TWI407962B - 喹唑啉衍生物 - Google Patents
喹唑啉衍生物 Download PDFInfo
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Description
本發明提供了一種喹唑啉衍生物,以及一種應用喹唑啉衍生物治療腫瘤方法。
表皮生長因子(Epidermal Growth Factor,EGF)與表皮生長因子受體(Epidermal Growth Factor Receptor,EGFR)結合可以啟動酪氨酸激酶的活性,並因此啟動導致細胞增殖的反應。EGFR的過度表達和活性增強可以最終導致不可控的細胞分裂,這也是腫瘤發生的前兆(Science, 2004, 304:1497-1500)。
因此,能夠抑制EGFR過度表達和活性增強的化合物可用來作爲治療腫瘤的候選化合物。
本發明是基於一發現,一些喹唑啉化合物能夠抑制EGFR的活性。
本發明一方面是有關於具有下列結構式的化合物:
其中R1
、R2
和R5
獨立地選自H、鹵素、硝基、氨基、氰
基、羥基、烷基、烯基、炔基、芳基、環烷基、雜環烷基、雜芳基、烷氧基、烷硫基、烷基羰基、羧基、烷氧基羰基、羰基氨基、磺醯基氨基、氨基羰基或氨基磺醯基;
其中R3
或R4
之一爲、或;其中n爲1、2、3、4或5;Ra
、Rb
、和Rc
獨立地選自H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基,或者Rb
和Rc
和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,其中雜原子爲N、O或S;Rd
和Re
獨立地選自H、烷基、烯基或炔基,或者Rd
和Re
和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,其中雜原子爲N、O或S;
其中另外一個R3
或R4
爲H、鹵素、硝基、氨基、氰基、羥基、烷基、烯基、炔基、芳基、環烷基、雜環烷基、雜芳基、烷氧基、烷硫基、烷羰基、羧基、烷氧基羰基、羰基氨基、磺醯基氨基、氨基羰基或氨基磺醯基;
其中X爲O、S或NRf
,其中Rf
爲H、烷基、烯基、炔基、芳基、環烷基、雜環烷基、雜芳基、烷基羰基、烷氧基羰基、氨基羰基或氨基磺醯基;
其中Y爲苯基,所述的苯基隨意地被鹵素、硝基、氰基、烷基、烯基或炔基所取代,或者隨意地與另外一個3-8員環合併;或者Y爲被苯基取代的烷基,所述的苯基隨意地被鹵素、硝基、氰基、烷基、烯基或炔基所取代,或者隨意地
與另外一個3-8員環合併;其中Z爲N或C-CN。
考慮到上述化合物,優選的一系列化合物爲:R3
或R4
之一爲,其中n爲1,Ra
、Rb
和Rc
,獨立的選自H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基。
另外優選的化合物爲:R3
或R4
之一爲,其中n爲1或2;其中Ra
爲H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基;其中Rb
和Rc
和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,如N、O和S;其中一些化合物中Rb
和Rc
和與它們連接的N原子一起組成如下的雙環結構:,其中m1
、m2
、m3
和m4
,獨立地選自0、1、2,或3;其中A爲N或CR;B爲NR或CRR',其中R和R'獨立地選自H、烷基或鹵素;Ri
、Rii
、Riii、
Riv
、Rv
、Rvi
、Rvii和
Rviii
獨立地選自H、烷基或鹵素。
另外的優選化合物爲:R3
或R4
之一爲,其中Ra
爲H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基。
另外的優選化合物爲:R3
或R4
之一爲,其中Ra
爲H、烷基、烯基、炔基、環烷基、雜環烷基、芳基、或雜芳基;其中Rd
和Re
,獨立地選自H、烷基、烯基或炔基;或者Ra
爲H、烷基、烯基或炔基,Rd
和Re
,和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,如N、O和S。
進一步優選的化合物特徵爲:X爲O、NH或N-CH3
;Z爲N;Y爲或。
術語“烷基”,指的是含有1-10個碳原子的直鏈或支鏈烴基。烷基基團的例子包括但不限於甲基,乙基,正丙基,異丙基,正丁基,異丁基和叔丁基。術語“烷氧基”指的是含氧的烷基。
術語“烯基”指得是含有一個或多個碳碳雙鍵的2-10個碳原子的直鏈或支鏈烴基。烯基的例子包括但不限於乙烯基、2-丙烯基和2-丁烯基。
術語“炔基”指得是含有一個或多個碳碳三鍵的2-10個碳原子的直鏈或支鏈烴基。炔基的例子包括但不限於乙炔基、2-丙炔基和2-丁炔基。
術語“芳基”,指的是含有6個碳原子的單環芳烴,10個碳原子的雙環芳烴,14個碳原子的三環芳烴,其中每個環
上可以有1-4個取代基。芳基的例子包括但不限於苯基,萘基和蒽基。
術語“環烷基”,指的是含有3-12個碳原子的飽和或者部分不飽和的環狀烴。“環烷基”的例子包括但不限於環丙基,環丁基,環戊基,環戊烯基,環己基,環己烯基,環庚基和環辛基。
術語“雜芳基”,指的是含有1個或多個雜原子(例如N,O,S)的5-8個原子的單環芳烴、8-12個原子的雙環芳烴或11-14個原子的三環芳烴。“雜芳基”的例子包括但不限於吡啶基,呋喃基,咪唑基,苯並咪唑基,嘧啶基,噻吩基,喹啉基,吲哚基和噻唑基。術語“雜芳烷基”指的是被一雜芳基所取代的烷基基團。
術語“雜環烷基”,指的是含有1個或多個雜原子(例如N,O,S)的3-8個原子的單環非芳烴烷基、8-12個原子的雙環或11-14個原子的三環烴基。雜環烷基的例子包括但不限於哌基、吡咯烷基、二噁烷基、嗎啉基和四氫呋喃基。雜環烷基可以爲糖環,如葡糖基。
所述的烷基、烯基、炔基、環烷基、雜環烷基、芳基、芳雜基、烷氧基均可以含有或不含有取代基。取代基的例子包括但不限於鹵素、羥基、氨基、氰基、硝基、巰基、烷氧羰基、羰基、烷磺醯基、烷基酮、氨基甲醯胺基、羧基、硫脲基、異硫氰基、磺醯胺基、烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基和雜環烷基,其中烷基、烯基、炔基、烷氧基、芳基、雜芳基、環烷基和雜環烷基
可以被進一步取代。
上面所述的喹唑啉化合物還包括其藥學上可接受的鹽、溶劑化物和前藥。
本發明的化合物的例子如下:
本發明的另一方面是有關於一種治療腫瘤的方法。該方法包括給予具有腫瘤的個體有效量的一種或多種本發明的喹唑啉化合物。可以治療的腫瘤包括,但不限於,肺癌、頭頸癌、直腸癌、胰腺癌、結腸癌、乳腺癌、卵巢癌、前列腺癌、胃癌、腎癌、肝癌、腦癌、骨癌或白血病。
同樣在本發明範圍內的是:(1)一種用於治療腫瘤的組合物,包含一種或多種上述的喹唑啉化合物和藥學上可接受的載體;(2)應用一種或多種喹唑啉化合物製備治療腫瘤的藥劑。
關於本發明之一個或更多實施例的內容,將揭示於以下的說明書中。本發明之其他特點、目的以及優點將可明顯見於說明書及申請專利範圍中。
本發明的喹唑啉化合物可利用市售原料、通過現有技術中公知的方法合成。例如,下面反應式可看出,適當的4-氯-喹唑啉衍生物與苯基化合物反應,得到本發明的化合物。
得到的化合物的外端可以被進一步修飾,得到本發明的其他的化合物。
對合成預期的喹唑啉化合物有幫助的合成化學改造是
現有技術中公知的,如R. Larock,Comprehensive Organic Transformations
, VCH Publishers (1989);T.W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis
, 3rd
Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser,Fieser and Fieser's Reagents for Organic Synthesis
, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis
, John Wiley and Sons (1995)中都有公開。
使用前,化合物可以通過柱色譜法、高效液相色譜法、結晶或其他合適的方法純化。
本發明的喹唑啉化合物,當與EGFR接觸時,能夠抑制該受體的活性。因此,有效量的一種或多種上述化合物可用於治療由於EGFR的過度表達或過度增活所引起的腫瘤。
術語“有效劑量”指得是使個體足以達到預想功效所需要的喹唑啉化合物的用量。其中,有效劑量的可有所差異,可經由熟悉本技術領域之通常知識者所推知,而取決於服藥的方式、賦形劑的使用、以及同時使用其他治療用藥物的可能下,加以考量其使用量。術語“治療”指得是應用或給予一具有上述疾病、具有疾病的症狀、或易患病體制之個體一種或多種上述的喹唑啉化合物,從而治癒、治療、緩和、抒解、修改、醫治、改善、改良或是影響疾病、疾病的症狀、或是易患病的個體。
爲了實施本發明的治療方法,可將一種或多種上述化合物與一醫藥學上可接受的載體,以口服、非經腸道式、
吸入劑噴霧、或是植入式貯器等方式給藥。在此,非經腸道式給藥,指的是包括皮下注射、皮內注射、靜脈注射、肌肉注射、關節內、動脈內、滑膜內、胸骨內、脊椎內、患處內、以及顱內注射或輸注技術。
口服用的組合物可以是任何一種可接受口服之方式,包括但不限於:片劑、膠囊、乳劑、以及液體狀的懸浮劑、分散劑以及溶液等。常用的片劑載體可包括乳糖以及玉米澱粉。片劑中也常加入如硬脂酸鎂之類的潤滑劑。以膠囊形式口服時,有效的稀釋劑可包括乳糖以及乾燥的玉米澱粉。當口服液體懸浮液或乳劑提供口服時,可利用乳化法或懸浮劑使活性成分懸浮或溶解于一油相中。若有需要,還可添加特定的甜味、香料、或色素。
一無菌之可注射組合物(如水狀或油狀懸浮液)可依任一種已知技術,使用適合的分散劑或溶劑(如:Tween 80)以及懸浮劑來完成製備。無菌可注射組合物的製備亦可將一無菌之可注射溶液或懸浮液,溶於一無毒性之非腸道式可接受之稀釋劑或溶劑中,例如,1,3-丁二醇溶液。在可接受的載體與溶劑中,可使用的是甘露糖醇、水、林格爾氏液、以及等張的氯化鈉溶液。此外,無菌且固定油,如合成的單-或雙-酸甘油酯,已知通常爲溶劑或懸浮液。脂肪酸,例如油酸以及甘油脂衍生物,有助於製備可注射溶液,其爲天然的藥理可接受油脂,例如橄欖油或蓖麻油,尤其是聚乙氧基化的形態。這些油脂溶液或懸浮液亦可含有一長鏈的醇類稀釋劑、分散劑、或羧甲基纖維素、或其類似
的分散劑。
一吸入劑組合物可依相關已知的藥物配方技術而制得,且可製備於生理鹽水中,再添加苯乙醇或其他合適的防腐劑、增加生物利用度之吸收促進劑、氟碳、以及/或本技術領域中其他已知之增溶劑或分散劑。
一種或多種活性化合物可經由直腸給藥。一個例子是直腸栓劑,包括活性化合物以及栓劑座。舉例來說,合適的栓劑座可爲天然或合成之三酸甘油酯、以及石蠟碳氫化合物。另一個例子爲,明膠直腸膠囊,包括活性化合物以及基座。可能的基座材質,包括,如液狀三酸甘油酯、聚乙二醇或是石蠟碳氫化合物。
用於皮膚的組合物可配方爲油脂、乳液、化妝水、軟膏、以及類似的産品。用於組合物的合適載體可包括:蔬菜或礦物油、白礦脂(一種白色軟石蠟)、支鏈脂肪或油脂、動物脂肪、以及高分子量的醇類(大於12個碳)。較佳的載體可以爲活性成分能溶解於其中者。此外,在添加增加顔色或香味成分之外,亦可依需要加入乳化劑、增溶劑、稀釋劑、以及抗氧化劑。而外皮滲透促進劑也可添加於這些典型配方中。這類促進劑的例子可見於美國專利號第3,989,816以及第4,444,762。
較佳的乳液配方是將礦物油、自體乳化之蜂蠟、以及水混合後之混合物,其中混合之活性成分系溶解於一小量的油脂中,例如杏仁油,再摻雜於其中。此類乳液的一範例是包括約40重量份的水、約20重量份的蜂蠟、約40重量
份的礦物油、以及約1重量份的杏仁油。
軟膏可混合一活性成分溶於一植物油中(例如杏仁油)、以及溫的軟石蠟,並讓混合物冷卻而製備。這類軟膏的一範例,依照重量比裏包括有約3成的杏仁油以及約7成的白軟石蠟。
用於藥物組合物之載體,必須爲“可接受”,系指能與配方中的活性成分相容,甚至能穩定活性成分,而且不能對於欲治療的個體産生危害。例如,環糊精之類的增溶劑,會與活性化合物形成專一、更爲穩定的複合物,可作爲醫藥用的載體來傳送活性化合物。其他載體的例子可包括膠態二氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉、以及D&C黃色10號色素(D&C Yellow # 10)。
合適的體外實驗可用於初步評價上述喹唑啉化合物抑制EGFR活性的效果,這些化合物可進一步通過體內實驗檢測其治療腫瘤的效果。例如,化合物可給予一有腫瘤的動物(如小鼠模型),然後檢測其治療效果。根據上述結果,還可以決定其適合的劑量和給藥方式。
無須進一步說明,可確信上述描述可使本發明能充分實施。以下的實施例僅爲本發明之例示,而非用以限定其他以任何形式結露本發明者。
其合成路線及方法如下所示:
將二甲基甲醯胺二甲基乙縮醛(0.88g, 7.36mmol)加入到5-硝基-2-氨基苯甲氰(1.00g, 6.13mmol)的二氧六環(25mL)溶液中,加熱至100℃回流2h。反應液冷卻至室溫後繼續冷去至0℃,有大量沈澱析出,過濾,濾餅用冷卻的乙醚洗滌2~3次後紅外乾燥,得到1.30g的(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺,黃色固體,産率97%。
