TWI835849B - 5-嗎啉-4-基-吡唑并[4,3-b]吡啶衍生物 - Google Patents
5-嗎啉-4-基-吡唑并[4,3-b]吡啶衍生物 Download PDFInfo
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- TWI835849B TWI835849B TW108132204A TW108132204A TWI835849B TW I835849 B TWI835849 B TW I835849B TW 108132204 A TW108132204 A TW 108132204A TW 108132204 A TW108132204 A TW 108132204A TW I835849 B TWI835849 B TW I835849B
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- Prior art keywords
- methyl
- pyrazolo
- cancer
- pyrazol
- pyridin
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- BBDPAZNVBQSVTO-UHFFFAOYSA-N 4-(1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine Chemical class N1(CCOCC1)C1=CC=C2C(=N1)C=NN2 BBDPAZNVBQSVTO-UHFFFAOYSA-N 0.000 title description 2
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- 201000011510 cancer Diseases 0.000 claims abstract description 28
- -1 1-methanesulfonyl-cyclopropane-1-yl Chemical group 0.000 claims description 256
- 239000000203 mixture Substances 0.000 claims description 81
- 150000003839 salts Chemical class 0.000 claims description 70
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 claims description 56
- 239000004480 active ingredient Substances 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 150000004677 hydrates Chemical class 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 101100293593 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) nar-1 gene Proteins 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 5
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- 229910052794 bromium Inorganic materials 0.000 claims description 4
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
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- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- JTUCORWPTZNKGR-UHFFFAOYSA-N 1,3-dihydroindole Chemical compound C1=CC=C2N[CH]CC2=C1 JTUCORWPTZNKGR-UHFFFAOYSA-N 0.000 claims description 3
- 125000005940 1,4-dioxanyl group Chemical group 0.000 claims description 3
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical compound [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 3
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 claims description 3
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 claims description 3
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- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
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- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 3
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- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
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- 206010057644 Testis cancer Diseases 0.000 claims description 2
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Abstract
本發明係關於式Ia及Ib化合物
其中R1
、R2
及R3
具有請求項1中所指示之含義,該等化合物為ATR抑制劑,且可用於治療諸如癌症之疾病。
Description
本發明之目標為發現具有寶貴特性之新穎化合物,尤其可用於製備藥物之彼等化合物。本發明係關於5-嗎啉-4-基-吡唑并[4,3-b]吡啶衍生物,其抑制ATR (共濟失調毛細管擴張症突變及Rad3相關激酶)。因此,本發明化合物適用於治療諸如癌症之疾病。本發明亦提供用於製備此等化合物之方法、包含此等化合物之醫藥組合物及利用包含此等化合物之醫藥組合物治療疾病的方法。
本發明之化學實體為ATR抑制劑且應用於多種治療,尤其用於治療癌症。
發明背景
癌症為多種不同組織之不受控細胞生長之結果。在許多情況下,新細胞滲透至現有組織中,或其轉移至遠端器官中。癌症出現於多種器官中且常常以特定於組織之方式發展。因此,術語「癌症」作為通用術語係描述一大類不同器官、組織及細胞類型之已定義之疾病。
2008年,全世界超過1200萬人診斷患有癌症。同年,此等疾病造成據假定大約750萬例死亡(Globocan 2008報告)。2012年,僅在美國,經預測超過160萬新病例及超過500 000例死亡係由於癌症。此等新病例中之大多數係關於結腸癌(約100 000)、肺癌(約230 000)、乳腺癌(約230 000)及前列腺癌(約240 000) (American Cancer Society, Cancer Facts and Figures 2012)。
許多當前癌症治療(包括化學治療劑及電離輻射)誘導DNA損傷及複製叉停滯,由此活化細胞週期檢查點路徑且引起細胞週期停滯。多種研究已顯示此反應為有助於癌細胞存活治療之重要機制。此等發現已促進開發靶向DNA損傷反應信號傳導路徑之藥劑。
ATR為磷脂醯肌醇激酶相關激酶(phosphatidylinositol kinase-related kinase,PIKK)蛋白質家族之成員,且藉由多種DNA損傷事件活化。特定言之,ATR為協調對複製應激(replicative stress,RS)之反應所必需的,其代表單股DNA (single stranded DNA,ssDNA)之病理性積累。ssDNA之重組基因性質引起染色體重排,其為癌症標誌。回應於RS,ATR藉由CHK1之磷酸化而觸發S及G2/M階段中之細胞週期停滯。
ATR可預防癌症發展,因為ATR檢查點反應可由於致癌基因活化而限制進行RS的癌變前細胞之擴增。此外,因為ATR-CHK1檢查點路徑用以確保RS之後的細胞存活,所以正常及穩固ATR-CHK1檢查點可為對化學療法具有抗性之機制且可允許具有高的RS內源性水準之癌細胞存活。
抑制ATR-CHK1路徑組分可潛在地增強複製抑制劑之有效度。此外,ATR抑制對於具有高水準RS之細胞(諸如表現致癌基因或缺乏腫瘤抑制劑之彼等細胞)可尤其具有毒性。在此等細胞中,(例如,藉由使用ATR抑制劑)強烈限制ATR活性將產生致死量之RS,從而引起細胞死亡。
以此方式使細胞敏化之潛在優勢將能降低複製抑制劑之劑量。若正常細胞在相同程度上未敏化,則此將導致尤其血液及胃腸器官系統之毒性降低。用於引起癌細胞死亡之複製抑制劑之特異性可藉由未轉化細胞比腫瘤細胞具有更穩定之S及G2檢查點之事實輔助。舉例而言,許多癌症具有p53或p53路徑之其他組分中之突變,從而依賴於S及G2檢查點來使細胞週期停滯且為修復及存活作準備。S及G2檢查點之抑制可隨後優先殺死此等p53缺陷型腫瘤細胞。
在本說明書中對明顯先前已公開的文獻之列舉或論述應不必視為承認該文獻為先前技術之一部分或為公共常識。
缺乏強力ATR抑制劑。因此,需要選擇性抑制ATR以供臨床使用或進一步研究ATR反應之化學實體。
已發現,根據本發明之化合物及其鹽具有寶貴藥理學特性,同時具有良好耐受性。
宿主或患者可屬於任何哺乳動物物種,例如靈長類動物物種,尤其人類;嚙齒動物,包括小鼠、大鼠及倉鼠;兔;馬;牛;犬;貓等。用於實驗研究、提供一種用於治療人類疾病之模型的動物模型備受關注。
可藉由活體外測試測定特定細胞對用根據本發明之化合物治療之易感性。通常,將細胞培養物與各種濃度之根據本發明之化合物組合一段時間(通常介於約一小時與一週之間),該段時間足以允許活性劑(諸如抗IgM)誘導細胞反應,諸如表面標記物之表現。活體外測試可使用來自血液或來自活體組織切片樣品之培養細胞進行。使用識別標記物之特定抗體,藉由流動式細胞測量術評估所表現之表面標記物的量。
劑量視所用特定化合物、特定疾病、患者狀態等而變化。治療劑量通常足以在維持患者活力的同時減少目標組織中之非所需細胞群體。一般繼續治療直至出現相當大的降低,例如細胞負荷降低至少約50%,且可繼續進行直至在體內基本上不再偵測到非所需細胞。
用於治療癌症之其他雙環雜環化合物已描述於WO 2013/130660 A1及WO 2017/121684 A1中。
本發明係關於式Ia及Ib化合物
其中
R1
表示H、Het、Ar、(CH2
)n
OH、1-甲磺醯基-環丙-1-基、CONH2
、CONHA、CONA2
、Cyc、OA或CH(A)SO2
A,
R2
表示H、A、(CH2
)n
Ar、(CH2
)n
Cyc或(CH2
)n
Het,
R3
表示H或A,
Het 表示具有1至4個N、O及/或S原子之單環或雙環芳族、不飽和或飽和雜環,其可未經取代或經NH2
、NHA、NA2
、COOH、COOA、CONH2
、CONHA、CONA2
、CONHAr、CN、OH、(CH2
)n
Ar1
、O(CH2
)n
Ar1
、A、SOA、SO2
A、Hal、=NH及/或=O單取代、二取代或三取代,
Ar 表示苯基、萘基或聯苯,其中之每一者未經取代或經NH2
、NHA、NA2
、COOH、COOA、CONH2
、CONHA、CONA2
、NHCOA、CHO、COA、SO3
H、SO2
NH2
、O(CH2
)p
NH2
、(CH2
)n
Het1
、O(CH2
)n
Het1
、(CH2
)n
Ar1
、O(CH2
)n
Ar1
、O(CH2
)p
CONH2
、O(CH2
)p
NHCOA、Hal、SOA、S(=O, =NH)A、SO2
A、A、CN及/或(CH2
)n
OH單取代、二取代或三取代,
Ar1
表示苯基,其未經取代或經Hal、A、OH及/或OA單取代、二取代或三取代,
Het1
表示具有1至4個N、O及/或S原子之單環或雙環芳族、不飽和或飽和雜環,其可未經取代或經Hal、A、COOA、NH2
、NHA及/或NA2
單取代、二取代或三取代,
A 表示具有1-6個C原子之未分支或分支鏈烷基,其中1-7個H原子可經OH、F、Cl及/或Br置換及/或其中一或兩個不相鄰CH2
基團可經O及/或NH基團置換,
Cyc 表示具有3、4、5、6或7個C原子之環烷基,
Hal 表示F、Cl、Br或I,
n 表示0、1、2、3或4,
p 表示1、2、3或4,
及其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物。
本發明亦係關於此等化合物之光學活性形式(立體異構體)、對映異構體、外消旋體、非對映異構體及水合物及溶劑合物。
此外,本發明係關於式Ia及Ib化合物之醫藥學上可接受之衍生物。
採用術語化合物之溶劑合物意謂將惰性溶劑分子加合於化合物上,該等溶劑分子由於其相互吸引力而形成。溶劑合物為例如單水合物或二水合物或醇鹽。
應瞭解,本發明亦係關於鹽類之溶劑合物。
採用術語醫藥學上可接受之衍生物意謂例如根據本發明之化合物之鹽類亦以及所謂的前藥化合物。
如本文中所用且除非另有指示,否則術語「前藥」意謂可在生物條件(活體外或活體內))下水解、氧化或以其他方式反應以提供活性化合物、尤其式I化合物之式I化合物衍生物。前藥之實例包括但不限於式I化合物之衍生物及代謝物,其包括可生物水解部分,諸如可生物水解醯胺、可生物水解酯、可生物水解胺基甲酸酯、可生物水解碳酸酯、可生物水解醯脲及可生物水解磷酸酯類似物。在某些實施例中,具有羧基官能基之化合物之前藥為羧酸之低碳烷基酯。羧酸酯宜藉由酯化分子上存在之任一羧酸部分而形成。前藥可通常使用眾所周知的方法來製備,諸如Burger之Medicinal Chemistry and Drug Discovery 第6版(Donald J. Abraham編, 2001, Wiley)及Design and Application of Prodrugs (H.Bundgaard編, 1985, Harwood Academic Publishers Gmfh)中所描述之彼等。
表達「有效量」表示於組織、系統、動物或人類中引起例如研究人員或醫師尋求或期望之生物學或醫學反應的藥物之量或醫藥活性成份之量。
另外,表達「治療有效量」表示與尚未接受此量之相應個體相比,具有以下結果的量:
疾病、症候群、病況、困苦、失調症或副作用之改良治療、治癒、預防或消除,或亦在疾病、困苦或失調症之前減少。
表達「治療有效量」亦涵蓋對增加正常生理功能有效之量。
本發明亦係關於式Ia及Ib化合物之混合物,例如兩種非對映異構體例如以比率1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000之混合物的用途。
此等混合物尤佳為立體異構化合物之混合物。
「互變異構體」係指彼此平衡之化合物之異構體形式。異構體形式之濃度將視化合物所存在之環境而定,且可視例如化合物是否為固體或呈有機或水溶液形式而不同。
除非另外明確說明,否則在上文及下文中,基團R1
、R2
及R3
具有針對式I所指示之含義。
A表示烷基,此為未分支(直鏈)或分支鏈,且具有1、2、3、4、5、6、7或8個C原子。A較佳表示甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基或第三丁基,此外亦表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,此外較佳地,例如三氟甲基。
A極其尤佳地表示具有1、2、3、4、5或6個C原子之烷基,較佳為甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟乙基。
此外,A較佳表示CH2
OCH3
、CH2
CH2
OH或CH2
CH2
OCH3
。
R3
較佳表示H或CH3
,最佳表示H。
Cyc表示環脯胺醯基、環丁基、環戊基、環己基或環庚基。
雜環取代基吡啶基(pyridyl)=吡啶基(pyridinyl)。
無關於其他取代基,Het表示例如2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,此外較佳1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-噠嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-異吲哚基、吲唑基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并異噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并異噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-異喹啉基、3-、4-、5-、6-、7-或8-㖕啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喏啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基、吡咯并吡啶基、嘌呤基,此外較佳1,3-苯并間二氧雜環戊烯-5-基、1,4-苯并二噁烷-6-基、2,1,3-苯并噻二唑-4-或-5-基、2,1,3-苯并噁二唑-5-基、氮雜雙環[3.2.1]-辛基或二苯并呋喃基。
雜環基亦可部分或完全氫化。
無關於其他取代基,Het可因此亦表示例如2,3-二氫-2-、-3-、-4-或-5-呋喃基、2,5-二氫-2-、-3-、-4-或5-呋喃基、四氫-2-或-3-呋喃基、1,3-二氧戊環-4-基、四氫-2-或-3-噻吩基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氫-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯啶基、四氫-1-、-2-或-4-咪唑基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡唑基、四氫-1-、-3-或-4-吡唑基、1,4-二氫-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-哌啶基、2-、3-或4-嗎啉基、四氫-2-、-3-或-4-哌喃基、1,4-二噁烷基、1,3-二噁烷-2-、-4-或-5-基、六氫-1-、-3-或-4-噠嗪基、六氫-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-異喹啉基、2-、3-、5-、6-、7-或8- 3,4-二氫-2H-苯并-1,4-噁嗪基,此外較佳2,3-亞甲基二氧基苯基、3,4-亞甲基二氧基苯基、2,3-伸乙二氧基苯基、3,4-伸乙基二氧基苯基、3,4-(二氟亞甲基二氧基)苯基、2,3-二氫苯并呋喃-5-或6-基、2,3-(2-側氧基亞甲基二氧基)苯基亦或3,4-二氫-2H-1,5-苯并二氧呯-6-或-7-基,此外較佳2,3-二氫苯并呋喃基、2,3-二氫-2-側氧基呋喃基、3,4-二氫-2-側氧基-1H-喹唑啉基、2,3-二氫苯并噁唑基、2-側氧基-2,3-二氫苯并噁唑基、2,3-二氫苯并咪唑基、1,3-二氫吲哚、2-側氧基-1,3-二氫吲哚或2-側氧基-2,3-二氫苯并咪唑基。
無關於其他取代基,Het1
表示例如2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,此外較佳1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-噠嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-異吲哚基、吲唑基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并異噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并異噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-異喹啉基、3-、4-、5-、6-、7-或8-㖕啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喏啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基、吡咯并吡啶基、嘌呤基,此外較佳1,3-苯并間二氧雜環戊烯-5-基、1,4-苯并二噁烷-6-基、2,1,3-苯并噻二唑-4-或-5-基、2,1,3-苯并噁二唑-5-基、氮雜雙環[3.2.1]-辛基或二苯并呋喃基。
雜環基亦可部分或完全氫化。
無關於其他取代基,Het1
可因此亦表示例如2,3-二氫-2-、-3-、-4-或-5-呋喃基、2,5-二氫-2-、-3-、-4-或5-呋喃基、四氫-2-或-3-呋喃基、1,3-二氧戊環-4-基、四氫-2-或-3-噻吩基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氫-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯啶基、四氫-1-、-2-或-4-咪唑基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡唑基、四氫-1-、-3-或-4-吡唑基、1,4-二氫-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-哌啶基、2-、3-或4-嗎啉基、四氫-2-、-3-或-4-哌喃基、1,4-二噁烷基、1,3-二噁烷-2-、-4-或-5-基、六氫-1-、-3-或-4-噠嗪基、六氫-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-哌嗪基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-異喹啉基、2-、3-、5-、6-、7-或8- 3,4-二氫-2H-苯并-1,4-噁嗪基,此外較佳2,3-亞甲基二氧基苯基、3,4-亞甲基二氧基苯基、2,3-伸乙基二氧基苯基、3,4-伸乙基二氧基苯基、3,4-(二氟亞甲基二氧基)苯基、2,3-二氫苯并呋喃-5-或6-基、2,3-(2-側氧基亞甲基二氧基)苯基亦或3,4-二氫-2H-1,5-苯并二氧呯-6-或-7-基,此外較佳2,3-二氫苯并呋喃基、2,3-二氫-2-側氧基呋喃基、3,4-二氫-2-側氧基-1H-喹唑啉基、2,3-二氫苯并噁唑基、2-側氧基-2,3-二氫苯并噁唑基、2,3-二氫苯并咪唑基、1,3-二氫吲哚、2-側氧基-1,3-二氫吲哚或2-側氧基-2,3-二氫苯并咪唑基。
Ar表示例如苯基、鄰、間或對甲苯基、鄰、間或對乙基苯基、鄰、間或對丙基苯基、鄰、間或對異丙基苯基、鄰、間或對第三丁基苯基、鄰、間或對羥苯基、鄰、間或對硝苯基、鄰、間或對胺基苯基、鄰、間或對(N-甲基胺基)苯基、鄰、間或對(N-甲基胺基羰基)苯基、鄰、間或對乙醯胺基苯基、鄰、間或對甲氧基苯基、鄰、間或對乙氧基苯基、鄰、間或對乙氧基羰基苯基、鄰、間或對(N,N-二甲基胺基)苯基、鄰、間或對(N,N-二甲基胺基羰基)苯基、鄰、間或對(N-乙基胺基)苯基、鄰、間或對(N,N-二乙基胺基)苯基、鄰、間或對氟苯基、鄰、間或對溴苯基、鄰、間或對氯苯基、鄰、間或對(甲基磺醯胺基)苯基、鄰、間或對(甲磺醯基)苯基、鄰、間或對氰基苯基、鄰、間或對羧苯基、鄰、間或對甲氧基羰基苯基、鄰、間或對胺基磺苯基、鄰、間或對(苯甲基胺基)苯基,此外較佳2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基、2,4-或2,5-二硝苯基、2,5-或3,4-二甲氧基苯基、3-硝基-4-氯苯基、3-胺基-4-氯-、2-胺基-3-氯-、2-胺基-4-氯-、2-胺基-5-氯-或2-胺基-6-氯苯基、2-硝基-4-N,N-二甲基胺基-或3-硝基-4-N,N-二甲基胺基苯基、2,3-二胺基苯基、2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基、2,4,6-三甲氧基苯基、2-羥基-3,5-二氯苯基、對碘苯基、3,6-二氯-4-胺基苯基、4-氟-3-氯苯基、2-氟-4-溴苯基、2,5-二氟-4-溴苯基、3-溴-6-甲氧基苯基、3-氯-6-甲氧基苯基、3-氯-4-乙醯胺基苯基、3-氟-4-甲氧基苯基、3-胺基-6-甲基苯基、3-氯-4-乙醯胺基苯基或2,5-二甲基-4-氯苯基。
Het較佳表示1H
-吡咯并[2,3-b]吡啶基、1H
-吡咯并[2,3-c]吡啶基、吲哚基、苯并咪唑基、咪唑基、1,2,3,4-四氫異喹啉基、吡啶基、嘧啶基、三唑基、吡唑基、喹啉基、異喹啉基、喹唑啉基、呋喃基、四氫呋喃基、哌喃基、3,6-二氫-2H-哌喃基、四氫哌喃基、3,6-二氫-2H-硫代哌喃基或六氫-硫代哌喃基,其中之每一者未經取代或經A、SOA、SO2
A、Hal及/或=O單取代、二取代或三取代。
Ar較佳表示苯基,其未經取代或經SOA、S(=O, =NH)A、SO2
A、A、CN及/或(CH2
)n
OH單取代、二取代或三取代。
在本發明通篇中,出現不止一次的所有自由基可為相同或不同的,亦即彼此獨立。
式Ia及Ib化合物可具有一或多個對掌性中心且因此可以各種立體異構形式出現。式Ia及Ib涵蓋所有此等形式。
因此,本發明尤其關於式Ia及Ib化合物,其中該等自由基中之至少一者具有上文所指示之較佳含義中之一者。化合物之一些較佳基團可由以下子式Iaa及Iba表示為Iad及Ibd,其符合式Ia及Ib且其中不更詳細地表示之自由基具有對於式Ia及Ib所指示之含義,但其中
在Iaa及Iba中 Het
表示1H
-吡咯并[2,3-b]吡啶基、1H
-吡咯并[2,3-c]吡啶基、吲哚基、苯并咪唑基、咪唑基、1,2,3,4-四氫異喹啉基、吡啶基、嘧啶基、三唑基、吡唑基、喹啉基、異喹啉基、喹唑啉基、呋喃基、四氫呋喃基、哌喃基、3,6-二氫-2H-哌喃基、四氫哌喃基、3,6-二氫-2H-硫代哌喃基或六氫-硫代哌喃基,其中之每一者未經取代或經A、SOA、SO2
A、Hal及/或=O單取代、二取代或三取代;
在Iab及Ibb中 Ar
表示苯基,其未經取代或經SOA、S(=O, =NH)A、SO2
A、A、CN及/或(CH2
)n
OH單取代、二取代或三取代;
在Iac及Ibc中 R3
表示H或甲基;
在Iad及Ibd中 R1
表示H、Het、Ar、(CH2
)n
OH、1-甲磺醯基-環丙-1-基、CONH2
、CONHA、CONA2
、Cyc、OA或CH(A)SO2
A;
R2
表示H、A、(CH2
)n
Ar、(CH2
)n
Cyc或(CH2
)n
Het,
R3
表示H或A,
Het 表示1H
-吡咯并[2,3-b]吡啶基、1H
-吡咯并[2,3-c]吡啶基、吲哚基、苯并咪唑基、咪唑基、1,2,3,4-四氫異喹啉基、吡啶基、嘧啶基、三唑基、吡唑基、喹啉基、異喹啉基、喹唑啉基、呋喃基、四氫呋喃基、哌喃基、3,6-二氫-2H-哌喃基、四氫哌喃基、3,6-二氫-2H-硫代哌喃基或六氫-硫代哌喃基,其中之每一者未經取代或經A、SOA、SO2
A、Hal及/或=O單取代、二取代或三取代,
Ar 表示苯基,其未經取代或經SOA、S(=O, =NH)A、SO2
A、A、CN及/或(CH2
)n
OH單取代、二取代或三取代,
A 表示具有1-6個C原子之未分支或分支鏈烷基,其中1-7個H原子可經OH、F、Cl及/或Br置換及/或其中一或兩個不相鄰CH2
基團可經O及/或NH基團置換,
Cyc 表示具有3、4、5、6或7個C原子之環烷基,
Hal 表示F、Cl、Br或I,
n 表示0、1、2、3或4,
及其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物。
根據本發明之最佳化合物為實例1、26、42及61。
式Ia及Ib化合物以及用於其製備之起始物質另外係藉由本身已知方法來製備,如文獻中(例如在標準著作中,諸如Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart)所描述,在已知且適於該等反應之反應條件下係確切的。在本文中亦可使用本身已知而未在本文中更詳細地提及之變體變化形式。
醫藥鹽及其他形式
根據本發明之該等化合物可以其最終非鹽形式使用。另一方面,本發明亦涵蓋此等化合物以其醫藥學上可接受之鹽之形式的用途,其可藉由此項技術中已知之程序衍生自各種有機及無機酸及鹼。式Ia及Ib化合物之醫藥學上可接受的鹽形式在很大程度上藉由習知方法來製備。若式Ia及Ib化合物含有甲基,則其適合之鹽中之一者可藉由使化合物與適合之鹼反應以得到相應鹼加成鹽來形成。此類鹼為例如鹼金屬氫氧化物,包括氫氧化鉀、氫氧化鈉及氫氧化鋰;鹼土金屬氫氧化物,諸如氫氧化鋇及氫氧化鈣;鹼金屬醇鹽,例如乙醇鉀及丙醇鈉;及各種有機鹼,諸如哌啶、二乙醇胺及N-甲基麩醯胺酸。同樣包括式Ia及Ib化合物之鋁鹽。在特定式Ia及Ib化合物之情況下,酸加成鹽可藉由用醫藥學上可接受之有機酸及無機酸,例如鹵化氫(諸如氯化氫、溴化氫或碘化氫)、其他無機酸及其對應鹽(諸如硫酸鹽、硝酸鹽或磷酸鹽及其類似物)及烷基及單芳基磺酸鹽(諸如乙磺酸鹽、甲苯磺酸鹽及苯磺酸鹽)及其他有機酸及其對應鹽(諸如乙酸鹽、三氟乙酸鹽、酒石酸鹽、順丁烯二酸鹽、丁二酸鹽、檸檬酸鹽、苯甲酸鹽、柳酸鹽、抗壞血酸鹽及其類似物)處理此等化合物來形成。因此,式Ia及Ib化合物之醫藥學上可接受之酸加成鹽包括以下:乙酸鹽、己二酸鹽、海藻酸鹽、精胺酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽(benzenesulfonate/besylate)、硫酸氫鹽、亞硫酸氫鹽、溴化物、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、辛酸鹽、氯化物、氯苯甲酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、磷酸二氫鹽、二硝基苯甲酸鹽、十二烷基硫酸鹽、乙磺酸鹽、反丁烯二酸鹽、甲酸鹽、半乳糖二酸鹽(來自黏液酸)、半乳糖醛酸鹽、葡糖庚酸鹽、葡糖酸鹽、麩胺酸鹽、甘油磷酸鹽、半丁二酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、馬尿酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽、碘化物、羥乙磺酸鹽、異丁酸鹽、乳酸鹽、乳糖酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、杏仁酸鹽、偏磷酸鹽、甲磺酸鹽、甲基苯甲酸鹽、磷酸單氫鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、草酸鹽、油酸鹽、棕櫚酸雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、苯基乙酸鹽、3-苯基丙酸鹽、磷酸鹽、膦酸鹽、鄰苯二甲酸鹽,但此並不表示限制。
此外,根據本發明之化合物之鹼鹽包括鋁鹽、銨鹽、鈣鹽、銅鹽、鐵(III)鹽、鐵(II)鹽、鋰鹽、鎂鹽、錳(III)鹽、錳(II)鹽、鉀鹽、鈉鹽及鋅鹽,但此不意欲表示限制。在上文所提及之鹽中,較佳為銨鹽;鹼金屬鈉鹽及鹼金屬鉀鹽,及鹼土金屬鈣鹽及鹼土金屬鎂鹽。衍生自醫藥學上可接受之有機無毒性鹼的式Ia及式Ib化合物之鹽包括以下之鹽:一級、二級及三級胺,經取代胺,亦包括天然存在之經取代胺、環狀胺;及鹼離子交換劑樹脂,例如精胺酸、甜菜鹼、咖啡鹼、氯普魯卡因(chloroprocaine)、膽鹼、N,N'-二苯甲基乙二胺(苯乍生)、二環己胺、二乙醇胺、二乙基胺、2-二乙基胺乙醇、2-二甲基胺乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、還原葡糖胺、葡糖胺、組胺酸、海卓胺、異丙基胺、利多卡因(lidocaine)、離胺酸、葡甲胺、N-甲基-D-還原葡糖胺、嗎啉、哌嗪、哌啶、多元胺樹脂、普魯卡因、嘌呤、可可豆鹼、三乙醇胺、三乙胺、三甲胺、三丙胺、及參(羥甲基)甲胺(緩血酸胺),但此不意欲表示限制。
含有基礎含氮基團的本發明化合物可使用以下試劑來四級銨化:諸如(C1
-C4
)烷基鹵化物,例如甲基、乙基、異丙基及第三丁基氯化物、溴化物及碘化物;二(C1
-C4
)烷基硫酸鹽,例如二甲基、二乙基及二戊基硫酸鹽;(C10
-C18
)烷基鹵化物,例如癸基、十二烷基、月桂基、肉豆蔻基及十八烷基氯化物、溴化物及碘化物;及芳基(C1
-C4
)烷基鹵化物,例如苯甲基氯化物及苯乙基溴化物。根據本發明之水溶性及油溶性化合物均可使用此類鹽製備。
上文所提及之醫藥鹽較佳包括乙酸鹽、三氟乙酸鹽、苯磺酸鹽、檸檬酸鹽、反丁烯二酸鹽、葡糖酸鹽、半丁二酸鹽、馬尿酸鹽、鹽酸鹽、氫溴酸鹽、羥乙磺酸鹽、杏仁酸鹽、葡甲胺、硝酸鹽、油酸鹽、膦酸鹽、特戊酸鹽、磷酸鈉、硬脂酸鹽、硫酸鹽、磺基水楊酸鹽、酒石酸鹽、硫代蘋果酸鹽、甲苯磺酸酯及緩血酸胺,但此不意欲表示限制。
尤其較佳為鹽酸鹽、二鹽酸鹽、氫溴酸鹽、順丁烯二酸鹽、甲磺酸鹽、磷酸鹽、硫酸鹽及丁二酸鹽。
鹼性式Ia及Ib化合物之酸加成鹽藉由使游離鹼形式與足夠量之所需酸接觸,以習知方式使得鹽形成來製備。游離鹼可藉由使鹽形式與鹼接觸及以習知方式分離游離鹼而再生。就某些物理特性(諸如在極性溶劑中之溶解性)而言,游離鹼形式在特定方面與其對應鹽形式不同;然而,出於本發明之目的,鹽另外對應於其各別游離鹼形式。
如所提及,式I化合物之醫藥學上可接受之鹼加成鹽由金屬或胺(諸如鹼金屬及鹼土金屬或有機胺)形成。 較佳金屬為鈉、鉀、鎂及鈣。較佳有機胺為N,N'-二苯甲基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、N-甲基-D-葡糖胺及普魯卡因。
根據本發明之酸性化合物之鹼加成鹽藉由使游離酸形式與足夠量之所需鹼接觸,以習知方式使得鹽形成來製備。游離酸可藉由使鹽形式與酸接觸及以習知方式分離游離酸而再生。就某些物理特性(諸如在極性溶劑中之溶解性)而言,游離酸形式在特定方面與其對應鹽形式不同;然而,出於本發明之目的,鹽另外對應於其各別游離酸形式。
若本發明化合物含有超過一個能夠形成此類型之醫藥學上可接受之鹽的基團,則本發明亦涵蓋多種鹽。典型的多種鹽形式包括例如酒石酸氫鹽、二乙酸鹽、富馬酸氫鹽(difumarate)、二葡甲胺、二磷酸鹽、二鈉及三鹽酸鹽,但此不意欲表示限制。
關於上文所述,可見採用本發明連接中之表述「醫藥學上可接受之鹽」意謂包含呈鹽中之一者形式之式Ia及Ib化合物的活性成份,尤其若此鹽形式與先前使用之活性成份之游離形式或活性成份之任何其他鹽形式相比對活性成份賦予改良之藥物動力學特性。活性成份之醫藥學上可接受之鹽形式亦可使此活性成份首次具有其先前沒有的所需藥物動力學性質且可甚至就其體內治療功效而論對此活性成份之藥效學具有積極影響。
同位素
此外,預期式Ia及Ib化合物包括其經同位素標記之形式。除了化合物之一或多個原子已由原子質量或質量數不同於通常天然存在之原子的原子質量或質量數的一或多種原子置換的事實以外,同位素標記形式之式Ia及Ib化合物與此化合物相同。容易購得且可藉由熟知方法併入式Ia及Ib化合物中的同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,分別例如2
H、3
H、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
Cl。含有一或多種上文提及之同位素及/或其他原子之其他同位素的式Ia及Ib化合物或其醫藥學上可接受之鹽預期為本發明之一部分。經同位素標記之式Ia及Ib化合物可以許多有益方式使用。舉例而言,已併入諸如3
H或14
C之放射性同位素的經同位素標記之式Ia及Ib化合物適合於藥物及/或受質組織分佈分析。此等放射性同位素,亦即氚(3
H)及碳-14 (14
C)由於製備簡單及可偵測性優良而尤其較佳。例如氘(2
H)之較重同位素併入式Ia及Ib化合物由於此經同位素標記之化合物之代謝穩定性較高而具有治療優點。較高代謝穩定性直接轉換成增加之活體內半衰期或更低劑量,在大部分情形下其將代表本發明之一較佳實施例。經同位素標記之式Ia及Ib化合物通常可藉由進行本發明正文中實例部分及製備部分中合成流程及相關描述中所揭示之程序,用容易獲得之同位素標記反應物替換非同位素標記反應物來製備。
氘(2
H)亦可併入式Ia及Ib化合物中,以達成藉助於基本動態同位素作用操縱化合物之氧化代謝的目的。基本動態同位素作用為由同位素核交換產生的化學反應之速率改變,同位素核交換又由此同位素交換後共價鍵形成所需之基態能量改變引起。較重同位素之交換通常導致化學鍵之基態能量的降低且因此引起速率限制鍵斷裂中之速率減小。若鍵斷裂發生在沿著多產物反應座標的鞍點區域中或附近,則可實質上改變產物分佈比率。出於解釋:若氘結合至不可交換位置之碳原子,則kM
/kD
= 2-7之速率差異為典型的。若此速率差異成功應用於易於氧化之式Ia及Ib化合物,則此化合物在活體內之型態由此可大幅度改變且引起藥物動力學特性改良。
當發現及研發治療劑時,熟習此項技術者嘗試在保留所希望之活體外特性時使藥物動力學參數達至最佳。合理假設許多具有不良藥物動力學型態之化合物易於氧化代謝。當前可用之活體外肝微粒體分析提供關於此類型氧化代謝過程之寶貴資訊,其繼而允許合理設計具有經由對此類氧化性偏醚之抗性改良之穩定性的式I之氘化化合物。由此獲得式I化合物之藥物動力學概況之顯著改良,且就活體內半衰期(t1/2)、最大治療效果下之濃度(Cmax
