TW201444797A - 治療化合物及組合物 - Google Patents
治療化合物及組合物 Download PDFInfo
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- TW201444797A TW201444797A TW103109338A TW103109338A TW201444797A TW 201444797 A TW201444797 A TW 201444797A TW 103109338 A TW103109338 A TW 103109338A TW 103109338 A TW103109338 A TW 103109338A TW 201444797 A TW201444797 A TW 201444797A
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
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- A61P35/02—Antineoplastic agents specific for leukemia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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- C07D495/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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Abstract
在此描述調節丙酮酸激酶之通式I化合物:□以及包含通式I化合物之組合物。在此還描述使用調節丙酮酸激酶的化合物來治療疾病之方法。
Description
本申請要求2013年3月15日提交的國際申請序號PCT/CN 2013/072688的優先權,其全部內容藉由引用結合在此。
丙酮酸激酶缺陷(PKD)係由於PKLR基因的常染色體隱性突變所導致的人類紅細胞中的最常見酶缺陷之一(紮納拉‧埃(Zanella,A.)等人,英國血液學雜誌(Br J Haematol)2005, 130(1),11-25)。它也是中心醣解途徑中的最經常的酶突變,並且僅次於磷酸己糖支路的葡萄糖-6磷酸脫氫酶(G6PD)缺陷(基達‧皮(Kedar,P.)等人,臨床遺傳學(Clin Genet)2009, 75(2),157-62)。
人類紅細胞是獨特的,因為它們在成熟是無核的。未成熟的紅細胞具有細胞核,但是在變成循環網狀細胞之前的早期紅細胞生成期間,它們將細胞核及其他細胞器如線粒體、內質網以及高基體擠出,以便為攜氧血紅蛋白騰出空間。由於缺乏線粒體,成熟的紅細胞無法像其他正常分化細胞那樣利用其轉運的任何氧來經濟地合成三磷酸腺苷(ATP)。替代地,紅細胞完全地依賴無氧醣解來使煙醯胺腺嘌呤二核苷酸(NAD+)循環以及製造ATP,其為主要用於驅動ATP酶依賴性K+/Na+以及Ca2+泵的主要能源,以便在紅細胞經由血管穿行時保持細胞膜完整性以及柔韌性。在PKD病症中,兩個主要不同的代謝異常係ATP耗竭以及與上游醣解中間物積聚一致的2,3-二磷酸甘油酸的伴隨增加。此外,ATP以及丙酮酸水平降低的後果之一係乳酸水平降低,從而導致不能經由乳酸脫氫酶來再生NAD+以便進一步用於醣解中。ATP的缺乏擾亂跨越紅細胞膜的陽離子梯度,從而導致鉀以及水
的損失,這導致細胞脫水、收縮以及皺縮,並且導致紅細胞(RBC)的過早破環以及壽命縮短。該等缺陷RBC在脾中被破壞,並且脾中的過量溶血率導致溶血性貧血顯現。PKD藉以將剛成熟的RBC隔離於脾中以便有效地縮短循環RBC的總半衰期的確切機制尚不清楚,但是最近的研究提示代謝失調不僅影響細胞存活,而且影響成熟過程,從而導致無效的紅細胞生成(相澤‧思(Aizawa,S.)等人,實驗血液學(Exp Hematol)2005, 33(11),1292-8)。
丙酮酸激酶催化磷醯基團從磷酸烯醇丙酮酸(PEP)轉移至ADP,從而產生一個丙酮酸分子及一個ATP分子。該酶具有對於Mg2+以及K+陽離子的絕對要求以便驅動催化。PK充當醣解中的最後關鍵步驟,因為它在生理條件下基本上是不可逆反應。除了它在葡萄糖至丙酮酸的代謝之中合成兩個ATP分子之一的作用以外,丙酮酸激酶也是重要的細胞代謝調控因數。它控制較低醣解中的碳通量以便提供關鍵代謝中間物,從而在維持健康細胞代謝的過程中為生物合成過程,如尤其戊糖磷酸途徑送料。由於該等關鍵功能,丙酮酸激酶在基因表達以及酶變構水平上受到嚴格控制。在哺乳動物中,完全活化的丙酮酸激酶作為四聚體酶而存在。四種不同的同功酶(M1、M2、L以及R)由兩個單獨基因來表達。紅細胞特異性同功酶PKR由位於染色體1q21上的PKLR基因(“L基因”)來表達。此同一基因也編碼PKL同功酶,它主要表達於肝中。PKLR由12個外顯子組成,其中外顯子1係紅細胞特異性的,而外顯子2係肝特異性的。兩種其他哺乳動物同功酶PKM1以及PKM2藉由受hnRNP蛋白質控制的替代性剪接事件由PKM基因(“M基因”)產生。PKM2同功酶表達於胎兒組織中以及成人增殖細胞(如癌細胞)中。PKR以及PKM2兩者實際上表達于原成紅細胞中。然而,紅細胞系分化以及成熟之後,PKM2逐漸地減少表達並且在成熟紅細胞中逐漸地被PKR取代。
在臨床上,遺傳性PKR缺陷病症顯現為非球形紅細胞溶血性貧血。此病症的臨床嚴重程度在完全補償的溶血之中的沒有可觀察到的症狀到在早期發展階段或在生理應激或嚴重感染期間的需要慢性輸血和/或脾切除術的潛在致死嚴重貧血的範圍內。自相矛盾的是,由於氧轉移能力增強,無症狀的大多數患病個體不需要任何治療。然而,對於一些最嚴重病例,雖然就人群而言極其罕見,估計發病率每百萬人中有51個(博伊特勒‧意(Beutler,E.)血液(Blood)2000, 95(11),3585-8),但除了姑息治療以外,沒有可用于該等患者的緩解疾病療法(塔瓦茲‧
蒂(Tavazzi,D.)等人,兒科年刊(Pediatr Ann)2008, 37(5),303-10)。該等遺傳性非球形紅細胞溶血性貧血(HNSHA)患者產生顯然未得到滿足的醫療需求。
PKR的異種遺傳突變導致其催化活性的失調。自從最初克隆PKR以及報告與HNSHA患者相關的單一點突變Thr384>Met(菅野‧何(Kanno,H.)等人,美國國家科學院院刊(Proc Natl Acad Sci U S A)1991, 88(18),8218-21),現在全世界報告了與此疾病相關的將近200種不同的報告突變(紮納拉‧埃(Zanella,A.)等人,英國血液學雜誌(Br J Haematol)2005, 130(1),11-25;基達‧皮(Kedar,P.)等人,臨床遺傳學(Clin Genet)2009, 75(2),157-62;費爾莫‧意(Fermo,E.)等人,英國血液學雜誌(Br J Haematol)2005, 129(6),839-46;皮薩爾‧思(Pissard,S.)等人,英國血液學雜誌(Br J Haematol)2006, 133(6),683-9)。雖然該等突變代表包括缺失以及轉錄或翻譯異常的廣泛範圍遺傳病變,但是迄今最常見類型係編碼區域中的錯義突變,其以某種方式或另一方式影響對於PKR的最佳催化功能來說在結構上至關重要的結構域內的保守殘基。突變發生模式似乎相對於特定種族背景不均勻地分佈。例如,對於北美以及歐洲患者報告的最經常密碼子取代似乎是Arg486>Trp以及Arg510>Gln,而突變Arg479>His、Arg490>Trp以及Asp331>Gly更經常地發現于亞洲患者中(基達‧皮(Kedar,P.)等人,臨床遺傳學(ClinGenet)2009, 75(2),157-62)。
癌細胞主要依賴醣解來產生細胞能量以及生物化學中間物以便生物合成脂質以及核苷酸,而成體組織中的大部分“正常”細胞利用需氧呼吸。癌細胞與正常細胞之間這一細胞代謝上的根本差異被稱為瓦伯格氏效應(Warburg Effect),其已用於診斷用途,但是尚未用於治療益處。
丙酮酸激酶(PK)係在醣解期間將磷酸烯醇丙酮酸轉化成丙酮酸的代謝酶。四個PK同種型存在於哺乳動物中:L以及R同種型表達於肝以及紅細胞中,M1同種型表達于大多數成體組織中,並且M2同種型係在胚胎發育期間表達的M1的剪接變異體。所有腫瘤細胞僅表達胚胎M2同種型。PK的M1與M2同種型之間的眾所周知的差異係M2係依賴上游醣解中間物果糖-1,6-二磷酸(FBP)的變構活化的低活性酶,而M1係組成性活性酶。
所有腫瘤細胞僅表達丙酮酸激酶的胚胎M2同種型,表明PKM2係癌症療法的
潛在靶標。PKM2還表達於脂肪組織以及活化T-細胞中。磷酸酪胺酸肽結合至PKM2導致FBP與PKM2的分離以及PKM2從活性、四聚體形式到無活性形式的構形變化。結合至PKM2並且將該酶鎖定於活性構型中的化合物將導致PKM2的變構控制的損失,這種變構控制係將來自醣解的生物化學中間物分流至核苷酸以及脂質的生物合成中所需要的。因此,PKM2的活化可抑制癌細胞、活化免疫細胞以及脂肪細胞的生長以及增殖。因此,PKM2的活化可有效治療癌症、肥胖、糖尿病、自身免疫病狀以及增殖依賴性疾病,例如良性前列腺增生(BPH)。
在此描述活化丙酮酸激酶之化合物及其藥學上可接受的鹽、溶劑合物以及水合物,例如,活化PKR和/或PKM2之化合物。
還提供包含在此提供的化合物之藥物組合物以及這類組合物在治療與丙酮酸激酶功能(例如PKR功能和/或PKM2功能)相關疾病以及病狀(包括例如癌症、糖尿病、肥胖、自身免疫病症以及良性前列腺增生(BPH))之方法中之用途。
在一個實施方式中,在此提供式(I)化合物:
,或其藥學上可接受的鹽,其中:
A係芳基或雜芳基,其中芳基或雜芳基任選地被取代,並且芳基或雜芳基任選地稠合至任選地被取代的碳環基或任選地被取代的雜環基;X選自-NH-S(O)2-、-S(O)2-NH-、-NH-S(O)2-CH2-、-CH2-S(O)-NH-、-NH-S(O)-CH2-、-NH-S(O)-、-S(O)-NH-或-CH2-S(O)2-NH-;Y係C(H)或N;其條件係不超過兩個Y基團係N;R1a係羥基、-CH2OH、-CHO、-CO2H、-N(R10a)2、-CO2-C1-6烷基、-OP(=O)(OH)2或-OCO2-CH2-OP(=O)(OH)2;R1b係任選地被一個至四個R5基團取代的C1-8烷基;任選地被一個至四個R5
基團取代的C1-8烯基;環烷基;雜環;芳基;雜芳基;環烷基烷基;環烷基烯基;雜環基烷基;雜環基烯基;芳烷基;芳烯基;雜芳烷基;雜芳烯基;或-OH,其條件係當R1a係OH時,R1b不是OH;其中環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基各自任選地被取代;每個R2獨立地選自鹵基、烷基、CN、OH以及烷氧基,其中所述烷基或烷氧基任選地被一個至四個R5基團取代;或兩個相鄰R2基團與其連接的環原子結合在一起形成5-或6-員碳環、芳基、雜環或雜芳基環;每個R4獨立地選自鹵基、烷基、烷氧基、鹵代烷基、鹵代烷氧基以及羥基;每個R5獨立地選自鹵基、OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基),以及-N(C1-6烷基)2;每個R10a獨立地選自氫或C1-6烷基;n係0、1、2或3;並且m係0、1或2;其條件係式(I)化合物並非以下化合物:(1)4-[[4-羥基-4-(4-甲基苯基)-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(2)4-[[4-(4-氯苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(3)4-[[4-(3-氟苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(4)4-[[4-(2-氟-5-甲基苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(5)4-苯基-1-[4-[(苯胺基)磺醯基]苯甲醯基]-4-哌啶甲酸甲酯;(6)1-[4-[[(2-甲基苯基)胺基]磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸甲酯;或(7)N-(4-氟苯基)-4-[[4-羥基-4-(甲氧基甲基)-1-哌啶基]羰基]-苯磺醯胺。
在另一個實施方式中,提供用於治療或預防(例如,治療)如在此描述的疾病、病狀或病症之方法,其包括給予在此提供的化合物、其藥學上可接受的鹽、溶劑合物或水合物,或其藥物組合物。
在另一個實施方式中,提供用於增加有需要的紅細胞(RBC)的壽命之方法,其包括使血液與有效量的以下物質接觸:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露的化合物或其鹽、溶劑合物或水合物以及載體的組合物;或(3)包含在此揭露的化合物或其藥學上可接受的鹽、
溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於調控有需要的血液中的2,3-二磷酸甘油酸水平的方法,其包括使血液與有效量的以下物質接觸:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其鹽、溶劑合物或水合物以及載體的組合物;或(3)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療遺傳性非球形紅細胞溶血性貧血的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療鐮狀細胞性貧血的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療溶血性貧血(例如由磷酸甘油酸激酶缺陷引起的慢性溶血性貧血,血細胞、分子與疾病(Blood Cells Mol Dis),2011;46(3):206)的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療與2,3-二磷酸甘油酸水平增加相關疾病或病狀(例如,肝病(美國胃腸病學雜誌(Am J Gastroenterol),1987;82(12):1283)以及帕金森氏病(Parkinson’s)(神經病學、神經外科以及精神病學雜誌(J.Neurol,Neurosurg,and Psychiatry)1976,39:952)之方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療地中海貧血(例如,β-地中海貧血)、遺傳性球形紅細胞症、遺傳性橢圓形紅細胞增多症、無β脂蛋白血症(或巴-科
二氏綜合征(Bassen-Kornzweig syndrome))、陣發性夜間血紅蛋白尿症、獲得性溶血性貧血(例如,先天性貧血(例如,酶病))或慢性疾病性貧血之方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療與2,3-二磷酸甘油酸水平增加相關的疾病或病狀(例如,肝病(美國胃腸病學雜誌(Am J Gastroenterol),1987;82(12):1283)以及帕金森氏病(Parkinson’s)(神經病學、神經外科以及精神病學雜誌(J.Neurol,Neurosurg,and Psychiatry)1976,39:952)之方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在此描述的化合物以及組合物係與野生型相比具有較低活性的PKR突變體之活化劑,因而可用于本發明的方法。PKR中的這類突變可影響酶活性(催化效率)、調控性質(藉由果糖二磷酸(FBP)/ATP進行的調節),和/或酶的熱穩定性。這類突變的實例描述於瓦倫蒂尼(Valentini)等人,JBC 2002中。由在此描述的化合物活化的突變體的一些實例包括G332S、G364D、T384M、G37E、R479H、R479K、R486W、R532W、R510Q以及R490W。不受理論約束,在此描述的化合物藉由活化FBP無反應PKR突變體、恢復穩定性降低的突變體的熱穩定性,或恢復受損突變體的催化效率來影響PKR突變體的活性。本發明化合物針對PKR突變體的活化活性可遵循實例2-5中描述的方法來測試。在此描述的化合物也是野生型PKR的活化劑。
在一個實施方式中,為了增加紅細胞壽命,將在此描述的化合物、組合物或藥物組合物直接地體外地添加至全血或疊集細胞或直接地(例如,藉由腹膜內、靜脈內、肌肉內、口服、吸入(霧化遞送)、經皮、舌下及其他遞送途徑)提供至受試者(例如,患者)。不受理論約束,在此描述的化合物藉由影響2,3-DPG從血液中的釋放速率來增加RBC壽命,由此抵消貯藏血液的老化。2,3-DPG濃度水平的降低誘導氧-血紅蛋白解離曲線的左移並且使變構平衡偏移至R,或氧化狀態,從而由於2,3-DPG耗竭而增加氧親和力,進而對於作為鐮狀細胞形成的基礎
的細胞內聚合產生治療性抑制,由此使更大可溶性的氧基-血紅蛋白穩定化。因此,在一個實施方式中,在此描述的化合物以及藥物組合物可用作抗鐮狀細胞形成劑。在另一個實施方式中,為了調控2,3-二磷酸甘油酸,將在此描述的化合物、組合物或藥物組合物直接地體外地添加至全血或疊集細胞或直接地(例如,藉由腹膜內、靜脈內、肌肉內、口服、吸入(霧化遞送)、經皮、舌下及其他遞送途徑)提供至受試者(例如,患者)。
在另一個實施方式中,提供增加有需要的患者體內的PKM2活性和/或醣解水平之方法。該方法包括將有效量的在此描述的化合物給予有需要的患者,從而增加患者體內的PKM2活性和/或醣解水平的步驟。在一些實施方式中,在此描述的化合物或組合物用於將PKM2保持於其活性構型或活化增殖細胞中的丙酮酸激酶活性,作為將患者體內的葡萄糖代謝物轉向分解代謝而非合成代謝過程的手段。
在另一個實施方式中,提供抑制有需要的患者體內的細胞增殖之方法。該方法包括將有效量的在此描述的化合物給予有需要的患者,從而抑制患者體內的細胞增殖的步驟。在一方面,此方法可抑制轉化細胞,更具體地說癌細胞的生長。在另一方面,該方法總體上抑制經歷有氧醣解的PKM2依賴性細胞的生長。
在另一個實施方式中,提供在有需要的患者中治療患有或易患與PKM2活性降低或醣解減少相關的疾病或病症的患者之方法。該方法包括將有效量的在此描述的化合物給予有需要的患者,從而治療、預防或緩解患者的疾病或病症的步驟。在某些實施方式中,在此描述的化合物以藥物組合物形式來提供。在某些實施方式中,該方法包括在治療之前識別或選擇將受益於PKM2活化的患者的步驟。識別或選擇這類患者可基於患者的細胞中的PKM2活性水平。在一方面,所選擇的患者患有或易患不需要的細胞生長或增殖,例如癌症、肥胖、糖尿病、動脈粥樣硬化、再狹窄以及自身免疫疾病。在另一方面,所選擇的患者患有與PKM2功能相關的癌症。
在另一個實施方式中,在此描述的化合物在足以增加乳酸產生或氧化磷酸化的劑量以及頻率下來給予。
在以下描述中闡明或在附圖中示出的組分的構建以及佈置的細節不意欲具有限制性。實施方式可以不同的方式來實施或執行。另外,在此使用的措辭以及術語係出於描述目的並且不應視為具有限制性。“包括”、“包含”或“具有”、“含有”、“涉及”及其在此的變化形式的使用意欲涵蓋其後列出之項目及其等效物以及額外項目。
術語“鹵基”或“鹵素”係指氟、氯、溴或碘的任何基團。
術語“烷基”係指可為直鏈或支鏈的一價烴鏈,其含有所指示數量碳原子。舉例來說,C1-C12烷基指示該基團可在其中具有從1至12個(包括在內)碳原子。在某些方面,術語“烷基”係指可為直鏈或支鏈的一價烴鏈,其含有1至6個碳原子。在其他方面,術語“烷基”係指可為直鏈或支鏈的一價烴鏈,其含有1至4個碳原子。
術語“鹵代烷基”係指一個或多個氫原子由鹵基來置換之烷基,並且包括所有氫由鹵基來置換的烷基部分(例如,全氟烷基)。術語“鹵代烷氧基”係指一個或多個氫原子由鹵基來置換的烷氧基。
術語“烯基”係指含有2-12個碳原子並且具有一個或多個雙鍵的一價直鏈或支鏈烴鏈。烯基的實例包括但不限於烯丙基、丙烯基、2-丁烯基、3-己烯基以及3-辛烯基。一個雙鍵碳可任選地為烯基取代基的連接點。在某些方面,術語“烯基”係指含有2-6個碳原子並且具有一個或多個雙鍵的一價直鏈或支鏈烴鏈。在其他方面,術語“烯基”係指含有2-4個碳原子並且具有一個或多個雙鍵的一價直鏈或支鏈烴鏈。
術語“烷氧基”係指-O-烷基。
術語“芳基”係指單環、雙環或三環芳烴環系統。芳基部分之實例包括但不限於苯基、萘基以及蒽基。
術語“芳基烷基”或“芳烷基”係指烷基氫原子由芳基來置換的烷基部分。芳烷基包括一個以上氫原子已經由芳基置換的基團。
“芳基烷基”或“芳烷基”的實例包括苄基、2-苯基乙基、3-苯基丙基、9-芴基、二苯甲基以及三苯甲基。
術語“碳環基”係指非芳香族、單環、雙環或三環烴環系統。碳環基包括完全飽和環系統(例如,環烷基),以及部分飽和環系統。
術語“環烷基”或“碳環基”係指具有3至12個碳的飽和或不飽和環狀、雙環、三環或多環非芳香烴基團。環烷基部分的實例包括但不限於環丙基、環己基、甲基環己基、金剛烷基以及降冰片烷基。
術語“雜芳基”係指完全芳香族5-8員單環、8-12員雙環或11-14員三環系統,其如果係單環則具有1-3個雜原子,如果係雙環則具有1-6個雜原子,或如果係三環則具有1-9個雜原子,所述雜原子選自O、N或S(例如,如果係單環、雙環或三環則分別具有碳原子以及獨立地選自N、O或S的1-3個、1-6個或1-9個雜原子)。
術語“雜環基”係指飽和或不飽和的3-10員非芳香族單環、8-12員非芳香族雙環或11-14員非芳香族三環系統,其如果係單環則具有1-3個雜原子,如果係雙環則具有1-6個雜原子,或如果係三環則具有1-9個雜原子,所述雜原子選自O、N或S(例如,如果係單環、雙環或三環則分別具有碳原子以及1-3個、1-6個或1-9個N、O或S雜原子)。雜原子可任選地為雜環基取代基的連接點。雜環基的實例包括但不限於四氫呋喃基、四氫吡喃基、哌啶基、啉代、吡咯啉基、嘧啶基以及吡咯烷基。
含有一個或多個雜原子以及芳香族以及非芳香族環的雙環以及三環系統被認為是根據本發明定義的雜環基。這類雙環或三環系統被認為是稠合至碳環基或雜環基的芳基或雜芳基,其中結合至分子的其餘部分的環需要是芳香族。
如在此使用,術語“雜芳基烷基”以及“雜芳烷基”係指被雜芳基取代的烷基。
如在此使用,術語“雜環基烷基”係指被雜環基取代的烷基。
所有環系統(即,芳基、雜芳基、碳環基、環烷基、雜環基等)或基團的環系統部分(例如,芳烷基的芳基部分)任選地在一個或多個可取代碳原子處被獨立地選自以下基團的取代基取代:鹵基、-C≡N、C1-C4烷基、=O、C3-7環烷基、
C1-6烷基、-OH、-O-(C1-6烷基)、-SO2-(C1-6烷基)、-(C1-4烷基)-N(Ro)(Ro)、-N(Ro)(Ro)、-O-(C1-4烷基)-N(Ro)(Ro)、-C(O)-N(Ro)(Ro)、-(C1-4烷基)-C(O)-N(Ro)Ro)、-O-(雜芳基)、-O-(雜環)、-O-苯基、-雜芳基、-雜環以及-苯基,其中:每個Ro獨立地選自氫以及-C1-4烷基;或兩個Ro與其結合的氮原子結合在一起以便形成4-至8-員飽和雜環,該雜環任選地包含選自N、S、S(=O)、S(=O)2以及O的一額外雜原子,任何烷基取代基任選地進一步被以下基團中的一個或多個取代:-OH、-O-(C14烷基)、鹵基、-NH2、-NH(C1-4烷基)或-N(C1-4烷基)2;並且苯基、環烷基、雜芳基或雜環取代基上的任何碳原子任選地進一步被以下基團中的一個或多個取代:-(C1-C4烷基)、-(C1-4氟烷基)、-OH、-O-(C1-4烷基)、-O-(C1-4氟烷基)、鹵基、-NH2、-NH(C1-4烷基)或-N(C1-4烷基)2。
所有雜環基環系統(以及任何環系統上的任何雜環基取代基)任選地在一個或多個任何可取代氮原子處被-C1-4烷基或氟基-取代的C1-4烷基取代。
術語“取代”係指氫原子被另一個基團置換。
術語“側氧基”係指氧原子,其在連接至碳時形成羰基,在連接至氮時形成N-氧化物,並且在連接至硫時形成亞碸或碸。
與PKM2活化劑相關的術語“選擇性”係指比PKM1大至少2倍、3倍、4倍、5倍、6倍或10倍的PKM2的活化。
如在此使用的術語丙酮酸激酶R的“活化劑”係指(可測量地)增加野生型丙酮酸激酶R(wtPKR)的活性或導致野生型丙酮酸激酶R(wt PKR)活性增加至大於wt PKR基礎活性水平的水平的試劑或(可測量地)增加突變型丙酮酸激酶R(mPKR)的活性或導致突變型丙酮酸激酶R(mPKR)活性增加至大於突變型PKR基礎活性水平的水平的試劑,例如,增加至野生型PKR的活性的20%、40%、50%、60%、70%、80%、90%或100%的水平。
如在此使用的術語丙酮酸激酶M2的“活化劑”係指(可測量地)增加PKM2的活性或導致PKM2活性增加至大於PKM2基礎活性水平的水平的試劑。舉例來說,活化劑可模擬由天然配位基(例如,FBP)產生的效果。由在此提供的化合物產生的活化劑效果可為與由天然配位基產生的活化效果相比相同,或更大,或更小的程度,但是產生相同類型的效果。在此提供的化合物可藉由直接地或間接
地測量經受所述化合物的丙酮酸激酶的活性來評估以便確定其是否為活化劑。PKM2的活性可例如藉由監測底物如ATP或NADH的濃度來測量。
縮寫Me、Et、pH、Tf、Nf、Ts、Ms分別代表甲基、乙基、苯基、三氟甲烷磺醯基、九氟丁烷磺醯基、對甲苯磺醯基以及甲烷磺醯基。由本領域的普通技能的有機化學家所使用的縮寫的更全面列表出現於有機化學雜誌(Journal of Organic Chemistry)的每一卷的第一期中;此清單通常呈現於題為標準縮寫清單的表格中。包含於所述列表中的縮寫,以及由本領域的普通技能的有機化學家所使用的所有縮寫藉由引用結合在此。
在此提供如上文在發明概述中所述的式(I)化合物或其藥學上可接受的鹽、溶劑合物或水合物,例如其適用於活化野生型PKR和/或各種突變型PKRs,如在此描述的那些突變體,且/或適用於選擇性活化PKM2。
在一個實施方式中,在此提供式(I)化合物:
,或其藥學上可接受的鹽,其中:
A係芳基或雜芳基,其中芳基或雜芳基任選地被取代,並且芳基或雜芳基任選地稠合至任選地被取代的碳環基或任選地被取代的雜環基;X選自-NH-S(O)2-、-S(O)2-NH-、-NH-S(O)2-CH2-、-CH2-S(O)-NH-、-NH-S(O)-CH2-、-NH-S(O)-、-S(O)-NH-或-CH2-S(O)2-NH-;Y係C(H)或N;其條件係不超過兩個Y基團係N;R1a係羥基、-CH2OH、-CHO、-CO2H、-N(R10a)2、-CO2-C1-6烷基、-OP(=O)(OH)2或-OCO2-CH2-OP(=O)(OH)2;R1b係任選地被一個至四個R5基團取代的C1-8烷基;任選地被一個至四個R5基團取代的C1-8烯基;環烷基;雜環;芳基;雜芳基;環烷基烷基;環烷基烯基;雜環基烷基;雜環基烯基;芳烷基;芳烯基;雜芳烷基;雜芳烯基;或-OH,其條件係當R1a是OH時,R1b不是OH;其中每個環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基任選地被取代;
每個R2獨立地選自鹵基、烷基、CN、OH和烷氧基,其中所述烷基或烷氧基任選地被一個至四個R5基團取代;或兩個相鄰R2基團與其連接的環原子結合在一起形成5-或6-員碳環、芳基、雜環或雜芳基環;每個R4獨立地選自鹵基、烷基、烷氧基、鹵代烷基、鹵代烷氧基和羥基;每個R5獨立地選自鹵基、OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基)以及-N(C1-6烷基)2;每個R10a獨立地選自氫或C1-6烷基;n係0、1、2或3;並且m係0、1或2;其條件係式(I)化合物並非以下化合物:(1)4-[[4-羥基-4-(4-甲基苯基)-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(2)4-[[4-(4-氯苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(3)4-[[4-(3-氟苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(4)4-[[4-(2-氟-5-甲基苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(5)4-苯基-1-[4-[(苯胺基)磺醯基]苯甲醯基]-4-哌啶甲酸甲酯;(6)1-[4-[[(2-甲基苯基)胺基]磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸甲酯;或(7)N-(4-氟苯基)-4-[[4-羥基-4-(甲氧基甲基)-1-哌啶基]羰基]-苯磺醯胺。
在一個實施方式中,在此提供式(I)化合物:
,或其藥學上可接受的鹽,其中:
A係芳基或雜芳基,其中芳基或雜芳基任選地被取代,並且芳基或雜芳基任選地稠合至任選地被取代的碳環基或任選地被取代的雜環基;X選自-NH-S(O)2-、-NH-S(O)2-CH2-、-CH2-S(O)-NH-或-CH2-S(O)2-NH-;Y係C(H)或N;其條件係不超過兩個Y基團係N;R1a係羥基、-CH2OH、-CHO、-CO2H或-CO2-C1-6烷基;R1b係任選地被一個至四個R5基團取代的C1-8烷基;任選地被一個至四個R5基團取代的C1-8烯基;環烷基;雜環;芳基;雜芳基;環烷基烷基;環烷基烯基;雜環基烷基;雜環基烯基;芳烷基;芳烯基;雜芳烷基;雜芳烯基;或-OH,其
條件係當R1a係OH時,R1b不是OH;其中每個環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基任選地被取代;每個R2獨立地選自鹵基、烷基、CN、OH和烷氧基,其中所述烷基或烷氧基任選地被一個至四個R5基團取代;或兩個相鄰R2基團與其連接的環原子結合在一起形成5-或6-員碳環、芳基、雜環或雜芳基環;每個R4獨立地選自鹵基、烷基、烷氧基、鹵代烷基、鹵代烷氧基和羥基;每個R5獨立地選自鹵基、OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基)以及-N(C1-6烷基)2;n係0、1、2或3;並且m係0、1或2;其條件係式(I)化合物並非以下化合物:(1)4-[[4-羥基-4-(4-甲基苯基)-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(2)4-[[4-(4-氯苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(3)4-[[4-(3-氟苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(4)4-[[4-(2-氟-5-甲基苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(5)4-苯基-1-[4-[(苯胺基)磺醯基]苯甲醯基]-4-哌啶甲酸甲酯;(6)1-[4-[[(2-甲基苯基)胺基]磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸甲酯;(7)1-[4-[甲基[(4-甲基苯基)磺醯基]胺基]苯甲醯基]-4-苯基-4-哌啶甲酸;(8)1-[4-[(甲基苯胺基)磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸;(9)1-[4-[(環丙胺基)磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸;或(10)4-苯基-1-[4-[[(2-噻吩基甲基)胺基]磺醯基]苯甲醯基]-4-哌啶甲酸甲酯。
在一個實施方式中,提供式(I)化合物,其中m係1。在該等實施方式的一些方面,R4係羥基。
在一個實施方式中,提供式(I)化合物,其中m係0(即,在哌啶基環上沒有R4取代基)並且R1a係羥基,該化合物具有式(Ia):
(其中每個Y係CH),或其藥學上可接受的鹽,
其中A、X、R1b、R2以及n如對於式(I)所描述。
在式(I)或(Ia)的某些方面,n係0。在式(I)或(Ia)的某些方面,n係1。在一個更具體方面,R2係C1-6烷基(例如甲基)。在另一個更具體方面,R2係C1-6烷氧基(例如甲氧基)。在另一個更具體方面,R2係鹵基(例如氟基或氟)。在另一個更具體方面,R2係C4鹵代烷氧基(例如三氟甲氧基或二氟甲氧基)。在另一個更具體方面,R2係氰基。
在式(I)或(Ia)的某些方面,n係2。在一個更具體方面,兩個R2部分與其連接的原子結合在一起形成任選地被取代的環基(例如,未被取代的苯基、未被取代的異噻唑基)。在另一個更具體方面,每個R2部分係鹵基(例如氟基)。
在式(I)或(Ia)的某些方面,A係任選地被取代的單環芳基。在一個更具體方面,A係任選地被取代的苯基(例如,2,3-二氯苯基、2-氯苯基、3-氯苯基、4-氯苯基、3-氰基苯基、4-氰基苯基、2-三氟甲基苯基、3-三氟甲基苯基、4-三氟甲基苯基、3-三氟甲氧基苯基、4-三氟甲氧基苯基、2,3-二胺基-4-氟苯基)。在式(I)或(Ia)的某些方面,A係任選地被取代的雙環芳基。在一個更具體方面,A係任選地被取代的萘基(例如未被取代的萘基)。
在式(I)或(Ia)的某些方面,A係任選地被取代的單環雜芳基。在一個更具體方面,A係任選地被取代的吡啶基(例如任選地被取代的3-吡啶基或任選地被取代的2-吡啶基)。在一個甚至更具體方面,A係未被取代的3-吡啶基。在一個甚至更具體方面,A係未被取代的2-吡啶基。
在式(I)或(Ia)的某些方面,A係任選地被取代的雙環雜芳基。在一個更具體方面,A係任選地被取代的喹啉-8-基(例如未被取代的喹啉-8-基)。在另一個更具體方面,A係被取代的喹啉-8-基(例如,2-氟喹啉-8-基、3-氟喹啉-8-基、5-氟喹啉-8-基或6-氟喹啉-8-基)。在另一個更具體方面,A係任選地被取代的喹啉-3-基(例如,未被取代的喹啉-3-基)。在另一個更具體方面,A係任選地被取代的喹啉-5-基(例如,未被取代的喹啉-5-基或2-氟喹啉-5-基)。在另一個更具體方面,A係任選地被取代的異喹啉-5-基(例如,未被取代的異喹啉-5-基)。在另一個更具體方面,A係任選地被取代的喹啉-5-基(例如,未被取代的喹啉-5-基)。在另一個更具體方面,A係被取代的喹啉-5-基(例如,2-氟喹啉-5-基)。在另一個更具體方面,A係任選地被取代的苯並[1,2,5]二唑(例如,未被取代的苯並
[1,2,5]二唑)。在另一個更具體方面,A係任選地被取代的喹啉-5-基(例如,未被取代的喹啉-5-基或8-羥基喹啉-5-基)。在另一個更具體方面,A係被取代的喹啉-5-基(例如,8-氟喹啉-5-基或8-羥基喹啉-5-基)。在另一個更具體方面,A係任選地被取代的色滿基(例如,色滿-8-基)。在另一個更具體方面,A係任選地被取代的2,3-二氫苯並[b][1,4]二基(例如,未被取代的2,3-二氫苯並[b][1,4]二-5-基)。在另一個更具體方面,A係任選地被取代的苯並[d]噻唑-4-基(例如,未被取代的苯並[d]噻唑-4-基、6-氟苯並[d]噻唑-4-基、7-氟苯並[d]噻唑-4-基、2-甲基苯並[d]噻唑-4-基或2-胺基-6-氟苯並[d]噻唑-4-基)。在另一個更具體方面,A係任選地被取代的苯並呋喃基(例如,苯並呋喃-7-基)。在另一個更具體方面,A係任選地被取代的苯並[1,2,5]噻二唑-5-基(例如,未被取代的苯並[1,2,5]噻二唑-5-基)。在另一個更具體方面,A係任選地被取代的苯並[1,2,5]噻二唑-4-基(例如未被取代的苯並[1,2,5]噻二唑-4-基)。在另一個更具體方面,A係任選地被取代的苯並[c]噻唑基(例如未被取代的苯並[c]噻唑-4-基)。在另一個更具體方面,A係任選地被取代的1,2,3,4-四氫喹啉-8-基(例如未被取代的1,2,3,4-四氫喹啉-8-基)。在另一個更具體方面,A係任選地被取代的1H-吲哚-2(7aH)-酮-5-基(例如1-甲基-1H-吲哚-2(7aH)-酮-5-基)。在另一個更具體方面,A係任選地被取代的噻吩並[3,2-b]吡啶-3-基(例如未被取代的噻吩並[3,2-b]吡啶-3-基)。在另一個更具體方面,A係任選地被取代的苯並[1,3]間二氧雜環戊烯-5-基(例如未被取代的苯並[1,3]間二氧雜環戊烯-5-基或2,2-二氟苯並[1,3]間二氧雜環戊烯-5-基)。在另一個更具體方面,A係任選地被取代的苯並[d]噻唑-7-基(例如未被取代的苯並[d]噻唑-7-基或6-甲基苯並[d]噻唑-7-基或6-氟苯並[d]噻唑-7-基)。在另一個更具體方面,A係任選地被取代的噌啉-8-基(例如未被取代的噌啉-8-基)。在另一個更具體方面,A係任選地被取代的咪唑並[1,2-a]吡啶-8-基(例如未被取代的咪唑並[1,2-a]吡啶-8-基)。在另一個更具體方面,A係任選地被取代的噻唑並[5,4-b]吡啶-7-基(例如未被取代的噻唑並[5,4-b]吡啶-7-基)。在另一個更具體方面,A係任選地被取代的1H-吡咯並[3,2-b]吡啶-3-基(例如未被取代的1H-吡咯並[3,2-b]吡啶-3-基)。在另一個更具體方面,A係任選地被取代的1H-吡咯並[2,3-b]吡啶-1-基(例如未被取代的1H-吡咯並[2,3-b]吡啶-1-基)。在另一個更具體方面,A係任選地被取代的苯並[d]唑-2(3H)-酮-6-基(例如3-甲基苯並[d]唑-2(3H)-酮-6-基)。在另一個更具體
方面,A係任選地被取代的苯並[c]異噻唑-7-基(例如未被取代的苯並[c]異噻唑-7-基)。
在式(I)、(Ia)或(Ib)的某些方面,A係:
在另一實施方式中,在此提供式(Ib)化合物:
或其藥學上可接受的鹽,其中:A係芳基或雜芳基,其中芳基或雜芳基任選地被取代,並且芳基或雜芳基稠合至任選地被取代的碳環基或任選地被取代的雜環基;R1b係任選地被一個至四個R5基團取代的C1-8烷基;任選地被一個至四個R5基團取代的C1-8烯基;環烷基;雜環;芳基;雜芳基;環烷基烷基;環烷基烯基;雜環基烷基;雜環基烯基;芳烷基;芳烯基;雜芳烷基;雜芳烯基;或-OH,其條件係當R1a係OH時,R1b不是OH;其中每個環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基任選地被取代;每個R2獨立地選自鹵基、烷基、CN、OH和烷氧基,其中所述烷基或烷氧基任選地被一個至四個R5基團取代;或兩個相鄰R2基團與其連接的環原子結合在一起形成5-或6-員碳環、芳基、
雜環或雜芳基環;每個R4獨立地選自鹵基、烷基、烷氧基、鹵代烷基、鹵代烷氧基和羥基;每個R5獨立地選自鹵基、OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基)以及-N(C1-6烷基)2;n係0、1、2或3;並且m係0、1或2。在式(I)、(Ia)或(Ib)某些方面,A係:
在式(I)或(Ia)某些方面,X係-NH-S(O)2-、-NH-S(O)2-CH2-或-CH2-S(O)2-NH-。在式(I)或(Ia)某些方面,X係-NH-S(O)2-。在式(I)或(Ib)甚至更具體方面,A係任選地被取代的喹啉-8-基並且X係-NH-S(O)2-並且該化合物具有在式(II)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2、R4、m以及n如式(I)中所定義。
在式(Ia)或(Ib)甚至更具體方面,A係任選地被取代的喹啉-8-基並且X係-NH-S(O)2-並且該化合物具有在式(IIa)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2以及n如式(Ia)中所定義。
在式(I)或(Ia)的某些方面,X係-NH-S(O)2-、-NH-S(O)2-CH2-或-CH2-S(O)2-NH-。在式(I)或(Ia)的某些方面,X係-NH-S(O)2-。在式(I)或(Ib)甚至更具體方面,A係任選地被取代的喹啉-5-基並且X係-NH-S(O)2-並且該化合物具有在式(III)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2、R4、m以及n如式(I)中所定義。
在式(Ia)甚至更具體方面,A係任選地被取代的喹啉-5-基並且X係-NH-S(O)2-並且該化合物具有在式(IIIa)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2以及n如式(Ia)中所定義。
在式(I)或(Ia)的某些方面,X係-NH-S(O)2-、-NH-S(O)2-CH2-或-CH2-S(O)2-NH-。在式(I)或(Ia)的某些方面,X係-NH-S(O)2-。在式(I)或(Ib)的甚至更具體方面,A係任選地被取代的苯並[d]噻唑-4-基並且X係-NH-S(O)2-並且該化合物具有在式(III)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2、R4、m以及n如式(I)中所定義。
在式(Ia)的甚至更具體方面,A係任選地被取代的苯並[d]噻唑-4-基並且X係-NH-S(O)2-並且該化合物具有在式(IIIa)中闡明的結構或其藥學上可接受的鹽:
其中R1b、R2以及n如式(Ia)中所定義。
在式(I)或(Ia)的某些實施方式中,A係任選地被取代的單環芳基(例如
任選地被取代的苯基)。在一些實施方式中,A係4-氯苯基。在一些實施方式中,A係3-氰基苯基。在一些實施方式中,A係2-氯苯基。在一些實施方式中,A係4-氰基苯基。在一些實施方式中,A係2-三氟甲基苯基。在一些實施方式中,A係4-三氟甲基苯基。在一些實施方式中,A係3-三氟甲基苯基。在一些實施方式中,A係3-氯苯基。在一些實施方式中,A係4-三氟甲氧基苯基。在一些實施方式中,A係2,3-二氯苯基。在一些實施方式中,A係2,4-二氟苯基。在一些實施方式中,A係3-三氟甲氧基苯基。
在式(I)或(Ia)的某些實施方式中,A係被相鄰碳上的兩個取代基取代的苯基,形成任選地被取代的雜環基或碳環基環(例如,導致A包含雙環)。
在式(I)的一些實施方式中,R1a係羥基。在式(I)的一些實施方式中,R1a係-C(O)H。在式(I)的一些實施方式中,R1a係-CH2OH。在式(I)的一些實施方式中,R1a係-CO2-C1-6烷基(例如-CO2Et)。在式(I)的一些實施方式中,R1a係-CO2H。在式(I)的一些實施方式中,R1a係-N(R10a)2。在式(I)的一些實施方式中,R1a係-OP(=O)(OH)2。在式(I)的一些實施方式中,R1a係-OCO2-CH2-OP(=O)(OH)2.
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基,其中每個環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基或雜芳烯基任選地被鹵基、C1-6烷基、-OH、C1-6烷氧基、-CN、-NH2、-SO2-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、芳基、鹵代烷基或鹵代烷氧基取代。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係芳基;雜芳基;芳烷基;或雜芳烷基,其中每個芳基;雜芳基;芳烷基;或雜芳烷基任選地被鹵基、C1-6烷基、-OH、C1-6烷氧基、-CN、-NH2、-SO2-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、芳基、鹵代烷基或鹵代烷氧基取代。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的芳烷基(例如,苄基、2,3-二氟苄基、2-氟苄基、3-氟苄基、2-甲基苄基、3-甲基苄基、2-三氟甲基苄基、3-三氟甲基苄基、2-甲氧基苄基、
3-甲氧基苄基)。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的芳基(例如,未被取代的苯基、2-(2-氯苯基)苯基、4-氰基苯基、3-氰基苯基、2-氰基苯基、2-羥基苯基、2-(甲磺醯基)苯基、3-(甲磺醯基)苯基、2-氯-4-甲基苯基、2-氯-4-氟苯基、2-氯-3-氟苯基、2-氯-5-氟苯基、2,3-二氟苯基、2,6-二氟苯基、2-甲基苯基、2-氟苯基、2-甲氧基苯基、2-三氟甲基苯基、2-二氟苯基、3-甲氧基苯基、3-三氟甲氧基苯基、3-三氟甲基苯基、2-三氟甲氧基苯基、3-氯苯基、2-氯苯基、3-氟苯基、2-乙基苯基、4-氟苯基或2-甲基-4-氟苯基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係苯基,任選地被氯、氟、溴、甲基、乙基、-CN、二氟甲基、三氟甲基、-OCF3、-SO2-CH3或-OCH3取代。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的雜芳烷基(例如,甲基-3-噠嗪基、甲基-3-吡啶基、甲基-2-吡啶基、3-甲基-甲基-2-吡啶基、2-氟-甲基-3-吡啶基或3-氟-甲基-2-吡啶基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的雜芳基(例如,3-氟-2-吡啶基、3-甲基-2-吡啶基、3-氟-4-吡啶基、4-吡啶基、4-異噻唑基、3-甲基-4-氟-2-吡啶基、2-氯-4-吡啶基、4-氟-2-甲基-3-吡啶基、4-氟-3-溴-2-吡啶基、2-甲氧基-3-吡啶基、6-甲氧基-2-吡啶基、6-氟-2-吡啶基、6-甲基-2-吡啶基、2-甲基-3-吡啶基、6-氯-2-吡啶基、3-三氟甲基-2-吡啶基、6-三氟甲基-2-吡啶基、2-氟-3-吡啶基、2-三氟甲基-3-吡啶基或6-二氟甲基-2-吡啶基)。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的C1-8烷基(例如,甲基、乙基、正丙基、異丙基、三級丁基、異丁基、正丁基、三級戊基、2-羥基乙基、1-羥基乙基、3-羥基丙基、2-羥基-2-甲基丙基、3-羥基-3-甲基丁基、3,3,3-三氟丙基、2-甲氧基乙基、3,3-二氟丙基、乙氧基甲基、N,N-二甲基甲基、吡咯甲基或2-羥基丙基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的環烷基(例如環丙基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的環烷基烷基(例如環丙基甲基、
1-甲基-環丙基甲基、環丁基甲基、2,2-二氟環丙基甲基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被取代的C2-8烯基(例如2-甲基-2-丙烯基或3,3-二氟-2-丙烯基)。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被一個至四個R5基團(例如鹵基、-OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基)以及-N(C1-6烷基)2)取代的C1-8烷基。在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係任選地被一個至四個R5基團(例如氯、氟、-OH、-OCH3、-OCH2CH3、-CN、-NH2、-SO2-CH3、-SO2-CH2CH3、-NH(CH3)、-N(CH3)2以及-N(CH3)(CH2CH3))取代的C1-8烷基。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係-NH-R5。在該等實施方式的一些其他方面,R5係任選地被取代的芳基(例如2-甲氧基苯基)。在該等實施方式的一些其他方面,R5係任選地被取代的芳烷基(例如未被取代的苄基)。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係-NH-C(O)-R5。在該等實施方式的一些其他方面,R5係任選地被取代的雜芳基(例如未被取代的2-吡啶基)。
在式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)或(IVa)的一些實施方式中,R1b係:
在又另一個實施方式中,該化合物選自下表1中闡明的化合物中的任何一者:
在此描述的化合物可用作與野生型相比具有較低活性的PKR突變體之活化劑,因而可用于本發明之方法。PKR中的這類突變可影響酶活性(催化效率)、調控性質(藉由果糖二磷酸(FBP)/ATP進行的調節),和/或酶的熱穩定性。這類突變的實例描述於瓦倫蒂尼(Valentini)等人,JBC 2002中。由在此描述的化合物
活化的突變體的一些實例包括G332S、G364D、T384M、G37E、R479H、R479K、R486W、R532W、R510Q以及R490W。不受理論約束,在此描述的化合物藉由活化FBP無反應PKR突變體、恢復穩定性降低的突變體的熱穩定性,或恢復受損突變體的催化效率來影響PKR突變體的活性。本發明化合物針對PKR突變體的活化活性可遵循實例8中描述的方法來測試。在此描述的化合物也可用作野生型PKR的活化劑。
在一實施方式中,為了增加紅細胞壽命,將在此描述的化合物、組合物或藥物組合物直接地體外地添加至全血或疊集細胞或直接地(例如,藉由腹膜內、靜脈內、肌肉內、口服、吸入(霧化遞送)、經皮、舌下及其他遞送途徑)提供至患者。不受理論約束,在此描述的化合物藉由影響2,3-DPG從血液中的釋放速率來增加RBC的壽命,由此抵消貯藏血液的老化。2,3-DPG濃度水平的降低誘導氧-血紅蛋白解離曲線的左移並且使變構平衡偏移至R,或氧化狀態,從而由於2,3-DPG耗竭而增加氧親和力,進而對於作為鐮狀細胞形成的基礎的細胞內聚合產生治療性抑制,由此使更大可溶性的氧基-血紅蛋白穩定化。因此,在一實施方式中,在此描述的化合物以及藥物組合物可用作抗鐮狀細胞形成劑。在另一個實施方式中,為了調控2,3-二磷酸甘油酸,將在此描述的化合物、組合物或藥物組合物直接地體外地添加至全血或疊集細胞或直接地(例如,藉由腹膜內、靜脈內、肌肉內、口服、吸入(霧化遞送)、經皮、舌下及其他遞送途徑)提供至患者。
在此描述的化合物可為PKR(例如野生型(wt)、突變PKR(例如R510Q或R532W))的活化劑。示例性化合物針對wt PKR(在酶法或基於細胞的測定中)以及突變型PKR的活性在表2中展示,如以下實例2-5中的測定所測量。如表2中展示,AA係指AC50小於100nM,BB係指AC50係從101nM至1.00μM,CC係指AC50係從1.01μM至10.00μM,DD係指AC50大於10.01μM並且EE係指AC50不可獲得。
表2.
