6.2Hz,1H),3.00-2.84(m,1H),2.08(s,3H),1.49(d,J=6.4Hz,3H)。
N-(4-(3-(5-氟代吡啶-2-基)-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例261顯示之一般方法由2-溴-5-氟代吡啶製備實例
265。HPLC:RT=0.60min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=392.2[M+H];1H NMR(400MHz,MeOH-d4)δ ppm 8.45(d,J=2.9Hz,1H),8.38(d,J=5.1Hz,1H),8.27(dd,J=5.3,0.4Hz,1H),8.19(s,1H),7.81-7.66(m,2H),7.36(d,J=5.1Hz,1H),7.18(dd,J=5.3,1.5Hz,1H),5.44(q,J=6.6Hz,1H),2.15(s,3H),1.62(d,J=6.6Hz,3H)。
N-(4-(7-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
266A)2-溴-4-甲氧基吡啶-3-胺
於冰浴溫度攪拌4-甲氧基吡啶-3-胺(3.1g,24.97mmol)含於TFA(38.5ml,499mmol)之溶液及分幾個批次向該混合物中添加NBS(4.89g,27.5mmol)。於室溫攪拌該反應混合物過夜。在真空中濃縮該反應混合物並使用飽和NaHCO3溶液及乙酸乙酯稀釋該殘留物。合併有機層(兩次萃取物)並使用飽和NaHCO3溶液清洗,經
MgSO4乾燥。在真空中濃縮該濾液。藉由急驟層析法純化該殘留物。使用0至20%乙酸乙酯之己烷溶液洗脫該產物以獲得白色固體之期望產物(3.9g,77%);HPLC:RT=0.47min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=202.8,204.8[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.75(d,J=5.5Hz,1H),6.69(d,J=5.5Hz,1H),4.11(d,J=6.2Hz,2H),3.92(s,3H)。
266B)N-(4-((3-胺基-4-甲氧基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
向2-溴-4-甲氧基吡啶-3-胺(2.1g,10.34mmol)、N-(4-乙炔基吡啶-2-基)乙醯胺(1.82g,11.38mmol)含於DMF(15mL)之溶液中添加TEA(21.62mL,155mmol)及CuI(0.12g,0.62mmol)。使用氮氣沖洗該反應混合物2min,接著添加Pd(PPh3)2Cl2(0.73g,1.03mmol)。隨後於100℃加熱該反應混合物3h。冷卻該反應混合物並使用乙酸乙酯及飽和NaHCO3溶液稀釋。合併該有機層(兩次萃取物),使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液。藉由急驟層析法純化該殘留物。使用DCM至50%之10% MeOH之DCM溶液洗脫該產物以獲得淺黃色期望產物(1.0g,34%);HPLC:RT=0.48min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=283.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 10.59(s,1H),8.34(dd,J=5.1,0.7Hz,1H),8.22(s,1H),7.79(d,J=5.3Hz,1H),7.34(dd,
J=5.2,1.4Hz,1H),6.91(d,J=5.3Hz,1H),5.35(s,2H),4.03(q,J=7.2Hz,1H),3.88(s,3H),2.11(s,3H)。
266C)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲氧基吡啶-3-基)-2,2,2-三氟乙醯胺
於冰浴溫度向N-(4-((3-胺基-4-甲氧基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺(0.6g,2.13mmol)含於DCE(14mL)之懸浮液(經超音波處理)中緩慢添加TEA(1.19mL,8.50mmol),接著添加三氟乙酸酐(0.53mL,3.83mmol)。於0℃攪拌該反應混合物15min並轉化為透明溶液。使用冷飽和NaHCO3溶液淬冷該反應混合物並使用乙酸乙酯萃取所得混合物三次。分離該有機層並使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液以獲得棕色固體。在該殘留物中添加醚並過濾該固體以獲得棕色固體之期望產物(0.42g,70%);HPLC:RT=0.63min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=379.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.32(s,1H),10.66(s,1H),8.52(d,J=5.7Hz,1H),8.42-8.36(m,1H),8.20(s,1H),7.32(d,J=5.7Hz,1H),7.13(dd,J=5.1,1.5Hz,1H),3.93(s,3H),2.11(s,3H)。
實例266)N-(4-(7-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-4-甲氧基吡啶-3-基)-
2,2,2-三氟乙醯胺(70mg,0.185mmol)、2-溴-5-甲氧基吡啶(70mg,0.37mmol)含於DMF(2mL)之懸浮液中添加Cs2CO3(121mg,0.37mmol)。使用氮氣沖洗該反應混合物,接著添加第二代Xphos預觸媒(7.5mg,9.3μmol)。於120℃加熱所得混合物3h。冷卻該反應混合物。在真空中濃縮該殘留物及過濾並藉由製備型HPLC純化。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(15.3mg,20.4%);HPLC:RT=0.77min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.45(s,1H),8.29(d,J=5.3Hz,1H),8.22(d,J=5.3Hz,2H),8.13(d,J=2.9Hz,1H),7.96(d,J=8.7Hz,1H),7.46(dd,J=8.7,3.0Hz,1H),7.11(d,J=5.1Hz,1H),6.89(d,J=5.4Hz,1H),4.03(s,3H),3.83(s,3H),2.07(s,3H)。
N-(4-(3-(6-(二氟甲基)吡啶-2-基)-7-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由2-溴-6-(二氟甲基)吡啶製備實例267。HPLC:RT=0.94min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=410.2[M+H]+;1H NMR(500MHz,
DMSO-d6)δ ppm 10.72(s,1H),8.65(d,J=6.6Hz,1H),8.43(d,J=5.0Hz,1H),8.34(s,1H),7.98(t,J=7.9Hz,1H),7.66(d,J=7.7Hz,1H),7.54(d,J=6.6Hz,1H),7.40(d,J=6.5Hz,1H),7.28(d,J=4.5Hz,1H),7.23-6.97(m,1H),4.27(s,3H),2.09(s,3H)。
N-(4-(3-(5-氟代吡啶-2-基)-7-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由2-溴-5-氟代吡啶製備實例268。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子;梯度=3min,波長=220nm);MS(ES):m/z=378.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.46(s,1H),8.38(d,J=2.9Hz,1H),8.31(d,J=5.3Hz,1H),8.25(d,J=5.1Hz,1H),8.18(br.s.,1H),8.11(dd,J=8.5,4.6Hz,1H),7.77(td,J=8.8,2.9Hz,1H),7.16(d,J=5.1Hz,1H),6.91(d,J=5.4Hz,1H),4.03(s,3H),2.06(s,3H)。
N-(4-(7-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由5-溴-2-甲氧基吡啶製備實例269。HPLC:RT=0.76min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390.3[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.11(s,1H),10.54(s,1H),8.28(dd,J=5.0,2.7Hz,3H),8.19(d,J=2.0Hz,1H),7.75(dd,J=8.5,2.3Hz,1H),7.12(d,J=6.1Hz,1H),6.89(d,J=5.4Hz,1H),6.83(d,J=8.5Hz,1H),4.03(s,3H),3.85(s,3H),2.07(s,3H)。
N-(4-(3-(4-(二氟甲基)噻唑-2-基)-7-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由2-溴-4-(二氟甲基)噻唑製備實例270。HPLC:RT=0.94min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波
長=220nm);MS(ES):m/z=416.0[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.59(s,1H),10.56(s,2H),8.50(s,2H),8.44(d,J=5.4Hz,2H),8.35(d,J=5.2Hz,2H),8.04(s,2H),7.46(d,J=4.0Hz,2H),7.00(d,J=5.5Hz,2H),7.12-6.80(m,2H),4.06(s,3H),2.10(s,3H)。
N-(4-(7-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由6-甲氧基吡啶-3-基硼酸製備實例271。HPLC:RT=0.57min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.38(br.s.,1H),10.59(s,1H),8.36(d,J=5.1Hz,1H),8.35-8.28(m,2H),8.25-8.15(m,1H),7.76(dd,J=8.6,2.4Hz,1H),7.41(d,J=5.1Hz,1H),7.16(dd,J=5.3,1.5Hz,1H),6.85(dd,J=8.6,0.7Hz,1H),3.87(s,3H),2.09(s,3H)。
N-(4-(6-溴-3-(6-(二氟甲基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由2-溴-6-(二氟甲基)吡啶製備實例272。HPLC:RT=0.75min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=458,460.1[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.39(s,1H),10.53(s,1H),8.54(d,J=2.2Hz,1H),8.35(s,1H),8.32-8.25(m,2H),8.11(d,J=2.0Hz,1H),8.07(t,J=7.9Hz,1H),7.56(d,J=7.7Hz,1H),7.23(dd,J=5.2,1.7Hz,1H),6.85-6.51(m,1H),2.08(s,3H)。
N-(4-(3-(6-氟代吡啶-2-基)-7-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例266顯示之一般方法由2-溴-6-氟代吡啶製備實例273。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220