)、劑量反應曲線下方之面積(AUC)及F之增加而言;及就降低之清除率、劑量及材料成本而言可定量地表現。
以下意欲說明上文:具有氧化代謝之多個潛在侵襲位點,例如鍵結至氮原子之苯甲基氫原子及氫原子的式Ia及Ib化合物製備為一系列類似物,其中氫原子之各種組合經氘原子置換,使得一些、大部分或所有此等氫原子經氘原子置換。半衰期之測定能夠有利且準確地測定對氧化代謝之抗性改良已改善的程度。 以此方式,確定由於此類型之氘-氫交換,母體化合物之半衰期可延長達至100%。
式Ia及Ib化合物中之氘-氫交換亦可用於實現起始化合物之代謝物譜的有利改變,從而減輕或消除非所需之有毒代謝物。舉例而言,若有毒代謝物經由氧化碳-氫(C-H)鍵裂解而出現,則可合理地假設,氘化類似物將大大減輕或消除不必要代謝物之產生,即使特定氧化不為速率決定步驟亦如此。關於氘-氫交換之目前先進技術之進一步資訊可在例如Hanzlik等, J. Org. Chem.55
, 3992-3997, 1990;Reider等, J. Org. Chem.52
, 3326-3334, 1987;Foster, Adv. Drug Res.14
, 1-40, 1985;Gillette等, Biochemistry33
(10) 2927-2937, 1994及Jarman等,Carcinogenesis16
(4), 683-688, 1993中發現。
本發明進一步係關於包含至少一種式Ia及Ib化合物及/或其醫藥學上可接受之鹽、溶劑合物及立體異構體(包括其所有比率之混合物)及視情況選用之賦形劑及/或佐劑的藥物。
醫藥調配物可呈劑量單位形式投與,該等劑量單位包含每劑量單位的預定量之活性成份。視所治療之病況、投與之方法及患者之體重及病況而定,此類單位可包含例如0.5 mg至1 g,較佳地1 mg至700 mg,尤其較佳地5 mg至100 mg之根據本發明之化合物;或醫藥調配物可呈包含每劑量單位的預定量之活性成份的劑量單位形式投與。較佳劑量單位調配物為包含如上文所指示之日劑量或部分劑量或其對應部分之活性成份的彼等調配物。 此外,此類型之醫藥調配物可使用一般在醫藥領域中已知之方法來製備。
醫藥調配物可適用於經由任何所需合適方法投與,例如藉由經口(包括頰內或舌下)、經直腸、經鼻、局部(包括頰內、舌下或經皮)、經陰道或非經腸(包括皮下、肌肉內、靜脈內或皮內)方法。此類調配物可使用醫藥技術中已知之所有方法,藉由例如將活性成份與(一或多種)賦形劑或(一或多種)佐劑組合來製備。
經調適以用於經口投與之醫藥調配物可作為離散單元投與,諸如例如膠囊或錠劑;散劑或顆粒劑;水性或非水性液體中之溶液或懸浮液;可食用發泡體或發泡食品;或水包油液體乳液或油包水液體乳液。
因此,舉例而言,在呈錠劑或膠囊形式經口投與之情況下,活性成份組分可與口服無毒及醫藥學上可接受之惰性賦形劑(諸如乙醇、甘油、水及其類似物)組合。散劑藉由將化合物粉碎至合適的精細尺寸且將其與以類似方式粉碎之醫藥賦形劑(諸如可食用碳水化合物,諸如澱粉或甘露醇)混合來製備。調味劑、防腐劑、分散劑及染料同樣可存在。
膠囊由製備如上文所述之粉末混合物並且用其充填成形的明膠外殼來生產。 可將助滑劑及潤滑劑,諸如呈固體形式之高度分散矽酸、滑石、硬脂酸鎂、硬脂酸鈣或聚乙二醇,在填充操作之前添加至粉末混合物中。可同樣添加崩解劑或增溶劑,諸如瓊脂、碳酸鈣或碳酸鈉,以便在已獲得膠囊之後改良藥物之可用性。
此外,視需要或必要,可同樣將適合的黏合劑、潤滑劑及崩解劑以及染料併入至混合物中。適合之黏合劑包括澱粉、明膠、天然糖(諸如葡萄糖或β-乳糖)、由玉米製得之甜味劑、天然合成橡膠合成橡膠(諸如阿拉伯膠、黃蓍或褐藻酸鈉)、羧甲基纖維素、聚乙二醇、蠟及其類似物。以此等劑型使用之潤滑劑包括油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及其類似物。崩解劑包括而不限制於澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠及類似者。錠劑藉由以下調配:例如製備粉末混合物,粒化或乾式壓製該混合物,添加潤滑劑及崩解劑並且壓製整個混合物以得到錠劑。粉末混合物藉由以合適的方式將粉碎之化合物與以下各者混合來製備:如上文所述之稀釋劑或鹼、及視情況選用之黏合劑(諸如羧甲基纖維素、海藻酸鹽、明膠或聚乙烯吡咯啶酮)、溶解阻滯劑(諸如石蠟)、吸收促進劑(諸如四級鹽)及/或吸收劑(諸如膨潤土、高嶺土或磷酸二鈣)。粉末混合物可藉由用黏合劑(諸如糖漿、澱粉糊、阿卡迪亞膠(acadia mucilage)或纖維素之溶液)或聚合物材料使其潤濕並且將其壓製通過篩來粒化。作為粒化之替代方案,可使粉末混合物穿過壓錠機,從而得到不均勻形狀之團塊,其分解以形成顆粒。可藉由添加硬脂酸、硬脂酸鹽、滑石或礦物油潤滑,以防止顆粒黏著於造錠模具。經潤滑之混合物接著經壓製得到錠劑。化合物亦可與自由流動之惰性賦形劑組合且接著直接壓製以得到錠劑,而無需進行粒化或乾式壓製步驟。可存在由蟲膠密封層、糖或聚合物材料層及蠟之光澤層組成之透明或不透明保護層。可將染料添加至此等塗層中,以便能夠區分不同的劑量單位。
口服液體,諸如溶液、糖漿及酏劑,可呈劑量單位之形式製備,使得給定的數量包含預定量之化合物。糖漿可藉由使化合物與合適的調味劑溶解於水溶液中來製備,同時使用無毒醇性媒劑製備酏劑。懸浮液可藉由將化合物分散於無毒媒劑中調配。可同樣添加增溶劑及乳化劑(諸如乙氧基化異硬脂醇及聚氧乙烯山梨醇醚)、防腐劑、調味添加劑(諸如薄荷油或天然甜味劑或糖精,或其他人工甜味劑)及其類似物。
用於經口投與之劑量單位調配物可視需要囊封於微膠囊中。調配物亦可以使得釋放延長或延遲之方式來製備,諸如藉由包衣或將粒狀材料包埋於聚合物、蠟及其類似物中。
亦可呈脂質體遞送系統形式,諸如小的單層囊泡、大的單層囊泡及多層囊泡,投與式Ia及Ib化合物及其醫藥學上之鹽、互變異構體及立體異構體。脂質體可由各種磷脂,諸如膽固醇、硬脂胺或磷脂醯膽鹼形成。
亦可使用單株抗體作為化合物分子所偶合之個別載劑來遞送式Ia及Ib化合物及其鹽、互變異構體及立體異構體。化合物亦可與作為靶向藥物載劑之可溶聚合物偶合。此類聚合物可涵蓋聚乙烯吡咯啶酮、哌喃共聚物、聚羥丙基甲基丙烯醯胺酚、或經軟脂醯基取代之聚氧化乙烯聚離胺酸。此外,化合物可與適合於達成控制釋放藥物之一類可生物降解聚合物偶合,該等可生物降解聚合物例如聚乳酸、聚ε-己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二羥吡喃、聚氰基丙烯酸酯及水凝膠之交聯或兩性嵌段共聚物。
適用於經皮投與之醫藥調配物可以獨立硬膏劑形式投與,用於與接受者之表皮層延長、密切的接觸。因此,舉例而言,可將活性成份藉由離子導入療法自硬膏劑遞送,如以通用術語於Pharmaceutical Research, 3(6), 318 (1986)中所描述。
適用於局部投與之醫藥化合物可調配為軟膏、乳膏、懸浮液、洗劑、散劑、溶液、糊劑、凝膠、噴霧劑、氣霧劑或油劑。
對於眼睛或其他外部組織,例如口腔及皮膚之治療,調配物較佳以局部軟膏或乳膏形式施用。在調配物為軟膏之情況下,活性成份可與石蠟或水可混溶性乳膏基劑一起採用。或者,活性成份可藉由水包油乳膏基劑或油包水基劑調配以得到乳膏。
適用於局部施用至眼睛之醫藥調配物包括滴眼劑,其中活性成份溶解或懸浮於適合之載劑、尤其水性溶劑中。
適用於局部施用於口中之醫藥調配物涵蓋口含錠、片劑及漱口劑。
適用於直腸投與之醫藥調配物可以栓劑或灌腸劑形式投與。
其中載劑物質為固體的適用於經鼻投與之醫藥調配物包含粒徑例如在20-500微米範圍內之粗粉末,其以鼻吸之方式投與,亦即自靠近鼻部之含有粉末的容器經由鼻腔通道快速吸入。用於與作為載劑物質之液體以鼻用噴霧或鼻滴劑形式投與之合適的調配物涵蓋活性成份於水或油中之溶液。
適用於藉由吸入投與之醫藥調配物涵蓋精細粒子粉塵或噴霧,其可由各種類型之加壓分配器以及噴霧劑、霧化器或吹入器產生。
適用於經陰道投與之醫藥調配物可以子宮托、棉塞、乳膏、凝膠、糊劑、發泡體或噴霧調配物形式投與。
適用於非經腸投與之醫藥調配物包括水性及非水性無菌注射溶液,該等溶液包含抗氧化劑、緩衝液、抑菌劑及溶解物,調配物借助於其呈現與待治療接受者之血液等滲;及水性及非水性無菌懸浮液,其可包含懸浮介質及增稠劑。調配物可以單次劑量或多次劑量容器形式(例如密封安瓿及小瓶)投與,並且儲存在冷凍乾燥(凍乾)狀態,使得僅需在使用之前立即添加無菌載劑液體(例如注射用水)。根據配方製備之注射溶液及懸浮液可由無菌粉劑、顆粒及錠劑來製備。
不言而喻,除以上特別提及之成分以外,根據調配物之具體類型,調配物亦可包含此項技術中常用之其他試劑;因此,例如適用於經口投與之調配物可包含調味劑。
式Ia及Ib化合物之治療有效量視多種因素而定,包括例如動物之年齡及體重、需要治療之確切病況及其嚴重程度、調配物之性質及投與方法,並且最終由治療醫生或獸醫來判定。然而,根據本發明之化合物之有效量一般在每天0.1至100 mg/kg接受者(哺乳動物)體重之範圍內且尤其通常在每天1至10 mg/kg體重之範圍內。因此,每天用於重量為70 kg之成人哺乳動物的實際量通常在70與700 mg之間,其中此量可每天以單次劑量形式投與,或通常每天以一系列部分劑量(諸如兩次、三次、四次、五次或六次)投與,使得總日劑量相同。鹽或溶劑合物或其生理學上功能衍生物之有效量可作為根據本發明化合物本身之有效量之分數來判定。可假定類似劑量適用於治療上文所提及之其他病況。
此類型之組合治療可藉助於同時、連續或單獨分配治療之個別組分來達成。此類型之組合產物採用根據本發明之化合物。
本發明進一步係關於包含至少一種式Ia及Ib化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體(包括其所有比率之混合物)及至少一種另一藥物活性成份的藥物。
本發明亦係關於一種套件(套組),其由以下獨立封裝組成:
(a) 有效量之式Ia及Ib化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物,
及
(b) 有效量之另一藥物活性成份。
套件包含適合之容器,諸如盒子、單獨的瓶子、袋子或安瓿。該套件可例如包含單獨的安瓿,其各含有有效量之式I化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物,
及呈溶解或凍乾形式之有效量之另一藥物活性成份。
如本文所使用,「治療」意謂全部或部分緩解與病症或疾病相關之症狀,或減緩或阻止彼等症狀之進一步進展或惡化,或預防或防治處於發展疾病或病症之風險下的個體之疾病或病症。
與式Ia及Ib化合物有關之術語「有效量」可意謂能夠全部或部分地緩解與病症或疾病有關之症狀,或減緩或阻止彼等症狀之進一步發展或惡化,或預防或提供對患有本文所揭示之疾病(諸如發炎病況、免疫病況、癌症或代謝病況)或處於罹患本文所揭示之疾病(諸如發炎病況、免疫病況、癌症或代謝病況)風險下之個體之疾病或病症的防治的量。
在一個實施例中,式Ia及Ib化合物之有效量為抑制ATR在細胞中(諸如活體外或活體內)之量。在一些實施例中,與未經處理之細胞中ATR之活性相比,有效量之式(I)化合物抑制細胞中10%、20%、30%、40%、50%、60%、70%、80%、90%或99%之端粒酶。式Ia及Ib化合物(例如在醫藥組合物中)之有效量可處於將實行所需作用之水準;例如,以約0.005 mg/kg個體體重至約10 mg/kg個體體重以單位劑量經口及非經腸投與。
用途
本發明化合物適用作用於哺乳動物之醫藥活性成份,尤其適用於人類以治療癌症。
本發明涵蓋式Ia及Ib化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體之用途,其用於製備治療或預防癌症之藥物。
此外,本發明涵蓋用於治療或預防癌症之所用之式Ia及Ib化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體。
亦涵蓋式Ia及Ib化合物及/或其醫藥學上可接受之鹽、互變異構體及立體異構體的用途,其用於製備供治療或預防哺乳動物之ATR誘導之疾病或ATR誘導之病況用之藥物,其中為此方法,向需要此類治療之患病哺乳動物投與治療有效量之本發明化合物。治療量根據特定疾病而變化且可由熟習此項技術者判定而無需過度努力。
本發明特定言之係關於式Ia及Ib化合物及其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物,其用於治療其中抑制、調節及/或調整抑制ATR起作用之疾病。
本發明尤其係關於用於抑制ATR之式Ia及Ib化合物及其醫藥學上可接受之鹽、互變異構體及立體異構體,包括其所有比率之混合物。
式Ia及Ib化合物適用於治療或預防之代表性癌症包括(但不限於)頭部癌、頸部癌、眼部癌、口腔癌、咽喉癌、食道癌、支氣管癌、喉癌、咽癌、胸部癌、骨癌、肺癌、結腸癌、直腸癌、胃癌、前列腺癌、膀胱癌、子宮癌、子宮頸癌、乳腺癌、卵巢癌、睾丸癌或其他生殖器官癌、皮膚癌、甲狀腺癌、血癌、淋巴結癌、腎臟癌、肝癌、胰臟癌、腦癌、中樞神經系統癌、實體腫瘤及血源性腫瘤。
較佳地,本發明係關於一種方法,其中該疾病為癌症。
尤其較佳地,本發明係關於一種方法,其中該疾病為癌症,其中投與係與至少一種其他活性藥劑同時、依序或交替投與。
所揭示之式Ia及Ib化合物可與其他已知治療劑(包括抗癌劑)組合投與。如此處所用,術語「抗癌劑」係指出於治療癌症之目的向患有癌症之患者投與之任何藥劑。
上文所定義之抗癌治療可以單藥療法形式應用或可涉及除本文所揭示之式I化合物以外的習知手術或放射療法或醫學療法。此等醫學療法(例如化學療法或靶向療法)可包括以下抗腫瘤劑中之一或多者,但較佳一者:
烷化劑
諸如六甲蜜胺(altretamine)、苯達莫司汀(bendamustine)、白消安(busulfan)、卡莫司汀(carmustine)、苯丁酸氮芥(chlorambucil)、氮芥(chlormethine)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、異環磷醯胺(ifosfamide)、英丙舒凡(improsulfan)、甲苯磺酸鹽(tosilate)、洛莫司汀(lomustine)、美法侖(melphalan)、二溴甘露醇(mitobronitol)、二溴衛矛醇(mitolactol)、尼莫司汀(nimustine)、雷莫司汀(ranimustine)、替莫唑胺(temozolomide)、噻替派(thiotepa)、曲奧舒凡(treosulfan)、氮芥(mechloretamine)、卡波醌(carboquone);
阿帕茲酮(apaziquone)、福莫司汀(fotemustine)、葡磷醯胺(glufosfamide)、帕利伐米(palifosfamide)、哌泊溴烷(pipobroman)、曲磷胺(trofosfamide)、烏拉莫司汀(uramustine)、TH-3024
、VAL-0834
;
鉑化合物
諸如卡鉑(carboplatin)、順鉑(cisplatin)、依鉑(eptaplatin)、米鉑水合物(miriplatine hydrate)、奧沙利鉑(oxaliplatin)、洛鉑(lobaplatin)、奈達鉑(nedaplatin)、吡鉑(picoplatin)、賽特鉑(satraplatin);
DNA 改變劑
諸如胺柔比星(amrubicin)、比生群(bisantrene)、地西他濱(decitabine)、米托蒽醌(mitoxantrone)、丙卡巴肼(procarbazine)、曲貝替定(trabectedin)、氯法拉濱(clofarabine);
安吖啶(amsacrine)、布洛利辛(brostallicin)、匹蒽醌(pixantrone)、拉羅司汀(laromustine)1,3
;
拓樸異構酶抑制劑
諸如依託泊苷(etoposide)、伊立替康(irinotecan)、雷佐生(razoxane)、索布佐生(sobuzoxane)、替尼泊苷(teniposide)、拓朴替康(topotecan);
胺萘非特(amonafide)、貝洛替康(belotecan)、依利醋銨(elliptinium acetate)、威若羅欣(voreloxin);
微管調節劑
諸如卡巴他賽(cabazitaxel)、多西他賽(docetaxel)、艾日布林(eribulin)、伊沙匹隆(ixabepilone)、太平洋紫杉醇(paclitaxel)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春瑞賓(vinorelbine)、長春地辛(vindesine)、長春氟寧(vinflunine);
福瑞布林(fosbretabulin)、替司他賽(tesetaxel);
抗代謝物
諸如天冬醯胺酶(asparaginase)3
、阿紮胞苷(azacitidine)、左醛酸鈣(calcium levofolinate)、卡培他濱(capecitabine)、克拉屈濱(cladribine)、阿糖胞苷(cytarabine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)、氟達拉賓(fludarabine)、氟尿嘧啶(fluorouracil)、吉西他濱(gemcitabine)、巰基嘌呤(mercaptopurine)、甲胺喋呤(methotrexate)、奈拉濱(nelarabine)、培美曲塞(pemetrexed)、普拉曲沙(pralatrexate)、硫唑嘌呤(azathioprine)、硫鳥嘌呤(thioguanine)、卡莫氟(carmofur);去氧氟尿苷(doxifluridine)、艾西拉濱(elacytarabine)、雷替曲塞(raltitrexed)、沙帕他濱(sapacitabine)、替加氟(tegafur)2 , 3
、曲美沙特(trimetrexate);
抗癌抗生素
諸如博萊黴素(bleomycin)、放線菌素D (dactinomycin)、小紅莓(doxorubicin)、表柔比星(epirubicin)、艾達黴素(idarubicin)、左旋咪唑(levamisole)、米替福新(miltefosine)、絲裂黴素C (mitomycin C)、羅米地辛(romidepsin)、鏈脲菌素(streptozocin)、伐柔比星(valrubicin)、淨司他丁(zinostatin)、左柔比星(zorubicin)、道諾黴素(daunurobicin)、普卡黴素(plicamycin);阿克拉黴素(aclarubicin)、培洛黴素(peplomycin)、吡柔比星(pirarubicin);
激素 / 拮抗劑
諸如阿巴瑞克(abarelix)、阿比特龍(abiraterone)、比卡魯胺(bicalutamide)、布舍瑞林(buserelin)、卡魯睾酮(calusterone)、氯三芳乙烯(chlorotrianisene)、地加瑞克(degarelix)、地塞米松(dexamethasone)、雌二醇(estradiol)、氟可龍(fluocortolone)氟甲睾酮(fluoxymesterone)、氟他胺(flutamide)、氟維司群(fulvestrant)、戈舍瑞林(goserelin)、組胺瑞林(histrelin)、亮丙瑞林(leuprorelin)、甲地孕酮(megestrol)、米托坦(mitotane)、那法瑞林(nafarelin)、諾龍(nandrolone)、尼魯胺(nilutamide)、奧曲肽(octreotide)、潑尼松龍(prednisolone)、雷諾昔酚(raloxifene)、他莫昔芬(tamoxifen)、促甲狀腺激素α、托瑞米芬(toremifene)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、己烯雌酚(diethylstilbestrol);阿考比芬(acolbifene)、達那唑(danazol)、德舍瑞林(deslorelin)、環硫雄醇(epitiostanol)、奧特羅那(orteronel)、恩雜魯胺(enzalutamide)1 , 3
;
芳香酶抑制劑
諸如胺格魯米特(aminoglutethimide)、阿那曲唑(anastrozole)、依西美坦(exemestane)、法屈唑(fadrozole)、來曲唑(letrozole)、睾內酯(testolactone);福美司坦(formestane);
小分子激酶抑制劑
諸如克卓替尼(crizotinib)、達沙替尼(dasatinib)、埃羅替尼(erlotinib)、伊馬替尼(imatinib)、拉帕替尼(lapatinib)、尼羅替尼(nilotinib)、帕佐泮尼(pazopanib)、瑞戈非尼(regorafenib)、蘆可替尼(ruxolitinib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、凡德他尼(vandetanib)、維羅非尼(vemurafenib)、伯舒替尼(bosutinib)、吉非替尼(gefitinib)、阿西替尼(axitinib);阿法替尼(afatinib)、阿立塞替(alisertib)、達拉菲尼(dabrafenib)、達可替尼(dacomitinib)、戴那西尼(dinaciclib)、多韋替尼(dovitinib)、恩紮妥林(enzastaurin)、尼達尼布(nintedanib)、樂伐替尼(lenvatinib)、立尼法尼(linifanib)、林斯替尼(linsitinib)、馬賽替尼(masitinib)、米哚妥林(midostaurin)、莫替沙尼(motesanib)、來那替尼(neratinib)、奧蘭替尼(orantinib)、哌立福新(perifosine)、普納替尼(ponatinib)、拉多替尼(radotinib)、日格塞尼(rigosertib)、替吡法尼(tipifarnib)、提瓦替尼(tivantinib)、替沃紮尼(tivozanib)、曲美替尼(trametinib)、皮馬瑟替(pimasertib)、丙胺酸布立尼布(brivanib alaninate)、西地尼布(cediranib)、阿帕替尼(apatinib)4
、S-蘋果酸卡博替尼(cabozantinib S-malate)1 , 3
、依魯替尼(ibrutinib)1 , 3
、埃克替尼(icotinib)4
、布帕立尼(buparlisib)2
、西帕替尼(cipatinib)4
、卡比替尼(cobimetinib)1 , 3
、艾德拉尼(idelalisib)1 , 3
、非拉替尼(fedratinib)1
、XL-6474
;
光敏劑
諸如甲氧沙林(methoxsalen)3
;卟吩姆鈉(porfimer sodium)、他拉泊芬(talaporfin)、替莫泊芬(temoporfin);
抗體
諸如阿侖單抗(alemtuzumab)、貝索單抗(besilesomab)、本妥昔單抗維多汀(brentuximab vedotin)、西妥昔單抗(cetuximab)、德諾單抗(denosumab)、伊匹單抗(ipilimumab)、奧伐木單抗(ofatumumab)、帕尼單抗(panitumumab)、利妥昔單抗(rituximab)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、貝伐單抗(bevacizumab)、帕妥珠單抗(pertuzumab)2 , 3
;卡托莫西單抗(catumaxomab)、埃羅妥珠單抗(elotuzumab)、依帕珠單抗(epratuzumab)、伐吐珠單抗(farletuzumab)、莫格利珠單抗(mogamulizumab)、萊西單抗(necitumumab)、尼妥珠單抗(nimotuzumab)、歐比托珠單抗(obinutuzumab)、奧卡拉珠單抗(ocaratuzumab)、奧戈伏單抗(oregovomab)、雷莫蘆單抗(ramucirumab)、里樂木單抗(rilotumumab)、思圖昔單抗(siltuximab)、托西利單抗(tocilizumab)、紮魯姆單抗(zalutumumab)、紮木單抗(zanolimumab)、馬妥珠單抗(matuzumab)、達羅珠單抗(dalotuzumab)1 , 2 , 3
、奧那珠單抗(onartuzumab)1 , 3
、拉克姆單抗(racotumomab)1
、
塔巴木單抗(tabalumab)1 , 3
、EMD-5257974
、納武單抗(nivolumab)1 , 3
;
細胞介素
諸如阿地白介素(aldesleukin)、干擾素α2
、干擾素α2a3
、干擾素α2b2 , 3
;西莫白介素(celmoleukin)、他索那明(tasonermin)、替西白介素(teceleukin)、奧普瑞白介素(oprelvekin)1 , 3
、重組干擾素β-1a4
;
藥物結合物
諸如地尼白介素迪夫托斯(denileukin diftitox)、替伊莫單抗(ibritumomab tiuxetan)、碘苄胍(iobenguane) I123、潑尼氮芥(prednimustine)、曲妥珠單抗恩他新(trastuzumab emtansine)、雌氮芥(estramustine)、吉妥單抗(gemtuzumab)、奧唑米星(ozogamicin)、阿柏西普(aflibercept);辛曲德開貝舒托(cintredekin besudotox)、艾多替德(edotreotide)、奧英妥珠單抗(inotuzumab ozogamicin)、他那莫單抗(naptumomab estafenatox)、奧普珠單抗莫納托克斯(oportuzumab monatox)、鎝(technetium) (99mTc)阿西莫單抗(arcitumomab)1 , 3
、
文塔立得(vintafolide)1 , 3
;
疫苗
諸如斯普留西(sipuleucel)3
;維特斯本(vitespen)3
、艾美派姆-S (emepepimut-S)3
、oncoVAX4
、林多派姆(rindopepimut)3
、troVax4
、MGN-16014
、MGN-17034
;
雜項
亞利崔托寧(alitretinoin)、貝瑟羅汀(bexarotene)、硼替佐米(bortezomib)、依維莫司(everolimus)、伊班膦酸(ibandronic acid)、咪喹莫特(imiquimod)、來那度胺(lenalidomide)、香菇多醣(lentinan)、甲酪胺酸(metirosine)、米伐木肽(mifamurtide)、帕米膦酸(pamidronic acid)、培門冬酶(pegaspargase)、噴司他丁(pentostatin)、斯普留西3
、西索菲蘭(sizofiran)、他米巴羅汀(tamibarotene)、坦羅莫司(temsirolimus)、沙立度胺(thalidomide)、維甲酸(tretinoin)、維莫德吉(vismodegib)、唑來膦酸(zoledronic acid)、伏立諾他(vorinostat);塞內昔布(celecoxib)、西侖吉肽(cilengitide)、恩替諾特(entinostat)、依他噠唑(etanidazole)、加利特皮(ganetespib)、艾朵諾西(idronoxil)、依尼帕瑞(iniparib)、依薩佐米(ixazomib)、氯尼達明(lonidamine)、尼莫唑(nimorazole)、帕比諾他(panobinostat)、普瑞替諾(peretinoin)、普替德新(plitidepsin)、泊利度胺(pomalidomide)、普科噠唑(procodazol)、地磷莫司(ridaforolimus)、他喹莫德(tasquinimod)、特洛翠他(telotristat)、胸腺法新(thymalfasin)、替拉紮明(tirapazamine)、托舍多特(tosedostat)、曲貝德生(trabedersen)、烏苯美司(ubenimex)、伐司撲達(valspodar)、今堤森(gendicine)4
、
必醫你舒(picibanil)4
、雷洛辛(reolysin)4
、鹽酸瑞他黴素(retaspimycin hydrochloride)1 , 3
、特雷巴納尼布(trebananib)2 , 3
、維如利金(virulizin)4
、卡非佐米(carfilzomib)1 , 3
、內皮抑素(endostatin)4
、伊姆穆科特爾(immucothel)4
、貝利司他(belinostat)3
、MGN-17034
;
PARP 抑制劑
歐拉帕瑞(Olaparib)、維利帕瑞(Veliparib)。 1 Prop. INN (
所提議之國際非專屬名稱) 2 Rec. INN (
所推薦之國際非專屬名稱) 3 USAN
(美國採納之名稱) 4 no INN 。
以下縮寫對應地指以下定義:
aq
(水溶液)、h (小時)、g
(克)、L (公升)、mg (毫克)、MHz
(兆赫茲)、min. (分)、mm (毫米)、mmol (毫莫耳)、mM
(毫莫耳)、m.p. (熔點)、eq (當量)、mL (毫升)、L
(微升)、ACN (乙腈)、AcOH (乙酸)、CDCl3
(氘化氯仿)、CD3
OD (氘化甲醇)、CH3
CN (乙腈)、c-hex (環己烷)、DCC (二環己基碳化二亞胺)、DCM (二氯甲烷)、DIC (二異丙基碳化二亞胺)、DIEA (二異丙基乙基胺)、DMF (二甲基甲醯胺)、DMSO (二甲亞碸)、DMSO (氘化二甲亞碸)、EDC (1-(3-二甲基-胺基-丙基)-3-乙基碳化二亞胺)、ESI (電噴霧電離)、EtOAc (乙酸乙酯)、Et2
O (乙醚)、EtOH (乙醇)、HATU (二甲基胺基-([1,2,3]三唑并[4,5-b]吡啶-3-基氧基)-亞甲基]-二甲基-六氟磷酸銨)、HPLC (高效液相層析)、i-PrOH (2-丙醇)、K2
CO3
(碳酸鉀)、LC
(液相層析法)、MeOH (甲醇)、MgSO4
(硫酸鎂)、MS (質譜分析法)、MTBE (甲基第三丁基醚)、NaHCO3
(碳酸氫鈉)、NaBH4
(硼氫化鈉)、NMM (N-甲基嗎啉)、NMR (核磁共振)、PyBOP (苯并三唑-1-基-氧基-三吡咯啶基-六氟磷酸鏻)、RT (室溫)、Rt
(滯留時間)、SPE (固相萃取)、TBTU (2-(1-H-苯并三唑-1-基)-1,1,3,3-四氟硼酸四甲基鈾)、TEA (三乙胺)、TFA (三氟乙酸)、THF (四氫呋喃)、TLC (薄層層析法)、UV (紫外)。
在上文及下文中,所有溫度均以℃指示。在以下實例中,「習知處理」意謂:視最終產物之組分而定,視需要添加水,將pH值調節至2與10之間,用乙酸乙酯或二氯甲烷萃取混合物,分離各相,有機相經硫酸鈉乾燥且蒸發,且藉由矽膠層析及/或藉由結晶純化殘餘物。矽膠上之Rf值;溶離劑:乙酸乙酯/甲醇9:1。
在Bruker DPX-300、DRX-400、AVII-400上或500 MHz光譜儀上,使用氘化溶劑之殘餘信號作為內部參考,記錄1
H NMR。化學位移(δ)相對於殘餘溶劑信號以ppm報告(對於在DMSO中之1
H NMR,δ = 2.49 ppm)。1
H NMR資料報告如下:化學位移(多重性、偶合常數及氫的數目)。多重性縮寫如下:s (單峰)、d (二重峰)、t (三重峰)、q (四重峰)、m (多重峰)、br (寬峰)。
LC-MS
給出具有滯留時間、純度及/或質量(以m/z表示)的提供於實例中之LCMS資料。如下獲得所得結果:質譜:LC/MS Waters ZMD (ESI)或HP 1100系列之Hewlett Packard System (離子源:電噴霧(陽性模式)或Waters Acquity H級SQD;掃描:100-1000 m/z;斷裂-電壓:60 V;氣-溫度:300℃,DAD:220 nm。流動速率:2.4 ml/Min。所使用之分裂器將用於在DAD之後降低MS之流動速率至0.75 ml/Min;管柱:Chromolith Speed ROD RP-18e 50-4.6;溶劑:來自Merck KGaA公司之LiChrosolv-品質或如方法中所提及。
方法A:Shimadzu LCMS-2020管柱:Poroshell HPH-C18,3.0*50 mm,2.7 µm;移動相A:水/5 mM NH4
HCO3
,移動相B:乙腈;流動速率:1.2 mL/min;梯度:在2.1 min內10% B至95% B,保持0.6 min;254 nm
方法B:Shimadzu LCMS-2020管柱:Shim-封裝XR-ODS,3.0*50 mm,2.2 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.2 mL/min;梯度:在3.8 min內5% B至100% B,保持1.0 min;254 nm
方法C:Waters Acquity H級SQD;管柱:BEH C-18 2.1-50 1.7 µm;管柱溫度:40℃;偵測:220 nm;溶離劑A:水+0.1% HCOOH;溶離劑B:乙腈+0.08% HCOOH;流速:0.9 ml/min;梯度:0 min 4% B,在1 min內達至100% B,直至1.3 min 100% B,直至1.4 min 4% B,直至2 min 4% B
方法D:Shimadzu LCMS-2020管柱:Ascentis Express C18,3.0*50mm,2.7 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.5 mL/min;梯度:在2.1 min內5% B至100% B,保持0.7 min;254 nm
方法E:Shimadzu LCMS-2020管柱:Shim-封裝XR-ODS,3.0*50 mm,2.2 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.2 mL/min;梯度:在2.0 min內5% B至100% B,保持0.7 min;254 nm
方法F:Agilent 1200-6120B;Chromolith Performance RP18e,長100 mm,內徑3 mm;波長220 nm;梯度:4.2 min;流速:2 ml/min 99:01至0:100;水+0.1%(Vol.) TFA:乙腈+0.1%(Vol.) TFA;0.0至0.2 min:99:01;0.2至3.8 min:99:01至0:100;3.8至4.2 min:0:100
方法G:Shimadzu LCMS-2020,LC20ADXR,管柱:Kinetex EVO C18,3.0*50 mm,2.6 µm;移動相A:水/5 mM NH4
HCO3
、移動相B:ACN;流動速率:1.3 mL/min;梯度:在2.1 min內10% B至95% B,保持0.6 min;254 nm
方法H:Shimadzu LCMS-2020管柱:Poroshell HPH-C18,3.0*50 mm,2.7 µm;移動相A:水/5 mM NH4
HCO3
、移動相B:乙腈;流動速率:1.3 mL/min;梯度:在2.1 min內10% B至95% B,保持 0.6 min;254 nm
方法I:Shimadzu LCMS-2020管柱:Poroshell HPH-C18,3.0*50 mm,2.7 µm;移動相A:水/5mM NH4
HCO3
,移動相B:乙腈;流動速率:1.3 mL/min;梯度:在4.0 min內10% B至95% B,保持 0.8 min;254 nm
方法J:Shimadzu LCMS-2020管柱:Shim-封裝XR-ODS,3.0*50 mm,2.2 um;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.2 mL/min;梯度:在1.1 min內5% B至100% B,保持0.6 min;254 nm
方法K:Waters Acquity H級SQD;管柱:kinetex EVO C18 2.1-50 1.7 µm;管柱溫度:40℃;偵測:220 nm;溶離劑A:水+0.1% HCOOH;溶離劑B:乙腈+0.08% HCOOH;流速:0.9 ml/min;梯度:0 min 4% B,在1 min內達至100% B,直至1.3 min 100% B,直至1.4 min 4% B,直至2 min 4% B
方法L:Shimadzu LCMS-2020管柱:CORTECS C18+ 100A,2.1*50 mm,2.7 um;移動相A:水/0.1% FA、移動相B:乙腈/0.1% FA;流動速率:1.0 mL/min;梯度:在1.1 min內10% B至100% B,保持0.5 min;254 nm
方法M:Shimadzu LCMS-2020管柱:Ascentis Express C18,3.0*50 mm,2.7µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.5mL/min;梯度:在2.0 min內5% B至100% B,保持 0.7 min;254 nm
方法N:Shimadzu LCMS-2020管柱:Shim-封裝XR-ODS,3.0*50 mm,2.2 µm;移動相A:水/0.05% TFA、移動相B:MeOH;流動速率:0.82 mL/min;梯度:在6.2 min內30% B至100% B,保持1.1 min;254 nm
方法O:Shimadzu LCMS-2020管柱:kinetex EVO C18 3.0-50 2.6 µm;移動相A:水/5 mM NH4
HCO3
,移動相B:乙腈;流動速率:1.2 mL/min;梯度:在2.1 min內10% B至95% B,保持0.6 min;254 nm
方法P:Shimadzu LCMS-2020管柱:Ascentis Express C18,3.0*50mm,2.7 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.5mL/min;梯度:在1.2 min內5% B至100% B,保持0.5 min;254 nm