在此描述的化合物可使用各種合成技術來制得,該等技術的一般以及具體實例在實例部分中闡明。
如熟習該項技術者可認識到,合成在此分子式的化合物的方法對於熟習該項技術者將是明顯的。另外,各種合成步驟可以交替序列或循序執行以便得到所需化合物。可用于合成在此描述的化合物的合成化學轉化以及保護基方法(保護以及脫保護)在本領域中為已知的,並且包括例如如以下文獻中描述的那些:阿‧拉洛克(R.Larock),綜合有機轉化(Comprehensive Organic Transformations),VCH出版社(VCH Publishers)(1989);替‧沃‧格林以及皮‧吉‧姆‧伍茲(T.W.Greene and P.G.M.Wuts),有機合成中的保護基團(Protective Groups in Organic Synthesis),第2版,約翰威利父子出版社(John Wiley and Sons)(1991);勒‧菲澤以及姆‧菲澤(L.Fieser and M.Fieser),菲澤和菲澤有機合成試劑(Fieser and Fieeser's Reagents for Organic Synthesis),約翰威利父子出版社(John Wiley and Sons)(1994);以及勒‧派克特(L.Paquette)編,有機合成試劑百科全書(Encyclopedia of Reagents for Organic Synthesis),約翰威利父子出版社(John Wiley and Sons)(1995),及其後續版本。
在此提供的化合物可含有一個或多個不對稱中心,並且因而以外消旋體以及外消旋混合物、單一對映異構物、個別非對映異構物以及非對映異構物混合物形式出現。該等化合物的所有這類異構物形式明確地包括於該範圍內。除非另外指示,否則當化合物在沒有指定立體化學的情況下藉由結構來命名或描繪並且具有一個或多個手性中心時,它應理解為代表該化合物的所有可能的立體異構物。在此提供的化合物還可含有可限制鍵旋轉的鍵聯(例如,碳-碳鍵)或取代基,例如由環或雙鍵的存在所產生的限制。因此,所有順/反以及E/Z異構物明確地包括在內。
在此提供的化合物(例如,具有式I)還可能包含一個或多個同位素取代。舉例來說,H可以呈任何同位素形式,包括1H、2H(D或氘)以及3H(T或氚);C可以呈任何同位素形式,包括12C、13C以及14C;O可以呈任何同位素形式,包括16O以及18O;等等。在此提供的化合物還可以由多種互變異構物形式來表示,在該等情況下,明確地包括在此描述的化合物的所有互變異構物形式,即使只可表示單一互變異構物形式(例如,環系統的烷化可能導致多個位點的烷基化;所有這類反應產物明確地包括在內)。這類化合物的所有這類異構物形式明確地包
括在內。在此描述的化合物的所有結晶形式明確地包括在內。
在此提供的化合物包括化合物本身,及其鹽及其前藥(如果可適用的話)。鹽例如可在陰離子與在此描述的化合物的帶正電荷取代基(例如,胺基)之間形成。合適的陰離子包括氯化物、溴化物、碘化物、硫酸根、硝酸根、磷酸根、檸檬酸根、甲烷磺酸根、三氟乙酸根以及乙酸根。同樣地,鹽還可以在陽離子與在此描述的化合物的帶負電荷取代基(例如,羧酸根)之間形成。合適的陽離子包括鈉離子、鉀離子、鎂離子、鈣離子以及銨陽離子如四甲基銨離子。前藥的實例包括酯及其他藥學上可接受的衍生物,其在給予受試者時能夠提供活性化合物。
在此提供的化合物可以藉由附加適當官能團來修飾以便增強所選擇的生物性質,例如,靶向一特定組織。這類修飾在本領域中為已知的並且包括增加生物滲透至給定生物區室(例如,血液、淋巴系統、中樞神經系統)、增加口服可用性、增加溶解性以便允許藉由注射來給予、改變代謝以及改變排泄速率的那些修飾。
在一個替代實施方式中,在此描述的化合物可以用作平臺或支架,其可以在製備化合物的衍生物和/或化學文庫的組合化學技術中使用。化合物的這類衍生物以及文庫具有生物活性並且可用於識別並且設計具有一種特定活性的化合物。適合於利用在此描述的化合物的組合技術在本領域中為已知的,如以下舉例說明:奧布萊克特‧迪以及維戈多‧吉‧姆(Obrecht,D.and Villalgrodo,J.M.)小分子量化合物文庫的固體支撐組合以及平行合成(Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries),佩加蒙-愛思唯爾科學有限公司(Pergamon-Elsevier Science Limited)(1998),並且包括如“混合裂分(split and pool)”或“平行”合成技術、固相和溶液相技術以及編碼技術的那些技術(參見例如查尼克‧艾‧沃(Czarnik,A.W.)生物化學目前視點(Curr.Opin.Chem.Bio.),(1997)1,60。因此,一個實施方式涉及使用在此描述的化合物產生衍生物或化學文庫的方法,其包括:1)提供包含多個孔的主體;2)將由在此描述的方法識別的一種或多種化合物提供于每個孔中;3)將額外一種或多種化學品提供于每個孔中;4)從每個孔中分離所得一種或多種產物。一替代實施方式涉及使用在此描述的化合物產生衍生物或化學文庫的方法,其包括:1)提供連接至固體支撐物的一種或多種在此描述的化合物;2)用一種或多種額外化學品處理連接至固體
支撐物的由在此描述的方法識別的一種或多種化合物;3)從固體支撐物中分離所得一種或多種產物。在如上所述的方法中,“標籤”或識別劑或標記部分可以連接至在此描述的化合物或其衍生物且/或從在此描述的化合物或其衍生物分離,以便促進跟蹤、識別或分離所需產物或其中間物。這類部分在本領域中為已知的。用於前述方法中的化學品可以包括例如溶劑、試劑、催化劑、保護基以及脫保護基團試劑等等。這類化學品的實例係出現於在此提及的不同合成以及保護基化學文本以及論文中的那些化學品。
在此描述的化合物可以藉由在本領域中已知的方法來評估調節PKM2(例如,活化PKM2)的能力。在一些實施方式中,在此描述的化合物在絲胺酸缺陷條件下評估調節PKM2(例如,活化PKM2)的能力。在一些實施方式中,示例性方法包括使化合物與基於細胞的測定接觸,從而允許評估調節(例如,活化)PKM2的能力。例如,候選化合物可以與細胞接觸,並且測量氧的消耗量或乳酸的產生。細胞磷酸烯醇丙酮酸的變化、甘油-磷酸的變化、核糖或去氧核糖的變化、脂質合成的變化或葡萄糖轉化成脂質或核酸或胺基酸或蛋白質的變化也可以用於評估化合物調節PKM2(例如,活化PKM2)的能力。評估也可以包括測量丙酮酸的變化或確定線粒體膜電位的改變,例如,如藉由螢光電位染料所測量。
用於篩選/測試方法中的PKM1以及PKM2可以藉由在本領域中已知用於表達重組蛋白質的任何方法來產生。舉例來說,編碼所需多肽之核酸可以被引入不同細胞類型或無細胞系統中以便表達。可產生真核(例如,COS、HEK293T、CHO以及NIH細胞系)以及原核(例如,大腸桿菌)表達系統,其中PKM序列被引入質粒或其他載體中,然後用於轉化活細胞。PKM cDNA含有整個開放閱讀框架的構建體,或其生物活性片段以正確定向插入表達質粒中並且可以用於蛋白質表達。原核以及真核表達系統允許表達並且回收融合蛋白質,在該等融合蛋白質中PKM蛋白質共價地連接至胺基末端或羧基末端側上的標籤分子,從而促進識別和/或純化。可使用的標籤的實例包括六組胺酸、HA、FLAG以及c-myc表位標籤。酶促或化學裂解位點可以在PKM蛋白質與標籤分子之間工程化以使得標籤可在純化之後得以移除。
篩選/測試測定中測量的PKM酶的活性可以藉由例如監測反應混合物中存在
的底物(例如,ATP或NADH)的濃度來測量。由丙酮酸激酶的酶活性產生的丙酮酸藉由乳酸脫氫酶轉化成乳酸,其需要消耗NADH(NADH→NAD+)。因此,PKM2的活性可藉由經由例如螢光測定來監測NADH的消耗而間接地測量。另外,PKM2酶的活性可藉由測量ATP的產生來直接地監測,因為ATP在磷酸烯醇丙酮酸轉化成丙酮酸時產生。監測反應混合物中的底物的量的方法包括例如吸光度、螢光、拉曼散射(Raman scattering)、磷光、發光、螢光素酶測定以及放射性。
篩選程序需要反應混合物中的特定組分的存在。用於測定中的組分包括例如核苷二磷酸(例如,ADP)、磷酸烯醇丙酮酸、NADH、乳酸脫氫酶、FBP、還原劑(例如,二硫蘇糖醇)、清潔劑(例如,玻雷吉(Brij)35)、甘油以及溶劑(例如,DMSO)。示例性反應條件存在於表3中。
可用作PKM2活化劑的化合物係在不存在FBP的情況下展現PKM2酶的特異性以及活化的那些化合物,所展現的特異性以及活化水平比在存在FBP的情況下的水平大10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或100%。此外,化合物可在存在或不存在磷酸酪胺酸肽的情況下進行評估。磷酸酪胺酸肽結合至PKM2導致FBP與PKM2的分離以及PKM2從活性、四聚體形式到無活性形式的構型變化。甚至在存在磷酸酪胺酸肽的情況下結合至PKM2並且將該酶鎖定於活性構型中的化合物將導致PKM2的變構控制的損失,這種變構控制係將來自醣解的生物化學中間物分流至其他中間物的生物合成中所需要的。這進而將導致癌細胞、活化免疫細
胞以及脂肪細胞的生長的抑制。
在一個實施方式中,提供用於治療或預防如在此描述的疾病、病狀或病症(例如,治療)的方法,其包括給予化合物、化合物的藥學上可接受的鹽或包含在此描述的化合物(例如,式(I)、(Ia)、(Ib)、(II)、(IIa)、(III)、(IIIa)、(IV)、(IVa)或在表1中的化合物)的藥物組合物。
在此描述的化合物以及組合物可例如體外或離體給予培養中的細胞,或例如體內給予受試者,以便治療、預防且/或診斷各種病症,包括在此如下描述的那些病症。
如在此使用,術語“治療(treat)”或“治療(treatment)”係定義為將單獨或與第二治療劑組合的化合物施加至或給予受試者(例如患者),或將化合物施加至或給予來自患有病症(例如,如在此描述的病症)、病症的症狀的受試者(例如患者)的分離的組織或細胞(例如細胞系),目的係治癒、恢復、減輕、緩解、改變、補救、改善、改進或影響病症,或病症的一種或多種症狀。
如在此使用,有效治療病症的化合物的量,或“治療有效量”係指在將單一或多個劑量給予受試者後有效治療細胞,或治癒、減輕、緩解或改進患有病症的受試者超過在不存在這類治療時的預期的化合物的量。
如在此使用,術語“預防”係定義為將單獨或與第二治療劑組合的化合物施加至或給予受試者(例如患者),或將化合物施加至或給予來自具有患上病症的傾向的受試者(例如患者)的分離的組織或細胞(例如細胞系),目的係預防病症的至少一種症狀的發生或延遲病症的至少一種症狀的發作。
如在此使用,有效預防病症的化合物的量,或化合物的“預防有效量”係指在單一或多個劑量給予受試者後有效預防或延遲病症或病症的症狀的發作或復發的發生的量。
如在此使用,術語“受試者”意欲包括人類以及非人類動物。示例性人類受試者包括患有病症(例如在此所述的病症)的人類患
者或正常受試者。術語“非人類動物”包括所有脊椎動物,例如非哺乳動物(如雞、兩棲動物、爬行動物)以及哺乳動物,如非人類靈長類動物、馴化的和/或農業上有用的動物,例如綿羊、狗、貓、牛、豬等。
血液相關病狀
在此描述的化合物或組合物可用於治療血液相關病狀。在一個實施方式中,提供用於增加有需要的紅細胞(RBC)的壽命的方法,其包括使血液與有效量的以下物質接觸:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其鹽、溶劑合物或水合物以及載體的組合物;或(3)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於調控有需要的血液中的2,3-二磷酸甘油酸水平的方法,其包括使血液與有效量的以下物質接觸:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其鹽、溶劑合物或水合物以及載體的組合物;或(3)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療遺傳性非球形紅細胞溶血性貧血的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療鐮狀細胞性貧血(例如藉由活化野生型PKR)的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療溶血性貧血(例如由磷酸甘油酸激酶缺陷引起的慢性溶血性貧血,血細胞、分子與疾病(Blood Cells Mol Dis),2011;46(3):206)的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之
化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療與2,3-二磷酸甘油酸水平增加相關的疾病或病狀(例如,肝病(美國胃腸病學雜誌(Am J Gastroenterol),1987;82(12):1283)以及帕金森氏病(Parkinson’s)(神經病學、神經外科以及精神病學雜誌(J.Neurol,Neurosurg,and Psychiatry)1976,39:952)的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療地中海貧血(例如,β-地中海貧血)、遺傳性球形紅細胞症、遺傳性橢圓形紅細胞增多症、無β脂蛋白血症(或巴-科二氏綜合征(Bassen-Kornzweig syndrome))、陣發性夜間血紅蛋白尿症、獲得性溶血性貧血(例如,先天性貧血(例如,酶病))或慢性疾病性貧血的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露的化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在另一個實施方式中,提供用於治療與2,3-二磷酸甘油酸水平增加相關的疾病或病狀(例如,肝病(美國胃腸病學雜誌(Am J Gastroenterol),1987;82(12):1283)以及帕金森氏病(Parkinson’s)(神經病學、神經外科以及精神病學雜誌(J.Neurol,Neurosurg,and Psychiatry)1976,39:952)的方法,其包括給予有需要的受試者治療有效量的以下物質:(1)在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物;(2)包含在此揭露之化合物或其藥學上可接受的鹽、溶劑合物或水合物以及藥學上可接受的載體的藥物組合物。
在此描述的化合物以及組合物係與野生型相比具有較低活性的PKR突變體的活化劑,因而可用于本發明之方法。PKR中的這類突變可影響酶活性(催化效率)、調控性質(藉由果糖二磷酸(FBP)/ATP進行的調節),和/或酶的熱穩定性。這類突變的實例描述於瓦倫蒂尼(Valentini)等人,JBC 2002中。由在此描述的化合物活化的突變體的一些實例包括G332S、G364D、T384M、G37E、R479H、R479K、R486W、R532W、R510Q以及R490W。不受理論約束,在此描述的化合物藉由活
化FBP無反應PKR突變體、恢復穩定性降低的突變體的熱穩定性,或恢復受損突變體的催化效率來影響PKR突變體的活性。本發明化合物針對PKR突變體的活化活性可遵循實例2-5中描述的方法來測試。在此描述的化合物也是野生型PKR的活化劑。
在一個實施方式中,為了增加紅細胞的壽命,將在此描述的化合物、組合物或藥物組合物直接地體外地添加至全血或疊集細胞或直接地(例如,藉由腹膜內、靜脈內、肌肉內、口服、吸入(霧化遞送)、經皮、舌下及其他遞送途徑)提供至受試者(例如,患者)。不受理論約束,在此描述的化合物藉由影響2,3-DPG從血液中的釋放速率來增加RBC的壽命,由此抵消貯藏血液的老化。2,3-DPG濃度水平的降低誘導氧-血紅蛋白解離曲線的左移並且使變構平衡偏移至R,或氧化狀態,從而由於2,3-DPG耗竭而增加氧親和力,進而對於作為鐮狀細胞形成的基礎的細胞內聚合產生治療性抑制,由此使更大可溶性的氧基-血紅蛋白穩定化。因此,在一個實施方式中,在此描述的化合物以及藥物組合物可用作抗鐮狀細胞形成劑。
在此描述的化合物或組合物可用於治療腫瘤病症。“腫瘤病症”係特徵為細胞具有自主生長或複製能力的疾病或病症,例如,特徵為增殖性細胞生長的異常狀態或病狀。示例性腫瘤病症包括:癌、肉瘤、轉移性病症(例如,由前列腺、結腸、肺、乳房以及肝起源產生的腫瘤)、造血腫瘤病症(例如白血病)、轉移性腫瘤。流行癌症包括:乳房、前列腺、結腸、肺、肝以及胰腺癌。用該化合物治療可以有效改善腫瘤病症的至少一種症狀(例如減少細胞增殖、減少腫瘤質量等)的量來進行。
所揭露之方法可用於預防並且治療癌症,包括例如實體腫瘤、軟組織腫瘤及其轉移。所揭露的方法還可用於治療非實體癌。示例性實體腫瘤包括不同器官系統的惡性腫瘤(例如,肉瘤、腺癌以及癌),如肺、乳房、淋巴、胃腸(例如,結腸)以及泌尿生殖(例如,腎、尿路上皮或睾丸腫瘤)道、咽喉、前列腺以及
卵巢的那些惡性腫瘤。示例性腺癌包括結直腸癌、腎細胞癌、肝癌、非小細胞肺癌以及小腸癌。
不受理論約束,申請人相信改變的PKM2水平表徵所有類型的癌症的一子集,而與其細胞性質或在體內的位置無關。因此,在此揭露的化合物以及方法可用於治療以改變的PKM2水平為特徵的任何類型的癌症。
在一些實施方式中,在此描述的化合物與一種或多種額外癌症治療一起給予。示例性癌症治療包括例如:化療、靶向療法(如抗體療法)、免疫療法以及激素療法。該等治療的每一者的實例提供於下文中。
化療
在一些實施方式中,在此描述的化合物與一種或多種化療一起給予。化療係用可破壞癌細胞的藥物來治療癌症。“化療”通常是指與靶向療法相比總體上影響快速分裂細胞的細胞毒性藥物。化療藥物以不同可能方式,例如,藉由DNA的複製或新形成染色體的分離來干擾細胞分裂。大多數形式的化療靶向所有快速分裂細胞並且對於癌細胞不具有特異性,但是由於許多癌細胞不能修復DNA損壞,而正常細胞總體上可修復DNA損壞,因此可產生一定程度的特異性。
用於癌症療法中的化學治療劑的實例包括例如抗代謝物(例如,葉酸、嘌呤以及嘧啶衍生物)以及烷基化劑(例如,氮芥、亞硝基脲、鉑、烷基磺酸鹽、肼、三氮烯、氮丙啶、紡錘體抑制劑、細胞毒性劑、拓撲異構酶抑制劑及其他試劑)。示例性試劑包括阿柔比星(Aclarubicin)、放線菌素(Actinomycin)、阿維A酸(Alitretinon)、六甲蜜胺(Altretamine)、胺基喋呤(Aminopterin)、胺基酮戊酸(Aminolevulinic acid)、氨柔比星(Amrubicin)、安吖啶(Amsacrine)、阿那格雷(Anagrelide)、三氧化二砷(Arsenic trioxide)、天門冬醯胺酶(Asparaginase)、阿曲生坦(Atrasentan)、貝洛替康(Belotecan)、蓓薩羅丁(Bexarotene)、苯達莫司汀(endamustine)、博來黴素(Bleomycin)、硼替佐米(Bortezomib)、白消安(Busulfan)、喜樹鹼(Camptothecin)、卡培他濱(Capecitabine)、卡鉑、卡波醌(Carboquone)、卡莫氟(Carmofur)、卡莫司汀(Carmustine)、塞來昔布(Celecoxib)、苯丁酸氮芥(Chlorambucil)、氮芥(Chlormethine)、順鉑、克拉屈濱(Cladribine)、氯法拉濱(Clofarabine)、左旋門冬醯胺酶(Crisantaspase)、環磷醯胺
(Cyclophosphamide)、阿糖胞苷(Cytarabine)、氮烯咪胺(Dacarbazine)、放線菌素D(Dactinomycin)、柔紅黴素(Daunorubicin)、地西他濱(Decitabine)、地美可辛(Demecolcine)、多烯紫杉醇(Docetaxel)、多柔比星(Doxorubicin)、乙丙昔羅(Efaproxiral)、伊利司莫(Elesclomol)、依沙蘆星(Elsamitrucin)、依諾他濱(Enocitabine)、表柔比星(Epirubicin)、雌莫司汀(Estramustine)、依託格魯(Etoglucid)、依託泊苷(Etoposide)、氟尿苷(Floxuridine)、氟達拉濱(Fludarabine)、氟尿嘧啶(Fluorouracil;5FU)、福莫司汀(Fotemustine)、吉西他賓(Gemcitabine)、卡氮芥(Gliadel)植入物、羥基脲(Hydroxycarbamide)、羥基脲(Hydroxyurea)、伊達比星(Idarubicin)、異環磷醯胺(Ifosfamide)、伊立替康(Irinotecan)、伊洛福芬(Irofulven)、伊沙匹隆(Ixabepilone)、拉洛他賽(Larotaxel)、亞葉酸(Leucovorin)、脂質體多柔比星(Liposomal doxorubicin)、脂質體柔紅黴素(Liposomal daunorubicin)、氯尼達明(Lonidamine)、洛莫司汀(Lomustine)、硫蒽酮(Lucanthone)、甘露舒凡(Mannosulfan)、馬索羅酚(Masoprocol)、美法侖(Melphalan)、巰基嘌呤(Mercaptopurine)、美司鈉(Mesna)、甲氨喋呤(Methotrexate)、氨乙醯丙酸甲酯(Methyl aminolevulinate)、二溴甘露醇(Mitobronitol)、米托胍腙(Mitoguazone)、米托坦(Mitotane)、絲裂黴素(Mitomycin)、米托蒽醌(Mitoxantrone)、奈達鉑(Nedaplatin)、尼莫司汀(Nimustine)、奧利默森納(Oblimersen)、奧馬他辛(Omacetaxine)、歐塔紫杉醇(Ortataxel)、奧克賽鉑(Oxaliplatin)、紫杉醇(Paclitaxel)、培門冬酶(Pegaspargase)、培美曲塞(Pemetrexed)、噴司他丁(Pentostatin)、吡柔比星(Pirarubicin)、匹杉瓊(Pixantrone)、普卡黴素(Plicamycin)、卟吩姆鈉(Porfimer sodium)、潑尼莫司汀(Prednimustine)、甲基苄肼(Procarbazine)、雷替曲賽(Raltitrexed)、雷諾莫司汀(Ranimustine)、魯比替康(Rubitecan)、沙帕他濱(Sapacitabine)、司莫司汀(Semustine)、腺病毒載體定位碼基因注射劑(Sitimagene ceradenovec)、沙鉑(Satraplatin)、鏈佐星(Streptozocin)、他拉泊芬(Talaporfin)、替加氟-尿嘧啶(Tegafur-uracil)、替莫泊芬(Temoporfin)、替莫唑胺(Temozolomide)、替尼泊苷(Teniposide)、紫杉烷(Tesetaxel)、睾內酯(Testolactone)、四硝酸酯(Tetranitrate)、塞替派(Thiotepa)、噻唑呋林(Tiazofurin)、硫鳥嘌呤(Tioguanine)、替吡法尼(Tipifarnib)、拓撲替康(Topotecan)、曲貝替定(Trabectedin)、三亞胺醌
(Triaziquone)、曲他胺(Triethylenemelamine)、三鉑(Triplatin)、維A酸(Tretinoin)、曲奧舒凡(Treosulfan)、曲洛磷胺(Trofosfamide)、烏拉莫司汀(Uramustine)、伐柔比星(Valrubicin)、維替泊芬(Verteporfin)、長春花鹼(Vinblastine)、長春新鹼(Vincristine)、長春地辛(Vindesine)、長春氟寧(Vinflunine)、長春瑞賓(Vinorelbine)、伏立諾他(Vorinostat)、左柔比星(Zorubicin)以及在此描述的其他細胞生長抑制或細胞毒性劑。
因為一些藥物在一起比單獨更好地起作用,所以兩種或更多種藥物經常同時給出。經常,兩種或更多種化療劑以組合化療形式來使用。在一些實施方式中,化療劑(包括組合化療)可與在此描述的化合物組合使用。
靶向療法
在一些實施方式中,在此描述的化合物與一種或多種靶向療法一起給予。靶向療法由使用對於癌細胞的失調蛋白質具有特異性的試劑來構成。小分子靶向療法藥物總體上是癌細胞內的突變的、過表達的或在其他方面關鍵性的蛋白質上的酶域的抑制劑。主要實例係酪胺酸激酶抑制劑,如阿西替尼(Axitinib)、博舒替尼(Bosutinib)、西地尼布(Cediranib)、達沙替尼(dasatinib)、厄洛替尼(erlotinib)、伊馬替尼(imatinib)、吉非替尼(gefitinib)、拉帕替尼(lapatinib)、來他替尼(Lestaurtinib)、尼祿替尼(Nilotinib)、司馬沙尼(Semaxanib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)以及凡德他尼(Vandetanib),以及週期蛋白依賴性激酶抑制劑,如夫拉平度(Alvocidib)以及塞利西利(Seliciclib)。單克隆抗體療法係另一個策略,其中治療劑係特異性地結合至癌細胞表面上的蛋白質的抗體。實例包括典型地用於乳房癌中的抗-HER2/neu抗體曲妥珠單抗(trastuzumab)(HERCEPTIN®),以及典型地用於各種B細胞惡性腫瘤中的抗-CD20抗體利妥昔單抗(rituximab)以及托西莫單抗(Tositumomab)。其他示例性抗體包括西妥昔單抗(Cetuximab)、帕尼單抗(Panitumumab)、曲司珠單抗(Trastuzumab)、阿侖單抗(Alemtuzumab)、貝伐單抗(Bevacizumab)、依決洛單抗(Edrecolomab)以及吉妥單抗(Gemtuzumab)。示例性融合蛋白質包括阿柏西普(Aflibercept)以及地尼白介素(Denileukin diftitox)。在一些實施方式中,靶向療法可與在此描述的化合物組合使用。
靶向療法還可能涉及作為“歸巢裝置(homing device)”的小肽,其可以結
合至細胞表面受體或包圍腫瘤的患病細胞外基質。連接至該等肽(例如,RGD)的放射性核素最後殺滅癌細胞(如果該核素在細胞附近衰變的話)。這類療法的實例包括BEXXAR®。
免疫療法
在一些實施方式中,在此描述的化合物與一種或多種免疫療法一起給予。癌症免疫療法係指被設計成誘導患者自身免疫系統抗擊腫瘤的一組不同治療策略。產生針對腫瘤的免疫回應的當代方法包括淺表性膀胱癌的膀胱內BCG免疫療法,以及使用干擾素及其他細胞因數來誘導腎細胞癌以及黑素瘤患者中的免疫回應。
同種異體造血幹細胞移植可以被認為是免疫療法的一種形式,因為供體的免疫細胞將經常以移植物抗腫瘤效應攻擊腫瘤。在一些實施方式中,免疫療法試劑可與在此描述的化合物組合使用。
激素療法
在一些實施方式中,在此描述的化合物與一種或多種激素療法一起給予。一些癌症的生長可以藉由提供或阻斷某些激素來加以抑制。激素敏感腫瘤的常見實例包括某些類型的乳房以及前列腺癌。移除或阻斷雌激素或睾酮經常是重要的額外治療。在某些癌症中,給予激素促效劑(如孕激素)可能為治療上有利的。在一些實施方式中,激素療法試劑可與在此描述的化合物組合使用。
肥胖以及脂肪病症
在此描述的化合物或組合物可用於治療或預防例如人類受試者(例如兒童或成人受試者)中的肥胖。“肥胖”係指受試者具有大於或等於30的身體質量指數的病狀。在此描述的許多化合物可用於治療或預防過重病狀。“過重”係指受試者具有大於或等於25.0的身體質量指數的病狀。身體質量指數(BMI)及其他定義係根據“關於成人超重和肥胖的識別和評估以及治療的NIH臨床準則(NIH Clinical Guidelines on the Identification and Evaluation,and Treatment of Overweight and Obesity in Adults)”(1998)。用化合物治療可以有效改變受試者體重,例如,至少2%、5%、7%、10%、12%、15%、20%、25%、30%、25%、40%、45%、50%或55%的量來進行。
用化合物治療可以有效減少受試者的身體質量指數,例如至小於30、28、27、25、22、20或18的量來進行。該等化合物可用於治療或預防異常或不適當重量增加、代謝率或脂肪沈積,例如厭食症、易餓病、肥胖、糖尿病或高脂血症(例如,升高的甘油三酯和/或升高的膽固醇),以及脂肪或脂質代謝的病症。
可給予在此描述的化合物或組合物以便治療與帕-魏二氏綜合征(Prader-Willi Syndrome;PWS)相關的肥胖。PWS係與肥胖(例如,病態肥胖)相關的遺傳性障礙。
在此描述的化合物或組合物可用於減少身體脂肪、防止身體脂肪增加、減少膽固醇(例如,總膽固醇和/或總膽固醇與HDL膽固醇的比率),且/或減少患有PWS相關肥胖的個體的食欲,且/或減少合併症,如糖尿病、心血管疾病以及中風。
在此描繪的組合物包括在此描繪的化合物(例如,在此描述的化合物),以及額外治療劑(如果存在的話),其量有效實現疾病或疾病症狀(包括在此描述的那些疾病或疾病症狀)的調節。
術語“藥學上可接受的載體或佐劑”係指如下載體或佐劑,其可與在此提供的化合物一起給予患者,並且不破壞其藥理學活性,並且在足以遞送治療量的該化合物劑量下給予時是無毒的。
可以用於在此提供的藥物組合物中的藥學上可接受的載體、佐劑以及媒劑包括但不限於離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、自乳化藥物遞送系統(SEDDS)(如d-α-生育酚聚乙二醇1000琥珀酸酯)、用於藥物劑型中的表面活性劑(如吐溫或其他類似的聚合物遞送基質)、血清蛋白(如人類血清白蛋白)、緩衝物質(如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸的偏甘油酯混合物、水、鹽或電解質(如魚精蛋白硫酸鹽)、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽、膠態二氧化矽、三矽酸鎂、聚乙烯基吡咯烷酮、基於纖維素的物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。環糊精(如α-、β-以及γ-環糊精),或化學修飾衍生物(如羥基烷基環糊精,包括2-以及3-羥基丙基-β-環糊精),或其他溶解衍生物也
可以有利地用於增強在此描述的式的化合物的遞送。
在此提供的藥物組合物可以口服、腸胃外、藉由吸入噴霧、局部地、經直腸、經鼻、經頰、經陰道或經由植入的儲槽給予,較佳的是藉由口服給予或藉由注射給予。在此提供的藥物組合物可以含有任何常規無毒的藥學可接受的載體、佐劑或媒劑。在一些情況下,配製品的pH可以用藥學上可接受的酸、鹼或緩衝劑來調整以便增強配製的化合物或其遞送形式的穩定性。如在此使用的術語腸胃外包括皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內以及顱內注射或輸注技術。
藥物組合物可以呈無菌可注射製劑形式,例如,以無菌可注射水性或油性懸浮液形式。此懸浮液可以根據在本領域中已知的技術使用合適分散或潤濕劑(例如,吐溫80)以及懸浮劑來配製。無菌可注射製劑還可以為無毒腸胃外可接受的稀釋劑或溶劑中的無菌可注射溶液或懸浮液,例如,以1,3-丁二醇中的溶液形式。在可以使用的可接受的媒劑以及溶劑中有甘露醇、水、林格氏溶液(Ringer’s solution)以及等滲氯化鈉溶液。另外,無菌、不揮發性油常規地用作溶劑或懸浮介質。為此目的,可以使用任何溫和的不揮發性油,包括合成甘油單酯或甘油二酯。脂肪酸(如油酸和其甘油酯衍生物)可用於製備可注射製劑,天然的藥學上可接受的油(如橄欖油或蓖麻油,尤其呈其聚氧乙烯化形式)同樣可用於製備可注射製劑。該等油溶液或懸浮液還可以含有長鏈醇稀釋劑或分散劑,或羧甲基纖維素或類似分散劑,其通常用於配製藥學上可接受的劑型,如乳液和或懸浮液。其他通常使用的表面活性劑(如吐溫或司盤和/或其他類似乳化劑)或通常用於製造藥學上可接受的固體、液體或其他劑型的生物利用率增強劑也可以用於配製目的。
在此提供的藥物組合物可以任何口服可接受的劑型(包括但不限於膠囊、片劑、乳液以及水性懸浮液、分散液以及溶液)來口服給予。在口服使用的片劑的情況下,通常使用的載體包括乳糖和玉米澱粉。還典型地添加潤滑劑,如硬脂酸鎂。對於以膠囊形式來口服給予,可用稀釋劑包括乳糖和乾燥玉米澱粉。當水性懸浮液和/或乳液口服給予時,活性成分可以懸浮或溶解於與乳化和/或懸浮劑組合的油性相中。如果需要,可以添加某些甜味劑和/或調味劑和/或著色劑。
在此提供的藥物組合物還可以供直腸給予的栓劑形式來給予。該等組合物可
以藉由將在此提供的化合物與合適非刺激性賦形劑混合來製備,該賦形劑在室溫下是固體但是在直腸溫度下是液體,並且因此將在直腸中融化以便釋放活性組分。這類材料包括但不限於可哥脂、蜂蠟以及聚乙二醇。
當所需治療涉及可藉由局部施加來接近的區域或器官時,在此提供的藥物組合物的局部給予係有用的。對於局部地施加至皮膚,藥物組合物應與含有懸浮或溶解於載體中的活性組分的合適軟膏一起配製。用於局部給予在此提供的化合物的載體包括但不限於礦物油、液體石油、白色石油、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蠟以及水。可替代地,藥物組合物可以用合適洗劑或乳膏來配製,該洗劑或乳膏含有懸浮或溶解於具有合適乳化劑的載體中的活性化合物。合適載體包括但不限於礦物油、山梨醇酐單硬脂酸酯、聚山梨醇酯60、鯨蠟酯蠟、鯨蠟硬脂醇、2-辛基十二烷醇、苄醇以及水。在此提供的藥物組合物還可以藉由直腸栓劑配製品或在合適灌腸配製品中局部地施加至下腸道。也包括局部經皮貼片。
在此提供的藥物組合物可以藉由鼻氣霧劑或吸入來給予。這類組合物根據在藥物配製領域中熟知的技術來製備並且可以使用苄醇或其他合適防腐劑、增強生物利用率的吸收促進劑、碳氟化合物和/或在本領域中已知的其他溶解或分散劑來製備成生理鹽水中的溶液。
當在此提供的組合物包含在此描述的式的化合物與一種或多種額外治療或預防劑的組合時,化合物和額外試劑應以在單一療法方案中通常給予的劑量的約1%與100%之間,並且更較佳的是約5%與95%之間的劑量水平存在。額外試劑可作為多劑量方案的一部分與在此提供的化合物分開地給予。或者,那些試劑可為單一劑型的一部分,與在此提供的化合物一起混合于單一組合物中。
在此描述的化合物可以每4至120小時,或根據具體藥物的要求,例如藉由注射、靜脈內、動脈內、皮下、腹膜內、肌肉內或皮下;或口服、經頰、經鼻、經粘膜、局部地、以眼用製劑形式,或藉由吸入來給予,劑量在約0.5至約100mg/kg體重範圍內,可替代地劑量在1毫克與1000毫克/劑量之間。該等方法在此涵蓋給予有效量的化合物或化合物組合物以便獲得所需或規定效果。典型地,在此提供的藥物組合物將每天給予約1至約6次或可替代地,以連續輸注形式給予。這類給予可用作慢性或急性療法。可以與載體材料組合以便產生單一劑型的活性成分的量將取決於所治療的宿主以及具體給予模式來變化。典型製劑將含有從約5%
至約95%的活性化合物(w/w)。可替代地,這類製劑含有從約20%至約80%的活性化合物。
可能需要比以上列舉的那些劑量更低或更高的劑量。任何具體患者的具體劑量以及治療方案將取決於各種因素,包括所使用的具體化合物的活性、年齡、體重、一般健康狀態、性別、飲食、給予時間、排泄速率、藥物組合、嚴重程度以及疾病、病狀或症狀的過程、患者對疾病、病狀或症狀的傾向,以及治療醫師的判斷。
在改進患者的病狀後,如果有必要,可給予在此提供的化合物、組合物或組合的維持劑量。隨後,當症狀已經緩解至所需水平時,給予劑量或頻率或兩者可能隨著症狀的變化而減少至改進的病狀得以保持的水平。然而,在疾病症狀的任何復發之後,患者可能需要長期的間歇治療。
在此描述的化合物可以調節PKM2。因此,患者和/或受試者可以使用在此描述的化合物來選擇以便進行治療,其中首先評估患者和/或受試者以便確定是否受試者需要調節PKM2,並且如果受試者被確定為需要調節PKM2,那麼向受試者給予在此描述的化合物。
受試者可以使用在本領域中已知的方法,例如藉由測量患者中的PKM2的存在和/或活性來評估為需要調節PKM2。在一些實施方式中,評估癌症中的PKM2的活性和/或水平。
接受在此描述的化合物的患者可以例如針對病狀和/或不利作用的改進來監測。患者的病狀的改進可以例如藉由監測癌症(例如,腫瘤)的生長、沒有生長或消退來評估。在一些實施方式中,患者使用溶血參數的放射線測定或評估來評估。
在此描述的化合物可以活化突變型PKR。因此,患者和/或受試者可以使用在此描述的化合物來選擇以便進行治療,其中首先評估患者和/或受試者以便確定是否受試者帶有PKR突變(例如,如在此描述的一種突變),並且如果受試者被確定為帶有PKR突變,因而需要活化突變型PKR的活性,那麼任選地向受試者給予在此描述的化合物。受試者可以使用在本領域中已知的方法來評估為帶有PKR突變。
在以下實例中,試劑(化學品)係購自商業來源(如阿爾法(Alfa)、安可樂斯(Acros)、西格瑪奧德里奇公司(Sigma Aldrich)、TCI以及上海化學試劑公司(Shanghai Chemical Reagent Company)),並且在未進行進一步純化的情況下使用。核磁共振(NMR)光譜在Brucker AMX-400 NMR(布魯克,瑞士)上獲得。化學位移以來自四甲基矽烷的低磁場百萬分率(ppm,δ)來報告。質譜藉由來自沃特世LCT TOF質譜儀(沃特世,美國)的電灑電離(ESI)來給出。微波反應在Initiator 2.5微波合成器(拜泰齊公司(Biotage),瑞典)上進行。
‧PKM2儲備酶溶液在反應緩衝液中稀釋
‧首先將2μL化合物添加至每個孔,並且然後添加180μL反應混合物。
‧具有化合物(沒有ADP)的反應混合物在4℃下孵育30分鐘。
‧將板重新平衡至室溫,然後添加20μL ADP以便開始反應。
‧反應進度以在室溫下(25℃)在340nm波長下吸光度的變化來測量。
反應混合物:反應緩衝液中的PKM2(50毫微克/孔)、ADP(0.7mM)、PEP(0.15mM)、NADH(180μM)、LDH(2單位)
反應緩衝液:100mM KCl、50mM Tris pH 7.5、5mM MgCl2、1mM DTT、0.03% BSA。
‧PKR或PKR突變型酶溶液在測定緩衝液中稀釋。
‧首先將2μL測試化合物添加至孔中,並且然後添加180μL反應混合物。
‧除了ADP以外,將具有測試化合物的反應混合物組合,並且板在室溫下存儲60分鐘。
‧在室溫下添加20uL ADP以便開始反應,並且反應進度以在室溫下在
340nm波長下吸光度的變化來測量。
測試化合物製備 :
‧測試化合物儲備物在100% DMSO(10mM)中以100x濃度制得
‧在11個點進行1比3稀釋(即,將50μl第一濃度添加至100μl 100% DMSO以便產生3.33mM,將50μl此濃度添加至100μl DMSO以便產生1.11mM,等等)
‧1比100稀釋於測定中(200μl中的2μl)產生100μM的起始濃度,歷經11個點降低3倍。
測定緩衝液 :100mM KCl、50mM Tris 7.5、5mM MgCl2、1mM DTT、0.03% BSA
反應混合物 :PKR突變型酶:80-400毫微克/孔;ADP:0.22-1.65mM;PEP:0.1-0.5mM;NADH:180uM;LDH:0.5單位(Sigma# 59023);DTT:1mM;BSA:0.03%。
在此描述的化合物以DMSO稀釋並且在1μM濃度下測試。該酶在1X緩衝液中稀釋:(100mM KCl、50mM Tris 7.5、5mM MgCl2、1mM DTT、0.03% BSA)。首先將2μL化合物溶液添加至孔中,並且然後添加180μL酶溶液。除了ADP以外,將測定物組合,並且板在RT下存儲60分鐘。添加20μL ADP以便開始測定並且測定輸出在SpectraMax下使用OD340來評估。測定在室溫下進行。
最終濃度:PKR wt(100毫微克/孔)、Tris pH 7.5(50mM)、KCl(100mM)、MgCl2(5mM)、ADP(0.48mM)、PEP(0.15mM)、NADH(180μM)、LDH(0.5單位,Sigma 59023)、DTT(1mM)以及BSA(0.03%)。
在此描述的化合物以DMSO稀釋並且在1μM濃度下測試。該酶在1X緩衝
液中稀釋:(100mM KCl、50mM Tris 7.5、5mM MgCl2、1mM DTT、0.03% BSA)。首先將2μL化合物溶液添加至孔中,並且然後添加180μL酶溶液。除了ADP以外,將測定物組合,並且板在RT下存儲60分鐘。添加20μL ADP以便開始測定並且測定輸出在SpectraMax下使用OD340來評估。測定在室溫下進行。
最終濃度:PKR R510Q(40毫微克/孔)、Tris pH 7.5(50mM)、KCl(100mM)、MgCl2(5mM)、ADP(0.2mM)、PEP(0.11mM)、NADH(180μM)、LDH(0.5單位,Sigma 59023)、DTT(1mM)以及BSA(0.03%)。
在此描述的化合物以DMSO稀釋並且在1μM濃度下測試。該酶在1X緩衝
液中稀釋:(100mM KCl、50mM Tris 7.5、5mM MgCl2、1mM DTT、0.03% BSA)。首先將2μL化合物溶液添加至孔中,並且然後添加180μL酶溶液。除了ADP以外,將測定物組合,並且板在RT下存儲60分鐘。添加20μL ADP以便開始測定並且測定輸出在SpectraMax下使用OD340來評估。測定在室溫下進行。
最終濃度:PKR R532W(100毫微克/孔)、Tris pH 7.5(50mM)、KCl(100mM)、MgCl2(5mM)、ADP(0.36mM)、PEP(0.1mM)、NADH(180μM)、LDH(0.5單位,Sigma 59023)、DTT(1mM)以及BSA(0.03%)。
在0℃下,向4-胺基苯甲酸(10g,73mmol)於100mL無水THF中的溶液中添加吡啶(1.15g,146mmol),以及喹啉-8-磺醯氯(20g,88mmol)。所得混合物在70℃下攪拌過夜。過濾之後,將殘餘物用EtOH洗滌並且獲得呈純產物形式的14g標題化合物。
1H NMR(DMSO-d6)δ:10.71(s,1H),9.12(dd,J=4.2,1.7Hz,1H),8.47(dd,J=7.5,1.3Hz,1H),8.51(dd,J=8.3,1.9Hz,1H),8.29(dd,J=8.2,1.2Hz,1H),7.62-7.79(m,4H),7.14-7.22(m,2H)。LC-MS:m/z 329.3(M+H)+
步驟A:在-78℃下,向相應芳基溴(1.0當量)于無水THF中的溶液逐滴添加n-BuLi於THF中的溶液(1.05當量)。添加之後,將混合物在-78℃下攪拌約0.5小時。然後,在-78℃下經由注射器來逐滴添加Boc-4-哌啶酮於THF中的溶液。添加之後,將所得混合物在-78℃下在N2下攪拌2h,然後允許溫至室溫。將反應混合物由飽和的NH4Cl溶液淬滅,所得混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。殘餘物藉由柱層析法(PE/EtOAc)純化以便提供化合物2B。
步驟B:向化合物2(1當量)於二中的溶液添加HCl於二中的溶液(3當量),反應混合物在室溫下攪拌約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物2C。
步驟C:向圓底燒瓶依序地添加化合物2C(1當量)、DMF(5mL)、DIPEA(3.0當量)、HBTU(1.2當量)以及1A(1當量)。將反應混合物在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥,過濾,並且將濾液濃縮。所需產物2D藉由標準方法來純化。
N-(4-(4-(3-氟苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.17(dd,J=4.3,1.7Hz,1H),8.56(s,1H),8.38(dd,J=7.3,1.4Hz,1H),8.32(dd,J=8.4,1.7Hz,1H),8.06(dd,J=8.2,1.3Hz,1H),7.69-7.57(m,2H),7.34(td,J=8.1,6.2Hz,1H),7.25-7.15(m,4H),7.14-7.07(m,2H),6.99(tdd,J=8.2,2.5,0.8Hz,1H),4.60(s,1H),3.60(s,1H),3.47(s,1H),3.26(s,1H),2.06(s,1H),1.82(s,2H),1.68(d,J=9.1Hz,2H)。LC-MS:m/z 506.6(M+H)+。
N-(4-(4-羥基-4-(2-(三氟甲基)苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.17(dd,J=1.8,4.1Hz,1 H),8.57(br.s.,1 H),8.42-8.30(m,2 H),8.06(dd,J=1.2,8.2Hz,1 H),7.80(d,J=7.9Hz,1 H),7.67-7.47(m,4 H),7.47-7.36(m,1 H),7.16-7.07(m,4 H),4.61(br.s.,1 H),3.58-3.50(m,4 H),2.30-1.85(m,4 H)。LC-MS:m/z 556.5(M+H)+
N-(4-(4-(2-乙基苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.18(dd,J=4.3Hz,J=1.6Hz,1H),8.63(br.s.,1H),8.31-8.43(m,2H),8.07(dd,J=8.4Hz,J=1.3Hz,1H),7.60-7.69(m,2H),7.30-7.33(m,2H),7.23-7.27(m,1H),7.14-7.23(m,3H),7.07-7.13(m,2H),4.58(br.s.,1H),3.58(br.s.,2H),3.33(br.s.,1H),3.01(q,J=7.6Hz,2H),2.03(d,J=5.9Hz,1H),1.93(br.s.,2H),1.69(br.s.,2H),1.25(t,J=7.5Hz,3H)。LC-MS:m/z 516.1(M+H)+
N-(4-(4-(4-氟-2-甲基苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.14(dd,J=1.6,4.3Hz,1 H),8.62(br.s.,1 H),8.39-8.24(m,2 H),8.04(dd,J=1.3,8.4Hz,1 H),7.66-7.52(m,2 H),7.25-7.02(m,5 H),6.86-6.70(m,2 H),4.45(br.s.,1 H),3.50(br.s.,2 H),3.33-3.20(m,1 H),2.52(s,3 H),2.05(d,J=9.1Hz,1 H),1.96(br.s.,2 H),1.84(br.s.,2 H)。LC-MS:m/z 520.6(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲氧基)苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.16(dd,J=1.6,4.3Hz,1 H),8.61(br.s.,1 H),8.42-8.26(m,2 H),8.05(dd,J=1.2,8.2Hz,1 H),7.67-7.49(m,3 H),7.36-7.06(m,7 H),4.55(br.s.,1 H),3.54(br.s.,1 H),3.48(s,2 H),3.24(br.s.,1 H),1.83(br.s.,2 H),1.76(br.s.,2 H)。LC-MS:m/z 572.6(M+H)+
N-(4-(4-羥基-4-(3-(三氟甲基)苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.15(dd,J=1.6,4.3Hz,1 H),8.62(br.s.,1 H),8.41-8.27(m,2 H),8.10-8.01(m,1 H),7.72(s,1 H),7.68-7.41(m,5 H),7.23-7.15(m,2 H),7.15-7.02(m,2 H),4.54(br.s.,1 H),3.57(br.s.,1 H),3.47(s,1 H),3.23(br.s.,1 H),2.12-1.91(m,2 H),1.80(br.s.,2 H),1.68(br.s.,1 H)。LC-MS:m/z 556.6(M+H)+
N-(4-(4-(3-氯苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.13(dd,J=1.6,4.3Hz,1 H),8.63(br.s.,1 H),8.31(dd,J=1.5,10.6Hz,1 H),8.37-8.23(m,1 H),8.03(dd,J=1.2,8.2Hz,1 H),7.65-7.51(m,2 H),7.44-7.35(m,1 H),7.27-7.10(m,5 H),7.10-7.01(m,2 H),4.45(br.s.,1 H),3.59-3.29(m,2 H),3.17(br.s.,1 H),1.98-1.61(br.s.,5 H)。LC-MS:m/z 522.5(M+H)+
N-(4-(4-(4-氟苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.16(dd,J=1.8,4.1Hz,1 H),8.58(br.s.,1 H),8.42-8.24(m,2 H),8.06(dd,J=1.5,8.2Hz,1 H),7.68-7.55(m,2 H),7.47-7.36(m,2 H),7.24-7.16(m,2 H),7.13-6.97(m,4 H),3.50(s,3 H),3.19(s,1 H),2.06(s,1 H),1.79(br.s.,3 H)。LC-MS:m/z 506.6(M+H)+
N-(4-(4-羥基-4-(3-(三氟甲氧基)苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ 9.16(dd,J=1.8,4.4Hz,1 H),8.67(br.s.,1 H),8.42-8.24(m,2 H),8.10-8.00(m,1 H),7.68-7.53(m,2 H),7.42-7.29(m,3 H),7.24-7.03(m,5 H),4.55(br.s.,1 H),3.57-3.23(br.s.,3 H),2.02-1.80(br.s.,5 H)。LC-MS:m/z 572.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15-9.21(m,1H),8.58(br.s.,1H),8.39(dd,J=7.3,1.3Hz,1H),8.32(dd,J=8.3,1.6Hz,1H),8.06(dd,J=8.2,1.2Hz,1H),7.59-7.68(m,2H),7.48-7.54(m,1H),7.39(dd,J=7.5,1.6Hz,1H),7.24-7.29(m,2H),7.18-7.23(m,2H),7.07-7.14(m,2H),3.58-3.29(br.s.,4H),2.34-1.97(br.m.,4H)。LC-MS:m/z 523.1(M+H)+
N-(4-(4-(2-氟苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.8Hz,1H),8.59(br.s.,1H),8.37(dd,J=7.4,1.4Hz,1H),8.31(dd,J=8.4,1.6Hz,1H),8.05(dd,J=8.3,1.3Hz,1H),7.56-7.67(m,2H),7.45(td,J=8.0,1.8Hz,1H),7.24-7.32(m,1H),7.17-7.23(m,2H),7.00-7.17
(m,4H),4.56(br.s.,1H),3.54(br.s.,2H),3.25(br.s.,1H),2.44(br.s.,1H),2.25(br.s.,1H),2.1(s,1H),1.85(s,1H)。LC-MS:m/z 506.6(M+H)+
N-(4-(4-羥基-4-(2-甲氧基苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(br.s.,1H),8.59(br.s.,1H),8.25-8.42(m,2H),8.05(d,J=7.9Hz,1H),7.53-7.69(m,2H),7.04-7.33(m,6H),6.89-7.02(m,2H),4.54(br.s.,1H),3.91(s,3H),3.55(br.s.,2H),3.32(br.s.,1H),2.20-1.90(m,4H)。LC-MS:m/z 518.6(M+H)+
N-[4-[4-(2,3-二氟苯基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(d,J=3.0Hz,1H),8.61(br.s.,1H),8.31(d,J=8.3Hz,1H),8.36(d,J=7.3Hz,1H),8.05(d,J=8.1Hz,1H),7.55-7.66(m,2H),7.23(t,J=7.1Hz,1H),7.18(d,J=8.3Hz,2H),7.02-7.12(m,4H),4.52(br.s.,1H),3.51(br.s.,2H),3.22(br.s.,1H),2.65(br.s.,1H),2.14-2.29(m,1H),2.09(br.s.,1H),1.79(br.s.,1H).LC-MS:m/z 523.6(M+H)+
N-[4-[4-[2-(二氟甲基)苯基]-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.02-9.07(m,2H),8.51(d,J=7.3Hz,1H),8.38(d,J=8.3Hz,1H),7.89(t,J=7.9Hz,1H),7.76(s,1H),7.50-7.54(m,1H),7.39(dd,J=7.5,1.3Hz,1H),7.29-7.32(m,1H),7.22-7.28(m,2H),7.16(s,1H),7.06(d,J=8.1Hz,1H),4.60(br.s.,1H),3.61(br.s.,1H),3.55(br.s.,1H),3.31(d,J=11.3Hz,1H),2.35(d,J=7.5Hz,
1H),2.20(d,J=14.8Hz,1H),2.01-2.12(m,2H),1.97(br.s.,2H)。LC-MS:m/z 537.6(M+H)+
N-(4-(4-(2-氰基苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.2,1.7Hz,1H),8.39(dd,J=7.3,1.3Hz,1H),8.33(dd,J=8.3,1.6Hz,1H),8.07(dd,J=8.2,1.2Hz,1H),7.92(d,J=7.5Hz,1H),7.71(s,1H),7.54-7.67(m,3H),7.38(d,J=7.5Hz,1H),7.26(d,J=8.9Hz,2H),7.13(d,J=8.3Hz,2H),4.66-4.84(m,1H),3.70-3.90(m,1H),3.46-3.64(m,1H),3.21-3.39(m,1H),2.23(s,2H),1.71-1.88(m,2H).LC-MS:m/z 514.7(M+H)+
N-[4-[4-(4-氰基苯基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.42(br.s.,1H),9.29(d,J=4.3Hz,1H),8.50(d,J=8.1Hz,2H),8.14(d,J=8.1Hz,1H),7.68-7.81(m,4H),7.60(d,J=7.5Hz,1H),7.50(t,J=7.8Hz,1H),7.18-7.26(m,4H),4.64(t,J=17.2Hz,1H),3.53-3.81(m,1H),3.51(s,1H),3.32(s,1H),2.07(br.s.,2H),2.00(br.s.2H)。LC-MS:m/z 512.6(M+H)+
N-(4-(4-(2-氯-5-氟苯基)-4-羥基哌啶-1-羰基)苯基)萘-1-磺醯胺
1H NMR(氯仿-d)δ:9.18(d,J=3.0Hz,1H),8.61(br.s.,1H),8.30-8.42(m,2H),8.07(d,J=8.3Hz,1H),7.58-7.68(m,2H),7.49(dd,J=7.0,2.7Hz,1H),7.30-7.37(m,1H),7.19-7.26(m,2H),7.11(d,J=8.3Hz,2H),6.95-7.04(m,1H),4.61(br.s.,1H),
3.60(br.s.,1H),3.50(br.s.,1H),3.23(br.s.,1H),2.16-2.31(m,1H),2.09(br.s.,1H),1.82(br.s.,2H)。LC-MS:m/z 541.1(M+H)+