nm);MS(ES):m/z=378.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.51(s,1H),8.35(d,J=5.3Hz,1H),8.30(d,J=5.1Hz,1H),8.20(s,1H),8.15(d,J=5.7Hz,1H),8.01(q,J=8.1Hz,1H),7.20(d,J=5.1Hz,1H),7.04-6.88(m,2H),4.04(s,3H),2.07(s,3H)。
N-(4-(7-(羥甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
274A)3-胺基-2,6-二溴異煙鹼酸乙酯
向3-胺基異煙鹼酸乙酯(7.0g,42.1mmol)含於DMF(40mL)之溶液中添加NBS(15.74g,88mmol)。在室溫下攪拌該反應混合物20小時。使用飽和NaHCO3溶液及乙酸乙酯稀釋該反應混合物。分離有機層並使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液。將該粗產物溶於DCM並藉由急驟層析法純化。使用0至15%乙酸乙酯之己烷溶液洗脫該產物以獲得白色固體之期望產物(9.6g,70%);HPLC:RT=1.02min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);
MS(ES):m/z=278.9,280.9[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 7.81(s,1H),6.26(br.s.,2H),4.39(q,J=7.0Hz,2H),1.42(t,J=7.2Hz,3H)。
274B)2-((2-乙醯胺基吡啶-4-基)乙炔基)-3-胺基-6-溴代異煙鹼酸乙酯
向3-胺基-2,6-二溴異煙鹼酸乙酯(4.0g,12.35mmol)及N-(4-乙炔基吡啶-2-基)乙醯胺(2.18g,13.6mmol)含於DMF(20mL)之溶液中添加CuI(0.19g,0.99mmol)及TEA(17.21mL,123mmol)。使用氮氣流沖洗該反應混合物3min,接著添加Pd(PPh3)2Cl2(0.52g,0.74mmol)。在氮氣流下於80℃加熱所得混合物2h。冷卻該反應混合物並使用乙酸乙酯及飽和NaHCO3溶液稀釋。合併乙酸乙酯萃取物(兩次),使用飽和NaHCO3溶液清洗,經MgSO4乾燥。在真空中濃縮該濾液。在該殘留物中添加DCM,及過濾該混合物以獲得淺棕色固體之期望產物(3.5g)。藉由急驟層析法純化該濾液。使用0至30%乙酸乙酯之DCM溶液洗脫該產物以獲得黃色固體之期望產物,總重量(4.0g,80%);HPLC:RT=0.92min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=402.9,404.9[M+H]+;1H NMR(400MHz,CDCl3)δ ppm 8.37(s,1H),8.29(d,J=5.1Hz,1H),8.01(s,1H),7.85(s,1H),7.20(dd,J=5.2,1.4Hz,1H),6.36(br.s.,2H),4.41(q,J=7.0Hz,2H),2.24(s,3H),1.43(t,J=7.2Hz,3H)。
274C)2-(2-乙醯胺基吡啶-4-基)-5-溴-1H-吡咯并[3,2-b]吡啶-7-羧酸乙酯
使用氮氣流沖洗2-((2-乙醯胺基吡啶-4-基)乙炔基)-3-胺基-6-溴代異煙鹼酸乙酯(2.0g,4.96mmol)及Cs2CO3(2.42g,7.44mmol)含於CH3CN(30mL)之懸浮液2min,添加Pd(PPh3)4(0.344g,0.298mmol)。於95℃加熱該反應混合物2h。使用乙酸乙酯稀釋該反應混合物並過濾以獲得黑色濾液。使用乙酸乙酯清洗漏斗上之固體。在真空中濃縮全部濾液以獲得黑色固體。向漏斗上之固體中添加水。使用刮刀攪拌該混合物並過濾以獲得黑色固體2,在高真空中乾燥。該黑色固體2與THF+MeOH混合,經超音波處理並過濾。在真空中濃縮該濾液以獲得黑色固體3,其係作為乙基及甲基酯混合物之期望產物(1.0g,50%);HPLC:RT=0.80min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=403.0、405.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.70(s,1H),10.62(s,1H),8.55(s,1H),8.43(d,J=5.3Hz,1H),7.76-7.62(m,2H),7.25(s,1H),4.49(q,J=7.2Hz,2H),2.14(s,3H),1.43(t,J=7.2Hz,3H)。
274D)2-(2-乙醯胺基吡啶-4-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯
向2-(2-乙醯胺基吡啶-4-基)-5-溴-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯(110mg,0.283mmol)含於MeOH(8mL)及THF(4mL)之反應混合物中添加Pd-C(20mg,0.028mmol)及該混合物經超音波處理、排空、隨後使用氫氣球氫化4h。過濾該反應混合物並在真空中濃縮該濾液。使用CHCl3:2-丙醇(2.5:1)萃取該殘留物。使用飽和NaHCO3溶液清洗該有機層,經MgSO4乾燥。在真空中濃縮該濾液以獲得黃色固體之期望產物(60mg,68%);HPLC:RT=0.51min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=311.0[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.44(s,1H),10.60(s,1H),8.60-8.51(m,2H),8.42(d,J=5.3Hz,1H),7.69(dd,J=5.3,1.5Hz,1H),7.64(d,J=4.8Hz,1H),7.25(d,J=2.0Hz,1H),4.07-4.00(m,3H),2.15(s,3H)。
274E)N-(4-(7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
分幾個批次向2-(2-乙醯胺基吡啶-4-基)-1H-吡咯并[3,2-b]吡啶-7-羧酸甲酯(0.6g,1.93mmol)含於MeOH(15mL)及THF(15mL)之溶液中添加LiBr(0.34g,3.87mmol)及NaBH4(0.37g,9.67mmol)。在室溫下攪拌該反應混合物3小時。在真空中濃縮該反應混合物。使用
CHCl3:2-丙醇(2:1)萃取該殘留物。使用飽和NaHCO3溶液清洗有機層,經MgSO4乾燥,在真空中濃縮以獲得黃色固體之期望產物(0.28g,51%)。HPLC:RT=0.44min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=283.1[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.58(d,J=5.9Hz,1H),8.48(d,J=5.3Hz,1H),7.84(d,J=6.2Hz,1H),7.70(dd,J=5.4,1.7Hz,1H),7.37(s,1H),5.27(s,2H),2.25(s,3H)。
274F)N-(4-(7-(羥甲基)-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向N-(4-(7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(25mg,0.089mmol)含於DMF(1mL)之溶液中添加NIS(22mg,0.097mmol)。在室溫下攪拌該反應混合物1小時。藉由製備型HPLC純化該反應混合物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(13mg,36%);HPLC:RT=0.48min(H2O/ACN及0.05% TFA,Waters Acquity SDS C18,2.1x50mm,1.7-μm粒子,梯度=1.8min,波長=220nm);MS(ES):m/z=408.8[M+H]+;1H NMR(400MHz,MeOH-d4)δ ppm 8.64(s,1H),8.60(d,J=6.2Hz,1H),8.52(d,J=5.3Hz,1H),7.89(d,J=6.2Hz,1H),7.59(dd,J=5.2,1.7Hz,1H),5.23(s,2H),2.24(s,3H)。
實例274 N-(4-(7-(羥甲基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用氮氣流沖洗N-(4-(7-(羥甲基)-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺(60mg,0.147mmol)及(6-甲氧基吡啶-3-基)硼酸(27.0mg,0.176mmol)含於二噁烷(2mL)及Na2CO3水溶液(0.37mL,0.37mmol)之懸浮液3min,接著添加PdCl2(dppf)(10.8mg,0.015mmol)。於90℃加熱所得混合物2h。在真空中濃縮該反應混合物。藉由製備型HPLC純化該殘留物。合併、濃縮、及凍乾含有期望產物之溶離份以獲得黃色固體之期望產物(23mg,39%);HPLC:RT=0.71min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.75(s,1H),10.58(s,1H),8.38(d,J=4.6Hz,1H),8.31(d,J=5.1Hz,1H),8.28(s,1H),8.21(d,J=1.9Hz,1H),7.77(dd,J=8.5,2.3Hz,1H),7.28(d,J=4.5Hz,1H),7.12(d,J=4.0Hz,1H),6.85(d,J=8.5Hz,1H),5.55(t,J=5.7Hz,1H),4.90(d,J=5.6Hz,2H),3.86(s,3H),2.08(s,3H)。
N-(4-(3-(6-氟代吡啶-2-基)-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由2-溴-6-氟代吡啶製備實例275。HPLC:RT=0.72min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220
nm);MS(ES):m/z=377.9[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.57(s,1H),8.46(d,J=4.7Hz,1H),8.34(d,J=5.1Hz,1H),8.24(d,J=4.2Hz,2H),8.03(q,J=8.1Hz,1H),7.32(d,J=4.6Hz,1H),7.22(d,J=5.1Hz,1H),6.97(dd,J=8.1,2.4Hz,1H),4.91(s,2H),2.08(s,3H)。
N-(4-(3-(6-氯代吡啶-2-基)-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由2-溴-6-氯代吡啶製備實例276。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.59(s,1H),8.49(d,J=4.8Hz,1H),8.35(d,J=5.1Hz,1H),8.28(s,1H),8.22(d,J=6.9Hz,1H),7.90(t,J=7.8Hz,1H),7.38(d,J=4.6Hz,1H),7.33(d,J=7.8Hz,1H),7.23(d,J=5.1Hz,1H),4.94(s,2H),2.09(s,3H)。
N-(4-(3-(6-氟代吡啶-3-基)-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由5-溴-2-氟代吡啶製備實例277。HPLC:RT=0.63min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=378.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.61(s,1H),8.45-8.33(m,2H),8.27(br.s.,2H),8.13-7.99(m,1H),7.31(d,J=4.5Hz,1H),7.25-7.12(m,2H),4.92(s,2H),2.08(s,3H)。