將(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺(1.00g, 4.58mmol)和3-氨基苯炔(0.64g, 5.49mmol)的冰乙酸(15mL)加熱至100℃攪拌3h。反應液冷卻至室溫,有沈澱析出,過濾,濾餅用乙醚洗滌,紅外乾燥,得到1.23g的N-(3-炔基苯基)-6-硝基喹唑啉-4-胺,黃色固體,産率93%。
N-(3-炔基苯基)-6-硝基喹唑啉-4-胺(1.00g, 3.45mmol)和SnCl2
.2H2
O (3.10g, 13.8mmol)的乙酸乙酯(35mL)溶液回流2h。反應液冷卻至室溫後,用5%的碳酸氫鈉水溶液將pH值調至9-10,混合液用乙酸乙酯萃取,有機相依次用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到0.79g的N-4-(3-炔基苯基)喹唑啉-4,6-二胺,黃色固體,産率89%。
在室溫下,向N-4-(3-炔基苯基)喹唑啉-4,6-二胺(100mg, 0.38mmol)的DMF(2mL)溶液中加入吡啶(37μL,
0.46mmol),然後緩慢滴加氯甲酸苯酯(49μL, 0.38mmol),攪拌10min後,加入(3-氟苄基)甲胺(52.9mg, 0.38mmol),並加熱至80℃攪拌1h。冷卻至室溫後,反應液倒入少量水中,用乙酸乙酯萃取,有機相用水洗滌,硫酸鈉乾燥,濃縮後柱色譜分離得到1-(3-氟苄基)-3-(4-(3-炔基苯基胺)喹唑啉-6-基-1-甲基脲,黃色固體,産率86%。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 8.89 (s, 1H), 8.55 (d,J
=8Hz, 2H), 8.04 (s, 1H), 7.79 (dd,J
=2.4Hz, 2.0Hz, 1H), 7.79 (dd,J
=2.0Hz, 2.4Hz, 1H), 7.74 (d,J
=2.0Hz 1H), 7.41~7.37 (m, 3H), 7.13~7.10 (m, 3H), 4.64 (s, 2H), 4.20 (s, 1H), 3.03 (s, 3H); MS (m/e): 426 (M+1)。
化合物2-59是應用與實施例1相似的方法合成的。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 8.88 (s, 1H), 8.79 (s, 1H) 8.43 (d,J
=8Hz, 2H), 8.10 (s, 1H), 7.94 (t,J
=2.4Hz, 1H), 7.82 (t,J
=2.0Hz, 1H), 7.80 (d,J
=2.0Hz, 1H), 7.42~7.36 (m, 3H), 7.09~7.06 (m, 3H), 4.48 (s, 2H), 3.53 (s, 1H); MS (m/e
): 412 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.42 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 8.44 (d,J
=3.2Hz, 2H), 8.21 (s, 1H), 7.35 (t,J
=2.4Hz,1H), 7.32~6.88 (m, 5H), 6.80 (d,J
=2.0Hz 1H), 6.68 (d,J
=2.4Hz, 1H), 6.65 (s, 1H), 4.44 (s,
2H), 4.04 (s, 1H); MS (m/e
): 395 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.68 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 8.51 (d,J
=2.0Hz, 1H), 8.11 (s, 1H), 7.89 (t,J
=2.0Hz,2H), 7.72 (d,J
=8Hz, 1H), 7.40 (t,J
=3.6Hz, 1H), 7.21 (d,J
=4Hz, 1H), 4.24 (s, 1H), 3.46(s, 4H), 1.53 (s, 6H): MS (m/e
): 372 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 8.88 (s, 1H), 8.79 (s,1H) 8.43 (d,J
=8Hz, 2H), 8.10 (s, 1H), 7.94 (t,J
=2.4Hz,1H), 7.82 (t,J
=2.0Hz, 1H), 7.80 (d,J
=2.0Hz,1H), 7.42~7.36(m, 3H), 7.09~7.06 (m, 3H), 4.48 (s, 2H), 3.53 (s, 1H); MS (m/e
): 412 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 8.87 (d, 1H), 8.79 (s, 1H) 8.43 (d, J=8Hz, 2H), 8.10 (s, 1H), 7.94 (t, J=2.4Hz, 1H), 7.80 (d,J
=2.0Hz, 1H), 7.42~7.36 (m, 3H), 7.09~7.06 (m, 3H), 4.48 (s, 2H), 3.53 (s, 1H); MS (m/e
): 430 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 8.57 (d,J
=10.8Hz, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.96 (d,J
=2Hz, 1H), 7.89 (d,J
=8Hz, 1H), 7.69 (d,J
=20Hz, 1H), 7.35 (t,J
=8.0Hz, 1H), 4.20 (s, 1H), 2.49 (s, 4H), 1.86 (s, 4H); MS
(m/e
): 358 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 9.02(s, 1H), 8.53 (s, 1H), 8.51(d,J
=2Hz, 1H), 8.05 (s, 1H), 7.88 (t,J
=8Hz, 2H), 7.72 (d,J
=8Hz, 1H), 7.38 (d,J
=8Hz, 1H), 7.20 (d,J
=7.2Hz, 1H), 4.18 (s, 1H), 3.65 (t,J
=4.4Hz, 4H), 3.51 (t,J
=4.8Hz, 4H); MS (m/e
): 374 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 8.99 (s, 1H), 8.52 (s, 2H), 8.05 (s, 1H), 7.93 (m, 2H), 7.69 (d,J
=8.8Hz, 1H), 7.38 (t,J
=8Hz, 1H), 7.19 (d,J
=8Hz, 1H), 4.23 (s, 1H), 2.23-0.91 (m, 8H), 0.91 (m,J
=2.8Hz, 6H); MS (m/e
): 400 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 7.90 (m, 2H), 7.71 (d,J
=8.4Hz, 2H), 7.39 (t,J
=8Hz, 1H), 7.20 (d,J
=8Hz, 1H), 4.20(s, 1H), 3.59 (s, 4H), 3.53 (s, 4H), 3.53 (s, 6H); MS (m/e
): 420 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.5 (s 1H), 8.06 (s 1H), 8.05 (s, 1H), 7.68-7.80 (d,J
=9.2 Hz, 3H), 7.39-7.42 (t,J
=8.0 Hz 1H), 7.29-7.31 (d,J
=3.2 Hz,1H), 7.20-7.20 (d,J
=0.4 Hz, 1H), 4.08-4.12 (t,J
=8.0 Hz, 2H), 3.67-3.73 (m, 4H),
3.21-3.25 (m, 6H), 1.65-1.85 (m, 6H); MS (m/e
): 459.3 (M+1)。
MS (m/e
): 399.2 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.81(s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H),7.92 (m, 2H), 7.70 (d,J
=12Hz, 1H), 7.37 (t,J
=2.4Hz, 1H), 7.19 (d,J
=4Hz, 1H), 4.17(s, 1H), 3.71(m, 2H), 3.76 (m, 2H), 3.16 (m, 1H), 2.70(m, 1H), 2.18-2.07 (m, 8H), 1.73 (m, 1H), 1.31 (m, 1H); MS (m/e
): 441 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.76 (s, 1H), 8.97 (s, 1H), 8.51 (d,J
=8.8, 2H), 8.05 (s, 1H), 7.89 (t,J
=8.8Hz, 2H), 7.71 (d,J
=8.8Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.20 (d,J
=8Hz, 1H), 4.19 (s, 1H), 3.54 (s, 4H), 2.26 (t,J
=2Hz, 2H), 0.87 (d,J
=4Hz, 1H), 0.49 (d,J
=8Hz, 2H), 0.11 (s, 2H); MS (m/e
): 427 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.95(s, 1H), 8.87 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.03 (s, 1H), 7.85 (m, 2H), 7.69 (d,J
=8.8Hz, 1H),7.37 (t,J
=8.0Hz, 1H), 7.19 (d,J
=8Hz, 1H), 4.41 (s, 1H), 4.08 (s, 1H), 4.05 (s, 1H), 2.94 (t,J
=10.8Hz, 2H), 2.17 (t,J
=4Hz, 1H), 1.86 (t,J
=6Hz, 2H),
1.66 (s, 4H), 1.33 (m, 2H); MS (m/e
): 401(M+1)。
MS (m/e
): 413.2 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.96 (s, 1H), 9.44 (s, 1H), 8.50 (s, 1H), 8.45 (s, 1H), 8.00 (s, 1H), 7.88 (t,J
=2.8Hz, 1H), 7.70 (d,J
=8.8Hz, 1H),7.36 (t,J
=8.0Hz, 1H), 7.19 (d,J
=7.6Hz, 1H), 6.85 (d,J
=6Hz, 1H), 4.19 (s, 1H), 3.33 (m, 4H), 3.22 (s, 3H); MS (m/e
): 362 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.51 (s, 1H), 8.47~8.46 (d,J
=2.4Hz, 1H), 7.97 (s, 1H), 7.93~7.91 (dd,J
=2.4Hz, 8.8Hz, 1H), 7.83~7.81 (dd,J
=1.6Hz, 8.4Hz, 1H), 7.77~7.74 (d,J
=8.8Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.28~7.26 (dd,J
=1.2Hz, 8Hz, 1H), 3.78~7.74 (t,J
=6.4Hz, 2H), 3.52 (s, 1H), 2.93~2.90 (m, 1H), 2.86~2.82 (t,J
=6.0Hz, 2H), 1.13~1.10 (m, 2H), 0.97~0.95 (m, 2H); MS (m/e
): 397.4 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 8.90 (s,1H), 8.55~8.55 (d,J
=2Hz, 1H), 8,44 (s, 1H), 8.18~8,17 (d,J
=1.2Hz, 1H), 8.07 (s, 1H), 7.94~7.91 (dd,J
=2Hz, 9.2Hz, 1H), 7.70~7.65 (m, 2H), 7.56~7.54 (d,J
=8.8Hz, 1H), 7.43~7.40 (m, 1H), 7.17~7.09 (m, 3H), 4.64 (s, 2H),