方法Q:Waters Acquity H級SQD;管柱:CORTECS C18 2.1-50 1.6 µm;管柱溫度:30℃;偵測:220 nm;溶劑A:水+0.05% HCOOH;溶劑B:乙腈+0.04% HCOOH;流速:0.9 ml/min;梯度:在1.0 min內2% B至100% B,保持0.3 min
方法R:Waters Acquity H級SQD;管柱:kinetex EVO C18 2.1-50 1.7 µm;管柱溫度:30℃;偵測:220 nm;溶離劑A:水+0.05% HCOOH;溶離劑B:乙腈+0.04% HCOOH;流速:0.9 ml/min;梯度:在1.0 min內1% B至99% B,保持0.3 min
方法S:Shimadzu LCMS-2020管柱:kinetex EVO C18 3.0-50 2.6 µm;移動相A:水/0.04%NH4
OH,移動相B:乙腈;流動速率:1.2 mL/min;梯度:在2.1 min內10% B至95% B,保持0.6 min;254 nm
方法T:Shimadzu LCMS-2020管柱:kinetex EVO C18 3.0-50 2.6 µm;移動相A:水/0.04%NH4
OH、移動相B:乙腈;流動速率:1.2 mL/min;梯度:在1.2 min內10% B至95% B,保持0.5 min;254 nm
方法U:Shimadzu LCMS-2020管柱:Shim-封裝XR-ODS,3.0*50 mm,2.2 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.2 mL/min;梯度:在4.2 min內5% B至100% B,保持0.8 min;254 nm
方法V:Agilent 1200-6120B;管柱:waters sunfire C18,3*100 mm,5 µm;梯度:4.3 min;流速:1.3 ml/min 99:01至0:100;水+0.1%(Vol.) TFA:乙腈+0.1%(Vol.) TFA;0.0至0.2 min:99:01;0.2至3.8 min:99:01至0:100;3.8至4.3 min:0:100
方法W:Shimadzu LCMS-2020管柱:CORTECS C18+ 100A,2.1*50 mm,2.7 um;移動相A:水/0.1% FA,移動相B:乙腈/0.1% FA;流動速率:1.0 mL/min;梯度:在2.0 min內10% B至100% B,保持0.6 min;254 nm
方法X:Shimadzu LCMS-2020管柱:Ascentis Express C18,3.0*50 mm,2.7 µm;移動相A:水/0.05% TFA,移動相B:ACN/0.05% TFA;流動速率:1.5 mL/min;梯度:在3.0 min內5% B至100% B,保持1.5 min;254 nm
藉由Teledyne Isco Combi Flash Rf (具有以下溶劑系統中之一者之矽膠濾筒)進行製備型管柱層析法:
方法A:二氯甲烷/甲醇10:1
方法B:乙酸乙酯/石油醚2:3)
方法C:(乙酸乙酯/石油醚3:7)
方法D:(正庚烷/EtOAc)
方法E:乙酸乙酯/石油醚1:1
方法F:乙酸乙酯/PE 1:10
方法G:乙酸乙酯/石油醚1:5
方法H:二氯甲烷/甲醇2:3
方法I:乙酸乙酯/PE 4:1
方法J:EA/PE 10:1
方法K:CH3
CN/H2
O 3:7
方法L:DCM-MeOH-梯度
方法M:正庚烷/EtOAc梯度
方法N:正庚烷/EtOAc/MeOH梯度
方法O:DCM/MeOH梯度
方法P:乙酸乙酯/石油醚梯度
在Agilent 1200上進行製備型HPLC。管柱:Chromolith製備型RP 18e Merck KGaA。移動相:A:含0.1%甲酸之水/含0.1%甲酸之乙腈。替代方法為:
方法A:1 min 99% A。在2.5 min內自99% A至100% B。接著1.5 min 100% B及1 min 99% A。管柱Chromolith SpeedRod RP-18e;50-4.6mm;偵測220 nM (溶劑A:H20 (0.1% TFA),溶劑B:ACN (0.1% TFA)
方法B:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(0.05% NH3
H2
O)及ACN (在8 min內20% ACN達至39%);偵測器,UV 254 nm
方法C:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD 管柱,19*150 mm 5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內25.0% ACN達至46.0%);偵測器,UV 254 nm。
方法D:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD管柱,19*150 mm 5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內31% ACN達至53%);偵測器,UV 254/220 nm
方法E:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在9 min內22% ACN達至58%);偵測器,uv 254 nm
方法F:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD管柱,19*150 mm 5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內45.0% ACN達至65.0%);偵測器,uv 254 nm
方法G:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在10 min內20.0% ACN達至35.0%);偵測器,uv 254 nm
方法H:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD 管柱,19*150 mm 5 um;移動相,及(在10 min內60%達至62%);偵測器,uv 254 nm。
方法I:對掌性製備型HPLC ():管柱,移動相,偵測器,獲得20 mg產品,α℃
方法J:2#SHIMADZU (HPLC-01)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在7 min內10% ACN達至33%);偵測器,uv 254 nm
方法K:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內10% ACN達至35%);偵測器,UV 254 nm
方法L:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內18.0% ACN達至53.0%);偵測器,uv 254 nm
方法M:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在9 min內18.0% ACN達至60.0%);偵測器,uv 254 nm。
方法N:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD管柱,19*150 mm 5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內25% ACN達至41%);偵測器,UV 254 nm。
方法O:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型OBD C18管柱,19*250 mm,5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內18% ACN達至41%);偵測器,UV 254 nm。
方法P:(2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge製備型C18 OBD管柱,19*150 mm 5 um;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在8 min內18% ACN達至38%);偵測器,UV 254 nm。
方法Q:2#-分析HPLC-SHIMADZU(HPLC-10)):管柱,XBridge Shield RP18 OBD管柱,5 um,19*150 mm;移動相,水(10 MMOL/L NH4
HCO3
+0.1% NH3
.H2
O)及ACN (在9 min內20%相B達至60%);偵測器,uv 254 nm。
方法R:Waters Acquity H級SQD;管柱:BEH C-18 2.1-50 1.7 µm;管柱溫度:40℃;偵測:220 nm;溶離劑A:水+0.1% HCOOH;溶離劑B:乙腈+0.08% HCOOH;流速:0.9 ml/min;梯度:0 min 4% B,在1 min內達至100% B,直至1.3 min 100% B,直至1.4 min 4% B直至2min 4%B。
微波化學方法在來自Personal Chemistry之單模微波反應器EmrysTM Optimiser上進行。
ATR / ATRIP 激酶分析 - ATR / ATRIP 抑制之量測
藉由ATR/ATRIP酶分析測定IC50
值。該分析包含兩個步驟:酶反應及偵測步驟。首先,在分析緩衝液中培育ATR/ATRIP蛋白(共濟失調毛細管擴張症及Rad3相關蛋白/ATR相互作用蛋白)之混合物、所討論之不同濃度化合物、作為受質蛋白之p53及三磷酸腺苷(ATP)。Ser15處之ATR膦酸p53及其他殘基。隨後使用特異性抗體及TR-FRET分析技術偵測磷酸化p53之量。
詳言之:ATR/ATRIP酶分析作為基於384孔分析之TR-FRET-(HTRFTM
,Cisbio生物分析)進行。在第一步驟中,將經純化之人類重組ATR/ATRIP (人類ATR,全長,Genbank ID:NM_001184.3及人類ATRIP,全長,Genbank ID AF451323.1,在哺乳動物細胞株中共表現)在分析緩衝液中、在22℃用不同濃度之測試化合物或不用測試化合物(作為陰性對照物)培育15分鐘。分析緩衝液含有25 mM HEPES pH 8.0、10 mM Mg(CH3
COO)2
、1 mM MnCl2
、0.1% BSA、0.01% Brij® 35及5 mM二硫蘇糖醇(DTT)。 Echo 555 (Labcyte)用於分配化合物溶液。隨後,在第二步驟中,添加經純化之人類重組cmyc標記之p53 (人類p53,全長,Genbank ID:BC003596,在Sf21昆蟲細胞中表現)及ATP且在22℃下培育反應混合物25-35分鐘,通常25分鐘。藥理學相關分析體積為5 µl。在培育反應混合物期間分析中之最終濃度為0.3-0.5 nM,通常0.3 nM,ATR/ATRIP,50 nM p53及0.5 µM ATP。藉由添加EDTA來中止酶反應。藉由使用能夠實現FRET之特異性抗體[用螢光銪(Eu)標記為供體且d2為受體(Cisbio生物分析)]來偵測由於ATR介導之反應在ATP存在下產生磷酸化p53。出於此目的,向反應混合物中添加2 µl含抗體中止溶液(12.5 mM HEPES pH 8.0、125 mM EDTA、30 mM氯化鈉、300 mM氟化鉀、0.006% Tween-20、0.005% Brij® 35、0.21 nM抗磷酸p53(Ser15)-Eu抗體、15 nM抗cmyc-d2抗體)。在信號發展2小時之後,在EnVision (PerkinElmer)微定量盤式讀取器中使用TRF模式用雷射激發來分析培養盤。在340 nm處激發供體銪後,量測665 nm處受體d2以及來自615 nm處供體Eu之所發射之螢光。磷酸化p53之量與所發射光之量之比率,亦即在665 nm及615 nm處相對螢光單位(rfu)之比率成正比。使用Genedata Screener軟體處理資料。特定言之,藉由使用非線性回歸分析將劑量-反應曲線擬合至資料點,以常見方式測定IC50
值。
IC50
=半最大抑制濃度
ATP=三磷酸腺苷
TR-FRET=螢光共振能量轉移
HTRF®=均相時間分辨螢光
HEPES=2-(4-(2-羥乙基)-1-哌嗪基)乙磺酸
Mg(CH3COO)2
=乙酸鎂
MnCl2
=錳(II)-氯化物
BSA=牛血清白蛋白
EDTA=乙二胺四乙酸鹽
TRF=時間分辨螢光
pCHK1 細胞分析
Chk1激酶在ATR下游起作用且在DNA損傷檢查點控制中起關鍵作用。 Chk1之活化涉及Ser317及Ser345之磷酸化(視為藉由ATR磷酸化/活化之優先目標)且回應於阻斷之DNA複製及某些形式之遺傳毒性應激而發生。Ser 345處之磷酸化用以在檢查點活化之後使Chk1定位於細胞核。
此分析量測HT29結腸腺癌細胞中Chk1 (Ser 345)在用化合物及羥基脲(由於dNTP耗盡而促進叉停滯)處理及使用免疫細胞化學程序及高含量成像後之磷酸化的降低。
對於該分析,將HT29細胞接種於培養基(DMEM高葡糖(無酚紅)、2 mM格魯塔瑪(Glutamax)、1 mM丙酮酸鹽、10% FCS於Greiner 384孔盤中,黑色,µclear # 781090 (2500細胞/孔/30 μl)及在37℃、10% CO2
及90% rH下至少培育20小時。同時添加經稀釋之測試化合物(1 nM-最終30 µM)及羥基脲(最終3 mM)且在37℃下培育細胞4小時。用100% MeOH (約-20℃低溫)固定/滲透且用0.2% Triton X-100滲透之後,使用特異性抗pChk1抗體(細胞信號傳導,#2348BF)及螢光標記二次抗體(Alexa Fluor®488山羊抗兔F(ab')2片段,Invitrogen A11070)及用於細胞計數之平行核染色進行完整免疫細胞化學程序。
在ImageXpress超共焦高容量讀取器上偵測核定位pChk1信號且報告為陽性細胞(核)%。
Kv11 . 1 ( hERG ) 離子通道活性
在此分析中,研究測試化合物對Kv11.1 (hERG)離子通道電流之潛在活體外作用,其介導快速活化、延遲整流心臟鉀電流(IKr)。藉由在室溫下進行全細胞箝膜技術,用穩定Kv11.1 (hERG)轉染之人類胚腎細胞株(HEK293)進行分析。
Kv11.1 (hERG)離子通道阻斷劑奎尼丁(quinidine)用作參考化合物。將測試化合物及奎尼丁之作用相對於相對應的媒劑對照物歸一化。全細胞記錄用自動化箝膜裝置PatchlinerTM, Nanion Technologies, Munich)進行。在此,箝膜量測在具有限定直徑之孔的經矽酸鹽塗佈之晶片上運行。溶液、細胞懸浮液及化合物藉由Teflon層壓移液管針經微流矽酸鹽層壓通道施用。市售箝膜放大器(EPC10,HEKA Elektronik Dr. Schulze GmbH,德國)用於箝膜記錄術。穩定表現hERG基因之HEK293細胞保持在約-80 mV下。使用具有以下固定振幅之脈衝圖案來量測歸因於測試/參考化合物應用之Kv11.1 (hERG)鉀電流之穩態抑制:51 ms/ -80 mV、500 ms/+40 mV、500 ms/ -40 mV、200 ms/ -80 mV。以10 s間隔重複hERG-比電壓協定。洩漏電流藉由P4漏減減去。將細胞再懸浮於細胞外箝膜溶液(extracellular patch clamp solution,EC)中且施加至晶片中。在捕獲細胞之後,藉由密封增強劑溶液(seal enhancer solution,SE)交換EC以改良密封程序。當達到全細胞組態時,藉由EC之施加洗掉密封增強劑。在EC中開始記錄,持續1.5 min。隨後施加DMSO (媒劑對照,0.1% DMSO)且量測對照電流3 min。在控制穩態電流之後,以相同濃度施加測試化合物兩次且量測尾電流各3.5 min。對於濃度關係之測定,測試化合物作為累積濃度-反應曲線應用且量測各濃度5分鐘。以相同方式處理參考化合物奎尼丁。自在-40 mV (相關電流(current of interest,COI))下監測之尾電流振幅判定對Kv11.1 (hERG)離子通道活性之作用。自最後記錄之電流跡線計算結果。將定義為100% Kv11.1 (hERG)離子通道活性之對照值、測試化合物之施加及奎尼丁之施加之間的Kv11.1 (hERG)離子通道活性之變化報告為COI之對照值之變化百分比。在記錄期間收集測試化合物之等分試樣用於濃度驗證。樣品立即藉由HPLC量測且分析內之最終化合物濃度根據校準曲線計算。
藥理學資料
表1
ATR-ATRIP之抑制(IC50
);
pCHK1細胞分析;
Kv11.1 (hERG)離子通道活性
pCHK1:
< 10 nM = xxxx xxx:10-100 nM xx:100-1000 nM x:1000-10000 nM
表1中所展示之化合物為根據本發明之尤佳化合物。
化合物編號 | ATR-ATRIP IC50 [M] | pCHK1 IC50 [M] | hERG Ki (nM/%效應@ conc) |
1 | 2.3 | xxx | >30.000 / -28%效應@ 30 µM |
2 | 0.8 | xxx | >10.000 / -3%效應@ 10 µM |
3 | 0.9 | xxx | |
4 | 0.8 | xxx | >10.000 / -12%效應@ 10 µM |
5 | 3.5 | xxx | >10.000 / -22%效應@ 10 µM |
6 | 8.9 | xx | |
7 | 2.3 | xxx | >10.000 / -16%效應@ 10 µM |
8 | 2.1 | xxxx | >10.000 / -6%效應@ 10 µM |
9 | 4.1 | xxx | |
10 | 1.9 | xxx | |
11 | 0.9 | xxx | >10.000 / -5%效應@ 10 µM |
12 | 0.8 | xx | |
13 | 1.4 | xx | |
14 | 99.0 | x | |
15 | 0.6 | xxx | >10.000 / -24%效應@ 10 µM |
16 | 67.0 | x | |
17 | 3.6 | xxx | >10.000 / 5%效應@ 10 µM |
18 | 6.2 | xx | >10.000 / -14%效應@ 10 µM |
19 | 3.4 | xxx | >10.000 / -6%效應@ 10 µM |
20 | 1.2 | xxx | >10.000 / -11%效應@ 10 µM |
21 | 510.0 | ||
22 | 3.3 | xx | |
23 | 1.0 | xxx | |
24 | 28.0 | xx | |
25 | 4.3 | xxx | >10.000 / -1%效應@ 10 µM |
26 | 0.8 | xxx | >30.000 / -24%效應@ 30 µM |
27 | 10.0 | xx | |
28 | 5.3 | xx | |
29 | 5.4 | x | |
30 | 15.0 | xx | |
31 | 33.0 | xx | |
32 | 20.0 | x | |
33 | 16.0 | xx | |
34 | 6.1 | xxx | >10.000 / -1%效應@ 10 µM |
35 | 0.5 | xxx | >10.000 / -23%效應@ 10 µM |
36 | 0.6 | xxx | >10.000 / -9%效應@ 10 µM |
37 | 7.9 | xx | |
38 | 4.3 | xx | |
39 | 7.9 | xx | |
40 | 50.6 | xx | >10.000 / 9%效應@ 10 µM |
41 | 1.3 | xxx | |
42 | 0.3 | xxxx | >30.000 / -26%效應@ 30 µM |
43 | 3.9 | xx | |
44 | 4.2 | xx | |
45 | 1800.0 | ||
46 | 25.0 | x | |
47 | 89.0 | x | |
48 | 2.0 | xxx | >10.000 / -32%效應@ 10 µM |
49 | 1.8 | xxx | >10.000 / -18%效應@ 10 µM |
50 | 1.3 | xxxx | >10.000 / -17%效應@ 10 µM |
51 | 1.2 | xx | |
52 | 1.4 | xxx | |
53 | 58.0 | x | |
54 | 2.2 | xxx | >10.000 / -2%效應@ 10 µM |
55 | 0.7 | xxx | >10.000 / -14%效應@ 10 µM |
56 | 25.0 | x | |
57 | 150.0 | x | |
58 | 10.0 | xx | |
59 | 21.0 | x | |
60 | 32.0 | x | |
61 | 0.6 | xxx | >30.000 / -12%效應@ 30 µM |
62 | 22.0 | x | |
63 | 27.0 | xx | |
64 | 51.0 | x | |
65 | 5.8 | xx | |
66 | 1.9 | xxxx | |
67 | 0.8 | xxx | >10.000 / -12%效應@ 10 µM |
68 | xxx | >30.000 / -35%效應@ 30 µM | |
69 | xxx | >30.000 / -29%效應@ 30 µM | |
70 | 2.2 | xxx | >10.000 / -20%效應@ 10 µM |
71 | xxx | >10.000 / -16%效應@ 10 µM | |
72 | xxx | ||
73 | 28.0 | xx | |
74 | 17.0 | ||
75 | 21.0 | xx | |
76 | 28.0 | xx | |
77 | 58.0 | x | |
78 | xxx | >30.000 / -12%效應@ 30 µM | |
79 | xxx | ||
80 | xx | ||
81 | 3 | xx | |
82 | 0.8 | xx | |
83 | x | ||
84 | xxx | ||
85 | 21 | x | |
86 | 24 | x | |
87 | 0.4 | xxx | |
88 | x | ||
89 | 0.9 | x | |
合成流程及化合物實例之描述 :
在以下式中,「abs」意謂如所指示之絕對立體化學。
氮雜吲唑衍生物可根據流程1合成。
流程 1 :
氮雜吲唑10
之合成途徑
經1'取代之硝基吡唑1
可藉由H2
/PdC或Fe或SnCl2
還原為胺2
。亞胺3
之形成可藉由與乙醯基嗎啉及磷醯氯反應進行。在鹼性條件(如LiHMDS)下可能環化氮雜吲唑4
。隨後羥基可轉化成離去基,如Tf或Cl,轉化成5
(R4=離去基)。鈴木類型(Suzuki type)反應產生氮雜吲唑6
。用NIS或NBS可能鹵化為化合物7
。與經保護之吡唑的鈴木類型反應產生1'或2'經保護之衍生物8
或9
。在去除保護基之後,可分離氮雜吲唑10
。
根據流程2可合成未經取代之氮雜吲唑衍生物。
流程 2 :
未經取代之氮雜吲唑13 之
合成途徑
始於3
(R2=H),保護基可在氮雜吲唑核心引入至11
。以下步驟如流程1中所描述。保護基可在最後步驟中自12
移除,得到未經取代之氮雜吲唑13
。
流程3中描述以吡啶衍生物為起始物質之氮雜吲唑衍生物之替代途徑。
流程 3 :
氮雜吲唑10
之替代合成途徑
2,6-二氯-3-硝吡啶-4-胺14
可在Sandmeyer條件下溴化成15
。鈴木類型反應產生16
。可在布赫瓦爾德(Buchwald)條件下或經由親核性芳族取代在鹼性條件下將甲基嗎啉引入至17
中。硝基可用H2
/PdC或Fe或SnCl2
還原成胺18
。在乙酸中有亞硝酸鈉之情況下,環化成19
係可能的。此化合物可用NBS、NIS、Br2
或I2
鹵化成20
及烷基化成7
。或者,可由19
藉由烷基化成21
及用NBS或NIS鹵化來製備7
。7
至10
之步驟如流程1中所描述。
亦可根據流程4合成氮雜吲唑衍生物。
流程 4 :
對氮雜吲唑6
及隨後10
之替代鈴木類型反應。
可將氮雜吲唑5
轉化成酸22
。鈴木類型反應產生6
,其可如流程1中所描述反應成10
。
可根據流程5合成在R1
(R1
=H)處無取代之氮雜吲唑衍生物。
流程 5 :
氮雜吲唑24
之合成途徑
以具有PdCl2
之氮雜吲唑5
及膦配體,如dppf為起始物質,可製備氮雜吲唑23
。或者,氮雜吲唑25
可在布赫瓦爾德條件下與氮雜吲唑23
反應。至24 之
反應步驟係如流程1中關於氮雜吲唑10
之合成所描述。
氮雜吲唑34
之替代合成途徑描述於流程6中。
流程 6 :
環丙基氮雜吲唑35
之合成途徑
氮雜吲唑5
可羰基化成26
,其可用NBS或NIS鹵化成27
。鈴木類型反應產生氮雜吲唑28
。用例如LiBH4
還原酯,產生醇29
,其可轉化成離去基,如Tf或Cl,轉化成30
(R4=離去基)。R4可與亞磺酸鹽交換成碸31
。用(二甲基胺基)甲基二甲胺,可合成烯烴32
。與甲磺醯基碘化物反應得到環丙基碸33
。在吡唑去除保護基之後,可分離氮雜吲唑34
。
如流程7中所描述,可替代地合成環丙基氮雜吲唑衍生物34
。
流程 7 :
環丙基氮雜吲唑衍生物之替代合成途徑
可例如用LiBH4
將氮雜吲唑27
還原成醇34
,其可轉化成離去基,如Tf或Cl,轉化成35
(R4=離去基)。R4可與亞磺酸鹽交換成碸36
。如上文反應流程中所描述,與二溴甲烷或二氯乙烷反應產生環丙基37
,其可經合成至氮雜吲唑34
。
架構基塊
4-胺基-1-甲基-1H-吡唑-5-甲酸甲酯
將1-甲基-4-硝基-1H-吡唑-5-甲酸甲酯(10 g,51.31 mmol,1當量)及鈀碳(11.50 g,103 mmol,2.00當量)懸浮於甲醇(100 mL)中。在25℃下在H2
氛圍下攪拌所得溶液16 h。過濾固體。所得混合物在真空下濃縮。藉由管柱層析法(方法A)純化殘餘物。將呈粉紅色固體狀之4-胺基-1-甲基-1H-吡唑-5-甲酸甲酯分離,(9 g,定量);LC/MS (方法J):Rt 0.641 min,[MH]+ 156.1 m/z。
1-[(3R)-3-甲基嗎啉-4-基]乙-1-酮
將(3R)-3-甲基嗎啉(12 g,112.71 mmol)、碳酸鉀(86.08 g,591.70 mmol,5.25當量)溶解於二氯甲烷(280 mL)中且在0℃下攪拌30 min。向其中添加乙醯氯(32.60 g,395 mmol,3.50當量)。在25℃下攪拌所得溶液16 h。濾出固體。在真空下濃縮所得混合物,獲得呈黃色油狀之1-[(3R)-3-甲基嗎啉-4-基]乙-1-酮(15 g,88%);LC/MS (方法J):Rt 1.151 min,[MH]+ 144.0 m/z。
1-甲基-4-[(E)-{1-[(3R)-3-甲基嗎啉-4-基]亞乙基}胺基]-1H-吡唑-5-甲酸甲酯
將4-胺基-1-甲基-1H-吡唑-5-甲酸甲酯(9 g,52.21 mmol)及1-[(3R)-3-甲基嗎啉-4-基]乙-1-酮(15 g,94.28 mmol,1.81當量)溶解於DCE (200 mL,2.40 mol)中且在0℃下攪拌0.5 h。向其中添加磷醯氯(40 g,247.95 mmol,4.75當量)。在40℃下攪拌所得溶液16 h。隨後藉由添加20 mL NH4
Cl淬滅反應物。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法B)純化殘餘物。將呈黃色固體狀之1-甲基-4-[(E)-[1-[(3R)-3-甲基嗎啉基-4-基]亞乙基]胺基]-1H-吡唑-5-甲酸甲酯(11 g,68%)分離;LC-MS (方法J) Rt:0.664 min,[MH]+ 281.2。
1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-醇
將1-甲基-4-[(E)-[1-[(3R)-3-甲基嗎啉-4-基]亞乙基]胺基]-1H-吡唑-5-甲酸甲酯(11 g,35.32 mmol,1當量)溶解於DMF (300 mL)中。在0℃下攪拌溶液30 min。向其中添加LiHMDS (100 mL,6.19 mmol)。將所得溶液在0℃下在水/冰浴中攪拌1 h。隨後藉由添加NH4
Cl水溶液淬滅反應物。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法A)純化殘餘物且藉由乙酸乙酯再結晶。獲得呈無色固體狀之1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-醇(6 g,68%);LC/MS (方法B):Rt 1.458 min,[MH]+ 249.2。
三氟甲烷磺酸1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-酯
將1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-醇(6 g,21.75 mmol,1.00當量)、DCM (700 mL)、DIEA (20.26 g,148.92 mmol,3.16當量)及1,1,1-三氟-N-苯基-N-(三氟甲烷)磺醯基甲磺醯胺(37.39 g,99.43 mmol,2.11當量)合併且在室溫下攪拌16 h。所得混合物在真空下濃縮。藉由管柱層析法(方法C)純化殘餘物。將呈黃色油狀之三氟甲烷磺酸1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-酯(18 g,90%)分離;LC/MS (方法L):Rt 0.978 min,[MH]+ 381.0。
三氟甲磺酸1-異丙基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶-7-基酯
類似於以上架構基塊製備三氟甲磺酸1-異丙基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶-7-基酯。將呈褐色固體狀之三氟甲磺酸1-異丙基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶-7-基酯(105 mg,86%)分離;LC/MS (方法F):Rt 2.781 min;[MH]+ 409.1 m/z。
4-胺基-2H-吡唑-3-甲酸甲酯
將4-硝基-2H-吡唑-3-甲酸甲酯(3 g,0.017 mol)及Pd-C 5% (0.75 g)懸浮於甲醇(30 mL)中且在氫氣下在室溫下攪拌14 h。過濾懸浮液且在真空下移除溶劑。將呈淺粉紅色固體狀之4-胺基-2H-吡唑-3-甲酸甲酯(2.4 g,定量)分離;LC/MS (方法F) Rt 0.363 min;[MNa]+ 164.1 m/z。
4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞乙基胺基]-2H-吡唑-3-甲酸甲酯
將1-((R)-3-甲基-嗎啉-4-基)-乙酮(3.409 g;23.808 mmol;1.40當量)溶解於1,2-二氯乙烷(24 ml)中且逐滴添加磷醯氯(4.684 ml;51.018 mmol;3當量)。在室溫下攪拌褐色溶液30分鐘且接著添加4-胺基-2H-吡唑-3-甲酸甲酯(2.400 g;17.006 mmol;1當量)且在80℃下攪拌2小時。將反應溶液蒸發至乾燥。將殘餘物懸浮於水(50 ml)中且用NaOH水溶液(32%)將pH調節至12且用EtOAc萃取。合併之有機相經硫酸鈉乾燥,過濾且蒸發至乾燥。將呈黃色固體狀之4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞乙基胺基]-2H-吡唑-3-甲酸甲酯(5 g,定量)分離;LC/MS (方法F):Rt 0.968 min;[MH]+ 267 m/z。
4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞甲基胺基]-2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-甲酸甲酯
將4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞乙基胺基]-2H-吡唑-3-甲酸甲酯(1 g;3.755 mmol)懸浮於THF (20 ml)及三乙胺(781 µl;5.633 mmol;1.50當量)且添加2-(三甲基矽烷基)乙氧基甲基氯化物(731.084 µl;4.131 mmol;1.10當量)及在室溫下攪拌1小時。在真空下移除溶劑且用EtOAc/水萃取。合併之有機相經硫酸鈉乾燥且蒸發至乾燥。藉由管柱層析法(方法D)純化粗產物。將呈無色固體狀之4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞甲基胺基]-2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-甲酸甲酯(580 mg,38%)分離;LC/MS (方法F):Rt 2.251 min,[MH]+ 397.2 m/z。
5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶-7-醇
將4-[1-((R)-3-甲基-嗎啉-4-基)-(E)-亞乙基胺基]-2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-甲酸甲酯(200 mg;0.494 mmol;1當量)溶解於THF (3 ml)中且添加含雙(三甲基矽烷基)胺基鋰溶液1 M之THF (1.977 ml;1.977 mL;4當量)及在室溫下攪拌2小時。向反應溶液中添加水(0.2 ml)且在真空下移除溶劑。將殘餘物懸浮於水(2 ml)中且用2 N HCl及飽和氯化銨溶液將pH調節至7且用DCM萃取。經合併之有機相乾燥,過濾且蒸發。將呈黃色固體狀之5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶-7-醇(182 mg,95%)分離;LC/MS (方法F):Rt 2.28 min;[MH]+ 365.2 m/z。
三氟甲磺酸5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[[4,3-b]吡啶-7-基酯
將5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶-7-醇(50 mg;0.137 mmol;1.0當量)溶解於DCM (1 ml)中且添加三乙胺(34.226 µl;0.247 mmol;1.80當量)。將反應混合物冷卻至5℃且添加三氟甲磺酸酐(41 µl;0.247 mmol;1.80當量)且攪拌1小時且升溫至室溫。用DCM及水萃取反應溶液且用鹽水洗滌合併之有機相,經硫酸鈉乾燥,過濾且蒸發至乾燥。將呈橙褐色固體狀之三氟甲磺酸5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶-7-基酯分離(61 mg,90%)分離。LC/MS (方法F):Rt 3.006 min,[MH]+ 497.1 m/z。
實例
實例1:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(1)
用於合成實例1之架構基塊:(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將三氟甲烷磺酸1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-酯(1 g,2.37 mmol,1.0當量)、(6-甲基吡啶-3-基)酸(680 mg,4.72 mmol,1.99當量)、Pd(dppf)Cl2
.CH2
Cl2
(210 mg,0.23 mmol,0.10當量)及碳酸鈉(790 mg,7.08mmol,2.99當量)懸浮於DMF (12mL)、水(3 ml)中。在微波中將最終反應混合物加熱至100℃持續1小時。將呈黃色固體狀之(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(600 mg,70%)分離。
用於合成實例1之架構基塊:(3R)-4-[3-溴-1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
將(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(12 g,33.40 mmol,1當量)及NBS (9.39 g,50.12 mmol,1.50當量)溶解於MeCN (480 mL)中且在25℃下攪拌1 h。所得混合物在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之(3R)-4-[3-溴-1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(15 g,100%)分離。
用於合成實例1之架構基塊:(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將(3R)-4-[3-溴-1-甲基-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(1.20 g,2.68 mmol,1.0當量)、1-(噁烷-2-基)-3-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(2.36 mmol,8.06 mmol,3當量)、Pd(pph3)4 (340 mg,0.26 mmol,0.10當量)及碳酸鈉(900 mg,8.07 mmol,3當量)懸浮於四氫呋喃(12 mL)、水(3 ml,158.20 mmol,58.93當量)中。在90℃下攪拌所得溶液1 h。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(700 mg,50%)分離。
