TWI825398B - Glp-1 受體促效劑、包含該促效劑之醫藥組成物及其製備方法 - Google Patents
Glp-1 受體促效劑、包含該促效劑之醫藥組成物及其製備方法 Download PDFInfo
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- TWI825398B TWI825398B TW110109865A TW110109865A TWI825398B TW I825398 B TWI825398 B TW I825398B TW 110109865 A TW110109865 A TW 110109865A TW 110109865 A TW110109865 A TW 110109865A TW I825398 B TWI825398 B TW I825398B
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- oxy
- fluorobenzyl
- chloro
- imidazole
- pyridin
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Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
本發明涉及一種新穎化合物、其異構體或藥學上可接受的鹽,包含該化合物的醫藥組成物及其製備方法,藉由優異的GLP-1促效劑活性和出色的DMPK特性而有效地用作治療或預防肥胖症或各種代謝性疾病如糖尿病和高脂血症的藥物,。
Description
本發明涉及具有GLP-1受體促效劑活性的新穎化合物、其異構體、其藥學上可接受的鹽,包括該化合物的醫藥組成物以及製備該化合物的方法。
胰高血糖素樣肽1(GLP-1)是飯後從腸道L細胞分泌的多肽激素,它可以刺激胰島β細胞分泌胰島素,從而穩定餐後血糖水平。GLP-1與GLP-1受體(GLP-1R)結合。GLP-1受體是G蛋白偶聯受體(GPCR)的B類受體亞類中的一種蛋白,可調節重要的生理和病理生理過程。其三級結構尚未確定,並且由於GLP-1受體具有藉由將其N末端與配體結合來確定親和力的獨特結合方式,因此被認為是非常難於開發出的低分子配體的藥物靶標。
GLP-1的外源給藥可使第2型糖尿病患者的血糖水平正常化。由於GLP-1對降低血糖水平的作用根據葡萄糖濃度而變化,因此,在
調節血糖水平的同時,降低低血糖症的風險。另外,基於GLP-1的藥物,例如Byetta®和Bydureon BCise®(exenatide),Ozempic®(semaglutide),Victoza®(liraglutide),Adlyxin®(lixisenatide);Tanzeum®(albiglutide)和Trulicity®(dulaglutide)是GLP-1受體促效劑,近年來已成功銷售,並且已確認它們提供血糖控制功能,除可治療第2型糖尿病患者外,還有效提供減肥效果,維持β細胞功能並緩解高血壓、低血糖和/或高脂血症。
但是,由於上述的GLP-1和GLP-1受體促效劑可能缺乏基於肽的口服藥物所需的足夠的口服生物利用度,因此需要具有口服生物利用度的GLP-1受體的小分子促效劑。
本發明旨在提供一種具有作為GLP-1促效劑之活性的新穎化合物。
另外,本發明涉及提供一種預防或治療代謝疾病或神經退化性疾病的醫藥組成物,其包含新穎化合物作為活性成分。
將詳細描述在說明書中使用的每個基團的定義。除非另有說明,否則每個基團均具有以下定義。
本文所用的「鹵素」可以是氟、氯、溴或碘。
本文所用的「烷基」是指直鏈或支鏈的脂族飽和烴基,並且具體地,可以是C1-6烷基、C1-4烷基或C1-3烷基。烷基的實例可以包括甲
基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、戊基、異戊基、新戊基、1-乙基丙基、己基、異己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基或2-乙基丁基。
本文所用的「烷氧基」是指單鍵性的直鏈或支鏈的飽和烴所鍵合的氧基,具體而言,可以為碳原子數為1至6的烷氧基、碳原子數為1至4的烷氧基或碳原子數為1至3的烷氧基。烷氧基的實例可包括甲氧基、乙氧基、丙氧基、正丁氧基、三級丁氧基或1-甲基丙氧基。
本文所用的「環烷基」是指環狀的單鍵飽和烴基,根據碳原子數,具體為C3-8環烷基或C3-6環烷基。環烷基的實例可以包括環丙基、環丁基、環戊基或環己基。
本文所用的「雜環烷基」是指包括一個或多個除碳原子以外的諸如N、O或S的雜原子作為環成員的環狀單鍵飽和烴基,並且可以是單環或稠合多環。具體地,雜環烷基可以是4至10員雜環烷基,4至7員雜環烷基或4至6員雜環烷基,其包括一種或多種,較佳地,一至三種選自由N、O和S所組成群組的雜原子。雜環烷基的實例可包括氧丹醯基、氮丙啶、吡咯烷、吡咯烷基、哌啶基、哌嗪基、嗎啉基、四氫呋喃基或四氫吡喃基。
本文所用的「芳基」是指具有至少一個環的芳族取代基,其具有共價π電子系統,並且可以是單環或稠合多環(即,每個具有相鄰的碳原子對的環)。具體地,取決於環中包括的碳原子數,這樣的芳基可以是C4-10芳基或C6-10芳基,例如,苯基或萘基。
本文所用的「雜芳基」是指除碳原子以外還包含一個或多個諸如N,O或S的雜原子作為環成員的芳環化合物,並且可以是單環或稠
合的多環。具體地,雜芳基可以是具有一種或多種,較佳地選自一種或多種雜原子的4至10員雜芳基,4至7員雜芳基或4至6員雜芳基。雜芳基的實例可以是呋喃基、吡喃基、咪唑基、噁唑基、異噁唑基、吡啶基、吡嗪基、嘧啶基、噠嗪基、惡二唑基、噻二唑基、四唑基、三嗪基、三嗪基或三唑基,但是本發明不限於此。
本文所用的「取代基」可以是選自由鹵素基團、腈基和C1-3烷基組成的組中的一種或多種。
在下文中,將詳細描述本發明。
為了實現上述目的,本發明提供由下述式1表示的化合物、其異構體或其藥學上可接受的鹽:
在此式中,
A為-(CH2)m-、-O-或-N(Ra)-,其中m為1至3的整數,且Ra為氫或烷基;
R1為(環烷基)烷基、(雜環烷基)烷基、(芳基)烷基或(雜芳基)烷基;
R2、R3或R4各自獨立地為氫、氘、鹵素、烷基、烷氧基、烷基胺或腈基;
n為1至4的整數,其中,n為2以上的整數時,R2、R3和R4可為相同或彼此不同;及
Z1、Z2、Z3、Z4、Z5、Z6或Z7各自獨立地表示CH、CF、CCl、CBr、CI或N;
其中該烷基、烷氧基、烷基胺、環烷基、雜環烷基、芳基或雜芳基是未經取代的或經取代的。
在一個示例性實施例中,A可為-CH2-、-O-或-N(Ra)-。
在一個示例性實施例中,Ra可為氫或C1-3烷基。
在一個示例性實施例中,R1可為(C3-8環烷基)C1-3烷基、(4至10員雜環烷基)C1-3烷基,(C6-10芳基)烷基或(4至10員雜芳基)C1-3烷基,其中該雜環烷基或雜芳基為含有1至3個選自由N、O和S所組成群組的雜原子的雜環烷基或雜芳基。
在一個示例性實施例中,R2、R3或R4各自獨立地為氫、氘、F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C1-3烷基胺或腈基。
在一個示例性實施例中,n為1至3的整數,其中,當n為2以上的整數時,各R2、R3和R4可為相同或彼此不同。
在一個示例性實施例中,Z1、Z2、Z3、Z4、Z5、Z6或Z7各自獨立地可為CH、CF或CCl。
在一個示例性實施例中,烷基、烷氧基、烷基胺、環烷基、雜環烷基、芳基或雜芳基可以是未經取代的,或被鹵素或C1-3烷基取代的。
在更多示例性實施例中,A可為-CH2-或-O-。
在更多示例性實施例中,R1可為環丙基甲基、環丁基甲基、環戊基甲基、環己基甲基、氧雜環丁烷基甲基、四氫呋喃基甲基、四氫吡
喃基甲基、噁唑基甲基、芐基、未經取代或經丙基取代的三唑基甲基、或未經取代或經乙基取代的咪唑基甲基。
在更多示例性實施例中,R2、R3或R4各自獨立地為氫、氘、F、Cl或腈基。
在更多示例性實施例中,n為2,並且各R2、R3或R4可為相同或彼此不同。
根據本發明的式1的化合物的代表性實例可包括以下化合物,但本發明不限於此:
1]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
2](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
3](S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
4]2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
5]2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
6](S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
7](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
8]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
9]2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
10](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
11]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
12](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
13](R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
14]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
15](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
16](S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
17](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
18](S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
19](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
20](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸;
21]2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
22]2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
23]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸;
24]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
25]2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
26]2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
27]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
28]2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
29](S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
30](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
31](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
32](S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
33](R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
34](S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
35](S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;
36](S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸;及
37](S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸。
在上述式1的類別中包括的化合物可以表現出優異的GLP-1受體促效劑活性,因此,它們對胰島β細胞表現出降血糖作用和積極作用,故它們可以有效地用於治療各種代謝性疾病。
同時,由式1表示的化合物可以具有不對稱碳中心,並且當其具有不對稱碳中心時,它可以以旋光異構體、部分旋光異構體或其外消旋物以及所有類型的異構體的形式存在。可以包括在根據本發明的一個實施例的化合物的類別中。顯然,任何類型的異構體也包括在一個實施例的化合物的類別中。在下文中,本文所用的術語「異構體」可以指具有相同分子式的不同化合物的統稱,「光學異構體」可以指一個實施例的化合物可能存在的所有立體異構體的統稱,包括相同的幾何異構體。
應理解在根據一個實施例的式1表示的化合物中,每個取代基可以連接至碳原子的手性中心。另外,一個實施例的化合物的任何不對
稱碳原子可以以(R)-,(S)-或(R,S)-構型的任何形式存在,並且合適地,可以以(R)-或(S)-構型的單獨形式存在。另外,一個實施例的化合物可以以任何形式的可能的異構體或其混合物存在,例如,任何形式的純幾何異構體、非對映異構體、旋光異構體、外消旋體及其混合物。另外,當一個實施例的化合物具有雙鍵時,與雙鍵結合的每個取代基可以是E或Z構型。另外,當一個實施例的化合物包含二取代的環烷基時,環烷基的每個取代基可具有順式或反式構型。
同時,本文所用的術語「藥學上可接受的鹽」可以是就藥學、生物學或其他性質而言較佳的鹽的通用術語,其等效地確保根據一個實施例的式1化合物的生物學功效和性質。鹽的非限制性實例可包括向式1的化合物中添加無機鹼或有機鹼的鹽或酸加成鹽。可以形成這樣的酸加成鹽的有機酸的實例可以包括乙酸、丙酸、乙醇酸、丙酮酸、草酸、馬來酸、丙二酸、琥珀酸、富馬酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、對甲苯磺酸或水楊酸,無機酸的實例可包括鹽酸、氫溴酸、硫酸、硝酸或磷酸。
上述實施例的化合物的藥學上可接受的鹽可以藉由一般化學方法由游離鹼型化合物或由其衍生的鹼性或酸性殘基合成。另外,第二藥學上可接受的鹽可以由第一藥學上可接受的鹽合成。作為一個具體實例,一個實施例的化合物的酸加成鹽可以藉由使游離鹼型化合物與化學計量的合適的酸反應而獲得。在此,反應可以在水、有機溶劑或它們的混合物中進行,並且具體地,在如醚、乙酸乙酯、乙醇、異丙醇或乙腈之非水介質中進行。另外,取決於藥學上可接受的鹽的類型,可以藉由發明所屬技術領域中具通常知識者眾所周知的一般反應來獲得每種類型的鹽。
同時,根據本發明的另一個實施例,提供一種用於預防或治療代謝疾病的醫藥組成物,其包含上述式1表示的化合物,其異構體或其藥學上可接受的鹽作為活性成分。如上所述,由於根據本發明的由式1表示的化合物可以表現出GLP-1受體(GLP-1R)的活化活性,因此含有該化合物的醫藥組成物可以具有有效的降血糖作用,並且對胰腺β細胞具有積極作用,並具有改善脂質代謝的作用,脂質代謝是一種慢性心血管疾病的危險因素,因此,它們可有效治療和/或預防與GLP-1受體活性相關的疾病,例如代謝疾病或神經退化性疾病。代謝疾病可以是選自由糖尿病(較佳第2型糖尿病)、高血壓、低血糖症、高脂血症(血脂異常)、動脈粥樣硬化、冠狀動脈疾病、心血管疾病、凝血異常、肥胖症、糖尿病併發症、糖尿病視網膜病變、肝臟疾病、肝膽疾病、脂肪肝、酒精性脂肪性肝炎、慢性腎臟疾病、胰島素阻抗和葡萄糖耐受性異常所組成群組的疾病。神經退化性疾病可以是選自由帕金森氏症和阿茲海默症所組成群組的疾病。
包含上述式1表示的化合物,其異構體或其藥學上可接受的鹽作為活性成分的醫藥組成物可以一般醫藥製劑的形式使用。即,醫藥組成物可以在實際臨床給藥中以各種劑型例如口服或腸胃外形式給藥,並且可以適當地以口服形式給藥。另外,根據劑型,可以藉由進一步添加藥學上可接受的稀釋劑或賦形劑,例如一般的填充劑、增稠劑、黏合劑、潤濕劑、崩解劑或表面活性劑來配製醫藥組成物。
用於口服的固體製劑可以是片劑、丸劑、散劑、顆粒劑或膠囊劑,並且可以藉由與諸如澱粉、碳酸鈣、蔗糖、乳糖或明膠的活性成分混合來提供固體製劑。另外,除了賦形劑之外,可以使用諸如硬脂酸鎂或滑石粉的潤滑劑。另外,用於口服的液體製劑可以是混懸劑、口服液體、
乳劑或糖漿,並且液體製劑可以包含各種賦形劑,例如,潤濕劑、甜味劑、矯味劑或防腐劑,以及簡單的稀釋劑(例如水或液體石蠟)。另外,腸胃外給藥的製劑可以是無菌水溶液、非水溶劑、懸浮液、乳劑、凍乾製劑或栓劑。腸胃外製劑可以包括非水溶劑,並且作為懸浮劑,可以使用丙二醇、聚乙二醇、植物油(例如橄欖油)或注射用酯(例如油酸乙酯)。作為栓劑的基質,可以使用Witepsol、Macrogol、Tween 61、可可脂、月桂酸酯或甘油明膠。
此外,包含本發明或其藥學上可接受的鹽作為活性成分的藥物發明的由式1表示的化合物及其異構體組成物在約0.1至1,000mg的給藥範圍內可以顯示有效量。所述組成物可以以各種劑量和以各種方式施用,例如每天一次或藉由劃分每日劑量數次,這取決於患者的體重、年齡、性別、健康狀況、飲食、施用時間、施用方法、排泄率和疾病的嚴重程度。
本發明還提供製備式1表示的組成物的方法。
在下文中,為了幫助理解本發明,將基於示例性反應方案描述由式1表示的化合物的製備方法。然而,本發明所屬技術領域中具通常知識者可以基於式1的結構藉由各種方法製備由式1表示的化合物,並且這些方法將被解釋為包括在本發明的範圍內。即,可以藉由說明書或相關領域中公開的各種合成方法的組合來製備由式1表示的化合物,這將被理解為包括在本發明的範圍內,並且該製備式1化合物的方法不限於以下描述的那些。
在一個示例性實施例中,當根據本發明的式1的化合物的A為碳時,式1的化合物可以藉由包括以下步驟的製備方法來製備:
1)在鈀催化劑的存在下,使下述式2的化合物與下述式3的化合物反應,得到下述式4的化合物;
2)在鈀催化劑的存在下,使步驟1)中獲得的以下述式4的化合物與以下述式5的化合物反應,接著水解所得的反應產物,得到以下述式6的化合物;及
3)將步驟2)中得到的下述式6的化合物與下述式7的化合物偶合,接著縮合和水解所得之反應產物,得到下述式1的化合物。
步驟1)和2)中使用的鹼可以是選自C1-4三烷基胺、二異丙基乙胺(DIPEA,Hunig鹼)、吡啶、K2CO3、KOH、NaOH、Na2CO3、NaOAc、Ca(OH)2、NaHCO3、Cs2CO3和LiOH,可以單獨使用或組合使用,以及在步驟1)和2)中使用的配體可以是三芳基膦、三烷基膦、聯芳基(二烷基)膦、二膦、N-雜環卡賓、環戊二烯、乙醯丙酮化物、二胺、聯吡啶、吡啶、DIOP、DiPAMP、BINAP、2,3-双(二苯基膦)丁烷(chiraphos)等,但不限於此。
步驟2)的水解可以在0℃至80℃、10℃至70℃、20℃至60℃、室溫或50℃下使用NaOH、KOH或LiOH進行,但不限於此。另外,反應可以藉由攪拌適當的時間來進行,該時間可以被適當地控制。
上述製備方法可以用反應方案1表示:
在一個示例性的實施例中,當本發明的式1的化合物的A為氧時,式1的化合物可以藉由包括以下步驟的製備方法來製備:
1’)將下述式4的化合物與下述式8的化合物偶合以獲得下述式9的化合物;及
2’)在鹼的存在下,將步驟1’)中獲得的下述式9的化合物與以下述式10的化合物進行取代反應,然後水解所得的反應產物,得到以下述式1的化合物。
製備方法中使用的所有鹼、配體和水解條件可以與當A為碳時所使用的製備方法中描述者相同。
上述製備方法可以由以下反應方案2表示。
反應方案2中使用的式10化合物可以藉由製備方法所製備,所述方法包括:
a)使下述式6的化合物進行環化反應,接著與芐基鹵化物進行取代反應,得到下述式11的化合物;及
b)使步驟a)中獲得的該式11的化合物進行氧化反應,得到式10的化合物。
步驟a)的環化反應可以使用合適的偶合劑進行。偶合劑的實例可以包括1,1’-硫代羰基二咪唑(TCDI)、1,1’-羰基二咪唑(CDI)等,但不限於此。另外,步驟a)中使用的鹼可以與在A為碳時使用的製備方法中所述者相同。
另外,步驟b)的氧化反應可以使用合適的氧化劑進行。氧化劑的實例可以包括間氯過氧苯甲酸(m-CPBA)、過氧化氫、過氧一硫酸鉀、高碘酸鈉、過碳酸鈉、高錳酸鉀、氧化釕等、但不限於此。氧化劑可以在一種或多種添加劑例如KF、KHCO3、Net3、AcONa等的存在下使用。發
明所屬技術領域中具通常知識者可以認識到,可以根據氧化劑和要使用的反應條件來選擇添加劑。
上述製備方法可以由以下反應方案3表示。
在一個示例性的實施例中,當式1的化合物的A為氮時,式1的化合物可以藉由包括以下步驟的製備方法來製備:
1”)將下述式4的化合物與下述式12的化合物偶合,以獲得下述式13的化合物;及
2”)在鹼的存在下,使步驟1”)中得到的下述式13的化合物與式14的化合物進行取代反應,接著水解所得的反應產物,得到下述式1的化合物。
上述製備方法可以由以下反應方案4表示。
製備方法中使用的所有鹼、配體和水解條件可以與當A為碳時所使用的製備方法中描述者相同。
另外,步驟2”)中使用的酸催化劑可以是選自由乙酸、硫酸、對甲苯磺酸、鹽酸、磷酸和硝酸所組成群組中的一種,但不限於此。
在反應方案1至4中,m、n、Ra、R1、R2、R3、R4、Z1、Z2、Z3、Z4、Z5、Z6和Z7如式1中所定義。
R5是烷基;及
X為鹵素,且較佳為Cl,Br或I。
在本說明書的製備方法中未具體描述的化合物是已知化合物,或可以藉由已知合成方法或與其類似的方法容易地從已知化合物合成的化合物。
藉由上述方法獲得的式1化合物可以藉由各種方法從反應產物中分離或純化,包括再結晶、離子電滲、矽膠管柱色譜法或離子交換樹脂色譜法。
如上所述,可以藉由各種方法合成根據本發明的化合物以及其製備起始原料或中間體,並且關於式1表示的化合物的製備,這些方法應被解釋為包括在本發明的範圍內。
由於優異的GLP-1促效劑活性和優異的藥物代謝動力學特性,根據本發明的新穎化合物可用作治療或預防肥胖症或各種如糖尿病和高脂血症之代謝性疾病的藥物。
在下文中,將參考以下實施例和實驗實施例更詳細地描述本發明。然而,以下實施例和實驗實施例僅是示例性的,並且僅僅是為了更容易地理解本發明而提供的,並且本發明不限於此。
在實施例中,定義以下縮寫來代表以下材料。
DMF:二甲基甲醯胺
THF:四氫呋喃
TEA:三乙胺
EtOAc:乙酸乙酯
MgSO4:硫酸鎂
MPLC:中壓液相色譜
Pd/C:鈀/碳
AcOH:乙酸
HCl:鹽酸
CS2:二硫化碳
NaH:氫化鈉
DCM:二氯甲烷
mCPBA:3-氯過苯甲酸
NaHCO3:碳酸氫鈉
t-BuOK:三級丁醇鉀
Cs2CO3:碳酸銫
K2CO3:碳酸鉀
BINAP:(2,2'-雙(二苯基膦基)-1,1'-聯萘基)
Pd2(dba)3:三(二亞芐基丙酮)二鈀
Fe:鐵
NH4Cl:氯化銨
CDI:碳二咪唑
DCE:1,2-二氯乙烷
POCl3:磷醯氯
NaOH:氫氧化鈉
H2O:水
MeOH:甲醇
HOBt:羥基苯并三唑
EDC:1-乙基-3-(3-二甲基胺基丙基)碳二亞胺
Dppf:1,1'-雙(二苯基膦基)二茂鐵
Na2SO4:硫酸鈉
NMR:核磁共振
HATU:(1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑並[4,5-b]吡啶鎓3-氧化物六氟磷酸鹽
[製備實施例1:2-氯-6-((4-氯-2-氟芐基)氧基)吡啶的製備]
2-氯-6-((4-氯-2-氟芐基)氧基)吡啶