3.03 (s, 3H); MS (m/e
): 417.5 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.78 (s, 1H), 8.71 (s, 1H), 8.54~8.53 (d,J
=1.6Hz, 1H), 8.52 (s, 1H), 8.06 (s, 1H), 7.96~7.90 (m, 2H)。7.71~7.69 (d,J
=9.2Hz, 1H), 7.40~7.36 (t,J
=8Hz, 1H), 7.20~7.19 (d,J
=7.2Hz, 1H), 4.20 (s, 1H), 3.43~3.41 (m, 2H), 2.99 (s, 3H), 1.13~1.09 (t,J
=7.2Hz, 3H); MS (m/e
): 346.4 (M+1)
MS (m/e
): 413.2 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.49 (s, 1H), 8.40~8.39 (d,J
=2.4Hz, 1H), 7.99 (s, 1H), 7.94 (s, 1H), 7.80~7.77 (d,J
=8.8Hz, 1H), 7.74~7.72 (d,J
=8.8Hz, 1H), 7.62~7.57 (m, 1H), 7.39~7.35 (t,J
=7.6Hz, 1H), 7.28~7.26 (d,J
=7.6Hz, 1H), 3.55 (s, 1H), 3.56~3.49 (m, 4H), 2.85~2.78 (m, 6H), 1.28~1.25 (t,J
=6.8Hz, 3H), 1.19~1.15 (t,J
=6.8Hz, 6H); MS (m/e
): 431.5 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.51 (s, 1H), 8.39~8.39 (d,J
=2.4Hz, 1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.81~7.78 (dd,J
=2Hz, 9.6Hz, 1H), 7.75~7.73 (d,J
=9.4Hz, 1H), 7.41~7.37 (t,J
=8Hz, 1H), 7.30~7.27 (m, 1H), 3.53 (s, 1H), 3.46~3.43 (t,J
=7.2Hz, 4H), 1.68~1.65 (m, 4H), 1.45~1.40
(m, 4H), 1.03~0.99 (t,J
=7.2Hz, 6H); MS (m/e
): 416.5 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.50 (s, 1H), 8.40~8.39 (d,J
=2.0Hz, 1H), 7.97 (s, 1H), 7.83~7.81 (d,J
=8.4Hz, 1H), 7.75~7.68 (m, 2H), 7.41~7.37 (t,J
=8.4Hz, 1H), 7.29~7.27 (m, 1H), 3.61~3.58 (t,J
=6.0Hz, 2H), 3.53 (s, 1H), 3.12 (s, 1H), 2.72~2.69 (t,J
=6.0Hz, 2H), 2.45 (s, 6H); MS (m/e
): 389.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.51 (s, 1H), 8.40~8.39 (d,J
=2Hz, 1H), 7.98 (s, 1H), 7.83~7.80 (dd,J
=2.4Hz, 9.2Hz, 1H), 7.75~7.73 ((d,J
=9.2Hz, 1H), 7.41~7.27 (t,J
=8Hz, 1H), 7.29~7.27 (d,J
=7.6Hz, 1H), 3.53 (s, 1H), 3.53~3.48 (t,J
=7.6Hz, 2H), 3.39~3.36 (t,J
=6.8Hz, 2H), 1.77~1.71 (m, 2H), 1.15~1.14 (m, 1H), 1.02~0.98 (t,J
=7.2Hz, 3H), 0.62~0.58 (m, 2H), 0.37~0.34 (m, 2H); MS (m/e
): 400.5 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.75 (s, 1H), 8.73~8.72 (d,J
=2Hz, 1H), 8.08~8.05 (dd,J
=2.4Hz, 9.2Hz, 1H), 7.92~7.92 (d,J
=1.2Hz,1H), 7.83 (s, 1H), 7.81 (s, 1H), 7.78~7.75 (m, 1H), 7.50~7.47 (m, 2H), 3.80~3.77 (t,J
=6.4Hz, 2H), 3.63 (s, 1H), 3.24 (s, 3H), 2.86~2.83 (t,J
=
6.4Hz, 2H); MS (m/e
): 371.4 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.50 (s, 1H), 8.40~8.39 (d,J
=2.4Hz, 1H), 7.79 (s, 1H), 7.82~7.79 (dd,J
=2.0Hz, 8.8Hz, 2H), 7.73~7.71 (d,J
=8.8Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.28~7.26 (d,J
=8.4Hz, 1H), 3.53 (s, 1H), 3.51~3.4 (q,J
=7.2Hz, 2H), 3.46~3.42 (t,J
=7.6Hz, 2H), 1.68~1.64 (m, 2H), 1.45~1.40 (m, 2H), 1.28~1.25 (t,J
=7.2Hz, 3H), 1.02~0.99 (t,J
=7.6Hz, 3H); MS (m/e
): 388.5 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.76(s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.04 (s, 1H), 7.90 (d,J
=8Hz,1H), 7.75 (d,J
=8.8Hz, 1H),7.39 (t,J
=8.0Hz, 1H), 7.20 (d,J
=7.6Hz, 1H), 4.19 (s, 1H), 3.50 (s, 8H), 2.43 (s, 4H), 2.16 (s, 6H); MS (m/e
): 444(M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.78 (s, 1H), 9.11 (s, 1H), 8.52 (s, 2H), 8.04 (s, 1H), 7.91 (d,J
=8Hz, 2H), 7.69 (t,J
=8.0Hz, 1H), 7.37 (d,J
=7.6Hz, 1H), 7.18 (d,J
=7.6Hz, 1H),4.19 (s, 1H), 3.65-3.23 (m, 12H), 3.14 (s, 3H); MS (m/e
): 431 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.78 (s, 1H), 9.15 (s,
1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.88 (d,J
=8Hz, 1H), 7.84 (d,J
=8.8Hz, 1H),7.70 (d,J
=8.8Hz, 1H),7.38 (t,J
=8.0Hz, 1H), 7.20 (d,J
=7.6Hz, 1H), 6.45 (t,J
=2.4Hz, 1H), 4.19 (s, 1H), 2.38 (t,J
=6.4Hz, 6H), 1.52 (m,J
=5.2, 4H), 1.40 (m, 2H), 1.23 (s, 2H); MS (m/e
): 415 (M+1)
MS (m/e
): 413.2 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77(s, 1H), 9.01 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.85 (t,J
=8.0Hz, 2H), 7.71 (d,J
=8.8Hz, 1H),7.39 (t,J
=8.0Hz, 1H), 7.20 (d,J
=6.8Hz, 1H), 6.44 (t,J
=2.4Hz, 1H), 4.19 (s, 1H), 3.27 (m, 4H), 2.54 (m, 4H), 1.70 (s, 4H); MS (m/e
): 401 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.46 (s, 1H), 8.87 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.03 (s, 1H), 7.88 (d,J
=8Hz, 2H), 7.70 (d,J
=5.2Hz, 1H),7.38 (t,J
=8.0Hz, 2H), 7.20 (d,J
=8Hz, 2H), 4.21 (s, 1H), 3.20 (m, 2H), 2.95 (m, 2H); MS (m/e
): 398 (M+1)
1
H NMR (CDCl3
, 400 MHz): δ 9.79 (s, 1H), 8.50 (s, 1H), 8.45~8.36 (m, 2H), 8.05 (s, 1H), 7.97~7.95 (d,J
=8.4Hz, 1H), 7.92~7.90 (d,J
=8.4Hz, 1H), 7.68~7.65 (d,J
=8.8Hz,
1H), 7.38~7.34 (t,J
=7.6Hz, 1H), 7.19~7.17 (d,J
=7.6Hz, 1H), 4.19 (s, 1H), 3.58~3.56 (m, 2H), 1.74~1.60 (m, 4H), 1.26~1.23 (m, 6H), 0.91~0.86 (m, 6H); MS (m/e
): 416.5 (M+1)
1
H NMR (CDCl3
, 400 MHz): δ 9.86 (s,1H), 9.20 (s,1H), 8,56~8.56 (d,J
=2Hz, 1H), 8.53 (s, 1H), 8.06 (s,1H), 7.98~7.95 (dd,J
=2Hz, 8.8Hz, 1H), 7.93~7.91 (d,J
=8.4Hz, 1H), 7.73~7.70 (d,J
=8.8Hz, 1H), 7.39~7.35 (t,J
=7.2Hz, 1H), 7.20~7.18 (d,J
=7.6, 1H), 4.20(s, 1H), 3.79~3.75 (t,J
=6.8Hz, 4H), 2.85~2.82 (t,J
=6.8Hz, 4H); MS (m/e
): 410.4 (M+1)
1
H NMR (CDCl3
MHz): δ 9.77 (s, 1H), 8,69 (s, 1H), 8,53~8.51 (m, 2H), 8.05 (s, 1H), 7.95~7.89 (m, 2H), 7.69~7.67 (d,J
=8.8, 1H), 7.39~7.35 (t,J
=7.2Hz, 1H), 7.19~7.17 (d,J
=7.2Hz, 1H), 4.19 (s, 1H), 2.98 (s, 3H), 1.51~1.50 (m, 2H), 1.26~1.25 (m, 6H), 0.84 (s, 3H); MS (m/e
): 402.5 (M+1)
1
H NMR (CD3
OD, 400 MHz): δ 8.50 (s, 1H), 8.40~8.40(d,J
=2.0Hz, 1H), 7.97 (s, 1H), 7.80~7.77 (m, 2H), 7.74~7.71 (d,J
=9.2Hz, 1H), 7.38~7.36 (t,J
=8.0Hz, 1H), 7.28~7.27 (d,J
=7.6Hz, 1H), 4.29~4.29 (d,J
=2.4Hz, 2H),
3.53 (s, 1H), 3.18 (s, 3H), 2.75~2.73 (t,J
=2.4Hz, 1H); MS (m/e
): 356.4 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 8.51 (s, 1H), 8.49 (s, 1H), 7.94 (s, 1H), 7.91~7.88 (dd,J
=1.6Hz, 9.2Hz, 1H), 7.80~7.78 (d,J
=8.8Hz, 1H), 7.76~7.76 (d,J
=0.8Hz, 1H), 7.46~7.44 (t,J
=8.8Hz, 1H), 7.38~7.36 (t,J
=7.6Hz, 1H), 7.29~7.28 (m, 1H), 7.27~7.24 (t,J
=8.4Hz, 1H), 4.60 (s, 4H), 3.51 (s, 1H); MS (m/e