N-[4-[4-(2-氯-4-甲基-苯基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.79(br.s.,1H),1.94(br.s.,1 H),2.05(br.s.,1 H),2.13(br.s.,1 H),2.32(s,3 H),2.98(br.s.,1 H),3.27(br.s.,1 H),3.56(br.s.,2 H),4.58(br.s.,1 H),7.07-7.11(m,3 H),7.18-7.22(m,3 H),7.37(d,J=8.03Hz,1 H),7.59-7.66(m,2 H),8.06(dd,J=8.16,1.13Hz,1 H)8.32(dd,J=8.28,1.51Hz,1 H),8.38(dd,J=7.28,1.25Hz,1H),8.60(br.s.,1 H),9.17(dd,J=4.27,1.51Hz,1 H)。LC-MS:m/z 537.0(M+H)+
N-[4-[4-(2-氯-4-氟-苯基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.57-1.76(m,4 H),2.04(br.s.,1 H),2.13(br.s.,1 H),3.57(br.s.,2 H),4.57(br.s.,1 H),6.97-7.04(m,1 H),7.10(d,J=8.06Hz,2 H),7.19-7.23(m,4 H),7.59-7.67(m,2 H),8.06(d,J=8.06Hz,1 H),8.32(d,J=8.33Hz,1 H),8.39(d,J=7.52Hz,1 H),8.59(br.s.,1 H),9.17(d,J=4.03Hz,1 H)。LC-MS:m/z 540.6(M+H)+
N-[4-[4-(2-氯-3-氟-苯基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.70-1.90(m,4 H),3.28(br.s.,1 H),3.51(s,2 H),3.60(br.s.,1 H),4.61(br.s.,1 H),7.09-7.15(m,3 H),7.22(d,J=8.33Hz,2 H),7.34-7.44(m,3 H),7.59-7.70(m,2 H),8.08(d,J=8.33Hz,1 H),8.36(d,J=8.06Hz,1 H),8.41(d,J=
7.25Hz,1 H),8.77(br.s.,1 H),9.20(d,J=3.76Hz,1 H)。LC-MS:m/z 540.6(M+H)+
N-(4-(4-羥基-4-(3-(甲磺醯基)苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.18(dd,J=4.3,1.3Hz,1H),8.63(br.s.,1H),8.37(dd,J=10.6,1.2Hz,1H),8.32-8.43(m,1H),8.07(dd,J=8.3,1.1Hz,1H),7.89-7.96(m,2H),7.57-7.74(m,5H),7.14-7.19(m,J=8.6Hz,2H),7.06-7.12(m,J=8.6Hz,2H),4.36(br.s.,1H),3.87(br.s.,1H),3.37-3.57(m,2H),3.24-3.33(m,2H),3.20(br.s.,1H),1.79(br.s.,2H),1.64(br.s.,2H)。LC-MS:m/z 566.7(M+H)+
N-[4-[4-羥基-4-(2-甲磺醯基苯基)哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.95(d,J=12.89Hz,3 H),1.99-2.11(m,2 H),3.27(br.s.,3 H),3.48(br.s.,2 H),3.87(br.s.,1 H),4.38(br.s.,1 H),7.10(m,J=8.60Hz,2 H),7.17(m,J=8.60Hz,2 H),7.61-7.65(m,3 H),7.69-7.74(m,1 H),7.93(d,J=8.60Hz,2 H),8.07(d,J=8.33Hz,1 H),8.34(d,J=8.33Hz,1 H),8.39(d,J=7.25Hz,1 H),8.64(br.s.,1 H),9.18(d,J=3.49Hz,1 H)。LC-MS:m/z 566.7(M+H)+
N-[4-[4-羥基-4-(2-羥基苯基)哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.94-2.09(m,4 H),2.21-2.27(m,1 H),2.50(br.s.,1 H),3.30(br.s.,1 H),3.50(br.s.,1 H),3.62(br.s.,1 H),4.63(br.s.,1 H),6.89(t,J=8.06Hz,2 H),7.05-7.12(m,3 H),7.17-7.24(m,3 H),7.60-7.67(m,2 H),8.07(d,J=8.06Hz,1 H),8.32(d,J=6.72Hz,1 H),8.39(d,J=7.25Hz,1 H),8.59(br.s.,1 H),9.17(d,J=
5.91Hz,1 H)。LC-MS:m/z 504.6(M+H)+
N-(4-(4-羥基-4-苯基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:9.05(1H),8.5(m,1H),8.4(m,1H),8.2(m,1H),7.7(m,2H),7.4(m,2H),7.4-7.05(m,7H),4.2(br,2H),3.2(br,2H),1.85(br,2H),1.6(br,2H)。LC-MS:m/z 488.6(M+H)+
N-(4-(4-羥基-4-(鄰甲苯基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(CD3OD)δ:9.1(1H),8.4(m,2H),8.2(m,1H),7.6(m,2H),7.4(m,1H),7.2-7.05(m,7H),4,4(br,1H),3.5(br,2H),2.5(s,3H),2.2-1.8(m,4H),1.4(br,2H)。LC-MS:m/z 502.6(M+H)+
N-[4-[4-(2-氟吡啶-4-基)-4-羥基-哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:2.08(br.s.,1 H),2.14-2.37(m,2 H),2.75(br.s.,1 H),3.22(br.s.,1 H),3.49(br.s.,2 H),3.56(br.s.,1 H),4.55(br.s.,1 H),7.09(d,J=8.60Hz,2 H),7.19(d,J=8.60Hz,3 H),7.56-7.66(m,2 H),7.94(t,J=8.19Hz,1 H),8.05(d,J=8.06Hz,1 H),8.12(d,J=4.57Hz,1 H),8.31(d,J=8.33Hz,1 H),8.37(d,J=7.25Hz,1 H),8.62(br.s.,1 H),9.16(d,J=5.91Hz,1 H)。LC-MS:m/z 507.6(M+H)+
N-[4-[4-羥基-4-(6-甲基吡啶-2-基)哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.70(br.s.,2 H),1.80(br.s.,2 H),2.02(br.s.,1 H),2.56(s,3 H),3.29(br.s.,1 H),3.63(br.s.,2 H),4.65(br.s.,1 H),7.07-7.12(m,4 H),7.24(d,J=8.60Hz,2 H),7.58-7.66(m,3 H),8.05(d,J=8.33Hz,1 H),8.31(d,J=6.72Hz,1 H),8.38(d,J=7.25Hz,1 H),8.58(br.s.,1 H),9.16(d,J=5.91Hz,1 H)。LC-MS:m/z 503.6(M+H)+
N-[4-[4-羥基-4-[6-(三氟甲基)吡啶-2-基]哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.63(br.s.,1H),8.37(dd,J=7.3,1.3Hz,1H),8.31(dd,J=8.3,1.6Hz,1H),8.02-8.08(m,1H),7.92(t,J=7.9Hz,1H),7.55-7.66(m,4H),7.20-7.25(m,J=8.6Hz,2H),7.07-7.13(m,J=8.3Hz,2H),4.50-4.71(m,2H),3.60-3.71(m,1H),3.50-3.60(m,1H),1.80-1.97(m,2H),1.74(br.s.,2H)。LC-MS:m/z 556.6(M+H)+
N-(4-(4-羥基-4-(2-甲氧基吡啶-3-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.12-9.19(m,1H),8.61(br.s.,1H),8.37(dd,J=7.3,1.2Hz,1H),8.30(dd,J=8.4,1.3Hz,1H),8.09(dd,J=5.0,1.5Hz,1H),8.02-8.07(m,1H),7.56-7.66(m,2H),7.50(dd,J=7.3,1.8Hz,1H),7.19(d,J=8.5Hz,2H),7.09(d,J=8.5Hz,2H),6.91(dd,J=7.3,5.0Hz,1H),4.57(br.s.,1H),4.02(s,3H),3.89(br.s.,1H),3.56(br.s.,2H),3.29(br.s.,1H),2.05-1.89(m,4H)。LC-MS:m/z 519.6(M+H)+
N-(4-(4-(6-氟-2-甲基吡啶-3-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.60(br.s.,1H),8.33(dd,J=19.9,1.3Hz,1H),8.35(dd,J=18.9,1.5Hz,1H),8.02-8.10(m,1H),7.70(t,J=8.2Hz,1H),7.56-7.66(m,2H),7.17(d,J=8.3Hz,2H),7.08(d,J=8.3Hz,2H),6.68(dd,J=8.6,3.5Hz,1H),4.55(br.s.,1H),3.56(br.s.,2H),3.28(br.s.,1H),2.70(s,3H),1.92-2.08(m,4H)。LC-MS:m/z 519.6(M+H)+
N-(4-(4-(5-氟-6-甲基吡啶-2-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(dd,J=4.3,1.9Hz,1H),8.64(br.s.,1H),8.36(dd,J=7.4,1.2Hz,1H),8.31(dd,J=8.3,1.6Hz,1H),8.20(d,J=5.1Hz,1H),8.05(dd,J=8.2,1.2Hz,1H),7.55-7.67(m,2H),7.26-7.32(m,1H),7.18(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,2H),4.53(br.s.,1H),3.53(br.s.,2H),3.19(br.s.,2H),2.50(d,J=3.5Hz,3H),2.04-2.23(m,2H),1.61-1.73(m,2H)。LC-MS:m/z 519.6(M+H)+
N-(4-(4-(3-氟吡啶-2-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.6Hz,1H),8.60(br.s.,1H),8.41-8.46(m,2H),8.39(dd,J=7.3,1.5Hz,1H),8.33(dd,J=8.4,1.6Hz,1H),8.07(dd,J=8.2,1.2Hz,1H),7.58-7.68(m,2H),7.51(dd,J=6.7,5.3Hz,1H),7.22(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),4.63(br.s.,1H),3.60-3.23(m,3H),2.32-1.86(br.m.,4H)。LC-MS:m/z 507.5(M+H)+
N-(4-(4-(2-氯-5-氟苯基)-4-羥基哌啶-1-羰基)苯基)萘-1-磺醯胺
1H NMR(氯仿-d)δ:9.18(d,J=3.0Hz,1H),8.61(br.s.,1H),8.30-8.42(m,2H),8.07(d,J=8.3Hz,1H),7.58-7.68(m,2H),7.49(dd,J=7.0,2.7Hz,1H),7.30-7.37(m,1H),7.19-7.26(m,2H),7.11(d,J=8.3Hz,2H),6.95-7.04(m,1H),4.61(br.s.,1H),3.60(br.s.,1H),3.50(br.s.,1H),3.23(br.s.,1H),2.16-2.31(m,1H),2.09(br.s.,1H),1.82(br.s.,2H)。LC-MS:m/z 541.0(M+H)+
N-(4-(4-(6-溴-5-氟吡啶-2-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.4,1.8Hz,1H),8.66(br.s.,1H),8.28-8.43(m,2H),8.13(d,J=5.0Hz,1H),8.07(dd,J=8.2,1.2Hz,1H),7.57-7.70(m,2H),7.44(t,J=5.3Hz,1H),7.19(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),4.55(br.s.,1H),3.18-3.56(m,3H),2.04-2.34(m,2H),1.63-1.65(m,2H)。LC-MS:m/z 586.4(M+H)+
N-(4-(4-羥基-4-(2-甲基吡啶-3-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.13(dd,J=1.6,4.3Hz,1 H),8.66(br.s.,1 H),8.38-8.26(m,2 H),8.22(d,J=4.7Hz,1 H),8.04(dd,J=1.2,8.2Hz,1 H),7.66-7.51(m,3 H),7.18-7.10(m,2 H),7.10-6.97(m,3 H),4.47(br.s.,1 H),3.53(br.s.,1 H),3.47-3.32(m,1 H),3.26(br.s.,1 H),2.70(s,3 H),2.09-1.71(m,5 H)。LC-MS:m/z 503.6(M+H)+
N-(4-(4-羥基-4-(3-(三氟甲基)吡啶-2-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.20(dd,J=4.3,1.6Hz,1H),8.75(d,J=3.5Hz,1H),8.71(s,1H),8.45-8.38(m,1H),8.35(d,J=8.4Hz,1H),8.12(d,J=6.9Hz,1H),8.08(dd,J=8.2,1.3Hz,1H),7.71-7.59(m,2H),7.43(dd,J=7.8,4.9Hz,1H),7.23(d,J=8.6Hz,2H),7.12(d,J=8.6Hz,2H),4.64(s,1H),3.61(s,2H),3.30(s,1H),2.37(s,2H),1.68(d,J=11.9Hz,3H)。LC-MS:m/z 577.7(M+H)+
N-(4-(4-(3-氯吡啶-2-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19(dd,J=4.3,1.7Hz,1H),8.68(s,1H),8.50(dd,J=4.6,1.3Hz,1H),8.40(dd,J=7.3,1.3Hz,1H),8.35(dd,J=8.3,1.7Hz,1H),8.08(dd,J=8.2,1.3Hz,1H),7.78(dd,J=8.0,1.3Hz,1H),7.65(ddd,J=13.7,7.9,4.4Hz,2H),7.32-7.29(m,1H),7.28-7.21(m,2H),7.18-7.09(m,2H),4.68(d,J=12.4Hz,1H),3.60(d,J=24.5Hz,2H),3.31(t,J=13.6Hz,1H),2.75(d,J=49.9Hz,2H),1.52(d,J=9.9Hz,2H)。LC-MS:m/z 523.6(M+H)+
N-(4-(4-羥基-4-(3-甲基吡啶-2-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.18(dd,J=4.3,1.7Hz,1H),8.56(s,1H),8.43-8.36(m,2H),8.33(dd,J=8.4,1.8Hz,1H),8.07(dd,J=8.3,1.3Hz,1H),7.69-7.59(m,2H),7.53(d,J=7.1Hz,1H),7.26-7.18(m,3H),7.14-7.08(m,2H),6.71(s,1H),4.65(s,1H),3.64(s,2H),3.35(s,1H),2.51(s,3H),2.39(s,1H),2.24(dd,J=10.2,4.5Hz,1H),1.56(m,2H)。LC-MS:m/z 503.6(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲基)吡啶-3-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(dd,J=1.3,4.3Hz,1 H),8.62(d,J=4.4Hz,1 H),8.42-8.26(m,2 H),8.11-7.92(m,2 H),7.69-7.55(m,2 H),7.47(dd,J=4.4,8.2Hz,1 H),7.22-7.06(m,4 H),3.61-3.40(m,6 H),3.40-3.17(m,2 H),2.07(br.s.,1 H),2.04-1.74(m,5 H)。LC-MS:m/z 557.6(M+H)+
N-(4-(4-(2-氟吡啶-3-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=1.8,4.4Hz,1 H),8.64(br.s.,1 H),8.42-8.27(m,2 H),8.13(td,J=1.6,4.7Hz,1 H),8.06(dd,J=1.3,8.4Hz,1 H),7.94(ddd,J=1.9,7.7,10.1Hz,1 H),7.69-7.55(m,2 H),7.26-7.16(m,3 H),7.14-7.05(m,2 H),4.58(br.s.,1 H),3.67-3.38(m,2 H),3.23(br.s.,1 H),2.22-2.09(br.s.,5 H)。LC-MS:m/z 507.5(M+H)+
N-(4-(4-羥基-4-(吡啶-4-基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19-9.14(m,1H),8.62(s,2H),8.39(d,J=7.3Hz,1H),8.32(d,J=8.3Hz,1H),8.07(d,J=3.9Hz,2H),7.68-7.58(m,2H),7.44(s,2H),7.23(d,J=8.5Hz,2H),7.12(d,J=8.5Hz,2H),4.66(s,1H),3.68(s,1H),3.49(s,1H),3.28(s,1H),1.87-1.64(m,4H)。LC-MS:m/z 489.4(M+H)+
N-(4-(4-(3-氯吡啶-4-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.2,1.5Hz,1H),8.62(s,1H),8.55(s,1H),8.50(s,1H),8.38(dd,J=7.3,1.1Hz,1H),8.32(dd,J=8.3,1.5Hz,1H),8.07(d,J=8.2Hz,1H),7.68-7.58(m,2H),7.54(d,J=4.9Hz,1H),7.21(d,J=8.5Hz,2H),7.11(d,J=8.5Hz,2H),4.61(s,1H),3.65(d,J=19.1Hz,1H),3.25(s,2H),2.83(s,1H),2.41(d,J=57.6Hz,2H),1.84(s,1H)。LC-MS:m/z 523.6(M+H)+
(4-羥基-4-(異噻唑-4-基)哌啶-1-基)(4-((喹啉-8-基磺醯基)甲基)苯基)甲酮
1H NMR(氯仿-d)δ:9.15(d,J=2.7Hz,1H),8.39-8.46(m,2H),8.38(s,1H),8.18(d,J=8.3Hz,1H),7.62-7.71(m,2H),7.17-7.25(m,5H),4.45(br.s.,1H),3.49(br.s.,2H),2.00(br.s.,3H),1.81(br.s.,1H),1.31(br.s.,1H)。LC-MS:m/z 495.6(M+H)+
步驟A:在-30℃下經由注射器向4-側氧基哌啶-1-甲酸三級丁酯(1當量)於THF中的溶液逐滴添加於THF中的相應RMgBr溶液(4當量)。添加之後,將所得混合物在-30℃下在N2下攪拌2h,然後允許溫至室溫。反應混合物由飽和的NH4Cl溶液淬滅,並且所得混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。殘餘物藉由柱層析法(PE/EtOAc)純化以便提供所需化合物3B。
步驟B:向化合物3B(1當量)於DCM中的溶液添加TFA(10當量),反應混合物在室溫下攪拌約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃
縮以便提供所需產物3C。粗產物未進行進一步純化直接地用於下一個步驟。
步驟C:向圓底燒瓶依序地添加化合物3C(1當量)、DMF(5mL)、DIPEA(3.0當量)、HBTU(1.2當量)以及1A(1當量)。將反應混合物在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥,過濾,並且將濾液濃縮。所需產物藉由標準方法來純化。
N-(4-(4-羥基-4-異丙基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.23(s,1H),8.96(s,1H),8.48-8.34(m,2H),8.10(d,J=8.1Hz,1H),7.76-7.61(m,2H),7.18(d,J=8.4Hz,2H),7.13(d,J=8.5Hz,2H),4.48(s,1H),3.50(s,1H),3.33(s,1H),3.11(s,1H),1.65-1.56(m,1H),1.41(d,J=53.9Hz,4H),0.92(d,J=6.9Hz,6H)。LC-MS:m/z 454.6(M+H)+
N-(4-(4-環丙基-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.7Hz,1H),8.58(s,1H),8.39(dd,J=7.3,1.3Hz,1H),8.33(dd,J=8.4,1.7Hz,1H),8.07(dd,J=8.2,1.3Hz,1H),7.69-7.59(m,2H),7.19(d,J=8.6Hz,2H),7.10(d,J=8.6Hz,2H),5.28(t,J=7.0Hz,1H),3.65(t,J=6.4Hz,4H),3.32(s,2H),2.40-2.22(m,4H),2.14(dd,J=23.1,12.0Hz,2H)。LC-MS:m/z 452.6(M+H)+
N-(4-(4-羥基-4-丙基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.7Hz,1H),8.55(s,1H),8.38(dd,J=7.3,
1.3Hz,1H),8.32(dd,J=8.4,1.7Hz,1H),8.06(dd,J=8.2,1.3Hz,1H),7.68-7.58(m,2H),7.17(d,J=8.6Hz,2H),7.08(d,J=8.6Hz,2H),4.34(s,1H),3.52-3.10(m,3H),1.46(dd,J=10.2,4.6Hz,4H),1.33(ddd,J=26.6,11.0,7.3Hz,4H),0.95(t,J=7.0Hz,3H)。LC-MS:m/z 454.6(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.7Hz,1H),8.56(s,1H),8.38(dd,J=7.3,1.3Hz,1H),8.32(dd,J=8.4,1.6Hz,1H),8.06(dd,J=8.2,1.3Hz,1H),7.68-7.58(m,2H),7.17(d,J=8.5Hz,2H),7.09(d,J=8.6Hz,2H),4.34(s,1H),3.43(s,1H),3.35(s,1H),3.20(s,1H),1.83(tt,J=13.0,6.5Hz,1H),1.49(s,2H),1.41(d,J=6.0Hz,2H),1.31(d,J=23.9Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 468.6(M+H)+
N-(4-(4-(三級丁基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19(dd,J=4.3,1.5Hz,1H),8.71(s,1H),8.40(dd,J=7.3,1.3Hz,1H),8.35(dd,J=8.3,1.4Hz,1H),8.08(dd,J=8.2,1.2Hz,1H),7.70-7.60(m,2H),7.18(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),4.52(s,1H),3.54(s,1H),3.32(s,1H),3.04(s,1H),1.71(s,4H),0.93(s,9H)。LC-MS:m/z 468.6(M+H)+
N-(4-(4-(環丁基甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.2,1.5Hz,1H),8.56(s,1H),8.38(dd,J=7.3,1.3Hz,1H),8.32(dd,J=8.3,1.5Hz,1H),8.06(dd,J=8.2,1.2Hz,1H),7.68-7.58(m.
2H),7.17(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H),4.33(s,1H),3.51-3.08(m,3H),2.57-2.43(m,1H),2.14-2.01(m,2H),1.91(dd,J=18.4,9.5Hz,1H),1.79(dd,J=10.5,8.5Hz,1H),1.76-1.64(m,4H),1.61(s,2H),1.43-1.35(m,2H)。LC-MS:m/z 480.6(M+H)+
步驟A:在氬氣下向含有催化量的1,2-二溴乙烷的乙醚溶液(從鈉/二苯甲酮中新蒸餾的)中添加鎂切屑(6.6當量)並且所得混合物在室溫下攪拌30分鐘。然後將被取代的苄基溴/氯(5當量)于無水乙醚中的溶液在2h時間內緩慢地添加至反應混合物並且在室溫下連續攪拌額外2h。然後將反應混合物冷卻至0℃,此時在氬氣氛下將溶于無水乙醚溶液中的化合物4A(1當量)緩慢地添加至反應混合物。所得反應混合物允許再在室溫下攪拌4小時。反應進度藉由TLC來監測。反應結束後,混合物用飽和的NH4Cl溶液淬滅,並且用EtOAc萃取。合併的有機層以水洗滌,經Na2SO4乾燥並且在減壓下濃縮以便得到粗產物。然後使用矽膠(100-200網目)以及乙烷中的20% EtOAc藉由柱層析法來純化粗產物以便提供所需化合物4B。
步驟B:化合物4B(1當量)溶解於DCM中並且冷卻至0℃,此時在0℃下添加TFA(10當量)。允許反應混合物溫至室溫並且在室溫下攪拌3-4小時直到LCMS和TLC證實反應完成為止。將反應混合物濃縮以便獲得粗產物,其用DCM和正戊烷濕磨3至4次以便提供化合物4C。
步驟C:在室溫下在氮氣氛下向化合物4C(1.2當量)於DMF中的溶液添加1A(1當量),隨後添加DIPEA(2當量)、HATU(1.2當量)以及DMAP(0.1當量)。允許反應混合物在室溫下攪拌16小時。反應進度藉由TLC來監測並且在反應完成後,粗混合物以EtOAc稀釋並且依序地用水和飽和碳酸氫鈉溶液來洗滌。然後將所得有機層分離,經Na2SO4乾燥並且在減壓下濃縮以便得到粗產物,藉由標準方
法純化粗產物以便提供所需化合物4D。
N-(4-(4-(2-氟苄基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14(s,1H),8.51(bs,1H),8.32(dd,2H,J=6.8Hz和J=7.6Hz),8.03(d,1H,J=8Hz),7.61-7.57(m,2H),7.18-7.05(m,8H),4.36(bs,1H),3.44(m,1H),3.27(m,1H),3.13(m,1H),2.96-2.88(m,2H),2.80(s,2H),1.33-1.25(m,3H)。LC-MS:m/z 520.2(M+H)+
N-(4-(4-(3-氟苄基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:10.40(s,1H),9.13-9.12(m,1H),8.45(dd,2H,J=8.4Hz和J=7.2Hz),8.27(d,1H,J=8Hz),7.74-7.69(m,2H),7.29-7.25(m,1H),7.18-6.98(m,7H),4.49(s,1H),4.06(m,1H),3.62-3.61(m,1H),3.18-3.12(m,2H),2.68(s,2H),1.38-1.33(m,4H)。LC-MS:m/z 520.2(M+H)+
N-(4-(4-羥基-4-(3-甲基苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15-9.13(m,1H),8.52(bs,1H),8.36-8.28(m,2H),8.03(d,1H,J=7.6Hz),7.63-7.57(m,2H),7.22-7.05(m,5H),6.99-6.93(m,2H),4.37(bs,1H),3.90-3.45(m,2H),3.27-2.98(m,2H),2.70(s,2H),2.33(s,2H),1.51-132(m,4H)。LC-MS:m/z 516.2(M+H)+
N-(4-(4-羥基-4-(2-甲基苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.13(m,1H),8.52(bs,1H),8.36-8.28(m,2H),8.03(d,1H,J=8.4Hz),7.63-7.57(m,2H),7.18-7.05(m,8H),4.35-4.48(m,1H),3.60-2.95(m,3H),2.80-2.79(m,3H),2.33(s,3H),1.52-1.39(m,4H)。LC-MS:m/z 516.2(M+H)+
N-(4-(4-羥基-4-(2-甲氧基苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:9.15-9.14(m,1H),8.51(bs,1H),8.36-8.28(dd,2H,J=4.2Hz和J=8Hz),8.03(d,1H,J=8Hz),7.63-7.57(m,2H),7.24-6.98(m,6H),6.94-6.89(m,2H),4.33(bs,1H),3.83(s,3H),3.41-3.12(m,3H),2.85-2.83(m,3H),1.57-1.29(m,4H)。LC-MS:m/z 532.6(M+H)+
N-(4-(4-羥基-4-(3-甲氧基苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15-9.14(m,1H),8.51(s,1H),8.32(dd,2H,J=7.2Hz和J=8Hz),8.03(d,1H,J=8Hz),7.63-7.57(m,2H),7.23-7.05(m,5H),6.90-6.68(m,3H),4.38(m,1H),3.79(s,3H),3.60-2.98(m,4H),2.71(s,2H),1.54-1.40(m,4H)。LC-MS:m/z 532.6(M+H)+
N-(4-(4-羥基-4-(3-(三氟甲基)苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.13(m,1H),8.53(bs,1H),8.32(dd,2H,J=6.8Hz,J
=8.4Hz),8.03(d,1H,J=8Hz),7.63-7.50(m,3H),7.45-7.33(m,3H),7.16-7.00(m,4H),4.38(m,1H),3.50-3.45(m,1H),3.28-2.91(m,2H),2.90-2.79(m,3H),1.58-1.33(m,4H).LC-MS:m/z 570.2(M+H)+
步驟A:4-(2,2,2-三氟乙醯胺基)苯甲酸(5B)向4-胺基苯甲酸(44g,0.32mmol)於TFA(300mL)中的混合物逐滴添加三氟乙酸酐(100mL),保持溫度低於10℃。添加之後,混合物在室溫下攪拌過夜。然後將混合物傾倒至碎冰中,將形成的沈澱物過濾,並且真空乾燥過夜以便得到標題化合物(2,72g)。1H NMR(DMSO-d6)δ:11.52(s,1H),7.93-8.07(m,2H),7.76-7.86(m,2H)。LC-MS:m/z 234.1(M+H)+
步驟B:向圓底燒瓶依序地添加相應化合物3(21mmol,1當量)、DMF(50mL)、DIPEA(3.0當量)、HBTU(1.2當量)以及中間物2(5g,21mmol,1當量)。將反應混合物在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥,過濾,並且將濾液濃縮。所需產物藉由矽膠層析法來純化。5C-1,LC-MS:m/z 427.8(M+H)+;5C-2,LC-MS:m/z 373.4(M+H)+;5C-3,LC-MS:m/z 429.4(M+H)+;5C-4,LC-MS:m/z 407.4(M+H)+
步驟C:向相應化合物5C(1當量)於甲醇中的混合物添加K2CO3(2當量)。將混合物在室溫下攪拌過夜,此時TLC指示s.m.消耗以及產物形成。然後將混合物真空濃縮,在鹽水與EtOAc之間分配,將有機層分離並且濃縮以便得到粗產物。
進一步純化藉由標準方法來進行。
1B:4-胺基苯基)(4-(2-氯苯基)-4-羥基哌啶-1-基)甲酮
1H NMR(氯仿-d)δ:7.55(dd,J=7.9,1.7Hz,1H),7.41(dd,J=7.8,1.3Hz,1H),7.29-7.34(m,3H),7.23-7.28(m,1H),6.66-6.71(m,2H),4.59(br.s.,1H),3.88(br.s.,2H),3.50(br.s.,2H),2.97(br.s.,1H),2.33(br.s.,2H),2.20-2.29(m,1H),1.97-2.16(m,2H)。LC-MS:m/z 331.8(M+H)+
1C:(4-胺基苯基)(4-羥基-4-異丁基哌啶-1-基)甲酮
1H NMR(氯仿-d)δ:7.21-7.33(m,2H),6.63-6.72(m,2H),3.35(br.s.,2H),1.87(dt,J=12.9,6.4Hz,1H),1.62(br.s.,4H),1.44(d,J=5.9Hz,2H),1.00(d,J=6.7Hz,6H)。LC-MS:m/z 277.4(M+H)+
1D:(4-胺基苯基)(4-(2,3-二氟苯基)-4-羥基哌啶-1-基)甲酮
LC-MS:m/z 333.3(M+H)+
1E:(4-胺基苯基)(4-苄基-4-羥基哌啶-1-基)甲酮
1H NMR(DMSO-d6)δ:7.44(d,2H,J=8Hz),7.32-7.16(m,5H),6.66(d,2H,J=8.4Hz),4.80(m,2H),4.37(m,2H),2.29(s,2H)。LC-MS:m/z 311.4(M+H)+
步驟D:在室溫下向1B-1E(0.5mmol)以及磺醯氯(80mg,0.55mmol)於30mL無水THF中的懸浮液添加吡啶(1.0mmol)。將所得混合物加熱並且在回流下攪拌6h。將反應混合物冷卻至室溫,然後以EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮。藉由標準純化方法獲得
標題化合物。
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.94(s,1H),7.54(dd,J=15.3,7.6Hz,2H),7.40(dd,J=7.6,1.3Hz,1H),7.32(d,J=6.5Hz,1H),7.27(d,J=9.2Hz,1H),7.24(d,J=8.2Hz,2H),7.13(d,J=7.9Hz,2H),4.61(s,1H),3.58(s,2H),3.32(s,1H),2.42-1.96(m,4H)。LC-MS:m/z 528.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-5-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.72(br.s.,2 H),1.96(br.s.,1 H),2.18(br.s.,1 H),2.33(br.s.,1 H),2.96(br.s.,1 H),3.28(br.s.,1 H),3.57(br.s.,2 H),4.61(br.s.,1 H),7.08(d,J=8.60Hz,2 H),7.21(d,J=8.33Hz,2 H),7.23-7.28(m,2 H),7.29-7.32(m,1 H),7.38(dd,J=7.52,1.34Hz,1 H),7.51(dd,J=7.66,1.48Hz,1 H),7.70(dd,J=8.33,4.30Hz,1 H),8.34-8.43(m,2 H),8.57(dd,J=8.46,1.48Hz,1 H),9.19-9.24(m,1 H)。LC-MS:m/z 540.1(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-2-氟喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.22(t,J=8.0Hz,1H),8.98(br.s.,1H),8.21(d,J=8.0Hz,1H),8.12(d,J=8.0Hz,1H),7.72(t,J=8.0Hz,1H),7.53(d,J=8.0Hz,1H),7.38(d,J=8.0Hz,1H),7.28-7.13(m,5H),6.94(d,J=8.0Hz,2H),4.64(br.s.,1H),3.55(br.s.,2H),3.35(br.s.,1H),3.17(br.s.,1H),2.42(br.s.,1H),2.21(s,1H),2.08(s,1H),1.95(s,
1H)。LC-MS:m/z 541.1(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)苯並[c]異噻唑-7-磺醯胺
1H NMR(氯仿-d)δ:9.45(s,1H),8.12(d,J=6.2Hz,1H),8.03(d,J=8.6Hz,1H),7.89(s,1H),7.51(dd,J=7.7,1.5Hz,1H),7.40(dd,J=7.7,1.5Hz,1H),7.30-7.35(m,2H),7.26(dd,J=7.5,1.6Hz,1H),7.22(d,J=8.6Hz,2H),7.11(d,J=8.3Hz,2H),4.59(br.s.,1H),3.57(br.s.,2H),3.34(br.s.,2H),2.26(br.s.,2H),2.04(br.s.,3H)。LC-MS:m/z 529.1(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.93(s,1H),7.54(t,J=7.9Hz,1H),7.20(d,J=8.3Hz,2H),7.11(d,J=8.4Hz,2H),3.28(s,2H),1.83(dt,J=12.8,6.5Hz,1H),1.56(s,7H),1.42(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 474.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-7-氟苯並[d]噻唑-4-磺醯胺
1H NMR(DMSO-d6)δ:10.87(s,1H),9.73(s,1H),8.19(dd,J=8.6,5.1Hz,1H),7.80(dd,J=7.9,1.5Hz,1H),7.57(t,J=8.7Hz,1H),7.32-7.40(m,2H),7.24-7.29(m,1H),7.19-7.23(m,J=8.6Hz,2H),7.10-7.16(m,J=8.6Hz,2H),5.41(s,1H),4.30(br.s.,1H),3.43(br.s.,1H),2.46(br.s.,2H)。LC-MS:m/z 529.1(M+H)+
5-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.22(d,J=2.8Hz,1H),8.58(dd,J=8.5,1.3Hz,1H),8.44-8.32(m,2H),7.71(dd,J=8.5,4.3Hz,1H),7.18(d,J=8.3Hz,2H),7.08(d,J=8.3Hz,2H),4.33(s,1H),3.31(s,3H),1.83(dt,J=12.8,6.3Hz,1H),1.57(s,4H),1.41(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 486.7(M+H)+
7-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.32(s,1H),8.12(dd,J=8.3,4.8Hz,1H),7.84(s,1H),7.22-7.27(m,1H),7.20(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,2H),4.25-4.46(m,1H),3.42(br.s.,2H),3.20(br.s.,1H),1.83(dt,J=12.9,6.4Hz,1H),1.55-1.70(m,3H),1.51(br.s.,1H),1.42(d,J=6.2Hz,2H),0.98(d,J=6.4Hz,6H)。LC-MS:m/z 492.6(M+H)+
2-胺基-6-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:8.09(s,1H),7.59(dd,J=8.2,2.5Hz,1H),7.49(dd,J=7.5,2.5Hz,1H),7.25(d,J=8.5Hz,2H),7.13(d,J=8.5Hz,2H),5.98(d,J=15.1Hz,2H),4.37(s,1H),3.43(d,J=30.3Hz,2H),3.22(s,1H),1.85(dt,J=12.9,6.4Hz,1H),1.49(d,J=28.9Hz,4H),1.43(d,J=6.0Hz,2H),0.99(d,J=6.6Hz,6H)。LC-MS:m/z 507.78(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]唑-4-磺醯胺
1H NMR(氯仿-d)δ:8.33(s,1H),7.92(d,J=7.7Hz,1H),7.83(d,J=8.2Hz,1H),7.61(s,1H),7.49(t,J=8.0Hz,1H),7.22(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),4.35(s,1H),3.40(d,J=25.4Hz,2H),3.21(s,1H),1.89-1.77(m,1H),1.65(s,4H),1.42(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 458.72(M+H)+
2-胺基-3-羥基-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯磺醯胺
1H NMR(氯仿-d)δ:10.54(s,1H),9.95(s,1H),7.24(d,J=8.6Hz,2H),7.10-7.03(m,3H),6.81(dd,J=7.7,1.2Hz,1H),6.45(t,J=8.0Hz,1H),5.47(s,2H),4.18(s,1H),4.08(s,1H),3.33-2.95(m,3H),1.80(dp,J=12.7,6.4Hz,1H),1.44(d,J=48.4Hz,4H),1.29(d,J=5.7Hz,2H),0.90(d,J=6.6Hz,6H)。LC-MS:m/z 448.69(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)苯並[d]唑-4-磺醯胺
1H NMR(氯仿-d)δ:8.33(s,1H),7.93(d,J=7.7Hz,1H),7.83(d,J=8.2Hz,1H),7.70(s,1H),7.56-7.46(m,2H),7.40(dd,J=7.6,1.3Hz,1H),7.35-7.30(m,1H),7.26(d,J=8.5Hz,3H),7.17(d,J=8.4Hz,2H),4.63(s,1H),3.60(s,2H),3.31(s,1H),2.94(s,1H)2.36(s,1H),2.20(s,1H),2.10(s,1H),1.99(s,1H)。LC-MS:m/z 512.67(M+H)+
2-胺基-N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-3-羥基苯磺醯胺
1H NMR(氯仿-d)δ:10.57(s,1H),9.94(d,J=3.7Hz,1H),7.81(dd,J=7.9,1.6Hz,1H),7.44-7.32(m,2H),7.32-7.23(m,3H),7.15-7.03(m,3H),6.81(d,J=7.7Hz,1H),6.45(t,J=7.9Hz,1H),5.48(s,2H),5.42(s,1H),4.36(s,1H),3.48(s,2H),3.11(s,1H),2.41(s,1H),1.53(d,J=38.6Hz,3H)。LC-MS:m/z 502.66(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-2-甲基苯並[d]唑-4-磺醯胺
1H NMR(氯仿-d)δ:7.83(d,J=7.8Hz,1H),7.78(s,1H),7.68(d,J=8.2Hz,1H),7.53(d,J=6.6Hz,1H),7.37(dd,J=13.5,7.1Hz,2H),7.32-7.21(m,4H),7.16(d,J=8.4Hz,2H),4.61(s,1H),3.60(s,2H),3.31(s,1H),3.04(s,1H),2.76(s,3H),2.38(s,1H),2.19(s,1H),2.02(d,J=45.1Hz,2H)。LC-MS:m/z 526.70(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)-2-甲基苯並[d]唑-4-磺醯胺
1H NMR(氯仿-d)δ:7.83(dd,J=7.8,0.7Hz,1H),7.68(d,J=8.1Hz,1H),7.59(s,1H),7.37(t,J=8.0Hz,1H),7.23(d,J=8.5Hz,2H),7.14(d,J=8.5Hz,2H),4.35(s,1H),3.39(dd,J=73.0,45.6Hz,3H),2.77(s,3H),1.84(dp,J=12.9,6.5Hz,1H),1.65(s,3H),1.52(s,1H),1.42(d,J=6.0Hz,2H),0.99(d,J=6.6Hz,6H)。LC-MS:m/z 472.70(M+H)+
6-氯-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)-2-(甲胺基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:7.98(br.s.,1H),7.78(d,J=1.9Hz,1H),7.71(d,J=1.9Hz,
1H),7.26(d,J=8.6Hz,2H),7.10-7.14(m,2H),3.44(br.s.,1H),3.22(d,J=3.2Hz,3H),1.82-1.87(m,1H),1.64-1.66(m,2H),1.42-1.44(m,2H),0.99(d,J=6.7Hz,6H)。LC-MS:m/z 538.1(M+H)+
2-胺基-N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-6-氟苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:8.01(s,1H),7.59(dd,J=8.2,2.5Hz,1H),7.53(dd,J=7.9,1.8Hz,1H),7.49(dd,J=7.5,2.6Hz,1H),7.41(dd,J=7.7,1.5Hz,1H),7.32(dd,J=7.5,1.5Hz,1H),7.30(d,J=3.8Hz,2H),7.25(dd,J=7.5,1.7Hz,1H),7.15(d,J=8.5Hz,2H),5.83(s,2H),4.64(s,1H),3.62(s,2H),3.34(s,1H),2.37(s,1H),2.26-2.17(m,1H),2.08(d,J=10.1Hz,1H),2.03(s,1H)。LC-MS:m/z 561.71(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.93(s,1H),7.54(t,J=7.9Hz,1H),7.20(d,J=8.3Hz,2H),7.11(d,J=8.4Hz,2H),3.28(s,2H),1.83(dt,J=12.8,6.5Hz,1H),1.56(s,7H),1.42(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 474.6(M+H)+
5-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.22(d,J=2.8Hz,1H),8.58(dd,J=8.5,1.3Hz,1H),8.44-
8.32(m,2H),7.71(dd,J=8.5,4.3Hz,1H),7.18(d,J=8.3Hz,2H),7.08(d,J=8.3Hz,2H),4.33(s,1H),3.31(s,3H),1.83(dt,J=12.8,6.3Hz,1H),1.57(s,4H),1.41(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 486.7(M+H)+
N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)苯基)-5-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.24(br.s.,1H),8.59(d,J=7.8Hz,1H),8.47(br.s.,1H),8.36-8.42(m,1H),7.68-7.76(m,1H),7.18-7.28(m,4H),7.10(d,m,4H),4.58(br.s.,1H),3.52(br.s.,2H),3.25(br.s.,1H),1.99-2.29(m,4H)。LC-MS:m/z 543.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)苯並[c][1,2,5]噻二唑-4-磺醯胺
1H NMR(DMSO-d6)δ:10.98(bs,1H),8.33(dd,2H,J=8.8Hz,J=6.8Hz),7.86-7.81(m,1H),7.25-7.12(m,7H),7.07(d,2H,J=8.4Hz),4.42(s,1H),4.25-3.90(m,1H),3.21-2.98(m,3H),2.65(s,2H),1.54-1.42(m,4H)。LC-MS:m/z 543.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)-2,3,4a,8a-四氫苯並[b][1,4]二-5-磺醯胺
1H NMR(DMSO-d6)δ:10.31(s,1H),7.38-7.16(m,8H),7.15-7.00(m,3H),6.90(t,1H,J=8Hz),4.44(bs,1H),4.28(d,4H,J=8.4Hz),4.19-4.10(m,1H),3.51-3.25(m,3H),2.68(s,2H),1.61-1.30(m,4H)。LC-MS:m/z 511.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)-6-氯環己-1,3-二烯-1-磺醯胺
1H NMR(DMSO-d6)δ:10.87(bs,1H),8.07(d,1H,J=8Hz),7.70-7.45(m,3H),7.37-6.96(m,9H),4.43(s,1H),4.25-3.98(m,1H),3.40-2.88(m,3H),2.66(s,2H),1.60-1.29(m,4H)。LC-MS:m/z 488.0(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)-2,3-二氯苯磺醯胺
1H NMR(DMSO-d6)δ:11.03(bs,1H),8.05(d,1H,J=7.6Hz),7.89(d,1H,J=8Hz),7.54(d,1H,J=8Hz),7.31-7.11(m,7H),7.07(d,2H,J=8.8Hz),4.43(s,1H),4.23-3.90(m,1H),3.41-2.90(m,3H),2.27(s,2H),1.58-1.30(m,4H)。LC-MS:m/z 520.4(M+H)+
步驟A:向化合物6A(1當量)於THF中的溶液添加吡啶(5當量),然後添加芳基磺醯氯(1.2當量)。將所得混合物在70℃下在微波照射下加熱20分鐘,此時LC-MS展示反應完成。然後將混合物濃縮並且藉由反相層析法(0-100% MeOH/H2O)來純化以便提供化合物6B。
步驟B:向相應化合物6B(1當量)於THF中的混合物添加LiOH(10當量),並且混合物在室溫下攪拌過夜。將反應混合物濃縮,殘餘物用水稀釋,並且用DCM萃取。水層用1N HCl中和,然後用DCM萃取。將有機層分離、濃縮以便獲得粗產物,藉由矽膠層析法來純化粗產物以便獲得化合物6C。
步驟C:向圓底燒瓶依序地添加相應化合物6C(1當量)、DMF(5mL)、DIPEA(3.0當量)、HBTU(1.2當量)以及化合物6D(1.0當量)。將反應混合物
在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥,過濾,並且將濾液真空濃縮。所需產物藉由標準方法來純化。
N-(4-(4-羥基-4-(吡啶-3-基甲基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:10.41(bs,1H),9.12(m,1H),8.52-8.26(m,5H),7.74-7.57(m,3H),7.27-7.24(m,1H),7.11-7.09(m,4H),4.54(s,1H),4.06-3.99(m,1H),3.18-2.99(m,3H),2.33(s,2H),1.37-1.34(m,4H)。LC-MS:m/z 503.6(M+H)+
N-(4-(4-羥基-4-(吡啶-2-基甲基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.12(m,1H),8.48-8.47(m,2H),8.31(dd,2H,J=8.4Hz和J=7.2Hz),8.02(d,1H,J=7.2Hz),7.65-7.56(m,3H),7.25-7.03(m,6H),4.13(bs,1H),3.39-3.23(m,4H),2.87(s,2H),1.53-1.28(m,4H)。LC-MS:m/z 503.6(M+H)+
N-(4-(4-羥基-4-((6-甲基吡啶-2-基)甲基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.13(m,1H),8.50(bs,1H),8.31(dd,2H,J=7.2和J=8Hz),8.03(d,1H,J=8Hz),7.62-7.49(m,3H),7.14(d,2H,J=8.4Hz),7.09-7.03(m,3H),6.88(d,1H,J=7.6Hz),5.29(s,1H),4.32-4.30(m,1H),3.48-3.21(m,3H),2.82(s,2H),2.50(s,3H),1.45-1.33(m,4H)。LC-MS:m/z 517.6(M+H)+