將(4-氯-2-氟苯基)甲醇(1236mg,7mmol)溶解在10mL DMF中,並在0℃下添加NaH(在礦物油中的60%分散液,420mg,10.5mmol)。在相同溫度下攪拌10分鐘後,加入2,6-二氯吡啶(1036mg,7mmol),然後在室溫下攪拌2小時。反應後加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(1.06g,4.21mmol,60%)。
1H NMR(500MHz,CDCl3)δ 7.54(t,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),7.16-7.11(m,2H),6.93(d,J=7.5Hz,1H),6.70(d,J=8.0Hz,1H),5.39(s,2H);LC-MS(ESI):272.14[M+H]+
[製備實施例2:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸
將在製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(520mg,2.06mmol),Pd(dppf)Cl2-DCM(163mg,0.2mmol),Cs2CO3(1879mg,5.77mmol)和2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸乙酯(707mg,2.43mmol)溶解在20mL THF/H2O(9/1),然後進行氮取代。將反應物在85℃下攪拌5小時。反應完成後,加入水,然後使用EtOAc進行萃取。
有機層用Na2SO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸乙酯。將所得中間體不經另外純化即溶於8mL MeOH中,並加入8mL 1N NaOH。將反應物在50℃下攪拌22小時。反應完成後,使用1N HCl將所得溶液的pH調整至4,然後用EtOAc萃取。有機層用Na2SO4乾燥並在減壓下濃縮,並藉由MPLC純化,從而獲得2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(358mg,0.962mmol,47%)。
1H NMR(500MHz,MeOD)δ 8.00(d,J=8.5Hz,2H),7.72(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.47(d,J=7.5Hz,1H),7.38(d,J=8.5Hz,2H),7.25-7.17(m,2H),6.76(d,J=8.5Hz,1H),5.53(s,2H),3.67(s,2H);LC-MS(ESI):372.28[M+H]+
[製備實施例3:4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1g,5.02mmol)溶解在DMF中,在室溫下加入(四氫呋喃-2-基)甲胺(660mg,6.53mmol)和K2CO3(693mg,5.02mmol)。將反應物在50℃下攪拌4小時。添加水,並使用DCM進行萃取。有機層用Na2SO4乾燥,減壓濃縮,並藉由MPLC純化,從而獲得4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.38g,4.92mmol,98%)。
1H NMR(500MHz,CDCl3)δ 8.25-8.12(m,2H),7.57(d,J=1.5Hz,1H),7.22(dd,J=9.0,1.5Hz,1H),4.25-4.18(m,1H),4.00-3.91(m,4H),3.87-3.77(m,1H),3.56-3.47(m,1H),3.44-3.34(m,1H),2.16-2.04(m,1H),2.02-1.91(m,2H),1.77-1.64(m,1H)
[製備實施例4:4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將製備實施例3中獲得的4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.38g,4.92mmol)溶於10%的MeOH/DCM(1/1)中加入Pd/C(138mg),並在室溫在氫氣下攪拌17.5小時。反應完成後,將Pd/C藉由矽藻土過濾,然後減壓濃縮,從而獲得4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.23g,4.92mmol,100%)。
1H NMR(400MHz,CDCl3)δ 7.46(dd,J=7.8,1.8Hz,1H),7.34(d,J=1.8Hz,1H),6.67(d,J=8.4Hz,1H),4.20(qd,J=7.3,3.3Hz,1H),3.92-3.77(m,7H),3.26(dd,J=11.9,3.2Hz,1H),3.09(dd,J=11.9,8.2Hz,1H),2.10-2.03(m,1H),1.98-1.91(m,2H),1.74-1.67(m,1H);LC-MS(ESI):251.28[M+H]+
[製備實施例5:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將在製備實施例4中獲得的4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(121mg,0.48mmol)和製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(150mg,0.40mmol)溶解在2mL DMF中,將EDC(155mg,0.81mmol)和HOBt(108.9mg,0.81mmol)加入,然後在室溫下攪拌15.5小時。反應完成後,加入水,並用EtOAc進行萃取。有機層用Na2SO4乾燥並在減壓下濃縮,從而獲得中間體甲基4-(2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。將所得中間體不經另外純化即溶於20mL乙酸中,並在120℃下攪拌2小時。添加水,並用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-(4-(6-((4-
氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(135mg,0.23mmol,48%)。
1H NMR(500MHz,CDCl3)δ 8.08(s,1H),7.98-7.94(m,3H),7.76(d,J=8.5Hz,1H),7.63(t,J=8.0Hz,1H),7.46(t,J=8.2Hz,1H),7.35-7.31(m,3H),7.13-7.11(m,2H),6.73(d,J=8.2Hz,1H),5.51(s,2H),4.51(dd,J=36.6,15.9Hz,2H),4.21(dd,J=14.2,2.3Hz,1H),4.17-4.07(m,2H),3.94(s,3H),3.86(dd,J=15.1,6.9Hz,1H),3.75-3.71(m,1H),2.04-1.99(m,1H),1.89-1.82(m,2H),1.57-1.50(m,1H);LC-MS(ESI):586.32[M+H]+
[製備實施例6:(S)-4-硝基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯的製備]
(S)-4-硝基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯
將(S)-氧雜環丁烷-2-基甲胺(539mg,6.19mmol)溶於DMF(7mL)和THF(約10mL),加入TEA(2.59mL,18.56mmol)和3-氟-4-硝基苯甲酸甲酯(1.23g,6.19mmol),然後在室溫下在氮氣中攪拌16小時。反應完成後,將反應溶劑減壓濃縮。添加水,使用EtOAc進行萃取,並且用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-4-硝基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(813mg,3.05mmol,49%)。
1H NMR(500MHz,CDCl3)δ 8.36(br s,1H),8.24(d,J=8.5Hz,1H),7.63(d,J=1.5Hz,1H),7.28(d,J=1.5Hz,1H),5.16-5.20(m,1H),4.73-4.76(m,1H),4.61-4.65(m,1H),3.94(s,3H),3.62-3.65(m,2H),2.76-2.80(m,1H),2.59-2.75(m,1H);LC-MS(ESI):267.26[M+H]+
[製備實施例7:(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯的製備]
(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯
將製備實施例6中獲得的(S)-4-硝基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(813mg,3.05mmol)溶於THF(13mL),加入10% Pd/C(325mg),並在室溫下在氫氣下攪拌4小時。反應完成後,將所得反應產物用EtOAc藉由矽藻土過濾,並在減壓下濃縮,從而獲得(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(720mg,3.05mmol,100%)。
1H NMR(500MHz,CDCl3)δ 7.48(dd,J=8.0,1.5Hz,1H),7.38(d,J=1.5Hz,1H),6.68(d,J=8.0Hz,1H),5.12-5.10(m,1H),4.77-4.73(m,1H),4.64-4.59(m,1H),3.86(s,5H),3.53(br s,1H),3.46-3.42(m,1H),3.37-3.34(m,1H),2.78-2.74(m,1H),2.61-2.57(m,1H);LC-MS(ESI):237.27[M+H]+
[製備實施例8:4-(((6-氯吡啶-2--2-基)氧基)甲基)-3-氟芐腈的製備]
4-(((6-氯吡啶-2-基)氧基)甲基)-3-氟芐腈
將2,6-二氯吡啶(1.18g,7.94mmol)溶於1,4-二噁烷(20mL),加入(2-氟-4-異氰基苯基)甲醇(600mg,3.97mmol)和Cs2CO3(2.59g,7.94mmol),然後充分進行氮取代。加入BINAP(124mg,0.198mmol)和Pd2(dba)3(109mg,0.119mmol),再次進行氮置換,然後在90℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-(((6-氯吡啶-2-基)氧基)甲基)-3-氟芐腈(678mg,2.58mmol,65%)。
1H NMR(500MHz,CDCl3)δ 7.65(t,J=7.3Hz,1H),7.57(t,J=8.6Hz,1H),7.48-7.47(m,1H),7.40-7.38(m,1H),6.96(d,J=7.5Hz,1H),6.74(d,J=8.5Hz,1H),5.49(s,2H)
[製備實施例9:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸乙酯的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸乙酯
將製備實施例8中獲得的4-(((6-氯吡啶基-2-基)氧基)甲基)-3-氟芐腈(160mg,0.609mmol)溶解在1.4-二噁烷/水(2mL/2mL)中,加入2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼硼烷-2-基)苯基)乙酸乙酯(194
mg,0.670mmol)和Na2CO3(129mg,1.218mmol),然後進行足夠的氮取代。加入Pd(PPh3)4(36mg,0.030mmol),並再次進行氮置換,然後在90℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-2-基)苯基)乙酸乙酯(132mg,0.338mmol,55%)。
1H NMR(500MHz,CDCl3)δ 7.94(d,J=8.5Hz,2H),7.67-7.65(m,2H),7.45(d,J=8.5Hz,1H),7.40-7.36(m,4H),6.78(d,J=8.5Hz,1H),5.63(s,2H),4.17(q,J=7.3Hz,2H),3.66(s,2H),1.27(t,J=7.0Hz,3H);LC-MS(ESI):391.34[M+H]+
[製備實施例10:3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯的製備]
3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(700mg,3.52mmol)溶於THF(12mL),加入(1-乙基-1H-咪唑-5-基)甲胺二鹽酸鹽(696mg,3.52mmol)和TEA(1.47mL,10.55mmol),然後在氮氣下於80℃攪拌24小時。反應完成後,將所得反應產物冷卻至室溫,然後在減壓下濃縮反應溶劑。添加水,使用EtOAc進行萃取,並且用MgSO4進行乾燥,然後在減壓下濃縮。藉
由MPLC純化所得濃縮物,從而獲得3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯(442mg,1.452mmol,41%)。
1H NMR(500MHz,CDCl3)δ 8.25(d,J=9.0Hz,1H),7.94(br s,1H),7.69(d,J=1.5Hz,1H),7.57(s,1H),7.34(dd,J=9.0,1.5Hz,1H),7.11(s,1H),4.54(d,J=5.0Hz,2H),3.99(m,5H),1.48(t,J=7.5Hz,3H);LC-MS(ESI):305.1[M+H]+
[製備實施例11:4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯的製備]
4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯
將製備實施例10中獲得的3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)-4-硝基苯甲酸甲酯(440mg,1.446mmol)溶於MeOH/H2O(6mL/2mL),加入Fe(242mg,4.34mmol)和NH4Cl(1.55g,28.9mmol),然後在氮氣下於80℃攪拌3小時。反應完成後,將所得反應產物冷卻至室溫,使用EtOAc進行萃取,用MgSO4進行乾燥,並且在減壓下進行濃縮。藉由MPLC純化所得濃縮物,從而獲得4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯(254mg,0.925mmol,64%)。
1H NMR(400MHz,CDCl3)δ 7.53-7.50(m,2H),7.46(d,J=1.6Hz,1H),7.03(s,1H),6.70(d,J=8.4Hz,1H),4.27(s,2H),4.01(q,J=7.4Hz,2H),3.87(s,3H),1.45(t,J=7.2Hz,3H);LC-MS(ESI):275.1[M+H]+
[製備實施例12:3-((1-乙基-1H-咪唑-5-基)甲基)-2-氧代-2,3-二氫-1H-苯并[d]咪唑-5-羧酸甲酯的製備]
3-((1-乙基-1H-咪唑-5-基)甲基)-2-氧代-2,3-二氫-1H-苯并[d]咪唑-5-羧酸甲酯
將製備實施例11中獲得的4-胺基-3-(((1-乙基-1H-咪唑-5-基)甲基)胺基)苯甲酸甲酯(80mg,0.292mmol)溶解在THF(1mL)中,加入CDI(118mg,0.729mmol),然後在室溫下攪拌24小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得3-((1-乙基-1H-咪唑-5-基)甲基)-2-氧代-2,3-二氫-1H-苯并[d]咪唑-5-羧酸甲酯(53mg,0.176mmol,61%)。
1H NMR(400MHz,CDCl3)δ 8.19(br s,1H),7.84(dd,J=1.6,1.6Hz,1H),7.75(s,1H),7.49(s,1H),7.22(s,1H),7.06(d,J=8.0Hz,1H),5.08(s,2H),4.08(q,J=7.3Hz,2H),3.90(s,3H),1.33(t,J=7.3Hz,3H)
[製備實施例13:2-氯-1-(((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-氯-1-(((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例12中獲得的3-((1-乙基-1H-咪唑-5-基)甲基)-2-氧代-2,3-二氫-1H-苯并[d]咪唑-5-羧酸甲酯溶解在DCE(1mL)中,加入TEA(2mL,14.35mmol)和POCl3(1.35mL,14.45mmol),然後在80℃下攪拌24小時。反應完成後,將所得反應產物冷卻至室溫,並將反應溶劑減壓濃縮。進行MPLC純化,從而獲得2-氯-1-(((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(30mg,0.094mmol,46%)。
1H NMR(500MHz,CDCl3)δ 8.04(d,J=1.0Hz,1H),8.00(dd,J=8.5,1.5Hz,1H),7.73(d,J=9.0Hz,1H),7.53(s,1H),7.08(s,1H),5.44(s,2H),3.94-3.90(m,5H),1.30(t,J=7.3Hz,3H)
[製備實施例14:3-氟-4-(((6-(4-羥基苯基)吡啶-2-基)氧基)甲基)芐腈的製備]
3-氟-4-(((6-(4-羥基苯基)吡啶-2-基)氧基)甲基)芐腈
將製備實施例8中獲得的4-(((6-氯吡啶-2-基)氧基)甲基)-3-氟芐腈(150mg,0.571mmol)溶解在1.4-二噁烷/水(1mL/1mL)中,加入(4-羥苯基)硼酸(95mg,0.685mmol)和K2CO3(95mg,0.685mmol),然
後進行充分的氮取代。加入Pd(PPh3)4(27mg,0.023mmol),並再次進行氮取代,然後在90℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得3-氟-4-(((6-(4-羥基苯基)吡啶-2-基)氧基)甲基)芐腈(65mg,0.203mmol,35%)。
1H NMR(500MHz,CDCl3)δ 7.39(d,J=8.5Hz,2H),7.67-7.63(m,2H),7.45(d,J=8.5Hz,1H),7.39(dd,J=9.5,1.5Hz,1H),7.31(d,J=7.5Hz,1H),6.91-6.89(m,2H),6.73(d,J=8.5Hz,1H),5.63(s,2H);LC-MS(ESI):321.28[M+H]+
[製備實施例15:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例14中獲得的3-氟-4-(((6-(4-羥基苯基)吡啶-2-基)氧基)甲基)芐腈(20mg,0.062mmol)溶解於DCM(1mL)中,並加入TEA(0.522mL,3.75mmol)和製備實施例13中獲得的2-氯-1-(((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(20mg,0.062mmol),然後在40℃下攪拌24小時。反應完成後,將所得反應產物冷卻至室溫,
並將反應溶劑減壓濃縮。進行MPLC純化,從而獲得2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(10mg,0.017mmol,27%)。
1H NMR(500MHz,MeOD)δ 7.90-7.66(m,8H),7.37(d,J=7.5Hz,1H),7.15(d,J=8.0Hz,1H),7.12(s,1H),7.03(d,J=7.5Hz,1H),6.87-6.82(m,2H),6.72(d,J=8.0Hz,1H),5.62(s,2H),5.20(s,2H),4.16-4.13(m,2H),3.90(s,3H),1.29(t,J=7.0Hz,3H)
[製備實施例16:(S)-2-巰基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-巰基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例7中獲得的(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(300mg,1.270mmol)溶於THF(5mL),加入TEA(0.354mL,2.54mmol),然後在室溫下在氮氣下攪拌15分鐘。在0℃下緩慢滴加CS2(0.115mL,1.905mmol),然後在90℃下攪拌24小時。反應完成後,將所得反應產物冷卻至室溫。加水後,將所得產物用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-巰基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(235mg,0.844mmol,67%)。
1H NMR(500MHz,CDCl3)δ 9.70(br s,1H),8.10(s,1H),7.96(dd,J=8.5,1.5Hz,1H),7.21(d,J=8.0Hz,1H),5.32-5.28(m,1H),4.66-
4.60(m,3H),4.47-4.42(m,1H),3.94(s,3H),2.81-2.68(m,2H);LC-MS(ESI):279.24[M+H]+
[製備實施例17:(S)-2-芐硫基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-芐硫基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例16中獲得的(S)-2-巰基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(235mg,0.844mmol)溶解在THF(5mL)中,加入NaH(在礦物油中的60%分散液,68mg,1.689mmol),然後在室溫下在氮氣下攪拌15分鐘。緩慢逐滴添加BnBr(0.131mL,1.098mmol),然後在室溫下攪拌4小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-芐硫基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(248mg,0.673mmol,80%)。
1H NMR(500MHz,CDCl3)δ 8.11(d,J=1.0Hz,1H),7.97(dd,J=8.5,1.5Hz,1H),7.70(d,J=8.5Hz,1H),7.43-7.41(m,2H),7.31-7.27(m,3H),5.14-5.11(m,1H),4.66(s,2H),4.59-4.57(m,1H),4.38-4.32(m,3H),3.94(s,3H),2.71-2.66(m,1H),2.47-2.43(m,1H);LC-MS(ESI):369.32[M+H]+
[製備實施例18:(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將mCPBA(348mg,2.019mmol)溶於DCM(3mL)中,將製備實施例17中獲得的(S)-2-芐硫基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(248mg,0.673mmol)在0℃下溶解於DCM(3mL)中,並緩慢滴加,隨後在室溫下在氮氣下攪拌4小時。反應完成後,加水,並將所得溶液用NaHCO3中和至pH約7。所得產物用EtOAc萃取,用MgSO4乾燥,然後在減壓下濃縮。所得濃縮物藉由MPLC純化,從而獲得(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(250mg,0.624mmol,93%)。