N-(4-(3-(6-氯代吡啶-3-基)-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由5-溴-2-氯代吡啶製備實例278。HPLC:RT=0.71min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=394.1[M+H]+;1H NMR(500MHz,DMSO-d6)δ
ppm 13.01(br.s.,1H),10.70(s,1H),8.60(d,J=5.6Hz,1H),8.47(d,J=2.1Hz,1H),8.40(d,J=5.0Hz,1H),8.26(s,1H),7.92(dd,J=8.2,2.3Hz,1H),7.68(d,J=5.4Hz,1H),7.61(d,J=8.2Hz,1H),7.17(d,J=3.5Hz,1H),5.10(s,2H),2.08(s,3H)。
N-(4-(7-(羥甲基)-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由2-溴-6-甲基吡啶製備實例279。HPLC:RT=0.58min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374.2[M+H]+。
N-(4-(7-(羥甲基)-3-(6-甲基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例274顯示之一般方法由5-溴-2-甲基吡啶製備實例
280。HPLC:RT=0.47min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374.2[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.66(s,1H),8.68(br.s.,1H),8.48(d,J=4.9Hz,1H),8.36(d,J=5.0Hz,1H),8.27(br.s.,1H),8.03(br.s.,1H),7.54(d,J=8.2Hz,1H),7.45(br.s.,1H),7.16(d,J=4.5Hz,1H),4.98(s,2H),2.59(s,3H),2.08(s,3H)。
N-(4-(3-(6-(二氟甲基)吡啶-2-基)-1H-吡咯并[3,2-b] 吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例1D及2-溴-6-(二氟甲基)吡啶製備實例281。HPLC:RT=0.83min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=380[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.56(s,1H),8.49(d,J=4.3Hz,1H),8.44-8.26(m,3H),8.07(t,J=7.8Hz,1H),7.93(d,J=8.1Hz,1H),7.55(d,J=7.7Hz,1H),7.38-7.22(m,2H),6.84-6.48(m,1H),2.09(s,3H)。
N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
282A):N-(4-((3-胺基-5-甲氧基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
藉由與針對實例1C顯示之相似方法由實例1B及2-溴-5-甲氧基吡啶-3-胺製備實例282A。HPLC:RT=0.80min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=283[M+H]+。
282B):N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-甲氧基吡啶-3-基)-2,2,2-三氟乙醯胺
藉由與針對實例1D顯示之彼等相似之方法由實例282A製備實例282B。HPLC:RT=0.97min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=379[M+H]+。
藉由針對實例1顯示之一般方法由實例282B及2-溴-6-(二氟甲基)吡啶製備實例282。HPLC:RT=0.94min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=410[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.65(s,1H),8.46-8.24(m,4H),8.14(br.s.,1H),8.09-7.99(m,1H),7.79-7.49(m,3H),7.25(d,J=4.9Hz,2H),6.97-6.56(m,2H),3.94(s,3H),2.09(s,3H)。
N-(4-(6-甲氧基-3-(6-甲基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例282B及2-溴-6-甲基吡啶製備實例283。HPLC:RT=0.74min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=374[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.67(s,1H),8.42(d,J=5.0Hz,1H),8.38-8.26(m,2H),8.19(br.s.,1H),7.84(d,J=7.9Hz,1H),7.71(d,J=6.8Hz,1H),7.53(s,1H),7.30(d,J=4.7Hz,1H),3.94(s,3H),2.66(s,3H),2.08(s,3H)。
N-(4-(6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-
基)吡啶-2-基)乙醯胺
藉由針對實例1顯示之一般方法由實例282B及2-溴-5-甲氧基吡啶製備實例284。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.81(br.s.,1H),10.51(br.s.,1H),8.40-8.07(m,4H),7.95(d,J=4.8Hz,1H),7.49(br.s.,1H),7.35(br.s.,1H),7.11(br.s.,1H),3.99-3.76(m,6H),2.09(br.s.,3H)。
N-(4-(6-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
285A):N-(4-(6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向282A含於THF(4mL)之溶液中添加1M第三丁醇鉀之THF(2.1mL,2.1mmol)溶液。將該混合物加熱至70℃並攪拌2.5h,隨後冷卻至室溫。將該半固體溶於MeOH,並以乾燥形式負載在矽藻土上,及隨後藉由矽膠層析法(24g,MeOH/DCM=0至10%)純化以獲得285A(187mg,94%)。HPLC:RT=0.82min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=283[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 11.84(s,1H),10.53(s,1H),8.46(s,1H),8.35(dd,J=5.3,0.7Hz,1H),8.15(d,J=2.6Hz,1H),7.54(dd,J=5.3,1.5Hz,1H),7.33-7.26(m,1H),7.11(d,J=1.5Hz,1H),3.87(s,3H),2.15(s,3H)。
285B):N-(4-(3-溴-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例14B顯示之一般方法由實例285A製備實例285B。HPLC:RT=0.84min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=361[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm
12.10(s,1H),10.62(s,1H),8.73(s,1H),8.49-8.39(m,1H),8.23(d,J=2.4Hz,1H),7.57(dd,J=5.3,1.8Hz,1H),7.33(d,J=2.4Hz,1H),3.90(s,3H),2.15(s,3H)。
藉由針對實例14顯示之一般方法由實例285B及(6-甲氧基吡啶-3-基)硼酸製備實例285。HPLC:RT=1.19min(H2O/ACN及10mM乙酸銨,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=390[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 11.86(s,1H),10.56(s,1H),8.29(d,J=5.0Hz,2H),8.23(s,1H),8.17(s,1H),7.77(d,J=8.5Hz,1H),7.36(s,1H),7.09(d,J=5.1Hz,1H),6.86(d,J=8.5Hz,1H),3.88(br.s.,3H),3.87(br.s.,3H),2.09(s,3H)。
N-(4-(3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-嗎啉乙醯胺
286A):2-氯-N-(4-(3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例74A顯示之一般方法由實例52製備實例286A。HPLC:RT=0.87min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=394[M+H]+。
N-(4-(3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-嗎啉乙醯胺
於室溫攪拌286A(30mg,0.076mmol)、嗎啉(19.91mg,0.229mmol)及K2CO3(31.6mg,0.229mmol)含於DMF(0.5mL)之混合物3h。使用EtOAc稀釋,所得混合物經矽藻土過濾,並使用10% MeOH/DCM洗脫。濃縮該濾液。藉由製備型HPLC(管柱:Waters XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至60% B在15分鐘內,隨後5於100% B維持5分鐘;流速:20mL/min)純化該殘留物以獲得實例286(19.6mg,58%)。HPLC:RT=0.62min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=445[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.08(br.s.,1H),10.12(s,1H),8.50-8.30(m,4H),8.25(br.s.,1H),7.88(d,J=8.2Hz,1H),7.80(d,J=8.5Hz,1H),7.26(dd,J=7.8,4.5Hz,1H),7.18(d,J=4.8Hz,1H),6.87(d,J=8.4Hz,1H),3.88(s,3H),3.63(br.s.,3H),3.44(br.s.,4H),3.20(s,2H)。
N-(4-(3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
藉由針對實例286顯示之一般方法由實例286A及1-甲基哌嗪製備實例287。HPLC:RT=0.59min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=458[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 10.04(s,1H),8.50-8.31(m,3H),8.26(s,1H),7.88(d,J=8.2Hz,1H),7.84-7.74(m,1H),7.26(dd,J=8.1,4.5Hz,1H),7.18(d,J=5.0Hz,1H),6.87(d,J=8.5Hz,1H),3.88(s,3H),2.53-2.36(m,10H),2.21(s,3H)。