N-(4-(4-((6-氟吡啶-2-基)甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.13(m,1H),8.511(bs,1H),8.32(dd,2H,J=7.2Hz和J=7.2),8.03(d,1H,J=8Hz),7.76-7.59(m,3H),7.14(d,2H,J=8.4Hz),7.04(d,2H,J=8.4Hz),7.00-6.98(m,1H),6.83-6.80(m,1H),4.61(s,1H),4.34-4.32(m,1H),3.40-3.19(m,3H),2.86(s,2H),1.58-1.43(m,4H)。LC-MS:m/z 521.6(M+H)+
N-(4-(4-((2-氟吡啶-3-基)甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(400MHz,CDCl3)δ:9.15(dd,J=4.4,1.6Hz,1H),8.54(s,1H),8.36(dd,J=7.2,1.2Hz,1H),8.30(dd,J=8.4,1.6Hz,1H),8.12(d,J=4.4Hz,1H),8.04(d,J=7.2Hz,1H),7.66-7.56(m,3H),7.18-7.11(m,3H),7.06(d,J=8.5Hz,2H),4.36(s,1H),3.49(s,1H),3.29-3.21(m,1H),3.21-3.07(m,1H),2.80(s,2H),2.17(s,1H),1.74-1.60(m,2H),1.40-1.29(m,2H)。LC-MS:m/z 521.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-2-氟苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.42(dd,J=7.3,1.3Hz,1H),8.33(dd,J=8.3,1.6Hz,1H),8.06-8.12(m,1H),7.60-7.68(m,2H),7.50(dd,J=7.8,1.6Hz,1H),7.39(dd,J=7.7,1.5Hz,1H),7.29-7.32(m,1H),7.22-7.27(m,1H),7.14(t,J=7.8Hz,1H),6.99(d,J=9.7Hz,1H),6.82(d,J=8.1Hz,1H),4.65(d,J=13.2Hz,1H),3.58(br.s.,1H),3.40(d,J=11.3Hz,1H),3.22-3.35(m,1H),2.93(br.s.,1H),2.32(td,J=13.3,4.6Hz,1H),2.20(s,3H),2.11(d,J=12.6Hz,1H),1.98(d,J=13.4Hz,1H)。LC-MS:m/z 540.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-氟苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.42(dd,J=7.3,1.3Hz,1H),8.33(dd,J=8.3,1.6Hz,1H),8.06-8.12(m,1H),7.60-7.68(m,2H),7.50(dd,J=7.8,1.6Hz,1H),7.39(dd,J=7.7,1.5Hz,1H),7.29-7.32(m,1H),7.22-7.27(m,1H),7.14(t,J=7.8Hz,1H),6.99(d,J=9.7Hz,1H),6.82(d,J=8.1Hz,1H),4.65(d,J=13.2Hz,1H),3.58(br.s.,1H),3.40(d,J=11.3Hz,1H),3.22-3.35(m,1H),2.93(br.s.,1H),2.32(td,J=13.3,4.6Hz,1H),2.20(s,3H),2.11(d,J=12.6Hz,1H),1.98(d,J=13.4Hz,1H)。LC-MS:m/z 540.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-2-甲基苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.11(dd,J=4.3,1.6Hz,1H),8.43(dd,J=7.3,1.1Hz,1H),8.31(dd,J=8.3,1.6Hz,1H),8.04-8.10(m,1H),7.59-7.66(m,2H),7.52(dd,J=7.8,1.9Hz,1H),7.36(dd,J=7.5,1.6Hz,1H),7.20-7.30(m,3H),7.13(s,1H),7.03(dd,J=8.3,1.6Hz,1H),4.56(br.s.,1H),3.61(br.s.,1H),3.52(br.s.,1H),3.26(br.s.,1H),2.29-2.43(m,1H),2.11-2.27(m,4H),1.96-2.07(m,3H),1.90(d,J=7.8Hz,1H)。LC-MS:m/z 536.3(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-甲基苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.13-9.19(m,1H),8.48(br.s.,1H),8.28-8.41(m,2H),8.07(d,J=8.1Hz,1H),7.57-7.67(m,2H),7.52(d,J=7.3Hz,1H),7.38(d,J=7.5Hz,1H),7.22-7.27(m,1H),6.92-7.01(m,1H),6.88(d,J=8.1Hz,2H),4.69(d,J=13.7Hz,1H),
3.48(br.s.,1H),3.22-3.36(m,2H),2.37(br.s.,1H),2.21(br.s.,1H),2.15(br.s.,2H),2.02-2.11(m,2H),1.99(br.s.,1H)。LC-MS:m/z 536.3(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-甲氧基苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(d,J=4.0Hz,1H),8.30-8.42(m,2H),8.04-8.12(m,1H)7.59-7.67(m,2H),7.35-7.57(m,2H),7.23-7.34(m,3H),6.83-6.99(m,2H),6.36-6.49(m,1H),3.64-3.78(m,3H),3.18-3.35(m,1H),3.04(s,1H),2.76(s,1H),2.27-2.40(m,1H),1.90-2.14(m,4H)。LC-MS:m/z 552.3(M+H)+
N-(N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-氰基苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.6Hz,1H),8.33-8.44(m,2H),8.08-8.14(m,1H),7.63-7.70(m,2H),7.49(dd,J=7.8,1.6Hz,1H),7.36.7.44(m,3H),4.66(d,J=13.2Hz,1H),3.65(t,J=12.0Hz,2H),3.29-3.41(m,2H),3.21(br.s.,1H),2.64(br.s.,1H),2.20-2.40(m,3H),2.15(d,J=12.6Hz,1H),2.06(d,J=7.3Hz,1H)。LC-MS:m/z 547.7(M+H)+。
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-2-(二氟甲氧基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:2.09(br.s.,4 H)2.35(br.s.,2 H),3.30(br.s.,1 H),3.61(br.s.,2 H),4.60(br.s.,1 H),6.21(t,J=72Hz1 H),7.04(s,1 H),7.17(dd,J=8.46,1.75Hz,1 H),7.25-7.28(m,1 H),7.30-7.33(m,1 H),7.40(dd,J=7.79,1.61Hz,1 H),7.51(dd,
J=7.66,1.75Hz,1 H),7.61(dd,J=4.57,3.76Hz,1 H),7.63-7.66(m,1 H),7.84(d,J=8.33Hz,1 H),8.08(dd,J=8.33,1.34Hz,1 H),8.30(dd,J=8.33,1.61Hz,1 H),8.43(dd,J=7.39,1.48Hz,1 H),8.97(br.s.,1 H),9.14(dd,J=4.30,1.88Hz,1 H)。LC-MS:m/z 589.0(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-(二氟甲氧基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.21(br.s.,1H),8.89(br.s.,1H),8.38-8.50(m,2H),8.13(d,J=7.8Hz,1H),7.66-7.75(m,2H),7.50(br.s.,1H),7.39(d,J=7.5Hz,1H),7.29-7.33(m,1H),7.21-7.27(m,1H),7.07-7.16(m,1H),6.94-7.06(m,2H),6.37(s,1H),4.66(d,J=14.5Hz,1H),3.50(br.s.,1H),3.31(d,J=13.4Hz,2H),2.29(br.s.,2H),2.11(br.s.,2H)。LC-MS:m/z 589.0(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3-(三氟甲氧基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(dd,J=4.3,1.3Hz,1H),8.67(br.s.,1H),8.41(dd,J=7.4,1.2Hz,1H),8.33(dd,J=8.3,1.3Hz,1H),8.05-8.13(m,1H),7.60-7.69(m,2H),7.45-7.54(m,1H),7.38(d,J=7.5Hz,1H),7.31(br.s.,1H),7.20-7.27(m,1H),7.09-7.20(m,2H),6.96-7.09(m,1H),4.65(d,J=13.2Hz,1H),3.43-3.64(m,1H),3.28(d,J=9.7Hz,2H),3.01(br.s.,1H),2.18-2.39(m,1H),2.02-2.18(m,2H),1.88-2.02(m,1H)。LC-MS:m/z 607.1(M+H)+
3-氟-N-(4-(4-羥基-4-苯基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.06(d,J=2.6Hz,1 H),8.36(dd,J=1.0,7.2Hz,1 H),8.24(s,1 H),8.07-8.02(m,1 H),7.96-7.89(m,1 H),7.65(tJ=7.8Hz,1 H),7.51-7.30(m,5 H),7.25-7.19(m,J=8.2Hz,2 H),7.14-7.04(m,J=8.5Hz,2 H),4.59(br.s.,1 H),3.71-3.42(m,2 H),3.33(br.s.,1 H),1.90-1.84(m,5 H)。LC-MS:m/z 506.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)-3-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.04(d,J=3.0Hz,1H),8.28-8.40(m,2H),8.02(dd,J=8.3,1.1Hz,1H),7.92(dd,J=8.2,2.8Hz,1H),7.63(t,J=7.8Hz,1H),7.22-7.36(m,3H),7.12-7.21(m,4H),7.02-7.12(m,2H),4.36(br.s.,1H),3.27-3.09(m,3H),2.74(s,2H),1.76(br.s.,3H),1.59(br.s.,2H)。LC-MS:m/z 520.6(M+H)+
6-氟-N-(4-(4-羥基-4-苯基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.08-9.19(m,1H),8.56(br.s.,1H),8.28(dd,J=8.4,1.3Hz,1H),8.18(dd,J=7.6,2.9Hz,1H),7.61-7.73(m,2H),7.44-7.49(m,2H),7.39(t,J=7.6Hz,2H),7.29-7.34(m,1H),7.21-7.27(m,J=8.5Hz,2H),7.07-7.13(m,J=8.5Hz,2H),4.58(br.s.,1H),3.58(br.s.,1H),3.51(br.s.,1H),3.30(br.s.,1H),1.95-2.20(m,2H),1.86(br.s.,3H)。LC-MS:m/z 506.6(M+H)+
1H NMR(氯仿-d)δ:8.94-9.05(m,1H),8.33(dd,J=8.3,1.6Hz,1H),8.20(dd,J=8.6,3.0Hz,1H),7.76-7.83(m,1H),7.67-7.74(m,1H),7.57(dd,J=8.3,4.3Hz,1H),7.26-7.39(m,2H),7.18-7.26(m,1H),7.09-7.18(m,J=8.6Hz,2H),6.96-7.09(m,J=8.6Hz,2H),4.45(br.s.,1H),2.71(br.s.,2H),1.47-1.68(m,6H)。LC-MS:m/z 540.6(M+H)+
N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)-2-甲基苯基)-5-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19(dd,J=4.3,1.6Hz,1H),8.63(dd,J=8.5,1.7Hz,1H),8.36(dd,J=8.3,5.9Hz,1H),7.78(dd,J=8.6,4.3Hz,1H),7.34-7.46(m,2H),7.09-7.20(m,4H),7.04(dd,J=8.3,1.6Hz,1H),4.58(br.s.,1H),4.48(d,J=10.2Hz,1H),3.52(br.s.,3H),2.06-2.36(m,7H)。LC-MS:m/z 556.7(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-3,5-二氟苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(dd,J=4.3,1.6Hz,1H),8.75(br.s.,1H),8.45(dd,J=7.4,1.2Hz,1H),8.36(dd,J=8.3,1.3Hz,1H),8.13(d,J=8.1Hz,1H),7.63-7.72(m,2H),7.50(dd,J=7.8,1.6Hz,1H),7.39(dd,J=7.7,1.5Hz,1H),7.31(d,J=7.5Hz,1H),7.25(td,J=7.5,1.6Hz,1H),6.69-6.80(m,2H),4.67(d,J=10.7Hz,1H),3.53-3.68(m,1H),3.26-3.46(m,2H),2.94(br.s.,1H),2.32-2.00(m,4H)。LC-MS:m/z 558.1(M+H)+
N-(4-(4-(乙氧基甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.10-9.20(m,1H),8.55(br.s.,1H),8.26-8.43(m,2H),8.05(d,J=8.2Hz,1H),7.55-7.70(m,2H),7.12-7.20(m,J=8.5Hz,2H),7.03-7.12(m,J=8.5Hz,2H),4.37(br.s.,1H),3.53(q,J=6.9Hz,2H),3.45(br.s.,1H),3.36(br.s.,1H),3.26(s,3H),2.29-2.41(m,1H),1.65(br.s.,3H),1.55(br.s.,1H),1.20(td,J=7.0,2.2Hz,3H)。LC-MS:m/z 470.6(M+H)+
N-[4-[4-羥基-4-(2-甲氧基乙基)哌啶-1-羰基]苯基]喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.28(br.s.,3 H),1.58(br.s.,2 H),1.73-1.79(m,4 H),2.04(d,J=4.99Hz,1 H),3.25(br.s.,1 H),3.45(br.s.,2 H),3.65(br.s.,2 H),4.38(br.s.,1 H),7.11(m,J=8.22Hz,2 H),7.18(m,J=8.51Hz,2 H),7.61-7.72(m,2 H),8.09(d,J=8.22Hz,1 H),8.36-8.44(m,2 H),8.86(br.s.,1 H),9.19-9.24(m,1 H)。LC-MS:m/z 470.6(M+H)+
N-(4-(4-(環丙基甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19(d,J=2.8Hz,1H),8.67(s,1H),8.40(dd,J=7.3,1.3Hz,1H),8.35(d,J=7.2Hz,1H),8.07(dd,J=8.2,1.2Hz,1H),7.70-7.58(m,2H),7.18(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),4.37(s,1H),3.42(d,J=38.4Hz,2H),3.20(s,1H),1.62(d,J=56.1Hz,4H),1.42(s,2H),0.80-0.66(m,1H),0.59-0.46(m,2H),0.10(q,J=4.9Hz,2H)。LC-MS:m/z 466.6(M+H)+
N-(4-(4-((2,2-二氟環丙基)甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.6Hz,1H),8.64(br.s.,1H),8.28-8.43(m,2H),8.07(dd,J=8.1,1.3Hz,1H),7.54-7.71(m,2H),7.13-7.21(m,2H),7.06-7.13(m,2H),4.23-4.51(m,1H),3.49(d,J=13.2Hz,1H),3.34(br.s.,1H),3.23(br.s.,1H),1.58(br.s.,2H),1.38-1.56(m,5H),0.77-1.02(m,3H)。LC-MS:m/z 502.6(M+H)+
N-(6-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-2-甲基吡啶-3-基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14(dd,J=4.4,1.6Hz,1H),8.46(dd,J=7.3,1.3Hz,1H),8.34(dd,J=8.3,1.5Hz,1H),8.09-8.14(m,1H),7.78(d,J=8.3Hz,1H),7.61-7.71(m,2H),7.50(dd,J=7.8,1.5Hz,1H),7.39(dd,J=7.7,1.4Hz,1H),7.31(s,1H),7.22-7.28(m,1H),4.63(d,J=13.1Hz,1H),3.84(d,J=13.6Hz,1H),3.54-3.64(m,1H),3.33(td,J=12.9,2.6Hz,1H),2.46(s,3H),2.24-2.38(m,2H),1.97-2.16(m,2H),1.60-1.75(m,2H)。LC-MS:m/z 537.7(M+H)+
N-(3-氰基-4-(4-羥基-4-苯基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.20(dd,J=4.3,1.6Hz,1H),8.43(dd,J=12.5,7.8Hz,1H),8.43(dd,J=15.6,7.9Hz,1H),8.14(dd,J=8.2,1.2Hz,1H),7.66-7.74(m,2H),7.45-7.49(m,4H),7.39(d,J=7.6Hz,4H),4.64(d,J=13.5Hz,2H),3.74(d,J=7.0Hz,2H),3.27(br.s.,1H),3.13(br.s.,1H),2.02(dd,J=14.2,4.0Hz,4H)。LC-MS:m/z 512.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)萘-1-磺醯胺
1H NMR(氯仿-d)δ:8.70(d,J=8.3Hz,1H),8.25(d,J=7.0Hz,1H),8.05(d,J=8.1Hz,1H),7.94(d,J=7.8Hz,1H),7.57-7.70(m,3H),7.46-7.55(m,2H),7.36-7.43(m,1H),7.19-7.27(m,3H),7.00(d,J=8.6Hz,2H),4.64(br.s.,1H),3.56(br.s.,1H),3.51(s,1H),3.31(br.s.,1H),2.36(br.s.,1H),2.15-2.23(m,1H),1.91-2.13(m,3H)。LC-MS:m/z 521.0(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)色滿-8-磺醯胺
1H NMR(氯仿-d)δ:7.68(d,J=7.8Hz,1H),7.54(dd,J=7.8,1.6Hz,1H),7.39(dd,J=7.7,1.5Hz,1H),7.29-7.33(m,2H),7.19-7.28(m,2H),7.17(d,J=8.6Hz,2H),6.87(t,J=7.8Hz,1H),4.63(br.s.,1H),4.36-4.47(m,2H),3.61(br.s.,2H),3.31(br.s.,1H),2.81(t,J=6.3Hz,2H),2.39(br.s.,1H),2.14-2.32(m,1H),2.01-2.12(m,3H),1.87-2.01(m,1H),1.71(d,J=14.2Hz,1H)。LC-MS:m/z 527.7(M+H)+
化合物186(一般程序6,步驟C)
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)苯並呋喃-7-磺醯胺
1H NMR(氯仿-d)δ:7.75-7.88(m,3H),7.52(dd,J=7.9,1.5Hz,1H),7.40(dd,J=7.5,1.3Hz,1H),7.30-7.35(m,2H),7.21-7.28(m,3H),7.10(d,J=8.6Hz,2H),6.90(d,J=2.1Hz,1H),4.64(br.s.,1H),3.59(br.s.,1H),3.51(s,1H),3.31(br.s.,1H),2.91(s,1H),2.14-2.31(m,1H),2.09(br.s.,1H),1.86-2.07(m,2H)。LC-MS:m/z 511.0(M+H)+
N-(3-氯-4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(d,J=4.0Hz,1H),8.42(d,J=7.3Hz,1H),8.35(d,J=8.1Hz,1H),8.10(d,J=8.3Hz,1H),8.03(d,J=5.4Hz,1H),7.61-7.69(m,2H),7.47-7.55(m,1H),7.39(d,J=7.5Hz,1H),7.19-7.25(m,1H),7.16(s,1H),6.95-7.13(m,3H),4.63-4.73(m,1H),3.61(d,J=11.0Hz,1H),3.21-3.35(m,2H),2.35(td,J=13.2,4.6Hz,2H),2.10(t,J=11.3Hz,2H)。LC-MS:m/z 556.5(M+H)+
N-(2-氯-4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.13(dd,J=4.3,1.6Hz,1H),8.92(br.s.,1H),8.48(dd,J=7.4,1.2Hz,1H),8.29(dd,J=8.3,1.6Hz,1H),8.05-8.12(m,1H),7.84(d,J=8.6Hz,1H),7.58-7.68(m,2H),7.51(dd,J=7.8,1.6Hz,1H),7.40(dd,J=7.7,1.5Hz,1H),7.30-7.34(m,1H),7.23-7.27(m,1H),7.19(dd,J=8.6,1.9Hz,1H),4.60(br.s.,1H),3.61(br.s.,2H),3.31(br.s.,1H),2.91(br.s.,1H),2.14-2.27(m,1H),1.91-2.14(m,3H)。LC-MS:m/z 556.5(M+H)+
N-(4-(4-羥基-4-(3-羥基丙基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:10.40(s,1H),9.13(dd,J=4.1,1.8Hz,1H),8.52(dd,J=8.5,1.8Hz,1H),8.42(dd,J=7.3,1.2Hz,1H),8.29(dd,J=8.2,1.5Hz,1H),7.63-7.85(m,2H),7.01-7.16(m,4H),4.39(br.s.,1H),4.25(s,1H),3.17(br.s.,2H),3.07(br.s.,1H),1.39-1.51(m,3H),1.34(dd,J=9.4,5.6Hz,5H)。LC-MS:m/z 470.2(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-2-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:8.33-8.48(m,2H),8.02-8.07(m,2H),7.60(t,J=7.8Hz,1H),7.49(dd,J=7.8,1.3Hz,1H),7.37(dd,J=7.7,1.5Hz,1H),7.28(br.s.,1H),7.21-7.25(m,2H),7.20(s,1H),7.11-7.16(m,2H),3.56(br.s.,3H),2.18-2.38(m,2H),1.64(br.s.,4H)。LC-MS:m/z 540.6(M+H)+
5-氟-N-(4-(4-(6-氟-2-甲基吡啶-3-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.21(dd,J=4.3,1.6Hz,1H),8.57(dd,J=8.6,1.6Hz,1H),8.34-8.45(m,2H),7.68-7.74(m,2H),7.27(s,1H),7.17-7.22(m,J=8.3Hz,2H),7.05-7.11(m,J=8.3Hz,2H),6.70(dd,J=8.5,3.6Hz,1H),3.46-3.65(m,2H),1.91-2.08(m,4H),1.62-1.82(m,4H)。LC-MS:m/z 539.7(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)-3-氟苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:10.67(s,1H),9.119-9.110(m,1H),8.48(dd,2H,J=8Hz和J=7.2Hz),8.29(d,1H,J=8.4Hz),7.77-7.69(m,2H),7.25-7.06(m,6H),6.94-6.90(m,2H),4.45(s,1H),4.12-4.09(m,1H),3.17-2.98(m,3H),2.68(s,2H),1.39-1.23(m,4H)。LC-MS:m/z 520.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)-2-氟苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:9.88(bs,1H),9.08-9.06(m,1H),8.57-8.54(m,1H),8.29(t,2H,J=8.4Hz),7.31-7.17(m,6H),7.08-7.03(m,2H),4.44(s,1H),4.09-4.01(m,1H),3.21-3.02(m,3H),2.65(s,2H),1.41-1.23(m,4H)。LC-MS:m/z 520.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)-2-甲基苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:9.35(s,1H),9.3-9.12(m,1H),8.57(d,1H,J=8.4Hz),8.28(dd,2H,J=8.8Hz和J=7.2Hz),7.77-7.68(m,2H),7.25-7.17(m,5H),7.04-6.95(m,3H),4.08(bs,1H),3.39-3.37(m,1H),3.22-3.01(m,3H),2.65(s,2H),2.04(s,3H),1.40-1.24(m,4H)。LC-MS:m/z 516.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)-3-甲氧基苯基)喹啉-8-磺醯胺
1H NMR(DMSO-d6)δ:10.26(bs,1H),9.13(bs,1H),8.49-8.21(m,2H),7.71-7.69(m,2H),7.23-7.17(m,5H),6.80-6.61(m,3H),4.08-4.07(m,1H),3.54(s,3H),3.18(s,2H),2.92-2.84(m,2H),2.66-2.62(m,2H),1.45-1.34(m,4H).LC-MS:m/z 532.6(M+H)+
N-(4-(4-苄基-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14-9.13(m,1H),8.36-8.27(m,2H),8.04-8.02(m,1H),7.62-7.56(m,2H),7.33-7.27(m,2H),7.16-7.15(m,3H),7.14-7.13(m,2H),4.36(bs,1H),3.72-3.66(m,1H),3.44-3.42(m,2H),3.18-3.12(m,1H),2.74(s,2H),1.48-1.42(m,4H)。LC-MS:m/z 502.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)萘-1-基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.27(d,J=4.3Hz,2H),8.39-8.48(m,2H),8.29-8.38(m,1H),8.12(dd,J=7.5,4.3Hz,1H),7.83-7.92(m,1H),7.65-7.76(m,2H),7.48-7.57(m,3H),7.39(d,J=7.5Hz,1H),7.20-7.27(m,2H),7.16(d,J=2.4Hz,1H),4.88(br.s.,1H),3.33-3.59(m,2H),3.17-3.33(m,2H),2.56(d,J=5.1Hz,1H),2.45(d,J=4.8Hz,1H),1.85(d,J=11.0Hz,1H),1.73(d,J=16.1Hz,1H)。LC-MS:m/z 573.1(M+H)+
N-(4-(4-(2,3-二氟苄基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(400MHz,CDCl3)δ:9.16(dd,J=4.2,1.4Hz,1H),8.38(d,J=7.3Hz,1H),8.31(d,J=8.4Hz,1H),8.06(d,J=8.2Hz,1H),7.69-7.57(m,2H),7.17-7.13(m,2H),7.13-7.05(m,3H),7.04-6.92(m,2H),6.73(s,1H),4.39(s,1H),3.87(s,1H),3.40(s,1H),3.23(s,1H),2.84-2.74(m,2H),1.74-1.60(m,2H),1.71-1.59(m,4H)。LC-MS:m/z 538.6(M+H)+
5-氟-N-(4-(4-(2-氟苄基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.19(s,1H),8.53(s,1H),8.41-8.33(m,1H),7.66(s,1H),7.24(dd,J=13.3,6.0Hz,2H),7.17(dd,J=14.0,7.9Hz,3H),7.13-7.08(m,2H),7.05(d,J=7.6Hz,3H),4.37(s,1H),3.49-3.05(m,3H),2.82(s,2H),1.78-1.50(m,4H)。LC-MS:m/z 538.1(M+H)+
N-(4-(4-(2,6-二氟苄基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.9Hz,1H),8.58(br.s.,1H),8.35(dd,J=18.0,7.8Hz,1H),8.35(dd,J=17.9,7.9Hz,1H),8.06(dd,J=8.3,1.3Hz,1H),7.57-7.69(m,2H),7.19-7.27(m,1H),7.14-7.19(m,2H),7.05-7.11(m,2H),6.86-6.94(m,2H),4.35-4.45(m,1H),3.41-3.53(m,1H),3.31(br.s.,1H),3.08-3.20(m,1H),2.88-2.92(m,1H),2.82(s,1H),1.70(br.s.,1H),1.64(dd,J=11.1,6.9Hz,2H),1.43-1.58(m,2H)。LC-MS:m/z 538.7(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲基)苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.15(dd,J=4.3,1.6Hz,1H),8.60(br.s.,1H),8.27-8.40(m,2H),8.04(dd,J=8.2,1.2Hz,1H),7.55-7.71(m,3H),7.43-7.54(m,2H),7.31-7.40(m,1H),7.12-7.21(m,J=8.6Hz,2H),7.01-7.12(m,J=8.6Hz,2H),4.41(br.s.,1H),3.46(d,J=9.1Hz,1H),3.27(br.s.,1H),3.05(br.s.,1H),2.98(s,2H),1.83(br.s.,1H),1.66(br.s.,2H),1.56(br.s.,2H),1.45(br.s.,1H)。LC-MS:m/z 570.7(M+H)+
N-(4-(4-羥基-4-新戊基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.20(d,J=2.9Hz,1H),8.73(s,1H),8.41(dd,J=7.3,1.2Hz,1H),8.36(d,J=7.3Hz,1H),8.08(dd,J=8.2,1.2Hz,1H),7.70-7.60(m,2H),7.18(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),4.36(s,1H),3.39(d,J=33.4Hz,2H),3.16(s,1H),1.75-1.57(m,4H),1.49(s,2H),1.05(s,9H)。LC-MS:m/z 482.7(M+H)+
N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(DMSO-d6)δ:10.79(s,1H),9.66(s,1H),8.50(d,J=8.1Hz,1H),8.12(d,J=7.5Hz,1H),7.65(t,J=7.8Hz,1H),7.41(t,J=7.4Hz,1H),7.33(q,J=8.2Hz,1H),7.16-7.24(m,3H),7.11-7.15(m,2H),4.31(br.s.,1H),3.32-3.13(br.s.,3H),2.00(d,J=7.3Hz,2H),1.63(br.s.,2H)。LC-MS:m/z 530.6(M+H)+
N-(4-(4-(2-(二氟甲基)苯基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(br.s.,1H),8.19(d,J=7.8Hz,1H),8.08-8.14(m,1H),7.93-8.03(m,1H),7.84(d,J=4.8Hz,1H),7.48-7.60(m,2H),7.44(br.s.,1H),7.37(br.s.,1H),7.23(d,J=8.3Hz,2H),7.10-7.18(m,2H),4.91-5.06(m,1H),4.54-4.73(m,1H),3.80(br.s.,2H),3.72(br.s.,1H),3.45-3.65(m,2H),2.32-2.61(m,2H)。LC-MS:m/z 544.7(M+H)+
N-(4-(4-羥基-4-(2-羥基-2-甲基丙基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.8Hz,1H),8.56(br.s.,1H),8.38(dd,J=7.3,1.3Hz,1H),8.31(dd,J=8.4,1.6Hz,1H),8.06(dd,J=8.3,1.1Hz,1H),7.57-7.67(m,2H),7.17(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H),4.31(br.s.,1H),3.40(br.s.,2H),3.21(br.s.,1H),1.86-1.65(br.m,6H),1.36(s,6H)。LC-MS:m/z 484.6(M+H)+
N-(4-(4-丁基-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(d,J=2.6Hz,1H),8.59(br.s.,1H),8.25-8.42(m,2H),8.06(d,J=7.9Hz,1H),7.55-7.68(m,2H),7.17(d,J=8.2Hz,2H),7.08(d,J=8.2Hz,2H),4.33(br.s.,1H),3.42(br.s.,1H),3.34(br.s.,1H),3.19(br.s.,1H),1.60(br.s.,2H),1.37-1.37(m,11H),0.9(t,J=6.6Hz,3H)。LC-MS:m/z 468.6(M+H)+
N-(4-(4-羥基-4-((1-甲基環丙基)甲基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.15-8.23(m,1H),8.06-8.13(m,1H),7.92(s,1H),7.54(t,J=7.8Hz,1H),7.16-7.24(m,J=8.3Hz,2H),7.07-7.14(m,J=8.3Hz,2H),4.34(br.s.,1H),3.29(br.s.,3H),1.66(br.s.,2H),1.47(s,2H),1.33(br.s.,1H),1.28(s,1H),1.17(s,3H),0.25-0.38(m,4H)。LC-MS:m/z 480.6(M+H)+
N-(4-(4-羥基-4-((1-甲基環丙基)甲基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.56(br.s.,1H),8.38(dd,J=7.5,1.3Hz,1H),8.32(dd,J=8.3,1.6Hz,1H),8.06(dd,J=8.2,1.2Hz,1H),7.58-7.67(m,2H),7.14-7.20(m,J=8.6Hz,2H),7.04-7.11(m,J=8.6Hz,2H),4.36(br.s.,1H),3.44(br.s.,1H),3.36(br.s.,1H),3.17(br.s.,1H),1.74(br.s.,1H),1.70(br.s.,1H),1.63(d,J=6.7Hz,3H),1.46(s,2H),1.17(s,3H),0.24-0.37(m,4H)。LC-MS:m/z 480.6(M+H)+
N-(4-(4-(環丙基甲基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(br.s.,1H),8.19(d,J=7.8Hz,1H),8.10(d,J=7.3Hz,1H),7.94(s,1H),7.54(t,J=7.7Hz,1H),7.20(br.s.,2H),7.12(br.s.,2H),4.38(br.s.,1H),3.51(br.s.,1H),3.36(br.s.,2H),2.06(br.s.,2H),1.69(d,J=8.6Hz,2H),1.43(br.s.,2H),0.74(br.s.,1H),0.53(d,J=7.5Hz,2H),0.11(d,J=4.3Hz,2H)。LC-MS:m/z 472.6(M+H)+
N-(4-(4-(環丁基甲基)-4-羥基哌啶-1-羰基)苯基)-5-氟喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.21(dd,J=4.2,1.5Hz,1H),8.57(dd,J=8.5,1.5Hz,1H),8.37(dd,J=8.2,5.7Hz,2H),7.70(dd,J=8.5,4.3Hz,1H),7.26(d,J=8.7Hz,1H),7.17(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H),4.33(s,1H),3.54-3.08(m,4H),2.49(dd,J=15.5,7.7Hz,1H),2.13-2.01(m,2H),1.91(dd,J=18.4,9.4Hz,1H),1.83-1.75(m,1H),1.60(d,J=7.0Hz,5H),1.48-1.51(m,2H),1.42(s,2H),1.27(s,2H)。LC-MS:m/z 498.6(M+H)+
N-(4-(4-羥基-4-新戊基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.3Hz,1H),8.10(d,J=8.3Hz,1H),7.91(s,1H),7.54(t,J=7.9Hz,1H),7.18-7.22(m,J=8.3Hz,2H),7.09-7.13(m,J=8.3Hz,2H),1.65(br.s.,4H),1.50(s,2H),1.28(s,4H),1.05(s,9H).LC-MS:m/z 488.6(M+H)+
5-氟-N-(4-(4-羥基-4-新戊基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.23(dd,J=4.3,1.5Hz,1H),8.60(dd,J=8.5,1.5Hz,1H),8.44(s,1H),8.39(dd,J=8.3,5.7Hz,1H),7.72(dd,J=8.5,4.3Hz,1H),7.31-7.26(m,1H),7.18(d,J=8.5Hz,2H),7.08(d,J=8.5Hz,2H),4.36(s,1H),3.50-3.02(m,3H),1.70-1.58(m,4H),1.49(s,2H),1.06(d,J=8.3Hz,9H)。LC-MS:m/z 500.71(M+H)+
5-氟-N-(4-(4-羥基-4-(2-(三氟甲基)苄基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:1.46-1.64(m,3H),1.81(br.s.,1H),2.98(s,2H),3.05(br.s.,1H),3.28(br.s.,1H),3.38-3.51(m,1H),4.42(br.s.,1H),7.06(m,J=8.33Hz,2H),7.16(m,J=8.33Hz,2H),7.23-7.27(m,1H),7.32-7.39(m,1H),7.44-7.53(m,2H),7.64-7.72(m,2H),8.37(dd,J=8.19,5.78Hz,1H),8.41(s,1H),8.55(dd,J=8.60,1.61Hz,1H),9.20(dd,J=4.30,1.61Hz,1H)。LC-MS:m/z 588.7(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲基)苄基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:1.44(br.s.,1 H),1.51-1.70(m,3H),2.99(s,2H),3.06(br.s.,1H),3.30(br.s.,1 H),3.39-3.47(m,1H),4.42(br.s.,1H),7.10(m,J=8.60Hz,2H),7.17(m,J=8.60Hz,2H),7.33-7.40(m,1H),7.45-7.56(m,3H),7.67(d,J=7.79Hz,1H),8.10(dd,J=7.52,1.07Hz,1H),8.17(dd,J=8.06,0.81Hz,1H),8.22(s,1H),9.29(s,1H)。LC-MS:m/z 576.7(M+H)+
N-(4-(4-羥基-4-(2-甲基烯丙基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.30(s,1H),8.18(dd,J=8.1,0.8Hz,1H),8.08-8.14(m,1H),8.06(s,1H),7.53(t,J=7.8Hz,1H),7.17-7.24(m,2H),7.06-7.15(m,2H),4.96-5.03(m,1H),4.78(s,1H),4.36(br.s.,1H),3.44(br.s.,1H),3.35(br.s.,1H),3.17(br.s.,1H),2.18-2.22(m,2H),1.82(s,3H),1.63(br.s.,2H),1.48(br.s.,2H)。LC-MS:m/z 472.69(M+H)+
1H NMR(氯仿-d)δ:9.14(d,J=5.6Hz,1H),8.80(br.s.,1H),8.43(d,J=7.3Hz,1H),8.36(d,J=8.3Hz,1H),8.13(d,J=8.1Hz,1H),7.62-7.72(m,2H),7.53(s,1H),7.23-7.33(m,2H),6.84(t,J=56Hz,1H),4.36(br.s.,1H),3.42(br.s.,2H),3.22(br.s.,1H),1.84(dt,J=12.9,6.4Hz,1H),1.64(br.s.,2H),1.52(br.s.,2H),1.42(d,J=5.9Hz,2H),0.98(d,J=6.7Hz,6H)。LC-MS:m/z 518.7(M+H)+
(E)-N-(4-(4-(3,3-二氟丙-1-烯-1-基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.21(dd,J=4.4,1.7Hz,1H),8.85(s,1H),8.40(ddd,J=9.9,7.9,1.4Hz,2H),8.09(dd,J=8.2,1.2Hz,1H),7.72-7.61(m,2H),7.19(d,J=8.6Hz,2H),7.13(d,J=8.6Hz,2H),6.28-5.84(m,3H),4.43(s,1H),3.51(s,1H),3.30(d,J=69.3Hz,2H),1.82-1.52(m,4H)。LC-MS:m/z 488.63(M+H)+
N-(4-(4-羥基-4-((2,2,2-三氟乙氧基)甲基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(甲醇-d4)δ:9.47(s,1H),8.31(dd,J=8.1,1.1Hz,1H),8.07-8.14(m,1H),7.55(t,J=7.8Hz,1H),7.11-7.25(m,4H),4.18-4.37(m,1H),3.98(q,J=9.0Hz,2H),3.48(s,2H),3.35-3.43(m,2H),3.19(br.s.,1H),1.65(br.s.,2H),1.38-1.59(m,2H).LC-MS:m/z 530.7(M+H)+
N-(4-(4-(3,3-二氟丁基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=7.3Hz,1H),7.92(s,1H),7.55(t,J=7.8Hz,1H),7.16-7.24(m,J=8.1Hz,2H),7.06-7.15(m,J=8.3Hz,2H),5.37(br.s.,1H),4.36(br.s.,1H),3.34(br.s.,2H),3.22(br.s.,1H),1.93-2.08(m,2H),1.56-1.71(m,9H)。LC-MS:m/z 510.7(M+H)+
4-羥基-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹唑啉-8-磺醯胺
1H NMR(甲醇-d4)δ:0.97(d,J=6.72Hz,6 H),1.39(d,J=5.91Hz,2 H),1.49(br.s.,2 H),1.56(br.s.,1 H),1.66(br.s.,1 H),1.80-1.91(m,1 H),7.21-7.26(m,4 H),7.58(t,J=7.92Hz,1 H),8.28(s,1 H),8.39(ddd,J=7.72,6.11,1.48Hz,2 H)。LC-MS:m/z 485.7(M+H)+
N-(4-(4-(4,4-二氟丁基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(400MHz,氯仿-d)δ:1.22-1.37(m,2 H),1.59(br.s.,6 H),1.75-1.94(m,2 H),3.19(d,J=4.57Hz,1 H),3.32(br.s.,1 H),3.47(br.s.,1 H),5.84(t,J=4.30Hz,1 H),7.11(m,J=8.33Hz,2 H),7.19(m,J=8.33Hz,2 H),7.54(t,J=7.92Hz,1 H),7.96(s,1 H),8.10(d,J=7.52Hz,1 H),8.19(d,J=8.06Hz,1 H),9.31(s,1 H)。LC-MS:m/z 510.5(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲基)烯丙基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(dd,J=8.1,0.8Hz,1H),8.10(dd,J=7.5,1.1Hz,1H),7.92(s,1H),7.53-7.59(m,1H),7.17-7.23(m,J=8.6Hz,2H),7.09-7.14(m,J=8.6Hz,2H),5.93(d,J=1.3Hz,1H),5.60(s,1H),4.42(br.s.,1H),3.50(br.s.,1H),3.35(br.s.,1H),3.17(br.s.,1H),2.42(s,2H),1.65(br.s.,2H),1.45(br.s.,2H)。LC-MS:m/z 526.7(M+H)+
N-(4-(4-羥基-4-(3,3,3-三氟-2-甲基丙基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=7.5Hz,1H),8.10(d,J=7.5Hz,1H),7.98(s,1H),7.54(t,J=7.8Hz,1H),7.15-7.24(m,J=8.3Hz,2H),7.05-7.15(m,J=8.3Hz,2H),4.34(br.s.,1H),3.51(s,1H),3.12-3.41(m,2H),2.44(d,J=7.0Hz,1H),1.87(dd,J=14.9,2.0Hz,1H),1.58(br.s.,4H),1.42(dd,J=14.9,7.4Hz,2H),1.21(d,J=7.0Hz,3H)。LC-MS:m/z 528.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)萘-1-基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.27(d,J=4.3Hz,2H),8.39-8.48(m,2H),8.29-8.38(m,1H),8.12(dd,J=7.5,4.3Hz,1H),7.83-7.92(m,1H),7.65-7.76(m,2H),7.48-7.57(m,3H),7.39(d,J=7.5Hz,1H),7.20-7.27(m,2H),7.16(d,J=2.4Hz,1H),4.88(br.s.,1H),3.33-3.59(m,2H),3.17-3.33(m,2H),2.56(d,J=5.1Hz,1H),2.45(d,J=4.8Hz,1H),1.85(d,J=11.0Hz,1H),1.73(d,J=16.1Hz,1H)。LC-MS:m/z 573.1(M+H)+
步驟A:向RBr(0.08mol)以及鎂切屑(4.8g,0.2mol)于無水四氫呋喃(80mL)中的混合物添加碘晶體並且混合物在室溫下攪拌直到已經發生完全反應為止。在0℃下向此混合物添加四氫呋喃(20mL)中的4-側氧基哌啶-1-甲酸三級丁酯(7.7g,0.039mol)。在0℃下1h,並且在室溫下3h之後,反應混合物用氯化銨溶液稀釋,並且混合物用乙酸乙酯萃取。經Na2SO4乾燥之後,將溶劑真空移除並且殘餘物經由快速層析法使用20%乙酸乙酯/己烷來純化以便提供標題化合物7B。
步驟B:相應化合物7B(3.0mmol)在HCl於1,4-二中的溶液(3M,5mL)中的溶液在室溫下攪拌3小時。溶液在減壓下蒸發至幹以便得到粗產物3,其未進行進一步純化即用於下一個步驟。
步驟C:向化合物7C(0.2mmol)於DMF(5mL)中的溶液添加HBTU(91mg,0.24mmol)並且混合物在室溫下攪拌20分鐘,然後添加中間物F(0.2mmol)以及DIPEA(0.6mmol)。攪拌過夜之後,使反應物在飽和的Na2CO3溶液與DCM之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮,並且然後藉由標準方法純化以便得到標題產物7D。
N-(4-(4-羥基-4-異戊基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:10.76(s,1H),9.65(s,1H),8.49(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.63(t,J=7.9Hz,1H),7.16(d,J=8.3Hz,2H),7.09(d,J=8.4Hz,2H),4.18(s,1H),4.08(s,1H),3.16(m,3H),1.05-1.3(m,9H),0.82(d,J=6.6Hz,6H)。LC-MS:m/z 488.6(M+H)+
N-(4-(4-(4,4-二氟丁-3-烯-1-基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(400MHz,氯仿-d)δ:0.89(d,J=6.98Hz,2 H),1.56(d,J=8.60Hz,2 H),1.70(br.s.,2 H),1.76(br.s.,2 H),2.02-2.13(m,2 H),4.09-4.23(m,1 H),7.11(d,J=8.33Hz,2 H),7.19(d,J=8.33Hz,2 H),7.54(t,J=7.79Hz,1 H),8.02-8.14(m,2 H),8.19(d,J=8.33Hz,1 H),9.30(s,1 H)。LC-MS:m/z 508.5(M+H)+
化合物394(一般程序7,步驟C)
N-(4-(4-羥基-4-(4,4,4-三氟丁基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