): 382.4 (M+1)
1
H NMR (CDCl3
, 400 MHz): δ 9.78 (s, 1H), 8.77 (s, 1H), 8.53~8.52 (d,J
=2Hz, 1H), 8.51 (s, 1H), 8.04 (s, 1H), 7.94~7.88 (m, 2H), 7.70~7.68 (d,J
=8.8Hz, 1H), 7.39~7.353 (t,J
=8Hz, 1H), 7.19~7.17 (d,J
=7.6Hz, 1H), 5.84~5.79 (m, 1H), 5.22~5.16 (m, 2H), 4,19 (s, 1H), 4.02~4.01 (d,J
=4.8Hz, 2H), 2,97 (s, 1H); MS (m/e
): 357.4 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.81 (s, 1H), 9.23 (s, 1H), 8.52 (s, 2H), 8.49 (s, 1H), 8.04 (s, 1H), 7.90 (m, 2H), 7.70 (d,J
=8.8Hz, 1H), 7.37 (t,J
=7.6Hz, 1H), 7.18 (d,J
=7.6Hz, 1H), 4.19(s, 1H), 3.87 (t,J
=8Hz, 2H), 3.59 (s, 2H), 2.06 (m, 2H), 1.72 (s, 2H); MS (m/e
): 408 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.78 (s, 1H), 9.11 (s,
1H), 8.51 (s, 2H), 8.04 (s, 1H), 7.90 (d,J
=8.8Hz, 2H), 7.69 (d,J
=8.8Hz, 1H),7.37 (t,J
=8.0Hz, 1H), 7.18 (d,J
=8.8Hz, 1H), 4.19 (s, 1H), 3.68(m, 4H), 2.59 (m, 6H), 1.07 (m, 3H);MS (m/e
): 401 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77(s, 1H), 9.13 (s, 1H), 8.51 (s, 2H), 8.04 (s, 1H), 7.92 (t,J
=7.6Hz, 2H), 7.69 (d,J
=8.8Hz, 1H),7.37 (t,J
=8.0Hz, 1H), 7.18 (d,J
=6.0Hz, 1H), 4.19 (s, 1H), 3.88 (s, 4H), 3.59 (t,J
=5.2Hz, 4H), 1.64 (t,J
=5.2Hz, 4H);MS (m/e
): 430 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.76(s, 1H), 9.92 (s, 1H), 8.51 (s, 2H), 8.04 (s, 1H), 7.90 (d,J
=8Hz, 2H), 7.68 (d,J
=8.8Hz, 1H),7.37 (t,J
=8.0Hz, 1H), 7.17 (d,J
=8.8Hz, 1H), 4.19 (s, 1H), 2.76 (t,J
=12Hz, 1H), 2.41 (t,J
=10.8Hz, 6H), 1.66-1.42 (m, 6H), 1.22-1.07 (m, 8H);MS (m/e
): 428(M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 8.90 (s, 1H), 8.51 (d,J
=6.8, 2H), 8.03 (s, 1H), 7.87 (t,J
=8.8Hz, 2H), 7.71 (d,J
=8.8Hz, 1H),7.37 (t,J
=8.0Hz, 1H), 7.18 (d,J
=8Hz, 1H), 4.18 (s, 1H), 3.67 (m, 8H), 1.15 (d,J
=2.0Hz, 1H), 0.79 (m, 4H); MS (m/e
): 441 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.79 (s, 1H), 9.18 (s, 1H), 8.54 (d,J
=4.4 Hz, 2H), 8.05 (s, 1H), 7.89 (m, 2H), 7.74~7.71 (d,J
=8.8 Hz, 1H), 7.41~7.37 (t,J
=8.0 Hz, 1H), 7.21~7.19 (d,J
=7.6 Hz, 1H), 4.20 (s, 1H), 3.65 (bs, 4H), 3.18 (bs, 4H), 2.94 (s, 3H); MS (m/e
): 451.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.51 (s 1H), 8.06 (s 1H), 8.05 (s, 1H), 7.68-7.80 (d,J
=9.2 Hz, 3H), 7.39-7.42 (t,J
=8.0 Hz, 1H), 7.29-7.31 (d,J
=3.2 Hz, 1H), 7.20-7.20 (d,J
=0.4 Hz, 1H), 4.08-4.12 (t,J
=8.0 Hz, 2H), 3.67-3.73 (t,J
=8.0 Hz, 2H); MS (m/e
): 348.1 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.82 (s, 1H), 8.93 (s, 1H), 8.52~8.46 (m, 4H), 8.03 (s, 1H), 7.90~7.88 (m, 2H), 7.72~7.70 (m, 2H), 7.37 (s, 2H), 7.19~7.18 (m, 1H), 4.74 (s, 2H), 4.20 (s, 1H), 3.33~3.35 (m, 2H), 1.07~1.05 (m, 1H), 0.42~0.41 (m, 2H), 0.23~0.19 (m, 2H); MS (m/e
): 449.5 (M+1)
1
H NMR (CDCl3
, 400 MHz): δ 9.78 (s, 1H), 8.70 (s, 1H), 8.53~8.48 (m, 4H), 8.02~7.97 (m, 2H), 7.88~7.84 (m, 1H), 7.74~7.65 (m, 2H), 7.32 (s, 2H), 7.19 (s, 1H), 4.54 (s, 2H), 4.19 (s, 1H), 2.65~2.58 (m, 1H), 0.96~0.89 (m, 2H), 0.76~0.75 (m, 2H); MS (m/e
): 435.5 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.79 (s, 1H), 9.04 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.90~7.84 (m, 2H), 7.71~7.69 (d,J
=8.8 Hz, 1H), 7.41~7.37 (t,J
=8.0 Hz, 1H), 7.21~7.19 (d,J
=7.6 Hz, 1H), 6.82~6.80 (d,J
=8.0Hz, 1H), 4.20 (s, 1H), 3.87~3.82 (m, 2H), 3.75~3.73 (bs, 1H), 3.43~3.38 (t,J
=9.2Hz, 2H), 1.85~1.81 (d,J
=5.6 Hz, 2H), 1.44~1.40 (m, 2H); MS (m/e
): 388.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.79 (s, 1H), 9.09~9.05 (m, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.89~7.84 (m, 2H), 7.72~7.70 (d,J
=9.2 Hz, 1H), 7.41~7.37 (t,J
=8.0 Hz, 1H), 7.21~7.19 (d,J
=7.2 Hz, 1H), 6.69~6.65 (m, 1H), 4.20 (s, 1H), 3.73~3.40 (t,J
=7.2Hz, 2H), 2.62~2.59 (t,J
=7.2Hz, 2H), 2.10 (s, 3H); MS (m/e
): 378.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.79 (s, 1H), 9.02 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 8.03 (s, 1H), 7.89~7.84 (m, 2H), 7.71~7.69 (d,J
=8.8 Hz, 1H), 7.41~7.37 (t,J
=8.8 Hz, 1H), 7.21~7.19 (d,J
=7.2 Hz, 1H), 6.69 (m, 1H), 4.20 (s, 1H), 3.24~3.20 (t,J
=6.8Hz, 2H), 2.55~2.53 (t,J
=7.2Hz, 2H), 2.06 (s, 3H), 2.55~2.53 (tt,J
=6.8Hz, 7.2Hz, 2H); MS (m/e
): 392.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.83 (s, 1H), 9.37 (s, 1H), 8.54 (d,J
=8.8, 2H), 8.08 (s, 1H), 7.93 (t,J
=8.8Hz, 2H), 7.74 (d,J
=9.2Hz, 1H),7.39 (t,J
=8.0Hz, 1H), 7.20 (d, J=7.6Hz, 1H), 4.23 (s, 1H), 3.55 (m, 8H); MS (m/e
): 469(M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.77 (s, 1H), 9.01 (s, 1H), 8.52 (d,J
=6.8, 2H), 8.05 (s, 1H), 7.88 (m, 2H), 7.72 (d,J
=7.2Hz, 1H),7.39 (t,J
=8.4Hz, 1H), 7.20 (d,J
=7.6Hz, 1H), 4.20 (s, 1H),3.66 (d,J
=6.4Hz, 2H), 3.54 (t,J
=5.2Hz, 4H), 2.66 (t,J
=4.8Hz, 4H); MS (m/e
): 455 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.49 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.81~7.79 (d,J
=7.2 Hz, 1H), 7.74~7.73 (m, 2H), 7.40~7.36 (t,J
=8.0 Hz, 1H), 7.27~7.25 (d,J
=7.2 Hz, 1H), 3.64~3.62 (bs, 4H), 3.52 (s, 1H), 2.53~2.51 (bs, 4H), 2.35 (s, 3H); MS (m/e
): 387.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.48 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.81~7.79 (d,J
=7.2 Hz, 1H), 7.74~7.73 (m, 2H), 7.40~7.36 (t,J
=8.0 Hz, 1H), 7.27~7.25 (d,J
=7.2 Hz, 1H), 3.64~3.61 (bs, 4H), 3.52 (s, 1H), 2.77~2.74 (m, 1H), 2.64~2.62 (bs, 4H), 1.12~1.10 (d,J
=6.4 Hz, 3H);
MS (m/e
): 415.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.48 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.81~7.79 (d,J
=7.2 Hz, 1H), 7.74~7.73 (m, 2H), 7.40~7.36 (t,J
=8.0 Hz, 1H), 7.27~7.25 (d,J
=7.2 Hz, 1H), 4.34~4.31 (d,J
=13.6 Hz, 2H), 3.51 (s, 1H), 2.97~2.91 (t,J
=12.4 Hz, 2H), 2.52~2.48 (m, 1H), 2.33 (s, 6H), 2.00~1.97 (d,J
=11.6 Hz, 2H), 1.49~1.45 (m, 2H); MS (m/e
): 415.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.48 (s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.81~7.79 (d,J