1H NMR(400MHz,CDCl3)δ 8.30(d,J=0.8Hz 1H),8.07(d,J=1.5Hz,1H),7.93(d,J=1.5Hz,1H),7.39-7.20(m,5H),4.95-4.91(m,1H),4.90(s,2H),4.60-4.51(m,2H),4.42-4.32(m,2H),3.95(s,3H),2.60-2.69(m,1H),2.31-2.39(m,1H);LC-MS(ESI):401.31[M+H]+
[製備實施例19:(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例14中獲得的3-氟-4-(((6-(4-羥基苯基)吡啶-2-基)氧基)甲基)芐腈(44mg,0.137mmol)溶解在DMF(2mL)中,並加入t-BuOK(23mg,0.206mmol),然後在室溫下在氮氣下攪拌15分鐘。加入製備實施例18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(55mg,0.137mmol),然後在室溫下攪拌3小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(41mg,0.073mmol,53%)。
1H NMR(500MHz,CDCl3)δ 8.13(s,1H),8.08(m,2H),7.94(dd,J=8.5,1.5Hz,1H),7.70-7.55(m,5H),7.47(d,J=2.0Hz,2H),7.45(d,J=1.5Hz,1H),7.37(d,J=7.5Hz,1H),6.79(d,J=8.0Hz,1H),5.63(s,2H),5.27-5.25(m,1H),4.68-4.65(m,1H),4.50-4.12(m,3H),3.94(s,3H),2.82-2.81(m,1H),2.63-2.61(m,1H)
[製備實施例20:4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚的製備]
4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(100mg,0.368mmol)溶解在THF/H2O(3mL/0.3mL)中,加入(4-羥基苯基)硼酸(56mg,0.404mmol)和Cs2CO3(300mg,0.919mmol),然後進行充分的氮取代。加入Pd(dppf)Cl2-DCM(30mg,0.037mmol),並再次進行氮置換,然後在90℃下攪拌6小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(30mg,0.091mmol,25%)。
1H NMR(500MHz,CDCl3)δ 7.93(d,J=8.5Hz,2H),7.62(t,J=8.0Hz,1H),7.48(t,J=8.3Hz,1H),7.29(d,J=7.5Hz,1H),7.14-7.12(m,2H),6.91(d,J=8.5Hz,2H),6.69(d,J=8.5Hz,1H),5.53(s,2H),4.83(s,1H)
[製備實施例21:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例20中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(60mg,0.182mmol)溶解在DMF(2mL)中,加入t-BuOK(31mg,0.273mmol),然後在室溫下在氮氣中攪拌15分鐘。加入製備實施例
18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(73mg,0.182mmol)並在室溫下攪拌3小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化所得的濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(86mg,0.150mmol,82%)。
1H NMR(500MHz,CDCl3)δ 8.13-8.09(m,3H),7.94(dd,J=8.5,1.5Hz,1H),7.67(t,J=8.0Hz,1H),7.58(d,J=8.5Hz,1H),7.50-7.46(m,3H),7.36(d,J=7.5Hz,1H),7.15-7.05(m,2H),6.76(d,J=8.5Hz,1H),5.54(s,2H),5.28-5.25(m,1H),4.69-4.65(m,1H),4.52-4.43(m,3H),3.94(s,3H),2.84-2.81(m,1H),2.63-2.59(m,1H)
[製備實施例22:4-硝基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯的製備]
4-硝基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(904mg,4.54mmol)溶解在THF(15mL)中,加入噁唑-5-基甲胺鹽酸鹽(600mg,4.33mmol)和TEA(1.81mL,12.98mmol),然後在室溫下在氮氣下攪拌16小時。反應完成後,將反應溶劑減壓濃縮。添加水,用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-硝基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(682mg,2.46mmol,57%)。
1H NMR(400MHz,CDCl3)δ 8.25-8.23(m,2H),7.87(s,1H),7.64(d,J=1.2Hz,1H),7.33(dd,J=2.0,1.2Hz,1H),7.09(s,1H),4.66(d,J=5.6Hz,2H),3.94(s,3H)
[製備實施例23:4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯的製備]
4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯
將製備實施例22中獲得的4-硝基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(682mg,2.46mmol)溶於THF(12mL)和10%Pd/C(262mg),然後在室溫下在氫氣下攪拌24小時。反應完成後,將所得反應產物用EtOAc藉由矽藻土過濾,並在減壓下濃縮,從而獲得4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(600mg,2.43mmol,99%)。
1H NMR(500MHz,CDCl3)δ 7.86(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.43(d,J=2.0Hz,1H),7.04(s,1H),6.72(d,J=8.0Hz,1H),4.41(d,J=5.5Hz,2H),3.86(s,3H),3.83(s,2H),3.46(s,1H);LC-MS(ESI):248.25[M+H]+
[製備實施例24:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(40mg,0.108mmol)溶解於DMF(1mL)中,加入製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(30mg,0.118mmol)、HATU(82mg,0.215mmol)和TEA(0.08mL,0.538mmol)。將所得反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化得到的濃度,從而獲得4-(2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯。將4-(2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯溶於AcOH(1.5mL,26.6mmol)中無需進一步純化,並在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮。添加水,用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(49mg,0.084mmol,63%)。
1H NMR(500MHz,CDCl3)δ 8.13(s,1H),8.02(dd,J=8.5,1.5Hz,1H),7.81(d,J=8.5Hz,1H),7.77(s,1H),7.56-7.53(m,4H),7.43(t,J=7.5Hz,2H),7.36-7.31(m,4H),6.84(s,1H),5.28(s,2H),4.48(s,2H),3.95(s,5H)
[製備實施例25:2-(芐硫基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(芐硫基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(300mg,1.213mmol)溶解在THF(12mL)中,並加入TCDI(360mg,1.820mmol)。然後在室溫下在氮氣下攪拌24小時。添加水,用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC進行所得濃縮,從而獲得2-巰基-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(350mg,1.210mmol,100%)。將2-巰基-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯溶解在THF(7mL)中,無需進一步純化,加入NaH(60%的礦物油分散液,97mg,2.420mmol),然後在室溫下在氮氣下攪拌15分鐘。緩慢滴加BnBr(0.187mL,1.573mmol),然後在室溫下攪拌4小時。反應完成後,加入水,用EtOAc萃取,並用MgSO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(芐硫基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(450mg,1.186mmol,98%)。
1H NMR(500MHz,CDCl3)δ 8.09(d,J=9.5Hz,1H),7.99(dd,J=8.5,1.5Hz,1H),7.79(s,1H),7.71(d,J=8.5Hz,1H),7.42(d,J=6.5Hz,2H),7.34-7.29(m,3H),7.05(s,1H),5.30(s,2H),4.66(s,2H),3.95(s,3H)
[製備實施例26:2-(芐基磺醯基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(芐基磺醯基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將mCPBA(877mg,3.56mmol)溶於DCM(5mL),然後將製備實施例25獲得的2-(芐硫基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(450mg,1.186mmol)溶解於DCM(5mL)中,並在0℃下緩慢滴加,然後在室溫下在氮氣下攪拌4小時。反應完成後,加水,並將所得溶液用NaHCO3中和至pH約7。所得產物用EtOAc萃取,用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(芐基磺醯基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(285mg,0.693mmol,58%)。
1H NMR(500MHz,CDCl3)δ 8.30(s,1H),8.13(d,J=8.5Hz,1H),7.96(d,J=8.5Hz,1H),7.73(s,1H),7.35(t,J=6.8Hz,1H),7.28-7.25(m,2H),7.20(d,J=7.0Hz,2H),7.05(s,1H),5.41(s,2H),4.84(s,2H),3.99(s,3H);LC-MS(ESI):412.28[M+H]+
[製備實施例27:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例14中獲得的3-氟-4-(((6-(4-羥基苯基)吡啶-2-基-氧基)甲基)甲基)芐腈(70mg,0.219mmol)溶解在DMF(2mL)中,並且加入t-BuOK(37mg,0.328mmol),然後在室溫下在氮氣下攪拌15分鐘。加入製備實施例26中獲得的2-(芐基磺醯基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(90mg,0.219mmol),然後攪拌3小時在室溫下。反應完成後,加入水,並將所得產物用EtOAc萃取,用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(64mg,0.111mmol,51%)。
1H NMR(500MHz,CDCl3)δ 8.09-8.05(m,3H),7.96(dd,J=8.5,1.5Hz,1H),7.87(s,1H),7.72-7.67(m,2H),7.58(d,J=8.0Hz,1H),7.47(d,J=9.0Hz,3H),7.41-7.38(m,2H),7.20(s,1H),6.81(d,J=8.0Hz,1H),5.64(s,2H),5.45(s,2H),3.96(s,3H)
[製備實施例28:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(908mg,3.34mmol)和Pd(dppf)Cl2-DCM(273mg,0.334mmol),Cs2CO3(2718mg,8.34mmol)和(4-(2-乙氧基-2-氧乙基)-3-氟苯基)硼酸(830mg,3.67mmol)溶於13mL THF/H2O(9/1)中,進行氮取代。將反應
物在85℃下攪拌5小時。反應完成後,加入水,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,並在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸乙酯。無需進一步純化,將中間體溶解在10mL的THF/H2O(1/1)中,並加入NaOH(210mg,5.24mmol)。將反應物在室溫攪拌24小時。反應完成後,使用1N HCl將所得溶液的pH調整至約2,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸(650mg,1.668mmol,95%)。
1H NMR(400MHz,CDCl3)δ 7.75-7.74(m,2H),7.65(t,J=8.4Hz,1H),7.46(t,J=8.0Hz,1H),7.34-7.32(m,2H),7.13(d,J=8.8Hz,2H),6.76(d,J=8.0Hz,1H),5.51(s,2H),3.77(s,2H);LC-MS(ESI):390.26[M+H]+
[製備實施例29:(S)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
(S)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1.39g,7.0mmol)溶解在DMF(2.5mL)中,並在室溫下加入(S)-(四氫呋喃-2-基)甲胺(0.868mL)和K2CO3(967mg)。將反應物在50℃下攪拌4小時。添加水,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並且藉由MPLC純化,從而
獲得(S)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.69g,6.86mmol,86%)。
1H NMR(400MHz,CDCl3)δ 8.26-8.12(m,2H),7.59(d,J=1.8Hz,1H),7.24(dd,J=9.1,1.8Hz,1H),4.22(qd,J=6.9,4.1Hz,1H),4.02-3.91(m,4H),3.87-3.77(m,1H),3.53(td,J=8.7,4.3Hz,1H),3.46-3.34(m,1H),2.18-2.04(m,1H),2.05-1.90(m,2H),1.82-1.61(m,1H);LC-MS(ESI):281.28[M+H]+
[製備實施例30:(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將製備實施例29中獲得的(S)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.69g,6.86mmol)溶於THF(50mL),加入10% Pd/C(169mg),然後在室溫下在氫氣下攪拌17.5小時。反應完成後,將Pd/C藉由矽藻土過濾,然後減壓濃縮,從而獲得(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.68g,6.72mmol,98%)。
1H NMR(500MHz,CDCl3)δ 7.46(dd,J=8.1,1.7Hz,1H),7.34(d,J=1.5Hz,1H),6.67(d,J=7.9Hz,1H),4.20(qd,J=7.3,3.2Hz,1H),3.96-3.76(m,5H),3.53(brs,1H),3.26(dd,J=11.9,3.1Hz,1H),3.15-3.03(m,1H),2.14-2.04(m,1H),2.00-1.90(m,2H),1.77-1.63(m,1H);LC-MS(ESI):251.29[M+H]+
[製備實施例31:(R)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
(R)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1.39g,7.0mmol)溶解在DMF(2.5mL)中,並在室溫下加入(R)-(四氫呋喃-2-基)甲胺(0.868mL)和K2CO3(967mg)。將反應物在50℃下攪拌4小時。添加水,然後使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得(R)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.82g,6.47mmol,92%)。
1H NMR(400MHz,CDCl3)δ 8.30-8.14(m,2H),7.58(d,J=1.8Hz,1H),7.24(dd,J=8.9,1.6Hz,1H),4.22(qd,J=6.9,4.1Hz,1H),4.06-3.90(m,4H),3.88-3.78(m,1H),3.53(dt,J=12.8,4.7Hz,1H),3.46-3.30(m,1H),2.17-2.04(m,1H),2.05-1.85(m,2H),1.78-1.61(m,1H);LC-MS(ESI):281.28[M+H]+
[製備實施例32:(R)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
(R)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯
將製備實施例31中獲得的(R)-4-硝基-3(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.82g,6.47mmol)溶於THF(50mL),加入10% Pd/C(182mg),然後在室溫下在氫氣下攪拌12小時。反應完成後,將Pd/C藉由矽藻土過濾,然後進行減壓濃縮,從而獲得(R)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(1.58g,6.34mmol,98%)。
1H NMR(500MHz,CDCl3)δ 7.48(dd,J=7.9,1.8Hz,1H),7.36(s,1H),6.69(d,J=7.9Hz,1H),4.27-4.18(m,1H),4.00-3.79(m,5H),3.56(brs,1H),3.27(dd,J=11.9,3.1Hz,1H),3.11(dd,J=11.9,8.2Hz,1H),2.16-2.06(m,1H),2.02-1.90(m,2H),1.79-1.66(m,1H);LC-MS(ESI):251.29[M+H]+
[製備實施例33:(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例32中獲得的(R)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(150mg,0.6mmol)和在製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(186mg,0.5mmol)溶解在2mL DMF中,且加入EDC(192mg,1.0mmol)和HOBt(135mg,1.0mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用EtOAc
進行萃取。有機層用Na2SO4乾燥,並在減壓下濃縮,從而獲得中間體(R)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化而溶於10mL乙酸中,然後在120℃下攪拌2小時。添加水,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(144mg,0.25mmol,49%)。
1H NMR(500MHz,CDCl3)δ 8.08(s,1H),7.98(d,J=8.5Hz,1H),7.93(d,J=8.0Hz,2H),7.75(d,J=8.5Hz,1H),7.64(t,J=7.5Hz,1H),7.46(t,J=8.1Hz,1H),7.35-7.28(m,3H),7.17-7.08(m,2H),6.73(d,J=8.2Hz,1H),5.54-5.43(m,2H),4.51(dd,J=38.1,15.9Hz,2H),4.25-4.17(m,1H),4.15-4.06(m,2H),3.94(s,3H),3.86(dd,J=15.1,6.9Hz,1H),3.75-3.69(m,1H),2.04-1.97(m,1H),1.92-1.80(m,2H),1.59-1.47(m,1H);LC-MS(ESI):586.33[M+H]+
[製備實施例34:4-硝基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
4-硝基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1.0g,5.0mmol)溶解在DMF(1.8mL)中,並在室溫下下加入(四氫-2H-吡喃-2-基)甲胺(0.868mL)和K2CO3
(693mg)。將反應物在50℃下攪拌4小時。添加水,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得4-硝基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯(1.37g,4.9mmol,98%)。
1H MR(500MHz,CDCl3)δ 8.29-8.15(m,2H),7.54(d,J=1.5Hz,1H),7.22(dd,J=8.8,1.8Hz,1H),4.07-4.04(m,1H),3.94(s,3H),3.68-3.58(m,1H),3.50(td,J=11.6,2.4Hz,1H),3.42(ddd,J=12.7,5.7,3.9Hz,1H),3.37-3.27(m,1H),2.00-1.84(m,1H),1.72-1.40(m,5H);LC-MS(ESI):295.31[M+H]+
[製備實施例35:4-胺基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯的製備]