N-(4-(4-羥基-4-(3,4,4-三氟丁-3-烯基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:1.38(br.s.,3 H),1.50(br.s.,1 H),1.54-1.63(m,2 H),2.33(br.s.,1 H),2.39(br.s.,1 H),2.98-3.14(m,2 H),3.14-3.28(m,2 H),4.07(br.s.,1 H),7.10(m,J=8.60Hz,2 H),7.17(m,J=8.60Hz,2 H),7.64(t,J=7.92Hz,1 H),8.11(d,J=6.72Hz,1 H),8.50(d,J=8.06Hz,1 H),9.65(s,1 H),10.76(s,1 H)。LC-MS:m/z 526.7(M+H)+
N-(4-(4-羥基-4-(3,3,3-三氟丙基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.31(s,1H),8.20(d,J=7.3Hz,1H),8.10(d,J=7.8Hz,1H),7.94(s,1H),7.55(t,J=7.8Hz,1H),7.20(d,J=8.6Hz,2H),7.12(d,J=8.6Hz,2H),4.33(s,1H),3.73(s,1H),3.53-3.44(m,1H),3.19(s,2H),2.29-2.18(m,2H),1.55-1.50(m,2H),1.47(d,J=6.7Hz,2H),0.9(t,J=6.8Hz,2H)。LC-MS:m/z 514.6(M+H)+
N-(4-(4-(環丁基甲基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.32(s,1H),8.24-8.15(m,1H),8.13-8.07(m,1H),7.96(s,1H),7.55(t,J=7.8Hz,1H),7.19(d,J=8.5Hz,2H),7.12(d,J=8.5Hz,2H),4.34(s,1H),3.70(dd,J=10.2,6.4Hz,2H),3.16(dd,J=7.4,4.2Hz,2H),2.55-2.43(m,1H),1.62(s,1H),1.43-1.45(m,5H),1.40-1.36(m,2H),1.26-1.31(m,4H)。LC-MS:m/z 486.6(M+H)+
步驟A:向相應4-胺基苯甲酸甲酯(8A,2.5mmol)於20mL DCM中的溶液添加吡啶(600mg,7.5mmol)以及苯並[c][1,2,5]噻二唑-4-磺醯氯(585mg,2.5mmol)。所得混合物在50℃下攪拌過夜。移除DCM之後,使殘餘物在水與EtOAc之間分配。將有機層用2N HCl、水以及鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到粗產物8B,該粗產物藉由LCMS來證實,並且未進行進一步純化即用於下一個反應。
步驟B:在70℃下向相應化合物8B(1.0mmol)於AcOH/H2O(8mL/3mL)中的溶液添加鋅粉(975mg,15mmol)並且將所得懸浮液在70℃下攪拌1h。將固體過濾掉並且用EtOAc洗滌。使濾液在飽和的NaHCO3與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經無水Na2SO4乾燥並且濃縮以便得到粗產物8C,該粗產物藉由LCMS來證實,並且未進行進一步純化即用於下一個反應。
步驟C:向相應化合物8C(0.9mmol)于乙醇/水(30mL/4mL)中的溶液添加乙二醛亞硫酸氫鈉水合物(975mg,15mmol)並且所得懸浮液在100℃下攪拌過夜。將溶劑真空移除並且使殘餘物在水與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮,藉由閃蒸塔純化以便得到標題產物8D,該產物藉由LCMS來證實。
步驟D:向相應化合物8D(0.2mmol)於EtOH/H2O(10mL/3mL)中的溶液添加LiOH.H2O(37mg,0.9mmol)並且所得懸浮液在70℃下攪拌過夜。將溶劑濃縮並且使殘餘物在2N HCl水溶液與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到所需粗產物8E,該粗產物藉由LCMS來證實,並且未進行進一步純化即用於後續反應。
步驟E:向化合物8E(0.2mmol)於DCM(10mL)中的溶液添加HBTU(91
mg,0.24mmol)並且在室溫下攪拌20分鐘,然後添加相應化合物8F(0.2mmol)以及DIPEA(0.6mmol)。攪拌30分鐘之後,使反應物在飽和的Na2CO3溶液與DCM之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮,並且然後藉由標準方法純化以便得到標題產物8G。
N-(4-(4-2-氯苯基)-4-羥基哌啶-1-羰基)-2-氟苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.06(s,2H),8.46(d,J=7.3Hz,1H),8.33-8.40(m,2H),7.83-7.88(m,1H),7.75(t,J=8.1Hz,1H),7.51(d,J=7.5Hz,1H),7.39(d,J=7.5Hz,1H),7.29(br.s.,1H),7.25(m,1H),7.11(d,J=8.3Hz,1H),6.98(d,J=8.9Hz,1H),4.58(br.s.,1H),3.58(br.s.,2H),3.31(br.s.,1H),2.36(br.s.,2H),2.18(br.s.,2H)。LC-MS:m/z 542.0(M+H)+
N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)-2-氟苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.06(s,2H),8.47(d,J=8.5Hz,1H),8.34-8.40(m,2H),7.83-7.89(m,1H),7.76(t,J=8.2Hz,1H),7.24(t,J=7.0Hz,1H),7.08-7.16(m,3H),6.99(d,J=10.5Hz,1H),4.59(br.s.,1H),3.57(br.s.,2H),3.28(br.s.,1H),2.25(br.s.,2H),2.13(br.s.,1H),1.88(br.s.,2H)。LC-MS:m/z 543.5(M+H)+
N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.07(s,2H),8.45(dd,J=7.3,1.3Hz,1H),8.35(dd,J=8.5,1.2Hz,1H),8.03(s,1H),7.82-7.88(m,1H),7.16-7.21(m,J=8.6Hz,2H),7.06-7.11
(m,J=8.3Hz,2H),4.33(br.s.,1H),3.35(br.s.,2H),3.19(br.s.,1H),1.82(dt,J=12.8,6.3Hz,1H),1.50(br.s.,4H),1.40(d,J=5.9Hz,2H),0.97(d,J=6.7Hz,6H)。LC-MS:m/z 469.5(M+H)+
N-(4-(4-羥基-4-苯基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.03-9.08(m,2H),8.45(dd,J=7.3,1.5Hz,1H),8.34(dd,J=8.5,1.5Hz,1H),8.14(s,1H),7.84(dd,J=8.4,7.5Hz,1H),7.41-7.46(m,2H),7.33-7.38(m,2H),7.29-7.31(m,1H),7.25-7.28(m,1H),7.19-7.23(m,J=8.5Hz,2H),7.07-7.11(m,J=8.5Hz,2H),4.54(br.s.,1H),3.53(br.s.,2H),3.20-3.36(m,1H),1.93(br.s.,2H),1.84(br.s.,2H)。LC-MS:m/z 488.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.05-9.10(m,2H),8.45(dd,J=7.5,1.3Hz,1H),8.36(dd,J=8.6,1.3Hz,1H),8.02-8.09(m,1H),7.85(dd,J=8.3,7.5Hz,1H),7.52(dd,J=7.8,1.9Hz,1H),7.38(dd,J=7.8,1.6Hz,1H),7.25-7.28(m,1H),7.24(s,1H),7.21-7.23(m,1H),7.10(d,J=8.6Hz,2H),4.60(d,J=10.7Hz,1H),3.56(br.s.,2H),3.50(s,1H),1.86-2.09(m,2H),1.72(br.s.,2H)。LC-MS:m/z 523.6(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)-2-甲基苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.02-9.07(m,2H),8.51(d,J=7.3Hz,1H),8.38(d,J=8.3Hz,1H),7.89(t,J=7.9Hz,1H),7.76(s,1H),7.50-7.54(m,1H),7.39(dd,J=7.5,1.3Hz,
1H),7.29-7.32(m,1H),7.22-7.28(m,2H),7.16(s,1H),7.06(d,J=8.1Hz,1H),4.60(br.s.,1H),3.61(br.s.,1H),3.55(br.s.,1H),3.31(d,J=11.3Hz,1H),2.35(d,J=7.5Hz,1H),2.25(s,3H),2.20(d,J=14.8Hz,1H),2.01-2.12(m,1H),1.97(br.s.,1H)。LC-MS:m/z 537.6(M+H)+
N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)-2-甲基苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.05(dd,J=9.2,1.6Hz,2H),8.51(dd,J=7.3,1.3Hz,1H),8.38(dd,J=8.4,1.1Hz,1H),7.89(dd,J=8.3,7.5Hz,1H),7.76(s,1H),7.22-7.27(m,1H),7.03-7.17(m,4H),4.58(br.s.,1H),3.60(br.s.,1H),3.39-3.57(m,1H),3.24(br.s.,1H),2.05-2.19(m,1H),1.83(br.s.,1H),1.75(br.s.,2H)。LC-MS:m/z 538.6(M+H)+
N-(3-(二氟甲氧基)-4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.07(d,J=5.4Hz,2H),8.48(d,J=7.3Hz,1H),8.38(d,J=8.6Hz,1H),8.04(s,1H),7.85-7.93(m,1H),6.99-6.90(m,3H),6.36(t,J=73.2Hz,1H),4.39(br.s.,1H),3.25-3.16(m,3H),1.82(m,1H),1.63(m.,5H),0.98(d,J=6.7Hz,6H)。LC-MS:m/z 535.8(M+H)+
N-(4-(4-羥基-4-(2-(三氟甲基)苄基)哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:1.60(br.s.,4 H),3.01(s,2H),3.12(br.s.,1H),3.30(br.s.,1H),3.48(br.s.,1 H),4.47(br.s.,1H),7.08(m,J=7.79Hz,2H),7.20(m,J=8.06Hz,
2H),7.39(dd,J=8.33,3.76Hz,1H),7.47-7.53(m,2H),7.69(d,J=7.79Hz,1H),7.82-7.89(m,1H),7.99(s,1H),8.36(dd,J=8.46,1.21Hz,1H),8.45(dd,J=7.39,1.21Hz,1H),9.08(s,2H)。LC-MS:m/z 571.7(M+H)+
N-(4-(4-羥基-4-(3,3,3-三氟丙基)哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.12(d,J=1.9Hz,1H),9.03(d,J=1.9Hz,1H),8.50(dd,J=7.3,1.3Hz,1H),8.32(dd,J=8.3,1.3Hz,1H),7.91(dd,J=8.3,7.5Hz,1H),7.15-7.26(m,4H),3.18(br.s.,1H),2.25(td,J=11.1,5.9Hz,2H),1.62-1.78(m,3H),1.56(br.s,1H),1.46(br.s.,2H),1.31(d,J=2.1Hz,1H)。LC-MS:m/z 509.62(M+H)+
N-(4-(4-羥基-4-新戊基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.08(s,2H),8.45(dd,J=7.4,1.2Hz,1H),8.36(dd,J=8.6,1.3Hz,1H),8.00(s,1H),7.85(dd,J=8.3,7.5Hz,1H),7.15-7.22(m,J=8.3Hz,2H),7.03-7.11(m,J=8.6Hz,2H),4.36(br.s.,1H),3.40(br.s.,2H),3.17(dd,J=12.6,5.9Hz,2H),1.62(br.s.,4H),1.49(s,2H),1.05(s,9H)。LC-MS:m/z 483.6(M+H)+
N-(4-(4-(環丙基甲基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.07(q,J=1.7Hz,2H),8.45(dd,J=7.3,1.3Hz,1H),8.35(dd,J=8.6,1.3Hz,1H),8.06(s,1H),7.85(dd,J=8.5,7.4Hz,1H),7.15-7.22(m,J=8.3Hz,2H),7.04-7.13(m,J=8.3Hz,2H),4.37(br.s.,1H),3.49(br.s.,1H),3.27(br.s.,3H),1.76(br.s.,1H),1.51-1.66(m,3H),1.41(d,J=6.4Hz,2H),0.65-0.80(m,1H),0.46-
0.58(m,2H),0.05-0.13(m,2H)。LC-MS:m/z 467.6(M+H)+
N-(4-(4-(3,3-二氟丁基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.08(s,2H),8.45(dd,J=7.3,1.1Hz,1H),8.36(dd,J=8.5,1.2Hz,1H),8.03(s,1H),7.86(dd,J=8.3,7.5Hz,1H),7.14-7.24(m,J=8.1Hz,2H),7.04-7.13(m,J=8.1Hz,2H),4.33(br.s.,1H),3.51(s,1H),3.28(br.s.,3H),1.88-2.02(m,2H),1.56-1.69(m,9H)。LC-MS:m/z 505.6(M+H)+
N-(4-(4-羥基-4-(4,4,4-三氟丁基)哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.08(s,2H),8.45(dd,J=7.3,1.3Hz,1H),8.36(dd,J=8.6,1.3Hz,1H),8.04(s,1H),7.82-7.89(m,1H),7.16-7.22(m,J=8.6Hz,2H),7.06-7.12(m,J=8.6Hz,2H),4.35(br.s.,1H),3.43(br.s.,1H),3.34(br.s.,1H),3.17(br.s.,1H),2.04-2.14(m,2H),1.48-1.58(m,4H),1.32(br.s.,2H),1.24(br.s.,2H)。LC-MS:m/z 523.7(M+H)+
N-(4-(4-羥基-4-(3,4,4-三氟丁-3-烯基)哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:1.44(br.s.,1 H),1.49-1.65(m,3 H),2.31-2.45(m,2 H),2.57(d,J=6.45Hz,1 H),3.10-3.38(m,3 H),7.08(m,J=8.60Hz,2 H),7.18(m,J=8.60Hz,2 H),7.84(dd,J=8.33,7.52Hz,1 H),8.34(dd,J=8.46,1.21Hz,1 H),8.45(dd,J=7.39,1.21Hz,1 H),9.03-9.10(m,2 H)。LC-MS:m/z 521.7(M+H)+
N-(4-(4-(4,4-二氟丁-3-烯-1-基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(400MHz,氯仿-d)δ:0.79-0.93(m,2 H),1.51-1.57(m,3 H),1.59-1.74(m,4 H),1.98-2.17(m,2 H),3.33(br.s.,2 H),3.50(s,1 H),4.08-4.24(m,1 H),7.08(m,J=8.33Hz,2 H),7.19(m,J=8.33Hz,2 H),7.85(dd,J=8.46,7.39Hz,1 H),8.04(s,1 H),8.36(dd,J=8.46,1.21Hz,1 H),8.45(dd,J=7.39,1.21Hz,1 H),9.08(s,2 H)。LC-MS:m/z 503.5(M+H)+
N-(4-(4-(4,4-二氟丁基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(400MHz,氯仿-d)δ:1.25-1.29(m,2 H),1.51-1.69(m,7 H),1.78-1.87(m,2 H),3.06-3.24(m,1 H),3.24-3.36(m,1 H),3.41(br.s.,1 H),4.32(br.s.,1 H),5.81(t,J=4.30Hz,1 H),7.08(m,J=8.60Hz,2 H),7.18(m,J=8.33Hz,2 H),7.84(dd,J=8.33,7.52Hz,1 H),8.12(s,1 H),8.34(dd,J=8.46,1.21Hz,1 H),8.45(dd,J=7.39,1.21Hz,1 H),8.98-9.14(m,2 H)。LC-MS:m/z 505.5(M+H)+
步驟A:1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(9B)
向4-側氧基哌啶-1-甲酸三級丁酯(5g,25mmol)於BuOH(20mL)中的溶液添加三級丁醇鉀(4.125g,18.75mmol)。混合物在50℃下攪拌1h。然後將三
甲基碘化鋶(11g,50mmol)添加至混合物,並且所得反應混合物在50℃下攪拌過夜。當TLC展示s.m.消耗完時,將混合物冷卻並且過濾。將濾液濃縮以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。
1H NMR(氯仿-d)δ:3.75(d,J=13.8Hz,2H),3.45(dd,J=13.2,9.4,3.8Hz,2H),2.72(s,2H),2.01-2.07(m,2H),1.78-1.86(m,2H),1.50(s,9H)
步驟B:4-(乙氧基甲基)-4-羥基哌啶-1-甲酸三級丁酯(9C)
在0℃下向無水EtOH(20mL)緩慢地添加NaH(124mg,52mmol),並且在添加完成之後,將混合物攪拌1.5h。然後添加1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(9B,45mmol),並且所得混合物在50℃下攪拌1h,此時TLC展示s.m.消耗完。然後混合物以1N HCl水溶液中和並且濃縮。將殘餘物藉由製備TLC純化以便得到呈無色油狀的所需產物9C(600mg)1H NMR(甲醇-d4)δ:3.78(d,J=12.6Hz,2H),3.51(q,J=7.0Hz,2H),3.22-3.29(m,2H),3.15(br.s.,2H),1.48-1.60(m,4H),1.43(s,9H),1.18(t,J=7.0Hz,3H)。
步驟C:4-(乙氧基甲基)哌啶-4-醇(9D)
向4-(乙氧基甲基)-4-羥基哌啶-1-甲酸三級丁酯(9C,1當量)於DCM中的溶液添加TFA(10當量)。混合物在室溫下攪拌0.5小時,此時TLC展示s.m.消耗完。將混合物濃縮以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 160.2(M+H)+
步驟A:在-78℃下在N2下向相應溴苯(4.7mmol)於30mL無水THF中的
溶液逐滴添加n-BuLi(7.04mmol)。在-78℃下攪拌1h之後,在-78℃下在N2下將THF(5mL)中的1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(7.04mmol)逐滴添加至以上獲得的溶液。在-78℃下在N2下將所得混合物攪拌2h,然後允許溫至室溫並且攪拌過夜。將反應混合物冷卻至-78℃並且藉由飽和的NH4Cl溶液來淬滅,然後將所得混合物用EtOAc(50mL,30mL)來萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮以便得到標題化合物10B。
步驟B:在室溫下將化合物10B(1.62mmol)於13mL含6N HCl的二中的溶液攪拌30分鐘。將反應混合物真空濃縮以便得到呈黃色液體狀的標題產物10C,該產物直接地用於下一個步驟。
步驟A:4-烯丙基-4-羥基哌啶-1-甲酸三級丁酯(11B)
在10℃以下,向4-側氧基哌啶-1-甲酸三級丁酯(10g,50.2mmol)、烯丙基溴(10.8mL,124mmol)於THF(10mL)以及飽和氯化銨溶液(50mL)中的溶液逐份添加Zn粉(6.5g,100mmol)。添加完成之後,將反應混合物攪拌過夜,此時TLC指示s.m.消耗完。將反應混合物用水(50mL)稀釋並且用幾滴10% H2SO4酸化至pH=6。反應混合物用EtOAc(3 x 200mL)萃取。將有機層合併並且用飽和的NaHCO3熔液、鹽水洗滌並且蒸發,以便得到粗產物,該粗產物藉由層析法純化以便得到呈無色油狀的標題化合物11B。1H NMR(氯仿-d)δ:5.77-5.92(m,1H),5.05-5.21(m,2H),3.76(br.s.,2H),3.05-3.22(m,2H),2.21(d,J=7.6Hz,2H),2.01(br.s.,1H),1.50(dd,J=7.2,4.0Hz,3H),1.47(s,1H),1.43(s,9H)。
步驟B:4-((2,2-二氟環丙基)甲基)-4-羥基哌啶-1-甲酸三級丁酯(11C)
向密封管添加4-烯丙基-4-羥基哌啶-1-甲酸三級丁酯11B(280mg,1.16mmol)、NaI(112mg,0.74mmol)、三甲基(三氟甲基)矽烷(0.6mL)以及THF(10mL)。將管密封,並且然後混合物在80℃下攪拌過夜。將所得混合物用DCM稀釋、過濾,並且將濾液真空濃縮以便得到粗產物11C,該粗產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 292.3(M+H)+
步驟C:4-((2,2-二氟環丙基)甲基)哌啶-4-醇(11D)
向化合物11C(1當量)於DCM中的溶液添加TFA(10當量),反應混合物在室溫下攪拌約2小時,此時TLC沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物11D。粗產物未進行進一步純化直接地用於下一個步驟。LC-MS:m/z 192.3(M+H)+
步驟A:4-羥基-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(12B)
將4-側氧基哌啶-1-甲酸三級丁酯(10g,0.05mol)溶解於3-溴-2-甲基丙-1-烯(16.9g,0.126mol)、THF(100mL)以及飽和氯化銨溶液(500mL)中。將反應冷卻至10℃並且逐份添加鋅粉(6.6g,0.01mol)。添加之後,反應混合物攪拌過夜,此時TLC(庚烷/EtOAc 7:1)指示反應完成。然後將反應混合物用水稀釋並且用10% H2SO4酸化至pH 6。反應混合物用乙酸乙酯(3 x 50mL)萃取。將有機層合併並且用飽和的NaHCO3熔液、鹽水洗滌並且蒸發以便得到4-羥基-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(12.28g)。1H NMR(氯仿-d)δ:4.94-5.04(m,1H),4.80(s,1H),3.85(dt,J=13.0,3.4Hz,2H),3.08-3.26(m,2H),2.21(s,2H),1.86(s,3H),1.52-1.60(m,4H),1.43-1.50(m,9H)。
步驟B:4-羥基-4-((1-甲基環丙基)甲基)哌啶-1-甲酸三級丁酯(12C)
在0℃下向CH2Cl2(20mL)添加二乙基鋅於己烷(11.75mL,11.75mmol)中的1M溶液,隨後逐滴添加三氟乙酸(0.6mL,7.83mmol)於CH2Cl2(8mL)中的溶液。攪拌15分鐘之後,添加二碘甲烷(0.65mL,7.83mmol)於CH2Cl2(8mL)中的溶液。將混合物攪拌15分鐘並且產生透明溶液。添加4-羥基-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(12B)(1g,3.92mmol)並且混合物在室溫下攪拌過夜。用0.1M HCl水溶液(50mL)淬滅後,將CH2Cl2層分離,用鹽水洗滌,乾燥(Na2SO4)並且濃縮以便得到粗產物,該粗產物未進行純化即直接用於下一個步驟。
步驟C:4-((1-甲基環丙基)甲基)哌啶-4-醇(12D)
向化合物12C(1當量)於DCM中的溶液添加TFA(10當量),反應混合物在室溫下攪拌約2小時,此時TLC沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物12D。粗產物未進行進一步純化直接地用於下一個步驟。LC-MS:m/z 170.3(M+H)+
步驟A:4-羥基-4-(3-羥基丙基)哌啶-1-甲酸三級丁酯(13B)
在0℃下在氮氣下,將BH3於THF(21mL,21.0mmol)中的混合物緩慢地添加至4-烯丙基-4-羥基哌啶-1-甲酸三級丁酯(500mg,2.07mmol)與THF(5mL)的混合物,並且然後攪拌30分鐘。允許所得混合物溫至室溫並且攪拌過夜。將
混合物冷卻至0℃並且添加3N氫氧化鈉(1mL),隨後添加30%過氧化氫(1mL)。允許所得混合物溫至室溫並且攪拌2.5小時。然後混合物用水(10mL)處理並且以EA(3 x 20mL)萃取。合併的有機萃取物經Na2SO4乾燥並且將溶劑真空移除。將殘餘物藉由矽膠柱層析法以(30% EtOAc/PE)來純化以便得到呈無色油狀的4-羥基-4-(3-羥基丙基)哌啶-1-甲酸三級丁酯13B(629mg)。1H NMR(氯仿-d)δ:3.65(t,J=5.7Hz,4H),3.36(br.s.,2H),3.16(br.s.,2H),1.63-1.71(m,2H),1.53-1.62(m,4H),1.41-1.48(m,9H)。
步驟B:4-(3-羥基丙基)哌啶-4-醇(13C)
向化合物2(1當量)於DCM中的溶液添加TFA(10當量),將反應混合物在室溫下攪拌約2小時,此時TLC沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物3。粗產物未進行進一步純化即直接地用於下一個步驟。LC-MS:m/z 160.2(M+H)+
步驟A:4-(環丙基甲基)-4-羥基哌啶-1-甲酸三級丁酯(14B)
在-78℃下在N2下向4,4'-二三級丁基聯苯(DTBB,30.33mg,0.114mmol)以及Li(56.7mg,8.09mmol)於50mL無水THF中的懸浮液逐滴添加(溴甲基)環丙烷(307.9mg,2.28mmol)以及4-側氧基哌啶-1-甲酸三級丁酯(500mg,2.5mmol)于無水THF(5mL)中的溶液。在-78℃下在N2下將所得混合物攪拌8h。在-78℃下藉由飽和的NH4Cl溶液來淬滅反應混合物。所得混合物用EtOAc(50mL x 2)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮。柱層析
法(15% PE/EtOAc)提供262.5mg呈無色油狀的標題化合物。1H NMR(氯仿-d)δ:3.90-3.78(m,2H),3.25-3.12(m,2H),1.60(dd,J=9.4,4.3Hz,4H),1.48(s,9H),1.42(d,J=6.9Hz,2H),0.82-0.70(m,1H),0.57-0.47(m,2H),0.16-0.06(m,2H)。
步驟B:4-(環丙基甲基)哌啶-4-醇(14C)
向化合物14B(1當量)於DCM中的溶液添加TFA(10當量),將反應混合物在室溫下攪拌約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物14C。粗產物未進行進一步純化直接地用於下一個步驟。LC-MS:m/z 156.2(M+H)+
步驟A:在室溫下將鈉(90mg,3.9mmol)(呈小碎片形式)添加至2,2,2-三氟乙醇(2mL),然後混合物在室溫下攪拌直到Na被完全地消耗為止,並且然後在室溫下將所得混合物逐滴添加至1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(500mg,2.35mmol)於10mL無水THF中的溶液。添加完成之後,在60℃下將混合物攪拌過夜,此時TLC(石油醚:乙酸乙酯=2:1)(I2染色)指示形成新的斑點,以及1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯的消耗。然後將所得混合物冷卻至室溫,添加H2O以便淬滅反應,並且混合物用乙酸乙酯萃取。有機層經無水Na2SO4乾燥,並且濃縮以便得到粗標題化合物,該化合物未進行進一步純化即用於下一個步驟。
步驟A:4-(丁-3-烯-1-基)-4-羥基哌啶-1-甲酸三級丁酯(16B)
向4-溴丁-1-烯(10.9g,0.08mol)與鎂切屑(4.8g,0.2mol)于無水四氫呋喃(80mL)中的混合物添加碘晶體並且混合物在室溫下攪拌直到已經發生完全反應為止。在0℃下向此混合物添加四氫呋喃(20mL)中的4-側氧基哌啶-1-甲酸三級丁酯(7.7g,0.039mol)。在0℃下1h,以及在室溫下3h之後,反應混合物用氯化銨溶液稀釋並且用乙酸乙酯萃取。經Na2SO4乾燥之後,將溶劑真空移除並且殘餘物經由快速層析法以25%乙酸乙基/己烷純化以便提供呈油狀的標題化合物16B(3.63g)。1H NMR(氯仿-d)δ 5.84(d,J=6.7Hz,1H),4.89-5.11(m,2H),3.16(br.s.,2H),2.16(d,J=9.4Hz,2H),1.48-1.66(m,6H),1.45(s,9H)。
步驟B:4-乙醯氧基-4-(丁-3-烯-1-基)哌啶-1-甲酸三級丁酯(16C)
4-(丁-3-烯-1-基)-4-羥基哌啶-1-甲酸三級丁酯(3.7g,14.51mmol)於二氯甲烷(20mL)中的溶液用二甲胺基吡啶(1.8g,14.51mmol)、乙酸酐(4.1mL,43.53mmol)以及三乙胺(6.1mL,43.53mmol)處理,在20℃下攪拌過夜。將溶劑在減壓下移除並且使殘餘物在水與乙酸乙酯之間分配。水層用乙酸乙酯萃取兩次。合併的有機萃取物用水洗滌,乾燥(Na2SO4)並且過濾。將濾液在減壓下濃縮,藉由快速層析法純化以便提供呈無色油狀的標題化合物16C(3.4g)。
步驟C:4-乙醯氧基-4-(3-側氧基丁基)哌啶-1-甲酸三級丁酯(16D)
向4-乙醯氧基-4-(丁-3-烯-1-基)哌啶-1-甲酸三級丁酯(1g,3.36mmol)於DMF(6mL)以及H2O(2mL)中的溶液添加CuCl(0.77g,7.73mmol)以及PdCl2(0.16g,0.91mmol)並且所得懸浮液在室溫下在氧氣氛攪拌24h。將不溶性物質藉由過濾移除,並且用乙酸乙酯洗滌。濾液經無水Na2SO4乾燥、過濾並且在減壓下濃縮。殘餘物藉由矽膠快速層析法純化以便得到呈無色油狀的16D(540mg)。1H NMR(氯仿-d)δ:3.84(br.s.,2H),2.97(t,J=12.1Hz,2H),2.38-2.47(m,2H),2.17-2.24(m,2H),2.15(s,3H),2.04(s,3H),1.39-1.51(m,9H)。
步驟D:4-乙醯氧基-4-(3,3-二氟丁基)哌啶-1-甲酸三級丁酯(16E)
向4-乙醯氧基-4-(3-側氧基丁基)哌啶-1-甲酸三級丁酯(2.66g,8.5mmol)於CH2Cl2(15mL)中的溶液添加DAST(4.5mL,34mmol)並且所得混合物在室溫下攪拌24h。添加飽和NaHCO3水溶液並且將所得兩相混合物強力地攪拌15分鐘。將兩個層分離並且水相用CH2Cl2萃取。合併的有機相經Na2SO4乾燥並且真空濃縮。將殘餘物藉由矽膠快速層析法純化以便得到標題化合物16E(1.27g)。
步驟E:4-(3,3-二氟丁基)-4-羥基哌啶-1-甲酸三級丁酯(16F)
向4-乙醯氧基-4-(3,3-二氟丁基)哌啶-1-甲酸三級丁酯(100mg,0.426mmol)於MeOH(10mL)以及H2O(2mL)中的溶液添加NaOH(145mg,8.45mmol)。將所得混合物在40℃攪拌4h。冷卻至室溫之後,將混合物用2N HCl溶液酸化。移除MeOH之後,所得溶液用乙酸乙酯萃取。將有機層經Na2SO4乾燥、過濾並且在減壓下蒸發至幹以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。
步驟F:4-(3,3-二氟丁基)哌啶-4-醇(16G)
將4-(3,3-二氟丁基)-4-羥基哌啶-1-甲酸三級丁酯(0.932g,3.2mmol)在HCl於1,4-二中的溶液(3M,5mL)中的溶液在室溫下攪拌1小時。將溶液在減壓下蒸發至幹以便得到產物,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 194.3(M+H)+。
步驟A:4-羥基-4-(2-(三氟甲基)烯丙基)哌啶-1-甲酸三級丁酯(17B)
將4-側氧基哌啶-1-甲酸三級丁酯(500mg,2.51mmol)以及烯丙基溴(1.2g,6.3mol,2.5當量)於THF(5mL)以及飽和氯化銨溶液(20mL)中的溶液冷卻至10℃,並且逐份添加鋅粉(328mg,5.0mol,2當量)。添加完成之後,反應混合物在室溫下攪拌過夜,此時TLC(庚烷/EtOAc 7:1)指示完全轉化。將反應混合物用水(5mL)稀釋,並且然後用EtOAc萃取。將有機層用飽和NaHCO3溶液、鹽水洗滌,並且蒸發以便得到標題化合物,該化合物未進行進一步純化即用於下一個步驟。
步驟B:4-(2-(三氟甲基)烯丙基)哌啶-4-醇(17C)
向4-羥基-4-(2-(三氟甲基)烯丙基)哌啶-1-甲酸三級丁酯17B(300mg,0.97mmol)於DCM(5mL)中的溶液添加HCl於二中的溶液(3M,1mL,3mmol),
並且然後將混合物在室溫下攪拌16小時。將混合物真空濃縮以便獲得所需化合物,該化合物直接地用於下一個步驟。LC-MS:m/z 210.2(M+H)+
步驟C:4-(3,3,3-三氟-2-甲基丙基)哌啶-4-醇(17D)
向4-羥基-4-(2-(三氟甲基)烯丙基)哌啶-1-甲酸三級丁酯(100mg,0.32mmol)於EtOH(5mL)中的混合物添加10% Pd/C(20mg)以及一滴AcOH。將混合物在40℃下在H2氣氛下攪拌16小時。反應混合物經由矽藻土墊過濾;將濾液濃縮以便獲得標題化合物,該化合物未進行純化即直接地用於下一個步驟。LC-MS:m/z 212.2(M+H)+
步驟A:將化合物18B(1當量)溶于無水THF中並且冷卻至-78℃,此時在-78℃下在氮氣氛下在15分鐘時間內添加正丁基鋰(1.2當量)於己烷中的溶液。將反應混合物在-78℃下攪拌30分鐘,並且然後允許其在-5℃下攪拌30分鐘。然後將所得混合物再次冷卻至-78℃,並且在15分鐘時間內添加THF中的4-側氧基哌啶-1-甲酸三級丁酯(18A,0.9當量)。然後允許所得反應混合物溫至室溫並且在室溫下攪拌16小時。藉由TLC來監測反應進度。反應完成後,用飽和的NH4Cl溶液(500mL)來淬滅混合物並且用EtOAc萃取。將合併的有機層用水洗滌,經Na2SO4乾燥並且在減壓下濃縮。將粗產物藉由柱層析法使用矽膠(100-200網目)以及己烷中的10% EtOAc純化以便提供呈淡黃色油狀的相應化合物18C-1、18C-2以及18C-3。
4-羥基-4-(吡啶-2-基甲基)哌啶-1-甲酸三級丁酯(18C-1)
1H NMR(氯仿-d)δ:8.49-8.48(m,1H),7.64(t,1H,J=8Hz),7.18(t,1H,J=8Hz),7.12(d,1H,J=7.6Hz),3.80-3.77(m,2H),3.24-3.22(m,2H),2.90(s,2H),1.54-1.47(m,4H),1.45(s,9H)。
4-羥基-4-((6-甲基吡啶-2-基)甲基)哌啶-1-甲酸三級丁酯(18C-2)
1H NMR(氯仿-d)δ:7.51(t,1H,J=7.6Hz),7.02(d,1H,J=7.6Hz),6.90(d,1H,J=7.6Hz),6.36(bs,1H),3.79-3.77(m,2H),3.24-3.22(m,2H),2.84(s,2H),2.51(s,3H),1.51-1.47(m,4H),1.45(s,9H)。
4-((6-氟吡啶-2-基)甲基)-4-羥基哌啶-1-甲酸三級丁酯(18C-3)
1H NMR(氯仿-d)δ:7.76-7.70(m,1H),7.02(d,1H,J=7.2Hz),6.82(d,1H,J=8Hz),4.44(s,1H),3.80-3.78(m,2H),3.21-3.20(m,2H),2.87(s,2H),1.63-1.49(m,4H),1.45(s,9H)。
步驟B:將化合物18C(1當量)溶解於DCM中,冷卻至0℃,並且在0℃下添加TFA(10當量)並且然後在室溫下將反應混合物攪拌3-4小時直到LCMS以及TLC證實反應完成為止。將反應混合物濃縮至幹,用DCM濕磨3至4次並且用正戊烷洗滌以便提供呈無色油狀的化合物18D。粗產物未進行進一步純化直接地用於下一個步驟。
步驟A:將相應2-R-3-甲基吡啶(1當量)溶于無水THF中並且冷卻至-78℃。在-78℃下在氮氣氛下在15分鐘內將二異丙基胺基鋰(1.8當量)2.5M於THF中的溶液添加至上述反應混合物並且在相同溫度下攪拌30分鐘。然後在-5℃下將反
應混合物攪拌30分鐘,然後將其再次冷卻至-78℃,此時在15分鐘內添加THF中的4-側氧基哌啶-1-甲酸三級丁酯(19A,0.9當量)。然後允許所得混合物在室溫下攪拌16小時。藉由TLC來監測反應進度。反應完成後,用飽和的NH4Cl溶液(500mL)來淬滅混合物並且用EtOAc萃取。合併的有機層用水洗滌,經Na2SO4乾燥並且在減壓下濃縮。粗產物藉由柱層析法使用矽膠(100-200網目)以及己烷中的10% EtOAc純化以便提供呈淡黃色油狀的標題化合物19B。
4-羥基-4-(吡啶-3-基甲基)哌啶-1-甲酸三級丁酯(19B-1)
1H NMR(氯仿-d)δ:8.51-8.46(m,2H),7.56(d,1H,J=8Hz),7.27-7.24(m,1H),3.88-3.81(m,2H),3.12-3.07(m,2H),2.76(s,2H),1.63-1.61(m,2H),1.49-1.47(m,2H),1.45(s,9H)。
步驟B:將化合物19B-1或19B-2(1當量)溶解於DCM,冷卻至0℃,在0℃下向其中添加TFA(10當量)並且然後在室溫下將反應混合物攪拌3-4小時直到LCMS以及TLC證實反應完成為止。將反應混合物濃縮至幹,用DCM濕磨3至4次並且用正戊烷洗滌以便分別提供呈無色油狀的化合物19C-1或19C-2。粗產物未進行純化即用於下一個步驟。
步驟A:2-氟喹啉(20B)
向2-氯喹啉(4.9g,30mmol)於200mL無水DMSO中的溶液添加氟化銫(9.13g,60mmol),並且所得混合物在130℃下攪拌過夜,此時LC-MS展示反應完成。冷卻之後,反應混合物用水稀釋,並且然後用乙酸乙酯萃取。然後將有機層用鹽水洗滌,經無水Na2SO4乾燥,並且真空濃縮。柱層析法(6% EtOAc/PE)提供3.34g標題化合物。1H NMR(氯仿-d)δ:8.23(d,J=8.6Hz,1H),7.89(d,J=8.6Hz,1H),
7.82-7.86(m,1H),7.67(d,J=8.5,7.0,1.5Hz,1H),7.47-7.53(m,1H),7.35(d,J=8.6Hz,1H)。LC-MS:m/z 148.2(M+H)+
步驟B:2-氟喹啉-8-磺醯氯(20C)
在-5℃-0℃下將2-氟喹啉(1.3g,8.9mmol)於氯磺酸(15mL)中的溶液攪拌15分鐘並且在130℃下攪拌過夜。將所得反應混合物傾倒至冰-水混合物(300mL)中,在室溫下攪拌20分鐘,並且用EtOAc萃取。然後將有機層用鹽水洗滌,經Na2SO4乾燥並且移除溶劑。殘餘物藉由柱層析法使用從100% PE至PE/EtOAc(100:6)的梯度洗脫來純化以便提供1.1g標題化合物。1H NMR(氯仿-d)δ:8.56(d,J=7.5Hz,1H),8.43(t,J=8.3Hz,1H),8.25(d,J=8.3Hz,1H),7.72(t,J=7.8Hz,1H),7.32(dd,J=8.9,3.0Hz,1H)。LC-MS:m/z 246.3(M+H)+
步驟A:3-氟喹啉(21B)
在室溫下將喹啉-3-胺(4g,27.7mmol)逐份添加至HBF4(26mL,48%水溶液),並且混合物在室溫下攪拌直到它變得均質為止。然後將混合物冷卻至0℃,並且逐滴添加NaNO2(2.4g,34.8mmol)於H2O(8mL)中的溶液,此時反應混合物變得不均質。將混合物在0℃下攪拌1小時,然後將混合物過濾,並且濾餅用冷EtOH,然後用Et2O來洗滌。所得固體真空乾燥,然後懸浮於圓底燒瓶中的甲苯並且回流1.5小時。將所得混合物冷卻至室溫,並且然後傾倒至冷水中。有機層經Na2SO4乾燥,並且然後真空濃縮以便獲得所需產物(1.6g)。LC-MS:m/z 148.1(M+H)+
步驟B:3-氟喹啉-8-磺醯氯(21C)
在裝備有冷凝器的圓底燒瓶中,將3-氟喹啉(0.6g,4.08mmol)以及HSO3Cl(2mL)的混合物在130℃下攪拌過夜。當TLC指示反應完成時,將所得混合物小心地傾倒至碎冰中,混合物用DCM(100mL x 3)萃取,並且合併的有機層經Na2SO4乾燥,並且濃縮。將粗混合物藉由層析法(5%乙酸乙酯/PE)純化以便得到所需3-氟喹啉-8-磺醯氯。1H NMR(氯仿-d)δ:9.15(d,J=2.6Hz,1H),8.53(d,J=7.6Hz,1H),8.23(dd,J=8.2,0.9Hz,1H),7.97(dd,J=8.1,2.8Hz,1H),7.69-7.83(m,1H)。LC-MS:m/z 246.7(M+H)+
步驟A:5-氟喹啉(22A)
在0℃下向喹啉-5-胺(2g,13.9mmol)於10mL 48% HBF4中的溶液逐份添加亞硝酸鈉(933mg,13.5mmol)。將其攪拌1小時,並且然後傾倒至1:1乙酸乙酯乙醚混合物(50mL)中。將所得懸浮液過濾並且將固體乾燥。此固體逐份添加至回流二甲苯(30mL)並且攪拌3小時,然後允許其冷卻。將二甲苯傾析出並且殘餘物溶解於1N HCl(50mL)。用NaHCO3中和之後,混合物用乙酸乙酯(3 x 50mL)萃取。萃取物經硫酸鈉乾燥,過濾並且揮發物在減壓下移除。殘餘物藉由矽膠層析法(3% EtOAc/PE)純化以便提供800mg呈無色油狀的標題化合物。LC-MS:m/z 148.2(M+H)+
步驟B:5-氟喹啉-8-磺醯氯(22C)
在0℃下將5-氟喹啉(800mg,5.4mmol)緩慢地添加至10mL氯磺酸。當
添加完成時,反應混合物在130℃下加熱過夜。允許溶液冷卻並且緩慢地傾倒於冰上。將水層用乙酸乙酯(3 x 50mL)萃取。將合併的有機萃取物乾燥並且蒸發以便得到粗產物,該粗產物藉由柱層析法(5% EtOAc/PE)純化以便提供400mg標題化合物。1H NMR(氯仿-d)δ:7.40(t,J=8.46Hz,1 H),7.74(dd,J=8.60,4.30Hz,1 H),8.55-8.64(m,2 H),9.32(dd,J=4.30,1.88Hz,1 H)。LC-MS:m/z 4246(M+H)+
步驟A:6-氟-8-硝基喹啉(23B)
在裝備有冷凝器的圓底燒瓶中,使6-氟喹啉(2g,13.6mmol)以及發煙HNO3(15mL)的混合物回流100小時,將所得混合物冷卻至室溫,緩慢地傾倒至碎冰/H2O中,並且然後將混合物用DCM(200mL x 3)萃取。合併的有機層經Na2SO4乾燥,並且濃縮。使殘餘物經過短矽膠墊以便得到1.6g標題化合物。1H NMR(氯仿-d)δ:9.08(dd,J=4.1,1.5Hz,1H),8.25(dd,J=8.5,1.5Hz,1H),7.89(dd,J=7.5,2.8Hz,1H),7.72(dd,J=8.1,2.8Hz,1H),7.62(dd,J=8.4,4.3Hz,1H)。LC-MS:m/z 466.6(M+H)+
步驟B:6-氟喹啉-8-胺(23C)
在裝備有回流冷凝器的圓底燒瓶中,在室溫下向6-氟-8-硝基喹啉(1.6g,8.3mmol)以及NH4Cl(2g,41.5mmol)於EtOH/H2O(10mL/10mL)中的混合物分多份添加Zn(5.4g,16.6mmol)粉,並且所得混合物在60℃攪拌過夜。將反應混合物過濾,並且濾液用EtOAc萃取。合併的有機層經Na2SO4乾燥,並且濃縮以便得到1.0g粗產物,該粗產物未進行進一步純化即直接地用於下一個步驟。LC-MS:m/z 163.2(M+H)+
步驟C:6-氟喹啉-8-磺醯氯(23D)
(a)在5℃下將亞硫醯氯(2.1mL)逐滴添加至水(12.5mL)中。允許此混合物溫至室溫並且攪拌過夜。然後添加CuCl(10mg)並且將所得黃色溶液冷卻至0℃。
(b)將濃鹽酸(6.75mL)冷卻至0℃,同時逐份添加6-氟喹啉-8-胺(1g)。允許混合物在添加之間稍微地升溫,在此期間反應混合物變成黃色。添加完成之後,將反應混合物冷卻至-5℃並且逐滴添加NaNO2(0.5g)于水(2mL)中的溶液。在完成添加之後並且在-5℃下,將所得混合物緩慢地添加至來自部分(a)的冷卻的亞硫醯氯/CuCI混合物。然後將混合物在0℃下攪拌約1小時。所得混合物用DCM萃取,合併的有機層經Na2SO4乾燥,濃縮以便產生500mg標題化合物,該化合物未進行進一步純化即用於下一個步驟。LC-MS:m/z 246.7(M+H)+
步驟A:苯並[d]噻唑-4-磺醯氯(24B)
在0℃下將苯並[d]噻唑(1g,7.45mol)逐滴添加至氯磺酸(5.5mmol)。添加完成之後,混合物在室溫下攪拌0.5h,並且然後在105℃下加熱並且攪拌過夜。所得混合物冷卻至-10℃並且藉由緩慢地傾倒於碎冰上來淬滅。所得混合物用EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供218mg標題化合物。1H NMR(氯仿-d)δ:9.41(s,1H),8.41(dd,J=8.1,1.0Hz,1H),8.29(dd,J=7.7,1.1Hz,1H),7.68(t,J=7.9Hz,1H)。LC-MS:m/z 234.7(M+H)+
步驟A:苯並[c]異噻唑(24B)
在0℃下,向鄰甲苯胺(10g,93.4mmol)於50mL甲苯中的溶液逐滴添加SOCl2(12.1g,102mmol)。添加完成之後,將反應混合物加熱至回流並且攪拌過夜。將反應混合物冷卻至室溫,並且在減壓下濃縮以便得到黃色油狀物。將該油狀物溶解於甲苯(100mL),然後逐滴添加N-亞硫醯基甲烷磺醯胺(20.6g,146mmol)溶液,隨後添加吡啶(7.3g,93.4mmol)。將混合物加熱至回流並且在此溫度下攪拌過夜。然後在減壓下移除甲苯,殘餘物溶解於EtOAc(200mL)並且用水(2 x 200mL)洗滌。有機層用鹽水洗滌、乾燥並且蒸發以便得到粗產物。粗產物藉由柱層析法(3% EtOAc/PE)純化以便提供6.2g呈無色油狀的標題化合物。1H NMR(氯仿-d)δ 9.22(s,1H),7.88(d,J=9.7Hz,1H),7.80(d,J=8.6Hz,1H),7.46(ddd,J=8.9,6.5,1.2Hz,1H),7.26(dd,J=7.9,6.6Hz,1H)。
步驟B:苯並[c]異噻唑-7-磺醯氯(24C)
在0℃下,將苯並[c]異噻唑24B(1g,7.45mmol)逐滴添加至氯磺酸(5.5mmol)。添加完成之後,混合物在室溫下攪拌0.5h,並且然後在105℃下加熱並且攪拌過夜。所得混合物冷卻至-10℃並且藉由緩慢地傾倒於碎冰上來淬滅。所得混合物用EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供200mg標題化合物。1H NMR(氯仿-d)δ:9.68(s,1H),8.66(d,J=1.9Hz,1H),8.10(d,J=9.4Hz,1H),7.99(dd,J=9.4,2.1Hz,1H)。
步驟A:1-氟-3-硝基-2-硫氰酸苯(25B)
在0-3℃下,用亞硝酸鈉水溶液(1.45g,0.021mol)使2-氟-6-硝基苯胺(3g,0.02mol)於濃硫酸(30mL)以及水(30mL)中的溶液重氮化90分鐘。將硫氰酸鉀(2.522g,0.026mol)添加于水(10mL)中之後,在5℃下將該重氮溶液強力地攪拌至硫氰酸亞銅(6.05g,0.05mol)于水(20mL)中的懸浮液中。在5℃下攪拌2小時之後,然後將混合物在70℃下加熱20分鐘,然後冷卻過夜,過濾,並且濾餅用EtOAc萃取以便獲得粗產物(3.96g),該粗產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 199.2(M+H)+
步驟B:7-氟苯並[d]噻唑-2-胺(25C)
在添加氫還原的鐵粉末(8g)期間,使1-氟-3-硝基-2-硫氰酸苯2(3.96g,0.02mol)、乙醇(30mL)、水(25mL)以及濃鹽酸(25mL)的混合物輕輕地回流。回流16小時之後,將溶液趁熱過濾、冷卻,將殘餘物過濾、溶解於熱水,並且用氨中和,並且然後用EtOAc萃取以便獲得呈無色油狀的化合物7-氟苯並[d]噻唑-2-胺(1g)。LC-MS:m/z 169.2(M+H)+
步驟C:7-氟苯並[d]噻唑(25D)
在室溫下向7-氟苯並[d]噻唑-2-胺25C(1g,5.95mmol)於THF(10mL)中的溶液添加亞硝酸異戊酯(1.51g,12.9mmol)。回流3小時之後,然後允許反應混合物冷卻至室溫並且傾倒至冰水(50mL)中,並且然後用EtOAc萃取。有機萃取物用水以及鹽水洗滌、乾燥並且蒸發。對殘餘物進行矽膠層析法以便獲得呈無色油狀的7-氟苯並[d]噻唑。LC-MS:m/z 154.2(M+H)+
步驟D:7-氟苯並[d]噻唑-4-磺醯氯(25E)
在0℃下將7-氟苯並[d]噻唑25D(500mg,3.26mmol)逐滴添加至氯磺酸(2.5mmol)中。添加完成之後,混合物在室溫下攪拌0.5h,並且然後在105℃下加熱並且攪拌過夜。所得混合物冷卻至-10℃並且藉由緩慢地傾倒於碎冰上來淬滅。所得混合物用EtOAc(20mL x 2)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供200mg標題化合物。1H NMR
(氯仿-d)δ:9.44(s,1H),8.32(dd,J=8.6,4.6Hz,1H),7.38(t,J=8.5Hz,1H)。
步驟A:2-胺基-6-氟苯並[d]噻唑-4-磺醯氯(26B)
在0℃下將6-氟苯並[d]噻唑-2-胺(1g,5.95mol)逐滴添加至氯磺酸(5.0mmol)。添加完成之後,混合物在室溫下攪拌0.5h,並且然後在105℃下加熱並且攪拌過夜。所得混合物冷卻至-10℃並且藉由緩慢地傾倒於碎冰上來淬滅。所得混合物用EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(50% PE/EtOAc)提供200mg標題化合物。LC-MS:m/z 266.7(M+H)+
步驟B:4-(2-胺基-6-氟苯並[d]噻唑-4-磺醯胺基)苯甲酸乙酯(26C)
向4-胺基苯甲酸乙酯(413mg,2.5mmol)於20mL DCM中的溶液添加吡啶(600mg,7.5mmol)以及2-胺基-6-氟苯並[d]噻唑-4-磺醯氯(668mg,2.5mmol)。所得混合物在50℃下攪拌過夜。移除DCM之後,使殘餘物在水與EtOAc之間分配。將有機層用2N HCl、水以及鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到粗產物,該粗產物藉由層析法純化以便得到純化合物26C。1H NMR(氯仿-d)δ:8.10(s,1H),7.93-7.82(m,2H),7.59(dd,J=8.2,2.6Hz,1H),7.47(dd,J=7.5,2.6Hz,1H),7.20-7.09(m,2H),5.73(s,2H),4.32(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H)。LC-MS:m/z 396.5(M+H)+
步驟A:6-氯-N-甲基苯並[d]噻唑-2-胺(27B)
向2,6-二氯苯並[d]噻唑(2g,10mmol)於10mL THF中的溶液逐滴添加水(3mL)中的25% MeNH2。添加完成之後,反應混合物在室溫下攪拌過夜。濾出產物並且用甲醇洗滌。真空乾燥,產生1.5g所需化合物。LC-MS:m/z 204.2(M+H)+
步驟B:6-氯-2-(甲胺基)苯並[d]噻唑-4-磺醯氯(27C)
將6-氯-N-甲基苯並[d]噻唑-2-胺(500mg,2.53mmol)於氯磺酸(5mL)中的溶液在130℃下攪拌過夜。允許溶液冷卻並且緩慢地添加至大量過量的冰中。水層用EtOAc(3 x 50mL)萃取。合併的有機層用鹽水洗滌,經Na2SO4乾燥並且在減壓下濃縮。殘餘物藉由層析法(矽膠)用PE/EA=1:1洗脫來純化以便獲得標題化合物。1H NMR(氯仿-d)δ:7.95(d,J=1.9Hz,1H),7.89(d,J=2.1Hz,1H),6.70(br.s.,1H),3.16(d,J=4.3Hz,3H)。LC-MS:m/z 297(M+H)+
步驟A:喹唑啉-4-醇(28B)
在回流下將2-胺基苯甲酸乙酯(5.0g,30mmol)於甲氧基乙醇(20mL)中的溶液用乙酸甲脒(8g,77mmol)處理17h。然後添加第二部分的乙酸甲脒(8g,77mmol),並且再連續回流7小時。將混合物冷卻,並且將溶劑真空移除。殘
餘物溶於飽和NaHCO3中並且用乙酸乙酯萃取。將有機層合併,用飽和NaHCO3洗滌,並且用硫酸鎂乾燥,並且將溶劑真空移除以便得到所需化合物(4.84g,91%),該化合物未進行進一步純化即用於下一個步驟。LC-MS:m/z 147.7(M+H)+
步驟B:4-羥基喹唑啉-8-磺醯氯(28C)
將氯磺酸(4.10mL,62.6mmol)緩慢地添加至喹唑啉-4-醇(1.09g,0.26mmol)。將所得混合物加熱至140℃並且在相同溫度下攪拌3小時。冷卻至室溫之後,將反應混合物傾倒於碎冰中。混合物用DCM(100mL x 3)萃取,合併的有機層經Na2SO4乾燥、過濾,並且將濾液真空濃縮。殘餘物經由快速層析法(5% PE:乙酸乙酯)純化以便得到370mg 4-羥基喹唑啉-8-磺醯氯。1H NMR(400MHz,DMSO-d 6)δ:7.76(t,J=7.79Hz,1 H)8.26(ddd,J=9.67,7.92,1.48Hz,2 H)9.02(s,1 H)。LC-MS:m/z 245.7(M+H)+
步驟A:2-(二氟甲氧基)-4-硝基苯甲酸甲酯(29B)
將2-羥基-4-硝基苯甲酸甲酯(1.1g,5.6mmol)、2-氯-2,2-二氟乙酸鈉(1.0g,6.6mmol)以及Na2CO3(710mg,6.7mmol)於DMF(10mL)中的混合物在100℃下攪拌過夜。冷卻至rt之後,使混合物在水與EtOAc之間分配。將有機層分離並且用水、然後鹽水洗滌兩次,經Na2SO4乾燥並且濃縮,並且藉由標準方法純化以便得到標題產物(330mg)。1H NMR(氯仿-d)δ:8.15-8.19(m,1H),8.13(s,1H),8.06(d,J=8.6Hz,1H),6.68(s,1H),3.98(t,J=72.8Hz,1H).