2-(4-(2-羥乙基)哌嗪-1-基)-N-(4-(3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例286顯示之一般方法由實例286A及2-(哌嗪-1-基)乙醇製備實例288。HPLC:RT=0.62min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=488[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 8.41(d,J=4.0Hz,1H),8.37-8.30(m,2H),8.24(s,1H),7.88(d,J=7.9Hz,1H),7.83-7.70(m,1H),7.26(dd,J=8.1,4.5Hz,1H),7.18(d,J=5.5Hz,1H),6.87(d,J=8.5Hz,1H),3.88(s,3H),3.51(br.s.,2H),2.51(br.s.,12H),1.91(s,2H)。
4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-胺
藉由針對實例14顯示之一般方法由實例43製備實例289。HPLC:RT=0.91min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,
2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=352[M+H]+;1H NMR(400MHz,DMSO-d6)δ ppm 12.07(s,1H),8.39(d,J=2.2Hz,1H),8.28(d,J=1.8Hz,1H),7.96(d,J=5.3Hz,1H),7.89(d,J=2.2Hz,1H),7.79(dd,J=8.6,2.4Hz,1H),6.88(d,J=8.6Hz,1H),6.62-6.50(m,2H),6.09(s,2H),3.89(s,3H)。
N-(4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-嗎啉乙醯胺
290A):2-氯-N-(4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
藉由針對實例74A顯示之一般方法由實例289製備實例290A。HPLC:RT=0.98min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);
MS(ES):m/z=428[M+H]+。
藉由針對實例286顯示之一般方法由實例290A及嗎啉製備實例290。HPLC:RT=1.01min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=479[M+H]+;1H NMR(500MHz,DMSO-d6)δ ppm 12.28(s,1H),10.14(br.s.,1H),8.42(s,1H),8.38-8.30(m,2H),8.23(s,1H),7.97(s,1H),7.77(d,J=8.5Hz,1H),7.17(d,J=5.0Hz,1H),6.88(d,J=8.6Hz,1H),3.88(s,3H),3.63(br.s.,4H),3.24-3.13(m,2H)。
N-(4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)-2-(4-乙基哌嗪-1-基)乙醯胺
藉由針對實例286顯示之一般方法由實例290A及1-乙基哌嗪製備實例291。HPLC:RT=1.05min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=506[M+H]+。
N-(4-(6-氯-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡
啶-2-基)-2-(4-甲基哌嗪-1-基)乙醯胺
藉由針對實例286顯示之一般方法由實例290A及1-甲基哌嗪製備實例292。HPLC:RT=1.03min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.1x50mm,1.7-μm粒子,梯度=3min,波長=220nm);MS(ES):m/z=492[M+H]+。
N-(4-(3-(5-甲氧基吡啶-2-基)-6-((甲胺基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
293A)N-(4-((3-胺基-5-溴代吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
使用N2沖洗2,5-二溴吡啶-3-胺(6.89g,27.3mmol,獲自Combi-Blocks,Inc.)、N-(4-乙炔基吡啶-2-基)乙醯胺(3.98g,24.85mmol)、碘化銅(I)(0.237g,1.242mmol)含於三乙胺(90mL)及DMF(70mL)之混合物。添加固體PdCl2(PPh3)2(0.174g,0.248mmol)並使用N2沖洗該反應混合物。在N2氛圍下於75℃加熱該反應混合物90min及隨後在真空中濃縮。向該殘留物中添加100mL CH2Cl2且所得混合物經簡單超音波處理並於室溫攪拌10分鐘。過濾該固體並使用CH2Cl2清洗以在乾燥後獲得期望化合物(5.1g)。濃縮該濾液及殘留物與矽藻土混合,使其經過SiO2急驟管柱(固體負載,梯度100% CH2Cl2至10% MeOH在CH2Cl2中)以獲得額外期望產物(0.9g)。共6g(73%)。MS(ES):m/z=331、333[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.62(s,1H),8.35(d,J=5.0Hz,1H),8.23(s,1H),7.86(d,J=1.7Hz,1H),7.37-7.33(m,2H),6.13(s,1H),2.11(s,3H)。
293B)N-(2-((2-乙醯胺基吡啶-4-基)乙炔基)-5-溴代吡啶-3-基)-2,2,2-三氟乙醯胺
於冰浴溫度向293A(4g,12.08mmol)及Et3N(6nL)含於CH2Cl2(100mL)之非均勻混合物中緩慢添加2,2,2-三氟乙酸酐(1.4
mL,10.07mmol)並於冰浴溫度攪拌1h。該反應混合物與二鹼式磷酸鹽緩衝液(4.5g K2HPO4在30mL水中)混合,分離有機層,經MgSO4乾燥,在真空中濃縮及該殘留物經過SiO2急驟管柱(梯度100% CH2Cl2至100% EtOAc,於40至55% EtOAc洗脫該產物)以獲得白色固體293B(2.8g,6.55mmol,54%)。MS(ES):m/z=427、429[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.94(d,J=2.0Hz,1H),8.69(br.s.,1H),8.58(d,J=2.0Hz,1H),8.50(br.s.,1H),8.31(d,J=4.6Hz,1H),2.27(s,3H)。
293C)N-{4-[6-溴-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺
使用N2沖洗密封管中之293B(1.5g,3.51mmol)、2-溴-5-甲氧基吡啶(1.651g,8.78mmol)及碳酸銫(2.86g,8.78mmol)含於MeCN(13mL)之混合物。添加Pd(Ph3P)4(0.406g,0.351mmol)並使用N2再次沖洗該混合物。將該反應混合物放入110℃預熱加熱器中,於該溫度攪拌3h並冷卻至室溫。向該反應混合物中添加15mL水,攪拌該混合物並隨後藉由過濾收集固體,先後使用水及CH2Cl2清洗以獲得293C(1g,2.282mmol,65%)。MS(ES):m/z=438、440[M+H]+;1H NMR(400MHz,DMSO-d6)δ 12.16(s,1H),10.53(s,1H),8.49(d,J=2.0Hz,1H),8.31(s,1H),8.28(d,J=5.3Hz,1H),8.20(d,J=2.9Hz,1H),8.06(d,J=2.0Hz,1H),7.95-7.92(m,1H),7.49(dd,J=8.6,3.1Hz,1H),
7.12(dd,J=5.1,1.5Hz,1H),3.86(s,3H),2.09(s,3H)。
293D)N-(4-(6-溴-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌293C(765mg,1.745mmol)、碳酸銫(1137mg,3.49mmol)及(2-(氯代甲氧基)乙基)三甲基矽烷(437mg,2.62mmol)含於THF(12mL)及DMF(12mL)之混合物30min。在該反應混合物中添加CH2Cl2及水。分離CH2Cl2層,經MgSO4乾燥,在真空中濃縮及藉由SiO2急驟管柱(梯度100% CH2Cl2至80% EtOAc在CH2Cl2中,於含於CH2Cl2之30至40% EtOAc洗脫產物)純化該殘留物以獲得294D(625mg,1.099mmol,63%)。MS(ES):m/z=568、570[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.65(d,J=2.0Hz,1H),8.33(s,1H),8.28-8.24(m,2H),8.05(d,J=2.0Hz,1H),7.80(d,J=8.6Hz,1H),7.30(dd,J=8.7,3.0Hz,1H),7.14(dd,J=5.2,1.4Hz,1H),5.43(s,2H),3.85(s,3H),3.42-3.36(m,2H),2.19(s,3H),0.85-0.80(m,2H),-0.08(s,9H)。
293E)N-(4-(6-甲醯基-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
伴隨攪拌,在N2下於-78℃向293D(740mg,1.302mmol)含於THF(8mL)之溶液中添加1mL含於醚之1.6M MeLi。在15分鐘內,於-78℃添加0.8mL 2M nBuLi溶液,攪拌15分鐘。向所得非均勻混合物中添加1mL DMF並攪拌40分鐘。添加HOAc(1mL),並將該混合物濃縮至體積約4mL並隨後使該殘留物經過SiO2急驟管柱使用100% CH2Cl2至10% MeOH之CH2Cl2溶液之梯度洗脫(於約50%之10% MeOH之CH2Cl2溶液洗脫產物)以獲得293E(130mg,0.251mmol,19%)。MS(ES):m/z=518[M+H]+;1H NMR(400MHz,氯仿-d)δ 10.18(s,1H),9.43(s,1H),9.04(d,J=1.5Hz,1H),8.42-8.40(m,2H),8.32-8.38(m,2H),7.84(d,J=8.6Hz,1H),7.18(dd,J=8.7,3.0Hz,1H),7.04(dd,J=5.2,1.2Hz,1H),5.53(s,2H),3.81(s,3H),3.44-3.37(m,2H),2.09(s,3H),0.86-0.77(m,2H),-0.45(s,9H)。
實例293)N-(4-(3-(5-甲氧基吡啶-2-基)-6-((甲胺基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌293E(40mg,0.077mmol)及0.6mL 2M MeNH2之THF溶液含於CH2Cl2(2mL)及iPrOH(2mL)之混合物20min。在冰浴中冷卻該反應混合物並添加NaBH4(約50mg)。攪拌該反應混合物30min。添加丙酮(5mL),並攪拌該混合物10分鐘。添加TFA(約1mL)及在真空中濃縮該混合物及藉由Prep HPLC純化該殘留物以獲得約17mg呈TFA鹽之SEM保護之甲胺基甲基中間物。Prep HPLC:管柱#1,20% B至
100% B在8min內,RT=3.6min。管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=533[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.84(d,J=1.5Hz,1H),8.64(d,J=1.8Hz,1H),8.59(dd,J=5.1,0.9Hz,1H),8.55(d,J=2.6Hz,1H),8.35(s,1H),7.76(dd,J=9.1,3.0Hz,1H),7.38(d,J=9.0Hz,1H),7.34(dd,J=5.1,1.5Hz,1H),4.55(s,2H),3.99(s,3H),3.48(dd,J=8.8,7.7Hz,2H),2.84(s,4H),2.18(s,3H),0.88-0.67(m,2H),-0.07(s,9H)。