4-胺基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯
將製備實施例34中獲得的4-硝基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯(1.45g,4.94mmol)溶解於MeOH(50mL)和DCM(30mL)中,加入10% Pd/C(145mg),然後在室溫下在氫氣下攪拌15小時。反應完成後,將Pd/C藉由矽藻土過濾,然後減壓濃縮,從而獲得4-胺基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯(1.28g,4.84mmol,98%)。
1H NMR(500MHz,CDCl3)δ 7.45(dd,J=8.1,1.7Hz,1H),7.33(d,J=1.8Hz,1H),6.67(d,J=8.2Hz,1H),4.09-3.97(m,1H),3.93-3.69(m,5H),3.62-3.55(m,1H),3.53-3.42(m,1H),3.19(dd,J=12.2,3.1Hz,1H),3.09(dd,J=12.2,8.2Hz,1H),1.91-1.80(m,1H),1.68-1.39(m,5H);LC-MS(ESI):265.32[M+H]+
[製備實施例36:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例35中獲得的4-胺基-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯(158mg,0.6mmol)和製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(186mg,0.5mmol)溶解在2mL DMF中,加入EDC(192mg,1.0mmol)和HOBt(135mg,1.0mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並用EtOAc進行萃取。有機層用Na2SO4乾燥並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫-2H-吡喃-2-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化而溶於10mL乙酸中,並在120℃下攪拌2小時。添加水,並使用EtOAc進行萃取有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐
基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(156mg,0.26mmol,52%)。
1H NMR(500MHz,CDCl3)δ 8.05(s,1H),8.00-7.91(m,3H),7.75(d,J=8.5Hz,1H),7.63(t,J=7.5Hz,1H),7.46(t,J=8.0Hz,1H),7.35-7.29(m,3H),7.15-7.06(m,2H),6.72(d,J=8.2Hz,1H),5.58-5.42(m,2H),4.49(s,2H),4.09(d,J=9.2Hz,1H),4.06-4.00(m,1H),3.94(s,3H),3.93-3.86(m,1H),3.55-3.44(m,1H),3.25-3.16(m,1H),1.84(d,J=11.9Hz,1H),1.66-1.29(5H);LC-MS(ESI):600.36[M+H]+
[製備實施例37:4-(6-((4-氯-2-氟-2-氟芐基)氧基)吡啶-2-基)-3-氟苯酚的製備]
4-(6-((4-氯-2-氟-2-氟芐基)氧基)吡啶-2-基)-3-氟苯酚
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(2.00g,7.35mmol)、Pd(dppf)Cl2-DCM(600mg,0.735mmol)、Cs2CO3(5.99g,18.38mmol)和3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯酚(1.84g,7.72mmol)溶於22mL THF/H2O(9/1),並進行氮取代。將反應物在85℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得4-(6-((4-氯-2-氟-2-氟芐基)氧基)吡啶-2-基)-3-氟苯酚(2.12g,6.10mmol,83%)。
1H NMR(500MHz,MeOD)δ 7.89(t,J=9.0Hz,1H),7.69(q,J=7.7Hz,1H),7.55(t,J=8.1Hz,1H),7.39(dd,J=7.6,1.5Hz,1H),7.21-7.28(m,2H),6.70-6.74(m,2H),6.60(td,J=6.8,2.2Hz,1H),5.50(d,J=5.2Hz,2H)
[製備實施例38:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸甲酯的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸甲酯
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(673mg,2.47mmol)、Pd(dppf)Cl2-DCM(202mg,0.247mmol)、Cs2CO3(2.01g,6.18mmol)和2-(3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯(800mg,2.72mmol)溶於8mL THF/H2O(9/1),並進行氮取代。將反應物在85℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。將所得濃縮物藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸甲酯(720mg,1.78mmol,72%)。
1H NMR(500MHz,MeOD)δ 7.99(t,J=8.1Hz,1H),7.76(t,J=7.9Hz,1H),7.47-7.57(m,2H),7.16-7.27(m,4H),6.83(d,J=8.2Hz,1H),5.52(s,2H),3.74(d,J=8.5Hz,5H)
[製備實施例39:2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚的製備]
2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(1.20g,4.41mmol)、Pd(dppf)Cl2-DCM(360mg,0.441mmol)、Cs2CO3(3.59g,11.03mmol)和(3-氯-4-羥基苯基)硼酸(798mg,4.63mmol)溶於18mL THF/H2O(9/1),並進行氮取代。將反應物在85℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(250mg,0.686mmol,16%)。
1H NMR(500MHz,CDCl3)δ 8.04(dd,J=6.4,2.1Hz,1H),7.85(dd,J=8.5,2.1Hz,1H),7.63-7.67(m,1H),7.43-7.58(m,2H),7.16-7.22(m,2H),7.11(d,J=8.5Hz,1H),6.72(dd,J=14.2,8.1Hz,1H),5.54-5.58(m,2H)
[製備實施例40:4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯酚的製備]
4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯酚
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(1.00g,3.68mmol)、Pd(dppf)Cl2-DCM(300mg,0.368mmol)、Cs2CO3
(2.99g,9.19mmol)和(3-氟-4-羥基苯基)硼酸(602mg,3.86mmol)溶於14mL THF/H2O(9/1),並進行氮取代。將反應物在85℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,並使用EtOAc藉由矽藻土過濾,隨後在減壓下濃縮。進行MPLC,從而獲得4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯酚(190mg,0.546mmol,15%)。
1H NMR(500MHz,MeOD)δ 7.79(dd,J=13.0,2.0Hz,1H),7.71(t,J=7.8Hz,1H),7.54-7.57(m,1H),7.37-7.42(m,2H),7.22-7.30(m,2H),6.97-7.01(m,1H),6.73(d,J=8.2Hz,1H),5.55(d,J=10.4Hz,2H)
[製備實施例41:2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸甲酯的製備]
2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸甲酯
將2-氯-6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶(1.78g,5.82mmol)、Pd(dppf)Cl2-DCM(476mg,0.582mmol)、Cs2CO3(4.74g,14.56mmol)和2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯(1.77g,6.41mmol)溶於15mL THF/H2O(9/1),並進行氮取代。將反應物在85℃下攪拌24小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。將得到的濃縮物藉由MPLC純化,從而獲得2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸甲酯(1.71g,4.07mmol,70%)。
1H NMR(400MHz,CDCl3)δ 7.94(dd,J=6.4,1.8Hz,2H),7.73-7.59(m,2H),7.46-7.31(m,5H),6.76(d,J=8.2Hz,1H),5.68-5.53(2H),3.70(s,3H),3.67(d,J=2.7Hz,2H)
[製備實施例42:4-硝基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯的製備]
4-硝基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(934mg,4.69mmol)溶於THF(10mL)/MeOH(6.67mL),加入(4-丙基-4H-1,2,4-三唑-3-基)甲胺二鹽酸鹽(696mg,4.69mmol)和TEA(3.27mL,23.46mmol),然後在室溫下在氮氣下攪拌24小時。反應完成後,將所得反應產物冷卻至室溫,然後在減壓下濃縮反應溶劑。添加水,使用EtOAc進行萃取,並且用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-硝基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(918mg,2.87mmol,61%)。
1H NMR(500MHz,MeOD)δ 8.54(s,1H),8.27(d,J=8.8Hz,1H),7.76(d,J=1.5Hz,1H),7.34(dd,J=8.5,1.5Hz,1H),4.91(d,J=3.4Hz,2H),4.15(t,J=7.5Hz,2H),3.93(s,3H),1.81-1.91(m,2H),0.98(t,J=7.3Hz,3H)
[製備實施例43:4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯的製備]
4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯
將製備實施例42中獲得的4-硝基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(918mg,2.87mmol)溶解在THF中(10mL),並加入10% Pd/C(922mg),然後在室溫在氫氣下攪拌24小時。反應完成後,將所得反應產物用EtOAc藉由矽藻土過濾,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(500mg,1.73mmol,60%)。
1H NMR(500MHz,MeOD)δ 8.55(d,J=25.0Hz,1H),7.39(dd,J=8.1,1.7Hz,1H),7.32-7.35(m,1H),6.70(d,J=8.2Hz,1H),4.62(d,J=18.3Hz,2H),4.12(t,J=7.5Hz,2H),3.80-3.88(m,3H),1.82-1.91(m,2H),0.92-1.02(m,3H)
[製備實施例44:2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例4中獲得的4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(322mg,1.213mmol)溶於THF(6.4mL),加入TCDI(344mg,1.930mmol),然後在室溫下在氮氣下攪拌4.5小時。添加水,用EtOAc萃取,並用Na2SO4乾燥,隨後在減壓下濃縮。藉由MPLC進行所得濃縮,從而獲得2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(321mg,1.098mmol,85%)。
1H NMR(500MHz,CDCl3)δ 11.34(brs,1H),8.04(s,1H),7.93(d,J=8.5Hz,1H),7.24(d,J=8.2Hz,1H),4.54(dd,J=14.3,3.7Hz,1H),4.38-4.48(m,1H),4.22-4.33(m,1H),3.94(s,3H),3.89(dd,J=14.8,6.6Hz,1H),3.72-3.76(m,1H),2.06-2.16(m,1H),1.89-1.95(m,2H),1.80-1.88(m,1H)
[製備實施例45:2-(芐硫基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(芐硫基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例44中獲得的2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(320mg,1.095mmol)溶解於THF(6.8mL)中,並在0℃下添加NaH(在礦物油中的60%分散液,88mg,2.189mmol),然後攪拌10分鐘。在室溫下在氮氣下10分鐘。緩慢逐滴加入BnBr(0.169mL,1.423mmol),並在室溫下攪拌4小時。反應完成後,加入水,用EtOAc萃取,並用Na2SO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,
從而獲得2-(芐硫基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(389mg,1.023mmol,93%)。
1H NMR(400MHz,CDCl3)δ 8.08(d,J=1.4Hz,1H),7.96(dd,J=8.2,1.4Hz,1H),7.69(d,J=8.7Hz,1H),7.27-7.44(m,5H),4.66(s,2H),4.22-4.29(m,1H),4.10-4.19(m,2H),3.94(s,3H),3.82-3.87(m,1H),3.69-3.75(m,1H),1.99(dt,J=18.9,6.7Hz,1H),1.81-1.88(m,2H),1.59-1.67(m,1H)
[製備實施例46:2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例45中獲得的2-(芐硫基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(410mg,1.072mmol)溶解在CH2Cl2中,並在0℃下加入m-CPBA(555mg,3.22mmol),然後在室溫下在氮氣中攪拌2小時。反應完成後,藉由添加NaHCO3(水溶液)將所得反應產物中和至pH 7。用CH2Cl2萃取,並用Na2SO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(322mg,0.777mmol,72.5%)。
1H NMR(500MHz,CDCl3)δ 8.26(s,1H),8.08(dd,J=8.5,1.5Hz,1H),7.92(d,J=8.5Hz,1H),7.23-7.35(m,5H),4.87(dd,J=19.8,14.0
Hz,2H),4.27-4.38(m,2H),4.06(qd,J=7.3,3.4Hz,1H),3.97(s,3H),3.84(q,J=7.3Hz,1H),3.66(dd,J=14.2,7.8Hz,1H),1.97-2.02(m,1H),1.80-1.90(m,2H),1.50-1.58(m,1H)
[製備實施例47:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例20中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(66mg,0.2mmol)溶解在DMF(2.94mL)中,並加入t-BuOK(33.7mg,0.3mmol),然後在室溫下在氮氣下攪拌10分鐘。加入製備實施例46中獲得的2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(82.9mg,0.20mmol),然後在室溫下攪拌2小時。反應完成後,加入水,所得溶液用EtOAc萃取,用Na2SO4乾燥,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(94.4mg,0.161mmol,80%)。
1H NMR(500MHz,CDCl3)δ 8.07-8.10(m,3H),7.92(dd,J=8.2,1.5Hz,1H),7.67(t,J=7.8Hz,1H),7.56(d,J=8.2Hz,1H),7.46-7.50(m,3H),7.36(d,J=7.6Hz,1H),7.12-7.15(m,2H),6.76(d,J=8.2
Hz,1H),5.54(s,2H),4.37-4.42(m,1H),4.28(d,J=5.8Hz,2H),3.95(s,3H),3.89(dd,J=15.1,6.9Hz,1H),3.79(dd,J=15.1,6.9Hz,1H),2.11(dt,J=19.2,6.9Hz,1H),1.90-1.96(m,2H),1.74-1.81(m,1H)
[製備實施例48:(S)-2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例30中獲得的(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(677mg,2.70mmol)溶於THF(6.1mL),並加入TCDI(723mg,4.06mmol),然後在室溫下在氮氣下攪拌4小時。添加水,用EtOAc萃取,並用Na2SO4乾燥,隨後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(648mg,2.216mmol,82%)。
1H NMR(400MHz,CDCl3)δ 10.14(brs,1H),8.03(d,J=1.4Hz,1H),7.94(dd,J=8.5,1.6Hz,1H),7.21(d,J=8.2Hz,1H),4.55(dd,J=14.2,3.7Hz,1H),4.44(qd,J=7.0,3.7Hz,1H),4.21-4.32(m,1H),3.95(s,3H),3.87-3.92(m,1H),3.71-3.77(m,1H),2.08-2.15(m,1H),1.78-1.96(m,3H)
[製備實施例49:(S)-2-(芐硫基)-1-(((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(芐硫基)-1-(((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例48中獲得的(S)-2-巰基-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(458mg,2.2mmol)溶解於THF(10.0mL)中,並在0℃下添加NaH(在礦物油中的60%分散液,176mg,4.4mmol),然後攪拌2小時。在室溫下在氮氣下10分鐘緩慢逐滴添加BnBr(0.340mL,2.86mmol),並在室溫下攪拌12小時。反應完成後,加入水,用EtOAc萃取,並用Na2SO4乾燥,然後減壓濃縮。藉由MPLC純化所得的濃縮物,從而獲得(S)-2-(芐硫基)-1-(((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(590.8mg,1.98mmol,90%)。
1H NMR(500MHz,CDCl3)δ 8.07(d,J=0.6Hz,1H),7.95(dd,J=8.4,1.1Hz,1H),7.68(d,J=8.2Hz,1H),7.27-7.43(m,5H),4.65(s,2H),4.23-4.28(m,1H),4.13-4.16(m,2H),3.94(s,3H),3.85(q,J=7.3Hz,1H),3.70-3.76(m,1H),1.98(dt,J=19.3,6.8Hz,1H),1.82-1.87(m,2H),1.59-1.66(m,1H)
[製備實施例50:(S)-2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例49中獲得的(S)-2-(芐硫基)-1-(((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(590mg,1.98mmol)溶於CH2Cl2中,並在0℃下添加m-CPBA(1023mg,5.93mmol),然後在室溫下在氮氣中攪拌5小時。反應完成後,藉由添加NaHCO3(水溶液)將所得反應產物中和至pH 7。用CH2Cl2萃取,並用Na2SO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(458mg,1.386mmol,70%)。
1H NMR(500MHz,CDCl3)δ 8.26(s,1H),8.08(d,J=7.6Hz,1H),7.92(d,J=8.5Hz,1H),7.23-7.36(m,5H),4.87(dd,J=20.1,14.0Hz,2H),4.27-4.37(m,2H),4.06(qd,J=7.3,3.4Hz,1H),3.97(s,3H),3.84(dd,J=15.0,6.7Hz,1H),3.66(dd,J=14.3,7.6Hz,1H),1.97-2.05(m,1H),1.82-1.92(m,2H),1.50-1.59(m,1H)
[製備實施例51:(R)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯的製備]
(R)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1315mg,6.60mmol)溶於DMF(5mL),在室溫下加入(R)-(四氫呋喃-3-基)甲胺鹽酸鹽(1000mg,7.267mmol)和K2CO3(1004mg,7.267mmol)。將反應物在室溫攪拌4小時。添
加水,並用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(R)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(1.0g,3.57mmol,54%)。