步驟B:4-胺基-2-(二氟甲氧基)苯甲酸甲酯(29C)
在室溫下在氫氣氛下將2-(二氟甲氧基)-4-硝基苯甲酸甲酯(330mg,1.3mmol)以及10% Pd/碳(50mg)於THF(10mL)中的混合物攪拌6小時。藉由過濾移除固體並且將溶劑濃縮以便得到粗苯胺。LC-MS:m/z 218.1(M+H)+
步驟A:2-氯-4-硝基苯甲酸甲酯(30B)
向2-氯-4-硝基苯甲酸(10g,0.06mol)於MeOH(120mL)中的溶液添加H2SO4(5mL)。所得混合物在60℃下攪拌過夜。冷卻至室溫之後,使用碳酸氫鈉溶液使混合物達到pH=8。移除MeOH之後,所得粗混合物藉由柱層析法(20% CH2Cl2/PE)純化以便提供4g標題化合物。LC-MS:m/z 216.6(M+H)+
步驟B:2-氰基-4-硝基苯甲酸甲酯(30C)
將2-氯-4-硝基苯甲酸甲酯(2g,9.3mmol)、CuCN(3.3g,37.2mmol)以及Pd(PPh3)4(1.075g,0.93mmol)的混合物懸浮於DMF(15mL)中,並且然後在150℃下經受微波照射4小時。混合物在減壓下濃縮之後,使殘餘物在乙酸乙酯與水之間分配。有機層經Na2SO4乾燥、過濾,並且濾液在減壓下蒸發至幹。原材料藉由柱層析法(20% EA/PE)純化以便提供0.9g標題化合物。LC-MS:m/z 207.1(M+H)+。
步驟C:4-胺基-2-氰基苯甲酸甲酯(30D)
向2-氰基-4-硝基苯甲酸甲酯(0.9g,4.4mmol)於MeOH(5mL)中的溶液
添加Pd/C(0.1g)。所得混合物在室溫下在氫氣氛下攪拌2小時。將混合物過濾,並且濾液在減壓下蒸發至幹以便得到標題產物(0.77g),該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 177.2(M+H)+
步驟A:6-甲基-5-硝基甲基吡啶腈(31B)
在N2下,向2-溴基-4-硝基苯甲酸甲酯(31A,4g,18.4mmol)於10mL DMA中的混合物添加CuCN(6.6g,74mmol)以及Pd(PPh3)4(1.06g,0.92mmol)。將混合物在150℃下在微波照射下攪拌4小時。然後混合物用水稀釋並且過濾。濾液用EtOAc(20mL)萃取。將有機層乾燥、濃縮,並且藉由矽膠層析法(PE:EtOAc=3:1)純化以便得到500mg標題化合物。1H NMR(氯仿-d)δ:8.08(d,J=7.9Hz,1H),7.68(d,J=7.9Hz,1H),2.85(s,3H)。
步驟B:6-甲基-5-硝基吡啶甲酸(31C)
向6-甲基-5-硝基甲基吡啶腈(31B,500mg,3.1mmol)於2-丙醇(1mL)以及水(5mL)中的溶液添加三級丁醇鉀(687mg,6.13mmol)。將混合物在100℃下攪拌過夜,此時LCMS指示反應完成。混合物用水稀釋,並且然後用DCM(10mL x 3)萃取。水相用1N HCl溶液酸化,並且用DCM萃取。將有機層乾燥並且濃縮以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 181(M-H)+
步驟C:5-胺基-6-甲基吡啶甲酸(31D)
向6-甲基-5-硝基吡啶甲酸(31C,500mg,2.75mmol)於甲醇(10ml)中的溶液添加Pd/C(50mg)。將溶液在室溫下在H2氣氛下攪拌1h,此時LC-MS展示s.m.消耗完。然後將混合物過濾並且濃縮以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 153(M+H)+
步驟D:5-胺基-6-甲基吡啶甲酸甲酯(31E)
向5-胺基-6-甲基吡啶甲酸(31D,240mg,1.5mmol)於甲醇中的溶液添加濃H2SO4。將溶液在60℃下攪拌過夜,此時LC-MS展示s.m.消耗完。然後將混合物濃縮並且用Na2CO3溶液中和至pH=7。混合物用DCM(10mL x 3)萃取。將有機層乾燥並且濃縮以便得到標題化合物31E。LC-MS:m/z 167(M+H)+
步驟A:在-65℃下在30分鐘內向4-乙基哌啶-1,4-二甲酸1-三級丁酯(36A,1.24g,4.0mmol)于無水THF(50mL)中的溶液逐滴添加LDA溶液(2.1mL,5.2mmol),並且將所得混合物在-65℃下攪拌15分鐘,並且然後再在-30℃下攪拌30分鐘。在-65℃下添加RBr(4.8mmol,1.2當量)之後,將混合物在-65℃下再攪拌15分鐘,並且然後允許它升溫至室溫持續2小時。藉由添加50mL NH4Cl溶液(1M)來淬滅反應,將有機相濃縮並且粗產物藉由標準方法純化以便得到標題化合物36B。
步驟B:相應化合物36B(2.0mol)以及HCl(10mL,1,4-二中的4M溶液)的混合物在室溫下攪拌4小時。然後將溶劑移除,並且殘餘物溶解於3.0mL
NaOH溶液以及2.0mL甲醇中。混合物在微波照射下在110℃下攪拌10分鐘並且然後濃縮。殘餘物藉由標準方法純化以便得到標題化合物36C。
步驟C:向小瓶中添加10mL THF中的化合物36C(24.36mmol),然後添加硼烷-四氫呋喃複合物(3.3mL,32.88mmol),並且混合物在回流下加熱3h。用飽和的NaHCO3、鹽水洗滌之後,合併的有機層經無水Na2SO4乾燥並且真空濃縮以便獲得粗產物36D以及36E,其未進行純化即直接地用於下一個步驟。
步驟D:向圓底燒瓶依序地添加化合物36E(或36B-1或36D-1,或36D-2,或36D-3)(0.2mmol,1當量)、DMF(5mL)、DIPEA(0.6mmol,3.0當量)、HBTU(2.4mmol,1.2當量)以及中間物36G(例如,Ar-8-喹啉)(0.2mmol,1.0當量)。將反應混合物在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥、過濾,並且將濾液真空濃縮。所需產物36F藉由標準方法來純化。
N-(4-(4-苄基-4-(羥基甲基)哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(400MHz,CDCl3)δ:9.17(dd,J=4.4,1.7Hz,1H),8.52(dd,J=8.4,1.6Hz,1H),8.43(dd,J=7.3,1.3Hz,1H),8.26-8.19(m,1H),7.78-7.65(m,2H),7.29-7.15(m,10H),4.17-4.06(m,1H),3.75(s,1H),3.60(t,J=5.7Hz,2H),2.74(s,2H),2.08-2.01(m,1H),1.64-1.60(m,3H),1.48-1.38(m,2H)。LC-MS:m/z 516.6(M+H)
4-異丁基-1-(4-(喹啉-8-磺醯胺基)苯甲醯基)哌啶-4-甲酸乙酯
1H NMR(氯仿-d)δ:9.16(dd,J=4.3,1.6Hz,1H),8.38(dd,J=7.3,1.1Hz,1H),8.32(dd,J=8.3,1.6Hz,1H),8.06(dd,J=8.3,1.1Hz,1H),7.59-7.67(m,2H),7.13-7.19(m,J=8.6Hz,2H),7.04-7.11(m,J=8.6Hz,2H),4.17(q,J=7.0Hz,2H),3.51(br.
s.,1H),3.10(br.s.,1H),2.93(br.s.,1H),2.15-2.24(m,1H),2.08(d,J=10.2Hz,1H),1.61-1.74(m,4H),1.47(d,J=12.9Hz,2H),1.29-1.36(m,2H),1.26(s,1H),0.83-0.91(m,6H)。LC-MS:m/z 524.7(M+H)+
N-(4-(4-甲醯基-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.50(s,1H),9.16(dd,J=4.3,1.3Hz,1H),8.27-8.41(m,2H),8.02-8.11(m,1H),7.55-7.68(m,2H),7.12-7.19(m,J=8.3Hz,2H),7.05-7.11(m,J=8.6Hz,2H),3.48(s,1H),2.93-3.17(m,2H),1.96(br.s.,2H),1.64(t,J=13.1,6.5Hz,1H),1.48(br.s.,3H),1.22-1.42(m,2H),0.82-0.94(m,6H)。LC-MS:m/z 480.7(M+H)+
N-(4-(4-(羥基甲基)-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.17(dd,J=4.3,1.6Hz,1H),8.27-8.42(m,2H),8.06(dd,J=8.1,1.3Hz,1H),7.58-7.67(m,2H),7.13-7.21(m,2H),7.05-7.12(m,2H),3.54(s,3H),3.30(br.s.,2H),1.69(dd,J=12.6,6.2Hz,2H),1.47(d,J=11.6Hz,3H),1.34(d,J=5.4Hz,3H),0.95(d,J=6.7Hz,6H)。LC-MS:m/z 482.7(M+H)+
(N-(4-(4-(羥基甲基)-4-苯基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:9.14(dd,J=4.3,1.6Hz,1H),8.36(dd,J=7.4,1.2Hz,1H),8.31(dd,J=8.5,1.5Hz,1H),8.02-8.07(m,1H),7.57-7.65(m,2H),7.36-7.42(m,2H),
7.30-7.34(m,2H),7.23-7.28(m,1H),7.11-7.16(m,J=8.6Hz,2H),7.04-7.09(m,J=8.6Hz,2H),3.53(s,2H),3.06-3.16(m,2H),2.16-2.30(m,1H),2.10-2.16(m,1H),1.71-1.91(m,3H),1.67(dt,J=5.7,2.9Hz,1H)。LC-MS:m/z 502.7(M+H)+
N-(4-(4-(羥基甲基)-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.49(s,1H),8.34(dd,J=8.2,0.9Hz,1H),8.12(dd,J=7.7,0.9Hz,1H),7.58(t,J=7.8Hz,1H),7.19(s,4H),4.62(s,1H),3.71(br.s.,1H),3.58(br.s.,1H),3.47(s,2H),1.75(s,1H),1.59(br.s.,1H),1.42-1.51(m,2H),1.35(d,J=5.1Hz,3H),1.31(br.s.,2H),0.95(d,J=6.7Hz,6H)LC-MS:m/z 488.7(M+H)+
N-(4-(4-(羥基甲基)-4-異丁基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.11(d,J=1.9Hz,1H),9.02(d,J=1.9Hz,1H),8.50(dd,J=7.5,1.3Hz,1H),8.31(dd,J=8.3,1.3Hz,1H),7.91(dd,J=8.5,7.4Hz,1H),7.14-7.24(m,4H),3.70(br.s.,1H),3.57(br.s.,1H),3.46(s,2H),3.37(s,1H),3.28(br.s.,2H),1.66-1.77(m,1H),1.55(br.s.,1H),1.43(br.s.,2H),1.24-1.37(m,3H),0.95(s,3H),0.93(s,3H)。LC-MS:m/z 483.6(M+H)+
步驟A:4-(3-((三級丁基二甲基矽烷基)氧基)丙-1-炔-1-基)-4-羥基哌啶-1-甲酸三級丁酯(37C)
在-78℃下在N2下向三級丁基二甲基(丙-2-炔-1-基氧基)矽烷(0.5mL,2.46mmol)於30mL無水THF中的溶液逐滴添加n-BuLi(1.2mL,2.95mmol)。在-78℃下攪拌1h之後,在-78℃下在N2下將THF(2mL)中的4-側氧基哌啶-1-甲酸三級丁酯(588.4mg,2.95mmol)逐滴添加至上述溶液。所得混合物在-78℃下在N2攪拌2h,然後允許溫至室溫並且再攪拌1.5h。將反應混合物冷卻至-78℃並且由飽和NH4Cl水溶液來淬滅,並且所得混合物用EtOAc(50mL,30mL)來萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮以便提供1.10g標題化合物。LC-MS:m/z 370.7(M+H)+。1H NMR(氯仿-d)δ:4.37(s,2H),3.74(d,J=6.2Hz,2H),3.35-3.24(m,2H),2.46(t,J=6.2Hz,1H),1.92-1.84(m,2H),1.71(ddd,J=12.9,9.1,3.8Hz,2H),1.47(s,9H),0.92(s,9H),0.13(s,6H)。
步驟B:4-(3-((三級丁基二甲基矽烷基)氧基)丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(37D)
在-78℃下在N2下向4-(3-((三級丁基二甲基矽烷基)氧基)丙-1-炔-1-基)-4-羥基
哌啶-1-甲酸三級丁酯(500mg,1.353mmol)於30mL無水THF中的溶液逐滴添加n-BuLi(0.65mL,1.623mmol)。在-78℃下攪拌1h之後,在-78℃下在N2下將THF(1mL)中的氯甲酸甲酯(176.2mg,1.623mmol)逐滴添加至上述溶液。在-78℃下在N2下將所得混合物攪拌2h,然後允許溫至室溫並且再攪拌8h。反應混合物冷卻至-78℃並且由飽和NH4Cl水溶液來淬滅,並且所得混合物用EtOAc(50mL,30mL)來萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供453mg標題化合物。1H NMR(氯仿-d)δ:4.40(s,2H),4.26-4.15(m,2H),3.80-3.67(m,2H),3.41-3.28(m,2H),2.27-2.14(m,2H),2.00(ddd,J=13.1,9.2,3.9Hz,2H),1.48(s,9H),1.33(t,J=7.1Hz,4H),0.92(s,9H),0.14(s,6H)。
步驟C:4-(3-羥基丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(37E)
在0℃下在N2下,向4-(3-((三級丁基二甲基矽烷基)氧基)丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(450mg,1.02mmol)於30mL無水THF中的溶液添加TBAF(800.5mg,3.06mmol)。在0℃下攪拌1h之後,反應混合物由飽和NH4Cl水溶液來淬滅,並且所得混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供290mg標題化合物。MS(ES)M+H期望值313.25,實驗值313.47。1H NMR(氯仿-d)δ:4.36(s,2H),4.21(q,J=7.1Hz,2H),3.80-3.70(m,2H),3.41-3.29(m,2H),2.24-2.13(m,2H),2.00(ddd,J=13.2,9.3,3.9Hz,2H),1.95(s,1H),1.48(s,9H),1.34(t,J=7.1Hz,3H)。
步驟D:4-((甲氧羰基)氧基)-4-(3-側氧基丙-1-炔-1-基)哌啶-1-甲酸三級丁酯(37F)
在室溫下向4-(3-羥基丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(130mg,0.398mmol)於30mL DCM中的溶液添加NaHCO3(334mg,3.98mmol)、DMP(338mg,0.796mmol)。將反應混合物在室溫下攪拌8h。將反應混合物過濾並且殘餘混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供110mg標題化合物。1H NMR(氯仿-d)δ:9.29(s,1H),4.25(q,J=7.1Hz,2H),3.80-3.64(m,2H),3.49-3.35(m,2H),2.30-2.18(m,2H),2.17-2.03(m,2H),1.48(s,9H),1.36(t,J=7.1Hz,3H)。
步驟E:4-(3,3-二氟丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(37G)
在0℃下在N2下向4-((甲氧羰基)氧基)-4-(3-側氧基丙-1-炔-1-基)哌啶-1-甲酸三級丁酯(60mg,0.1846mmol)於5mL DCM中的溶液添加DAST(89.3mg,0.5583mmol)。在室溫下攪拌8h之後,反應混合物由飽和NH4Cl水溶液來淬滅,並且所得混合物用DCM(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供63mg標題化合物。1H NMR(氯仿-d)δ:6.27(t,J=54.4Hz,1H),4.30-4.18(m,2H),3.75(d,J=7.0Hz,2H),3.46-3.28(m,2H),2.32-2.14(m,2H),2.10-1.99(m,2H),1.48(s,9H),1.35(t,J=7.1Hz,3H)。
步驟F:4-(3,3-二氟丙-1-炔-1-基)-4-羥基哌啶-1-甲酸三級丁酯(37H)
在室溫下向4-(3,3-二氟丙-1-炔-1-基)-4-((甲氧羰基)氧基)哌啶-1-甲酸三級丁酯(6.0g,18.5mmol)於100mL MeOH以及15mL水中的溶液添加K2CO3(3.822g,27.7mmol)。將反應混合物在48℃下攪拌3h。將反應混合物冷卻至室溫,並且用EtOAc(150mL,100mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供4.81g標題化合物。
步驟G:4-(3,3-二氟丙基)-4-羥基哌啶-1-甲酸三級丁酯(37I)
在H2氣氛下在15psi下在48℃下將4-(3,3-二氟丙-1-炔-1-基)-4-羥基哌啶-1-甲酸三級丁酯(350mg,1.273mmol)於30mL無水THF中的溶液與Pd/C(200mg)一起攪拌8h。將反應混合物冷卻至室溫並且過濾,並且所得混合物真空濃縮以便提供293mg標題化合物。1H NMR(氯仿-d)δ:5.89(tt,J=56.9,4.3Hz,1H),3.84(dd,J=9.8,3.5Hz,2H),3.24-3.10(m,2H),2.05-1.89(m,2H),1.67-1.60(m,2H),1.55(m,4H),1.47(s,9H)。
步驟H:4-(3,3-二氟丙基)哌啶-4-醇(37J)
在室溫下將4-(3,3-二氟丙基)-4-羥基哌啶-1-甲酸三級丁酯(293mg,1.075mmol)於5mL含3.5N HCl的二中的溶液攪拌30分鐘。反應混合物真空濃縮以便得到301mg標題產物,該產物直接地用於下一個步驟。
步驟I:在室溫下向相應(芳基-磺醯胺基)苯甲酸(1.05mmol)於15mL DMF中的溶液依序地添加HBTU(479mg,1.26mmol)、DIPEA(203mg,1.58mmol)以及4-(3,3-二氟丙基)哌啶-4-醇(226.3mg,1.05mmol)。反應混合物在室溫下攪拌1小時。將混合物傾倒至水中並且以EtOAc(50mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥。將合併的有機層真空濃縮。藉由標準方法來純化標題化合物。
N-(4-(4-(3,3-二氟丙基)-4-羥基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
1H NMR(氯仿-d)δ:10.41(s,1H),9.13(dd,J=4.2,1.7Hz,1H),8.52(dd,J=8.4,1.7Hz,1H),8.42(dd,J=7.3,1.3Hz,1H),8.36-8.24(m,1H),7.80-7.64(m,2H),7.11(q,J=8.7Hz,4H),6.06(td,J=59.4,55.3Hz,1H),4.44(m,1H),4.16-3.92(m,1H),3.16-2.91(m,2H),1.84(dqt,J=19.9,13.0,6.6Hz,2H),1.51-1.40(m,3H),1.40-1.29(m,3H)。LC-MS:m/z 490.68(M+H)+
N-(4-(4-(3,3-二氟丙基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:10.76(s,1H),9.66(s,1H),8.50(dd,J=8.1,1.0Hz,1H),8.11(dd,J=7.6,1.0Hz,1H),7.65(t,J=7.9Hz,1H),7.17(d,J=8.7Hz,2H),7.10(d,J=8.7Hz,2H),6.06(t,J=57.1,4.3Hz,1H),4.10(d,J=5.3Hz,1H),3.11(dd,J=51.3,35.5Hz,3H),1.83(dd,J=18.4,11.9Hz,2H),1.55-1.28(m,6H)。LC-MS:m/z 496.59(M+H)+
N-(4-(4-(3,3-二氟丙基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:10.65(s,1H),9.13(dd,J=13.1,1.8Hz,2H),8.50(dd,J=7.4,1.3Hz,1H),8.37(dd,J=8.4,1.2Hz,1H),8.05-7.93(m,1H),7.12(dd,J=25.5,8.7Hz,4H),6.06(t,J=57.1,4.2Hz,1H),4.10-3.93(m,1H),3.04(m,3H),1.84(m,2H),1.54-1.27(m,6H)。LC-MS:m/z 491.58(M+H)+
步驟A:(E)-4-(3,3-二氟丙-1-烯基)-4-羥基哌啶-1-甲酸三級丁酯(38B)
在-78℃下在N2下向4-(3,3-二氟丙-1-炔-1-基)-4-羥基哌啶-1-甲酸三級丁酯(280mg,1.016mmol)於30mL無水THF中的溶液逐滴添加二氫-雙-(2-甲氧基乙氧基)鋁酸鈉(587mg,2.032mmol,70%)。添加之後,將反應混合物在-78℃下在N2下攪拌5h。由飽和NH4Cl水溶液來淬滅反應混合物,並且所得混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮以便提供291mg標題化合物。MS(ES)M+H期望值278.15,實驗值178.30。1H NMR(氯仿-d)δ:6.29-6.08(m,2H),6.01-5.84(m,1H),3.98-3.84(m,2H),3.20(t,J=11.4Hz,2H),1.76-1.62(m,4H),1.48(s,9H)。
步驟B:(E)-4-(3,3-二氟丙-1-烯基)哌啶-4-醇(38C)
將(E)-4-(3,3-二氟丙-1-烯基)-4-羥基哌啶-1-甲酸三級丁酯(38C)(293mg,1.075mmol)於5mL含3.5N HCl的二中的溶液在室溫下攪拌30分鐘。將反應混合物真空濃縮以便得到300mg呈黃色液體狀的標題產物,該產物直接地用於下一個步驟。
步驟A:N,N'-二亞硫醯基-3-氟-1,2-二胺基苯(39B)
在0℃下向3-氟苯-1,2-二胺(7.9g,62.7mmol)於80mL吡啶中的溶液逐滴添加SOCl2(16mL)。將反應混合物在100℃下攪拌8小時。將混合物傾倒至水中並且以EtOAc(50mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥。將合併的有機層真空濃縮。柱層析法(15%石油/EtOAc)提供11.5g標題化合物。
步驟B:7-氟苯並[c][1,2,5]噻二唑-4-磺醯氯(39C)
在110℃下將N,N'-二亞硫醯基-3-氟-1,2-二胺基苯39B(11.5g,52.75mmol)於80mL氯磺酸中的溶液加熱8小時。將混合物冷卻至室溫並且傾倒至水中並且用EtOAc(50mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥。將合併的有機層真空濃縮。柱層析法(15%石油/EtOAc)提供7.1g標題化合物。1H NMR(氯仿-d)δ:8.48(dd,J=8.4Hz,4.4Hz,1H),7.45(t,J=8.4Hz,1H)。LC-MS:m/z 253.2(M+H)+。
步驟C:4-(7-氟苯並[c][1,2,5]噻二唑-4-磺醯胺基)苯甲酸乙酯(39D)
向4-胺基苯甲酸乙酯(412mg,2.5mmol)於20mL DCM中的溶液添加吡啶(600mg,7.5mmol)以及7-氟苯並[c][1,2,5]噻二唑-4-磺醯氯(39C)(633mg,2.5mmol)。所得混合物在50℃下攪拌過夜。移除DCM之後,使殘餘物在水與EtOAc之間分配。有機層用2N HCl、水以及鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到粗產物39D,該粗產物藉由LCMS來證實,並且未進行進一步純化即用於下一個反應。1H NMR(氯仿-d)δ:8.33(dd,J=8.0,4.6Hz,1H),7.85(d,J=8.7Hz,2H),7.66(s,1H),7.35-7.30(m,1H),7.12(d,J=8.7Hz,2H),4.31(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H)。LC-MS:m/z 382.4(M+H)+。
步驟D:4-(2,3-二胺基-4-氟苯基磺醯胺基)苯甲酸乙酯(39E)
在70℃下向化合物39D(382mg,1.0mmol)於AcOH/H2O(8mL/3mL)中的溶液添加鋅粉末(975mg,15mmol)並且所得懸浮液在70℃下攪拌1h。將固體過濾掉並且用EtOAc洗滌。使濾液在飽和的NaHCO3與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經無水Na2SO4乾燥並且濃縮以便得到粗產物39E,該粗產物藉由LCMS來證實,並且未進行進一步純化即用於下一個反應。LC-MS:m/z 354.4(M+H)+。
步驟E:4-(2,3-二胺基-4-氟苯基磺醯胺基)苯甲酸(39F)
向化合物39E(350mg,1mmol)於EtOH/H2O(10mL/3mL)中的溶液添加LiOH.H2O(200mg,5mmol)並且所得懸浮液在70℃下攪拌過夜。將溶劑濃縮並且使殘餘物在2NHCl水溶液與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到所需粗產物39F,該粗產物藉由LCMS
來證實,並且未進行進一步純化即用於後續反應。LC-MS:m/z 326.3(M+H)+。
步驟F:向化合物39F(0.2mmol)於DCM(10mL)中的溶液添加HBTU(91mg,0.24mmol)並且在室溫下攪拌20分鐘,然後添加相應化合物7(0.2mmol)以及DIPEA(0.6mmol)。攪拌30分鐘之後,使反應物在飽和的Na2CO3溶液與DCM之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮,並且然後藉由標準方法純化以便得到標題產物39G。
2,3-二胺基-N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-4-氟苯磺醯胺
1H NMR(氯仿-d)δ:10.56(s,1H),7.81(dd,J=7.9,1.6Hz,1H),7.42-7.33(m,2H),7.27(m,3H),7.08(d,J=8.6Hz,2H),6.99(dd,J=9.0,5.9Hz,1H),6.46(dd,J=9.2Hz,1H),5.71(s,2H),5.43(s,1H),4.87(s,2H),4.35(s,1H),3.45(s,2H),3.12(s,1H),1.78-1.12(m,4H)。LC-MS:m/z 519.70(M+H)+
2,3-二胺基-4-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯磺醯胺
1H NMR(氯仿-d)δ:7.27(d,J=8.5Hz,2H),7.20(dd,J=9.0,5.9Hz,1H),7.15(s,1H),7.06(d,J=8.5Hz,2H),6.49(t,J=9.1Hz,1H),4.38(s,1H),3.44(s,2H),3.25(s,1H),1.85(td,J=12.9,6.5Hz,1H),1.67(s,4H),1.44(d,J=6.0Hz,2H),1.00(d,J=6.6Hz,6H)。LC-MS:m/z 465.66(M+H)+
步驟G:向相應化合物39G(0.9mmol)于乙醇/水(30mL/4mL)中的溶液添加1,4-二-2,3-二醇(130mg,1.08mmol)並且所得懸浮液在30℃下攪拌過夜。將溶劑真空移除並且使殘餘物在水與EtOAc之間分配。將有機層分離並且用水以及鹽水洗滌,經Na2SO4乾燥並且濃縮,並且然後藉由標準方法純化以便得到標題產物39H。
8-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.14(d,J=8.8Hz,2H),8.46(dd,J=8.3,5.2Hz,1H),7.88(s,1H),7.54(t,J=8.5Hz,1H),7.20(d,J=8.1Hz,2H),7.07(d,J=8.1Hz,2H),4.31(s,1H),3.29(s,3H),1.82(td,J=12.9,6.5Hz,1H),1.57(s,4H),1.41(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 487.68(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-8-氟喹啉-5-磺醯胺
1H NMR(氯仿-d)δ:9.15(d,J=9.5Hz,2H),8.47(dd,J=8.3,5.1Hz,1H),7.87(s,1H),7.53(dd,J=17.0,8.5Hz,2H),7.40(d,J=7.6Hz,1H),7.31(d,J=7.8Hz,1H),7.25(d,J=7.2Hz,3H),7.09(d,J=7.2Hz,2H),4.61(s,1H),3.58(m,2H),3.32(m,1H),2.38-2.01(m,4H)。LC-MS:m/z 541.79(M+H)+
步驟A:向2-胺基-6-氟-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺(化合物145)(200mg,0.4mmol)於THF(5mL)中的溶液添加亞硝酸異戊酯(94mg,0.8mmol)。反應混合物在70℃下在氮氣氛下攪拌3小時。反應完成之後(藉由TLC監測),將反應混合物真空濃縮。將殘餘物溶解于水中,並且用乙酸乙酯(3 x 50mL)萃取。合併的有機萃取物用鹽水(20mL)洗滌,經無水硫酸鈉乾燥、過濾並且在減壓下濃縮以便獲得粗產物,該粗產物藉由標準方法來純化。
1H NMR(氯仿-d)δ:9.26(s,1H),7.89(s,1H),7.88-7.84(m,2H),7.22(d,J=8.4Hz,2H),7.11(d,J=8.5Hz,2H),4.33(s,1H),3.30(s,3H),1.90-1.79(m,1H),1.52(d,J=51.2Hz,4H),1.42(d,J=6.0Hz,2H),0.98(d,J=6.6Hz,6H)。LC-MS:m/z 492.68(M+H)+
N-(4-(4-(2-氯苯基)-4-羥基哌啶-1-羰基)苯基)-6-氟苯並[d]噻唑-4-磺醯胺
1H NMR(氯仿-d)δ:9.26(s,1H),7.89(s,1H),7.87(d,J=7.6Hz,2H),7.52(dd,J=7.8,1.7Hz,1H),7.40(dd,J=7.7,1.6Hz,1H),7.34-7.29(m,1H),7.25(dd,J=10.0,5.0Hz,3H),7.13(d,J=8.5Hz,2H),4.64(s,1H),3.60(s,2H),3.31(s,1H),2.39-1.99(m,4H)。LC-MS:m/z 546.7(M+H)+
步驟A:6-氯喹啉-2-胺(42B)
在圓底燒瓶中,將2.6-二氯喹啉(500mg,2.5mmol)、乙醯胺(3g,50.8mmol)
以及K2CO3(1.75g,12.7mmol)的混合物在200℃下攪拌1.5小時直到TLC指示2,6-二氯喹啉消耗完為止。將所得混合物冷卻至室溫,並且在二氯甲烷與H2O之間分配,有機層經無水Na2SO4乾燥、濃縮,並且殘餘物藉由標準方法純化以便得到440mg標題化合物。LCMS(m/z):179.7(M+1)+
步驟B:2-胺基-6-氯喹啉-8-磺醯氯(42C)
在0℃下將6-氯喹啉-2-胺(350mg)分多份添加至5mL HClSO3,並且然後混合物在100℃下攪拌1小時。將所得混合物冷卻至室溫,然後將它小心地傾倒至碎冰以及H2O中,並且所得混合物用二氯甲烷萃取。合併的有機層經無水Na2SO4乾燥、濃縮以便提供粗標題化合物,該化合物未進行進一步純化即用於下一個步驟。LCMS(m/z):278.1(M+1)+
步驟C:4-(2-胺基-6-氯喹啉-8-磺醯胺基)苯甲酸(42D)
在30℃下將2-胺基-6-氯喹啉-8-磺醯氯(500mg,1.8mmol)、4-胺基苯甲酸(300mg,2.2mmol)以及吡啶(1mL)於10mL THF中的混合物攪拌過夜,此時LCMS指示反應完成。將所得混合物濃縮,並且殘餘物藉由標準方法純化以便產生標題化合物。LCMS(m/z):378.8(M+1)+
步驟D:4-(2-胺基喹啉-8-磺醯胺基)苯甲酸(42E)
4-(2-胺基-6-氯喹啉-8-磺醯胺基)苯甲酸(150mg,0.44mmol)、10% Pd/C(20mg)於甲醇(5mL)中的混合物在H2氣氛下攪拌過夜,此時LCMS指示反應完成。將所得混合物過濾,並且濃縮濾液以便產生100mg標題化合物,該化合物未進行進一步純化即用於下一個步驟。LCMS(m/z):344.6(M+1)+
步驟E:化合物402:2-胺基-N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)喹啉-8-磺醯胺
在室溫下向4-異丁基哌啶-4-醇(70mg,0.44mmol)、4-(2-胺基喹啉-8-磺醯胺基)苯甲酸(100mg,0.44mmol)以及HBTU(134mg,0.53mmol)於DCM(5mL)中的混合物逐滴添加DIPEA(1mL),並且然後混合物在室溫下攪拌1小時。將所得混合物濃縮,藉由標準方法純化以便產生標題化合物。1H NMR(氯仿-d)δ:8.10-8.20(m,1H),7.89(d,J=9.1Hz,1H),7.69-7.82(m,1H),7.06-7.26(m,5H),6.80(d,J=9.1Hz,1H),5.41(s,2H),4.33(br.s.,1H),3.41-3.19(m.,3H),1.82(dt,J=12.9,6.4Hz,1H),1.63-1.46(m,4H),1.40(d,J=5.9Hz,2H),0.97(d,J=6.7Hz,6H)。LCMS(m/z):483.7(M+1)+
步驟A:4-羥基-4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸苄酯(43B)
向含有Zn粉(2.3g,36mmol)的圓底燒瓶添加二溴乙烷(585mg,3.11mmol)。將所得混合物溫至60℃並且允許冷卻1分鐘。此加熱-冷卻過程再重複三次,並且然後允許燒瓶再冷卻3分鐘。添加THF(5mL)中的三甲基氯矽烷(456mg,4.2mmol),隨後添加THF(8mL)中的2-溴乙酸乙酯(2g,12mmol)。將反應物
溫至60℃再持續兩個小時直到獲得暗灰色懸浮液為止。將混合物冷卻至室溫;然後添加THF(20mL)中的4-側氧基哌啶-1-甲酸苄酯(1.9g,8.2mmol)。將所得混合物攪拌3天,並且然後用水淬滅。將固體過濾掉,並且水溶液用乙酸乙酯萃取。合併的有機層用鹽水洗滌並且經Na2SO4乾燥。藉由標準方法純化給出所需產物。1H NMR(氯仿-d)δ:7.33-7.43(m,5H),5.14(s,2H),3.89-4.05(m,2H),3.68-3.79(m,3H),3.22-3.36(m,2H),2.49(s,2H),2.19(s,1H),1.71(d,J=12.6Hz,2H),1.53(dd,J=12.5,4.2Hz,2H)。LCMS(m/z):308.1(M+1)+
步驟B:4-(苄氧基甲氧基)-4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸苄酯(43C)
化合物43B(0.5g,1.63mmol)以及二異丙基乙胺(1.26g,9.8mmol)於CH2Cl2(10mL)中的溶液用苄基氯甲醚(636mg,4.1mmol)處理並且在室溫下攪拌16h。藉由標準方法純化給出所需產物。1H NMR(氯仿-d)δ:7.30-7.44(m,9H),5.15(s,2H),4.92(s,2H),4.69(s,2H),3.91(br.s.,2H),3.65(s,3H),3.29(br.s.,2H),2.63(s,2H),2.20(s,1H),2.02(d,J=13.7Hz,2H),1.69(ddd,J=14.1,11.7,4.6Hz,3H)。LC-MS:m/z 428.6(M+H)+
步驟C:4-(苄氧基甲氧基)-4-(2-羥基-2-甲基丙基)哌啶-1-甲酸苄酯(43D)
在0℃下向4-(苄氧基甲氧基)-4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸苄酯(500mg,1.17mmol)于無水THF(15mL)中的溶液逐滴添加甲基溴化鎂(2mL,6mmol)於乙醚中的溶液。添加完成之後,混合物在室溫下攪拌1.5h,並且然後再次在冰浴中冷卻。逐滴添加飽和的氯化銨溶液。所得沈澱物藉由添加水(30mL)來溶解。混合物用EtOAc萃取三次。合併的有機層經Na2SO4乾燥並且蒸發以便獲得粗產物,該粗產物未進行進一步純化即直接地用於下一個步驟。LCMS(m/z):428.2(M+1)+
步驟D:4-(苄氧基甲氧基)-4-(2-氟-2-甲基丙基)哌啶-1-甲酸苄酯(43E)
向(4-羥基-4-(異噻唑-4-基)哌啶-1-基)(4-((喹啉-8-基磺醯基)甲基)苯基)甲酮(500mg,1.17mmol)於DCM(10mL)中的溶液逐滴添加DAST(282mg,1.75mmol),同時在冰-水浴上冷卻。允許混合物從0℃升溫至室溫,並且攪拌16小時。藉由逐滴添加飽和氯化銨溶液來淬滅反應物,然後用飽和NaHCO3洗滌並且用EtOAc萃取。有機層用鹽水洗滌,並且然後濃縮以便獲得粗產物。藉由標準方法純化給出所需產物。1H NMR(氯仿-d)δ:7.30-7.59(m,10H),5.15(s,2H),4.85(s,2H),4.71(s,2H),3.83(br.s.,2H),3.38(br.s.,2H),1.91-2.05(m,3H),1.59-1.70(m,2H),1.47(s,3H),1.42(s,3H),1.36(s,1H)。
步驟E:4-(2-氟-2-甲基丙基)哌啶-4-醇(43F)
向圓底燒瓶添加-4-(苄氧基甲氧基)-4-(2-氟-2-甲基丙基)哌啶-1-甲酸苄酯(50mg,0.12mmol)、Pd/C(20mg)以及甲醇(5mL)。混合物在室溫下在氫氣氛下攪拌16小時。將反應混合物過濾以便獲得溶液,濃縮該溶液以便得到所需產物。粗產物直接地用於下一個步驟。LC-MS:m/z 176.2(M+H)+
步驟F:化合物403:N-(4-(4-(2-氟-2-甲基丙基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
向圓底燒瓶添加4-(2-氟-2-甲基丙基)哌啶-4-醇(25mg,0.143mmol)、4-(苯並[d]噻唑-4-磺醯胺基)苯甲酸(47mg,0.143mmol)、DIPEA(110mg,0.85mmol)、HATU(54mg,0.143mmol)以及DCM(5mL)。混合物在室溫下攪拌16小時。用飽和的NaHCO3、鹽水洗滌之後,合併的有機層經無水Na2SO4乾燥並且真空濃縮。藉由標準方法純化給出所需化合物。1H NMR(氯仿-d)δ:9.31(s,1H),8.19(dd,J=8.1,0.8Hz,1H),8.10(dd,J=7.5,1.1Hz,1H),7.93(s,1H),7.54(t,J=7.9Hz,1H),
7.16-7.23(m,J=8.3Hz,2H),7.05-7.15(m,J=8.3Hz,2H),4.19-4.47(m,1H),3.46(d,J=15.6Hz,1H),3.35(d,J=15.3Hz,2H),1.89(s,3H),1.84(s,3H),1.49-1.55(m,3H),1.46(s,3H)。LC-MS:m/z 492.65(M+H)+
步驟A:4-乙醯氧基-4-烯丙基哌啶-1-甲酸三級丁酯(44B)
4-烯丙基-4-羥基哌啶-1-甲酸三級丁酯(3.7g,14.51mmol)於二氯甲烷(20mL)中的溶液用二甲胺基吡啶(1.8g,14.51mmol)、乙酸酐(4.1mL,43.53mmol)以及三乙胺(6.1mL,43.53mmol)處理,並且在20℃下攪拌過夜。將溶劑在減壓下移除並且使殘餘物在水與乙酸乙酯之間分配。水層用乙酸乙酯萃取兩次。合併的有機萃取物用水洗滌、乾燥(Na2SO4)並且過濾。濾液在減壓下濃縮,並且藉由標準方法純化以提供標題化合物44B(3.4g)。LC-MS:m/z 284.4(M+H)+
步驟B:(E)-4-乙醯氧基-4-(4,4,4-三氟丁-1-烯基)哌啶-1-甲酸三級丁酯(44C)
向裝備有磁性攪拌棒的火焰乾燥的小瓶饋入託尼試劑(2.0g,7.0mmol)以及CuI(34mg,0.35mmol),並且用隔膜密封。將小瓶排空並且以N2回填三次。然後經由注射器添加MeOH(8mL)以及4-乙醯氧基-4-烯丙基哌啶-1-甲酸三級丁
酯(4.5g,14mmol)。將小瓶保持於80℃下2h。將反應混合物真空濃縮並且粗殘餘物藉由標準方法純化以便提供產物(2.1g)。1H NMR(400MHz,氯仿-d)δ:1.47(s,9 H),1.66-1.77(m,2 H),2.00-2.07(m,3 H),2.22(d,J=13.43Hz,2 H),2.85(qdd,J=10.61,10.61,10.61,7.25,1.21Hz,2 H),3.11(t,J=11.82Hz,2 H),3.81(br.s.,2 H),5.58(dt,J=15.98,7.19Hz,1 H),6.05(d,J=16.12Hz,1 H)。
步驟C:(E)-4-羥基-4-(4,4,4-三氟丁-1-烯基)哌啶-1-甲酸三級丁酯(44D)
向(E)-4-乙醯氧基-4-(4,4,4-三氟丁-1-烯基)哌啶-1-甲酸三級丁酯(200mg,0.57mmol)於甲醇(5mL)中的混合物添加2M NaOH(2mL,4mmol),混合物保持在室溫下攪拌16小時,此時TLC(20% EA/PE)指示反應完成。將混合物真空濃縮,殘餘物用鹽水稀釋並且用EtOAc萃取,並且有機層真空濃縮以便獲得粗產物,該粗產物直接地用於下一個步驟。
步驟D:(E)-4-(4,4,4-三氟丁-1-烯基)哌啶-4-醇(44E)
將(E)-4-羥基-4-(4,4,4-三氟丁-1-烯基)哌啶-1-甲酸三級丁酯(200mg,0.65mmol)於3M HCl/1,4-二(5mL)中的溶液在室溫下攪拌2小時。溶液在減壓下蒸發至幹以便得到產物,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 210.2(M+H)+。
步驟E:化合物404:(E)-N-(4-(4-羥基-4-(4,4,4-三氟丁-1-烯基)哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
向圓底燒瓶添加(E)-4-(4,4,4-三氟丁-1-烯基)哌啶-4-醇(50mg,0.24mmol)、4-(苯並[d]噻唑-4-磺醯胺基)苯甲酸(80mg,0.24mmol)、DIPEA(155mg,1.2mmol)、HATU(110mg,0.29mmol)以及DCM(5mL)。混合物在室溫下攪拌16小時。
用鹽水洗滌之後,合併的有機層經無水Na2SO4乾燥並且真空濃縮。藉由標準方法純化給出所需化合物。1H NMR(氯仿-d)δ:9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.99(s,1H),7.54(t,J=7.8Hz,1H),7.17-7.24(m,J=8.3Hz,2H),7.08-7.15(m,J=8.1Hz,2H),5.78-5.94(m,1H),5.64-5.76(m,1H),4.28-4.47(m,1H),3.51(s,1H),3.32-3.48(m,1H),3.27(br.s.,1H),2.84(dd,J=10.5,7.0Hz,1H),1.66(br.s.,4H),1.46(d,J=9.7Hz,2H)。LC-MS:m/z 526.7(M+H)+