=7.2 Hz, 1H), 7.74~7.73 (m, 2H), 7.40~7.36 (t,J
=8.0 Hz, 1H), 7.27~7.25 (d,J
=7.2 Hz, 1H), 4.34~4.31 (d,J
=13.6 Hz, 2H), 3.51 (s, 1H), 2.98~2.91 (t,J
=13.2 Hz, 3H), 2.73 (m, 4H), 1.96~1.93 (d,J
=12.4 Hz, 2H), 1.56~1.53 (m, 2H), 1.14~1.10 (t,J
=7.6 Hz, 6H); MS (m/e
): 443.5 (M+1)。
MS (m/e
): 443 (M+1)。
MS (m/e
): 45.2 (M+1)。
合成路線及方法如下:
2-胺基-4-氟苯甲酸(1.55g, 10mmol)溶於甲醯胺(5mL)並加熱至150℃攪拌6h。反應液在攪拌下冷卻至室溫,析出的沈澱過濾,濾餅用乙酸乙酯洗滌,紅外工乾燥得到1.3g的7-氟喹唑啉-4-羥基,産率78%。
7-氟喹唑啉-4-羥基(1g, 6.0mmol)在0℃下溶於濃硫酸(3mL),然後在15min內緩慢滴入濃硝酸HNO3
(3mL),滴加完畢後,反應液加熱至100℃攪拌3h。冷卻至室溫後,反應液倒入攪拌中的冰水,有固體析出,過濾,粗品在冰乙酸中進行重結晶,得到0.60g的7-氟-6-硝基喹唑啉-4-羥基,産率38%。
7-氟-6-硝基喹唑啉-4-羥基(518mg, 2mmol)溶於氯化亞碸(3mL),加入2-3滴的DMF,反應液回流3h。減壓蒸餾除去溶劑,剩餘的固體産物4-氯-7-氟-6-硝基喹唑啉可直接用於下一步反應,無需進一步分離。
4-氯-7-氟-6-硝基喹唑啉(458mg, 2.0mmol)和3-炔基苯胺(234mg, 2.0mmol)溶於異丙醇(5mL)後加熱回流3h。冷卻至室溫後,析出的固體過濾,濾餅用少量水洗滌,紅外乾燥後,得到0.59g的N-(3-炔基苯基)-7-氟-6-硝基喹唑啉-4-
胺,産率95%。
N-(3-炔基苯基)-7-氟-6-硝基喹唑啉-4-胺(310mg, 1mmol)和SnCl2
.2H2
O (171mg, 4.5mmol)的乙酸乙酯溶液回流2h。反應液冷卻至室溫,用5%的碳酸氫鈉水溶液調節pH值至9-10後,以乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到225mg的N-4-(3-炔基苯基)-7-氟喹唑啉-4, 6-二胺,黃色固體,産率81%。
N-4-(3-炔基苯基)-7-氟喹唑啉-4, 6-二胺(100mg, 0.36mmol)溶於DMF(3mL)後,在室溫下依次加入吡啶(35μL, 0.432mmol),氯甲酸苯酯(46μL, 0.36mmol),加熱至70℃攪拌1h,得到苯基-4-(3-炔基苯基胺)-7-氟喹唑啉-6-基-甲酸胺,可直接用於下一步反應,無需處理。此時,在同一溫度下繼續加入哌啶(0.36mmol)並攪拌2.5h。冷卻至室溫後,反應液倒入水中,用乙酸乙酯萃取,有機相用飽和食鹽水洗滌,硫酸鈉乾燥,濃縮後得到的粗品用柱色譜分離,得到目標産物105mg,産率75%。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.22 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.63 (s 1H), 8.02 (s, 1H), 7.90 (d,J
=8Hz, 1H), 7.62 (d,J
=12Hz, 1H), 7.42 (t,J
=8.4Hz, 1H), 7.25 (d,J
=7.6Hz, 1H), 4.23 (s, 1H), 3.49 (m, 4H), 1.53 (m, 6H); MS (m/e
): 390 (M+1)。
化合物61-65是用類似於化合物60的方法合成的。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.88 (s, 1H), 8.71 (s, 1H), 8.59 (d,J
=6.4Hz, 2H), 8.05 (s 1H), 7.90 (d,J
=9.2Hz, 1H), 7.61 (d,J
=7.6Hz,1H), 7.41 (t,J
=8.0Hz, 1H), 7.24(d,J
=8.8Hz, 1H), 4.22 (s, 1H), 3.65 (m, 4H), 3.49 (m, 6H); MS (m/e
): 392 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.04 (s, 1H), 8.79 (s, 1H), 8.67 (d,J
=0.4Hz, 1H), 8.56 (s, 1H), 8.07 (s, 1H), 7.92 (d,J
=8.8Hz, 1H), 7.60 (d,J
=10.8Hz, H), 7.41 (m, 2H), 7.23 (d,J
=7.6Hz, 1H), 7.12 (m, 3H), 4.62 (s, 1H), 4.23 (s, 1H), 3.01 (s, 1H); MS (m/e
): 444 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.00 (s, 1H), 8.83 (s, 1H), 8.73 (d,J
=4Hz, 1H), 8.56 (s, 1H), 8.00 (s, 1H), 7.78 (d,J
=8Hz, 1H), 7.61(d,J
=12Hz, 1H), 7.40 (m,J
=7.6Hz, 1H), 7.23 (d,J
=7.2Hz, 1H), 4.22 (s, 1H), 3.57 (s, 8H), 3.37 (s, 6H); MS (m/e
): 438 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.96 (s, 1H), 8.67 (s, 1H), 8.59 (s,1H), 8.60 (s, 1H), 8.39 (s, 1H), 8.05 (d,J
=8.4Hz, 1H), 7.91 (d,J
=8.8Hz, 1H), 7.59 (d,J
=10.8Hz, 1H), 7.39 (d,J
=7.6Hz, 1H), 7.22 (d,J
=6Hz, 1H), 7.13 (d,J
=2.0Hz, 1H), 4.22 (s, 1H), 3.68 (m, 4H), 2.22 (s, 6H), 1.80 (m, 2H); MS (m/e
): 419 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.93 (s, 1H), 8.73 (s, 1H), 8.58 (s,2H), 8.06 (s, 1H), 7.91 (d,J
=8.0Hz, 1H), 7.58 (d,J
=8.8Hz, 1H), 7.40 (t,J
=6.8Hz, 1H), 7.23 (d,J
=8Hz, 1H), 4.22 (s, 1H), 2.92 (t,J
=5.2Hz, 2H), 2.51 (m, 4H), 1.99-1.91 (m, 4H), 1.72-1.42(m, 4H), 1.23-1.16 (m, 4H); MS (m/e
): 459 (M+1)。
合成路線及方法如下:
在0℃下將金屬鈉(92mg, 4mmol)溶於甲醇(4mL),同時用氮氣保護,然後將7-氟-6-硝基喹唑啉-4-羥基(418mg, 2mmol)加入,回流3h。冷卻至室溫,用2N HCl將pH值調至3-4後,減壓蒸餾除去溶劑,剩餘物用乙酸乙酯溶解後,用水洗滌2次,硫酸鈉乾燥,濃縮後得到405mg的7-甲氧基-6-硝基喹唑啉-4-羥基,産率92%。
接下來的合成方法與實施例60相同。
1
H NMR (DMSO-d6
, 400 MHz): 9.81 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.89 (d,J
=8.8Hz, 1H), 7.38 (t,J
=8Hz, 1H), 7.25(s, 1H), 7.19 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 3.98 (s, 3H), 3.53-3.51 (m, 4H), 1.60-1.53 (s, 6H); MS (m/e
): 402 (M+1)。
化合物67-84是用類似於化合物66的方法合成的。
1
H NMR (DMSO-d6
, 400 MHz): 9.69 (s, 1H), 8.58 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 7.90 (d,J
=8.8Hz, 1H), 7.38 (t,J
=8Hz, 1H), 7.26 (s, 1H), 7.19 (d,J
=7.2Hz, 1H), 4.19 (s, 1H), 3.99 (s, 3H), 3.64 (t,J
=4.8Hz, 4H), 3.49 (s,J
=4.8Hz, 4H); MS (m/e
): 404 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.71 (s, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.91 (d,J
=8.8Hz, 1H), 7.37 (t,J
=6.4Hz, 1H), 7.24 (s, 1H), 7.18(d,J
=5.2Hz, 1H), 4.19 (s, 1H), 3.98 (s, 3H), 3.50 (m, 4H), 2.48 (m, 6H), 1.04 (s, 3H); MS (m/e
): 431 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.65 (s, 1H), 8.73 (s, 1H), 8.57(s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.87 (d,J
=7.6Hz, 1H), 7.37 (t,J
=8Hz, 1H), 7.24 (s, 1H), 7.17 (d,J
=7.6Hz, 1H), 4.19 (s, 1H), 4.01 (s, 3H), 3.56 (s, 8H), 3.36 (s,
6H); MS (m/e
): 450 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.73 (s, 1H), 8.66 (s, 1H), 8.53(s, 1H), 8.49 (s, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.89 (d,J
=7.2Hz, 1H), 7.46-7.36 (m, 3H), 7.25-7.13 (m, 6H), 4.63 (s, 2H), 4.19 (s, 1H), 3.98 (s, 3H), 3.04 (s, 3H); MS (m/e
): 456 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.66 (s, 1H), 8.88 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 7.98 (s, 1H), 7.85 (d,J
=8.0Hz, 1H), 7.37 (t,J
=8.0Hz, 1H), 7.12 (s, 1H), 7.15 (d,J
=7.2Hz, 1H), 4.18(s, 1H), 4.03 (s, 3H), 3.43-3.30 (m, 7H); MS (m/e
): 392 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.76 (s, 1H), 8.62 (s, 1H), 8.51(s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.87 (d,J
=7.6Hz, 1H), 7.37 (t,J
=8.0Hz, 1H), 7.26 (s, 1H), 7.18 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 4.01 (s, 3H), 3.54 (dd,J
=4.0Hz, 4.0Hz, 4H), 3.46 (s, 3H), 3.16 (s, 3H); MS (m/e
): 406 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.68 (s, 1H), 8.57 (s, 1H), 8.50(s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.89 (d,J
=7.6Hz, 1H), 7.35 (t,J
=8.0Hz, 1H), 7.24 (s, 1H), 7.17 (d,J
=
7.6Hz, 1H), 4.20 (s, 1H), 3.98 (s, 3H), 3.42-3.40 (m, 2H), 2.99 (s, 3H), 2.80-2.74 (m, 6H), 1.09 (m,6H); MS (m/e