1H NMR(500MHz,CDCl3)δ 8.20(d,J=8.8Hz,1H),8.00(s,1H),7.54(s,1H),7.24(dd,J=8.8,1.5Hz,1H),3.88-3.98(m,5H),3.79(q,J=7.8Hz,1H),3.71-3.61(m,1H),3.32-3.41(m,2H),2.64-2.69(m,1H),2.14-2.21(m,1H),1.70-1.79(m,1H)
[製備實施例52:(R)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯的製備]
(R)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯
將製備實施例51中獲得的(R)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(1.0g,3.57mmol)溶解在10mL THF中,並加入10% Pd/C(100mg),然後在室溫下在氫氣下攪拌15小時。反應完成後,藉由矽藻土過濾Pd/C,然後減壓濃縮,從而獲得(R)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(879mg,3.51mmol,98%)。
1H NMR(500MHz,CDCl3)δ 7.60(d,J=7.9Hz,1H),7.48(s,1H),6.82(d,J=7.9Hz,1H),4.02-4.11(m,2H),3.99(s,3H),3.84-3.97(m,3H),3.79(dd,J=8.5,5.5Hz,1H),3.27-3.34(m,3H),2.69-2.75(m,1H),2.24-2.30(m,1H),1.87(dt,J=19.4,6.9Hz,1H)
[製備實施例53:2-(4-溴-3-氯苯基)乙酸甲酯的製備]
2-(4-溴-3-氯苯基)乙酸甲酯
將2-(4-溴-3-氯苯基)乙酸(5g,20.04mmol)溶解在MeOH(100mL)中,並添加硫酸(1mL),然後回流24小時。在0℃下添加NaHCO3(水溶液)以將所得產物中和至pH 7,然後在減壓下濃縮。用CH2Cl2萃取有機材料,並用Na2SO4乾燥有機層,在減壓下濃縮並藉由MPLC純化,從而獲得2-(4-溴-3-氯苯基)乙酸甲酯(4418mg,16.77mmol,84%)。
1H NMR(500MHz,CDCl3)δ 7.56(d,J=8.2Hz,1H),7.39(d,J=1.8Hz,1H),7.04(dd,J=8.1,1.7Hz,1H),3.71(s,3H),3.57(s,2H)
[製備實施例54:2-(3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯的製備]
2-(3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯
將製備實施例53中獲得的2-(4-溴-3-氯苯基)乙酸甲酯(2108mg,8mmol)溶於DMSO(47mL),加入4,4,4',4',5,5,5',5'-八甲基-2,2'-聯(1,3,2-二氧雜硼烷)(2437mg,9.6mmol)和KOAc(2198mg,22.4mmol),然後氮置換3次。加入Pd(dppf)Cl2-DCM(653mg,0.8mmol),並再次進行氮置換,然後在85℃下攪拌21小時。反應完成後,將得到的反應產物冷卻至室溫,並使用EtOAc藉由矽藻土過濾。添加水,並用EtOAc進行萃取。將萃取物用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而
獲得2-(3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯(1630mg,5.25mmol,65.6%)。
1H NMR(400MHz,CDCl3)δ 7.64(d,J=7.8Hz,1H),7.27(s,1H),7.14(d,J=7.8Hz,1H),3.67(s,3H),3.58(s,2H),1.35(brs,12H)
[製備實施例55:2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸甲酯的製備]
2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸甲酯
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(1.19g,4.376mmol)溶解在THF/H2O(38.7mL/4.3mL)中,加入製備實施例54中獲得的2-(3-氯-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)苯基)乙酸甲酯(1.63g,5.25mmol)和Cs2CO3(3.99g,12.25mmol),然後進行3次氮置換。加入Pd(dppf)Cl2-DCM(357mg,0.4376mmol),並再次進行氮置換,然後在85℃下攪拌21小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。所得濃縮物藉由MPLC純化,從而獲得2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸甲酯(1198mg,2.85mmol,65.2%)。
1H NMR(400MHz,CDCl3)δ 7.65(t,J=8.0Hz,1H),7.54(d,J=8.2Hz,1H),7.45(t,J=8.2Hz,1H),7.40(d,J=1.4Hz,1H),7.23-7.27(m,2H),7.09-7.13(m,2H),6.78(d,J=8.2Hz,1H),5.44(s,2H),3.72(s,3H),3.65(s,2H)
[製備實施例56:2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸的製備]
2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸
將製備例55中獲得的2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸甲酯(1198mg,2.85mmol)溶解於10mL MeOH,加入10mL 1N NaOH。將反應物在40℃下攪拌15小時。反應完成後,使用1N HCl將pH調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(1024mg,2.52mmol,88%)。
1H NMR(500MHz,CDCl3)δ 7.66(t,J=7.8Hz,1H),7.56(d,J=7.9Hz,1H),7.43-7.47(m,2H),7.26-7.31(m,2H),7.10-7.14(m,2H),6.79(d,J=8.2Hz,1H),5.45(s,2H),3.70(s,2H)
[製備實施例57:(S)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯的製備]
(S)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯
將3-氟-4-硝基苯甲酸甲酯(1g,5.02mmol)溶於DMF(2mL),在室溫下加入(S)-(四氫呋喃-3-基)甲胺鹽酸鹽(760mg,5.522mmol)
和K2CO3(762mg,5.52mmol)。將反應物在室溫攪拌19小時。添加水,並使用EtOAc進行萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(1.198g,4.27mmol,85%)。
1H NMR(500MHz,CDCl3)δ 8.20(d,J=8.8Hz,1H),8.05(br s,1H),7.54(s,1H),7.24(dd,J=8.8,1.5Hz,1H),3.89-3.98(m,5H),3.79(q,J=7.8Hz,1H),3.59-3.73(m,1H),3.32-3.41(m,2H),2.65-2.70(m,1H),2.15-2.22(m,1H),1.74(td,J=12.8,7.3Hz,1H)
[製備實施例58:(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯的製備]
(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯
將製備實施例57中獲得的(S)-4-硝基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(1204mg,4.295mmol)溶解在42mL THF,加入10% Pd/C(120mg),然後在室溫在氫氣下攪拌17小時。反應完成後,將Pd/C藉由矽藻土過濾,然後減壓濃縮,從而獲得(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯。(1053mg,4.209mmol,98%)。
1H NMR(500MHz,CDCl3)δ 7.46(dd,J=7.9,1.5Hz,1H),7.35(d,J=1.5Hz,1H),6.69(d,J=8.2Hz,1H),3.90-3.94(m,2H),3.86(s,3H),3.71-3.81(m,3H),3.66(dd,J=8.5,5.5Hz,1H),3.13-3.20(m,
3H),2.56-2.61(m,1H),2.10-2.17(m,1H),1.74(td,J=13.0,7.1Hz,1H)
[製備實施例59:4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯酚的製備]
4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯酚
將製備實施例1中獲得的2-氯-6-((4-氯-2-氟芐基)氧基)吡啶(680mg,2.5mmol)溶解在THF/H2O(15.8mL/9.1mL)中,加入(3,5-二氟-4-羥基苯基)硼酸(608.7mg,3.5mmol)和Cs2CO3(2280mg,7mmol),然後進行三次氮取代。加入Pd(dppf)Cl2-DCM(204mg,0.25mmol),再次進行氮置換,然後在85℃下攪拌21小時。反應完成後,將得到的反應產物冷卻至室溫,使用EtOAc藉由矽藻土過濾,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯酚(586.3mg,1.603mmol,64.1%)。
1H NMR(500MHz,CDCl3)δ 7.57-7.65(m,3H),7.46(t,J=7.9Hz,1H),7.24(d,J=7.3Hz,1H),7.14(d,J=8.5Hz,2H),6.73(d,J=8.2Hz,1H),5.50(s,2H)
[製備實施例60:(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯的製備]
(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯
將製備實施例7中獲得的(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(97mg,0.411mmol)溶解在DMF(3mL)中,加入2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(139mg,0.374mmol)、EDC(143mg,0.748mmol)和HOBt(28.6mg,0.187mmol)。將所得混合物在氮氣下於室溫攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(100mg,0.169mmol,45%)。
1H NMR(500MHz,CDCl3)δ 8.08(d,J=8.0Hz,2H),7.80(d,J=8.5Hz,1H),7.68(t,J=7.5Hz,1H),7.57-7.55(m,2H),7.47(t,J=7.3Hz,3H),7.40(d,J=7.0Hz,1H),7.15-7.13(m,2H),6.77(d,J=8.0Hz,1H),5.55(s,2H),4.87-4.85(m,1H),4.59-4.57(m,1H),4.45-4.43(m,1H),3.88-3.85(m,5H),3.58(br s,1H),3.28-3.25(m,1H),3.17-3.14(m,1H),2.59-2.55(m,1H),2.40-2.36(m,1H)
[製備實施例61:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例60中獲得的(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯溶解在AcOH(2mL,34.9mmol)中,並在120℃下攪拌3小時。反應完成後,將得到的反應產物在減壓下濃縮。添加水,使用EtOAc進行萃取,並且用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(89mg,0.156mmol,92%)。
1H NMR(500MHz,CDCl3)δ 8.07(d,J=1.0Hz,1H),8.00-7.96(m,3H),7.79(d,J=8.5Hz,1H),7.64(t,J=7.8Hz,1H),7.43-7.49(m,1H),7.36-7.33(m,3H),6.73-6.74(m,2H),6.73(d,J=8.0Hz,1H),5.52(s,2H),5.09-5.07(m,1H),4.62-4.50(m,3H),4.40-4.35(m,2H),4.33-4.27(m,1H),3.94(s,3H),2.66-2.64(m,1H),2.36-2.32(m,1H)
[製備實施例62:(S)-4-(2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯的製備]
(S)-4-(2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯
將製備實施例9中獲得的2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸乙酯(60mg,0.154mmol)溶解於EtOH/H2O(1mL/1mL),加入NaOH(18mg,0.461mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液中和至pH約2。使用EtOAc進行萃取,使用MgSO4進行乾燥,並且在減壓下進行濃縮,從而獲得未經純化的2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(55mg,100%,0.154mmol)。
將(s)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(88mg,0.373mmol)溶於DMF(2mL),加入2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(123mg,0.339mmol)、EDC(195mg,1.018mmol)和HOBt(26mg,0.170mmol)。將所得混合物在氮氣下於室溫攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮。藉由MPLC純化所得的濃縮物,從而獲得(S)-4-(2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(100mg,0.172mmol,51%)。
1H NMR(500MHz,CDCl3)δ 8.02(m,2H),7.58-7.55(m,5H),7.47-7.38(m,5H),6.81(d,J=8.0Hz,1H),5.64(s,2H),4.89-4.88(m,1H),
4.62-4.59(m,1H),4.47-4.44(m,1H),3.88-3.84(m,5H),3.28-3.27(m,1H),3.19-3.16(m,1H),2.63-2.56(m,1H),2.44-2.37(m,1H)
[製備實施例63:(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的製備]
(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯
將製備實施例62中獲得的(S)-4-(2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(100mg,0.172mmol)溶解於AcOH(2mL,34.9mmol)中,並在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮。添加水,使用EtOAc進行萃取,並且用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(34mg,0.060mmol,35%)。
1H NMR(500MHz,CDCl3)δ 8.07(brs,1H),7.99(dd,J=8.5,1.5,1H),7.92(d,8.5Hz,2H),7.79(d,J=8.5Hz,1H),7.69-7.63(m,2H),7.44(d,J=7.5Hz,1H),7.41-7.30(m,4H),6.77(d,J=8.0Hz,1H),5.61(s,2H),5.11-5.02(m,1H),4.64-4.57(m,1H),4.56-4.47(m,2H),
4.41-4.30(m,2H),4.26(dd,J=15.5,3.0Hz,1H),3.96(s,3H),2.70-2.61(m,1H),2.41-2.28(m,1H)
[實施例1:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例5中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(62.5mg,0.107mmol)溶解在0.5mL MeOH中,並將0.5mL的1N NaOH加入到反應物中,然後在50℃下攪拌24小時。加入1N HCl以將pH調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(45.4mg,0.079mmol,74%)。
1H NMR(500MHz,MeOD)δ 8.25(s,1H),8.02(d,J=8.0Hz,2H),7.97(d,J=8.5Hz,1H),7.72(t,J=8.0Hz,1H),7.67(d,J=8.5Hz,1H),7.53(t,J=8.0Hz,1H),7.46(d,J=7.5Hz,1H),7.36(d,J=8.0Hz,2H),7.27-7.14(m,2H),6.76(d,J=8.5Hz,1H),5.52(s,2H),4.50(s,2H),4.41(dd,J=15.5,3.0Hz,1H),4.25(dd,J=15.5,8.5Hz,1H),4.15-
4.05(m,1H),3.90-3.80(m,1H),3.72-3.65(m,1H),2.09-2.00(m,1H),1.91-1.80(m,2H),1.66-1.57(m,1H);LC-MS(ESI):572.30[M+H]+
[實施例2:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例61中獲得的(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(89mg,0.156mmol)溶解在MeOH/H2O(2mL/1mL)中,並在50℃下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,使用MgSO4進行乾燥,並且在減壓下進行濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(30mg,0.054mmol,35%)。
1H NMR(500MHz,CDCl3)δ 8.17(s,1H),8.07(dd,J=8.5,1.5Hz,1H),8.00(d,J=8.0Hz,2H),7.86(d,J=8.5Hz,1H),7.66(t,J=8.0Hz,1H),7.48(t,J=8.0Hz,1H),7.37(m,3H),7.18-7.10(m,2H),6.76(d,J=8.0Hz,1H),5.54(s,2H),5.14-5.08(m,1H),4.67-4.54(m,3H),
4.43-4.36(m,2H),4.30(dd,J=16.0,3.0Hz,1H),2.71-2.64(m,1H),2.40-2.33(m,1H);LC-MS(ESI):558.27[M+H]+
[實施例3:(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例63中獲得的(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(34mg,0.060mmol)溶解在MeOH/H2O(1mL/1mL)中,並在50℃下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(4mg,0.007mmol,11%)。
1H NMR(500MHz,MeOD)δ 8.17(br s,1H),7.93-7.86(m,3H),7.63(t,J=8.0Hz,1H),7.59-7.51(m,4H),7.37(d,J=7.5Hz,1H),7.26(d,J=8.5Hz,2H),6.70(d,J=8.0Hz,1H),5.50(s,2H),4.95-4.89(m,1H),4.52-4.45(m,2H),4.43(s,2H),4.37-4.29(m,2H),2.61-2.53(m,1H),2.33-2.66(m,1H)
[實施例4:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例11中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(200mg,0.729mmol)和2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(220mg,0.608mmol)溶解於3mL DMF,加入EDC(232mg,1.215mmol)和HOBt(164mg,1.215mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((1-乙基-1H-咪唑-5-yl)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶於20mL乙酸中,並在120℃下攪拌2小時。添加水,並用EtOAc進行萃取。有機層用Na2SO4乾燥,並在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將該中間體不經另外純化即溶於0.5mL MeOH中,將0.5mL 1N NaOH加入反應物中,並在50℃下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,減壓濃縮並藉由MPLC純化,從而獲得2-(4-
(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸(10mg,0.017mmol,2.8%)。
1H NMR(500MHz,MeOD)δ 8.09(brs,1H),7.99(brs,1H),7.91(d,J=8.0Hz,2H),7.76-7.69(m,3H),7.64-7.58(m,2H),7.55(d,J=8.0Hz,1H),7.45(d,J=7.5Hz,1H),7.28(d,J=8.0Hz,2H),6.81(d,J=8.0Hz,1H),6.44(s,1H),5.62(s,2H),5.55(s,2H),3.85(q,J=7.5Hz,2H),1.17(t,J=7.5Hz,3H);LC-MS(ESI):587.37[M+H]+