上文獲得之SEM保護之甲胺基甲基中間物與1.5mL CH2Cl2及1.5mL TFA於室溫混合並於室溫攪拌1h。在真空中濃縮該混合物並藉由prep HPLC純化該殘留物以獲得實例294(1.6mg,5%總產率)。Prep HPLC:管柱#1,10% B至60% B在8min內,RT=2.7至4min。管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-5mmol NH4OAc;溶劑B=90% CH3CN/10% H2O--5mmol NH4OAc。分析型HPLC:RT=0.48min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=403[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.47(d,J=2.0Hz,1H),8.28(d,J=2.6Hz,1H),8.27-8.24(m,2H),8.08(d,J=2.0Hz,1H),7.63(dd,J=8.6,0.4Hz,1H),7.53(dd,J=8.7,3.0Hz,1H),7.11-7.08(m,1H),4.37(s,2H),3.95(s,3H),2.77(s,3H),2.16(s,3H)。
N-(4-(3-(5-甲氧基吡啶-2-基)-6-((丙胺基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
以如實例293之相似方式製備實例294。HPLC:RT=0.55min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=431[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.54(s,1H),8.43(s,1H),8.31(br.s.,1H),8.27(d,J=5.0Hz,1H),8.18(d,J=2.5Hz,1H),8.00(d,J=8.7Hz,1H),7.88(s,1H),7.49(dd,J=8.5,2.7Hz,1H),7.12(d,J=4.9Hz,1H),4.04(s.,2H),3.44(br.s.,3H),2.66(t,J=7.3Hz,2H),2.54(s,2H),2.09(s,3H),1.58-1.48(m,2H),0.89(t,J=7.4Hz,3H)。
3-(2-(2-乙醯胺基吡啶-4-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-6-基)-2,2-二氟-3-羥基丙醯胺
295A)3-(2-(2-乙醯胺基吡啶-4-基)-3-(5-甲氧基吡啶-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-6-基)-2,2-二氟-3-羥基丙醯胺
在N2氛圍下向醛293E(100mg,0.193mmol)含於THF(3mL)之溶液中添加7mL(2-乙氧基-1,1-二氟-2-氧乙基)溴化鋅(II)(0.5M溶液在THF中,獲自Rieke Metals,RiekeMetals.com)。於室溫攪拌該反應混合物4h。於室溫添加7N NH3之MeOH溶液(4mL)。過濾所得固體並在真空中濃縮該濾液。該殘留物經過SiO2急驟管柱使用10% MeOH之CH2Cl2溶液-CH2Cl2溶劑系統之梯度洗脫以獲得實例295A(20mg,0.033mmol,17%)。MS(ES):m/z=613[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.56(d,J=5.1Hz,1H),8.54(br.s.,1H),8.34(br.s.,1H),8.02(br.s.,1H),7.94(s,1H),7.34(dd,J=9.2,2.9Hz,1H),7.28(d,J=4.0Hz,1H),7.10(d,J=9.2Hz,1H),5.58(s,2H),3.77(s,3H),3.45-3.39(m,2H),3.27(dt,J=3.2,1.6Hz,1H),2.17(s,3H),0.81-0.75(m,2H),-0.12(s,9H)。
實例295)3-(2-(2-乙醯胺基吡啶-4-基)-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-6-基)-2,2-二氟-3-羥基丙醯胺
於室溫向295A(20mg,0.033mmol)含於CH2Cl2(5mL)之溶液中添加1mL TFA並攪拌3h。濃縮該反應混合物,及向該殘留物中添加0.3mL Et3N。濃縮該混合物及該殘留物與0.3mL Et3N混合,及隨後經過使用CH2Cl2至10% MeOH之CH2Cl2溶液之梯度洗脫之SiO2急驟管柱。接著經20% MeOH及1% Et3N之CH2Cl2溶液洗脫以獲得約24mg輕微不純產物。藉由prep HPLC(RT=2.7至3.4min)再次純化此材料以獲
得實例295(4.5mg,8.39μmol,26%)。Prep HPLC:管柱#1,20% B至100% B在8min內;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-5mmol NH4OAc;Solvent B=90% CH3CN/10% H2O--5mmol NH4OAc。分析型HPLC:RT=0.54min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=483[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.45(s,1H),8.27(d,J=2.9Hz,1H),8.25-8.22(m,2H),8.05(d,J=1.1Hz,1H),7.64(d,J=8.6Hz,1H),7.53(dd,J=8.6,2.9Hz,1H),7.12-7.09(m,1H),5.37(dd,J=16.3,8.6Hz,1H),3.95(s,3H),2.15(s,3H)。
N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟乙醯基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
296A)N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟乙醯基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,2(99893-307)
於-78℃向實例293D(300mg,0.528mmol)含於THF(5mL)之溶液中添加0.4mL含於醚之1.6M MeLi溶液。在10分鐘後添加0.25mL含於己烷之2.5M BuLi溶液並於-78℃攪拌該混合物30min。添加2,2,2-三氟-N-甲基-N-(2,2,2-三氟乙醯基)乙醯胺(0.2mL,0.528mmol)(獲自TCI公司)及攪拌該混合物1h。向該反應混合物中添加MeOH及100μL TFA。將該混合物溫熱至室溫及直接藉由prep HPLC純化以獲得部分純化產物,其按原樣用於下一步驟。Prep HPLC:管柱#1,20% B至100% B在8min內,RT=5.2至6min。管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。LCMS顯示水合質量,MS(ES):m/z=604[M+H2O+H]+。
實例296)N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟乙醯基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
上文獲得之部分純化材料(實例296A)與5mL CH2Cl2及2mL TFA於室溫混合並攪拌7.5h。隨後在真空中濃縮該反應混合物及藉由prep HPLC純化該殘留物:RT=3.1min。Prep HPLC:管柱#1,20% B至100% B在8min內,管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。獲得之材料藉由prep HPLC再次純化以獲得實例297(9mg,0.018mmol,3%)。管柱#1=Waters Sunfire C-18,19x150mm;
溶劑A=10% CH3CN/90% H2O-5mmol NH4OAc;溶劑B=90% CH3CN/10% H2O--5mmol NH4OAc,9mg,(0.018mmol,3.37%產率)。分析型HPLC:RT=0.63min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。LCMS顯示水合質量。MS(ES):m/z=474[M+H2O+H]+;1H NMR(400MHz,甲醇-d4)δ 8.70(d,J=1.1Hz,1H),8.31-8.23(m,4H),7.67-7.60(m,1H),7.55-7.50(m,1H),7.13(dd,J=5.2,1.7Hz,1H),3.94(s,3H),2.14(s,3H)。
N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟-1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
297A)N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟-1-羥乙基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
伴隨攪拌,於冰浴溫度一小份一小份地向含於MeOH(5mL)中之部分純化實例296A(110mg)添加50mg NaBH4。在1h後,該反應混合物經3mL丙酮處理,攪拌10min,並使用0.4mL HOAc淬冷。在真空中濃縮該混合物並藉由prep HPLC純化該殘留物以獲得65mg呈TFA鹽之醇。Prep HPLC:管柱#1,20% B至100% B在8min內,RT=5.6min管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90%
H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA MS(ES):m/z=588[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.86(s,1H),8.78(s,1H),8.59(dd,J=5.1,0.4Hz,1H),8.51(d,J=2.6Hz,1H),8.36(s,1H),7.58(dd,J=9.1,3.0Hz,1H),7.35(dd,J=5.1,1.5Hz,1H),7.23(d,J=9.0Hz,1H),5.63(s,2H),5.55(q,J=6.8Hz,1H),3.94(s,3H),3.52-3.47(m,2H),2.20(s,3H),0.87-0.81(m,2H),-0.09(s,9H)。
實例297:N-(4-(3-(5-甲氧基吡啶-2-基)-6-(2,2,2-三氟-1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫向實例297A之TFA鹽(65mg,0.093mmol)含於CH2Cl2(4mL)之溶液中添加2mL TFA。於室溫4h後,在真空中濃縮該混合物並藉由prep HPLC純化該殘留物以獲得實例297(23mg,0.048mmol,52%產率)。Prep HPLC:管柱#1,20% B至100% B在8min內,RT=4.8min;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-5mmol NH4OAc;溶劑B=90% CH3CN/10% H2O--5mmol NH4OAc。分析型HPLC:RT=0.64min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=458[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.46(d,J=1.1Hz,1H),8.27(d,J=2.9Hz,1H),8.23(d,J=4.8Hz,2H),8.08(s,1H),7.65(d,J=8.6Hz,1H),7.52(dd,J=8.7,3.0Hz,1H),7.12-7.09(m,1H),5.29(q,J=7.0Hz,1H),3.94(s,3H),
2.15(s,3H)。
N-(4-(7-乙醯基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