步驟A:4-((苄氧基)甲氧基)-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(45B)
向4-((苄氧基)甲氧基)-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(2.55g,10.0mmol)於二氯甲烷(50mL)中的溶液添加BOMCl(3.12g,20.0mmol)以及TEA(3.03g,30.0mmol),並且混合物在45℃下攪拌16小時。然後移除溶劑並且殘餘物藉由標準方法純化以便獲得所需產物(3g)。LC-MS:m/z 376.6(M+H)+
步驟B:4-((苄氧基)甲氧基)-4-(3-羥基-2-甲基丙基)哌啶-1-甲酸三級丁酯(45C)
向4-((苄氧基)甲氧基)-4-(2-甲基烯丙基)哌啶-1-甲酸三級丁酯(3.05g,8.1mmol)於THF(50mL)中的溶液添加THF中的BH3溶液(32mL,1mol/L,32.4mmol),並且混合物在室溫下攪拌16小時。然後將30% H2O2溶液(30mL)以及10%氫氧化鈉溶液(50mL)緩慢地添加至混合物,並且混合物再攪拌2小時。然後將混合物用水(10mL)處理並且用EtOAc(3 x 20mL)萃取。合併的有機萃取物經Na2SO4乾燥並且將溶劑真空移除。殘餘物藉由標準方法純化以便得到產物
(1.97g)。LC-MS:m/z 394.5(M+H)+
步驟C:4-((苄氧基)甲氧基)-4-(2-甲基-3-側氧基丙基)哌啶-1-甲酸三級丁酯(45D)
在室溫下將4-((苄氧基)甲氧基)-4-(3-羥基-2-甲基丙基)哌啶-1-甲酸三級丁酯(1.97g,5.0mmol)與戴斯-馬丁(Dess-martin)試劑(3.18g)的混合物在二氯甲烷(60mL)中攪拌16小時。反應混合物藉由添加25%碳酸氫鈉溶液(100mL)來淬滅,然後混合物由EtOAc(60mL x 2)萃取。將有機相合併並且濃縮以便得到殘餘物,該殘餘物藉由標準方法來進一步純化以便得到產物(0.88g)。LC-MS:m/z 392.5(M+H)+
步驟D:4-((苄氧基)甲氧基)-4-(3,3-二氟-2-甲基丙基)哌啶-1-甲酸三級丁酯(45E)
在室溫下將4-((苄氧基)甲氧基)-4-(2-甲基-3-側氧基丙基)哌啶-1-甲酸三級丁酯(0.88g,2.25mmol)以及DAST(0.8g)於DCM(5mL)中的混合物攪拌20小時。反應混合物藉由添加25%碳酸氫鈉溶液(20mL)來淬滅。然後將混合物用DCM萃取兩次。將有機相合併並且濃縮以便得到殘餘物,該殘餘物藉由標準方法進一步純化以便獲得標題化合物(0.33g)。LC-MS:m/z 414.5(M+H)+
步驟E:4-(3,3-二氟-2-甲基丙基)哌啶-4-醇(45F)
將4-((苄氧基)甲氧基)-4-(3,3-二氟-2-甲基丙基)哌啶-1-甲酸三級丁酯(0.33g)與含5M HCl的MeOH(4mL)的混合物在甲醇(15mL)中攪拌3小時。然後將溶劑真空移除以便獲得粗產物(4-(3,3-二氟-2-甲基丙基)哌啶-4-醇(0.11g)。LC-MS:m/z 194.2(M+H)+
步驟F:化合物405:N-(4-(4-(3,3-二氟-2-甲基丙基)-4-羥基哌啶-1-羰基)苯基)苯並[d]噻唑-4-磺醯胺
向圓底燒瓶添加4-(3,3-二氟-2-甲基丙基)哌啶-4-醇(110mg,0.57mmol)、4-(苯並[d]噻唑-4-磺醯胺基)苯甲酸(190mg,0.57mmol)、DIPEA(367mg,2.8mmol)、HATU(261mg,0.69mmol)以及DCM(5mL)。混合物在室溫下攪拌16小時。用鹽水洗滌之後,合併的有機層經無水Na2SO4乾燥並且真空濃縮。藉由標準方法純化給出所需化合物。1H NMR(氯仿-d)δ:9.31(s,1H),8.20(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.94(s,1H),7.55(t,J=7.9Hz,1H),7.20(d,J=8.5Hz,2H),7.12(d,J=8.6Hz,2H),5.90-5.61(m,1H),4.36(s,1H),3.57-3.42(m,1H),3.21(s,2H),2.24(d,J=7.6Hz,1H),2.05(s,1H),1.86-1.77(m,2H),1.36(dd,J=14.8,6.3Hz,4H),1.10(d,J=7.0Hz,3H)。LC-MS:m/z 510.5(M+H)+
步驟A:苯並[d]噻唑-4-磺醯氯(46B)
在0℃下將苯並[d]噻唑(1g,7.45mol)逐滴添加至氯磺酸(5.5mmol)。添加完成之後,混合物在室溫下攪拌0.5h,並且然後在105℃下加熱並且攪拌過夜。所得混合物冷卻至-10℃並且藉由緩慢地傾倒於碎冰上來淬滅。所得混合物用EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。柱層析法(15% PE/EtOAc)提供218mg標題化合物。1H NMR(氯仿-d)δ:9.41(s,1H),8.41(dd,J=8.1,1.0Hz,1H),8.29(dd,J=7.7,1.1Hz,1H),7.68(t,J=7.9
Hz,1H)。LC-MS:m/z 234.7(M+H)+
步驟B:4-(苯並[d]噻唑-4-磺醯胺基)苯甲酸(46C)
向4-胺基苯甲酸(10g,73mmol)於DCM(100mL)中的溶液添加吡啶(29g,365mmol),然後添加芳基-磺醯氯(20g,88mmol)。將所得混合物在40℃下加熱16小時,此時LC-MS展示反應完成。然後將混合物過濾,並且濾餅用Et2O洗滌,並且乾燥以便提供標題產物(23g)。1H NMR(DMSO-d6)δ:12.56(br.s.,1H),11.05(s,1H),9.63-9.68(m,1H),8.51(dd,J=8.1,1.1Hz,1H),8.12-8.18(m,1H),7.70(d,J=8.6Hz,2H),7.64-7.69(m,1H),7.11-7.20(m,2H)。LC-MS:m/z 335.2(M+H)+
步驟C:4-(2-胺基-3-巰基苯基磺醯胺基)苯甲酸(46D)
在室溫下向4-(苯並[d]噻唑-4-磺醯胺基)苯甲酸(500mg,1.5mmol)於6mL EtOH中的溶液添加水合肼(479mg,15mmol)。然後將反應混合物在130℃下在微波中攪拌1.5h。然後將所得混合物冷卻,並且在水與EtOAc之間分配。有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮以便提供標題化合物(449.0mg)。LC-MS:m/z 323.4(M+H)+
步驟D:4-(2-胺基苯並[d]噻唑-4-磺醯胺基)苯甲酸(46E)
在室溫下向4-(2-胺基-3-巰基苯基磺醯胺基)苯甲酸(671mg,2.07mmol)於THF(15mL)中的溶液添加溴化氰(439.1mg,4.14mmol)。反應混合物在80℃下攪拌8h。然後將所得混合物冷卻,並且在水與EtOAc之間分配。有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮以便提供標題化合物(730mg)。LC-MS:m/z 348.7(M+H)+
步驟E:與一般程序2,步驟C相同的程序
1H NMR(氯仿-d)δ:7.93(s,1H),7.82(dd,J=7.8,1.0Hz,1H),7.75(dd,J=7.9,1.0Hz,1H),7.23(d,J=8.5Hz,2H),7.16(t,J=7.6Hz,1H),7.13(d,J=8.6Hz,2H),5.71(s,2H),4.36(s,1H),3.47-3.19(m,3H),1.84(dt,J=13.0,6.4Hz,1H),1.67(s,2H),1.51(s,2H),1.42(d,J=6.0Hz,2H),0.99(d,J=6.6Hz,6H)。LC-MS:m/z 489.70(M+H)+
1H NMR(氯仿-d)δ:7.81(d,J=7.9Hz,1H),7.76(dd,J=16.1,7.8Hz,2H),7.38(d,J=7.8Hz,1H),7.33(t,J=7.6Hz,1H),7.30-7.19(m,5H),7.07(t,J=7.8Hz,1H),4.51(d,J=13.9Hz,1H),3.52(d,J=16.0Hz,2H),2.84-2.72(m,1H),2.68-2.56(m,1H),1.72(d,J=18.4Hz,1H),1.56(d,J=15.3Hz,1H),1.34(d,J=14.7Hz,1H)。LC-MS:m/z 543.67(M+H)+
步驟A:將化合物47A(1.23mol)於MeCN(10mL)中的溶液與水(5mL)、CuCl(243mg,2.46mmol)、NaCl(500mg)以及18-冠-6(0.5mL)混合。然後在攪拌下逐滴添加亞硝酸三級丁酯(165mg)溶液,將溶液在回流下加熱15小時。然後所得混合物傾倒至水(20mL)中,水層用EtOAc(3 x 50mL)萃取。合併的有機層用鹽水洗滌,經Na2SO4乾燥並且蒸發以便獲得標題化合物。粗產物未進行進一步純化即用於下一個步驟。
步驟B:向化合物47B(0.6mmol)於THF(10mL)中的溶液逐滴添加水(3mL)中的25% MeNH2。添加完成之後,反應混合物在室溫下攪拌過夜。將粗產物
過濾掉,用甲醇洗滌,然後充分地乾燥並且然後藉由標準方法純化以便得到所需產物。
1H NMR(氯仿-d)δ:8.33(br.s.,1H),7.77-7.84(m,1H),7.70-7.77(m,1H),7.22(d,J=8.3Hz,2H),7.13(d,J=8.6Hz,2H),7.07-7.11(m,1H),6.25(br.s.,1H),4.35(br.s.,1H),3.44(br.s.,1H),3.36(br.s.,1H),3.22(br.s.,1H),3.13(s,3H),1.83(dd,J=12.9,6.4Hz,2H),1.65(br.s.,2H),1.49(br.s.,1H),1.41(d,J=5.9Hz,2H),0.98(d,J=6.7Hz,6H)。LC-MS:m/z 503.6(M+H)+
1H NMR(氯仿-d)δ:8.25(br.s.,1H),7.82(d,J=7.8Hz,1H),7.75(d,J=8.1Hz,1H),7.52(dd,J=7.7,1.7Hz,1H),7.40(dd,J=7.7,1.5Hz,1H),7.29-7.33(m,1H),7.23-7.28(m,3H),7.10-7.19(m,3H),6.12(br.s.,1H),4.62(br.s.,1H),3.62(br.s.,1H),3.52(br.s.,1H),3.32(br.s.,1H),3.20(s,3H),2.92(s,1H),2.09(br.s.,2H),1.84(br.s.,2H)。LC-MS:m/z 558.1(M+H)+
步驟A:在-78℃下,向相應芳基溴(1.0當量)于無水THF中的溶液逐滴添加n-BuLi於THF中的溶液(1.05當量)。添加之後,將混合物在-78℃下攪拌約0.5小時。然後,在-78℃下經由注射器逐滴添加Cbz-4-哌啶酮於THF中的溶液。添加完成之後,將所得混合物在-78℃下在N2下攪拌2h,並且然後允許溫至室溫。
反應混合物藉由添加飽和的NH4Cl溶液淬滅,並且所得混合物用EtOAc(50mL,30mL)萃取。合併的有機相用鹽水洗滌、經無水Na2SO4乾燥並且真空濃縮。殘餘物藉由標準方法純化以便提供化合物48B,該化合物藉由LCMS來證實。
步驟B:向圓底燒瓶添加相應化合物48B(0.2mmol)、Pd/C(20mg)以及甲醇(5mL)。混合物在室溫下在氫氣氛下攪拌16小時。將反應混合物過濾,並且將所得溶液濃縮以便得到所需產物48C。粗產物未進行進一步純化即直接地用於下一個步驟。
步驟C:向圓底燒瓶依序地添加化合物48C(0.1mmol,1當量)、DMF(5mL)、DIPEA(0.3mmol,3.0當量)、HBTU(0.12mmol,1.2當量)以及48E(0.1mmol,1當量)。將反應混合物在室溫下攪拌過夜或直到TLC指示s.m.消耗完為止。將混合物以鹽水稀釋,用乙酸乙酯萃取,有機層用無水Na2SO4乾燥、過濾,並且將濾液濃縮。所需產物48D藉由方法方法來純化。
1H NMR(氯仿-d)δ:12.57(s,1H),10.76(s,1H),9.66(s,1H),8.50(dd,J=8.1,1.0Hz,1H),8.11(dd,J=7.6,1.0Hz,1H),7.65(t,J=7.9Hz,1H),7.58(s,1H),7.43(s,1H),7.20(d,J=8.6Hz,2H),7.12(t,J=9.8Hz,2H),4.90(s,1H),4.07(s,1H),3.21(s,3H),1.73(s,4H)。LC-MS:m/z 484.7(M+H)+
1H NMR(氯仿-d)δ:9.31(s,1H),8.23-8.16(m,1H),8.10(dd,J=7.5,0.9Hz,1H),7.93(s,1H),7.55(t,J=7.9Hz,1H),7.41(d,J=2.0Hz,1H),7.22(d,J=8.5Hz,2H),7.13(d,J=8.6Hz,2H),6.10(d,J=2.0Hz,1H),4.50(s,1H),4.10(s,3H),3.59(s,1H),3.40(m,2H),1.99(s,2H),1.87(s,2H)。LC-MS:m/z 498.7(M+H)+
1H NMR(甲醇-d4)δ:9.47(s,1H),8.29(d,J=7.8Hz,1H),8.11(d,J=7.5Hz,1H),7.54(t,J=7.9Hz,1H),7.29-7.37(m,1H),7.12-7.26(m,4H),6.10-6.21(m,1H),4.27-4.48(m,1H),4.03(s,3H),3.39-3.60(m,2H),1.81-2.11(m,5H)。LC-MS:m/z 498.7(M+H)+
在以下表4描繪的以下化合物使用如上所述的相同一般程序來製備。
步驟A:在0℃下在N2氣氛下向4-碘-3-甲基異噻唑(50A,225mg,1.0mmol)在THF(10mL)中的溶液中添加乙基溴化鎂(2N,0.55mL,1.1mmol)。在0℃下攪拌反應混合物3h,並且然後在-10℃下在N2氣氛下向以上溶液中逐滴添加4-甲醯基哌啶-1-甲酸三級丁酯(213mg,1.0mmol)在THF(1mL)中的溶液。在室溫下在N2下攪拌反應混合物過夜。將反應混合物由飽和的NH4Cl溶液淬滅,並且將所得混合物用EtOAc萃取兩次。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供50B。LC-MS:m/z 313.5(M+H)+。
1H NMR(氯仿-d)δ:8.52(s,1H),4.62(d,J=7.1Hz,1H),4.18(dd,J=24.2,9.9Hz,2H),3.52(s,1H),2.68(m,2H),2.51(s,3H),1.93(d,J=13.0Hz,1H),1.72-1.62(m,2H),1.47(s,9H),1.39-1.11(m,2H)。
步驟B:在0℃下向4-(羥基(3-甲基異噻唑-4-基)甲基)哌啶-1-甲酸三級丁酯(50B,60mg,0.192mmol)在DCM(5mL)中的溶液中添加DIPEA(28mg,0.212mmol),隨後添加MsCl(24.3mg,0.212mmol)。在0℃下攪拌反應混合物0.5h。
然後允許反應混合物溫至室溫並且再攪拌1h。將混合物用DCM(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供50C。LC-MS:m/z 331.1(M+H)+。
1H NMR(氯仿-d)δ:8.57(s,1H),4.77(d,J=8.4Hz,1H),4.17(d,J=37.5Hz,2H),2.82-2.59(m,2H),2.54(s,3H),2.19-1.99(m,2H),1.47(s,9H),1.36-1.14(m,3H)。
步驟C:在室溫下向4-(氯(3-甲基異噻唑-4-基)甲基)哌啶-1-甲酸三級丁酯(50C,78mg,0.236mmol)在DCM(0.5mL)中的溶液中添加DBU(3mL)。在120℃下在微波中攪拌反應混合物0.5h。然後將反應混合物冷卻至室溫。所得混合物用EtOAc(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供50D。LC-MS:m/z 295.1(M+H)+。1H NMR(氯仿-d)δ:8.27(s,1H),6.13(s,1H),3.59-3.49(m,2H),3.47-3.38(m,2H),2.46(s,3H),2.38(m,4H),1.50(s,9H)。
步驟D:在0-5℃下向4-((3-甲基異噻唑-4-基)亞甲基)哌啶-1-甲酸三級丁酯(50D,147mg,0.5mmol)在丙酮(12mL)和H2O(2mL)中的溶液中逐滴添加在H2O(0.6mL)中的H2SO4(123mg,1.25mmol),接著添加NBS(134mg,0.75mmol)。在0-5℃下攪拌反應混合物3h。然後將反應混合物用EtOAc(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供50E。LC-MS:m/z 391.1(M+H)+。
步驟E:在0℃下向4-溴-4-(羥基(3-甲基異噻唑-4-基)甲基)哌啶-1-甲酸三級丁酯(50E,39.1mg,0.1mmol)在THF(2mL)中的溶液中添加NaH(4.0mg,0.1mmol)。在室溫下攪拌反應混合物2h。然後將反應混合物用飽和的NH4Cl淬滅。將混合物用EtOAc(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供50F。LC-MS:m/z 211.2(M+H-100)+。
步驟F:在0℃下向2-(3-甲基異噻唑-4-基)-1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(10mg,0.032mmol)和四丁基溴化銨(21mg,0.065mmol)在DCM(3mL)中的溶液中逐滴添加三氟化硼乙醚複合物(15mg,0.048mmol)。在0℃下攪拌反應混合物10min。然後將反應混合物用DCM(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供
50G。LC-MS:m/z 211.2(M+H-56)+。
1H NMR(氯仿-d)δ:9.03(s,1H),5.02(s,1H),4.12-3.83(m,2H),3.20-2.93(m,2H),2.52(s,3H),2.18-2.03(m,2H),1.55(dd,J=13.5,2.7Hz,2H),1.47(s,9H)。
步驟G:在室溫下在N2下向4-(溴(3-甲基異噻唑-4-基)甲基)-4-羥基哌啶-1-甲酸三級丁酯(50G,58mg,0.15mmol)和AIBN(4.9mg,0.03mmol)在甲苯(5mL)中的溶液中添加氫化三丁基錫(65.1mg,0.223mmol)。在90℃下攪拌反應混合物8h,此時TLC展示反應完成。將反應混合物真空濃縮以便提供50H。LC-MS:m/z 313.2(M+H)+。
步驟H:向4-羥基-4-((3-甲基異噻唑-4-基)甲基)哌啶-1-甲酸三級丁酯(50H,55mg)在DCM(5mL)中的溶液中添加TFA(1mL),在室溫下攪拌反應混合物約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物50I。粗產物未進行進一步純化直接地用於下一個步驟。LC-MS:m/z 213.2(M+H)+。
步驟I:在室溫下向4-(芳基磺醯胺基)苯甲酸(0.18mmol)在DCM(5mL)中的溶液中依序地添加HBTU(80mg,0.22mmol)、DIPEA(70mg,0.54mmol)以及4-((3-甲基異噻唑-4-基)甲基)哌啶-4-醇(50I,38mg,0.18mmol)。在室溫下攪拌反應混合物1小時。將混合物傾倒至水中並且用EtOAc(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥。將合併的有機層真空濃縮並且使用標準技術純化以便提供所需產物。
以下化合物根據一般程序50來製備。
1H NMR(氯仿-d)δ:9.08(s,2H),8.45(dd,J=7.3,1.4Hz,1H),8.40-8.32(m,2H),8.05(s,1H),7.86(dd,J=8.4,7.4Hz,1H),7.19(d,J=8.5Hz,2H),7.09(d,J=8.6Hz,2H),4.43(s,1H),3.47(s,1H),3.32(s,1H),3.10(s,1H),2.79(s,2H),2.47(s,3H),1.60-1.35(m,4H)。LC-MS:m/z 524.4(M+H)+。
1H NMR(氯仿-d)δ:9.49(s,1H),8.56(s,1H),8.33(dd,J=8.1,0.9Hz,1H),8.12(dd,J=7.6,1.0Hz,1H),7.57(t,J=7.9Hz,1H),7.20(s,4H),4.32(d,J=6.8Hz,1H),3.39(s,1H),3.19(m,2H),2.81(s,2H),2.46(s,3H),1.66-1.40(m,4H)。LC-MS:m/z 529.77(M+H)+
步驟A:在0℃下向苯並[d][1,3]間二氧雜環戊烯-4-胺(800mg,5.84mmol)在HCl(30mL)中的懸浮液中逐滴添加在水(2mL)中的NaNO2(604.4mg,8.76mmol)。添加之後,在0℃下攪拌反應混合物2h。在20℃下向CuCl(867.2mg,8.76mmol)在CH3COOH(30mL)中的溶液中泵入SO2並持續3h,並且在室溫下將所得反應混合物添加至先前溶液中。然後在40℃下攪拌反應混合物過夜。將反應混合物由飽和的NH4Cl溶液淬滅,並且將所得混合物用EtOAc(50mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮以便得到51B。LC-MS:m/z 221.6(M+H)+。
步驟B:化合物448:N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)苯並[d][1,3]間二氧雜環戊烯-4-磺醯胺
在室溫下向相應的51C(124mg,0.45mmol)和磺醯氯(100mg,0.45mmol)在30mL無水THF中的懸浮液中添加吡啶(1.0mmol)。將所得混合物加熱並且
在回流下攪拌6h。將反應混合物冷卻至室溫,並且然後用EtOAc(100mL x 2)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,真空濃縮並且藉由標準方法純化。1H NMR(氯仿-d)δ:7.32(d,J=7.5Hz,2H),7.26(d,J=8.3Hz,1H),7.15(d,J=7.4Hz,2H),6.99(d,J=7.6Hz,1H),6.90(dd,J=10.3,5.6Hz,2H),6.12(s,2H),4.40(s,1H),3.58-3.15(m,3H),1.86(dt,J=12.8,6.3Hz,1H),1.58(dd,J=29.1,11.7Hz,4H),1.44(d,J=5.9Hz,2H),1.00(d,J=6.6Hz,6H)。LC-MS:m/z 461.7(M+H)+。
步驟A:在-78℃下在N2下向相應的4-氯芳基試劑(0.9mmol)在THF(10mL)中的溶液中逐滴添加n-BuLi(0.392mL,0.98mmol)。在-78℃下攪拌1h之後,在-78℃下在N2下將1-氧雜-6-氮雜螺[2.5]辛烷-6-甲酸三級丁酯(200mg,0.98mmol)在1mL THF中的溶液逐滴添加至反應混合物中,接著添加BF3.OEt2(299.3mg,0.98mmol)。在-78℃下攪拌反應混合物3h,並且然後允許反應混合物溫至室溫且在室溫下攪拌過夜。將反應混合物冷卻至-30℃並且由飽和的NH4Cl淬滅。所得混合物用EtOAc(50mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮。將殘餘物藉由標準方法純化以便提供52B。
步驟B:向化合物52B(150mg)在DCM(5mL)中的溶液中添加TFA(1mL),在室溫下攪拌反應混合物約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物52C。粗產物未進行進一步純化直接地用於下一個步驟。
步驟C:在室溫下向4-(芳基-4-磺醯胺基)苯甲酸(0.45mmol)在DCM(5mL)中的溶液中依序地添加HBTU(180mg,0.54mmol)、DIPEA(174mg,1.35mmol)
以及化合物52C(0.45mmol)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供所需化合物。
以下化合物根據一般程序52來製備。
1H NMR(氯仿-d)δ:9.31(s,1H),8.19(dd,J=8.2,1.0Hz,1H),8.09(dd,J=7.5,1.0Hz,1H),7.92(s,1H),7.54(t,J=7.9Hz,1H),7.19(d,J=8.5Hz,2H),7.10(d,J=8.6Hz,2H),7.02(s,1H),4.36(s,1H),3.37(dd,J=50.3,26.0Hz,3H),3.10(s,2H),1.57(dd,J=28.7,9.8Hz,4H)。LC-MS:m/z 549.2(M+H)+。
1H NMR(氯仿-d)δ:9.49(s,1H),8.34(dd,J=8.1,1.0Hz,1H),8.13(dd,J=7.6,1.1Hz,1H),7.58(t,J=7.8Hz,1H),7.38(d,J=1.9Hz,1H),7.19(d,J=4.6Hz,4H),6.15(d,J=1.9Hz,1H),4.29(s,1H),3.85(d,J=4.4Hz,3H),3.40(s,2H),3.28(s,1H),2.85(s,2H),1.71-1.45(m,4H)。LC-MS:m/z 512.1(M+H)+。
1H NMR(甲醇-d4)δ:9.48(s,1H),8.30(d,J=8.1Hz,1H),8.10(d,J=7.6Hz,1H),7.55(t,J=7.8Hz,1H),7.37(d,J=1.9Hz,1H),7.19(s,4H),6.13(d,J=1.9Hz,1H),4.29(s,1H),3.83(s,3H),3.33(s,2H),3.28(s,1H),2.84(s,2H),1.49-1.65(m,4H)。
LC-MS:m/z 512.1(M+H)+。
1H NMR(甲醇-d4)δ:9.07(s,2H),8.45(dd,J=7.3,1.3Hz,1H),8.36(dd,J=8.6,1.3Hz,1H),8.06(s,1H),7.85(dd,J=8.5,7.4Hz,1H),7.45(d,J=1.6Hz,1H),7.14-7.25(m,J=8.6Hz,2H),6.98-7.14(m,J=8.6Hz,2H),6.10(d,J=1.6Hz,1H),4.41(br.s.,1H),3.87(s,3H),3.43(br.s.,1H),3.31(br.s.,1H),3.12(br.s.,1H),2.81(s,2H),1.64(br.s.,2H),1.51-1.60(m,2H)。LC-MS:m/z 507.5(M+H)+
步驟A:將4-側氧基哌啶-1-甲酸三級丁酯(1g,5.02mmol)溶解於2-(溴甲基)-3,3,3-三氟丙-1-烯(1900mg,10.038mol)的THF(20mL)和飽和氯化銨溶液(5mL)中。將反應冷卻至10℃並且逐份添加鋅粉(656mg,10mmol)。添加之後,攪拌反應混合物過夜。執行TLC(庚烷/EtOAc 7:1)並且展示s.m.完全轉化為產物。將反應混合物用水(5mL)稀釋並且用MTBE萃取。合併有機層並且用飽和NaHCO3溶液、鹽水洗滌,乾燥且蒸發以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。
步驟B:向小瓶中添加4-羥基-4-(2-(三氟甲基)烯丙基)哌啶-1-甲酸三級丁酯(400mg,1.29mmol)、EtOH(10mL)、10% Pd/C(250mg)以及AcOH(0.5mL)。在40℃下在H2氣氛下攪拌混合物16h。然後將反應混合物過濾且蒸發以便得到粗產物,該粗產物未進行進一步純化即用於下一個步驟。
步驟C:向小瓶中添加化合物53C(100mg,0.323mmol)、DCM(5mL)以及HCl/MeOH(4.5M,1mL),在0-15℃下攪拌混合物16h。將混合物真空濃縮以便得到粗產物,該粗產物直接地用於下一個步驟。
步驟D:在室溫下向相應的4-(芳基-4-磺醯胺基)苯甲酸(0.45mmol)在DCM(5mL)中的溶液中依序地添加HBTU(180mg,0.54mmol)、DIPEA(174mg,1.35mmol)以及化合物53D(0.45mmol)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供所需產物。
以下化合物根據一般程序53來製備。
1H NMR(氯仿-d)δ:7.79(dd,J=7.9,1.2Hz,1H),7.73(dd,J=7.8,1.1Hz,1H),7.19-7.31(m,4H),7.07(t,J=7.8Hz,1H),4.23-4.34(m,1H),3.40(br.s.,2H),3.21(br.s.,1H),2.51(d,J=7.3Hz,1H),1.84(d,J=14.8Hz,1H),1.67(d,J=17.5Hz,1H),1.48-1.59(m,2H),1.43(dd,J=14.6,7.9Hz,1H),1.33(d,J=18.0Hz,1H),1.22(d,J=7.0Hz,3H)。LC-MS:m/z 543.5(M+H)+
1H NMR(甲醇-d4)δ:8.36-8.44(m,2H),8.28(s,1H),7.58(tt,J=7.9,1.0Hz,1H),7.24(s,4H),4.27(br.s.,1H),3.35-3.50(m,2H),3.20(br.s.,1H),2.50(d,J=7.5Hz,1H),
1.84(d,J=14.5Hz,1H),1.67(d,J=15.6Hz,1H),1.51(br.s.,2H),1.43(dd,J=14.6,7.9Hz,1H),1.24-1.37(m,1H),1.21(d,J=6.7Hz,3H)。LC-MS:m/z 539.6(M+H)+
步驟A:在0℃下向4-亞甲基哌啶-1-甲酸三級丁酯(9.0g,45.4mmol)在氯仿(150mL)中的攪拌溶液中添加3-氯過氧苯甲酸(12.2g,70.4mmol)並且在0℃下攪拌反應混合物30min並且然後允許溫至室溫。藉由TLC監測反應進程,並且需要時添加額外份的m-CPBA。一旦完成,即將反應混合物用氯仿(100mL)稀釋並且用10% Na2SO3水溶液(2 x 60mL)、10% NaHCO3水溶液(2 x 150mL)以及鹽水(150mL)洗滌。將有機層經Na2SO4乾燥,過濾且濃縮並且藉由標準方法純化以便得到54B。1H NMR(400MHz,氯仿-d)δ:1.41-1.52(m,11 H)1.81(ddd,J=13.50,9.34,4.30Hz,2 H)2.70(s,2 H)3.44(ddd,J=13.23,9.60,3.76Hz,2 H)3.67-3.80(m,2 H)。
步驟B:在0℃下在惰性氣氛下向丙二睛(1.45g,22.0mmol)在THF(20mL)中的攪拌溶液中逐份添加NaH(60%於油中,845mg,21mmol)。在0℃下攪拌30min之後,在0℃下將化合物2(900mg,4.22mmol)在THF(10mL)中的溶液添加至反應混合物中,並且在RT下繼續攪拌16h。藉由TLC監測反應進程。將反應用冰冷的水(100mL)淬滅並且用EA(2 x 50mL)萃取。將合併的有機層用水(40mL)和鹽水(40mL)洗滌,經無水Na2SO4乾燥並且在減壓下濃縮以獲得原材料。藉由矽膠柱層析法(用45% EA/PE洗脫)進行純化以便提供化合物
54C。LC-MS:m/z 280.3(M+H)+。1H NMR(400MHz,氯仿-d)δ:1.48(s,13 H),2.68(s,2 H),3.17-3.37(m,3 H),3.71(d,J=12.36Hz,2 H),3.93(br.s.,1 H)。
步驟C:向化合物54C(630mg,2.26mmol)在EtOH(20mL)中的攪拌溶液中添加50%水合肼(0.7mL),並且將反應混合物加熱至回流溫度並持續4h。藉由TLC監測反應的進程。在減壓下蒸發揮發物以便提供化合物54D。LC-MS:m/z 312.3(M+H)+。1H NMR(400MHz,氯仿-d)δ 1.35-1.58(m,13 H),2.25(br.s.,2 H),3.05(br.s.,2 H),3.76(d,J=11.55Hz,2 H),4.79(br.s.,6 H)。
步驟D:在0℃下在攪拌時向54D(100mg,0.32mmol)在50%次磷酸水溶液(10ml)中的溶液中添加水(5.0mL)。逐滴添加NaNO2(500mg,7.2mmol)在水(2.0mL)中的溶液。然後將反應混合物在0℃下連續地攪拌30min並且最終允許溫至RT,並且然後攪拌3.0h,此時LC-MS展示s.m.完全轉化為產物。在用飽和NaOH水溶液中和之後,將反應混合物用EA(2 x 50mL)萃取。將合併的有機層用水(40mL)和鹽水(40mL)洗滌,並且然後經無水Na2SO4乾燥,過濾,並且將濾液在減壓下濃縮以便獲得粗產物54E。LC-MS:m/z 182.2(M+H)+。
步驟E:在室溫下向相應的4-(芳基-4-磺醯胺基)苯甲酸(0.45mmol)在DCM(5mL)中的溶液中依序地添加HBTU(180mg,0.54mmol)、DIPEA(174mg,1.35mmol)以及化合物5(0.45mmol)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供所需化合物。
以下化合物根據一般程序54來製備。
1H NMR(氯仿-d)δ:1.47(d,J=6.18Hz,2 H),1.62(br.s.,2 H),2.67(s,2 H),3.09(br.s.,3 H),4.39(br.s.,1 H),7.08(m,J=8.60Hz,2 H),7.19(m,J=8.60Hz,2 H),7.48(s,2 H),7.85(dd,J=8.46,7.39Hz,1 H),8.04(s,1 H),8.36(dd,J=8.33,1.34Hz,1 H),8.45(dd,J=7.25,1.34Hz,1 H),9.08(s,2 H)。LC-MS:m/z 493.4(M+H)+
1H NMR(氯仿-d)δ 1.32(br.s.,4 H),2.60(s,2 H),3.03(br.s.,1 H),3.20(br.s.,2 H),4.05(br.s.,1 H),7.11(q,J=8.87Hz,4 H),7.36(br.s.,2 H),7.65(t,J=7.92Hz,1 H),8.11(dd,J=7.52,1.07Hz,1 H),8.50(dd,J=8.06,1.07Hz,1 H),9.65(s,1 H),10.75(s,1 H),12.50(br.s.,1 H)。LC-MS:m/z 498.1(M+H)+
步驟A:在室溫下向硝酸鈰銨(CAN)(1.1g,1.88mmol)在乙腈(20mL)中的溶液中添加在乙腈(10mL)中的4-亞甲基哌啶-1-甲酸三級丁酯(197mg,1.0mmol)和戊烷-2,4-二酮(200mg,2.0mmol),並且在室溫下攪拌反應混合物2h。將混合物傾倒至水(50mL)中並且用EtOAC(3 x 60mL)萃取,然後將有機層用水(60mL)和鹽水(60mL)洗滌,經無水Na2SO4乾燥並且真空濃縮。將殘餘物藉由標準方法(PE/EA=4/1)純化以便得到55B。1H NMR(氯仿-d)δ 1.42-1.44(m,9 H),1.52-1.65(m,3 H),1.76(br.s.,1 H),2.16(s,3 H),2.18(s,3 H),2.65-2.71(m,2 H),3.35(ddd,J=13.30,9.81,3.22Hz,2 H),3.59(d,J=13.16Hz,2 H)。LC-MS:m/z 296.4(M+H)+
步驟B:向化合物3-乙醯基-2-甲基-1-氧雜-8-氮雜螺[4.5]癸-2-烯-8-甲酸三級丁酯(570mg,1.93mmol)在EtOH(20mL)中的攪拌溶液中添加50%水合肼(1.0mL),並且在室溫下攪拌反應混合物過夜。將反應混合物在減壓下蒸發以便提供55C。LC-MS:m/z 310.4(M+H)+
採用與製備55D類似的程序。LC-MS:m/z 311.4(M+H)+
步驟C:將55C或55D(200mg,0.65mmol)添加至氯化氫的二溶液(4
M,3.0mL)中並且在室溫下攪拌所得溶液過夜。將溶劑真空蒸發並且將殘餘物用乙醚處理。將所得懸浮液過濾以便獲得所需化合物。LC-MS:m/z 210.4(M+H)+
步驟D:使用與一般程序54步驟E類似的程序。
以下化合物根據一般程序55來製備。
1H NMR(氯仿-d)δ 1.44-1.51(m,2 H),1.57(dd,J=12.36,6.98Hz,2 H),2.24(s,6 H),2.51(s,2 H),3.32(br.s.,3 H),4.44(br.s.,1 H),7.09(m,J=8.60Hz,2 H),7.20(m,J=8.60Hz,2 H),7.86(dd,J=8.46,7.39Hz,1 H),8.08(br.s.,1 H),8.36(dd,J=8.60,1.34Hz,1 H)8.46(dd,J=7.39,1.21Hz,1 H),9.08(s,2 H),11.22(br.s.,1 H)。LC-MS:m/z 521.5(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.51-1.60(m,4 H),2.25(s,6 H),2.54(s,2 H),3.09-3.40(m,3 H),4.35(br.s.,1 H),7.13-7.30(m,4 H),7.58(t,J=7.92Hz,1 H),8.12(dd,J=7.52,1.07Hz,1 H),8.34(dd,J=8.19,0.94Hz,1 H),9.49(s,1 H)。LC-MS:m/z 526.5(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.33-1.47(m,2 H),1.57(br.s.,2 H),2.18(s,3 H),2.30(s,3 H),2.39-2.46(m,2 H),3.05(br.s.,1 H),3.26(br.s.,1 H),3.35(d,J=4.30
Hz,1 H),4.32(d,J=12.89Hz,1 H),7.17(s,4 H),7.84-7.93(m,1 H),8.28(dd,J=8.60,1.07Hz,1 H),8.48(dd,J=7.39,1.21Hz,1 H),9.00(d,J=1.88Hz,1 H),9.09(d,J=1.61Hz,1 H)。LC-MS:m/z 522.8(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.43(d,J=16.12Hz,1 H),1.51(br.s.,1 H),1.61(br.s.,2 H),2.17-2.24(m,3 H),2.29-2.39(m,3 H),2.47(s,2 H),3.10(br.s.,2 H),3.41(br.s.,1 H),4.32(d,J=6.98Hz,1 H),7.19(s,4 H),7.59(t,J=7.79Hz,1 H),8.06-8.20(m,1 H),8.34(d,J=8.06Hz,1 H),8.51(br.s.,1 H),9.50(br.s.,1 H)。LC-MS:m/z 527.6(M+H)+
步驟A:在0℃下將1,4-環己二酮單乙二醇縮酮56A(5.00g,32.0mmol)在MeOH(30mL)中的磁性攪拌溶液用硼氫化鈉(1.57g,41.5mmol)處理。0.5h之後,將反應混合物溫至18℃並且在此溫度下再攪拌0.5h。然後在減壓下除去溶劑,並且將所得殘餘物在H2O(30mL)與CH2Cl2(30mL)之間分配。將分離的水相用CH2Cl2(20mL)萃取並且然後將合併的有機部分經MgSO4乾燥,過濾
並且將濾液在減壓下濃縮以便提供56B。LC-MS:m/z 159.1(M+H)+
步驟B:將醇56B(3.00g,19.0mmol)在乾燥的CH2Cl2(20mL)中的磁性攪拌溶液用四溴化碳(7.55g,22.8mmol)處理並且將所得混合物冷卻至0℃。然後添加三苯基膦(5.97g,22.8mmol)並且在0℃下在氮氣氛下繼續攪拌5h。在此之後,將H2O(50mL)、接著CH2Cl2(80mL)添加至反應混合物中,將有機相分離並且將水相用CH2Cl2(80mL)萃取。然後將合併的有機部分乾燥(MgSO4),過濾並且將濾液在減壓下濃縮,並且藉由標準方法純化以便提供56C。LC-MS:m/z 221.1(M+H)+
步驟C:在-78℃下在N2下向Li(70mg,1.1mmol)在THF(10mL)中的溶液中逐滴添加1-苄基哌啶-4-酮(103mg,0.55mmol)。1h之後,在-78℃下在N2下將在THF(1mL)中的8-溴-1,4-二氧雜螺[4.5]癸烷(120mg,0.55mmol)逐滴添加至反應混合物中。在-78℃下攪拌反應混合物3h,並且然後允許反應混合物溫至室溫並且在室溫下攪拌過夜。將反應混合物冷卻至-30℃並且由飽和的NH4Cl淬滅。所得混合物用EtOAc(50mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥並且真空濃縮。將殘餘物藉由標準方法純化以便提供56D。LC-MS:m/z 332.2(M+H)+
步驟D:將56D(300g,1.1mmol)溶解于水(5mL)中,添加濃鹽酸(5mL)並且將混合物在室溫下攪拌2h。將反應混合物用乙醚(10mL,兩次)萃取,在用冰冷卻時將水相用2N NaOH中和。將混合物用DCM(10mL,兩次)萃取並且將萃取物合併,乾燥並且濃縮以便提供56E(213mg)。LC-MS:m/z 288.2(M+H)+
步驟E:向化合物56E(213mg,0.74mmol)在乙醇(10mL)中的溶液中添加硼氫化鈉(80mg,2.1mmol),並且將混合物在室溫下攪拌3h。將反應混合物真空濃縮,將水添加至殘餘物中,並且用乙酸乙酯(10mL,兩次)進行萃取。將合併的萃取物用水和飽和氯化鈉溶液洗滌,乾燥(Na2SO4)並且真空濃縮以便提供56F。LC-MS:m/z 290.2(M+H)+
步驟F:在室溫下在3巴氫氣壓力下將化合物56H(182mg,0.63mmol)與Pd/C(10%,20mg)在MeOH(20mL)中的懸浮液氫化2小時。將反應混合物過濾掉並且將濾液在真空下蒸發以便提供56G。LC-MS:m/z 200.2(M+H)+
步驟G:在室溫下向相應的4-(芳基-4-磺醯胺基)苯甲酸(1當量)在DCM(5
mL)中的溶液中依序地添加HBTU(1.2當量)、DIPEA(3當量)以及化合物7(1.0當量)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌,經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供所需化合物。
以下化合物根據一般程序56來製備。
1H NMR(氯仿-d)δ 1.68(br.s.,28H),1.84(s,4 H),1.81(s,5H),2.07(s,4H),2.05(s,4H),3.09(br.s.,4H),3.30(d,J=18.27Hz,4H),3.41-3.60(m,8H),4.46(br.s.,3H),7.08(d,J=8.60Hz,7H),7.19(d,J=8.33Hz,7H),7.85(dd,J=8.46,7.39Hz,4H),8.04(s,4H),8.35(dd,J=8.33,1.34Hz,3H),8.45(dd,J=7.52,1.34Hz,3H),9.07(s,7H)。LC-MS:m/z 511.7(M+H)+
1H NMR(氯仿-d)δ 1.68(br.s.,28H),1.84(s,4H),1.81(s,5H),2.07(s,4H),2.05(s,4H),3.09(br.s.,4H),3.30(d,J=18.27Hz,4H),3.41-3.60(m,8H),4.46(br.s.,3H),7.08(d,J=8.60Hz,7H),7.19(d,J=8.33Hz,7H),7.85(dd,J=8.46,7.39Hz,4H),8.04(s,4H),8.35(dd,J=8.33,1.34Hz,3H),8.45(dd,J=7.52,1.34Hz,3H),9.07(s,7H)。LC-MS:m/z 516.7(M+H)+