[實施例5:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例15中獲得的2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(10mg,0.017mmol)溶解在MeOH/H2O(1mL/1mL)中,並在50℃下攪拌24小時。反應完成後,加水,並用1N-HCl酸化所得溶液至pH約2。使用EtOAc進行萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((1-乙基-1H-咪唑-5-基)甲基)-1H-苯并[d]咪唑-6-羧酸(5mg,0.008mmol,51%)。
1H NMR(400MHz,CDCl3)δ 8.75(s,1H),8.18-8.14(m,1H),7.97-7.91(m,4H),7.87-7.82(m,1H),7.70-7.64(m,1H),7.58-7.50(m,4H),7.38-7.35(m,1H),6.93-6.91(m,1H),6.71(d,J=8.4Hz,1H),5.59(s,2H),4.34(s,2H),4.26(q,J=7.6Hz,2H),1.52(t,J=7.0Hz,3H)
[實施例6:(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例19中獲得的(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(40mg,0.071mmol)溶解在MeOH/H2O(1mL/1mL)中,並加入NaOH(9mg,0.213mmol),然後在50℃下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(20mg,0.036mmol,52%)。
1H NMR(500MHz,MeOD)δ 8.24(s,1H),8.19(d,J=8.8Hz,2H),7.91-7.94(m,1H),7.80(t,J=7.8Hz,1H),7.66-7.71(m,3H),7.55(d,J
=7.6Hz,1H),7.48(dd,J=8.4,6.6Hz,3H),6.86(d,J=8.2Hz,1H),5.64(d,J=20.1Hz,2H),5.28-5.31(m,1H),4.60-4.70(m,2H),4.47-4.54(m,2H),2.86-2.91(m,1H),2.62-2.68(m,1H)
[實施例7:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例21中獲得的(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(86mg,0.150mmol)溶解在MeOH/H2O(1mL/1mL),並加入NaOH(18mg,0.449mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(62mg,0.111mmol,74%)。
1H NMR(500MHz,CDCl3)δ 8.23(s,1H),8.11-8.14(m,2H),8.01-8.03(m,1H),7.69(t,J=7.8Hz,1H),7.63(d,J=8.2Hz,1H),7.45-7.52(m,3H),7.34-7.39(m,1H),7.15-7.17(m,2H),6.79(d,J=8.2Hz,1H),5.53(d,J=34.5Hz,2H),5.29-5.33(m,1H),4.72(dd,J=14.2,7.8Hz,
1H),4.47-4.57(m,3H),2.83-2.91(m,1H),2.61-2.68(m,1H);LC-MS(ESI):560.26[M+H]+
[實施例8:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例24中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(49mg,0.084mmol)溶解在MeOH/H2O(1mL/1mL),並添加NaOH(10mg,0.252mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下進行濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(27mg,0.047mmol,57%)。
1H NMR(500MHz,MeOD)δ 8.50(s,1H),8.24(s,1H),8.03(s,1H),7.98(d,J=8.5Hz,1H),7.66(d,J=8.5Hz,1H),7.59-7.55(m,4H),7.41(t,J=7.8Hz,2H),7.32(d,J=7.5Hz,3H),6.88(s,1H),5.58(s,2H),4.52(s,2H);LC-MS(ESI):569.26[M+H]+
[實施例9:2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例27中獲得的2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(64mg,0.111mmol)溶解在MeOH/H2O(1mL/1mL)中,並加入NaOH(14mg,0.334mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氰基-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(27mg,0.048mmol,43%)。
1H NMR(500MHz,CDCl3)δ 8.14(s,1H),8.07(d,J=8.5Hz,2H),8.01(d,J=8.0Hz,1H),7.88(s,1H),7.72-7.66(m,2H),7.61(d,J=8.0Hz,1H),7.48-7.47(m,3H),7.41-7.38(m,2H),7.22(s,1H),6.81(d,J=8.5Hz,1H),5.64(s,2H),5.46(s,2H)
[實施例10:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例28中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸(150mg,0.385mmol)溶解在DMF(2.5mL)中,加入製備實施例7中獲得的(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(91mg,0.385mmol)、HATU(439mg,1.154mmol)和TEA(161ml,1.154mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體,(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙醯胺基)-3-((氧雜環丁烷-2-甲基(甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶於AcOH(4.4mL,77mmol)中,並在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮,添加水,然後將所得溶液用EtOAc萃取,用在減壓下濃縮的MgSO4乾燥,從而得到中間體,(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯甲基[d]咪唑-6-羧酸甲酯,無需另外純化,將中間體溶解在THF/H2O(1mL/1mL)中,並加入NaOH(34mg,0.859mmol),然後攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-
2-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(50mg,0.087mmol,30%)。
1H NMR(500MHz,MeOD)δ 8.29(s,1H),7.97(d,J=8.5Hz,1H),7.84-7.89(m,2H),7.76(t,J=7.8Hz,1H),7.65(d,J=8.5Hz,1H),7.48-7.57(m,2H),7.36(q,J=8.1Hz,1H),7.21-7.26(m,2H),6.82(d,J=8.2Hz,1H),5.49-5.57(m,2H),4.60(d,J=16.5Hz,1H),4.41-4.50(m,2H),4.29(dd,J=14.8,9.3Hz,1H),3.75-3.80(m,2H),1.85-1.89(m,1H),1.77(td,J=14.2,5.5Hz,1H);LC-MS(ESI):594.33[M+H+H2O]+
[實施例11:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例28中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸(150mg,0.385mmol)溶解在DMF(2.5mL)中,加入在製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(95mg,0.385mmol)、HATU(439mg,1.154mmol)和TEA(0.161ml,1.154mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體甲基4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)
乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶於AcOH(4.4mL,77mmol)中,並在120℃下攪拌3小時。反應後,將中間體減壓濃縮,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯,無需另外純化。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(17mg,0.424mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並使用1N-HCl將所得溶液酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(48mg,0.082mmol,58%)。
1H NMR(500MHz,MeOD)δ 8.32(s,1H),8.07(s,1H),7.98(dd,J=8.5,1.5Hz,1H),7.85-7.79(m,2H),7.74(t,J=8.0Hz,1H),7.66(d,J=8.0Hz,1H),7.55-7.48(m,3H),7.29-7.19(m,3H),7.07(s,1H),6.80(d,J=8.0Hz,1H),5.70(s,2H),5.47(s,2H),4.54(s,2H);LC-MS(ESI):587.27[M+H]+
[實施例12:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例30中獲得的(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(150mg,0.6mmol)和製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(186mg,0.5mmol)溶解於2mL DMF中,並加入EDC(192mg,1.0mmol)和HOBt(135mg,1.0mmol),然後在室溫下攪拌24小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,並在減壓下濃縮,從而獲得中間體(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。無需進一步純化即可將中間體溶於10mL乙酸中,然後在120℃下攪拌2小時。加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在1.5mL的MeOH中,並將1.5mL的1N NaOH添加至反應物,然後在50℃下攪拌24小時。加入1N HCl,並將所得溶液調整至pH 4,並用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(60.4mg,0.105mmol,21%)。
1H NMR(500MHz,CDCl3)δ 8.17(s,1H),8.10-8.05(m,1H),7.95(d,J=8.5Hz,2H),7.86(d,J=8.5Hz,1H),7.62(t,J=7.9Hz,1H),7.45(t,J=8.1Hz,1H),7.35(d,J=8.0Hz,2H),7.31(d,J=7.3Hz,1H),
7.15-7.08(m,2H),6.72(d,J=8.5Hz,1H),5.61-5.36(m,2H),4.57(dd,J=48.5,15.9Hz,2H),4.22(d,J=12.5Hz,1H),4.19-4.06(m,2H),3.87(dd,J=15.1,6.9Hz,1H),3.73(q,J=7.4Hz,1H),2.09-1.94(m,1H),1.92-1.76(m,2H),1.58-1.50(m,1H);LC-MS(ESI):572.30[M+H]+
[實施例13:(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例33中獲得的(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(144mg,0.245mmol)溶解於1.3mL的MeOH和1.3mL的TH中,並將1.3mL的1N NaOH添加至反應物中,然後在50℃下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(25.2mg,0.044mmol,18%)。
1H NMR(500MHz,CDCl3)δ 8.16(s,1H),8.06(d,J=9.5Hz,1H),7.96(d,J=8.2Hz,2H),7.85(d,J=9.0Hz,1H),7.62(t,J=7.8Hz,1H),
7.45(t,J=8.2Hz,1H),7.36(d,J=8.0Hz,2H),7.32(d,J=7.3Hz,1H),7.11(d,J=9.5Hz,2H),6.72(d,J=7.9Hz,1H),5.61-5.41(m,2H),4.70-4.47(m,2H),4.30-4.06(m,3H),3.88(dd,J=15.1,6.9Hz,1H),3.74(q,J=7.3Hz,1H),2.08-1.97(m,1H),1.96-1.81(m,2H),1.62-1.48(m,1H);LC-MS(ESI):572.31[M+H]+
[實施例14:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例36中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(156mg,0.26mmol)溶解於1.3mL的MeOH和1.3mL的THF中,並將1.3mL的1N NaOH添加至反應物中,然後在50℃下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫-2H-吡喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(44.7mg,0.076mmol,29%)。
1H NMR(500MHz,CDCl3)δ 8.13(s,1H),8.06(d,J=8.5Hz,1H),7.96(d,J=8.2Hz,2H),7.84(d,J=8.5Hz,1H),7.63(t,J=7.8Hz,1H),
7.46(t,J=8.1Hz,1H),7.36(d,J=8.2Hz,2H),7.32(d,J=7.6Hz,1H),7.12(d,J=9.2Hz,2H),6.72(d,J=8.0Hz,1H),5.61-5.41(m,2H),4.53(dd,J=18.8,16.0Hz,2H),4.18-3.99(m,2H),3.97-3.87(m,1H),3.59-3.45(m,1H),3.30-3.12(m,1H),1.89-1.78(m,1H),1.65-1.24(m,5H);LC-MS(ESI):586.33[M+H]+
[實施例15:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例38中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸甲酯(720mg,1.78mmol)溶解在8mL的THF/H2O(1/1)中,並添加NaOH(214mg,5.35mmol)。將反應物在室溫攪拌24小時。反應完成後,加入1N HCl以將所得溶液調整至pH約2,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸(680mg,1.75mmol,98%)。
1H NMR(500MHz,MeOD)δ 7.99(t,J=8.1Hz,1H),7.76(t,J=7.8Hz,1H),7.56(t,J=8.1Hz,1H),7.48(d,J=7.6Hz,1H),7.17-7.27(m,4H),6.82(d,J=8.2Hz,1H),5.52(s,2H),3.70(s,2H)
將2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸(150mg,0.385mmol)溶於DMF(1.5mL),加入製備實施例7中獲得的(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(91mg,0.385mmol)、EDC(148mg,0.770mmol)和HOBt(118mg,0.770mmol)加入其中。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,添加水,將所得溶液用EtOAc萃取,用MgSO4乾燥,在減壓下濃縮,從而獲得中間體,(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙醯胺基-3-((氧雜環丁烷-2-基甲基))胺基)苯甲酸甲酯(200mg,0.329mmol)。將中間體溶於AcOH(3.77mL,65.8mmol),無需進一步純化,然後在120℃下攪拌3小時,反應後,減壓濃縮,加入水,用EtOAc萃取,用MgSO4乾燥,濃縮。減壓下得到中間體(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(150mg,0.254mmol)。中間體無需進一步純化即可溶於THF/H2O(1mL/1mL),加入NaOH(30mg,0.763mmol),接著在室溫下攪拌24小時。反應完成後,加入水,並加入1N HCl以酸化所得溶液至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(氧雜環丁烷)-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(70mg,0.122mmol,48%)。
1H NMR(500MHz,MeOD)δ 8.30(s,1H),8.01(t,J=7.9Hz,2H),7.73(dd,J=20.8,7.9Hz,2H),7.54(s,1H),7.47(d,J=7.6Hz,1H),7.15-7.25(m,4H),6.83(d,J=8.2Hz,1H),5.51(s,2H),5.19-5.04(1H),
4.62-4.65(m,2H),4.53-4.56(m,3H),4.44(d,J=9.2Hz,1H),2.81-2.69(1H),2.56-2.39(1H)
[實施例16:(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例41中獲得的2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸甲酯(1.71g,4.07mmol)溶解在20mL的THF/H2O(1/1)中,並添加NaOH(488mg,12.2mmol)。將反應物在室溫攪拌24小時。反應完成後,加入1N HCl以將所得溶液調整至pH約2,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮,並藉由MPLC純化,從而獲得2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸(1.53g,3.77mmol,93%)。
1H NMR(400MHz,CDCl3)δ 7.96(dd,J=6.4,1.8Hz,2H),7.73-7.56(m,2H),7.44-7.32(m,5H),6.76(d,J=8.2Hz,1H),5.62(s,2H),3.71(s,2H)
將2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸(150mg,0.370mmol)溶於DMF(2mL),加入製備實施例7中獲得的(S)-4-胺基-3-((氧雜環丁烷-2-基甲基)胺基)苯甲酸甲酯(87mg,0.370
mmol)、HATU(422mg,1.110mmol)和TEA(0.155mL,1.110mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮,從而獲得中間體,(S)-4-(2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙醯胺基甲基)-3-((氧雜環丁烷-2-甲基(甲基)胺基)苯甲酸甲酯(230mg,0.369mmol)。將該中間體不經另外純化即溶於AcOH(4.22mL,73.8mmol)中,並在120℃下攪拌3小時。反應後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮,從而獲得中間體,(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(220mg,0.363mmol)。將該中間體不經另外純化而溶於THF/H2O(1mL/1mL)中,並加入NaOH(44mg,1.090mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並加入1N HCl以酸化所得溶液至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(36mg,0.061mmol,17%)。
1H NMR(500MHz,MeOD)δ 8.28(s,1H),8.00(q,J=8.2Hz,3H),7.74-7.78(m,2H),7.69(d,J=8.5Hz,1H),7.50(t,J=7.8Hz,3H),7.39(d,J=8.2Hz,2H),6.82(d,J=7.9Hz,1H),5.64(s,2H),4.54(dd,J=29.6,16.2Hz,2H),4.34(dd,J=14.6,3.1Hz,1H),4.20(dd,J=14.8,9.3Hz,1H),4.05-4.11(m,1H),3.72-3.77(m,2H),1.82(d,J=7.3Hz,1H),1.73-1.76(m,1H)
[實施例17:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例40中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯酚(76mg,0.219mmol)溶解在DMF(2mL)中,並加入t-BuOK(45mg,0.397mmol),然後在室溫下在氮氣下攪拌15分鐘。加入製備實施例18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(80mg,0.199mmol),並在室溫下攪拌3小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮,從而獲得中間體,(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-(氧雜環丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(27mg,0.046mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(5.5mg,1.137mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並加入1N HCl以酸化所得溶液至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(10mg,0.017mmol,38%)。