298A)3-胺基-2,6-二溴異煙鹼腈
於室溫下伴隨攪拌,在45min內分若干部分向3-胺基異煙鹼腈(9g,76mmol)含於MeOH(120mL)之溶液中添加固體N-溴代丁二醯亞胺(26.9g,151mmol)。於室溫攪拌該反應混合物2h。在該反應混合物中添加額外5g NBS並繼續於室溫攪拌1h。在真空中濃縮該反應混合物及向該殘留物添加iPrOH(約120mL)。過濾所得固體並使用Et2O清洗以獲得15g黃色固體。該固體與水(45mL)混合,經超音波處理並攪拌。隨後藉由過濾收集所得固體並使用水清洗以獲得10g期望產物。在真空中濃縮初始iPrOH濾液且該殘留物與水混合,過濾該固體,經Et2O清洗以獲得棕黑色固體。將其懸浮於CHCl3中,藉由過濾移除不溶性黑色固體並濃縮該濾液。該殘留物與水混合、經超音波處理、攪拌及藉由過濾收集該固體以獲得2.78g第二批次之實例298A。共12.8g(61%)。MS(ES):m/z=276、278、280[M+H]+;1H NMR(400MHz,
CDCl3)δ 7.29(s,1H),2.80(s,2H)。
298B)N-(4-((3-胺基-6-溴-4-氰基吡啶-2-基)乙炔基)吡啶-2-基)乙醯胺
使用N2沖洗實例298A(7.4g,26.7mmol)、實例1B(3.85g,24.05mmol)及碘化銅(I)(0.254g,1.336mmol)含於DMF(60mL)及Et3N(60mL)之混合物。添加固體PdCl2(Ph3P)2(0.938g,1.336mmol)並於75℃在N2氛圍下加熱該混合物30min。過濾所得固體,使用CH2Cl2清洗並乾燥以獲得第一批次之實例298B(6.8g)。將該濾液濃縮至體積25mL。添加水(100mL)及CH2Cl2(100mL),並攪拌混合物20分鐘。過濾所得固體並依次使用水、CH2Cl2及iPrOH清洗,以獲得不純產物(約2.1g)。再次使用CH2Cl2研磨此不純材料以獲得第二批次之產物(900mg)。共7.7g(81%)。MS(ES):m/z=356,358[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.38(s,1H),8.31(dd,J=5.2,0.8Hz,1H),7.97(br.s.,1H),7.46(s,1H),7.21(dd,J=5.1,1.5Hz,1H),5.10(br.s.,2H),2.25(s,3H)。
298C)N-(4-(5-溴-7-氰基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用N2沖洗實例298B(6.4g,17.97mmol)及碳酸銫(6.44g,
19.77mmol)含於DMF(100mL)之不均勻混合物並經Pd(Ph3P)4(1.038g,0.898mmol)處理。再次使用N2沖洗該混合物並於80℃在N2氛圍下加熱1h。隨後將其濃縮至體積約60mL並添加水(350mL)及40mL CH2Cl2(40mL)。於室溫攪拌該混合物,及收集所得固體並先後使用少量iPrOH及CH2Cl2清洗,以在乾燥後獲得實例298C(5.3g,14.88mmol,83%)。MS(ES):m/z=356、358[M+H]+;1H NMR(400MHz,DMSO-d6)δ 13.08(br.s.,1H),10.65(br.s.,1H),8.57(br.s.,1H),8.44(br.s.,1H),7.92(br.s.,1H),7.72(s.,1H),7.32(s.,1H),2.15(s.,3H)。
298D)N-(4-(5-溴-7-氰基-3-碘-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌實例298C(600mg,1.685mmol)及N-碘代丁二醯亞胺(379mg,1.685mmol)含於THF(10mL)之不均勻混合物1h。在真空中濃縮大部分該反應混合物,及該殘留物與CH2Cl2及水混合並過濾該固體。使用水及CH2Cl2清洗該固體以獲得實例298D(670mg,1.390mmol,83%)。MS(ES):m/z=482、484[M+H]+;1H NMR(400MHz,DMSO-d6)δ 13.49(s,1H),10.72(s,1H),8.65(s,1H),8.51(d,J=5.1Hz,1H),8.05(s,1H),7.55(dd,J=5.1,1.5Hz,1H),2.15(s,3H)。
298E)N-(4-(5-溴-7-氰基-3-碘-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌實例298D(4.5g,9.33mmol)、許尼希氏鹼(Hunig's Base)(2.119mL,12.14mmol)及(2-(氯代甲氧基)乙基)三甲基矽烷(1.712g,10.27mmol)含於CH2Cl2(70mL)之不均勻混合物。其緩慢變為均勻溶液及該反應在1h內完成。向該反應混合物中添加水,分離CH2Cl2層,經MgSO4乾燥,及在真空中濃縮。所得殘留物經過SiO2急驟管柱並使用己烷-EtOAc梯度洗脫以獲得實例298E(4.2g,6.86mmol,74%)。於含於己烷之40至55%EtOAc洗脫期望產物。MS(ES):m/z=612、614[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.51(br.s.,1H),8.46(d,J=5.3Hz,1H),7.69(s,1H),7.34(d,J=4.4Hz,1H),7.28-7.28(m,1H),5.65(s,2H),3.56-3.35(m,2H),2.29(s,3H),0.97-0.77(m,2H),0.00--0.19(m,9H)。
298F)N-(4-(5-溴-7-氰基-3-(6-甲氧基吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
使用N2沖洗實例298E(1.8g,2.94mmol)、(6-甲氧基吡啶-3-基)硼酸(0.899g,5.88mmol)及0.25mL 3M K3PO4含於二噁烷(20mL)之混合物。添加PdCl2(dppf)(0.215g,0.294mmol),再次使用N2沖洗該
反應並將該混合物置入預熱之100℃加熱器中。於100℃在N2下攪拌60min,隨後冷卻至室溫。該反應混合物與CH2Cl2及無水Na2SO4混合、攪拌、過濾該固體、使用CH2Cl2清洗並在真空中濃縮該濾液。藉由SiO2急驟管柱純化並使用梯度(己烷-EtOAc)洗脫該殘留物以獲得實例298F(800mg,1.348mmol,46%)。MS(ES):m/z=593、595[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.32(br.s.,1H),8.03(s,1H),7.95(d,J=4.6Hz,1H),7.77(d,J=2.2Hz,1H),7.33(dd,J=8.6,2.2Hz,1H),6.89(s,1H),6.66(d,J=4.4Hz,1H),6.36(d,J=8.6Hz,1H),5.27(s,2H),3.54(s,3H),3.16-3.10(m,2H),1.85(s,3H),0.56-0.50(m,2H),-0.43(s,9H)。
298G)N-(4-(7-乙醯基-3-(6-甲氧基吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於-78℃在N2下向實例298F(45mg,0.076mmol)含於THF之溶液中添加MeLi溶液(0.5mL,1.6M在醚中)並攪拌30min。添加nBuLi溶液(0.2mL,2.5M在己烷中)並攪拌該混合物6min。向該反應混合物中添加0.5mL HOAc,並攪拌5min。添加CH2Cl2及水,分離有機層,在真空中濃縮及prep HPLC獲得實例298G(7mg,0.013mmol,17%)。Prep HPLC:管柱#1,20% B至100% B在8min內,管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=
532[M+H]+;1H NMR(400MHz,氯仿-d)δ 12.01(br.s.,1H),8.81(d,J=4.2Hz,1H),8.67(s,1H),8.27(br.s.,1H),8.18(br.s.,1H),7.98(d,J=7.0Hz,1H),7.61(d,J=3.3Hz,1H),7.22(br.s.,1H),7.00(d,J=6.2Hz,1H),5.44(s,2H),4.04(s,3H),3.26-3.19(m,2H),2.80(s,3H),2.33(s,3H),0.80-0.73(m,2H),-0.05(s,9H)。
實例298)N-(4-(7-乙醯基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌實例298G(7mg,0.013mmol)及TFA(0.5mL)含於CH2Cl2(7mL)之混合物5h,並隨後在真空中濃縮。藉由prep HPLC純化該殘留物以獲得實例298之TFA鹽(4mg,6.89μmol,53%)。Prep HPLC:管柱#1,20% B至100% B在8min內,RT=2.5min;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。分析型HPLC:RT=0.62min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=402[M+H]+;1H NMR(400MHz,DMSO-d6)δ 11.74(br.s.,1H),10.58(s,1H),8.66-8.60(m,1H),8.34-8.27(m,2H),8.22(d,J=2.0Hz,1H),7.81(d,J=5.1Hz,1H),7.77(dd,J=8.5,2.3Hz,1H),7.14(d,J=4.0Hz,1H),6.85(d,J=8.6Hz,1H),3.87(s,3H),2.77(s,3H),2.09(s,3H)。
N-(4-(7-(2-羥基丙-2-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
向實例298之TFA鹽(50mg,0.097mmol)含於THF(2.5mL)之溶液中於冰浴溫度在N2氛圍下緩慢添加MeMgCl(0.8mL含3M溶液之THF)並攪拌。在40分鐘後,緩慢添加含於MeOH之TFA(0.4mL含於3mL MeOH中)並在真空中濃縮該反應混合物。該殘留物與EtOAc(15mL)混合,在真空中濃縮並藉由製備型HPLC純化以獲得實例299(10.9mg,0.026mmol,27%)。Prep HPLC:XBridge C18,19 x 200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速;20mL/min。分析型HPLC:RT=0.55min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C1,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=418[M+H]+;1H NMR(500MHz,DMSO-d6)δ 10.96-10.91(br.s,1H),10.60(s,1H),8.34(d,J=4.8Hz,1H),8.30(m,1H),8.27(s.,1H),8.19(,1H),7.80-7.74(m,1H),7.18(d,J=4.8Hz,1H),7.10(d,J=4.5Hz,1H),6.84(d,J=8.5Hz,1H),3.85(s,3H),2.54(s,1H),2.08(s,3H),1.64(s,6H)。
N-(4-(7-(1-羥基-2-甲基丙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
300A)N-(4-(5-溴-7-氰基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫攪拌實例298F(100mg,0.168mmol)及TFA(1mL)含於CH2Cl2(5mL)之混合物8h。在真空中濃縮該混合物以獲得約100mg粗產物。此材料直接用於下一步驟。HPLC:RT=0.86min(H2O/ACN及0.1% TFA,Waters Acquity UPLC BEH C18,2.0x50mm,1.7-μm粒子,梯度=2min,波長=220nm);MS(ES):m/z=462.9,464.9[M+H]+。
300B)N-(4-(5-溴-7-異丁醯基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