實例1:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(1)
將(3R)-3-甲基-4-[1-甲基-7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(10 g,19.00 mmol,1當量)溶解於甲醇HCl (200 mL)中。在25℃下攪拌所得溶液1 h。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由製備型HPLC純化粗產物。將呈黃色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(2 g,28%)分離;熔點:118-120℃;1
H NMR (300 MHz, DMSO-d6
): δ 12.81 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.88 (dd, J = 7.9, 2.4 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.89 - 6.81 (m, 1H), 4.46 (s, 1H), 4.07 - 3.90 (m, 2H), 3.72 (s, 1H), 3.62 - 3.48 (m, 1H), 3.23 (td, J = 12.5, 11.7, 3.7 Hz, 1H), 3.01 (s, 1H), 2.58 (d, J = 2.8 Hz, 4H), 2.02 (d, J = 2.7 Hz, 0H), 1.21 (dd, J = 6.9, 2.6 Hz, 3H); LC/MS (方法A) Rt 1.338 min, [MH]+ 390.0。
實例2:5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(2)
用於合成實例2之架構基塊:6-氯-2-甲基-3-硝基吡啶-4-胺
將2,6-二氯-3-硝基吡啶-4-胺(1 g,4.33 mmol,1當量)、Pd (PPh3
)4
(557 mg,0.46 mmol,0.11當量)及AlMe3
(2.64 mL,23.94 mmol,5.53當量)溶解於DMF (15 mL)中且在70℃下攪拌3 h。藉由添加50 mL冰/鹽淬滅反應物。濾出固體。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法B)純化殘餘物。將呈黃色固體狀之6-氯-2-甲基-3-硝基吡啶-4-胺(500 mg,55%)分離。
用於合成實例2之架構基塊:4-溴-6-氯-2-甲基-3-硝基吡啶
將6-氯-2-甲基-3-硝基吡啶-4-胺(1 g,4.80 mmol,1當量)、CuBr2
(1601.79 mg,6.81 mmol,1.42當量)及tBuONO (697.86 mg,6.43 mmol,1.34當量)溶解於MeCN (20 mL)中且在65℃下攪拌2 h。用氯化氫將溶液的pH值調節至2。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法F)純化殘餘物。將呈黃色固體狀之4-溴-6-氯-2-甲基-3-硝基吡啶(1 g,75%)分離。
用於合成實例2之架構基塊:6-氯-2-甲基-4-(6-甲基吡啶-3-基)-3-硝基吡啶
將4-溴-6-氯-2-甲基-3-硝基吡啶(500 mg,1.79 mmol,1當量)、(6-甲基吡啶-3-基)酸(326.75 mg,2.15 mmol,1.20當量)、Pd (pph3
)2
Cl2
(130 mg,0.18 mmol,0.10當量)及碳酸鈉(604.65 mg,5.42 mmol,3.03當量)溶解於二噁烷(2 mL)、水(0.4 mL)中且在80℃下攪拌3 h。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法G)純化殘餘物。將呈黃色固體狀之6-氯-2-甲基-4-(6-甲基吡啶-3-基)-3-硝基吡啶(400 mg,76%)分離。
用於合成實例2之架構基塊:(3R)-3-甲基-4-[6-甲基-4-(6-甲基吡啶-3-基)-5-硝基吡啶-2-基]嗎啉
將6-氯-2-甲基-4-(6-甲基吡啶-3-基)-3-硝基吡啶(500 mg,1.71 mmol,1當量)、(3R)-3-甲基嗎啉(230.16 mg,2.05 mmol,1.20當量)、DIPEA (696.53 mg,5.12 mmol,3當量)溶解於DMA (25 mL)中且在110℃下攪拌16 h。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。將呈粗產物形式之(3R)-3-甲基-4-[6-甲基-4-(6-甲基吡啶-3-基)-5-硝基吡啶-2-基]嗎啉分離且不經進一步純化即用於下一步驟中。
用於合成實例2之架構基塊:2-甲基-6-[(3R)-3-甲基嗎啉-4-基]-4-(6-甲基吡啶-3-基)吡啶-3-胺
將(3R)-3-甲基-4-[6-甲基-4-(6-甲基吡啶-3-基)-5-硝基吡啶-2-基]嗎啉(200 mg,0.55 mmol,1當量)、Fe (170 mg,2.89 mmol,5.28當量)及NH4
Cl (170 mg,3.02 mmol,5.51當量)溶解於水(10 mL)及異丙醇(10 mL)中且在70℃下攪拌5 h。濾出固體。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法H)純化殘餘物。將呈黃色油狀之2-甲基-6-[(3R)-3-甲基嗎啉-4-基]-4-(6-甲基吡啶-3-基)吡啶-3-胺(70 mg,38%)分離。
用於合成實例2之架構基塊:(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將2-甲基-6-[(3R)-3-甲基嗎啉-4-基]-4-(6-甲基吡啶-3-基)吡啶-3-胺(480 mg,1.45 mmol,1當量)及NaNO2
(95.69 mg,1.32 mmol,0.91當量)溶解於AcOH (96 mL)中且在25℃下攪拌2 h。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法B)純化殘餘物。將呈黃色固體狀之(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(100 mg,20%)分離。
用於合成實例2之架構基塊:(3R)-4-[3-碘-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
將(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(100 mg,0.29 mmol,1當量)、氫氧化鉀(59.96 mg,1.02 mmol,3.49當量)及I2 (150.01 mg,0.56 mmol,1.93當量)溶解於甲醇(10 mL)中且在25℃下攪拌16 h。用乙酸乙酯萃取所得溶液且合併有機層且經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法I)純化殘餘物。將呈黃色固體狀之(3R)-4-[3-碘-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(90 mg,64%)分離。
用於合成實例2之架構基塊:(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將(3R)-4-[3-碘-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(90 mg,0.19 mmol,1.0當量)、1-(噁烷-2-基)-3-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(180 mg,0.58 mmol,3.13當量)、Pd(PPh3
)4
(27 mg,0.02 mmol,0.12當量)、水(3 mL),四氫呋喃(12 mL)及碳酸鈉(65 mg,0.58 mmol,3.13當量)合併且在80℃下攪拌所得溶液1 h。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法B)純化殘餘物。將呈黃色固體狀之(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉[75 mg,77%)分離。
實例2:5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(2)
將(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(70 mg,0.14 mmol,1當量)溶解於含氯化氫之甲醇(3 mL)中且在25℃下攪拌1 h。用碳酸氫鈉(0.5mL mol/L)將溶液之pH值調節至9。所得混合物在真空下濃縮。藉由製備型HPLC純化粗產物。將呈黃色固體狀之5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(4 mg,8%)分離;熔點180-182℃;1
H NMR (400 MHz, DMSO-d6
): δ 13.31 (s, 1H), 8.89 (s, 1H), 8.12 (s, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 4.54 (s, 1H), 4.08 (d, J = 13.1 Hz, 1H), 3.99 (dd, J = 11.3, 3.4 Hz, 1H), 3.80- 3.66 (m, 2H), 3.54 (m, 1H), 3.25 -3.13 (m, 1H), 2.57 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H);LC/MS (方法B): Rt 1.544 min, [MH]+ 376.0。
實例3:(3R)-3-甲基-4-[3-(3-甲基-1H-吡唑-5-基)-7-(6-甲基吡啶-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(3)
用於合成實例3之架構基塊:5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-[5-甲基-2-(四氫-哌喃-2-基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶
將(3R)-4-[3-碘-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(56 mg;0.114 mmol;0.789當量)及(3R)-4-[3-碘-7-(6-甲基吡啶-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(15 mg;0.031 mmol;0.211當量)溶解於四氫呋喃(1.42 ml)及水(142.00 µl)中添加1-BOC-3-甲基吡唑-5-酸(49 mg;0.217 mmol;1.5當量)、碳酸鈉(0.02 ml;0.434 mmol;3當量)及四(三苯基膦)-鈀(0) (20 mg;0.017 mmol;0.120當量)。在80℃下攪拌反應懸浮液1小時。添加3-甲基-1-(噁烷-2-基)-5-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(66.67 mg;0.217 mmol;1.5當量)及四(三苯基膦)-鈀(0) (20.04 mg;0.017 mmol;0.120當量)且將其在80℃下攪拌1小時。濾出固體且在減壓下濃縮濾液。產物藉由急驟層析(正庚烷/EtOAc梯度)純化,產生35 mg (47.9%)呈褐色固體;LC/MS (方法C):Rt 0.946 min;[MH]+ 474.2。
實例3:(3R)-3-甲基-4-[3-(3-甲基-1H-吡唑-5-基)-7-(6-甲基吡啶-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(3)
將5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-[5-甲基-2-(四氫-哌喃-2-基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(35 mg;0.069 mmol;1當量)溶解於含氯化氫溶液之二噁烷(0.86 ml)中。在室溫下攪拌懸浮液48 h。在減壓下濃縮反應混合物且藉由急驟層析(方法O)純化。將呈黃色固體狀之(3R)-3-甲基-4-[3-(3-甲基-1H-吡唑-5-基)-7-(6-甲基吡啶-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(10 mg,37%)分離;1
H NMR (400 MHz, DMSO-d6
/90 ℃) δ 9.09 - 9.04 (m, 1H), 8.37 - 8.32 (m, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 6.78 (s, 1H), 4.56 - 4.49 (m, 1H), 4.10 - 4.03 (m, 1H), 4.01 - 3.96 (m, 1H), 3.76 - 3.71 (m, 2H), 3.58 (td, J = 11.5, 3.1 Hz, 1H), 3.32 - 3.23 (m, 1H), 2.62 (s, 3H), 2.30 (s, 3H), 1.23 (d, J = 6.7 Hz, 3H);LC/MS (方法C): Rt 0.821 min; [MH]+ 390.2。
實例4:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(2-甲基-吡啶-3-基)-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(4)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(2-甲基-吡啶-3-基)-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(160 mg,36%)分離,熔點228-230℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.24 (s, 1H), 8.64 (dd, J = 4.9, 1.7 Hz, 1H), 7.83 (dt, J = 7.6, 2.1 Hz, 1H), 7.69 (s, 1H), 7.43 (dd, J = 7.6, 4.9 Hz, 1H), 7.09 (s, 1H), 6.97 (s, 1H), 4.46 (s, 1H), 4.13- 3.94 (m, 2H), 3.82- 3.62 (m, 2H), 3.62 -3.49 (m, 1H),3.46 (s,3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 2.33 (d, J = 1.4 Hz, 3H), 1.20 (dd, J = 6.7, 3.0 Hz, 3H);LC/MS (方法D): Rt 0.782 min, [MH]+ 390.2。
實例5:7-(4-甲烷亞磺醯基-苯基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(5)
類似於以上實例製備7-(4-甲烷亞磺醯基-苯基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(90 mg,23%)分離形式;熔點155-157℃。1
H NMR (甲醇-d4
): δ 7.89 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.68 (s, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 4.47 (t, J = 6.8 Hz, 1H), 4.04 (dd, J = 11.3, 3.2 Hz, 2H), 3.82 (d, J = 2.2 Hz, 2H), 3.73 - 3.62 (m, 4H), 3.38 - 3.32 (m, 1H), 2.65 (s, 1H), 1.29 (d, J = 6.7 Hz, 3H);LC/MS (方法B): Rt 1.993 min, [MH]+ 437.1。
實例6:亞胺基(甲基)(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯基)-λ6-硫酮(sulfanone) (6)
用於合成實例6之架構基塊:2,2,2-三氟-N-[甲烷(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基}苯)亞磺醯基]乙醯胺
將(3R)-4-[7-(4-甲烷亞磺醯基苯基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(70 mg,0.12 mmol,1當量)、MgO (25.67 mg,0.61 mmol,5.當量)、二氯甲烷(5 mL)、Rh2
(OAc)4
(5.63 mg,0.01 mmol,0.10當量)及苯碘二醋酸酯(82.05 mg,0.24 mmol,2當量)合併且在25℃下攪拌溶液12 h。所得混合物在真空下濃縮。將呈黃色固體狀之2,2,2-三氟-N-[甲烷(4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]苯)亞磺醯基]乙醯胺分離(70 mg,74%)且不經進一步純化即用於下一步驟中。
用於合成實例6之架構基塊:(3R)-4-(7-{4-[亞胺基(甲烷)亞磺醯基]苯基}-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉
將含2,2,2-三氟-N-[甲烷(4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]苯)亞磺酸基]乙醯胺(70 mg,0.08 mmol,1.0當量70%)之甲醇(5 mL)及碳酸鉀(33.86 mg,0.23 mmol,3當量)合併且在25℃下攪拌溶液1 h。所得混合物在真空下濃縮。將呈黃色固體狀之(3R)-4-(7-[4-[亞胺基(甲烷)亞磺醯基]苯基]-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(70 mg,定量)分離且不經進一步純化即用於下一步驟中。
實例6:亞胺基(甲基)(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯基)-λ6-硫酮(6)
將(3R)-4-(7-[4-[亞胺基(甲烷)亞磺醯基]苯基]-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(70 mg,0.09 mmol,1.0當量70%)溶解於含氯化氫之二噁烷(5 mL)中且在25℃下攪拌1 h。用乙酸乙酯萃取所得溶液且合併有機層且經硫酸鈉乾燥且在真空下濃縮。藉由製備型HPLC (方法B)純化粗產物。將呈黃色固體狀之亞胺基(甲基)(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯基)-λ6-硫酮(14 mg,34%)分離;熔點180℃;1
H NMR (300 MHz, DMSO-d6
) δ 13.17(br, 1H) 8.10 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.67 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.93 (s, 1H), 4.56-4.41 (m, 1H), 4.37 (s, 1H), 4.02 (ddd, J = 24.4, 11.9, 3.1 Hz, 2H), 3.80-3.64 (m, 2H), 3.61 (s, 3H), 3.58-3.44 (m, 1H), 3.34-3.16 (m, 4H), 1.18 (d, J = 6.5 Hz, 3H). LC/MS (方法B): Rt 1.857 min, [MH]+ 452.1。
實例7:7-(4-甲磺醯基-苯基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(7)
類似於以上實例製備7-(4-甲磺醯基-苯基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(18 mg,31%)分離,熔點>300℃;1
H NMR (300 MHz, DMSO-d6
) δ 13.09 (d, J = 90.7 Hz, 1H), 8.28-7.99 (m, 2H), 7.71 (d, J = 67.8 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 4.46 (d, J = 11.2 Hz, 1H), 4.18-3.92 (m, 2H), 3.81- 3.64 (m, 2H), 3.64- 3.44 (m, 4H), 3.32 (s, 4H), 3.24-3.04 (m, 1H), 1.18 (d, J = 6.5 Hz, 3H);LC/MS (方法F): Rt 1.298 min, [MH]+ 453.1。
實例8:7-(6-甲烷亞磺醯基-2-甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(8)
用於合成實例8之架構基塊:3-溴-2-甲基-6-(甲基硫基)吡啶
將3-溴-6-氟-2-甲基吡啶(3 g,15.00 mmol,1.0當量)、DMF (300 mL)及(甲基硫基)鈉(1.44 g,19.52 mmol,1.30當量)合併且在0℃下攪拌4小時。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。將呈黃色油狀之3-溴-2-甲基-6-(甲基硫基)吡啶分離(2.5 g,69%);LC/MS (方法J):Rt 1.324 min,[MH]+ 220.0。
用於合成實例8之架構基塊:3-溴-6-甲烷亞磺酸基-2-甲基吡啶
將3-溴-2-甲基-6-(甲基硫基)吡啶(2.50 g,10.32 mmol,1.0當量)、二氯甲烷(200 mL)及m-CPBA (1.87 g,10.29 mmol,1.0當量)合併且在25℃下攪拌2 h。用乙酸乙酯萃取所得溶液且合併有機層且經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法J)純化殘餘物。呈黃色油狀之3-溴-6-甲烷亞磺酸基-2-甲基吡啶(1.8 g,67%);LC/MS (方法J): Rt 0.937 min, [MH]+ 233.9。
用於合成實例8之架構基塊:6-甲烷亞磺醯基-2-甲基-3-(四甲基-1,3,2-二氧硼㖦-2-基)吡啶
在25℃下將3-溴-6-甲烷亞磺酸基-2-甲基吡啶(1.80 g,6.92 mmol,1.0當量)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧硼㖦-2-基)-1,3,2-二氧硼㖦(7.77 g,29.07 mmol,4.20當量)、二噁烷(120 mL,1.35 mol,194.47當量)、CH3
COOK (3 g,29.04 mmol,4.19當量)及Pd(dppf)Cl2
.CH2
Cl2
(820 mg,0.90 mmol,0.13當量)合併3 h。用乙酸乙酯萃取所得溶液且合併有機層且經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法J)純化殘餘物。呈黃色油狀之6-甲烷亞磺醯基-2-甲基-3-(四甲基-1,3,2-二氧硼㖦-2-基)吡啶(1.8 g,83%);LC/MS (方法J): Rt 1.131 min [MH]+ 282.1。
實例8:7-(6-甲烷亞磺醯基-2-甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(8)
類似於以上實例製備7-(6-甲烷亞磺醯基-2-甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(150 mg,41%)分離,熔點174-176℃;1
H NMR (300 MHz, CD3
OD
): δ 8.05 (dd, J = 7.9, 1.8 Hz, 1H), 7.94 (dd, J = 7.9, 3.0 Hz, 1H), 7.64 (s, 1H), 7.08 (s, 1H), 6.90 (s, 1H), 4.44 (d, J = 7.0 Hz, 1H), 4.09 -3.96 (m, 2H), 3.80 (d, J = 1.9 Hz, 2H), 3.64 (td, J = 11.8, 3.1 Hz, 1H), 3.51 (s, 3H), 3.38 -3.30 (m, 0H), 2.93 (d, J = 6.0 Hz, 3H), 2.40 (d, J = 2.6 Hz, 3H), 1.27 (dd, J = 6.7, 4.4 Hz, 3H);LC/MS (方法E): Rt 1.199 min, [MH]+ 452.0。
實例9:(3R)-4-(7-{6-[(S)-甲烷亞磺醯基]-2-甲基吡啶-3-基}-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(9)
藉由對掌性層析法(ChiralPak AS-H,具有溶劑系統CO2
:2-丙醇+0.5% DEA 60:40)來分離(3R)-4-[7-(6-甲烷亞磺醯基-2-甲基吡啶-3-基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉之非對映異構體,以將呈黃色固體狀之(3R)-4-(7-{6-[(S)-甲烷亞磺醯基]-2-甲基吡啶-3-基}-1-甲基-3-(1H
-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(30 mg,40%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.26 - 12.90 (m, 1H), 8.15 - 8.12 (m, 1H), 7.94 - 7.89 (m, 1H), 7.86 - 7.56 (m, 1H), 7.14 - 6.96 (m, 2H), 4.50 - 4.38 (m, 1H), 4.15 - 4.02 (m, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.71 - 3.67 (m, 1H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.49 - 3.44 (m, 3H), 3.21 - 3.14 (m, 1H), 2.90 - 2.86 (m, 3H), 2.39 - 2.36 (m, 3H), 1.21 - 1.16 (m, 3H), LC/MS (方法F): Rt 2.017 min; [MH]+ 452.2。
實例10:(3R)-4-(7-{6-[(R)-甲烷亞磺醯基]-2-甲基吡啶-3-基}-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(10)
藉由對掌性層析法(ChiralPak AS-H,具有溶劑系統CO2
:2-丙醇+0.5% DEA 60:40)來分離(3R)-4-[7-(6-甲烷亞磺醯基-2-甲基吡啶-3-基)-1-甲基-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉之非對映異構體,以將呈黃色固體狀之(3R)-4-(7-{6-[(R)-甲烷亞磺醯基]-2-甲基吡啶-3-基}-1-甲基-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基)-3-甲基嗎啉(33 mg,44%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.25 - 12.90 (m, 1H), 8.16 - 8.11 (m, 1H), 7.93 - 7.89 (m, 1H), 7.86 - 7.55 (m, 1H), 7.14 - 6.97 (m, 2H), 4.51 - 4.38 (m, 1H), 4.13 - 4.02 (m, 1H), 3.98 (dd, J = 11.4, 3.5 Hz, 1H), 3.77 - 3.72 (m, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.49 - 3.43 (m, 3H), 3.22 - 3.13 (m, 1H), 2.90 - 2.86 (m, 3H), 2.39 - 2.36 (m, 3H), 1.21 - 1.16 (m, 3H);LC/MS (方法F): Rt 2.024 min; [MH]+ 452。
實例11:(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(11)
將(3R)-4-[7-(6-甲烷亞磺醯基-2-甲基吡啶-3-基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(20 mg,0.04 mmol,1.0當量)、甲醇 (0.1 mL)、水(1.5 mL)及過硫酸氫鉀(7.69 mg,0.04 mmol,1.23當量)合併且在25℃下攪拌16 h。所得混合物在真空下濃縮。藉由製備型HPLC (方法C)純化粗產物。呈黃色固體狀之(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(3 mg,16%);熔點276-278℃;1
H NMR (400 MHz, 甲醇-d4
): δ 8.12 (d, J = 1.4 Hz, 2H), 7.71 (s, 1H), 7.16 (s, 1H), 6.95 (s, 1H), 4.49 (q, J = 6.8, 6.2 Hz, 1H), 4.08 (dq, J = 11.1, 3.9, 3.3 Hz, 2H), 3.90 - 3.82 (m, 2H), 3.69 (td, J = 11.7, 3.1 Hz, 1H), 3.56 (d, J = 1.2 Hz, 3H), 3.41 - 3.36 (m, 1H), 2.50 (d, J = 3.8 Hz, 3H), 1.31 (d, J = 4.9 Hz, 3H); LC/MS (方法G): Rt 1.213 min [MH]+ 468.2。
實例12:7-(6-甲磺醯基-2-甲基-吡啶-3-基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(12)
類似於以上實例製備7-(6-甲磺醯基-2-甲基-吡啶-3-基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以淡黃色固體形式(58 mg,72%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 13.09 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 7.9 Hz, 1H), 7.73-7.65 (m, 1H), 7.09 (d, J = 2.2 Hz, 2H), 4.46 (d, J = 7.3 Hz, 1H), 4.14-4.06 (m, 1H), 4.00 (dd, J = 11.3, 3.5 Hz, 1H), 3.81-3.66 (m, 2H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.32 (s, 3H), 3.20 (td, J = 12.8, 3.8 Hz, 1H), 2.49 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H);LC/MS (方法E): Rt 1.191; [MH]+ 454.0。
實例13:(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-3-(3-甲基-1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(13)
類似於以上實例製備(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-3-(3-甲基-1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(2 mg,15%)分離;LC/MS (方法F): Rt 2.049 min; [MH]+ 468.2。
實例14:2-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-2H
-吡唑并[4,3-b]吡啶(14)
用於合成實例14之架構基塊:(3R)-3-甲基-4-[2-甲基-7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-2H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將(3R)-3-甲基-4-[7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(75.000 mg,0.15 mmol,1.當量)、DMF (5 mL)及氫化鈉(8.812 mg,0.22 mmol,1.5當量)合併且在0-5℃下攪拌0.5 h。向其中添加CH3
I (32.919 mg,0.22 mmol,1.50當量)。在25℃下攪拌所得溶液2 h。隨後藉由添加NH4
Cl水溶液淬滅反應物。所得混合物在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之(3R)-3-甲基-4-[2-甲基-7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-2H-吡唑并[4,3-b]吡啶-5-基]嗎啉(20 mg,25%)分離。
實例14:2-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-2H
-吡唑并[4,3-b]吡啶(14)
將(3R)-3-甲基-4-[2-甲基-7-(6-甲基吡啶-3-基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-2H-吡唑并[4,3-b]吡啶-5-基]嗎啉(20 mg,0.04 mmol,1.0當量)溶解於甲醇(5 mL)中且在25℃下攪拌2 h。所得混合物在真空下濃縮。藉由製備型HPLC (方法D)純化粗產物。將呈黃色固體狀之2-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-3-基)-3-(1H
-吡唑-3-基)-2H
-吡唑并[4,3-b]吡啶分離(6 mg,38%);熔點140-142℃;1
H NMR (400 MHz, DMSO-d6
); δ 13.19 (s, 1H), 9.32 (d, J = 2.4 Hz, 1H), 8.51 (dd, J = 8.0, 2.5 Hz, 1H), 7.93 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.32 (s, 1H), 4.57 (d, J = 7.6 Hz, 1H), 4.46 (s, 3H), 4.10 (d, J = 13.2 Hz, 1H), 4.00 (dd, J = 11.7, 3.6 Hz, 1H), 3.75 (q, J = 11.0 Hz, 2H), 3.56 (t, J = 10.9 Hz, 1H), 3.23 (dt, J = 14.5, 7.2 Hz, 1H), 2.57 (s, 3H), 1.21 (d, J = 6.6 Hz, 3H); LC/MS (方法G): Rt 1.303 min, [MH]+ 390.2。
實例15:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-7-(1H
-吡咯并[2,3-b]吡啶-4-基)-1H
-吡唑并[4,3-b]吡啶(15)
用於合成實例15之架構基塊:(3R)-3-甲基-4-(1-甲基-7-{1-[(4-甲基苯)磺醯基]-1H-吡咯并[2,3-b]吡啶-4-基}-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基)嗎啉
類似於以上實例製備(3R)-3-甲基-4-(1-甲基-7-[1-[(4-甲基苯)磺醯基]-1H-吡咯并[2,3-b]吡啶-4-基]-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基)嗎啉且其以淡黃色固體形式(100 mg,83%)分離;
實例15:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-7-(1H
-吡咯并[2,3-b]吡啶-4-基)-1H-吡唑并[4,3-b]吡啶(15)