1H NMR(400MHz,CDCl3)δ 8.20(s,1H),7.90-7.98(m,2H),7.85(d,J=9.1Hz,1H),7.67(t,J=8.0Hz,1H),7.56-7.60(m,2H),7.46(t,J=8.0Hz,1H),7.32-7.35(m,1H),7.12-7.15(m,2H),6.78(d,J=8.2Hz,1H),5.49(d,J=26.1Hz,2H),5.28(d,J=7.3Hz,1H),4.67(q,J=7.2Hz,1H),4.46-4.51(m,3H),2.81(d,J=5.9Hz,1H),2.65(d,J=11.9Hz,1H)
[實施例18:(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例39中獲得的2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(77mg,0.211mmol)溶解在DMF(2mL)中,加入t-BuOK(32mg,0.288mmol),然後在室溫下在氮氣下攪拌15分鐘。加入製備實施例18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(77mg,0.192mmol),然後在室溫下攪拌3小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體,(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(50mg,0.082mmol)。無需進一步純化即可溶解THF/H2O(1mL/1mL),並
加入NaOH(10mg,0.247mmol),然後在室溫下攪拌24小時。反應後,加入水,並加入1N HCl以酸化所得溶液至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(23mg,0.039mmol,47%)。
1H NMR(500MHz,CDCl3)δ 8.28(s,1H),8.17-8.19(m,1H),7.98-8.03(m,2H),7.60-7.71(m,3H),7.44-7.51(m,1H),7.34-7.40(m,1H),7.16(dd,J=9.8,7.0Hz,2H),6.80(dd,J=14.6,8.2Hz,1H),5.48-5.60(m,2H),5.34-5.39(m,1H),4.66-4.75(m,1H),4.48-4.61(m,3H),2.84-2.92(m,1H),2.63-2.78(m,1H)
[實施例19:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例59中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯酚(200mg,0.547mmol)溶解在TEA(0.08mL)中,並加入製備實施例18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(44mg,0.109mmol),隨後在120℃攪拌24
小時。反應完成後,將所得溶液減壓濃縮並藉由MPLC純化,從而獲得中間體(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(22mg,0.036mmol,33%)。
1H NMR(500MHz,MeOD)δ 8.30(s,1H),7.93-7.96(m,3H),7.83(t,J=7.8Hz,1H),7.55-7.62(m,2H),7.49(d,J=8.5Hz,1H),7.23-7.28(m,2H),6.91(d,J=8.2Hz,1H),5.58(s,2H),5.31-5.35(m,1H),4.65-4.71(m,2H),4.59(dd,J=15.4,3.5Hz,1H),4.40-4.44(m,1H),3.94(d,J=6.1Hz,3H),2.85-2.90(m,1H),2.65-2.71(m,1H)
中間體(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(22mg,0.036mmol,33%)溶解在THF/H2O(1mL/1mL)中,加入NaOH(4mg,0.108mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並加入1N HCl以酸化所得溶液至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2,6-二氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(8mg,0.013mmol,37%)。
1H NMR(500MHz,MeOD)δ 8.28-8.30(m,1H),7.88-8.01(m,3H),7.77-7.85(m,1H),7.54-7.64(m,2H),7.44-7.53(m,1H),7.18-7.30(m,2H),6.88(dd,J=22.9,8.2Hz,1H),5.53-5.59(m,2H),5.30-5.37(m,1H),4.65-4.70(m,2H),4.58(dd,J=15.3,3.4Hz,1H),4.41-4.48(m,1H),2.84-2.91(m,1H),2.63-2.70(m,1H)
[實施例20:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例37中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯酚(150mg,0.431mmol)溶解在DMF(2mL)中,並且加入t-BuOK(73mg,0.647mmol),然後在氮氣下於室溫攪拌15分鐘。加入製備實施例18中獲得的(S)-2-芐基磺醯基-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(173mg,0.431mmol),然後在室溫下攪拌3小時。反應完成後,加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮,從而獲得中間體,(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯氧基)-1-(氧雜環丁-2-基甲基)-1H-苯甲基[d]咪唑-6-羧酸甲酯(125mg,0.211mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,加入NaOH(25mg,0.633mmol),然後在室溫下攪拌24小時。反應後,加入水,並加入1N HCl以酸化所得溶液至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯氧基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-6-羧酸(64mg,0.111mmol,52%)。
1H NMR(500MHz,MeOD)δ 8.25(d,J=9.2Hz,1H),8.18(t,J=8.5Hz,1H),7.96(d,J=8.5Hz,1H),7.80(t,J=7.8Hz,1H),7.48-7.59(m,3H),7.37-7.41(m,2H),7.23-7.27(m,2H),6.87(d,J=8.2Hz,1H),5.51-5.55(m,2H),5.27-5.32(m,1H),4.64-4.70(m,2H),4.47-4.54(m,2H),2.84-2.89(m,1H),2.60-2.65(m,1H)
[實施例21:2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將2-(4-(6-((2-氟-4-(三氟甲基)芐基)氣基)吡啶-2-基)苯基)乙酸(170mg,0.419mmol)溶解在DMF(2.5mL)中,並加入製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(110mg,0.445mmol)、HATU(478mg,1.258mmol)和TEA(0.175mL,1.258mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(260mg,0.410mmol)。將該中間體不經另外純化即溶於AcOH(4.69mL,82.0mmol)中,然後在120℃下攪拌3小時。反應後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,
用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(248mg,0.402mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(48mg,1.207mmol),然後在室溫下攪拌24小時。反應完成後,加入水,並加入1N HCl以酸化所得溶液至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(60mg,0.100mmol,25%)。
1H NMR(500MHz,MeOD)δ 8.33(s,1H),7.94-8.05(m,4H),7.68-7.78(m,3H),7.48-7.54(m,3H),7.33-7.37(m,2H),6.91-6.95(m,1H),6.83(d,J=8.2Hz,1H),5.59-5.70(m,4H),4.56(s,2H)
[實施例22:2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例56中獲得的2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(110mg,0.271mmol)溶解於DMF(1.5mL),加入製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(67
mg,0.271mmol)、EDC(104mg,0.542mmol)和HOBt(83mg,0.542mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並且在減壓下濃縮,從而獲得中間體4-(2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(147mg,0.231mmol)。無需進一步純化即可將中間體溶解於AcOH(2.65mL,46.3mmol)中,然後在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥,並在減壓下濃縮,從而獲得中間體2-(3-氯-4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(112mg,0.181mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(22mg,0.544mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(20mg,0.033mmol,18%)。
1H NMR(500MHz,MeOD)δ 8.39(d,J=40.9Hz,1H),8.08-8.14(m,1H),8.03(dd,J=8.5,1.5Hz,1H),7.73-7.83(m,2H),7.51-7.58(m,2H),7.36-7.42(m,1H),7.20-7.31(m,4H),6.99(d,J=32.3Hz,1H),6.85(d,J=8.2Hz,1H),5.64-5.77(m,2H),5.48(d,J=24.4Hz,2H),4.56(d,J=7.6Hz,2H)
[實施例23:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸
將2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙酸(110mg,0.282mmol)溶於DMF(1.5mL)中,加入製備實施例23中獲得的4-胺基-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(70mg,0.282mmol)、EDC(108mg,0.564mmol)和HOBt(86mg,0.564mmol)。將反應物在室溫下在氮氣下攪拌24小時反應完成後,加入水,用EtOAc進行萃取,並且將所得的萃取物用MgSO4進行乾燥並且在減壓下進行濃縮,從而獲得了中間體4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙醯胺基)-3-((噁唑-5-基甲基)胺基)苯甲酸甲酯(98mg,0.158mmol)。將該中間體不經另外純化即溶於AcOH(1.81mL,31.7mmol)中,並在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮。加入水,用EtOAc進行萃取,並且將所得的萃取物用MgSO4乾燥並且在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(93mg,0.155mmol)。將中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(19mg,0.464mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化
至pH約2。用EtOAc萃取,並用MgSO4乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-(噁唑-5-基甲基)-1H-苯并[d]咪唑-6-羧酸(34mg,0.058mmol,37%)。
1H NMR(400MHz,MeOD)δ 8.29(s,1H),7.93-8.03(m,3H),7.70(q,J=7.6Hz,2H),7.50(t,J=8.0Hz,1H),7.42(d,J=5.9Hz,1H),7.16-7.21(m,3H),7.08(d,J=12.3Hz,1H),6.98(s,1H),6.78(d,J=8.2Hz,1H),5.64(s,2H),5.46(s,2H),4.53(s,2H)
[實施例24:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(116mg,0.311mmol)溶解於DMF(1.5mL)中。,加入製備實施例43中獲得的4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(90mg,0.311mmol)、EDC(119mg,0.622mmol)和HOBt(95mg,0.622mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)
乙醯胺基)-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(158mg,0.246mmol)。將該中間體不經另外純化即溶於AcOH(2.81mL,49.1mmol)中,並在120℃下攪拌3小時。反應後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-(甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(118mg,0.189mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(38mg,0.944mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(33mg,0.054mmol,29%)。
1H NMR(500MHz,MeOD)δ 8.38-8.41(m,1H),8.19(s,1H),8.03(dd,J=8.4,1.4Hz,1H),7.95(d,J=8.2Hz,2H),7.72-7.76(m,2H),7.55(t,J=8.1Hz,1H),7.45(d,J=7.6Hz,1H),7.31(d,J=8.2Hz,2H),7.21-7.27(m,2H),6.78(d,J=8.2Hz,1H),5.76(s,2H),5.48-5.60(m,2H),4.50(s,2H),3.83(t,J=7.5Hz,2H),1.49-1.55(m,2H),0.75(t,J=7.5Hz,3H)
[實施例25:2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸(126mg,0.311mmol)溶於DMF(1.5mL)中,加入製備實施例43中獲得的4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(90mg,0.311mmol)、EDC(119mg,0.622mmol)和HOBt(95mg,0.622mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(135mg,0.200mmol)。將該中間體不經另外純化即溶於AcOH(2.28mL,39.9mmol)中,並在120℃下攪拌3小時。反應完成後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(126mg,0.191mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(23mg,0.574mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。所得濃縮物藉由
MPLC純化,從而獲得2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(60mg,0.093mmol,49%)。
1H NMR(500MHz,MeOD)δ 8.39-8.42(m,1H),8.19(s,1H),8.02-8.04(m,1H),7.94(d,J=8.2Hz,2H),7.74-7.78(m,3H),7.50-7.53(m,2H),7.47(d,J=7.3Hz,1H),7.31(d,J=8.2Hz,2H),6.83(d,J=8.2Hz,1H),5.76(s,2H),5.60-5.70(m,2H),4.49(s,2H),3.83(t,J=7.5Hz,2H),1.49-1.54(m,2H),0.74(t,J=7.5Hz,3H)
[實施例26:2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例56中獲得的2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(110mg,0.271mmol)溶解於DMF(1.5mL),加入製備實施例43中獲得的4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(78mg,0.271mmol)、EDC(104mg,0.542mmol)和HOBt(83mg,0.542mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並且在
減壓下濃縮,從而獲得中間體4-(2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(178mg,0.263mmol)。將該中間體不經另外純化即溶於AcOH(3.00mL,52.5mmol)中,並在120℃下攪拌3小時。反應後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(158mg,0.240mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(29mg,0.719mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(63mg,0.098mmol,41%)。
1H NMR(500MHz,MeOD)δ 8.45(s,1H),8.23(s,1H),8.04(d,J=8.5Hz,1H),7.75-7.78(m,2H),7.53(t,J=8.1Hz,1H),7.46(d,J=7.9Hz,1H),7.38(s,1H),7.21-7.25(m,4H),6.85(d,J=8.2Hz,1H),5.83(s,2H),5.46(s,2H),4.50(s,2H),3.92(t,J=7.5Hz,2H),1.58(q,J=7.3Hz,2H),0.81(t,J=7.3Hz,3H)
[實施例27:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2--2-基)-3-氟苯基)乙酸(110mg,0.282mmol)溶於DMF(1.5mL)中,加入製備實施例43中獲得的4-胺基-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(82mg,0.282mmol)、EDC(108mg,0.564mmol)和HOBt(86mg,0.564mmol)。將反應物在室溫下在氮氣下攪拌24小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟苯基)乙醯胺基)-3-(((4-丙基-4H-1,2,4-三唑-3-基)甲基)胺基)苯甲酸甲酯(180mg,0.272mmol)。無需進一步純化即可將中間體溶解於AcOH(3.10mL,54.5mmol)中,並在120℃下攪拌3小時。反應後,在減壓下進行濃縮。添加水,並將所得溶液用EtOAc萃取,用MgSO4乾燥並在減壓下濃縮,從而獲得中間體2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(170mg,0.264mmol)。將該中間體不經另外純化即溶於THF/H2O(1mL/1mL)中,並加入NaOH(32mg,0.793mmol),然後在室溫下攪拌24小時。反應完成後,加水,並將所得溶液用1N HCl酸化至pH約2。使用EtOAc進行萃取,並且使用MgSO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化所得濃
縮物,從而獲得2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-3-氟芐基)-1-((4-丙基-4H-1,2,4-三唑-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(35mg,0.056mmol,21%)。
1H NMR(400MHz,MeOD)δ 8.40(s,1H),8.19(d,J=10.1Hz,1H),7.98-8.01(m,1H),7.89(t,J=8.2Hz,1H),7.69-7.73(m,2H),7.50(t,J=8.0Hz,1H),7.40(d,J=5.9Hz,1H),7.17-7.22(m,2H),7.03-7.12(m,2H),6.78(d,J=7.8Hz,1H),5.77(s,2H),5.46(s,2H),4.46(s,2H),3.87(t,J=7.5Hz,2H),1.52(q,J=7.5Hz,2H),0.75(t,J=7.3Hz,3H)
[實施例28:2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例47中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(43.8mg,0.074mmol)溶解於THF/H2O(5mL/5mL)中,並將0.5mL的1N NaOH添加至反應物中,並在50℃下攪拌14小時。反應完成後,加入水,並使用1N HCl將所得溶液酸化至pH 4,用EtOAc萃取,用Na2SO4乾燥,並在減壓下濃縮。藉由MPLC純化所得濃縮物,從而獲得2-(4-(6-