伴隨攪拌,於-78℃向實例300A TFA鹽(110mg,0.191mmol)含於THF(3mL)之溶液中添加2mL含於THF之2M iPrMgCl溶液。在2h後,在2h內將該混合物緩慢溫熱至室溫。將該反應混合物再次冷卻至-78℃並添加額外2mL 2M iPrMgCl溶液及隨後在1h內將該混合物溫熱至室溫。向該反應混合物中添加EtOAc(5mL)及HOAc(2mL)並攪拌10min。該混合物與CH2Cl2及NaHCO3水溶液混合。分離CH2Cl2層,隨後使用CH2Cl2清洗水層並在真空中濃縮己合併之CH2Cl2層。藉由prep HPLC純化該殘留物以獲得黃色固體之實例300B之TFA鹽(25mg,21%)。管柱#1,20% B至100% B在8min內,RTt=6.8min。管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=508、510[M+H]+;1H NMR(400MHz,氯仿-d)δ 12.65(br.s.,1H),10.59(br.s.,1H),8.91(s,1H),8.29(br.s.,1H),8.08(br.s.,1H),7.89-7.85(m,1H),7.84(s,1H),7.29(d,J=4.2Hz,1H),6.92(d,J=8.6Hz,1H),4.01(s,3H),3.66(hept,J=6.6Hz,1H),2.35(s,3H),1.33(d,J=6.6Hz,6H)。
實例300)N-(4-(7-(1-羥基-2-甲基丙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
在1atm H2下於室溫攪拌溴代甲酮實例300B(25mg)及20%
Pd(OH)2/C(25mg)含於MeOH(10mL)之混合物1.5h。過濾該固體,使用MeOH清洗,並在真空中濃縮該濾液。藉由prep HPLC純化該殘留物以獲得實例300(14.9mg,0.035mmol,86%)。Prep HPLC:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。分析型HPLC:RT=0.61min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=432[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.63(s,1H),10.60(br.s.,1H),8.37(d,J=4.6Hz,1H),8.32(d,J=5.1Hz,1H),8.27(br.s.,1H),8.21(br.s.,1H),7.78(d,J=8.3Hz,1H),7.23(d,J=4.6Hz,1H),7.12(d,J=4.6Hz,1H),6.84(d,J=8.6Hz,1H),5.45(br.s.,1H),4.96(t,J=5.0Hz,1H,應係dd,但顯示似乎係三重態),3.85(s,3H),2.08(s,3H),1.90(m,1H),0.89(t,J=6.5Hz,6H,應係d或dd,但顯示似乎其係三重態)。
N-(4-(7-(1-羥丙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
301A)N-(4-(5-溴-3-(6-甲氧基吡啶-3-基)-7-丙醯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
伴隨攪拌,於室溫向實例298F(358mg,0.603mmol)含於THF(3mL)之溶液中緩慢添加3mL含於THF之1M EtMgBr溶液。在30min後,將該反應混合物冷卻至-78℃並添加額外2mL 2M iPrMgCl溶液。在1h內將該混合物溫熱至室溫。向該反應混合物中添加EtOAc(5mL)及HOAc(2mL),並攪拌10min。該反應混合物與CH2Cl2及NaHCO3水溶液混合,分離有機層,使用CH2Cl2清洗水層。在真空中濃縮已合併之CH2Cl2層。藉由prep HPLC純化該殘留物以獲得實例301A(80mg,0.155mmol,26%)。管柱#1,20% B至100% B在8min內,RT=11min。管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=624、626[M+H]+;1H NMR(400MHz,氯仿-d)δ 11.92(br.s.,1H),8.71(s,1H),8.17(d,J=5.7Hz,1H),8.08(d,J=2.2Hz,1H),7.82(dd,J=8.6,2.4Hz,1H),7.46(s,1H),7.13(dd,J=5.7,1.3Hz,1H),6.85(d,J=8.6Hz,1H),5.33(s,2H),3.95(s,3H),3.15-3.13(m,2H),3.06(q,J=7.2Hz,2H),2.31(s,3H),1.29(t,J=7.2Hz,3H),0.74-0.69(m,2H),-0.08(s,9H)。
301B)N-(4-(5-溴-3-(6-甲氧基吡啶-3-基)-7-丙醯基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫向實例301A(40mg,0.064mmol)含於CH2Cl2(5mL)之溶液中添加1mL TFA。攪拌該混合物6h,隨後在真空中濃縮並藉由prep HPLC純化該殘留物以獲得實例301B之TFA鹽(20mg,0.033mmol,51%)。管柱#1,20% B至100% B在8min內,RT=6.3min;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=494、496[M+H]+;1H NMR(400MHz,甲醇-d4)δ 8.35(br.s.,1H),8.29(d,J=1.8Hz,1H),8.00(s,1H),7.94(dd,J=8.7,2.3Hz,1H),7.78(br.s.,1H),7.52(br.s.,1H),7.03(d,J=8.8Hz,1H),4.01(s,3H),3.22(q,J=7.1Hz,2H),2.26(s.,3H),1.28(t,J=7.0Hz,3H)。
實例301)N-(4-(7-(1-羥丙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於室溫在1atm H2下攪拌實例301B(20mg,0.033mmol)及12mg含20% Pd(OH)2/C含於MeOH(10mL)之混合物3.5h。過濾該反應混合物,並使用MeOH清洗該固體。在真空中濃縮該濾液及藉由prep HPLC純化該殘留物以獲得實例301(9.5mg,67%)。Prep HPLC:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。分析型HPLC:RT=0.57min(H2O/MeCN及0.1% TFA,Waters Acquity
BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=418[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.66(s,1H),10.61(s,1H),8.37(d,J=4.7Hz,1H),8.33(d,J=5.0Hz,1H),8.29(br.s.,1H),8.21(s,1H),7.80-7.76(m,1H),7.26(d,J=4.6Hz,1H),7.12(d,J=4.8Hz,1H),6.84(d,J=8.5Hz,1H),5.46(d,J=4.4Hz,1H),5.13(br.s.,1H),3.86(s,3H),2.09(s,3H),1.84-1.69(m,2H),0.92(t,J=7.2Hz,3H)。
1-(2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-基)胺基甲酸丙酯
302A)N-(4-(3-(6-甲氧基吡啶-3-基)-7-丙醯基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
伴隨攪拌,於-78℃在N2氛圍下向實例298F(1.6g,2.70mmol)含
於THF(30mL)之溶液中添加EtLi溶液(30mL含於苯-環己烷之0.5M溶液,Aldrich)。在1.5h後,將該混合物溫熱至-20℃並添加3mL HOAc,以及15mL甲醇及1.5mL水。攪拌該混合物,大部分在真空中濃縮及該殘留物經過SiO2急驟管柱並使用己烷-EtOAc梯度洗脫以獲得實例302A(400mg,0.733mmol,27%)。MS(ES):m/z=546[M+H]+;1H NMR(400MHz,氯仿-d)δ 8.85(s,1H),8.64(d,J=4.8Hz,1H),8.35(br.s.,1H),8.29(d,J=5.1Hz,1H),8.15-8.13(m,1H),7.81(dd,J=8.6,2.4Hz,1H),7.28(s,1H),6.98(dd,J=5.1,1.5Hz,1H),6.76(dd,J=8.6,0.4Hz,1H),5.38(s,2H),3.91(s,3H),3.11-3.05(m,4H),2.20(s,3H),1.29(t,J=7.0Hz,3H),0.69-0.64(m,2H),-0.11(s,9H)。
302B)N-(4-(7-(1-羥丙基)-3-(6-甲氧基吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺
於冰浴溫度下,分若干部分向實例302A(400mg,0.733mmol)含於MeOH(15mL)之溶液中添加NaBH4固體(160mg)。攪拌該混合物2h並添加2mL丙酮。攪拌該混合物10min並添加2mL HOAc。在真空中濃縮該混合物及該殘留物經過SiO2急驟管柱並使用CH2Cl2-EtOAc梯度(於含於CH2Cl2之80至100% EtOAc中洗脫產物)洗脫以獲得實例302B(310mg,0.566mmol,77%)。MS(ES):m/z=548[M+H]+;1H NMR(400MHz,氯仿-d)δ 9.34(br.s.,1H),8.47(d,J=4.8Hz,1H),8.34(br.s.,1H),8.22-8.19(m,1H),8.04(d,J=2.2Hz,1H),7.76(dd,
J=8.6,2.4Hz,1H),7.36(d,J=5.4Hz,1H),6.95(dd,J=5.2,1.2Hz,1H),6.70(d,J=8.6Hz,1H),5.53-5.41(m,2H),5.30(dd,J=7.9,4.6Hz,1H),3.86(s,3H),3.19(dd,J=9.2,7.5Hz,2H),2.15(s,3H),1.99-1.86(m,2H),1.07(t,J=7.4Hz,3H),0.73(t,J=8.5,2H),-0.14(s,9H)。
302C)1-(2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-吡咯并[3,2-b]吡啶-7-基)胺基甲酸丙酯
伴隨攪拌,於冰浴溫度向實例302B(165mg,0.301mmol)含於CH2Cl2(5mL)之溶液中緩慢添加200μL三氯乙醯異氰酯。於30min內添加NH3水含於MeOH之溶液(0.6mL含28% NH3之水溶液+4mL MeOH),繼續於冰浴溫度攪拌30分鐘隨後於室溫攪拌5h。在真空中濃縮大部分該混合物及藉由prep HPLC純化該殘留物以獲得實例302C之TFA鹽(124mg,0.151mmol,50.3%產率)。Prep HPLC:管柱#1,20% A至100% B在8min內,RT=5.2min;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。MS(ES):m/z=591[M+H]+;1H NMR(400MHz,氯仿-d)δ 10.91(br.s.,1H),8.67(s,1H),8.64(d,J=5.7Hz,1H),8.19(d,J=5.7Hz,1H),8.01(d,J=2.2Hz,1H),7.65(dd,J=8.6,2.4Hz,1H),7.61(d,J=5.7Hz,1H),7.09(dd,J=5.6,1.4Hz,1H),
6.81(d,J=8.6Hz,1H),6.30(dd,J=7.9,5.1Hz,1H),6.06(d,J=10.8Hz,1H),5.25(d,J=10.6Hz,1H),5.11(br.s,2H),3.93(s,3H),3.50(dd,J=9.1,8.3Hz,2H),2.27(s,3H),2.04-1.95(m,2H),1.12(t,J=7.3Hz,3H),1.07-0.90(m,2H),-0.01(s,9H)。