): 447 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.69 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.05 (s, 1H), 8.04 (s, 1H), 7.90 (d,J
=7.6Hz, 1H), 7.38 (t,J
=8Hz, 1H), 7.26 (s, 1H), 7.19 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 3.99 (s, 3H), 3.58 (m, 4H), 2.36 (m, 4H), 2.23(s, 3H); MS (m/e
): 417 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.70 (s,1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.04 (s, 2H), 7.90 (d,J
=8.0Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.25 (s, 1H), 7.19 (d,J
=8.0Hz, 1H), 4.21 (s, 1H), 3.99 (s, 3H), 3.50 (m, 4H), 2.49 (m, 4H), 2.24 (m, 2H), 0.85-0.11 (m, 5H); MS (m/e
): 457 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.69 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.04 (s, 2H), 7.90 (d,J
=8.0Hz,1H), 7.38 (t, J= 8.0Hz, 1H), 7.25 (s, 1H), 7.19 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 4.11 (m, 2H), 4.03 (s, 3H), 2.95 (m, 2H), 2.73 (m, 4H), 2.21 (m, 1H), 1.88 (m, 2H), 1.71 (m, 4H), 1.41 (m, 2H); MS (m/e
): 458 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.69 (s, 1H), 8.56 (s,
1H), 8.53 (s, 1H), 8.04 (s, 2H), 7.90 (d,J
=7.6Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.25 (s, 1H), 7.19 (d,J
=7.6Hz, 1H), 4.21(s, 1H), 4.14 (m, 2H), 3.99 (s, 3H), 2.86 (m, 2H), 2.20 (s, 6H), 1.78 (m, 2H), 1.35 (m, 2H), 1.24 (m, 1H); MS (m/e
): 445 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.66 (s, 1H), 8.61 (s, 1H), 8.52 (s, 2H), 8.04 (s, 1H), 7.91 (d,J
=7.2Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.22 (s, 1H), 7.21 (d,J
=7.2Hz, 1H), 4.26 (m, 2H), 4.18 (s, 1H), 3.50 (m, 4H), 2.51 (m, 2H), 2.41 (m, 4H), 1.49 (m, 3H), 1.04 (m, 3H); MS (m/e
): 445 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 8.53 (s, 1H), 8.34-8.31 (m, 3H), 7.83 (dd,J
=2.0Hz,J
=1.6Hz, 1H), 7.60 (d,J
=9.2Hz, 1H), 7.47 (s,1H), 7.7.45 (s,1H), 7.31 (t,J
=7.6Hz, 2H), 7.21 (t,J
=7.2Hz, 1H), 5.61-5.58 (m,1H), 3.79-3.77 (m,1H), 3.66-3.64 (m,1H), 3.39-3.37 (m,2H), 3.18-3.17 (m, 2H), 2.40 (s, 6H), 2.25-2.24 (m, 1H), 1.58 (d,J
=7.6Hz, 3H); MS (m/e
): 405 (M+1)。
1
H NMR (DMSO, 400 MHz): 8.52 (s, 1H), 8.28 (s, 2H), 7.63 (s,1H), 7.48 (d,J
=7.6Hz, 2H), 7.24-7.14 (m, 4H), 5.80-5.77 (m,1H), 3.99 (s,3H), 3.78-3.89 (m, 4H), 3.29-3.22 (m, 2H), 2.33 (s, 6H), 2.25-2.24 (m, 1H), 1.56 (d,J
=7.2Hz,
3H); MS (m/e
): 453 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 8.74 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.56 (s, 1H), 7.23-7.15 (m, 6H), 3.96 (s,3H), 3.72-3.57 (m, 3H), 3.32-3.29 (m, 2H),2.82-2.78 (m, 2H), 2.23 (s, 6H), 1.34(s, 4H); MS (m/e
): 447 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.54 (s, 1H), 8.61 (s, 1H), 8.44 (s, 1H), 7.69 (s, 2H), 7.48 (d,J
=8.0Hz, 2H), 7.23-7.19 (m, 3H), 3.99 (s,3H), 3.80-3.66 (m, 2H), 3.45-3.40 (m, 2H),3.18-3.06 (m, 3H), 2.90-2.83 (m, 6H), 2.08-2.01 (m, 3H), 1.24-1.18 (m, 3H); MS (m/e
): 447 (M+1)。
合成路線及方法如下:
將醋酸脒(6.80g, 65.32mmol)加入到2-氨基-4-硝基苯甲酸(6.00g, 32.94mmol)的乙醇溶液中,加熱至回流,攪拌
5h。冷卻至室溫後,有沈澱析出,過濾,濾餅用冷的乙醇洗滌2次,紅外乾燥,得到5.60g的7-硝基喹唑啉-4-羥基,黃色固體,産率89%。
7-硝基喹唑啉-4-羥基(3.4g, 17.79mmol)溶於氯化亞碸(20mL),加入0.5mL滴的DMF,反應液回流48h。減壓蒸餾除去溶劑,得到2.61g的4-氯-7-硝基喹唑啉,可直接用於下一步反應,無需進一步分離。
4-氯-7-硝基喹唑啉(2.0g, 9.54mmol)和3-炔基苯胺(1.2g, 10.00mmol)溶於異丙醇(30mL)後加熱回流5h。冷卻至室溫後,析出的固體過濾,濾餅用少量水洗滌,紅外乾燥後,得到2.6g的N-(3-炔基苯基)-7-硝基喹唑啉-4-胺,黃色固體,産率94%。
N-(3-炔基苯基)-7-硝基喹唑啉-4-胺(2.0g, 6.89mmol)和SnCl2
.2H2
O (5.0g, 26.37mmol)的乙酸乙酯溶液回流3h。反應液冷卻至室溫,用5%的碳酸氫鈉水溶液調節pH值至9-10後,以乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到1.6的N-4-(3-炔基苯基)喹唑啉-4, 7-二胺,黃色固體,産率86%。
N-4-(3-炔基苯基)喹唑啉-4, 6-二胺(48mg, 0.18mmol)溶於DMF(2mL)後,在室溫下依次加入吡啶(32μL),氯甲酸苯酯(25.2μL, 0.18mmol),攪拌1.5h後,加入N, N, N-三甲基乙基-1,2-二胺(20mg, 0.19mmol),加熱至80℃攪拌3h。冷卻至室溫後,反應液倒入水中,用乙酸乙酯萃取(20mL, 3次),有機相用飽和食鹽水洗滌,硫酸鈉乾燥,濃縮後得到
的粗品用柱色譜分離,得到目標産物55mg,産率78%。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.92 (s, 1H), 9.66 (s, 1H), 8.69~8.58 (d,J
=8.8Hz, 1H), 8.52 (s, 1H), 8.15 (s, 1H), 8.00~7.98 (dd,J
=0.8Hz, 8.8Hz, 1H), 7.92~7.91 (d,J
=1.6Hz, 1H), 7.72~7.70 (d,J
=9.2Hz, 1H), 7.39~7.35 (t,J
=7.6Hz, 1H), 7.19~7.17 (d,J
=7.6Hz, 1H), 4.20 (s, 1H), 3.48~3.45 (m, 2H), 3.00 (s, 3H), 2.53~2.48 (m, 2H), 2.28 (s, 6H); MS (m/e
): 389.5 (M+1)
化合物86-90採用的合成方法類似於化合物85的合成方法。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.85 (s,1H), 8.56~8.54 (d,J
=9.2, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.98~7.96 (d,J
=8.8Hz, 1H), 7.84 (s, 1H), 7.69~7.66 (d,J
=9.6Hz, 1H), 7.40~7.36 (t,J
=7.6Hz, 1H), 7.20~7.18 (d,J
=7.5Hz, 1H), 4.20 (s, 1H), 2.99 (s, 3H), 2.87~2.85 (m, 2H), 2.66~2.56 (m, 6H), 1.03~0.99 (t,J
=7.2Hz, 6H); MS (m/e
): 417.5 (M+1)。
1
H NMR (DMSO-d6
, 400 Hz): δ 9.90 (s, 1H), 8.97 (s, 1H), 8.59~8.457 (d,J
=9.2Hz, 1H), 8.53 (s, 1H), 8.15 (s, 1H), 8.02~8.02 (d,J
=1.6Hz, 1H), 8.00~7.98 (d,J
=7.6Hz, 1H), 7.85~7.83 (dd,J
=1.6Hz, 8.8Hz, 1H), 7.39~7.35 (t,J
=8.0Hz, 1H), 7.20~7.18 (d,J
=7.6Hz, 1H), 5.88~5.79 (m, 1H), 5.21~5.16 (m, 2H), 4.20 (s, 1H), 4.03~4.02 (d,J
=5.2Hz, 2H), 3.15 (s, 3H); MS (m/e
): 358.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.13 (s, 1H), 9.86 (s, 1H), 8.56~8.54 (d,J
=9.2Hz, 1H), 8.52 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.58~7.56 (d,J
=9.2Hz, 1H), 7.49~7.46 (t,J
=6.4Hz, 1H), 7.39~7.33 (m, 5H), 7.27~7.23 (m, 1H), 7.20~7.18 (d,J
=7.2Hz, 1H), 4.36~4.34 (d,J
=6.0Hz, 2H), 4.21 (s, 1H); MS (m/e
): 394.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.91 (s, 1H), 8.59~8.57 (d,J
=9.2Hz, 1H), 8.53 (s, 1H), 8.14 (s, 1H), 8.02~8.01 (d,J
=2.0Hz, 1H), 7.99~7.98 (d,J
=7.6Hz, 1H), 7.85~7.82 (dd,J
=1.6Hz, 8.8Hz, 1H), 7.39~7.35 (t,J
=8Hz, 1H), 7.20~7.18 (d,J
=8Hz, 1H), 4.21 (s, 1H), 3.64~3.62 (m, 4H), 3.54~3.52 (m, 4H); MS (m/e
): 374.4 (M+1)
1
H NMR (DMSO-d6
, 400 MHz): δ 9.73 (s, 1H), 8.79 (s, 1H), 8.54 (s, 1H), 8.46~8.44 (d,J
=9.6Hz, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.95~7.93 (d,J