步驟A:經5min的時段向4-(2,3-二胺基苯基磺醯胺基)苯甲酸乙酯(5g,15mmol)在乙醇(50mL)中的攪拌懸浮液中添加乙醛酸乙酯在甲苯(1.6M,3mL,18mmol)中的溶液。在加熱至45℃並持續10h之後,將混合物在攪拌下留置於室溫下。將沈澱物過濾並且將餅用水洗滌並乾燥以便得到57B。LC-MS:m/z 374(M+H)+。將濾液濃縮並且藉由標準方法純化以便提供57C。LC-MS:m/z 374(M+H)+
步驟B:在回流下加熱4-(3-側氧基-3,4-二氫喹啉-5-磺醯胺基)苯甲酸乙酯(500mg,1.34mol)在10mL POCl3(10mL)中的溶液3h,將所得混合物小心地添加至水(40mL)中,將水層用EtOAc(50mL,兩次)萃取,將合併的有機層用鹽水洗滌,經Na2SO4乾燥並且蒸發以便提供。將粗產物藉由標準方法純化以便提供57D。LC-MS:m/z 392(M+H)+
步驟C:使用與步驟B類似的程序。
步驟D:向4-(3-氯喹啉-5-磺醯胺基)苯甲酸乙酯(360mg,0.92mmol)與CuI(174mg,0.92mmol)在10mL DMSO中的溶液中逐滴添加氨水。添加完成之後,在110℃下攪拌反應混合物過夜。然後將反應混合物冷卻至室溫,並且傾倒至水(50mL)中,將水層用EtOAc(5 x 50mL)萃取,將合併的有機層用鹽水洗滌,經Na2SO4乾燥,並且濃縮以便提供粗的57E,並且該粗產物未進行進一步純化即用於下一個步驟。1H NMR(氯仿-d)d:8.33(br.s.,1H),7.77-7.84(m,1H),7.70-7.77(m,1H),7.22(d,J=8.3Hz,2H),7.13(d,J=8.6Hz,2H),7.07-7.11(m,1H),6.25(br.s.,1H),4.35(br.s.,1H),3.44(br.s.,1H),3.36(br.s.,1H),3.22(br.s.,1H),3.13(s,3H),1.83(dd,J=12.9,6.4Hz,2H),1.65(br.s.,2H),1.49(br.s.,1H),1.41(d,J=5.9Hz,2H),0.98(d,J=6.7Hz,6H)。LC-MS:m/z 373(M+H)+
步驟E:使用與步驟D類似的程序。
步驟F:向相應的化合物57E(300mg,0.8mmol)在EtOH/H2O(10mL/3mL)中的溶液中添加LiOH.H2O(160mg,4.0mmol)並且在70℃下攪拌所得懸浮液過夜。將溶劑濃縮並且將殘餘物在2N HCl水溶液與EtOAc之間分配。將有機層分離並且用水和鹽水洗滌,經Na2SO4乾燥並且濃縮以便得到所需粗產物57F,該產物未進行進一步純化即用於後續反應。LC-MS:m/z 345.1(M+H)+
步驟G:使用與步驟F類似的程序。
步驟H:在室溫下向相應的4-(芳基-4-磺醯胺基)苯甲酸(1當量)在DCM(5mL)中的溶液中依序地添加HBTU(1.2當量)、DIPEA(3當量)以及化合物57F(1.0當量)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供465。
步驟I:使用與步驟H類似的程序。
以下化合物根據一般程序57來製備。
1H NMR(400MHz,甲醇-d 4)δ:8.39(s,1H),8.14(dd,J=7.5,1.3Hz,1H),7.97(dd,J=8.2,1.5Hz,1H),7.32-7.40(m,1H),7.17-7.25(m,4H),4.23(d,J=12.9Hz,1H),3.37(s,2H),3.12-3.26(m,1H),1.79-1.90(m,1H),1.61-1.73(m,1H),1.51-1.61(m,1H),1.47(br.s.,2H),1.38(d,J=5.6Hz,2H),0.96(d,J=6.7Hz,6H)。LC-MS:m/z 484.5(M+H)+
1H NMR(DMSO-d6)δ 10.30(s,1H),8.48(s,1H),7.90(d,J=8.6Hz,1H),7.71(d,J=9.7Hz,1H),7.56-7.67(m,1H),7.33(s,2H),7.16(d,J=8.6Hz,2H),7.09(d,J=8.6Hz,2H),4.16(s,1H),4.06(br.s.,1H),3.21(br.s.,2H),3.06(br.s.,1H),1.78(dt,J=12.8,6.2Hz,1H),1.49(br.s.,1H),1.36(br.s.,3H),1.27(d,J=5.6Hz,2H),0.89(d,J=6.7Hz,6H)。LC-MS:m/z 484.5(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:8.52(s,1H),7.97(dd,J=7.5,1.3Hz,1H),7.73(dd,J=8.6,1.3Hz,1H),7.56-7.64(m,1H),7.15-7.26(m,4H),4.26(br.s.,1H),3.37(s,3H),3.14-3.26(m,1H),1.87-2.02(m,2H),1.43-1.68(m,9H)。LC-MS:m/z 520.2(M+H)+
化合物493:2-胺基-N-(4-(4-(2,3-二氟苯基)-4-羥基哌啶-1-羰基)苯基)喹啉-5-磺醯胺
1H NMR(氯仿-d)δ 8.50(s,1H),8.06(d,J=8.3Hz,1H),7.96(s,1H),7.85(d,J=9.4Hz,1H),7.63(t,J=7.9Hz,1H),7.26(d,J=8.6Hz,2H),7.11(d,J=6.7Hz,4H),
5.24(s,2H),4.62(br.s.,1H),3.59(br.s.,1H),3.51(br.s.,1H),3.26(br.s.,1H),2.29(br.s.,1H),2.12(br.s.,1H),1.89(br.s.,1H),1.76(br.s.,1H)。LC-MS:m/z 540.1(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.41-1.58(m,24H),1.58-1.70(m,15H),2.08-2.22(m,9H),3.37(br.s.,6H),7.20(s,19H),7.60(d,J=7.52Hz,4H),7.73(dd,J=8.33,1.34Hz,5H),7.97(dd,J=7.39,1.21Hz,5H),8.52(s,4H)。LC-MS:m/z 537.7(M+H)+
步驟A:在室溫下向4-(2-乙氧基-2-側氧基乙基)-4-羥基哌啶-1-甲酸三級丁酯(10g,35mmol)在THF(100mL)中的攪拌懸浮液中添加氫氧化鋰單水合物(5.1g,122mmol)在水(20mL)中的溶液。加熱至回流並持續3h之後,將混合物冷卻至室溫。將溶劑蒸發,將殘餘物溶解于水(50mL)中並且用乙醚(3 x 50mL)萃取,藉由添加1N HCl將水層酸化至pH=3-5。然後將混合物用EtOAc(3 x 60mL)萃取,將合併的有機層用鹽水洗滌,經Na2SO4乾燥,過濾並且將濾液在減壓下濃縮以便得到58B。LC-MS:m/z 260.1(M+H)+。1H NMR(氯仿-d)δ 3.84(d,J=13.4Hz,2H),3.22(t,J=11.3Hz,2H),2.54(s,2H),1.73(d,J=12.6Hz,2H),1.49-1.58(m,2H),1.47(s,9H)
步驟B:在室溫下攪拌2-(1-(第三丁氧羰基)-4-羥基哌啶-4-基)乙酸(1g,3.86
mol)、N,O-二甲基羥胺鹽酸鹽(412mg,4.25mmol)、HBTU(1.6g,4.25mmol)以及DIPEA(1.5g,11.58mmol)在DCM(20mL)中的混合物3h。將所得混合物用水(3 x 20mL)洗滌,然後用鹽水洗滌,經Na2SO4乾燥,蒸發,並且藉由標準方法純化以便得到58C。LC-MS:m/z 303(M+H)+
步驟C:將0.5M乙炔基溴化鎂在THF(10mL,5mmol)中的溶液添加至4-羥基-4-(2-(甲氧基(甲基)胺基)-2-側氧基乙基)哌啶-1-甲酸三級丁酯(500mg,1.65mmol)中,然後將混合物加熱至50℃並持續1h。然後將反應混合物冷卻至周圍溫度並且用飽和氯化銨水溶液(20mL)處理,並且接著加熱至50℃並持續1h。在此之後,將反應冷卻至周圍溫度,用乙酸乙酯(20mL)萃取,用鹽水洗滌,經Na2SO4乾燥並且過濾。將濾液在減壓下濃縮並且藉由標準方法純化以便提供58D。LC-MS:m/z 329(M+H)+
步驟D:向(E)-4-羥基-4-(4-(甲氧基(甲基)胺基)-2-側氧基丁-3-烯基)哌啶-1-甲酸三級丁酯(250mg,0.762mmol)在EtOH(10mL)中的溶液中添加水合肼(50%,0.5mL)並且然後將混合物在回流下攪拌1h。然後將反應混合物冷卻至室溫並且在減壓下除去溶劑。將殘餘物溶解於EtOAc(20mL)中並且用水(3 x 20mL)洗滌,將有機層收集並且用鹽水洗滌,經Na2SO4乾燥並且在減壓下濃縮以便得到58E,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 282.1(M+H)+
步驟E:向4-((1H-吡唑-3-基)甲基)-4-羥基哌啶-1-甲酸三級丁酯(120mg,0.43mmol)在DCM(10mL)中的溶液中添加4M HCl的二溶液(5滴),然後在室溫下攪拌混合物10min。然後除去溶劑並且58F未進行進一步純化即用於下一個步驟。LC-MS:m/z 182.1(M+H)+
步驟F:在室溫下向相應的4-(芳基-4-磺醯胺基)苯甲酸(1當量)在DCM(5mL)中的溶液中依序地添加HBTU(1.2當量)、DIPEA(3當量)以及化合物58F(1.0當量)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥。將合併的有機層真空濃縮,並且藉由標準方法純化以便得到500。
1H NMR(400MHz,甲醇-d 4)δ:9.11(d,J=1.9Hz,1H),9.03(d,J=1.6Hz,1H),8.50(dd,J=7.4,1.2Hz,1H),8.32(d,J=8.6Hz,1H),7.91(t,J=7.9Hz,1H),7.53(s,1H),7.11-7.21(m,4H),6.19(s,1H),4.25(br.s.,1H),3.12-3.22(m,1H),2.81(s,2H),1.60(br.s.,2H),1.48(br.s.,1H),1.43(br.s.,1H)。LC-MS:m/z 493.4(M+H)+
步驟A:向4-胺基苯甲酸乙酯(405mg,2.5mmol)在DCM(15mL)中的溶液中添加吡啶(395mg,5.0mmol)和5-側氧基-5,6-二氫-1,6-萘啶-8-磺醯氯(61A,600mg,2.5mmol)。將混合物在40℃下攪拌12h,並且然後用水洗滌。將固體藉由過濾分離,用水洗滌,並且在真空下乾燥以便提供61B。LC-MS:m/z 374.1(M+H)+
步驟B:在80℃下攪拌4-(5-羥基-1,6-萘啶-8-磺醯胺基)苯甲酸乙酯61B(800mg,2.1mmol)與NaOH(260mg,6.3mmol)在甲醇(30mL)中的混合物12h。將混合物冷卻至室溫並且用HCl水溶液(1N)調整至pH=7。將固體藉由過濾
分離,用水洗滌,並且在真空下乾燥以便提供61C。LC-MS:m/z 346.1(M+H)+
步驟C:在攪拌下向10mL磷醯氯中添加4-(5-羥基-1,6-萘啶-8-磺醯胺基)苯甲酸(61C,450mg,1.3mol)。將混合物回流12h。冷卻之後,將混合物濃縮並且傾倒至冰水中。將固體藉由過濾分離,用水洗滌,並且在真空下乾燥以便提供61D。LC-MS:m/z 364.0(M+H)+
步驟D:在65℃下攪拌4-(5-氯-1,6-萘啶-8-磺醯胺基)苯甲酸61D(400mg)與水合肼(50mg,1.0mmol)在THF(15mL)中的混合物1h。冷卻之後,將混合物濃縮並且傾倒至冰水中。將固體藉由過濾分離,用水洗滌,並且在真空下乾燥以便提供61E,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 360.1(M+H)+
步驟E:4-(1,6-萘啶-8-磺醯胺基)苯甲酸(61F)
在70℃下攪拌4-(5-肼基-1,6-萘啶-8-磺醯胺基)苯甲酸(400mg,來自上一步驟的粗產物)與硫酸銅(110mg,0.69mmol)在水(10mL)中的混合物2h。冷卻之後,將混合物過濾。將產物收集,用水洗滌,並且在真空下乾燥以便提供61F,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 330.1(M+H)+
步驟F:化合物513 N-(4-(4-羥基-4-異丁基哌啶-1-羰基)苯基)-1,6-萘啶-8-磺醯胺
向4-(1,6-萘啶-8-磺醯胺基)苯甲酸61F(350mg)在DCM(15mL)中的溶液中添加HBTU(644mg,1.7mmol)、TEA(222mg,2.2mmol)以及4-異丁基哌啶-4-醇(204mg,1.3mmol)。在室溫下攪拌混合物1h並且用水洗滌。將有機層濃縮並且藉由Prep-TLC(PE/EA=1/1)純化以便提供513。1H NMR(氯仿-d)δ 9.50(br,1 H),9.35(br,1 H),9.29(br,1 H),8.50(br,1 H),8.20(s,1 H),7.79(br,1 H),7.18(d,J=8.0Hz,2 H),7.08(d,J=8.0Hz,2 H),4.30(br,1 H),3.47(br,3 H),2.04-1.98(m,4 H),1.85
-1.78(m,1 H),1.39(d,J=5.6Hz,2 H),0.95(d,J=6.8Hz,6 H)。LC-MS:m/z 469.2(M+H)+
步驟A:使用在此所述的程序來製備62B。
步驟B:向4-羥基-4-(2-甲基烯丙基)哌啶-1-甲酸苄酯62B(2.9g,10mmol)在50mL DCM中的溶液中添加吡啶(2.4g,30mmol)和氯甲基碳醯氯(1.9g,15mmol)。在50℃下攪拌所得混合物過夜。除去DCM之後,將殘餘物在水與EtOAc之間分配。將有機層用2N HCl、水以及鹽水洗滌,經Na2SO4乾燥,濃縮,並且藉由標準方法純化以便得到62C。LC-MS:m/z 382.1(M+H)+。
步驟C:在45℃下攪拌4-((氯甲氧基)羰氧基)-4-(2-甲基烯丙基)哌啶-1-甲酸苄酯62C(382mg,1.0mmol)與二三級丁基磷酸鉀(496mg,2mmol)在DMF(15mL)中的混合物過夜。在減壓下除去溶劑並且將殘餘物在水與EtOAc之間
分配。將有機層用水和鹽水洗滌,經Na2SO4乾燥並且濃縮,然後藉由標準方法純化以便提供62D。LC-MS:m/z 556.3(M+H)+。
步驟D:在室溫下在氫氣氛下攪拌4-(((((二三級丁氧基磷醯基)氧基)甲氧基)羰基)氧基)-4-(2-甲基烯丙基)哌啶-1-甲酸苄酯62D(1.2g,2.2mmol)與Pd/碳在乙醇(20mL)中的混合物3h。將固體藉由過濾除掉並且將溶劑濃縮以便得到62E,該產物未進行進一步純化即用於下一個步驟。LC-MS:m/z 424.5(M+H)+。
步驟E:甲酸(二三級丁氧基磷醯氧基)甲基4-異丁基-1-(4-(喹啉-5-磺醯胺基)苯甲醯基)哌啶-4-酯(62F)
在室溫下向4-(喹啉-5-磺醯胺基)苯甲酸(1當量)在DCM(5mL)中的溶液中依序地添加HBTU(1.2當量)、DIPEA(3當量)以及甲酸(二三級丁氧基磷醯氧基)甲基4-異丁基哌啶-4-酯62E(1.0當量)。在室溫下攪拌反應混合物過夜。將混合物傾倒至水中並且用DCM(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供62F。LC-MS:m/z 735.3(M+H)+。
步驟F:化合物527甲酸4-異丁基-1-(4-(喹啉-5-磺醯胺基)苯甲醯基)哌啶-4-基膦酸基氧基甲酯
在0℃下向甲酸(二三級丁氧基磷醯氧基)甲基4-異丁基-1-(4-(喹啉-5-磺醯胺基)苯甲醯基)哌啶-4-酯62F(360mg,0.5mmol)在DCM(15mL)中的溶液中逐滴添加TFA(1mL)在DCM(2mL)中的溶液並且在0℃下攪拌混合物1h。
然後在減壓下除去溶劑,並且藉由標準方法純化殘餘物以便提供527。1H NMR(DMSO-d6)δ 10.70(br.s.,1H),9.10(s,d,J=8.0Hz,2H),8.51(br.s.,1H),8.38(br.s.,1H),7.99-7.77(m,1H),7.17(br.s.,2H),7.09(br.s.,2H),5.26-5.49(m,2H),4.06(br.s.,1H),3.25(br.s.,2H),2.97(br.s.,1H),2.14(br.s.,1H),1.99(br.s.,1H),1.74(br.s.,3H),1.50(br.s.,2H),0.84(d,J=5.9Hz,6H)。LC-MS:m/z 623.1(M+H)+。
步驟A:在0℃下在N2氣氛下向5-碘-3-甲基異噻唑(63A,225mg,1.0mmol)在THF(10mL)中的溶液中添加乙基溴化鎂(2N,0.55mL,1.1mmol)。在0℃下攪拌反應混合物3h,並且然後在-10℃下在N2氣氛下向以上溶液中逐滴添加4-甲醯基哌啶-1-甲酸三級丁酯(213mg,1.0mmol)在THF(1mL)中的溶液。在室溫下在N2下攪拌反應混合物過夜。將反應混合物由飽和的NH4Cl溶液淬滅,並且將所得混合物用EtOAc萃取兩次,用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供63B。LC-MS:m/z 313.5(M+H)+。
步驟B:在0℃下向4-(羥基(3-甲基異噻唑-5-基)甲基)哌啶-1-甲酸三級丁酯(63B,60mg,0.192mmol)在DCM(5mL)中的溶液中添加DIPEA(28mg,0.212
mmol),接著添加MsCl(24.3mg,0.212mmol)。在0℃下攪拌反應混合物0.5h。然後允許反應混合物溫至室溫並再攪拌1h。將混合物用DCM(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供63C。LC-MS:m/z 331.1(M+H)+。
步驟C:在室溫下向4-(氯(3-甲基異噻唑-5-基)甲基)哌啶-1-甲酸三級丁酯(63C,78mg,0.236mmol)在DCM(0.5mL)中的溶液中添加DBU(3mL)。在120℃下在微波下攪拌反應混合物0.5h。然後將反應混合物冷卻至室溫,並且用EtOAc(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供63D。1H NMR(氯仿-d)δ 6.82(s,1H),6.44(s,1H),3.51(dd,J=11.2,5.3Hz,4H),2.54(t,J=5.7Hz,2H),2.45(d,J=12.6Hz,3H),2.38(t,J=5.7Hz,2H),1.49(s,9H)。LC-MS:m/z 295.1(M+H)+。
步驟D:在0-5℃下向4-((3-甲基異噻唑-5-基)亞甲基)哌啶-1-甲酸三級丁酯(63D,147mg,0.5mmol)在丙酮(12mL)和H2O(2mL)中的溶液中逐滴添加H2O(0.6mL)中的H2SO4(123mg,1.25mmol),接著添加NBS(134mg,0.75mmol)。在0-5℃下攪拌反應混合物3h。然後將反應混合物用EtOAc(10mL,兩次)萃取。合併的有機相用鹽水洗滌,經無水Na2SO4乾燥,過濾並且將濾液真空濃縮以便提供63E。LC-MS:m/z 391.1(M+H)+。
步驟E:在N2下在室溫下向4-(溴(3-甲基異噻唑-5-基)甲基)-4-羥基哌啶-1-甲酸三級丁酯(63E,58mg,0.15mmol)和AIBN(4.9mg,0.03mmol)在甲苯(5mL)中的溶液中添加氫化三丁基錫(65.1mg,0.223mmol)。在90℃下攪拌反應混合物8h,此時TLC展示反應完成。將反應混合物真空濃縮以便提供63F。1H NMR(氯仿-d)δ 6.82(s,1H),3.84(s,2H),3.16(s,2H),3.06(s,2H),2.48(s,3H),1.77(s,2H),1.58(s,2H),1.47(s,9H)LC-MS:m/z 313.2(M+H)+。
步驟F:向4-羥基-4-((3-甲基異噻唑-5-基)甲基)哌啶-1-甲酸三級丁酯(63F,55mg)在DCM(5mL)中的溶液中添加TFA(1mL),在室溫下攪拌反應混合物約2小時,此時LCMS沒有檢測到s.m.。將反應混合物濃縮以便提供所需產物63G,其未進行進一步純化直接地用於下一個步驟。LC-MS:m/z 213.2(M+H)+。
以下化合物根據一般程序63來製備。
步驟G:化合物511 N-(4-(4-羥基-4-((3-甲基異噻唑-5-基)甲基)哌啶-1-羰基)苯
基)喹啉-5-磺醯胺
在室溫下向4-(喹啉-5-磺醯胺基)苯甲酸(0.18mmol)在DCM(5mL)中的溶液中依序地添加HBTU(80mg,0.22mmol)、DIPEA(70mg,0.54mmol)以及4-((3-甲基異噻唑-5-基)甲基)哌啶-4-醇(7,38mg,0.18mmol)。在室溫下攪拌反應混合物1小時。將混合物傾倒至水中並且用EtOAc(20mL)萃取兩次。合併的有機層用鹽水洗滌並且經無水Na2SO4乾燥,真空濃縮,並且藉由標準方法純化以便提供511。
1H NMR(氯仿-d)δ 9.08(s,2H),8.45(dd,J=7.3,1.3Hz,1H),8.36(dd,J=8.5,1.4Hz,1H),8.01(s,1H),7.85(dd,J=8.4,7.4Hz,1H),7.19(d,J=8.4Hz,2H),7.09(d,J=8.4Hz,2H),6.82(s,1H),4.40(s,1H),3.38(m,3H),3.07(s,2H),2.50(s,3H),1.53(s,4H)。LC-MS:m/z 524.52(M+H)+
以下化合物根據一般程序6步驟C)來製備。
1H NMR(氯仿-d)δ 9.31(s,1H),8.22(d,J=8.3Hz,1H),8.12(d,J=6.7Hz,1H),8.04(s,1H),7.57(t,J=7.8Hz,1H),7.09(d,J=7.8Hz,1H),6.92-7.04(m,2H),6.35(t,J=72Hz,1H),4.42(br.s.,1H),3.20(br.s.,3H),1.96(br.s.,2H),1.55-1.70(m,7H),1.43-1.53(m,2H)。LC-MS:m/z 576.1(M+H)+
1H NMR(氯仿-d)δ 1.55-1.70(m,9 H)1.87-2.04(m,2 H)3.12-3.33(m,2 H)
3.43(br.s.,1 H)4.43(d,J=12.63Hz,1 H)7.24(d,J=8.33Hz,1 H)7.36-7.48(m,2 H)7.60(t,J=7.79Hz,1 H)8.14(d,J=7.52Hz,1 H)8.21-8.32(m,2 H)9.33(s,1 H)。LC-MS:m/z 535.1(M+H)+
1H NMR(氯仿-d)δ 1.31(s,1 H)1.51-1.72(m,8 H),1.87-2.04(m,2 H),3.20(dd,J=12.22,9.27Hz,2 H),3.37(s,1 H),4.31(d,J=13.43Hz,1 H),6.95-7.08(m,2 H),7.14(t,J=8.06Hz,1 H),7.62(t,J=7.79Hz,1 H),8.17(dd,J=7.52,1.07Hz,1 H),8.37(dd,J=8.19,0.94Hz,1 H),9.48(s,1 H)。LC-MS:m/z 528.1(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.47-1.69(m,9 H),1.86-2.07(m,2 H),3.08-3.20(m,1 H),3.20-3.29(m,1 H),3.36-3.47(m,1 H),4.37(d,J=12.89Hz,1 H),7.37(d,J=8.33Hz,1 H),7.44-7.62(m,3 H),7.68(dd,J=7.92,2.55Hz,1 H)。LC-MS:m/z 568.1(M+H)+
1H NMR(400MHz,甲醇-d 4)δ:1.45-1.73(m,9 H),1.87-2.05(m,2 H),3.17-3.29(m,2 H),3.37(s,1 H),4.33(d,J=13.16Hz,1 H),7.03(d,J=9.40Hz,2 H),7.21(t,J=7.66Hz,1 H),7.52(dd,J=8.60,2.69Hz,1 H),7.66(dd,J=8.06,2.69Hz,1 H)。
LC-MS:m/z 561.1(M+H)+
1H NMR(氯仿-d)δ 9.31(s,1H),8.19(d,J=8.1Hz,1H),8.10(d,J=6.7Hz,1H),7.94(s,1H),7.54(t,J=7.9Hz,1H),7.16-7.25(m,J=8.3Hz,2H),7.05-7.16(m,J=8.6Hz,2H),4.38(br.s.,1H),3.35(br.s.,2H),3.23(br.s.,1H),1.60(s,3H),1.63(s,2H),1.48-1.57(m,4H),0.91-1.02(m,1H)。LC-MS:m/z 508.6(M+H)+
1H NMR(DMSO-d6)δ 8.35(td,J=7.8,1.5Hz,2H),8.26(s,1H),7.62(t,J=7.8Hz,1H),7.19(d,J=8.4Hz,2H),7.12(d,J=8.4Hz,2H),4.37(s,1H),4.05(s,1H),3.0-3.3(m,3H),2.21(m,2H),1.36-1.53(m,8H)。LC-MS:m/z 539.1(M+H)+
1H NMR(400MHz,MeOD)δ:8.40(td,J=7.8,1.5Hz,2H),8.28(s,1H),7.59(t,J=7.8Hz,1H),7.24(s,4H),4.28(s,1H),3.38(d,J=8.4Hz,2H),3.20(d,J=3.6Hz,1H),2.34-2.20(m,2H),1.66-1.72(m,4H),1.45-1.55(m,2H)。LC-MS:m/z 525.5(M+H)+
1H NMR(氯仿-d)δ 8.41(dt,J=7.7,1.8Hz,2H),8.28(s,1H),7.59(t,J=7.8Hz,
1H),7.42(t,J=6.8Hz,1H),7.31-7.24(m,4H),7.18(pd,J=8.5,3.6Hz,2H),4.50(s,1H),3.53(s,2H),3.30-3.20(m,1H),2.22(d,J=57.2Hz,2H),1.73(d,J=58.7Hz,2H)。LC-MS:m/z 541.42(M+H)+
以下化合物根據一般程序8步驟E來製備。
1H NMR(400MHz,氯仿-d)δ 1.45-1.67(m,10 H),1.84-2.04(m,2 H),3.08-3.30(m,2 H),3.34(br.s.,1 H),4.39(d,J=13.16Hz,1 H),6.73-6.86(m,1 H),6.98(dd,J=10.75,1.61Hz,1 H),7.13(t,J=7.79Hz,1 H),7.89(dd,J=8.33,7.52Hz,1 H),8.14(s,1 H),8.39(dd,J=8.46,1.21Hz,1 H),8.49(dd,J=7.25,1.34Hz,1 H),9.03-9.12(m,2 H)。LC-MS:m/z 523.5(M+H)+
1H NMR(DMSO-d6)δ 10.84(br.s.,1H),9.12(dd,J=7.5,1.9Hz,2H),8.52(d,J=6.2Hz,1H),8.35-8.42(m,1H),7.97-8.05(m,1H),7.11(br.s.,1H),7.00(s,1H),6.99(t,J=72Hz,1H),6.93-6.97(m,1H),4.42(s,1H),4.12(d,J=12.9Hz,1H),3.12(br.s.,1H),3.01(br.s.,1H),2.93(br.s.,1H),1.87(br.s.,2H),1.58(t,J=18.9Hz,3H),1.47(br.s.,2H),1.25-1.27(br.s.,2H),1.26(m,2H)。LC-MS:m/z 535.32(M+H)+
以下化合物根據一般程序44步驟E來製備。
1H NMR(DMSO-d6)δ 7.68-7.83(m,2H),7.17-7.33(m,4H),7.07(t,J=7.8Hz,
1H),5.89(d,J=15.6Hz,1H),5.71(dt,J=15.5,7.0Hz,1H),4.28(br.s.,1H),3.43(br.s.,1H),3.37(s,1H),3.25(d,J=7.8Hz,1H),2.83-3.06(m,2H),1.64(br.s.,3H),1.48(br.s.,1H)。LC-MS:m/z 555.5(M+H)+
1H NMR(400MHz,MeOD)δ:8.42(dd,J=7.9,1.5Hz,1H),8.34(dd,J=7.7,1.5Hz,1H),8.20(s,1H),7.53(t,J=7.8Hz,1H),7.44(s,1H),7.11-7.23(m,4H),5.72-5.82(m,1H),5.59-5.72(m,1H),3.42(br.s.,2H),3.37(s,1H),2.82(dd,J=10.3,7.1Hz,2H),1.66(br.s.,2H),1.49(br.s.,2H)。LC-MS:m/z 537.6(M+H)+
以下化合物根據一般程序46步驟E來製備。
1H NMR(400MHz,MeOD)δ:1.28-1.41(m,4H),1.44-1.59(m,23H),1.60-1.72(m,14H),2.09-2.23(m,9H),3.22(br.s.,5H),3.40(br.s.,7H),4.25(br.s.,4H),7.07(t,J=7.79Hz,5H),7.19-7.25(m,19H),7.73(dd,J=7.79,1.07Hz,5H),7.79(dd,J=7.79,1.07Hz,5H)。LC-MS:m/z 543.7(M+H)+
1H NMR(400MHz,MeOD)δ:7.79(dd,J=7.8,1.1Hz,1H),7.73(dd,J=7.8,1.0Hz,1H),7.27-7.19(m,4H),7.07(t,J=7.8Hz,1H),4.28(s,1H),3.42(s,1H),3.26-3.12(m,2H),2.34-2.2.1(m,2H),1.70(dd,J=11.4,5.6Hz,2H),1.49(s,2H),1.38(t,J=6.2
Hz,2H)。LC-MS:m/z 529.5(M+H)+
1H NMR(氯仿-d)δ 7.76(ddd,J=16.2,7.8,1.2Hz,2H),7.45-7.39(m,1H),7.31-7.21(m,4H),7.17(tdd,J=11.4,7.4,3.7Hz,2H),7.07(t,J=7.8Hz,1H),4.51(d,J=12.2Hz,1H),3.54(s,2H),3.27(s,1H),2.23(d,J=52.7Hz,2H),1.74(dd,J=67.6,12.8Hz,2H)。LC-MS:m/z 545.73(M+H)+
1H NMR(DMSO-d6)δ 10.26(s,1H),7.94(d,J=5.6Hz,1H),7.90(s,2H),7.45(dd,J=8.9,2.7Hz,1H),7.21-7.27(m,J=8.6Hz,2H),7.10-7.17(m,J=8.6Hz,2H),4.43(s,1H),4.10(br.s.,1H),3.26(br.s.,2H),3.08(br.s.,1H),1.89(br.s.,2H),1.59(t,J=18.8Hz,3H),1.49(d,J=11.0Hz,2H),1.39(br.s.,2H),1.24-1.27(m,2H)。LC-MS:m/z 543.5(M+H)+
以下化合物根據一般程序48來製備。
1H NMR(400MHz,MeOD)δ:1.83(br.s.,1 H),2.00(br.s.,3 H),3.50(br.s.,3 H),4.46(br.s.,1 H),7.13-7.30(m,5 H),7.58(t,J=7.79Hz,1 H),8.13(dd,J=7.66,0.94Hz,1 H),8.28-8.43(m,2 H),9.49(s,1 H)。LC-MS:m/z 501.4(M+H)+
1H NMR(氯仿-d)δ 9.31(s,1H),8.20(d,J=8.1Hz,1H),8.10(d,J=7.5Hz,1H),7.96(s,1H),7.55(t,J=7.9Hz,1H),7.23(d,J=8.5Hz,2H),7.13(d,J=8.5Hz,2H),6.89(s,1H),4.55(s,1H),3.69-3.23(m,3H),2.56(s,3H),2.19-1.69(m,4H)。LC-MS:m/z 515.48(M+H)+
1H NMR(氯仿-d)δ 9.12(d,J=1.8Hz,1H),9.03(d,J=1.8Hz,1H),8.51(dd,J=7.4,1.3Hz,1H),8.32(dd,J=8.5,1.3Hz,1H),7.92(dd,J=8.4,7.5Hz,1H),7.29-7.16(m,4H),7.01(s,1H),4.44(s,1H),3.48(s,2H),3.24(s,1H),2.42(s,3H),1.89(m,4H)。LC-MS:m/z 510.5(M+H)+
1H NMR(氯仿-d)δ 9.32(s,1H),8.61(s,1H),8.20(dd,J=8.1,1.0Hz,1H),8.11(dd,J=7.6,1.0Hz,1H),7.97(s,1H),7.55(t,J=7.8Hz,1H),7.26-7.19(m,2H),7.16-7.10(m,2H),4.60(s,1H),3.63(s,1H),3.36(d,J=63.1Hz,2H),2.30(s,2H),1.97(s,2H)。LC-MS:m/z 535.32(M+H)+
1H NMR(氯仿-d)δ 9.08(s,2H),8.46(d,J=6.7Hz,1H),8.36(d,J=8.3Hz,1H),8.26(s,1H),8.04(s,1H),7.86(t,J=7.8Hz,1H),7.24(d,J=6.2Hz,2H),7.06-7.18(m,2H),4.60(br.s.,1H),3.62(br.s.,1H),3.45-3.56(m,1H),3.23(br.s.,1H),2.37(br.s.,
1H),2.19(s,1H),1.87(br.s.,2H)。LC-MS:m/z 530.5(M+H)+
1H NMR(甲醇-d4)δ 9.50(s,1H),8.34(dd,J=8.2,0.9Hz,1H),8.29(s,1H),8.13(dd,J=7.8,1.1Hz,1H),7.58(t,J=7.9Hz,1H),7.17-7.27(m,4H),4.52(br.s.,1H),3.50(br.s.,2H),3.21(br.s.,1H),2.72(br.s.,1H),2.44(br.s.,1H),2.30(br.s.,1H),1.70(br.s.,2H)。LC-MS:m/z 535.5(M+H)+
以下化合物根據在此所述程序來製備。
已經如此描述多個實施方式之多個方面,應認識到熟習該項技術者容易思及各種改變、修飾以及改進。這類改變、修飾以及改進旨在係本揭露一部分,並且旨在位於本發明精神和範圍內。因此,上述描述以及附圖僅用於舉例。
Claims (24)
- 一種式(I)化合物: ,或其藥學上可接受的鹽,其中: A係芳基或雜芳基,其中該芳基或雜芳基任選地被取代,並且該芳基或雜芳基任選地稠合至任選地被取代的碳環基或任選地被取代的雜環基;X選自-NH-S(O)2-、-S(O)2-NH-、-NH-S(O)2-CH2-、-CH2-S(O)-NH-、-NH-S(O)-CH2-、-NH-S(O)-、-S(O)-NH-、或-CH2-S(O)2-NH-;Y係C(H)或N;限制條件係不超過兩個Y基團係N;R1a係羥基、-CH2OH、-CHO、-CO2H、-N(R10a)2、-CO2-C1-6烷基、-OP(=O)(OH)2、或-OCO2-CH2-OP(=O)(OH)2;R1b係任選地被一個至四個R5基團取代的C1-8烷基;任選地被一個至四個R5基團取代的C1-8烯基;環烷基;雜環;芳基;雜芳基;環烷基烷基;環烷基烯基;雜環基烷基;雜環基烯基;芳烷基;芳烯基;雜芳烷基;雜芳烯基;或-OH,其限制條件係當R1a係OH時,R1b不是OH;其中每個環烷基、雜環、芳基、雜芳基、環烷基烷基、環烷基烯基、雜環基烷基、雜環基烯基、芳烷基、芳烯基、雜芳烷基、或雜芳烯基任選地被取代;每個R2獨立地選自鹵基、烷基、CN、OH、和烷氧基,其中所述烷基或烷氧基任選地被一個至四個R5基團取代;或兩個相鄰R2基團與其連接的多個環原子結合在一起形成5或6員碳環、芳基、雜環或雜芳基環;每個R4獨立地選自鹵基、烷基、烷氧基、鹵代烷基、鹵代烷氧基和羥基;每個R5獨立地選自鹵基、OH、C1-6烷氧基、CN、NH2、-SO2-C1-6烷基、-NH(C1-6烷基)、以及-N(C1-6烷基)2;每個R10a獨立地選自氫或C1-6烷基;n係0、1、2或3;並且m係0、1或2;其限制條件係式(I)化合物並非以下化合物:(1)4-[[4-羥基-4-(4-甲基苯基)-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺; (2)4-[[4-(4-氯苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(3)4-[[4-(3-氟苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(4)4-[[4-(2-氟基-5-甲基苯基)-4-羥基-1-哌啶基]羰基]-N-2-噻唑基-苯磺醯胺;(5)4-苯基-1-[4-[(苯胺基)磺醯基]苯甲醯基]-4-哌啶甲酸甲酯;(6)1-[4-[[(2-甲基苯基)胺基]磺醯基]苯甲醯基]-4-苯基-4-哌啶甲酸甲酯;或(7)N-(4-氟苯基)-4-[[4-羥基-4-(甲氧基甲基)-1-哌啶基]羰基]-苯磺醯胺。
- 如申請專利範圍第1項所述之化合物,其中該化合物係式(Ia)化合物:
- 一種式(Ib)化合物:
- 如申請專利範圍第3項所述之化合物,其中A係:
- 如申請專利範圍第3項所述之化合物,其中該化合物係式(II)化合物:
- 如申請專利範圍第3項所述之化合物,其中該化合物係式(III)化合物:
- 如申請專利範圍第3項所述之化合物,其中該化合物係式(IV)化合物:
- 如申請專利範圍第3項所述之化合物,其中R1b係任選地被一個至四個R5基團取代的C1-8烷基;芳基;雜芳基;芳烷基;或雜芳烷基;其中每個芳基;雜芳基;芳烷基;或雜芳烷基任選地被取代。
- 如申請專利範圍第8項所述之化合物,其中每個芳基;雜芳基;芳烷基;或雜芳烷基任選地被以下基團取代:鹵基、C1-6烷基、-OH、C1-6烷氧基、-CN、-NH2、-SO2-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、芳基、鹵代烷基、或鹵代烷氧基。
- 如申請專利範圍第3項所述之化合物,其中R1b係任選地被一個至四個R5基團取代的C1-8烷基。
- 如申請專利範圍第3項所述之化合物,其中R5係氟、-OH、或-SO2-CH3。
- 如申請專利範圍第3項所述之化合物,其中R1b係苯基,其任選地被氯、氟、溴、甲基、乙基、-CN、二氟甲基、三氟甲基、-OCF3、-SO2-CH3、或-OCH3取代。
- 如申請專利範圍第1項所述之化合物,其中該式(I)化合物選自表1之化合物100-529。
- 一種藥物組合物,其包含如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽及一藥學上可接受的載體。
- 一種調節有需要的受試者的PKM2活性之方法,該方法包括給予所述受試者如申請專利範圍第14項所述之藥物組合物。
- 一種治療有需要的受試者的與PKM2活性相關的癌症之方法,該方法包括給予該受試者如申請專利範圍第14項所述之藥物組合物。
- 如申請專利範圍第14項所述之藥物組合物在製造用於調節PKM2活性的藥物中之用途。
- 如申請專利範圍第14項所述之藥物組合物在製造用於治療與PKM2活性相關之癌症的藥物中之用途。
- 一種用於增加有需要的紅細胞(RBC)的生命期之方法,該方法包括使血液與有效量的(1)如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽;或(2)如申請專利範圍第14項所述之組合物接觸。
- 如申請專利範圍第19項所述之方法,其中該化合物體外直接添加至全血或疊集細胞。
- 如申請專利範圍第19項所述之方法,其中該藥物組合物給予有需要的受試者。
- 一種用於調控有需要的血液中的2,3-二磷酸甘油酸水平之方法,該方法包括使血液與有效量(1)如申請專利範圍第1項所述之化合物;或(2)如申請專利範圍第14項所述之組合物接觸。
- 一種用於治療遺傳性非球形紅細胞溶血性貧血之方法,該方法包括給予有需要的受試者治療有效量之有效量(1)如申請專利範圍第1項所述之化合物;或(2)如申請專利範圍第14項所述之藥學上可接受的組合物。
- 一種用於治療鐮狀細胞性貧血之方法,該方法包括給予有需要受試者治療有效量之有效量(1)如申請專利範圍第1項所述之化合物;或(2)如申請專利範圍第14項所述之藥學上可接受的組合物。
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2013
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2014
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- 2014-03-13 JP JP2015561914A patent/JP6374413B2/ja not_active Expired - Fee Related
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- 2014-03-13 MX MX2015012882A patent/MX2015012882A/es unknown
- 2014-03-13 CA CA2903067A patent/CA2903067A1/en not_active Abandoned
- 2014-03-13 PE PE2015002010A patent/PE20151793A1/es not_active Application Discontinuation
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IL241352A0 (en) | 2015-11-30 |
WO2014139325A1 (en) | 2014-09-18 |
JP2017105832A (ja) | 2017-06-15 |
WO2014139144A1 (en) | 2014-09-18 |
NI201500140A (es) | 2015-11-24 |
CA2903067A1 (en) | 2014-09-18 |
PE20151793A1 (es) | 2015-12-10 |
US9365545B2 (en) | 2016-06-14 |
BR112015023760A2 (pt) | 2017-07-18 |
JP6374413B2 (ja) | 2018-08-15 |
AU2014231564A2 (en) | 2015-10-22 |
US20140288081A1 (en) | 2014-09-25 |
EP2970189A4 (en) | 2016-08-10 |
AR095557A1 (es) | 2015-10-28 |
JP2016512203A (ja) | 2016-04-25 |
ES2803548T3 (es) | 2021-01-27 |
CL2015002767A1 (es) | 2016-12-30 |
EP2970189A1 (en) | 2016-01-20 |
US20150336931A1 (en) | 2015-11-26 |
MX2015012882A (es) | 2015-12-03 |
ZA201506487B (en) | 2016-11-30 |
US9108921B2 (en) | 2015-08-18 |
CN105121425A (zh) | 2015-12-02 |
AU2014231564A1 (en) | 2015-09-10 |
RU2015143908A (ru) | 2017-04-21 |
EP2970189B1 (en) | 2020-05-06 |
CR20150571A (es) | 2016-01-06 |
AU2014231564B2 (en) | 2018-07-12 |
SG11201507332SA (en) | 2015-10-29 |
PH12015502161A1 (en) | 2016-01-25 |
US20160046579A1 (en) | 2016-02-18 |
HK1216175A1 (zh) | 2016-10-21 |
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