將(3R)-3-甲基-4-(1-甲基-7-[1-[(4-甲基苯)磺醯基]-1H-吡咯并[2,3-b]吡啶-4-基]-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基)嗎啉(50.000 mg,0.08 mmol,1.0當量)溶解於甲醇(5 mL)及氫氧化鈉(9.995 mg,0.24 mmol,3.0當量)中。在25℃下攪拌所得溶液6 h。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由製備型HPLC (方法E)純化粗產物。將呈黃色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-7-(1H
-吡咯并[2,3-b]吡啶-4-基)-1H
-吡唑并[4,3-b]吡啶(4 mg,12%)分離;熔點200℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.09 (d, J = 86.7 Hz, 1H), 11.97 (s, 1H), 8.39 (d, J = 4.8 Hz, 1H), 7.57 (t, J = 2.9 Hz, 2H), 7.25 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 29.0 Hz, 2H), 6.18 (dd, J = 3.4, 1.6 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 4.21-3.86 (m, 2H), 3.85-3.63 (m, 2H), 3.54 (td, J = 11.7, 2.9 Hz, 1H), 3.42 (s, 3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.5 Hz, 3H);LC/MS (方法H): Rt 1.258 min [MH]+ 415.3。
實例16:2-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-7-(1H
-吡咯并[2,3-b]吡啶-4-基)-2H
-吡唑并[4,3-b]吡啶(16)
類似於以上實例製備2-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-7-(1H
-吡咯并[2,3-b]吡啶-4-基)-2H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(74 mg,99%)分離,熔點280℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.16 (s, 1H), 11.83 (s, 1H), 8.33 (d, J = 4.9 Hz, 1H), 7.91 (s, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.58 ? 7.44 (m, 1H), 7.30 (d, J = 3.7 Hz, 2H), 6.55 (dd, J = 3.5, 1.7 Hz, 1H), 4.39 (s, 4H), 4.10-3.83 (m, 2H), 3.73 (t, J = 9.4 Hz, 2H), 3.54 (t, J = 11.2 Hz, 1H), 3.19 (d, J = 12.6 Hz, 1H), 1.21 (d, J = 6.5 Hz, 4H); LC/MS (方法I): 2.41 min, [MH]+ 415.3。
實例17:7-(6-甲磺醯基-4-甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(17)
類似於以上實例製備7-(6-甲磺醯基-4-甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(30 mg,22%)分離,熔點189-190℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.24 (m, 1H), 8.79 (s, 1H), 8.17 (s, 1H), 7.61 (m, 1H), 7.04 (d, J = 11.1 Hz, 2H), 4.44 (s, 1H), 4.08-3.99 (m, 2H), 3.81- 3.63 (m, 2H), 3.62 - 3.51 (m, 1H), 3.47 (s, 3H), 3.36 (s, 3H), 3.18 (m, 1H), 2.29 (s, 3H), 1.19 (t, J = 6.4 Hz, 3H);LC/MS (方法G): Rt 1.212 min, [MH]+ 468.3。
實例18:7-(1-異丙基-1H
-吡唑-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(18)
類似於以上實例製備7-(1-異丙基-1H
-吡唑-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以白色固體形式(50 mg,41%)分離;熔點114-115℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.22 - 13.14 (m, 1H), 8.27 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.01 (s, 1H), 6.87 (d, J = 11.2 Hz, 1H), 4.70 - 4.56 (m, 1H), 4.56 -4.44 (m, 1H), 4.09-3.93 (m, 2H), 3.80 -3.65 (m, 2H), 3.88 (s, 3H),3.53 (td, J = 11.6, 2.9 Hz, 1H), 3.17 (td, J = 12.7, 3.7 Hz, 1H), 1.50 (d, J = 6.6 Hz, 6H), 1.17 (d, J = 6.5 Hz, 3H); LC/MS (方法G): Rt 1.295 min [MH]+ 407.3。
實例19:7-(1,3-二甲基-1H
-吡唑-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(19)
類似於以上實例製備7-(1,3-二甲基-1H
-吡唑-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以無色固體形式(35 mg,28%)分離;熔點139-140℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.17 -12.90 (m,1H), 7.95 (s, 1H), 7.79-7.61 (m, 1H), 7.02 (s, 1H), 6.80 (s, 1H), 4.42 (s, 1H), 4.09- 3.95 (m, 2H), 3.89(s, 3H),3.77-3.70 (m,5H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 2.12 (s, 3H), 1.16 (d, J = 6.5 Hz, 3H); LC/MS (方法G): Rt 1.158 min [MH]+ 393.3。
實例20:7-(3-氟-吡啶-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(20)
類似於以上實例製備7-(3-氟-吡啶-4-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶且其以黃色固體形式(33 mg,40%)分離,熔點145-147℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.05 (s, 1H), 8.78 (d, J = 1.4 Hz, 1H), 8.62 (dd, J = 4.8, 1.2 Hz, 1H), 7.77-7.61 (m, 2H), 7.07-6.99 (m, 2H), 4.43 (q, J = 7.0 Hz, 1H), 4.07-3.89 (m, 2H), 3.78-3.42 (m, 6H), 3.15 (td, J = 12.7, 3.7 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H);LC/MS (方法E): Rt 1.285 min, [MH]+ 394.0。
實例21:7-(6-甲磺醯基-4-甲基-吡啶-3-基)-2-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-2H
-吡唑并[4,3-b]吡啶(21)
類似於以上實例製備7-(6-甲磺醯基-4-甲基-吡啶-3-基)-2-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-2H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(2 mg,4%)分離,熔點188-190℃;1
H NMR (300 MHz, CDCl3
): δ 8.67 (s, 1H), 8.06 (s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 14.0 Hz, 2H), 4.32 (s, 3H), 4.15- 3.94 (m, 2H), 3.84 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.8, 3.0 Hz, 1H), 3.40 (td, J = 12.6, 3.7 Hz, 1H), 3.25 (s, 3H), 2.43 (s, 3H), 1.34 (d, J = 6.7 Hz, 3H), 1.23 (s, 1H);LC/MS (方法G): Rt 1.265 min, [MH]+ 468.0。
實例22:7-(2,4-二甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(22)
類似於以上實例製備7-(2,4-二甲基-吡啶-3-基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶且其以黃色固體形式(11 mg,18%)分離,熔點128-130℃;1
H NMR (300 MHz, DMSO-d6
): δ 8.48 (d, J = 5.1 Hz, 1H), 7.69 (s, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 4.42 (d, J = 7.5 Hz, 1H), 4.16-3.95 (m, 2H), 3.73 (d, J = 4.6 Hz, 2H), 3.64-3.49 (m, 1H), 3.33 (s, 3H), 3.17 (td, J = 12.7, 3.7 Hz, 1H), 2.23 (d, J = 1.7 Hz, 3H), 2.06 (d, J = 2.1 Hz, 3H), 1.28-1.14 (m, 3H); LC/MS (方法B): Rt 2.095 min, [MH]+ 404.0。
實例23:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(3-甲基-吡啶-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(23)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(3-甲基-吡啶-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(32 mg,44%)分離,熔點145℃;1
H NMR (300 MHz, DMSO-d6
) δ 13.15 (s, 1H), 8.64 (s, 1H), 8.57 (d, J = 4.9 Hz, 1H), 7.67 (s, 1H), 7.44 (dd, J = 5.0, 2.0 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 4.55-4.33 (m, 1H), 4.02 (ddd, J = 23.6, 11.5, 4.7 Hz, 2H), 3.83- 3.61 (m, 2H), 3.53 (td, J = 11.7, 3.0 Hz, 1H), 3.44 (d, J = 1.1 Hz, 3H), 3.16 (td, J = 12.6, 3.7 Hz, 1H), 2.11 (s, 3H), 1.17 (dd, J = 6.6, 4.0 Hz, 3H);LC/MS (方法E): RT 1.021 min, [MH]+ 390.1。
實例24:[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-甲醇(24)
用於合成實例24之架構基塊:1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將7-氯-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(2.95 g,11.06 mmol)、Pd(dppf)Cl2
.CH2
Cl2
(271 mg,0.332 mmol,0.03當量)、1,1-雙-(二苯膦基)-二茂鐵(184 mg,0.332 mmol)、三乙胺(1.5 g,14.4 mmol,1.3當量)、THF (30 ml)及甲醇 (30 mL)合併且在6.3 bar CO氛圍下在100℃下攪拌16 h。在真空下濃縮所得溶液且藉由管柱層析法純化。將呈黃色固體狀之1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸酯(3.1 g,96%)分離;LC/MS (方法K): RT 0.872 min, [MH]+ 291.1。
用於合成實例24之架構基塊:3-溴-1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(200 mg,0.62 mmol,1.0當量)、NBS (147.13 mg,0.74 mmol,1.20當量)及MeCN (20 mL)合併且在25℃下攪拌1 h。所得混合物在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之3-溴-1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(120 mg,43%)分離。LC/MS (方法J): RT 1.238 min, [MH]+ 369.0。
用於合成實例24之架構基塊:1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將3-溴-1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(110 mg,0.27 mmol,1.0當量)、1-(噁烷-2-基)-3-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(235.53 mg,0.80 mmol,3當量)、Pd(pph3
)4
(34.43 mg,0.03 mmol,0.10當量)、碳酸鈉(89.75 mg,0.80 mmol,3.0當量)、四氫呋喃(17.60 mL)及水(4.40 mL)合併且在80℃下於微波中攪拌1 h。用乙酸乙酯萃取所得溶液且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(80 mg,61%)分離;LC/MS (方法J): RT 1.242 min, [MH]+ 441.0。
用於合成實例24之架構基塊:{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基}甲醇
在0℃下在氮氣氛圍下向1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(16 g,32.69 mmol)於THF (400 mL)中之攪拌混合物中逐滴添加LiBH4
(1117 mg,48.71 mmol,1.5當量 95%)。將所得混合物在室溫下在氮氣氛圍下攪拌2 h。在0℃下用飽和NH4
Cl (水溶液)淬滅反應物。在減壓下濃縮所得混合物。用CH2
Cl2
萃取水層。在減壓下濃縮所得混合物。藉由管柱層析法(方法O)純化殘餘物以得到呈黃色固體狀之[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]甲醇(13 g,87%)。
實例24:[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-甲醇
將[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]甲醇(50 mg,0.11 mmol,1當量)溶解於含HCl之甲醇(3.000 mL)中。在25℃下攪拌所得溶液1 h。用碳酸氫鈉(0.5mL)將溶液之pH值調節至9。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。藉由製備型HPLC (方法F)純化粗產物。將呈無色固體狀之[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]甲醇(30 mg,82%)分離;熔點195-197℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.09 (s, 1H), 7.55 (s, 1H), 6.99 (d, J = 14.7 Hz, 2H), 5.59 (t, J = 5.5 Hz, 1H), 4.90 (d, J = 4.4 Hz, 2H), 4.36 (d, J = 10.8 Hz, 1H), 3.96 (dd, J = 11.1, 3.6 Hz, 2H), 3.79- 3.60 (m, 2H), 3.50 (td, J = 11.7, 3.0 Hz, 1H), 3.28 (s, 2H), 3.12 (td, J = 12.8, 3.8 Hz, 1H), 1.12 (d, J = 6.6 Hz, 3H). LC/MS (方法E): RT 0,932 min, [MH]+ 329.1。
實例25:2-[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-丙-2-醇(25)
用於合成實例25之架構基塊:2-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基}丙-2-醇
將1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(700 mg,1.43 mmol)及CH3
MgBr (575.11 mg,4.58 mmol,3.0當量)於四氫呋喃(20 mL)中之溶液合併且在25℃下攪拌2 h。藉由添加NH4
Cl淬滅反應物。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。將呈黃色固體狀之2-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]丙-2-醇(600 mg,86%)分離。
實例25:2-[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-基]-丙-2-醇
類似於以上實例製備2-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]丙-2-醇且其以無色固體形式(80 mg,18%)分離;熔點123-125℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.11 (s, 1H), 12.85 (s, 0H), 7.75 (s, 0H), 7.53 (s, 1H), 7.08 (s, 0H), 6.96 (s, 1H), 6.81 (s, 1H), 5.70 (s, 1H), 4.38 (s, 4H), 3.95 (dd, J = 11.1, 3.5 Hz, 2H), 3.79 - 3.60 (m, 2H), 3.50 (td, J = 11.7, 2.9 Hz, 1H), 3.12 (td, J = 12.6, 3.8 Hz, 1H), 2.04 (s, 0H), 1.62 (d, J = 3.5 Hz, 5H), 1.12 (d, J = 6.6 Hz, 3H);LC/MS (方法D): Rt 0.867 min, [MH]+ 357.2。
實例26:7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(26)
用於合成實例26之架構基塊:甲磺酸{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基}甲酯
將[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]甲醇(700 mg,1.53 mmol,1.0當量)溶解於二氯甲烷(34.48 mL)中且在0℃下攪拌0.5 h。向其中添加三乙胺(700 mg,6.57 mmol,3當量)、MsCl (340 mg,2.82 mmol,1.30當量)。在25℃下攪拌所得溶液1 h。隨後藉由添加2 mL NH4
Cl溶液淬滅反應物。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之甲磺酸[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]甲酯(1 g,定量)分離。LC/MS (方法J): RT 1.165 min, [MH]+ 491.0。
用於合成實例26之架構基塊:(3R)-4-[7-(甲磺醯基甲基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
將甲磺酸[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-7-基]甲酯(900 mg,1.65 mmol,1當量)、甲烷亞磺酸鈉(230.66 mg,2.15 mmol,1.30當量)、三乙胺(527.61 mg,4.95 mmol,3.0當量)、CH3
CN (90 mL)及DMF (9 mL)合併且在120℃下攪拌16 h。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之(3R)-4-[7-(甲磺醯基甲基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(700 mg,80%)分離。LC/MS (方法L): RT 0.788 min, [MH]+ 413.1。
用於合成實例26之架構基塊:(3R)-4-[7-(1-甲磺醯基乙烯基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
將(3R)-4-[7-(甲磺醯基甲基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(100 mg,0.19 mmol,1.當量)、[(二甲基胺基)甲基]二甲基胺(44.87 mg,0.42 mmol,2.20當量)、乙酸酐(44.83 mg,0.42 mmol,2.20當量)及DMF (20 mL)合併且在60℃下攪拌16 h。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色固體狀之(3R)-4-[7-(1-甲磺醯基乙烯基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(60 mg,58%)分離;LC/MS (方法J): Rt 1.119 min [MH]+ 487.2。
用於合成實例26之架構基塊:(3R)-4-[7-(1-甲磺醯基環丙基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
合併甲磺醯基碘化物(24.06 mg,0.11 mmol,1.20當量)及DMSO (10 mL)且在0℃下攪拌30 min。向其中添加氫化鈉(4.40 mg,0.11 mmol,1.19當量,60%)及(3R)-4-[7-(1-甲磺醯基乙烯基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(50 mg,0.09 mmol,1.0當量)。在微波中在25℃下攪拌混合物1 h。隨後藉由添加NH4
Cl淬滅反應物。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。將呈黃色固體狀之(3R)-4-[7-(1-甲磺醯基環丙基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(40 mg,80%)分離。LC/MS (方法L): RT: 0.887 min, [MH]+ 501.0。
實例26:7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶
將(3R)-4-[7-(1-甲磺醯基環丙基)-1-甲基-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(30 mg,0.05 mmol,1.當量)溶解於含氯化氫之甲醇(3 mL)中。在25℃下攪拌所得溶液1 h。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。藉由製備型HPLC (方法G)純化粗產物。將呈淡黃色固體狀之(3R)-4-[7-(1-甲磺醯基環丙基)-1-甲基-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(5 mg,24%)分離;熔點180-182℃;1
H NMR (400 MHz, 甲醇-d4
): δ 7.64 (s, 1H), 7.25 (s, 2H), 7.06 (s, 1H), 4.51 (d, J = 7.1 Hz, 2H), 4.38 (s, 5H), 4.07 (d, J = 12.5 Hz, 4H), 3.86 (s, 3H), 3.76-3.65 (m, 2H), 3.05 (s, 4H), 2.28 (dd, J = 10.7, 5.6 Hz, 2H), 1.82 (p, J = 5.1 Hz, 2H), 1.70 (q, J = 6.7, 5.9 Hz, 4H), 1.30 (t, J = 6.0 Hz, 7H); LC/MS (方法E): Rt 1.235 min [MH]+ 417.0。
實例26可經由替代合成途徑來合成。
實例26之替代合成路徑之架構基塊:3-溴-7-氯甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將[3-溴-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶-7-基]-甲醇(500 mg,1.46 mmol)、二氯甲烷 (3.72 ml)及亞硫醯氯(0.32 ml;4.37 mmol;3當量)合併且在室溫下攪拌14 h。在減壓下濃縮反應混合物且用飽和NaHCO3
溶液及DCM萃取。在減壓下濃縮合併有機層。將呈褐色固體狀之3-溴-7-氯甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(519 mg,99%)分離;LC/MS (方法F):Rt 2.798 min;[MH]+ 359.0。
實例26之替代合成路徑之架構基塊:3-溴-7-甲磺醯基甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將3-溴-7-氯甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(518.70 mg;1.44 mmol;1當量)、2-丙醇(3.86 ml)及甲烷亞磺酸鈉(250 mg;2.45 mmol;1.70當量)合併且在80℃下攪拌14 h。在減壓下濃縮反應懸浮液。用水處理殘餘物且過濾所得沈澱且用水洗滌且乾燥5天。將呈黃色固體狀之3-溴-7-甲磺醯基甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(484 mg,83%)分離;LC/MS (方法F): Rt 2.339 min; [MH]+ 403.1。
實例26之替代合成路徑之架構基塊:3-溴-7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將3-溴-7-甲磺醯基甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(800 mg;1.9 mmol;1.0當量)、碳酸銫(12.63 g;38.8 mmol;20當量)及四丁基溴化銨(126 mg;0.39 mmol;0.2當量)合併。在氮氣氛圍下,添加無水二甲烷亞碸(20 ml)及1,2-二溴甲烷(506 µl;5.8 mmol;3.0當量)且在60℃下攪拌反應懸浮液2天。將反應混合物倒入水中且濾出固體,用水洗滌且在減壓下乾燥。
用DCM萃取水層且合併有機層經MgSO4
乾燥,過濾且在減壓下濃縮。將呈褐色固體狀之3-溴-7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(311 mg,37.4%)分離;LC/MS (方法K), RT: 0.967 min [MH]+429.1。
實例26之替代合成路徑之架構基塊:7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶
添加1-(2-三甲基矽烷基乙氧基)甲基吡唑-5-酸、四甲基乙二醇酯(421 mg;1.2 mmol;1.5當量)、碳酸鈉(264 mg;2.5 mmol;3.0當量)及四(三苯基膦)-鈀(0) (116 mg;0.1 mmol;0.1當量)。隨後添加含3-溴-7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(357 mg;0.8 mmol;1.0當量)之四氫呋喃(7 ml)及水(0.65 ml),同時用氮氣沖洗。將反應懸浮液在90℃下攪拌3小時。過濾反應混合物且在減壓下濃縮。將殘餘物溶解於DCM中且藉由管柱層析法(方法M)純化。將呈黃色固體狀之7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(364;80.1%)分離;LC/MS (方法K): Rt 1.176 min, [MH]+ 547.2。
實例26之替代合成路徑:1-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶
將7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(364 mg;0.666 mmol;1當量)溶解於含HCl之MeOH (10.7 ml,1.25 M)中。將溶液在室溫下攪拌14小時。在減壓下濃縮反應溶液且用1 M NaOH稀釋且濾出所得沈澱,用水洗滌且在50℃下在減壓下乾燥14 h。將呈黃色固體狀之7-(1-甲磺醯基-環丙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶(230 mg,83%)分離;LC/MS (方法K), RT:0.843min [MH]+ 417.2。
實例27:5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸二甲醯胺(27)
用於合成實例27之架構基塊:5-[(3R)-3-甲基嗎啉-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將三氟甲烷磺酸5-[(3R)-3-甲基嗎啉-4-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-酯(2 g,3.6 mmol,1.0當量,90%)、Pd(dppf)Cl2
.CH2
Cl2
(165 mg,0.18 mmol,0.05當量,90%)、甲醇(20 ml)及三乙胺(1.5 g,3.9當量)合併且用氮氣吹掃2 min且隨後用一氧化碳在80℃下加壓14 h至10 atm。用乙酸乙酯萃取所得溶液且合併有機層且經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法P)純化殘餘物。將呈黃色固體狀之5-[(3R)-3-甲基嗎啉-4-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(1.5 g,92%)分離。
用於合成實例27之架構基塊:3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(350 mg,1.14 mmol,1.0當量)、甲醇 (4 mL)、碳酸鉀(261 mg,1.8 mmol,1.6當量)及I2
(481 mg,1.8 mmol,1.6當量)合併。在25℃下攪拌所得溶液1 h且用乙酸乙酯萃取且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。將呈黃色固體狀之3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(130 mg,26%)分離。
用於合成實例27之架構基塊:3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(75 mg,0.17 mmol,1.0 當量)、四氫呋喃(10 mL)及氫化鈉(8.06 mg,0.20 mmol,1.2當量,60%)合併且在0-5℃下於水/冰浴中攪拌0.5 h。向其中添加SEMCl (32.37 mg,0.20 mmol,1.20當量)。在25℃下攪拌所得溶液1 h。隨後藉由添加NH4
Cl水溶液淬滅反應物。在真空下濃縮所得混合物且用乙酸乙酯萃取且合併有機層且在真空下濃縮。將呈黃色固體狀之3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(90 mg,91%)分離。
用於合成實例27之架構基塊: 5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯
將3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(90 mg,0.15 mmol,1.0 當量)、1-(噁烷-2-基)-3-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(67 mg,0.23 mmol,1.50當量)、Pd(PPh3
)4
(18.50 mg,0.02 mmol,0.10當量)、碳酸鈉(50.92 mg,0.46 mmol,3當量)、四氫呋喃(18 mL)及水(4.50 mL)合併且在80℃下攪拌2 h。在真空下濃縮所得混合物且藉由管柱層析法(方法O)純化殘餘物。將呈黃色固體狀之5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸甲酯(90 mg,96%)分離。
用於合成實例27之架構基塊:5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑并[4,3-b]吡啶-7-甲酸
將5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸酯(85 mg,0.14 mmol)、四氫呋喃(17 mL,199 mmol)、水(4.25 mL)及LiOH (17.3 mg,0.69 mmol,5.0當量)合併.在25℃下攪拌所得溶液14 h。用氯化氫將溶液之pH值調節至5。用乙酸乙酯萃取所得溶液且合併有機層且在真空下濃縮。將呈黃色固體狀之5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸(60 mg,72%)分離。
用於合成實例27之架構基塊: N,N-二甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-{[2-(三甲基矽烷基)乙氧基]甲基}-1H-吡唑并[4,3-b]吡啶-7-甲醯胺
將5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲酸(10 mg,0.02 mmol,1.0當量)溶解於二氯甲烷(2 mL)及N,N-二甲基甲醯胺(0.5 mL)中且添加HATU (7.965 mg,0.02 mmol,1.2當量)、二甲胺鹽酸鹽(2.847 mg,0.03 mmol)及DIEA (6.768 mg,0.05 mmol,3.0當量)。在25℃下攪拌所得溶液2 h。在真空下濃縮所得混合物以獲得呈黃色固體狀之N,N-二甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲醯胺(5 mg,48%)。
實例27:5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-甲酸二甲醯胺
將N,N-二甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1-[[2-(三甲基矽烷基)乙氧基]甲基]-1H-吡唑并[4,3-b]吡啶-7-甲醯胺(50 mg,0.08 mmol,1當量)溶解於含HCl之甲醇(5 mL)中。在25℃下攪拌所得溶液5 h。所得混合物在真空下濃縮。藉由製備型HPLC (方法K)純化粗產物,獲得呈黃色固體狀之5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸二甲醯胺(5 mg,17%);熔點168-170℃。1H NMR (400 MHz, 甲醇-d4