=8Hz, 1H), 7.80~7.77 (t,J
=1.2Hz, 9.2), 7.41~7.37 (t,J
= 15.2Hz, 1H), 7.21~7.19 (d,J
=8Hz, 1H), 4.21 (s, 1H), 3.55~3.51 (m, 2H), 3.30 (s, 1H), 3.04 (s, 1H); MS (m/e
): 376.4 (M+1)。
合成路線及方法如下:
將二甲基甲醯胺二甲基乙縮醛(0.88g, 7.36mmol)加入到5-硝基-2-氨基苯甲氰(1.00g, 6.13mmol)的二氧六環(25mL)溶液中,加熱至100℃回流2h。反應液冷卻至室溫後繼續冷去至0℃,有大量沈澱析出,過濾,濾餅用冷卻的乙醚洗滌2~3次後紅外乾燥,得到1.30g的(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺,黃色固體,産率97%。
將(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺(1.00g, 4.58mmol)和3-氨基苯炔(0.64g, 5.49mmol)的冰乙酸(15mL)加熱至100℃攪拌3h。反應液冷卻至室溫,有沈澱析出,過濾,濾餅用乙醚洗滌,紅外乾燥,得到1.23g的N-(3-炔基苯基)-6-硝基喹唑啉-4-胺,黃色固體,産率93%。
N-(3-炔基苯基)-6-硝基喹唑啉-4-胺(1.00g, 3.45mmol)和SnCl2
.2H2
O (3.10g, 13.8mmol)的乙酸乙酯(35mL)溶液回流2h。反應液冷卻至室溫後,用5%的碳酸氫鈉水溶液將pH值調至9-10,混合液用乙酸乙酯萃取,有機相依次用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到0.79g的N-4-(3-
炔基苯基)喹唑啉-4,6-二胺,黃色固體,産率89%。
在室溫下,向N-4-(3-炔基苯基)喹唑啉-4,6-二胺(100mg, 0.38mmol)的DMF (2mL)溶液中依次加入N,N-二異丙基乙胺(124μL, 0.76mmol),氯乙醯氯(32μL, 0.38mmol)。攪拌10min後,加入1-甲基哌(209μL, 1.90mmol),並加熱至80℃攪拌5h,反應液濃縮後,用TLC進行分離,得到目標産物,産率94%。
1
H NMR (CD3
OD, 400 MHz): δ 8.65 (s, 1H), 8.54 (s, 1H), 7.99~7.97 (m, 2H), 7.84~7.79 (m, 2H), 7.43~7.39 (t,J
=8.0Hz, 1H), 7.31~7.29 (d,J
=8.0Hz, 1H), 4.62 (s, 2H), 3.54 (s, 1H), 2.75~2.67 (bs, 8H), 2.41 (s, 3H); MS (m/e
): 401.5 (M+1)。
化合物92-125的合成方法類似於化合物91的合成方法。
1
H NMR (CD3
OD, 400 MHz): 8.59 (d,J
=2.0Hz, 1H), 8.37 (s, 1H), 7.93 (dd,J
=2.4Hz,J
=2.4Hz, 1H), 7.72 (d,J
=8.8Hz, 1H), 7.47 (t,J
=6.8Hz, 1H), 7.28-7.25 (m, 1H), 7.11 (q, 1H), 5.87-5.84 (m, 1H), 3.38 (s, 2H), 3.04 (m, 4H), 2.86 (m, 4H), 2.66 (s, 3H), 1.71 (d,J
=7.2Hz, 3H), MS (m/e
): 423 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.99 (s, 1H), 9.88 (s,
1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.06 (d,J
=9.2Hz, 1H), 8.03 (s, 1H), 7.89 (d,J
=8.0Hz, 1H), 7.78 (d,J
=8.8Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=7.2Hz, 1H), 4.23(s, 1H), 3.20 (d, 2H), 3.17 (d,J
=4.4Hz, 1H), 2.60 (m, 8H), 2.6 (m, 8H), 2.35 (t,J
=6.8Hz, 3H); MS (m/e
): 415 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.97 (s, 1H), 9.88 (s, 1H), 8.66 (d,J
=1.6Hz, 1H), 8.57 (s, 1H), 8.06 (d,J
=9.2Hz, 1H), 8.03 (s, 1H), 7.89 (d,J
=8.0Hz, 1H), 7.78 (d,J
=9.2Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=8.0Hz, 1H), 4.23(s, 1H), 3.19 (d, 2H), 2.6 (m, 8H), 0.99 (d,J
=6.8Hz, 6H); MS (m/e
): 429 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.96 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 8.12 (d,J
=8.8Hz, 1H), 8.07 (s, 1H), 7.92 (d,J
=7.6Hz, 1H), 7.80 (d,J
=8.4Hz, 1H), 7.40 (t,J
=7.2Hz, 1H), 7.22 (d,J
=7.2Hz, 1H), 4.23 (s, 1H), 3.39 (s, 2H), 2.98 (m, 8H), 1.13 (s, 6H); MS (m/e
): 417 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.94 (s, 1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.11 (d,J
=6.4Hz, 1H), 8.05 (s, 1H), 7.90 (d,J
=8.0Hz, 1H), 7.79 (d,J
=9.2Hz, 1H), 7.39 (t,J
=7.6Hz, 1H), 7.21 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 3.39 (s, 2H), 3.34 (m, 4H), 2.79 (s, 6H); MS (m/e
): 389 (M+1)。
MS (m/e
): 413.2 (M+1)。
1
H NMR (DMSO, 400 MHz): δ 10.09 (s, 1H), 9.92 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.10 (d,J
=8.8Hz, 1H), 8.02 (s, 1H), 7.99 (d,J
=8.0Hz, 1H), 7.81 (d,J
=8.8Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.22 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 3.47 (t,J
=4.2Hz, 4H), 3.39 (s, 2H), 3.26 (s, 6H), 2.85 (t,J
=3.9Hz, 4H); MS (m/e
): 434 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.98 (s, 1H), 9.85 (s, 1H), 8.62 (d,J
=2.0Hz, 1H), 8.57 (s, 1H), 8.10 (dd,J
=8.8, 2.0Hz 1H), 8.03 (s, 1H), 7.88 (dd,J
=8.4, 1.2Hz 1H), 7.78 (d,J
=9.2Hz, 1H), 7.41 (t,J
=7.6Hz, 1H), 7.23 (d,J
=8.0Hz, 1H), 4.23 (s, 1H), 3.18 (s, 2H), 2.90 (d,J
=12.0Hz, 2H), 2.48 (s, 3H), 2.22 (t,J
=11.2Hz, 2H), 1.97 (t,J
=9.6Hz, 1H), 1.85 (d,J
= 12.0Hz, 2H), 1.67 (d, 4H), 1.55 (m, 2H); MS (m/e
): 455 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.98 (s, 1H), 9.86 (s, 1H), 8.64 (d,J
=1.6Hz, 1H), 8.57 (s, 1H), 8.05 (dd,J
=8.8, 2.0Hz 1H), 8.03 (s, 1H), 7.89 (dd,J
=8.4, 1.2Hz 1H), 7.78 (d,J
=9.2Hz, 1H), 7.41 (t,J
= 8.0Hz, 1H), 7.23 (d,J
=8.0Hz, 1H), 4.23 (s, 1H), 3.20 (s, 2H), 2.56 (m, 8H), 2.37 (m, 4H),
2.14 (s, 6H); MS (m/e
): 458 (M+1)。
MS (m/e
): 475 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.97 (s, 1H), 9.86 (s, 1H), 8.64 (d,J
=1.6Hz, 1H), 8.57 (s, 1H), 8.06 (dd,J
=9.2, 2.0Hz 1H), 8.03 (s, 1H), 7.89 (dd,J
=8.4, 1.2Hz 1H), 7.78 (d,J
=8.4Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=7.6Hz, 1H), 4.23 (s, 1H), 3.21 (s, 2H), 2.56 (m, 8H), 2.20 (d,J
=6.4Hz, 2H), 1.24 (s, 1H), 0.83 (m, 1H), 0.46 (m, 2H), 0.80 (m, 2H); MS (m/e
): 441 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.99 (s, 1H), 9.86 (s, 1H), 8.65 (d,J
=1.2Hz, 1H), 8.57 (s, 1H), 8.06 (dd,J
=8.8, 2.0Hz 1H), 8.03 (s, 1H), 7.89 (dd,J
=8.4, 1.2Hz 1H), 7.79 (d,J
=9.2Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=7.6Hz, 1H), 4.23 (s, 1H), 3.38 (s, 2H), 3.17 (d,J
=5.2Hz, 1H), 2.86 (t,J
=5.6Hz, 4H), 2.62 (d,J
=4.8Hz, 4H) 2.31 (s, 3H), 1.80 (m, 2H), 1.24 (s, 1H); MS (m/e
): 415 (M+1)
MS (m/e
): 431 (M+1)。
MS (m/e
): 427.2 (M+1)。
1
H NMR (DMSO-d6
, 400MHz): δ 9.94 (s, 1H), 9.84 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.03 (m, 2H), 7.88 (d,J
=8.0Hz, 1H), 7.77 (d,j
=9.2Hz, 1H), 7.37 (t,J
=8.0Hz, 1H), 7.20 (d,j
=7.6Hz, 1H), 4.20 (s, 1H), 3.16 (s, 2H), 2.95 (d,j
=11.2Hz, 2H), 2.39 (m, 5H), 2.17 (t,j
=8.8Hz, 2H), 1.62 (m, 4H), 1.35 (m, 4H), 0.83 (t,j
=7.6Hz, 6H); MS (m/e): 485.3 (M+1)。
1
H NMR (DMSO-d6
, 400MHz): δ 10.09 (s, 1H), 9.86 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.02 (m, 2H), 7.88 (d,J
=8.0Hz, 1H), 7.79 (d,j
=9.2Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=7.6Hz, 1H), 4.20 (s, 1H), 3.78 (s, 2H), 3.58 (s, 2H), 3.28 (s, 2H), 2.63 (s, 2H), 2.51 (s, 2H), 1.99 (s, 1H), 0.73 (m, 4H); MS (m/e): 455.2 (M+1)。