實例302)1-(2-(2-乙醯胺基吡啶-4-基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-7-基)胺基甲酸丙酯。
於室溫向實例302C之2 TFA鹽(124mg,0.151mmol)含於CH2Cl2(5mL)之溶液中添加2.3mL TFA。攪拌該混合物7h,隨後濃縮並藉由prep HPLC純化該殘留物以獲得部分純化材料。Prep HPLC:管柱#1,20% A至100% B在8min內;管柱#1=Waters Sunfire C-18,19x150mm;溶劑A=10% CH3CN/90% H2O-0.1% TFA;溶劑B=90% CH3CN/10% H2O-0.1% TFA。藉由prep HPLC再次純化此材料以獲得實例302(13mg,0.028mmol,18.64%產率)。Prep HPLC:管柱:XBridge C18,19x200mm,5-μm粒子;流動相A:5:95乙腈:水及10-mM乙酸銨;流動相B:95:5乙腈:水及10-mM乙酸銨;梯度:10至50% B在20分鐘內,隨後於100% B維持5分鐘;流速:20mL/min。分析型HPLC:RT=0.59min(H2O/MeCN及0.1% TFA,Waters Acquity BEH C18,2.0x50mm,1.7-μm粒子,梯度=1.5min,波長=220nm)。MS(ES):m/z=461[M+H]+;1H NMR(500MHz,DMSO-d6)δ 11.87(s,1H),10.57(s,1H),8.35(d,J=4.7Hz,1H),8.30(d,J=5.1Hz,1H),8.27(s,1H),8.18(d,J=1.9Hz,1H),7.74(dd,J=8.5,2.1Hz,1H),7.11(d,J=4.8Hz,2H),6.81(d,J=8.6Hz,1H),6.07(m,1H),3.82(s,3H),),2.05(s,3H),1.91-1.75(m,2H),0.91(t,J=7.2Hz,3H)。
在1536孔板中進行分析並藉由在分析緩衝液(20mM HEPES pH 7.4,10mM MgCl2,0.015% Brij35,4mM DTT,及0.05mg/ml BSA)
中添加HIS-TGFβR1 T204D或HIS-TGFβR2 WT、抗HIS檢測抗體、經標記之小分子探針(Kd=<100nM;koff=<0.001s-1)及測試化合物製備2μL反應。此反應於室溫培養1小時及在Envision板讀數器(Ex:340nm;Em:520nm/495nm)上測量HTRF信號。藉由與對應100%抑制之無酶對照反應及對應0%抑制之僅有賦形劑之反應比較計算抑制數據。分析中試劑之最總濃度係1nM HIS-TGFβR1 T204D或HIS-TGFβR2 WT、抗HIS檢測抗體、經標記之小分子探針(於Kd)及0.5% DMSO。生成劑量反應曲線以測量抑制50%激酶活性需要之濃度(IC50)。以10mM將化合物溶於二甲基亞碸(DMSO)中及於十一種濃度下評估。由非線性回歸分析得到IC50值。
Claims (21)
- 一種下式化合物
- 如請求項1之化合物,其具有式(II)
- 如請求項2之化合物,其具有下式
- 如請求項3之化合物,其具有下式
- 如請求項4之化合物,其具有下式
- 如請求項1之化合物,其具有式(III)
- 如請求項6之化合物,其具有下式
- 如請求項7之化合物,其具有下式
- 如請求項8之化合物,其具有下式
- 如請求項9之化合物,其具有下式
- 如請求項1之化合物,其係選自下列物質N-{4-[6-氟-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-{4-[6-氯-3-(5-氟代吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}-2-{[3-(嗎啉-4-基)丙基]胺基}乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-(甲氧基-d3)-1H-吡啶并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-乙氧基-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(二甲胺基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(羥甲基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(1-羥乙基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1R)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(1S)-1-羥乙基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-[(甲胺基)甲基]-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺,N-(4-{3-[6-(二氟甲基)吡啶-2-基]-7-(2-羥基丙-2-基)-1H-吡咯并[3,2-b]吡啶-2-基}吡啶-2-基)乙醯胺, N-(4-(7-(1-羥乙基)-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-6-甲氧基-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,或N-(4-(6-甲氧基-3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺;或其醫藥上可接受之鹽、互變異構體或立體異構體。
- 如請求項1之化合物,其係選自下列物質N-{4-[3-(6-甲氧基吡啶-3-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-{4-[6-氯-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基]吡啶-2-基}乙醯胺,N-(4-(3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-氯-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-氟-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(6-甲氧基-3-(5-(甲氧基-d3)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,N-(4-(3-(6-(二氟甲基)吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺,或N-(4-(6-甲氧基-3-(5-甲氧基吡啶-2-基)-1H-吡咯并[3,2-b]吡啶-2-基)吡啶-2-基)乙醯胺或其醫藥上可接受之鹽、互變異構體或立體異構體。
- 如請求項1至12中任一項之化合物或其醫藥上可接受之鹽,其係 用於治療。
- 如請求項1至12中任一項之化合物或其醫藥上可接受之鹽,其係用於治療TGFβR拮抗劑適用之疾病或病狀。
- 如請求項14之化合物,其中該疾病或病狀係癌症。
- 如請求項15之化合物,其中該癌症係小細胞肺癌、非小細胞肺癌、三陰性乳癌、卵巢癌、結腸直腸癌、前列腺癌、黑色素瘤、胰臟癌、多發性骨髓瘤、T-急性淋巴母細胞白血病或AML。
- 一種醫藥組合物,其包括如請求項1至12中任一項之化合物或其醫藥上可接受之鹽及一或多種醫藥上可接受載劑、稀釋劑或賦形劑。
- 一種組合醫藥產品,其包括如請求項1至12中任一項之化合物或其醫藥上可接受之鹽連同一或多種其他治療活性劑。
- 一種如請求項1至12中任一項之化合物或其醫藥上可接受之鹽之用途,其係用於製造治療TGFβR拮抗劑適用之疾病或病狀的藥物。
- 如請求項19之用途,其中該疾病或病狀係癌症。
- 如請求項20之用途,其中該癌症係小細胞肺癌、非小細胞肺癌、三陰性乳癌、卵巢癌、結腸直腸癌、前列腺癌、黑色素瘤、胰臟癌、多發性骨髓瘤、T-急性淋巴母細胞白血病或AML。
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US (1) | US9708316B2 (zh) |
EP (1) | EP3237415A1 (zh) |
JP (1) | JP2018501315A (zh) |
CN (1) | CN107257798A (zh) |
AR (1) | AR103232A1 (zh) |
TW (1) | TW201630907A (zh) |
WO (1) | WO2016106266A1 (zh) |
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CN108779100B (zh) | 2016-11-14 | 2021-11-16 | 江苏恒瑞医药股份有限公司 | 3,4-二吡啶基吡唑类衍生物、其制备方法及其在医药上的应用 |
WO2018171611A1 (zh) * | 2017-03-22 | 2018-09-27 | 江苏恒瑞医药股份有限公司 | 6-吡唑-[1,2,4]三唑并[4,3-a]吡啶-3-酰胺类衍生物、其制备方法及其在医药上的应用 |
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CN111819176B (zh) | 2017-12-18 | 2023-12-15 | 百时美施贵宝公司 | 4-氮杂吲哚化合物 |
TWI748194B (zh) * | 2018-06-28 | 2021-12-01 | 德商菲尼克斯 Fxr有限責任公司 | 含有雙環核心部分之新穎lxr調節劑 |
CN112694477B (zh) * | 2019-10-22 | 2024-02-06 | 四川科伦博泰生物医药股份有限公司 | 吡唑并环类化合物,包含其的药物组合物,其制备方法及其用途 |
CN110885329B (zh) * | 2019-12-16 | 2020-12-15 | 诚达药业股份有限公司 | 一种1,7-萘啶衍生物的合成方法 |
WO2023147015A1 (en) * | 2022-01-27 | 2023-08-03 | The Broad Institute, Inc. | Substituted heterocyclic csnk1 inhibitors |
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2015
- 2015-12-21 TW TW104142991A patent/TW201630907A/zh unknown
- 2015-12-21 AR ARP150104241A patent/AR103232A1/es unknown
- 2015-12-22 US US14/977,709 patent/US9708316B2/en active Active
- 2015-12-22 CN CN201580076649.4A patent/CN107257798A/zh active Pending
- 2015-12-22 WO PCT/US2015/067252 patent/WO2016106266A1/en active Application Filing
- 2015-12-22 JP JP2017552007A patent/JP2018501315A/ja active Pending
- 2015-12-22 EP EP15823892.3A patent/EP3237415A1/en not_active Withdrawn
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US9708316B2 (en) | 2017-07-18 |
WO2016106266A1 (en) | 2016-06-30 |
EP3237415A1 (en) | 2017-11-01 |
AR103232A1 (es) | 2017-04-26 |
CN107257798A (zh) | 2017-10-17 |
JP2018501315A (ja) | 2018-01-18 |
US20160176871A1 (en) | 2016-06-23 |
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