): δ 7.70 (m, 1H), 7.06 (m, 2H), 4.46 (d, J = 7.2 Hz, 1H), 4.05 (dd, J = 11.8, 4.8 Hz, 2H), 3.83 (d, J = 2.3 Hz, 2H), 3.67 (td, J = 11.7, 3.1 Hz, 1H), 3.34 (dd, J = 12.8, 3.2 Hz, 1H), 3.01 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H); LC/MS (方法B): Rt 2.075 min, [MH]+ 356.0。
實例28:5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H -
吡唑并[4,3-b]吡啶-7-甲酸甲醯胺(28)
類似於以上實例製備5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸甲醯胺且其以淡黃色固體形式(8 mg,38%)分離;熔點186-188℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.68 (d, J = 2.1 Hz, 1H), 7.39 (s, 1H), 7.09 (d, J = 2.1 Hz, 1H), 4.47 (d, J = 6.9 Hz, 1H), 4.03 (dd, J = 11.4, 3.3 Hz, 2H), 3.82 (d, J = 2.2 Hz, 2H), 3.66 (td, J = 11.4, 2.9 Hz, 1H), 3.36 (dd, J = 13.1, 3.8 Hz, 1H), 2.99 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H); LC/MS (方法M): Rt 0.824 min, [MH]+ 342.1。
實例29:5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸醯胺(29)
類似於以上實例製備5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-甲酸醯胺且其以黃色固體形式(2 mg,10%)分離;熔點>280℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.68 (s, 1H), 7.48 (s, 1H), 7.11 (s, 1H), 4.52 (d, J = 7.1 Hz, 1H), 4.14 - 3.99 (m, 2H), 3.85 (d, J = 2.2 Hz, 2H), 3.69 (t, J = 10.4 Hz, 1H), 3.44 - 3.35 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H); LC/MS (方法N) Rt 2.694 min, [MH]+ 327.9。
實例30:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H -
吡唑并[4,3-b]吡啶-7-甲酸二甲醯胺(30)
以類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-7-甲酸二甲醯胺且其以黃色固體形式(10 mg,29%)分離;熔點128-130℃。1
H NMR (400 MHz, DMSO-d6
): δ 13.23 (s, 1H), 7.58 (s, 1H), 7.14 - 6.88 (m, 2H), 4.44 (s, 1H), 4.12 - 3.94 (m, 2H), 3.88 (d, J = 9.3 Hz, 3H), 3.80 - 3.66 (m, 2H), 3.54 (td, J = 11.9, 3.0 Hz, 1H), 3.11 (m, 4H), 2.90 (d, J = 2.1 Hz, 3H), 1.16 (d, J = 6.5 Hz, 3H); LC/MS (方法O): Rt 1.045 min, [MH]+ 370.3。
實例31:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸甲醯胺(31)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸甲醯胺且其以淡黃色固體形式(10 mg,31%)分離;熔點146-148℃;1
H NMR (400 MHz, DMSO-d6
): δ 13.22 (s, 1H), 8.82 (d, J = 5.8 Hz, 1H), 7.57 (s, 1H), 7.20 - 6.91 (m, 2H), 4.46 (s, 1H), 3.99 (d, J = 10.3 Hz, 5H), 3.82 - 3.64 (m, 2H), 3.53 (td, J = 11.9, 3.0 Hz, 1H), 3.18 (t, J = 11.6 Hz, 1H), 2.86 (d, J = 4.6 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H); LC/MS (方法O): Rt 0.983 min, [MH]+ 356.3。
實例32:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸醯胺(32)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-甲酸醯胺且其以黃色固體形式分離(5 mg,15%);熔點228-230℃;1
H NMR (400 MHz, DMSO-d6
): δ 13.23 (s, 1H), 8.34 (m, J = 10.1 Hz, 1H), 8.09 - 7.53 (m, 2H), 7.21 - 6.89 (m, 2H), 4.48 (d, J = 8.0 Hz, 1H), 4.15 - 3.92 (m, 4H), 3.84 - 3.66 (m, 2H), 3.54 (td, J = 11.7, 2.9 Hz, 1H), 3.26 - 3.12 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法O): Rt 0.920 min, [MH]+ 342.3。
實例33:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(33)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-7-(6-甲基-吡啶-2-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶且其以黃色固體形式(14 mg,33%)分離,熔點115℃;1
H NMR (400 MHz, DMSO-d6
): δ 13.21 (s, 1H), 7.92 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 2H), 7.43 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 11.8 Hz, 2H), 4.50 (s, 1H), 4.11- 3.94 (m, 2H), 3.73 (s, 5H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.20 (td, J = 12.9, 3.7 Hz, 1H), 2.60 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法E): RT1.190 min, [MH]+ 390.1。
實例34:7-[1-(2-氟-乙基)-1H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(34)
用於合成實例34之架構基塊:(3R)-3-甲基-4-[1-甲基-7-(1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將(3R)-3-甲基-4-[1-甲基-7-[1-(噁烷-2-基)-1H-吡唑-5-基]-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(340 mg,0.84 mmol,1.0當量 95%)溶解於含氯化氫之甲醇(10 mL)溶液中且在室溫下攪拌2 h。所得混合物在真空下濃縮。用碳酸氫鈉將溶液之pH值調節至7-8。用二氯甲烷萃取所得溶液且合併有機層且在真空下濃縮。將呈黃色油狀之(3R)-3-甲基-4-[1-甲基-7-(1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(250 mg,96%)分離;LC/MS (方法P): Rt 0.566 min, [MH]+ 299.2。
用於合成實例34之架構基塊:(3R)-4-{7-[1-(2-氟乙基)-1H-吡唑-3-基]-1-甲基-1H-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉
將(3R)-3-甲基-4-[1-甲基-7-(1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉 (150 mg,0.48 mmol,1.0當量 96%)、DMF (5 mL)、氫化鈉(80.3 mg,2 mmol,4.2當量,60%)及1-氟-2-碘乙烷(174.6 mg,0.95 mmol,1.98當量)合併且在室溫下攪拌2 h。隨後藉由添加NH4
Cl淬滅反應物。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法K)純化殘餘物。將呈黃色油狀之(3R)-4-[7-[1-(2-氟乙基)-1H-吡唑-3-基]-1-甲基-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(110 mg,66%)分離;LC/MS (方法P): Rt 0.667 min, [MH]+ 345.3。
實例34:7-[1-(2-氟-乙基)-1H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶
類似於以上實例製備7-[1-(2-氟-乙基)-1H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以淡黃色固體形式(8 mg,21%)分離;熔點106-107℃;淡黃色固體;1
H NMR (300 MHz, 甲醇-d4): δ 7.86 (d, J = 2.4 Hz, 1H), 7.63 (s, 1H), 7.04 (s, 2H), 6.71 (d, J = 2.3 Hz, 1H), 4.91 (t, J = 4.7 Hz, 2H), 4.75 (t, J = 4.7 Hz, 1H), 4.62 (t, J = 4.7 Hz, 1H), 4.53 (t, J = 4.7 Hz, 1H), 4.04 (d, J = 11.9 Hz, 2H), 3.95 (s, 3H), 3.83 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.1 Hz, 1H), 1.29 (d, J = 6.7 Hz, 3H); LC/MS (方法E): Rt 1.238 min, [MH]+ 411.2。
實例35:(3R)-3-甲基-4-[7-(2-甲基苯基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(35)
類似於以上實例製備(3R)-3-甲基-4-[7-(2-甲基苯基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式分離(17 mg,64%);1
H NMR (400 MHz, DMSO-d6
): δ d 7.74 (d, J = 1.9 Hz, 1H), 7.47 - 7.34 (m, 5H), 7.08 (d, J = 1.9 Hz, 1H), 6.91 (s, 1H), 4.49 - 4.42 (m, 1H), 4.10 - 4.04 (m, 1H), 4.02 - 3.96 (m, 1H), 3.77 - 3.73 (m, 1H), 3.70 (dd, J = 11.1, 2.9 Hz, 1H), 3.56 (td, J = 11.7, 3.0 Hz, 1H), 3.21 (td, J = 12.5, 3.6 Hz, 1H), 2.20 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 2.102 min; [MH]+ 375.2。
實例36:7-[2-(2-氟-乙基)-2H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(36)
用於合成實例36之架構基塊:(3R)-4-{7-[1-(2-氟乙基)-1H-吡唑-5-基]-1-甲基-1H-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉
將(3R)-3-甲基-4-[1-甲基-7-(1H-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(450 mg,1.49 mmol,1.0當量 99%)、DMF (10 mL)、氫化鈉(240.8 mg,6.02 mmol,4.03當量,60%)及1-氟-2-碘乙烷(523.7 mg,2.86 mmol,1.92當量)合併且在室溫下攪拌2 h。隨後藉由添加NH4
Cl淬滅反應物。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由製備型HPLC (方法H)純化粗產物。將呈黃色油狀之(3R)-4-[7-[1-(2-氟乙基)-1H-吡唑-5-基]-1-甲基-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(60 mg,12%)分離;LC/MS (方法P): Rt 0.668 min, [MH]+ 345.3
實例36:7-[2-(2-氟-乙基)-2H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶
類似於以上實例製備7-[2-(2-氟-乙基)-2H
-吡唑-3-基]-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以淡黃色固體形式(15 mg,30%)分離;熔點120-121℃;1
H NMR (300 MHz, DMSO-d6
): δ 12.93-13.24 (m,1H), 7.89 - 7.59 (m, 2H), 7.13 -6.94 (m, 2H), 6.66 (s, 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.39 (dd, J = 27.7, 16.9 Hz, 3H), 4.04 (dd, J = 29.2, 12.1 Hz, 2H), 3.79- 3.64 (m, 2H), 3.62-3.42 (m, 4H), 3.17 (t, J = 13.0 Hz, 1H), 1.18 (d, J = 6.5 Hz, 3H); LC/MS (方法B): Rt 2.294 min, [MH]+ 411.2。
實例37:2-{3-[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-吡唑-1-基}-乙醇(37)
類似於以上實例製備2-{3-[1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-吡唑-1-基}-乙醇且其以淡黃色固體形式(60 mg,33%)分離;熔點110-111℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.18 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.04 (d, J = 11.3 Hz, 2H), 6.78 (d, J = 2.3 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.54 -4.41 (m, 1H), 4.28 (t, J = 5.6 Hz, 2H), 4.05-3.97 (m, 5H),3.88-3.64 (m, 4H), 3.55 (td, J = 11.8, 3.0 Hz, 1H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC/MS (方法E): Rt 1.073 min, [MH]+ 409.2。
實例38:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-7-(吡啶-2-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(38)
用於合成實例38之架構基塊:[5-[(3R)-3-甲基嗎啉-4-基]-1-(2-三甲基矽烷基乙氧基甲基)吡唑并[4,3-b]吡啶-7-基]酸
將5-((R)-3-甲基-嗎啉-4-基)-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶-7-基酯(50 mg;0.101 mmol;1.0當量)溶解於1,4-二噁烷(2 ml)中,且添加乙酸鉀(19.764 mg;0.201 mmol;2.0當量)、雙(頻哪醇根基)二硼(38.353 mg;0.151 mmol;1.50當量)及(1,1'-雙(二苯膦基)二茂鐵)-二氯鈀(II) (7.067 mg;0.010 mmol;0.10當量)且在110℃下攪拌4小時。反應溶液未經進一步純化即用於下一反應步驟中。
用於合成實例38之架構基塊:5-((R)-3-甲基-嗎啉-4-基)-7-吡啶-2-基-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶
向[5-[(3R)-3-甲基嗎啉-4-基]-1-(2-三甲基矽烷基乙氧基甲基)吡唑并[4,3-b]吡啶-7-基]酸的反應混合物中添加2-溴吡啶(19.149 mg;0.121 mmol;1.20當量)、碳酸鉀(42.038 mg;0.304 mmol;3.01當量)、水(0.300 ml)及1,1'-雙(二苯膦基)-二茂鐵二氯鈀-(II) * DCM (8.248 mg;0.010 mmol;0.10當量)且在100℃下攪拌2小時。濃縮反應混合物且藉由管柱層析法(方法L)純化粗產物。將呈褐色樹脂狀之5-((R)-3-甲基-嗎啉-4-基)-7-吡啶-2-基-1-(2-三甲基矽烷基-乙氧基甲基)-1H-吡唑并[4,3-b]吡啶(64 mg,79%)分離;LC/MS (方法F): Rt 2.464 min; [MH]+ 426.2。
實例38:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-7-(吡啶-2-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉
類似於以上實例製備(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-7-(吡啶-2-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(7 mg,38%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 8.86 - 8.83 (m, 1H), 8.49 - 8.44 (m, 1H), 8.03 (td, J = 7.8, 1.9 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.55 - 7.51 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 4.65 - 4.57 (m, 1H), 4.15 - 4.10 (m, 1H), 4.03 (dd, J = 11.3, 3.5 Hz, 1H), 3.83 - 3.78 (m, 1H), 3.75 (dd, J = 11.2, 3.0 Hz, 1H), 3.63 - 3.55 (m, 1H), 3.28 - 3.20 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 2.026 min; [MH]+ 362.2。
實例39:(3R)-3-甲基-4-[7-(3-甲基吡啶-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(39)
類似於以上實例製備(3R)-3-甲基-4-[7-(3-甲基吡啶-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(11 mg,50%)分離;1
H NMR (400 MHz, DMSO-d6
) δ 13.28 - 13.10 (m, 1H), 12.99 - 12.78 (m, 1H), 8.63 - 8.58 (m, 1H), 7.88 - 7.83 (m, 1H), 7.68 - 7.53 (m, 1H), 7.45 (dd, J = 7.7, 4.7 Hz, 1H), 7.11 - 7.03 (m, 2H), 4.48 - 4.42 (m, 1H), 4.11 - 4.03 (m, 1H), 4.00 (dd, J = 11.4, 3.5 Hz, 1H), 3.79 - 3.74 (m, 1H), 3.71 (dd, J = 11.4, 2.9 Hz, 1H), 3.57 (td, J = 11.7, 2.9 Hz, 1H), 3.19 (td, J = 12.7, 3.7 Hz, 1H), 2.34 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 1.836 min; [MH]+ 376。
實例40:(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(40)
用於合成實例40之架構基塊:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將三氟-甲磺酸1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶-7-基酯(350 mg;0.810 mmol;1當量)、二噁烷(7.00 ml)、三乙基胺(354.48 µl;2.429 mmol;3當量)、乙酸鈀(II) (18.18 mg;0.081 mmol;0.1當量)、1,1´-雙-(二苯膦基)-二茂鐵(47.12 mg;0.081 mmol;0.1當量)及甲酸(61.10 µl;1.620 mmol;2當量)合併且在80℃下攪拌45 min。將反應混合物蒸發至乾燥且藉由管柱層析法(方法M)純化粗產物。將呈黃色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(104 mg,55%)分離;LC/MS (方法C): Rt 0.662 min; [MH]+ 233.1。
實例40:(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(52 mg,82%)分離;1
H NMR (700 MHz, DMSO-d6
): δ 7.99 (d, J = 9.3 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 4.60 - 4.27 (m, 1H), 4.07 - 3.95 (m, 5H), 3.76 (d, J = 11.1 Hz, 1H), 3.70 (dd, J = 11.2, 3.1 Hz, 1H), 3.54 (td, J = 11.8, 3.1 Hz, 1H), 3.15 (td, J = 12.8, 3.9 Hz, 1H), 1.15 (d, J = 6.7 Hz, 3H); LC/MS (方法C): Rt 0.832 min; [MH]+ 299.1。
實例41:(3R)-4-[7-(4-甲磺醯基苯基)-1-(丙-2-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(41)
類似於以上實例製備(3R)-4-[7-(4-甲磺醯基苯基)-1-(丙-2-基)-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(21 mg,34%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 8.13 - 8.09 (m, 2H), 7.91 - 7.86 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.87 (s, 1H), 4.50 - 4.43 (m, 1H), 4.12 - 4.01 (m, 2H), 3.98 (dd, J = 11.3, 3.5 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.3, 3.1 Hz, 1H), 3.57 - 3.53 (m, 1H), 3.33 (s, 3H), 3.18 (td, J = 12.6, 3.6 Hz, 1H), 1.30 - 1.25 (m, 6H), 1.19 (d, J = 6.7 Hz, 3H); LC/MS (方法F): Rt 2.273 min; [MH]+ 481.2。
實例42:1-甲基-7-(3-甲基-3H-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(42)
用於合成實例42之架構基塊:1-甲基-7-(3-甲基-3H-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶
將3-溴-1-甲基-7-(3-甲基-3H-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(63 mg;0.161 mmol;0.694當量)、1-(2-三甲基矽烷基)乙氧基甲基-1H-吡唑-5-酸四甲基乙二醇酯(158.45 mg;0.464 mmol;2當量)、碳酸鈉(73.80 mg;0.696 mmol;3當量)、四(三苯基膦)鈀(0) (32.51 mg;0.028 mmol;0.120當量)合併且添加THF (1.90 ml)及水(190.00 µl)且在90℃下攪拌1.5 h。過濾反應混合物且在減壓下濃縮。藉由管柱層析法(方法N)純化粗產物。將呈褐色固體狀之1-甲基-7-(3-甲基-3H-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(61.50 mg;52.1%)分離;LC/MS (方法Q): Rt 0.946 min; [MH]+ 509.8。
實例42:1-甲基-7-(3-甲基-3H
-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶
添加1-甲基-7-(3-甲基-3H
-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-[2-(2-三甲基矽烷基-乙氧基甲基)-2H
-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(61.50 mg;0.121 mmol;1當量)且將其溶解於含HCl之MeOH (1.93 ml)中且在室溫下攪拌21 h。在減壓下濃縮反應溶液。藉由管柱層析法(方法O)純化粗產物。將呈黃色固體狀之1-甲基-7-(3-甲基-3H
-咪唑-4-基)-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(35 mg;75.0%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.27 - 12.88 (m, 1H), 7.93 - 7.53 (m, 2H), 7.30 - 6.94 (m, 3H), 4.47 (s, 1H), 4.08 (d, J = 13.7 Hz, 1H), 3.99 (dd, J = 11.3, 3.6 Hz, 1H), 3.75 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.61 (s, 3H), 3.56 - 3.50 (m, 4H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H); LC/MS (方法R): Rt 0.399 min; [MH]+ 379.2。
實例43:7-環丙基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(43)
類似於以上實例製備7-環丙基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶鹽酸鹽且其以黃色固體形式(5 mg,26%)分離;熔點234-235℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.88 (d, J = 2.4 Hz, 1H), 6.95 -6.84 (m, 2H), 4.46 (s, 4H), 4.12 (d, J = 9.3 Hz, 1H), 3.96- 3.84 (m, 3H), 3.73 (q, J = 12.5, 12.0 Hz, 2H), 2.65 (p, J = 5.9, 4.8 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.40 -1.31 (m, 2H), 1.19 (q, J = 4.5, 3.8 Hz, 2H); LC/MS (方法S): Rt 1.340 min [MH]+ 339.3。
實例44:7-異丙氧基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(44)
用於合成實例44之架構基塊:(3R)-3-甲基-4-[1-甲基-7-(丙-2-基氧基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-醇(500 mg,1.81 mmol,1當量)、DMF (50 mL)、碳酸鉀(545.1 mg,3.75 mmol,2.07當量)及2-碘丙烷(450 mg,2.51 mmol,1.39當量)合併且在室溫下攪拌2 h。將反應混合物過濾且在真空下濃縮。藉由管柱層析法(方法E)純化粗產物。將呈黃色油狀之(3R)-3-甲基-4-[1-甲基-7-(丙-2-基氧基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(500 mg(89%)分離;LC/MS (方法T): Rt 0.997 min, [MH]+ 291.3。
實例44:7-異丙氧基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶
類似於以上實例製備7-異丙氧基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以白色固體形式(10 mg,31%)分離;熔點134-135℃;1
H NMR (300 MHz, DMSO-d6
): δ 12.72 (s, 1H), 7.54 (s, 1H), 6.90 (s, 1H), 6.41 (s, 1H), 4.96 (h, J = 6.0 Hz, 1H), 4.39 (d, J = 7.3 Hz, 1H), 4.12 (s, 3H), 3.97 (d, J = 3.4 Hz, 1H), 3.93 (d, J = 3.3 Hz, 1H), 3.71 (t, J = 2.2 Hz, 2H), 3.54 (td, J = 11.4, 3.0 Hz, 1H), 3.26 -3.10 (m, 1H), 1.42 (d, J = 6.0 Hz,6H), 1.18 (d, J = 6.6 Hz, 3H); LC/MS (方法E): Rt 1.219 min, [MH]+ 357.2。
實例45:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-醇(45)
用於合成實例45之架構基塊:乙酸1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-酯
將1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-醇(300 mg,1.09 mmol,1.當量)、二氯甲烷(10 mL)、NEt3
(366.8 mg,3.44 mmol,3.17當量)及乙醯氯(189.7 mg,2.30 mmol,2.11當量)合併且在室溫下攪拌2 h。所得混合物在真空下濃縮。用碳酸氫鈉將溶液之pH值調節至7-8。用二氯甲烷萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色油狀之乙酸1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-酯(310 mg,88%)分離;LC/MS (方法P): Rt 0.621 min,[MH]+ 291.3。
實例45:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-醇
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-醇且其以無色固體形式(20 mg,70%)分離;熔點190-191℃;1
H NMR (300 MHz, DMSO-d6
): δ 7.67 - 7.59 (m, 1H), 6.80 (s, 1H), 5.94 (s, 1H), 4.16 (m, 4H), 3.93 (d, J = 7.9 Hz, 1H), 3.70 (d, J = 2.4 Hz, 2H), 3.65 -3.47 (m, 3H), 3.20 (m, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC/MS (方法E): Rt 1.035 min, [MH]+ 315.1。
實例46:1-(4-甲磺醯基-苯基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(46)
將(3R)-4-[1-(4-甲磺醯基苯基)-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(200 mg,0.34 mmol,1.當量)溶解於含氯化氫之甲醇(10 mL)中且在25℃下攪拌1 h。用乙酸乙酯萃取所得溶液且合併有機層且經無水硫酸鈉乾燥且在真空下濃縮。藉由製備型HPLC (方法I)純化粗產物。將呈黃色固體狀之1-(4-甲磺醯基-苯基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(20 mg,13%)分離;熔點155-157℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.22 (s, 1H), 8.37 (d, J = 9.5 Hz, 1H), 8.22-8.07 (m, 4H), 7.80 (s, 1H), 7.29-7.19 (m, 2H), 4.54-4.43 (m, 1H), 4.15-3.97 (m, 2H), 3.86-3.66 (m, 2H), 3.57 (td, J = 11.8, 2.8 Hz, 1H), 3.37-3.12 (m, 3H), 1.21 (d, J = 6.6 Hz, 3H); LC/MS (方法E): Rt 1.396 min [MH]+ 439.1。
實例47:1-(3-甲磺醯基-苯基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(47)
類似於以上實例製備1-(3-甲磺醯基-苯基)-5-((R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶且其以黃色固體形式(4 mg,10%)分離;熔點133-135℃;1
H NMR (300 MHz, CD3
OD): δ 8.46 (s, 2H), 8.22 (t, J = 8.5 Hz, 4H), 8.00-7.80 (m, 4H), 7.71 (s, 1H), 7.37 (s, 1H), 7.28 (s, 1H), 7.18 (d, J = 9.5 Hz, 2H), 4.52 (d, J = 7.1 Hz, 2H), 4.09 (dd, J = 12.4, 6.1 Hz, 4H), 3.86 (d, J = 2.6 Hz, 3H), 3.70 (td, J = 11.8, 3.2 Hz, 2H), 3.38 (dd, J = 12.7, 3.9 Hz, 2H), 3.26 (s, 5H), 1.33 (d, J = 6.7 Hz, 7H); LC/MS (方法E): Rt 1.395 min [MH]+ 439.2。
實例48:3-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯甲腈(48)