((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(2mg,0.0034mmol,4.4%)。
1H NMR(500MHz,CDCl3)δ 8.17(s,1H),8.10(d,J=8.8Hz,2H),7.99(d,J=8.2Hz,1H),7.67(t,J=7.8Hz,1H),7.60(d,J=8.5Hz,1H),7.46-7.50(m,3H),7.36(d,J=7.3Hz,1H),7.12-7.15(m,2H),6.76(d,J=7.9Hz,1H),5.54(s,2H),4.41(q,J=6.3Hz,1H),4.30(d,J=5.5Hz,2H),3.90(dd,J=15.0,6.7Hz,1H),3.80(dd,J=15.1,6.9Hz,1H),2.10-2.15(m,1H),1.91-1.97(m,2H),1.75-1.83(m,1H);LC-MS(ESI):574.26[M+H]+
[實施例29:(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例30中獲得的(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸(203mg,0.5mmol)溶於2mL DMF中,並加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體,(S)-4-(2-(4-(6-
((2-氟-4-(三氟甲基)芐基)氧基)吡啶基-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化而溶於10mL乙酸中,並在120℃下攪拌2小時。在減壓下濃縮乙酸,並進行MPLC,從而獲得中間體(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶基-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在10mL的THF和2mL的MeOH中,將2.5mL的1N NaOH加入到反應物中,並在40℃下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(138mg,0.228mmol,45.5%)。
1H NMR(500MHz,CDCl3)δ 8.16(s,1H),8.06(d,J=8.5Hz,1H),7.94(d,J=8.2Hz,2H),7.84(d,J=8.5Hz,1H),7.63-7.68(m,2H),7.40(d,J=7.9Hz,1H),7.32-7.37(m,4H),6.76(d,J=7.9Hz,1H),5.60(s,2H),4.55(dd,J=43.3,15.9Hz,2H),4.22(d,J=12.5Hz,1H),4.09-4.18(m,2H),3.87(q,J=7.3Hz,1H),3.74(q,J=7.3Hz,1H),2.03(td,J=12.7,6.2Hz,1H),1.83-1.90(m,2H),1.51-1.58(m,1H);LC-MS(ESI):606.35[M+H]+
[實施例30:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
製備實施例30中獲得的(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和製備實施例28中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙酸(195mg,0.5mmol)溶解在2mL DMF中,並加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體,(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化而溶於10mL乙酸中,並在120℃下攪拌2小時。減壓濃縮乙酸,並進行MPLC,從而獲得中間體,(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在10mL的THF和2mL的MeOH中,並將2.5mL的1N NaOH添加至反應物,並在40℃下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,減壓濃縮並藉由MPLC純化,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(9.3mg,0.015mmol,3%)。
1H NMR(500MHz,CDCl3)δ 8.19(s,1H),8.05(d,J=8.5Hz,1H),7.78-7.83(m,2H),7.69(d,J=7.0Hz,1H),7.63(t,J=7.9Hz,1H),7.42-7.47(m,1H),7.36(t,J=7.6Hz,1H),7.28-7.30(m,1H),7.11-7.16(m,2H),6.74-6.76(m,1H),5.50(s,2H),4.53(dd,J=39.7,16.2Hz,2H),4.30(d,J=12.2Hz,1H),4.16-4.20(m,2H),3.88(q,J=7.3Hz,1H),3.74(q,J=7.2Hz,1H),2.05-2.09(m,1H),1.86-1.92(m,2H),1.55-1.57-1.63(m,1H);LC-MS(ESI):590.31[M+H]+
[實施例31:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例40中獲得的4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯酚(69.5mg,0.2mmol)溶解在DMF(3mL)中,並且加入t-BuOK(33.7mg,0.3mmol),然後在室溫下在氮氣下攪拌10分鐘。加入製備實施例50中獲得的(S)-2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(82.9mg,0.20mmol),然後在室溫下攪拌12小時。反應完成後,加入水,所得溶液用EtOAc萃取,用Na2SO4乾燥,在減壓下濃縮,並且藉由MPLC純化,從而獲得中間體,(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]
咪唑-6-羧酸甲酯。將該中間體不經另外純化而溶於MeOH/THF(2mL/2mL)中,並將0.26mL的1N NaOH添加至反應物中,然後在40℃下攪拌15小時。反應完成後,添加水,並添加1N-HCl以將所得溶液調整至pH 4,用EtOAc進行萃取,用Na2SO4進行乾燥,然後在減壓下濃縮。藉由MPLC純化得到的濃縮物,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)-2-氟苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(10.7mg,0.018mmol,9%)。
1H NMR(500MHz,CDCl3)δ 8.20(s,1H),7.99(d,J=8.2Hz,1H),7.94(dd,J=11.6,1.8Hz,1H),7.85(d,J=8.5Hz,1H),7.68(t,J=7.8Hz,1H),7.58-7.62(m,2H),7.48(t,J=8.1Hz,1H),7.33-7.36(m,1H),7.13-7.15(m,2H),6.79(d,J=8.2Hz,1H),5.53(s,2H),4.41-4.46(m,1H),4.27-4.36(m,2H),3.92(q,J=7.3Hz,1H),3.79-3.83(m,1H),2.14(dt,J=19.4,6.7Hz,1H),1.92-1.99(m,2H),1.78-1.86(m,1H);LC-MS(ESI):592.26[M+H]+
[實施例32:(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例39中獲得的2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯酚(72.8mg,0.2mmol)溶解在DMF(3mL)中,加入t-BuOK(33.7mg,0.3mmol),然後在室溫下在氮氣下攪拌10分鐘。加入製備實施例50中獲得的(S)-2-(芐基磺醯基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯(82.9mg,0.20mmol),然後在室溫下攪拌12小時。反應完成後,加入水,並將所得溶液用EtOAc萃取,用Na2SO4乾燥,並在減壓下濃縮。所得濃縮物藉由MPLC純化,從而獲得中間體(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將該中間體不經另外純化而溶於MeOH/THF(2mL/2mL)中,並將0.22mL的1N NaOH添加至反應物中,隨後在40℃下攪拌15小時。反應完成後,加入水,加入1N-HCl以將所得溶液調整至pH 4,用EtOAc萃取,並用Na2SO4乾燥,然後減壓濃縮。藉由MPLC純化所得濃縮物,從而獲得(S)-2-(2-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯氧基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(10mg,0.016mmol,8%)。
1H NMR(500MHz,CDCl3)δ 8.20(d,J=1.2Hz,1H),8.16(d,J=2.1Hz,1H),7.95-8.01(m,2H),7.66(t,J=8.5Hz,2H),7.59(d,J=8.2Hz,1H),7.46-7.49(m,1H),7.34(d,J=7.3Hz,1H),7.13-7.16(m,2H),6.79(d,J=8.2Hz,1H),5.53(s,2H),4.44-4.49(m,1H),4.34(t,J=4.0Hz,2H),3.93(dd,J=15.0,6.7Hz,1H),3.81(dd,J=15.1,6.9Hz,1H),2.12-2.18(m,1H),1.93-1.98(m,2H),1.80-1.87(m,1H);LC-MS(ESI):608.24[M+H]+
[實施例33:(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
在製備實施例52中獲得的(R)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(202mg,0.807mmol)和在製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(300mg,0.807mmol)溶解在5mL DMF中,並加入EDC(309mg,1.614mmol)和HOBt(247mg,1.614mmol),然後在室溫下攪拌4小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體(R)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化而溶於5mL乙酸中,並在120℃下攪拌12小時。減壓濃縮乙酸,並進行MPLC,從而得到中間體(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在10mL的THF中,將0.9mL的1N NaOH加入到反應物中,然後在室溫下攪拌24小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,
從而獲得(R)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(40mg,0.070mmol,8.7%)。
1H NMR(400MHz,CDCl3)δ 8.19(s,1H),8.10(dd,J=8.2,1.4Hz,1H),7.97(d,J=8.2Hz,2H),7.89(d,J=8.2Hz,1H),7.61(t,J=8.0Hz,1H),7.44(t,J=8.2Hz,1H),7.35(d,J=8.2Hz,2H),7.31(d,J=7.8Hz,1H),7.09-7.12(m,2H),6.72(d,J=8.2Hz,1H),5.50(s,2H),4.49(dd,J=26.5,16.0Hz,2H),3.95-4.10(m,3H),3.68-3.80(m,1H),3.55-3.64(m,2H),2.77-2.83(m,1H),1.95-2.04(m,1H),1.58-1.66(m,1H);LC-MS(ESI):572.29[M+H]+
[實施例34:(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸
製備實施例30中獲得的(S)-4-胺基-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和製備實施例56中獲得的2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(203mg,0.5mmol)溶解在3mL DME中,並加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲
得中間體,(S)-4-(2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-2-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶於5mL乙酸中,並在120℃下攪拌2小時。在減壓下濃縮乙酸,並進行MPLC,從而獲得中間體(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在5mL的THF中,並將1.0mL的1N NaOH加入到反應物中,然後在室溫下攪拌15小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-2-基)甲基)-1H-苯并[d]咪唑-6-羧酸(63mg,0.104mmol,20.8%)。
1H NMR(400MHz,CDCl3)δ 8.18(d,J=0.9Hz,1H),8.07(dd,J=8.7,1.4Hz,1H),7.85(d,J=8.2Hz,1H),7.63(t,J=8.0Hz,1H),7.54(d,J=7.8Hz,1H),7.39-7.46(m,2H),7.22-7.28(m,2H),7.08-7.13(m,2H),6.77(d,J=8.2Hz,1H),5.42(s,2H),4.53(dd,J=36.6,16.0Hz,2H),4.30(d,J=11.9Hz,1H),4.11-4.22(m,2H),3.85-3.91(m,1H),3.75(q,J=7.5Hz,1H),2.04-2.12(m,1H),1.84-1.94(m,2H),1.53-1.62(m,1H);LC-MS(ESI):606.28[M+H]+
[實施例35:(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將在製備實施例58中獲得的(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和在製備實施例2中獲得的2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(186mg,0.5mmol)溶解在2mL DMF中,加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體,(S)-4-(2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯。將該中間體不經純化即溶於5mL乙酸中,並在120℃下攪拌2小時。減壓濃縮乙酸,並進行MPLC,從而獲得中間體,(S)-2-(4-(6-(((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并甲基[d]咪唑-6-羧酸甲酯。將中間體溶解在5mL的THF中,並將1.0mL的1N NaOH添加至反應物,然後在40℃下攪拌15小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(49mg,0.086mmol,17%)。
1H NMR(500MHz,CDCl3)δ 8.19(s,1H),8.10(d,J=8.5Hz,1H),7.97(d,J=8.2Hz,2H),7.89(d,J=8.5Hz,1H),7.62(t,J=7.9Hz,1H),7.45(t,J=8.1Hz,1H),7.35(d,J=8.2Hz,2H),7.31(d,J=7.3Hz,1H),7.10-7.12(m,2H),6.72(d,J=7.9Hz,1H),5.50(s,2H),4.49(q,J=15.8Hz,2H),4.03-4.12(m,2H),3.95-4.01(m,1H),3.76(dd,J=15.3,8.2Hz,1H),3.56-3.64(m,2H),2.65-2.88(m,1H),1.96-2.05(m,1H),1.63(td,J=12.4,7.0Hz,1H);LC-MS(ESI):572.29[M+H]+
[實施例36:(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
在製備實施例58中獲得的(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)苯基)乙酸(202mg,0.5mmol)溶於2mL DMF中,並加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體,(S)-4-(2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶基-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶
於5mL乙酸中,並在120℃下攪拌2小時。在減壓下濃縮乙酸,並進行MPLC,從而獲得中間體(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶基-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將中間體溶解在5mL的THF中,並將0.7mL的1N NaOH加入到反應物中,然後在40℃下攪拌15小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(4-(6-((2-氟-4-(三氟甲基)芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(23.2mg,0.038mmol,7.6%)。
1H NMR(500MHz,CDCl3)δ 8.18(s,1H),8.09(d,J=8.5Hz,1H),7.95(d,J=8.2Hz,2H),7.87(d,J=8.5Hz,1H),7.63-7.67(m,2H),7.40(d,J=7.9Hz,1H),7.32-7.36(m,4H),6.76(d,J=7.9Hz,1H),5.60(s,2H),4.48(dd,J=29.6,15.9Hz,2H),4.03-4.11(m,2H),3.98(dd,J=14.0,8.2Hz,1H),3.75(dd,J=15.3,8.5Hz,1H),3.56-3.64(m,2H),2.73-2.91(m,1H),1.92-2.04(m,1H),1.61-1.66(m,1H);LC-MS(ESI):606.35[M+H]+
[實施例37:(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸的製備]
(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸
將製備實施例58中獲得的(S)-4-胺基-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯(138mg,0.55mmol)和製備實施例56中獲得的2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙酸(203mg,0.5mmol)溶解於2mL DMF,加入EDC(192mg,1.0mmol)和HOBt(153mg,1.0mmol),然後在室溫下攪拌16小時。反應完成後,加入水,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得中間體,(S)-4-(2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)苯基)乙醯胺基)-3-(((四氫呋喃-3-基)甲基)胺基)苯甲酸甲酯。將該中間體不經另外純化即溶於5mL乙酸中,並在120℃下攪拌2小時。在減壓下濃縮乙酸,並進行MPLC,從而獲得中間體(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸甲酯。將所得的中間體溶解在5mL的THF中,並將0.6mL的1N NaOH添加至反應物,然後在40℃下攪拌15小時。加入1N HCl以將所得溶液調整至pH 4,然後用EtOAc萃取。有機層用Na2SO4乾燥,在減壓下濃縮並藉由MPLC純化,從而獲得(S)-2-(3-氯-4-(6-((4-氯-2-氟芐基)氧基)吡啶-2-基)芐基)-1-((四氫呋喃-3-基)甲基)-1H-苯并[d]咪唑-6-羧酸(35.7mg,0.059mmol,12%)。
1H NMR(500MHz,CDCl3)δ 8.20(s,1H),8.10(d,J=8.5Hz,1H),7.87(d,J=8.5Hz,1H),7.64(t,J=7.8Hz,1H),7.56(d,J=7.9Hz,1H),7.43(t,J=7.9Hz,1H),7.40(s,1H),7.24-7.26(m,2H),7.08-7.12(m,
2H),6.78(d,J=8.2Hz,1H),5.42(s,2H),4.44(dd,J=30.7,16.0Hz,2H),4.11-4.14(m,2H),4.03(td,J=8.3,5.9Hz,1H),3.79(dd,J=15.3,8.5Hz,1H),3.58-3.66(m,2H),2.83-2.86(m,1H),2.02-2.09(m,1H),1.65-1.71(m,1H);LC-MS(ESI):606.28[M+H]+
[實驗實施例1:GLP-1R促效劑活性的測定(基於細胞的螢光素酶測定)]
將15,000個CHO-K1/hGLP-1R/CRE螢光素酶細胞株的細胞接種到96孔盤中。本文使用的培養基是Ham’s F-12營養培養基。將細胞在保持在37℃的5%CO2培養箱中培養18小時,然後用藥物處理。將以9種不同濃度分配的每種藥物溶解在DMEM/F-12+1%FBS培養基中,並用100μl的每種細胞處理細胞株。培養4小時後,使用Bright-GloTM螢光素酶分析系統試劑盒向每孔添加30μl分析試劑。將盤在室溫下保存15分鐘,然後使用SpectraMax M5讀取器測量發光。藉由實驗獲得的示例化合物的GLP-1R活性以EC50(nM)為單位在表1中示出。
如表1所確認,本發明的式1對應的化合物作為優異的GLP-1受體促效劑,具有優異的效果。另外,藉由與藥物代謝有關的實驗,例如
細胞色素P(CYP)抑制/誘導實驗和代謝穩定性(MS)實驗以及與藥物代謝動力學有關的實驗,可以證實式1的化合物具有優異的藥物代謝動力學特性。
Claims (8)
- 一種式1的化合物、其異構體或其藥學上可接受的鹽:
- 一種預防或治療代謝疾病或神經退化性疾病的醫藥組成物,包含請求項1所述的化合物、其異構體或其藥學上可接受的鹽,以及藥學上可接受的賦形劑、稀釋劑或載體。
- 如請求項2所述的醫藥組成物,其中,該代謝疾病選自由糖尿病、高血壓、低血糖症、高脂血症、動脈粥樣硬化、冠狀動脈疾病、心血管疾病、凝血異常、肥胖症、糖尿病併發症、糖尿病性視網膜病變、肝臟疾病、肝膽疾病、脂肪肝、酒精性脂肪性肝炎、慢性腎臟疾病、胰島素阻抗和葡萄糖耐受性異常所組成之群組。
- 如請求項2所述的醫藥組成物,其中,該神經退化性疾病係選自由帕金森氏症和阿茲海默症所組成之群組。
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