類似於以上實例製備3-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯甲腈且其以黃色固體形式(34 mg,25%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 8.16 - 8.14 (m, 1H), 8.03 - 8.00 (m, 1H), 7.98 - 7.94 (m, 1H), 7.79 - 7.73 (m, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 6.96 (s, 1H), 4.53 - 4.46 (m, 1H), 4.09 - 4.03 (m, 1H), 4.01 - 3.96 (m, 1H), 3.78 - 3.74 (m, 1H), 3.68 (dd, J = 11.4, 3.0 Hz, 1H), 3.60 (s, 3H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 2.226 min; [MH]+ 400.2。
實例49:(3R)-3-甲基-4-[1-甲基-7-(2-甲基苯基)-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(49)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-7-(2-甲基苯基)-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以米色固體形式(27 mg;18%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 7.68 (d, J = 1.9 Hz, 1H), 7.48 - 7.32 (m, 4H), 7.06 (dd, J = 1.9, 0.9 Hz, 1H), 6.84 (s, 1H), 4.43 (t, J = 7.6 Hz, 1H), 4.12 - 3.94 (m, 2H), 3.77 - 3.66 (m, 2H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.40 (d, J = 0.8 Hz, 3H), 3.17 (td, J = 12.6, 3.8 Hz, 1H), 2.10 (s, 3H), 1.99 (s, 1H), 1.91 (s, 0H), 1.20-1.15 (m, 3H).L C/MS (方法C): Rt 1.116 min; [MH]+ 389.2。
實例50:(3R)-4-[7-(4-甲磺醯基-2-甲基苯基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(50)
類似於以上實例製備(3R)-4-[7-(4-甲磺醯基-2-甲基苯基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(41 mg,31%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 8.01 - 7.99 (m, 1H), 7.93 - 7.89 (m, 1H), 7.70 - 7.65 (m, 2H), 7.08 - 7.06 (m, 1H), 6.91 (s, 1H), 4.47 - 4.39 (m, 1H), 4.12 - 4.03 (m, 1H), 4.01 - 3.95 (m, 1H), 3.77 - 3.66 (m, 2H), 3.58 - 3.50 (m, 1H), 3.43 - 3.40 (m, 3H), 3.30 (s, 3H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 2.21 (s, 3H), 1.21 - 1.16 (m, 3H); LC/MS (方法F): Rt 2.136 min; [MH]+ 467.1。
實例51:(3R)-4-{7-[4-(甲氧基甲基)苯基]-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉(51)
類似於以上實例製備(3R)-4-{7-[4-(甲氧基甲基)苯基]-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉且其以黃色固體形式(104 mg,74%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 7.68 - 7.67 (m, 1H), 7.59 - 7.56 (m, 2H), 7.51 - 7.48 (m, 2H), 7.06 (d, J = 1.9 Hz, 1H), 6.87 (s, 1H), 4.53 (s, 2H), 4.50 - 4.44 (m, 1H), 4.07 - 4.02 (m, 1H), 3.98 (dd, J = 11.4, 3.6 Hz, 1H), 3.77 - 3.73 (m, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.60 (s, 3H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.36 (s, 3H), 3.18 (td, J = 12.7, 3.7 Hz, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 2.259 min; [MH]+ 419.2。
實例52:(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯基)甲醇(52)
類似於以上實例製備(4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-7-基}苯基)甲醇且其以黃色固體形式(112 mg,65%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 7.69 (d, J = 1.9 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.51 - 7.48 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.85 (s, 1H), 4.61 (s, 2H), 4.51 - 4.43 (m, 1H), 4.07 - 4.01 (m, 1H), 4.01 - 3.95 (m, 1H), 3.78 - 3.66 (m, 2H), 3.61 (s, 3H), 3.54 (td, J = 11.8, 3.0 Hz, 1H), 3.19 (td, J = 12.6, 3.7 Hz, 1H), 1.19 - 1.18 (m, 3H); LC/MS (方法F): Rt 1.997 min; [MH]+ 405.2。
實例53:3-[5-((3R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基]-苯甲腈(53)
類似於以上實例製備3-[5-((3R)-3-甲基-嗎啉-4-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基]-苯甲腈且其以黃色固體形式(8 mg,26%)分離,熔點115-117℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.50 (s, 1H), 13.15 (s, 1H), 8.37 (s, 4H), 8.24 (s, 3H), 7.84 (s, 5H), 7.68 (s, 1H), 7.22 (d, J = 16.2 Hz, 4H), 4.50 (s, 2H), 4.03 (d, J = 9.7 Hz, 3H), 3.86-3.67 (m, 4H), 3.65-3.50 (m, 2H), 3.29-3.14 (m, 2H), 1.21 (d, J = 6.5 Hz, 7H); LC/MS (方法U): Rt 2.952min [MH]+ 386.2。
實例54:(3R)-4-[7-(3,6-二氫-2H
-哌喃-4-基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(54)
類似於以上實例製備(3R)-4-[7-(3,6-二氫-2H
-哌喃-4-基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(35 mg,65%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.19 - 12.86 (m, 1H), 7.82 - 7.53 (m, 1H), 7.11 - 6.95 (m, 1H), 6.86 - 6.77 (m, 1H), 6.01 - 5.96 (m, 1H), 4.50 - 4.39 (m, 1H), 4.29 - 4.25 (m, 2H), 4.04 - 3.95 (m, 5H), 3.90 (t, J = 5.4 Hz, 2H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.2, 3.0 Hz, 1H), 3.52 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 2.50 - 2.45 (m, 2H), 1.16 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 1.941 min; [MH]+ 381.2。
實例55:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-4-基)-1H
-吡唑并[4,3-b]吡啶(55)
用於合成實例55之架構基塊:(3R)-3-甲基-4-[1-甲基-7-(噁烷-4-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉
將(3R)-4-[7-(3,6-二氫-2H-哌喃-4-基)-1-甲基-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(400 mg,1.15 mmol,1.當量)、甲醇(30 mL)及Pd/C (2437.24 mg,2.29 mmol,2.0當量 10%)合併且在25℃下攪拌5小時。過濾反應混合物且在真空下濃縮。將呈黃色固體狀之(3R)-3-甲基-4-[1-甲基-7-(噁烷-4-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(300 mg,74%)分離;LC/MS (方法J): Rt 0.752 min, [MH]+ 317.2。
實例55:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-4-基)-1H
-吡唑并[4,3-b]吡啶
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H-吡唑-3-基)-7-(四氫-哌喃-4-基)-1H-吡唑并[4,3-b]吡啶且其以無色固體形式(20 mg (27%)分離;熔點240-242℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.62 (s, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.25 (s, 3H), 4.15 -4.03 (m, 2H), 4.07 -3.91 (m, 2H), 3.80 (d, J = 2.2 Hz, 2H), 3.64 (dtd, J = 14.3, 11.1, 6.6 Hz, 2H), 3.32 (d, J = 4.0 Hz, 0H), 3.23 (d, J = 3.7 Hz, 0H), 2.04 -1.85 (m, 4H), 1.23 (d, J = 6.7 Hz, 3H); LC/MS (方法E): Rt 1.150 min, [MH]+ 383.2。
實例56:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(56)
用於合成實例56之架構基塊:3-溴-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將3-溴-5-氯-1H-吡唑并[4,3-b]吡啶(2 g,8.6 mmol)、(R)-3-甲基-嗎啉(957 mg,9.5 mmol)、XPhos-Pd-G2 (339 mg,0.43 mmol)、雙-cy-xPhos (205 mg,0.43 mmol)、LHMDS (3 g,17 mmol)及二噁烷(20 ml)合併且在60℃下攪拌3小時。過濾反應物且在減壓下濃縮。藉由管柱層析法(正庚烷/EtOAc-梯度)純化粗產物。將呈黃色固體狀之3-溴-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(280 mg,6%)分離;LC/MS (方法V): Rt 2.802 min; [MH]+ 297。
用於合成實例56之架構基塊:5-((R)-3-甲基-嗎啉-4-基)-3-[1-(四氫-哌喃-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶
將3-溴-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(280 mg;0.518 mmol;1.0當量)溶解於THF (8 ml)及水(0.800 ml)中。將1-(四氫-哌喃-2-基)-3-(4,4,5,5-四甲基-[1,3,2]二氧硼㖦-2-基)-1H-吡唑(294.194 mg;1,037 mmol;2.0當量)、碳酸鈉(164.786 mg;1.555 mmol;3.0當量)及四(三苯基膦)-鈀(0) (72.591 mg;0.062 mmol;0.12當量)合併且在90℃下攪拌3 h。添加1-(四氫-哌喃-2-基)-3-(4,4,5,5-四甲基-[1,3,2]二氧硼㖦-2-基)-1H-吡唑(294.194 mg;1.037 mmol;2.0當量及四(三苯基膦)-鈀(0) (72.591 mg;0.062 mmol;0.12當量)且在90℃下攪拌14 h。在減壓下濃縮反應混合物且藉由管柱層析(正庚烷/EtOAc-梯度)純化粗產物。將呈黃色固體狀之5-((R)-3-甲基-嗎啉-4-基)-3-[1-(四氫-哌喃-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(131 mg,61%)分離;LC/MS (方法F): Rt 1.903 min; [MH]+ 369.2。
實例56:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉
將5-((R)-3-甲基-嗎啉-4-基)-3-[1-(四氫-哌喃-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶(131 mg;0.316 mmol;1.0當量)溶解於甲醇(3.500 ml)及含氯化氫溶液之二噁烷(3.164 ml;4.0 M)中。在室溫下攪拌反應溶液2小時。在減壓下濃縮反應混合物且經由管柱層析(DCM/MeOH-梯度)純化粗產物。將呈黃色固體狀之(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(90 mg,99%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 13.21 - 12.76 (m, 2H), 7.89 - 7.53 (m, 2H), 7.11 - 6.96 (m, 2H), 4.45 - 4.36 (m, 1H), 4.06 - 3.93 (m, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.70 (dd, J = 11.3, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.15 (td, J = 12.7, 3.8 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 1.586 min; [MH]+ 285.1。
實例57:(3R)-4-{1-[(3-甲磺醯基苯基)甲基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉(57)
將5-((R)-3-甲基-嗎啉-4-基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶(56 mg;0.197 mmol;1.0當量)、乙腈(2.8 ml)、碳酸鉀(42.981 mg;0.295 mmol;1.50當量)及1-溴甲基-3-甲磺醯基-苯(51.651 mg;0.197 mmol;1.0當量)合併且在80℃下攪拌2小時。用EtOAc/水萃取反應溶液且有機層經硫酸鈉乾燥,過濾且在真空中移除溶劑。藉由製備型HPLC純化粗產物。將呈黃色固體狀之(3R)-4-{1-[(3-甲磺醯基苯基)甲基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉(27 mg,28%)分離;1
H NMR (700 MHz, DMSO-d6
): δ 8.14 (d, J = 9.4 Hz, 1H), 7.90 - 7.88 (m, 1H), 7.87 - 7.84 (m, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.53 - 7.50 (m, 1H), 7.18 (d, J = 9.5 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 5.80 (s, 2H), 4.44 - 4.40 (m, 1H), 4.04 - 4.01 (m, 1H), 3.99 (dd, J = 11.3, 3.7 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.69 (dd, J = 11.2, 3.1 Hz, 1H), 3.53 (td, J = 11.7, 3.1 Hz, 1H), 3.20 (s, 3H), 3.19 - 3.15 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H);LC/MS (方法F): Rt 1.981 min; [MH]+ 453.1。
實例58:(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-(吡啶-2-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(58)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-(吡啶-2-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以橙色固體形式(40 mg,72.9%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 8.82 - 8.79 (m, 1H), 8.07 (td, J = 7.7, 1.8 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.62 - 7.57 (m, 1H), 7.09 (d, J = 1.9 Hz, 1H), 7.08 (s, 1H), 4.54 - 4.47 (m, 1H), 4.09 - 4.03 (m, 1H), 3.99 (dd, J = 11.2, 3.5 Hz, 1H), 3.77 (d, J = 11.3 Hz, 1H), 3.71 (s, 3H), 3.73 - 3.68 (m, 1H), 3.55 (td, J = 11.8, 3.0 Hz, 1H), 3.26 - 3.17 (m, 1H), 1.20 (d, J = 6.6 Hz, 3H);LC/MS (方法C): Rt 0.947 min; [MH]+ 376.2。
實例59:(3R)-4-[1-苄甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(59)
類似於以上實例製備(3R)-4-[1-苄甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉鹽酸鹽且其以米色固體形式(120 mg;52.3%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 8.04 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.28 - 7.22 (m, 3H), 7.12 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.65 (s, 2H), 4.44 - 4.38 (m, 1H), 4.03 - 3.97 (m, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.2, 3.1 Hz, 1H), 3.54 - 3.50 (m, 1H), 3.16 (td, J = 12.8, 3.9 Hz, 1H), 1.16 (d, J = 6.6 Hz, 3H); LC/MS (方法C): Rt 1.075 min; [MH]+ 375.2。
實例60:4-[5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基]苯甲腈(60)
類似於以上實例製備4-[5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基]苯甲腈且其以黃色固體形式(10 mg,26%)分離,熔點140-142℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.20 (s, 1H), 8.33 (d, J = 9.5 Hz, 1H), 8.05 (q, J = 8.9 Hz, 4H), 7.76 (s, 1H), 7.23-7.14 (m, 2H), 4.53-4.40 (m, 1H), 4.11-3.94 (m, 2H), 3.83-3.63 (m, 2H), 3.53 (td, J = 11.8, 2.9 Hz, 1H), 3.26-3.09 (m, 1H), 1.17 (d, J = 6.5 Hz, 3H); LC/MS (方法D): Rt 1.295 min [MH]+ 386.0。
實例61:(3R)-3-甲基-4-[1-甲基-7-(1-甲基-1H
-吡唑-5-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(61)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-7-(1-甲基-1H
-吡唑-5-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(30 mg,16%)分離;1
H NMR (300 MHz, DMSO-d6
): δ 13.11 (s, 1H), 7.85 -7.51 (m, 2H), 7.06 (d, J = 1.7 Hz, 2H), 6.61 (d, J = 1.9 Hz, 1H), 4.47 (d, J = 7.4 Hz, 1H), 4.22- 3.88 (m, 2H), 3.72 (d, J = 6.5 Hz, 5H), 3.32 (s, 4H), 3.25- 3.01 (m, 1H), 1.18 (d, J = 6.6 Hz, 3H);LC/MS (方法K): Rt 1.177 min [MH]+ 379.3。
實例62:(3R)-3-甲基-4-[1-甲基-7-(3-甲基吡啶-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(62)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-7-(3-甲基吡啶-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(15.70 mg,18.2%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.24 - 12.88 (m, 1H), 8.59 - 8.57 (m, 1H), 7.89 - 7.86 (m, 1H), 7.84 - 7.56 (m, 1H), 7.49 (dd, J = 7.7, 4.8 Hz, 1H), 7.15 - 6.92 (m, 2H), 4.49 - 4.40 (m, 1H), 4.13 - 4.01 (m, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.76 - 3.72 (m, 1H), 3.70 (dd, J = 11.4, 3.0 Hz, 1H), 3.55 (td, J = 11.7, 3.0 Hz, 1H), 3.42 - 3.36 (m, 3H), 3.17 (td, J = 12.7, 3.8 Hz, 1H), 2.20 (s, 3H), 1.17 (d, J = 6.6 Hz, 3H); LC/MS (方法C): Rt 0.953 min; [MH]+ 390.2。
實例63:(3R)-4-[1-(環丙基甲基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(63)
類似於以上實例製備(3R)-4-[1-(環丙基甲基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以無色固體形式(20 mg,43%)分離;熔點80℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.07 (s, 1H), 8.05 (d, J = 9.3 Hz, 1H), 7.67 (s, 1H), 7.11 (d, J = 9.4 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 4.43 (d, J = 7.1 Hz, 1H), 4.29 (d, J = 6.9 Hz, 2H), 4.10- 3.90 (m, 2H), 3.83-3.62 (m, 2H), 3.62 -3.47 (m, 1H), 3.23- 3.08 (m, 1H), 1.29 (q, J = 5.6 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H), 0.58- 0.45 (m, 2H), 0.4- 0.33 (m, 2H); LC/MS (方法A): RT 1.475 min, [MH]+ 339.3。
實例64:5-((R)-3-甲基-嗎啉-4-基)-1-苯乙基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶(64)
類似於以上實例製備呈無色固體狀之(3R)-3-甲基-4-[1-(2-苯基乙基)-3-(1H-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]嗎啉(27 mg,52%);熔點83℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.04 (d, J = 86.7 Hz, 1H), 7.95-7.45 (m, 2H), 7.38- 6.82 (m, 7H), 4.60 (s, 2H), 4.36 (s, 1H), 3.96 (d, J = 10.0 Hz, 2H), 3.86 -3.62 (m, 2H), 3.59 -3.39 (m, 1H), 3.22-3.01 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H);LC/MS (方法J): RT 1.030 min, [MH]+ 389.1。
實例65:(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-[6-(三氟甲基)吡啶-3-基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(65)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-[6-(三氟甲基)吡啶-3-基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(26 mg,93%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.29 - 12.89 (m, 1H), 9.05 - 9.03 (m, 1H), 8.41 - 8.37 (m, 1H), 8.12 - 8.09 (m, 1H), 7.85 - 7.54 (m, 1H), 7.13 - 7.00 (m, 2H), 4.55 - 4.45 (m, 1H), 4.08 (q, J = 5.3 Hz, 1H), 3.99 (dd, J = 11.4, 3.6 Hz, 1H), 3.76 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.3, 3.0 Hz, 1H), 3.63 (s, 3H), 3.54 (td, J = 11.7, 3.1 Hz, 1H), 3.23 - 3.16 (m, 1H), 1.19 (d, J = 6.6 Hz, 3H); LC/MS (方法F): Rt 2.351 min; [MH]+ 444.1。
實例66:(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-[2-(三氟甲基)吡啶-3-基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(66)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-3-(1H
-吡唑-3-基)-7-[2-(三氟甲基)吡啶-3-基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉鹽酸鹽且其以橙色固體形式(90 mg,定量)分離;1
H NMR (700 MHz, DMSO-d6
): δ 8.95 - 8.93 (m, 1H), 8.24 - 8.21 (m, 1H), 7.93 - 7.91 (m, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.08 - 7.06 (m, 1H), 7.03 (d, J = 10.1 Hz, 1H), 4.41 - 4.35 (m, 1H), 4.08 - 4.03 (m, 1H), 4.01 - 3.96 (m, 1H), 3.75 - 3.66 (m, 2H), 3.54 (tt, J = 11.7, 2.8 Hz, 1H), 3.41 - 3.39 (m, 3H), 3.16 (td, J = 12.8, 3.9 Hz, 1H), 1.19 - 1.13 (m, 3H);LC/MS (方法C): Rt 1.058 min; [MH]+ 444.2。
實例67:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-3-基)-1H
-吡唑并[4,3-b]吡啶(67) (非對映異構混合物)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-3-基)-1H
-吡唑并[4,3-b]吡啶且其以無色固體形式(30 mg,41%)分離;熔點198-200℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.60 (s, 1H), 6.99 (s, 1H), 6.90 (d, J = 5.7 Hz, 1H), 4.42 (d, J = 7.6 Hz, 1H), 4.25 (s, 3H), 4.08 (dd, J = 10.1, 2.6 Hz, 1H), 4.07 - 3.90 (m, 3H), 3.80 (d, J = 2.2 Hz, 2H), 3.71 - 3.50 (m, 4H), 3.32 (s, 0H), 3.23 (d, J = 3.7 Hz, 0H), 2.16 (d, J = 12.2 Hz, 1H), 2.04 - 1.71 (m, 2H), 1.27 - 1.18 (m, 3H); LC/MS (方法W): Rt 0.970 min, [MH]+ 383.1。
實例68:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(R)-四氫-哌喃-3-基-1H
-吡唑并[4,3-b]吡啶(68)
藉由對掌性SFC (ChiralCel OJ-H;CO2
:甲醇 +0.5% DEA 88:12)分離1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-3-基)-1H
-吡唑并[4,3-b]吡啶之非對映異構體。將呈無色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(R)-四氫-哌喃-3-基-1H
-吡唑并[4,3-b]吡啶(14 mg;41.5%)分離;LC/MS (方法C): Rt 0.932 min; [MH]+ 383.3 ; Rt最先自管柱溶離。
實例69:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(S)-四氫-哌喃-3-基-1H
-吡唑并[4,3-b]吡啶(69)
藉由對掌性SFC (ChiralCel OJ-H;CO2
:甲醇+0.5% DEA 88:12)分離1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-哌喃-3-基)-1H
-吡唑并[4,3-b]吡啶之非對映異構體。將呈無色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(S)-四氫-哌喃-3-基-1H
-吡唑并[4,3-b]吡啶(17.80 mg;52.7%)分離;LC/MS (方法C): Rt 0.93 min; [MH]+ 383.3; Rt其次自管柱溶離。
實例70:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-呋喃-3-基)-1H
-吡唑并[4,3-b]吡啶(70) (非對映異構混合物)
類似於以上實例製備1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-呋喃-3-基)-1H
-吡唑并[4,3-b]吡啶且其以無色固體形式(40 mg (53%)分離;熔點98-100℃;1
H NMR (300 MHz, 甲醇-d4
): δ 7.59 (s, 1H), 7.14 (s, 0H), 6.98 (s, 1H), 6.87 (s, 1H), 4.25 (s, 3H), 4.24 - 3.88 (m, 7H), 3.79 (d, J = 2.2 Hz, 2H), 3.78 - 3.54 (m, 2H), 3.35 - 3.18 (m, 1H), 2.52 (ddd, J = 13.1, 8.1, 6.6 Hz, 1H), 2.19 - 2.05 (m, 1H), 1.52 (s, 0H), 1.22 (dd, J = 6.7, 1.3 Hz, 3H);LC/MS (方法W): Rt 0.870min, [MH]+ 369.0。
實例71:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(S)-四氫-呋喃-3-基-1H
-吡唑并[4,3-b]吡啶(71)
藉由對掌性SFC (ChiralCel OJ-H;CO2
:甲醇 +0.5% DEA 90:10)分離1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-呋喃-3-基)-1H
-吡唑并[4,3-b]吡啶之非對映異構體。將呈無色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(S)-四氫-呋喃-3-基-1H
-吡唑并[4,3-b]吡啶(7 mg;41.2%)分離;LC/MS (方法C): Rt 0.867 min; [MH]+ 369.3 ; Rt最先自管柱溶離。
實例72:1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(R)-四氫-呋喃-3-基-1H
-吡唑并[4,3-b]吡啶(72)
藉由對掌性SFC (ChiralCel OJ-H;CO2
:甲醇 +0.5% DEA 90:10)分離1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(四氫-呋喃-3-基)-1H
-吡唑并[4,3-b]吡啶之非對映異構體。將呈無色固體狀之1-甲基-5-((R)-3-甲基-嗎啉-4-基)-3-(2H
-吡唑-3-基)-7-(R)-四氫-呋喃-3-基-1H
-吡唑并[4,3-b]吡啶(7 mg;41.2%)分離;LC/MS (方法C): Rt 0.867 min; [MH]+ 369.2; Rt其次自管柱溶離。
實例73:(3R)-3-甲基-4-[1-(丙-2-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(73)
類似於以上實例製備呈無色固體狀之(3R)-3-甲基-4-[1-(丙-2-基)-3-(1H-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(18 mg,28%);熔點94-95℃;1
H NMR (400 MHz, DMSO-d6
): δ 12.99 (d, J = 89.2 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 89.7 Hz, 1H), 7.03 (d, J = 49.1 Hz, 2H), 4.98 - 4.89 (m, 1H), 4.41 (s, 1H), 3.99 (dd, J = 11.2, 3.6 Hz, 2H), 3.76 (d, J = 11.2 Hz, 1H), 3.69 (dd, J = 11.2, 3.0 Hz, 1H), 3.54 (td, J = 11.7, 3.0 Hz, 1H), 3.14 (td, J = 12.7, 3.8 Hz, 1H), 1.51 (d, J = 6.5 Hz, 6H), 1.15 (d, J = 6.6 Hz, 3H); LC/MS (方法E): RT 1.241 min, [MH]+ 327.4。
實例74:(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-1-甲基-3-[3-(三氟甲基)-1H
-吡唑-5-基]-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(74)
類似於以上實例製備(3R)-4-[7-(6-甲磺醯基-2-甲基吡啶-3-基)-1-甲基-3-[3-(三氟甲基)-1H
-吡唑-5-基]-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(19 mg;64%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 14.14 (s, 1H), 8.22 - 8.19 (m, 1H), 8.07 - 8.04 (m, 1H), 7.33 - 7.31 (m, 1H), 7.12 - 7.10 (m, 1H), 4.48 - 4.39 (m, 1H), 4.15 - 4.07 (m, 1H), 4.00 (dd, J = 11.4, 3.6 Hz, 1H), 3.76 (dd, J = 11.3, 7.0 Hz, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.58 - 3.51 (m, 1H), 3.52 - 3.50 (m, 3H), 3.36 (s, 3H), 3.19 (td, J = 12.8, 3.8 Hz, 1H), 2.46 - 2.43 (m, 3H), 1.21 - 1.17 (m, 3H); LC/MS (方法C): Rt 1.146 min; [MH]+ 536.2。
實例75:(3R)-4-[7-(5-甲磺醯基-2-甲基苯基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(75)
類似於以上實例製備(3R)-4-[7-(5-甲磺醯基-2-甲基苯基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(144 mg;定量)分離;1
H NMR (700 MHz, DMSO-d6
): δ 8.00 - 7.97 (m, 1H), 7.92 - 7.90 (m, 1H), 7.76 - 7.74 (m, 1H), 7.72 - 7.70 (m, 1H), 7.11 - 7.09 (m, 1H), 6.98 - 6.96 (m, 1H), 4.48 - 4.44 (m, 1H), 4.09 - 4.04 (m, 1H), 4.00 - 3.96 (m, 1H), 3.77 - 3.73 (m, 1H), 3.72 - 3.65 (m, 1H), 3.54 (dd, J = 11.6, 3.1 Hz, 1H), 3.42 - 3.40 (m, 3H), 3.29 - 3.27 (m, 3H), 3.22 - 3.16 (m, 1H), 2.22 - 2.20 (m, 3H), 1.21 - 1.16 (m, 3H);LC/MS (方法C): Rt 0.991 min; [MH]+ 467。
實例76:(3R)-4-[7-(3-甲磺醯基苯基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(76)
類似於以上實例製備(3R)-4-[7-(3-甲磺醯基苯基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(47 mg;30%)分離;1
H NMR (700 MHz, DMSO-d6
): δ 8.15 - 8.13 (m, 1H), 8.10 - 8.08 (m, 1H), 8.00 - 7.98 (m, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.70 - 7.68 (m, 1H), 7.09 - 7.07 (m, 1H), 6.99 (s, 1H), 4.53 - 4.49 (m, 1H), 4.07 - 4.04 (m, 1H), 3.99 (dd, J = 11.2, 3.8 Hz, 1H), 3.78 - 3.75 (m, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.59 (s, 3H), 3.54 (td, J = 11.6, 3.1 Hz, 1H), 3.33 (s, 3H), 3.19 (td, J = 12.7, 3.8 Hz, 1H), 1.19 (d, J = 6.7 Hz, 3H); LC/MS (方法C): Rt 0.992 min; [MH]+ 453.2。
實例77:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[2-(吡啶-4-基)乙基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(77)
類似於以上實例製備(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[2-(吡啶-4-基)乙基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(10 mg,20%)分離,熔點180-181℃;1
H NMR (300 MHz, DMSO-d6
): δ 13.18 (s, 1H), 8.41-8.32 (m, 2H), 7.84 (d, J = 9.4 Hz, 1H), 7.23-7.14 (m, 2H), 7.00 (d, J = 9.6 Hz, 2H), 4.65 (t, J = 7.0 Hz, 2H), 4.37 (s, 1H), 4.02-3.91 (m, 2H), 3.79-3.60 (m, 2H), 3.57-3.42 (m, 1H), 3.24-3.02 (m, 3H), 1.11 (d, J = 6.6 Hz, 3H); LC/MS (方法E): Rt 0.929 min, [MH]+ 390.0。
實例78:(3R)-4-{7-[1-(二氟甲基)-1H
-吡唑-5-基]-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉(78)
類似於以上實例製備(3R)-4-{7-[1-(二氟甲基)-1H
-吡唑-5-基]-1-甲基-3-(1H
-吡唑-5-基)-1H-吡唑并[4,3-b]吡啶-5-基}-3-甲基嗎啉且其以黃色固體形式(49 mg;94%)分離;1
H NMR (400 MHz, DMSO-d6
): δ 13.27 - 12.85 (m, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.90 - 7.57 (m, 1H), 7.16 - 6.98 (m, 2H), 6.94 (d, J = 1.8 Hz, 1H), 4.53 - 4.28 (m, 1H), 4.12 - 3.95 (m, 2H), 3.80 - 3.49 (m, 6H), 3.24 - 3.10 (m, 2H), 1.18 (dd, J = 6.8, 5.3 Hz, 3H); LC/MS (方法C): Rt 0.989 min; [MH]+ 415.3。
實例79:(3R)-4-[7-(3,6-二氫-2H
-硫代哌喃-4-基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(79)
類似於以上實例製備(3R)-4-[7-(3,6-二氫-2H
-硫代哌喃-4-基)-1-甲基-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(10 mg,18%)分離,熔點215-216℃;1
H NMR (400 MHz, DMSO-d6
): δ 13.05 (d, J = 108.8 Hz, 1H), 7.60 (s, 1H), 7.02 (s, 1H), 6.79 (s, 1H), 6.05 (d, J = 4.9 Hz, 1H), 4.44 (s, 1H), 4.01 (d, J = 9.5 Hz, 5H), 3.75 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.3, 3.0 Hz, 1H), 3.52 (td, J = 11.6, 3.1 Hz, 1H), 3.36 (d, J = 3.7 Hz, 2H), 3.14 (td, J = 12.6, 3.8 Hz, 1H), 2.92 (t, J = 5.7 Hz, 2H), 2.61 (s, 2H), 1.16 (d, J = 6.6 Hz, 3H);LC/MS (方法D) Rt 1.129 min, [MH]+ 397.1。
實例80: 4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ4-硫代哌喃-1-酮(80)
用於合成實例80之架構基塊: 4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-5-基]-1H-吡唑并[4,3-b]吡啶-7-基}-3,6-二氫-2H-1λ4-硫代哌喃-1-酮
將4-[3-溴-1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H-1λ4-硫代哌喃-1-酮(100 mg,0.21 mmol,1.0當量)、1-(噁烷-2-基)-5-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(123.91 mg,0.42 mmol,2.0當量)、Pd(dppf)Cl2
.CH2
Cl2
(19.20 mg,0.02 mmol,0.10當量)、K3
PO4
(141.83 mg,0.63 mmol,3.0當量)、二噁烷(12 mL)及水(3 mL)合併且在100℃下於微波中攪拌1 h。所得混合物在真空下濃縮。藉由管柱層析法(方法E)純化殘餘物。將呈黃色油狀之4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-5-基]-1H-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H-1λ4-硫代哌喃-1-酮(70 mg,60%)分離;LC/MS (方法P): Rt 0.875 min, [MH]+ 425.2。
實例80:4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ4-硫代哌喃-1-酮
將4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-5-基]-1H-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H-1λ4-硫代哌喃-1-酮(60 mg,0.11 mmol,1.0當量)、二氯甲烷(5 mL)及三氟乙酸(1 mL)合併且在室溫下攪拌5 h。所得混合物在真空下濃縮。藉由製備型HPLC (方法J)純化粗產物。獲得20 mg呈紅色油狀之4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ4-硫代哌喃-1-酮(20 mg,32%);1
H NMR (400 MHz, 甲醇-d4
): δ 7.81 (s, 1H), 7.06 (d, J = 14.8 Hz, 2H), 5.95 (d, J = 4.6 Hz, 1H), 4.44 (d, J = 7.6 Hz, 1H), 4.11 (d, J = 26.7 Hz, 4H), 4.00 (d, J = 13.0 Hz, 1H), 3.92 -3.80 (m, 2H), 3.77 - 3.66 (m, 2H), 3.62 (dd, J = 18.3, 5.1 Hz, 1H), 3.47 (td, J = 12.5, 3.7 Hz, 1H), 3.39 (d, J = 12.8 Hz, 1H), 3.19 -2.97 (m, 2H), 2.79- 2.65 (m, 1H), 1.37 (d, J = 6.7 Hz, 3H);LC/MS (方法X): Rt 0.953 min, [MH]+ 413.1。
實例81:4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ6-硫代哌喃-1,1-二酮(81)
合成實例81之架構基塊:4-{1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-基}-3,6-二氫-2H-1λ6-硫代哌喃-1,1-二酮
將4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H-1λ4-硫代哌喃-1-酮(500 mg,1.30 mmol,1.0當量)、甲醇(20 mL)及過硫酸氫鉀(484 mg,2.73 mmol,2.10當量)於水(5 mL)中之溶液合併且在室溫下攪拌2 h。所得混合物在真空下濃縮。藉由管柱層析法(方法A)純化殘餘物。將呈黃色油狀之4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H-1λ6-硫代哌喃-1,1-二酮(500 mg,96%)分離;LC/MS (方法T): Rt 0.833 min, [MH]+ 363.2。
實例81:4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ6-硫代哌喃-1,1-二酮
類似於以上實例製備4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-3,6-二氫-2H
-1λ6-硫代哌喃-1,1-二酮且其以黃色固體形式(15 mg,25%)分離,熔點167-168℃;1
H NMR (400 MHz, 甲醇-d4
): δ 7.87 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.00 - 5.92 (m, 1H), 4.43 (d, J = 7.3 Hz, 1H), 4.16 (s, 3H), 4.09 (dd, J = 11.6, 3.8 Hz, 1H), 3.98 (d, J = 10.2 Hz, 3H), 3.89 - 3.81 (m, 2H), 3.73 -3.66 (m, 1H), 3.53 (dd, J = 12.6, 3.9 Hz, 1H), 3.45 (d, J = 6.3 Hz, 2H), 3.15 (s, 2H), 1.38 (d, J = 6.8 Hz, 3H); LC/MS (方法D): Rt 0.869min, [MH]+ 429.1。
實例82:4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-2H-1λ6-硫代哌喃-1,1-二酮(82)
4-[1-甲基-5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-5-基)-1H
-吡唑并[4,3-b]吡啶-7-基]-2H-1λ6-硫代哌喃-1,1-二酮且其以黃色固體形式(10 mg,16%)分離,熔點189-190℃;1
H NMR (400 MHz, 甲醇-d4
): δ 7.83 (d, J = 2.3 Hz, 1H), 7.07 (s, 1H), 6.98 (d, J = 2.2 Hz, 1H), 4.45 (d, J = 7.3 Hz, 1H), 4.36 (s, 3H), 4.10 (dd, J = 11.7, 3.7 Hz, 1H), 3.97 (d, J = 12.4 Hz, 1H), 3.91- 3.67 (m, 4H), 3.61 -3.47 (m, 3H), 3.22 (d, J = 13.9 Hz, 2H), 2.52- 2.38 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H); LC/MS (方法D): Rt 0.831 min, [MH]+ 431.1。
實例83:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[(吡啶-3-基)甲基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(83)
類似於以上實例製備(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[(吡啶-3-基)甲基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(6 mg;75%)分離;1
H NMR (700 MHz, DMSO-d6
): δ 8.82 - 8.80 (m, 1H), 8.76 - 8.74 (m, 1H), 8.16 - 8.13 (m, 2H), 7.82 (dd, J = 8.1, 5.4 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.16 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.83 (s, 2H), 4.44 - 4.40 (m, 1H), 4.02 (dd, J = 13.4, 2.8 Hz, 1H), 3.99 (dd, J = 11.3, 3.7 Hz, 1H), 3.76 (d, J = 11.1 Hz, 1H), 3.68 (dd, J = 11.2, 3.1 Hz, 1H), 3.53 (td, J = 11.7, 3.1 Hz, 1H), 3.15 (td, J = 12.7, 3.8 Hz, 1H), 1.16 (d, J = 6.7 Hz, 3H);LC/MS (方法R): Rt 0.483 min; [MH]+ 376.2。
實例84:(3R)-4-[7-(1,5-二甲基-1H
-1,2,3-三唑-4-基)-1-甲基-3-(1H
-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(84)
類似於以上實例製備(3R)-4-[7-(1,5-二甲基-1H
-1,2,3-三唑-4-基)-1-甲基-3-(1H
-吡唑-3-基)-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(34 mg;85%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.23 - 12.90 (m, 1H), 7.84 - 7.57 (m, 1H), 7.14 - 7.01 (m, 1H), 6.95 - 6.87 (m, 1H), 4.48 - 4.37 (m, 1H), 4.07 (s, 3H), 4.10 - 4.05 (m, 1H), 4.02 - 3.97 (m, 1H), 3.82 - 3.74 (m, 4H), 3.70 (dd, J = 11.3, 3.0 Hz, 1H), 3.55 (td, J = 11.7, 3.0 Hz, 1H), 3.21 - 3.13 (m, 1H), 2.40 - 2.37 (m, 3H), 1.18 (d, J = 6.6 Hz, 3H); LC/MS (方法C): Rt 0.877 min; [MH]+ 394.3。
實例85:2-甲基-1-{5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基}丙-2-醇(85)
用於合成實例85之架構基塊:2-{3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-1-基}乙酸甲酯
(3R)-4-[3-碘-1H-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(200 mg,0.52 mmol,1當量)、DMF (2 mL)、2-溴乙酸甲酯(126.33 mg,0.78 mmol,1.50當量)及Cs2
CO3
(358.76 mg,1.05 mmol,2.0當量)合併且在25℃下攪拌2 h。所得混合物在真空下濃縮。藉由管柱層析法(方法P)純化殘餘物。將呈黃色固體狀之2-[3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-1-基]乙酸甲酯分離。
用於合成實例85之架構基塊:2-{5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-1-基}乙酸甲酯
將2-[3-碘-5-[(3R)-3-甲基嗎啉-4-基]-1H-吡唑并[4,3-b]吡啶-1-基]乙酸甲酯(200 mg,0.43 mmol,1.0當量)、四氫呋喃(2 mL)、碳酸鈉(96.50 mg,0.86 mmol,2.當量)、水(0.2 mL)、1-(噁烷-2-基)-3-(四甲基-1,3,2-二氧硼㖦-2-基)-1H-吡唑(189.94 mg,0.65 mmol,1.50當量)及Pd(PPh3
)4
(55.53 mg,0.04 mmol,0.10當量)合併且在80℃下於微波中攪拌1 h。所得混合物在真空下濃縮。藉由管柱層析法(方法P)純化殘餘物。將呈黃色固體狀之2-[5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-1-基]乙酸甲酯(100 mg;48%)分離。
用於合成實例85之架構基塊:2-甲基-1-{5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-1-基}丙-2-醇
2-[5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-1-基]乙酸甲酯(90 mg,0.18 mmol,1.0當量)、四氫呋喃(1 mL)及溴基(甲基)鎂(461.62 mg,3.68 mmol,20當量)合併且在25℃下攪拌5 h。隨後藉由添加水來淬滅反應。所得混合物在真空下濃縮。藉由管柱層析法(方法P)純化殘餘物。將呈褐色固體狀之2-甲基-1-[5-[(3R)-3-甲基嗎啉-4-基]-3-[1-(噁烷-2-基)-1H-吡唑-3-基]-1H-吡唑并[4,3-b]吡啶-1-基]丙-2-醇(60 mg;68%)分離。
實例85:2-甲基-1-{5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基}丙-2-醇
類似於以上實例製備2-甲基-1-{5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基}丙-2-醇且其以無色固體形式(8 mg,22%)分離;熔點235-236℃;1
H NMR (400 MHz, 甲醇-d4
): δ 7.93 (d, J = 9.4 Hz, 1H), 7.66 (s, 1H), 7.07 (d, J = 9.4 Hz, 2H), 4.46 (d, J = 7.0 Hz, 1H), 4.35 (s, 2H), 4.10-3.99 (m, 2H), 3.84 (d,J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.1 Hz, 1H), 3.29 (d, J = 3.7 Hz, 1H), 1.27 (d, J = 10.4 Hz, 9H);LC/MS (方法E): Rt 1.034 min, [MH]+ 357.2。
實例86:2-甲基-2-{5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基}丙-1-醇(86)
類似於以上實例製備2-甲基-2-{5-[(3R)-3-甲基嗎啉-4-基]-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-1-基}丙-1-醇且其以黃色固體形式(50 mg,52%)分離,熔點210-212℃;1
H NMR (400 MHz, 甲醇-d4
): δ 8.11 (d, J = 9.5 Hz, 1H), 7.64 (s, 1H), 7.27-6.97 (m, 2H), 4.45 (d, J = 13.1 Hz, 1H), 4.09-3.97 (m, 4H), 3.84 (d, J = 2.2 Hz, 2H), 3.68 (td, J = 11.7, 3.0 Hz, 1H), 3.36-3.25 (m, 1H), 1.75 (s, 6H), 1.27 (d, J = 6.7 Hz, 3H); LC/MS (方法E): Rt 1.102 min, [MH]+ 357.2。
實例87:(3R)-3-甲基-4-[1-甲基-7-(4-甲基嘧啶-5-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(87)
類似於以上實例製備(3R)-3-甲基-4-[1-甲基-7-(4-甲基嘧啶-5-基)-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉且其以黃色固體形式(15 mg,20%)分離,熔點140-142℃;1
H NMR (300 MHz, DMSO-d6
): δ 9.17 (s, 1H), 8.76 (s, 1H), 7.63 (s, 1H), 7.01 (s, 1H), 6.96 (s, 1H), 4.44 (s, 1H), 4.14 - 3.90 (m, 2H), 3.72 (s, 2H), 3.65 - 3.52 (m, 1H), 3.50 (s, 3H), 3.25 (d, J = 10.7 Hz, 1H), 2.35 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H); LC/MS (方法A) Rt 1.146 min, [MH]+ 391.2。
實例88:(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[(吡啶-2-基)甲基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉(88)
類似於以上實例製備(3R)-3-甲基-4-[3-(1H
-吡唑-3-基)-1-[(吡啶-2-基)甲基]-1H
-吡唑并[4,3-b]吡啶-5-基]嗎啉鹽酸鹽且其以黃色固體形式(62 mg;92%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 8.60 - 8.57 (m, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.88 (td, J = 7.7, 1.8 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.17 - 7.13 (m, 2H), 7.08 (d, J = 2.0 Hz, 1H), 5.82 (s, 2H), 4.45 - 4.39 (m, 1H), 4.05 - 3.97 (m, 2H), 3.79 - 3.75 (m, 1H), 3.69 (dd, J = 11.3, 3.1 Hz, 1H), 3.54 (td, J = 11.4, 2.8 Hz, 1H), 3.17 (td, J = 12.9, 3.8 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H); LC/MS (方法C): Rt 0.875 min; [MH]+ 376.2。
實例89:(3R)-4-[7-(1-甲磺醯基乙基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉(89)
用於合成實例89之架構基塊:3-溴-7-(1-甲磺醯基-乙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶
將3-溴-7-甲磺醯基甲基-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(100 mg;0.25 mmol;1當量)、甲苯(1523 µl)、水(170 µl)、氫氧化鈉(199 mg;20.07當量)、四-正丁銨碘(8.24 mg;0.02 mmol;0.09當量)、二氯甲烷(170 µl)及碘甲烷(30.99 µl;0.50 mmol;2當量)合併且在80℃下攪拌3 h。用水及DCM萃取反應混合物。在減壓下濃縮合併有機層。將呈黃色固體狀之3-溴-7-(1-甲磺醯基-乙基)-1-甲基-5-((R)-3-甲基-嗎啉-4-基)-1H-吡唑并[4,3-b]吡啶(130 mg,55%)分離;LC/MS (方法F): Rt 2.433 min; [MH]+ 417.1。
實例89:(3R)-4-[7-(1-甲磺醯基乙基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉
類似於以上實例製備(3R)-4-[7-(1-甲磺醯基乙基)-1-甲基-3-(1H
-吡唑-3-基)-1H
-吡唑并[4,3-b]吡啶-5-基]-3-甲基嗎啉且其以黃色固體形式(20 mg,30%)分離;1
H NMR (500 MHz, DMSO-d6
): δ 13.42 - 12.64 (m, 1H), 7.68 - 7.62 (m, 1H), 7.04 (d, J = 5.0 Hz, 1H), 7.02 - 6.99 (m, 1H), 5.29 - 5.22 (m, 1H), 4.45 - 4.38 (m, 1H), 4.28 (s, 3H), 4.04 - 3.97 (m, 2H), 3.79 - 3.75 (m, 1H), 3.73 - 3.69 (m, 1H), 3.59 - 3.52 (m, 1H), 3.20 - 3.12 (m, 1H), 3.13 (d, J = 9.9 Hz, 3H), 1.85 (d, J = 6.9 Hz, 3H), 1.18 - 1.13 (m, 3H); LC/MS (方法F): Rt 2.022 min; [MH]+ 405.2。
以下實例係關於藥物:
實例 A : 注射小瓶
100 g式I活性成份及5 g磷酸氫二鈉於3 l重蒸餾水中之溶液,使用2 N鹽酸調節至pH 6.5,無菌過濾,轉移至注射小瓶中,在無菌條件下凍乾且在無菌條件下密封。各注射瓶含有5 mg活性成份。
實例 B : 栓劑
將20 g式I活性成份與100 g大豆卵磷脂及1400 g可可脂之混合物熔融,倒入模具中且使其冷卻。各栓劑含有20 mg活性成份。
實例 C : 溶液
溶液係由以下來製備:含1 g式I活性成份、9.38 g NaH2
PO4
∙ 2 H2
O、28.48 g Na2
HPO4
∙ 12 H2
O及0.1 g氯化苯甲烴銨之940 ml重蒸餾水。將pH調節至6.8,且溶液補足至1 l且藉由照射滅菌。此溶液可用於形成滴眼劑。
實例 D : 軟膏
在無菌條件下,將500 mg式I活性成份與99.5 g凡士林(Vaseline)混合。
實例 E : 錠劑
以習知方式壓製1 kg式I活性成份、4 kg乳糖、1.2 kg馬鈴薯澱粉、0.2 kg滑石及0.1 kg硬脂酸鎂之混合物,以使得各錠劑含有10 mg活性成份之方式得到錠劑。
實例 F : 糖衣藥丸
類似於實例E壓製錠劑且隨後以習知方式用蔗糖、馬鈴薯澱粉、滑石、黃蓍及染料包衣塗佈。
實例 G : 膠囊
以習知方式,以使得各膠囊含有20 mg活性成份之方式將2 kg式I活性成份引入硬明膠膠囊中。
實例 H : 安瓿
將1 kg 式I活性成份於60 l重蒸餾水中之溶液無菌過濾,轉移至安瓿中,在無菌條件下凍乾及在無菌條件下密封。各安瓿含有10 mg活性成份。
Claims (11)
- 一種式Ia或Ib化合物
- 如請求項1之化合物,其中Ar 表示苯基,其未經取代或經SOA、S(=O,=NH)A、SO2A、A、CN及/或(CH2)nOH單取代、二取代或三取代,及其醫藥學上可接受之鹽、水合物、互變異構體及立體異構體,包括其所有比率之混合物。
- 如請求項2之化合物,其中R1 表示H、Het、Ar、(CH2)nOH、1-甲磺醯基-環丙-1-基、CONH2、CONHA、CONA2、Cyc、OA或CH(A)SO2A,R2 表示H、A、(CH2)nAr、(CH2)nCyc或(CH2)nHet,R3 表示H或A,Het 表示1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、吲哚基、苯并咪唑基、咪唑基、1,2,3,4-四氫異喹啉基、吡啶基、嘧啶基、三唑基、吡唑基、喹啉基、異喹啉基、喹唑啉基、呋喃基、四氫呋喃基、哌喃基、3,6-二氫-2H-哌喃基、四氫哌喃基、3,6-二氫-2H-硫代哌喃基或六氫-硫代哌喃基,其中之每一者未經取代或經A、SOA、SO2A、Hal及/或 =O單取代、二取代或三取代,Ar 表示苯基,其未經取代或經SOA、S(=O,=NH)A、SO2A、A、CN及/或(CH2)nOH單取代、二取代或三取代,A 表示具有1-6個C原子之未分支或分支鏈烷基,其中1-7個H原子可經OH、F、Cl及/或Br置換及/或其中一或兩個不相鄰CH2基團可經O及/或NH基團置換,Cyc 表示具有3、4、5、6或7個C原子之環烷基,Hal 表示F、Cl、Br或I,n 表示0、1、2、3或4,及其醫藥學上可接受之鹽、水合物、互變異構體及立體異構體,包括其所有比率之混合物。
- 一種藥物,其包含至少一種如請求項1至4中任一項之化合物及/或其 醫藥學上可接受之鹽、水合物、互變異構體及立體異構體,包括其所有比率之混合物,及醫藥學上可接受之載劑、賦形劑或媒劑。
- 一種如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽、水合物、互變異構體或立體異構體、包括其所有比率之混合物之用途,其用於製備供治療及/或預防癌症、年齡相關之黃斑部變性(age-related macular degeneration,AMD)、脈絡膜新生血管(choroidal neovascularization,CNV)、糖尿病性視網膜病變、糖尿病性黃斑部水腫(diabetic macula edema,DME)、進行性骨化纖維發育不良及細菌感染之藥物。
- 一種如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽、水合物、互變異構體或立體異構體、包括其所有比率之混合物之用途,其用於製備供治療及/或預防炎症或血管生成相關病症之藥物。
- 如請求項6之用途,其中該癌症係選自以下之群:頭部癌、頸部癌、眼部癌、口腔癌、咽喉癌、食道癌、支氣管癌、喉癌、咽癌、胸部癌、骨癌、肺癌、結腸癌、直腸癌、胃癌、前列腺癌、膀胱癌、子宮癌、子宮頸癌、乳癌、卵巢癌、睾丸癌或其他生殖器官癌、皮膚癌、甲狀腺癌、血癌、淋巴結癌、腎臟癌、肝癌、胰臟癌、腦癌及中樞神經系統癌。
- 如請求項6之用途,其中該癌症係選自實體腫瘤或血源性腫瘤。
- 一種藥物,其包含至少一種如請求項1至4中任一項之化合物及/或其醫藥學上可接受之鹽、水合物、互變異構體及立體異構體,包括其所有比率之混合物,及至少一種另一藥物活性成份。
- 一種套組(set/kit),其由以下獨立封裝組成:(a)有效量之如請求項1至4中任一項之化合物及/或其醫藥學上可接受之鹽、水合物、互變異構體及立體異構體,包括其所有比率之混合物,及(b)有效量之另一藥物活性成份。
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CN117355524A (zh) * | 2021-05-21 | 2024-01-05 | 江苏恒瑞医药股份有限公司 | 一种吡唑并杂芳基类衍生物的可药用盐及其结晶形式 |
CA3220274A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
KR20240041354A (ko) | 2021-07-27 | 2024-03-29 | 릿츠뜨 메디시네스 엘티디 | 8-옥소-3-아자비시클로[3.2.1]옥탄계 화합물 또는 이의 염 및 이의 제조 방법과 용도 |
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CA3111878A1 (en) | 2020-03-12 |
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