1
H NMR (DMSO-d6
, 400MHz): δ 9.96 (s, 1H), 9.84 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.09 (d,J
=8.8Hz, 1H), 8.02 (s, 1H), 7.88 (d,J
=8.0Hz, 1H), 7.79 (t,J
=8.8Hz, 1H), 7.41 (t,J
=8.0Hz, 1H), 7.23 (d,J
=8.0Hz, 1H), 4.22 (s, 1H), 3.57 (m, 1H), 3.17 (s, 2H), 2.80 (m, 2H), 2.30 (m, 2H), 1.78 (m, 2H), 1.54 (m, 2H); MS (m/e): 402.1 (M+1)。
1
H NMR (DMSO-d6
, 400MHz): δ 9.95 (s, 1H), 9.84 (s, 1H), 8.61 (s, 1H), 8.55 (s, 1H), 8.09 (m, 2H), 7.86 (d,j
=
8.8Hz, 1H), 7.76 (d,j
=9.2Hz, 1H), 7.79 (t,j
=8.0Hz, 1H), 7.21 (d,j
= 7.6Hz, 1H), 4.21 (s, 1H), 3.42 (t,j
=6.0Hz, 2H), 3.22 (s, 3H), 3.17 (s, 2H), 2.49 (m,10H); MS (m/e): 445.2 (M+1)。
1
H NMR (DMSO-d6
, 400MHz): δ 9.95 (s, 1H), 9.84 (s, 1H), 8.64 (s, 1H), 8.57 (s, 1H), 8.08 (d,j
=8.8Hz, 1H), 8.03 (s, 1H), 7.89 (d,j
=8.1Hz, 1H), 7.78 (d,j
=9.2Hz, 1H), 7.40 (t,j
=8.4Hz, 1H), 7.23 (d,j
=7.6Hz, 1H), 4.21 (s, 1H), 3.18 (s, 2H), 2.95 (d,j
=10.8Hz, 2H), 2.40 (s, 3H), 2.30 (m, 4H), 2.18 (m, 7H), 1.76 (m, 2H), 1.56 (m, 2H); MS (m/e): 484.0 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.69 (s, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 7.81~7.75 (m, 3H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.28~7.26 (d,J
=8.0Hz, 1H), 3.51 (s, 1H), 2.86~2.82 (m, 2H), 2.69~2.65 (m, 10H), 1.11~1.09 (d,J
=6.0Hz, 6H); MS (m/e
): 443.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.65 (s, 1H), 8.52 (s, 1H), 7.95~7.89 (m, 2H), 7.81~7.77 (m, 2H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.29~7.27 (d,J
=8.0Hz, 1H), 3.50 (s, 1H), 2.72 (m, 8H), 1.38~1.36 (d,J
=6.8Hz, 3H), 1.12~1.01 (d,J
=6.4Hz, 6H); MS (m/e
): 443.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 10.27 (s, 1H), 10.04 (s, 1H), 9.28 (s, 1H), 8.58 (s, 1H), 8.44(d,J
=7.2Hz, 1H), 8.29 (s, 1H), 8.16 (d,J
=7.6Hz, 1H), 7.78 (d,J
=8.8Hz, 1H), 7.39 (t,J
=7.6Hz, 1H), 7.21 (d,J
=7.2Hz, 1H), 4.22 (s, 1H), 2.51 (s, 8H), 1.26 (s, 6H), 1.21 (s, 3H); MS (m/e
): 429 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.97 (s, 1H), 9.84 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.16 (d,J
=9.2Hz, 1H), 8.07 (s, 1H), 7.93 (d,J
=8.4Hz, 1H), 7.78 (d,J
=9.2Hz, 1H), 7.41 (t,J
=8.4Hz, 1H), 7.22 (d,J
=8.0Hz, 1H), 4.23 (s, 1H), 2.61 (s, 8H), 1.24 (s, 6H), 1.01 (d,J
=10.8Hz, 1H), 0.98-0.96 (m, 1H); MS (m/e
): 457 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.99 (s, 1H), 9.87 (s, 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.15 (d,J
=7.6Hz, 1H), 8.08 (s, 1H), 8.7.95 (d,J
=7.2Hz, 1H), 7.78 (d,J
=10.2Hz, 1H), 7.41 (t,J
=7.6Hz, 1H), 7.22 (d,J
=8.0Hz, 1H), 4.23 (s, 1H), 3.15 (d,J
=4.8Hz, 1H), 2.55 (s, 8H), 1.25 (s, 6H), 1.02-0.971 (m, 3H); MS (m/e
): 443 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 9.86 (s, 1H), 9.42 (s,1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.18 (d,J
=7.2Hz, 1H),
8.05 (s, 1H), 7.92 (d,J
=7.6Hz, 1H), 7.58 (d,J
=7.2Hz, 1H), 7.39 (t,J
=6.0Hz,1H), 7.22 (d,J
=7.6Hz,1H), 6.14 (s,1H), 4.22 (s,1H), 3.09-3.06 (m, 2H), 1.49 (s,3H), 1.32 (s, 6H); MS (m/e
): 374 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.00 (s, 1H), 9.82 (s, 1H), 9.04 (s, 1H), 8.52 (s, 1H), 7.96 (s, 1H), 7.85~7.83 (d,J
=7.2Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.19 (s, 1H), 4.20 (s, 1H), 4.07 (s, 3H), 3.34 (s, 2H), 2.61~2.58 (m, 4H), 2.48~2.36 (m, 4H), 1.05~1.02 (t,J
=9.6Hz, 3H); MS (m/e
): 445.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.04 (s, 1H), 9.82 (s, 1H), 9.04 (s, 1H), 8.52 (s, 1H), 7.96 (s, 1H), 7.85~7.83 (d,J
=7.2Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.19 (s, 1H), 4.20 (s, 1H), 4.07 (s, 3H), 3.2 (s, 2H), 2.61~2.58 (m, 4H), 2.48~2.36 (m, 8H), 1.10 (bs, 6H); MS (m/e
): 459.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 10.00 (s, 1H), 9.83 (s, 1H), 9.04 (s, 1H), 8.53 (s, 1H), 7.96 (s, 1H), 7.84 (d,J
=7.6Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.32 (s, 1H), 7.20 (d,J
=7.6Hz, 1H), 4.21 (s, 1H), 4.08 (s, 3H), 3.22 (s, 2H), 2.60 (m, 8H), 2.23 (s, 3H); MS (m/e
): 431 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.16 (s, 1H), 9.81 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 7.97 (s, 1H), 7.84 (d,J
=8.8Hz, 1H), 7.38 (t,J
= 8.0Hz, 1H), 7.32 (s, 1H), 7.20 (d,J
=8.0Hz, 1H), 4.21 (s, 1H), 4.06 (s, 3H), 3.46 (t,J
=5.2Hz, 1H), 3.26 (s, 3H), 2.76 (t,J
=5.2Hz, 1H), 1.24 (s, 1H); MS (m/e
): 406 (M+1)。
1
H NMR (CD3
OD, 400 MHz): δ 8.93 (s,1H), 8.48 (s, 1H), 7.93 (s, 1H), 7.77 (d,J
=8.0Hz, 1H), 7.38 (t,J
=7.6Hz, 1H), 7.27 (t,J
=7.2Hz, 2H), 4.14 (s, 3H), 3.37 (s, 1H), 3.25 (s, 2H), 3.12-3.09 (m, 3H), 2.42-2.37 (m, 2H), 2.02-2.00 (m, 2H), 1.80-1.77 (m, 2H), 1.31-1.25 (m, 4H),1.20 (s, 6H); MS (m/e
): 487 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ10.04 (s,1H), 9.81 (s, 1H), 9.02 (s, 1H), 8.53 (s, 1H), 7.97 (s,1H), 7.85 (d,J
=8.0Hz, 1H), 7.38 (t,J
=8.0Hz, 1H), 7.32 (s,1H), 7.20 (d,J
=7.6Hz, 1H), 4.19 (s, 1H), 4.07 (s, 3H), 3.21 (s, 2H), 2.68-2.60 (m, 4H), 1.22 (s, 3H), 1.02-0.97 (m, 6H); MS (m/e
): 445 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): δ 10.52 (s, 1H), 9.94 (s,1H), 8.95 (s, 1H), 8.57 (s, 1H), 7.99 (s, 1H), 7.86 (d,J
=9.2Hz, 1H), 7.39 (t,J
=8.4Hz, 1H), 7.33 (s, 1H), 6.76 (d,J
=
7.6Hz, 1H), 4.23 (s,1H), 4.04 (s,3H), 2.98 (s, 8H), 2.78-2.75 (m, 3H), 2.34-2.30 (m, 2H),1.37 (s, 6H); MS (m/e
): 473 (M+1)。
合成路線及方法如下:
將二甲基甲醯胺二甲基乙縮醛(0.88g, 7.36mmol)加入到5-硝基-2-氨基苯甲氰(1.00g, 6.13mmol)的二氧六環(25mL)溶液中,加熱至100℃回流2h。反應液冷卻至室溫後繼續冷去至0℃,有大量沈澱析出,過濾,濾餅用冷卻的乙醚洗滌2~3次後紅外乾燥,得到1.30g的(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺,黃色固體,産率97%。
將(E)-N'-(2-氰基-4-硝基苯基)-N,N-二甲基甲醯胺(1.00g, 4.58mmol)和3-氨基苯炔(0.64g, 5.49mmol)的冰乙酸(15mL)加熱至100℃攪拌3h。反應液冷卻至室溫,有沈澱析出,過濾,濾餅用乙醚洗滌,紅外乾燥,得到1.23g的N-(3-炔基苯基)-6-硝基喹唑啉-4-胺,黃色固體,産率93%。
N-(3-炔基苯基)-6-硝基喹唑啉-4-胺(1.00g, 3.45mmol)
和SnCl2
.2H2
O (3.10g, 13.8mmol)的乙酸乙酯(35mL)溶液回流2h。反應液冷卻至室溫後,用5%的碳酸氫鈉水溶液將pH值調至9-10,混合液用乙酸乙酯萃取,有機相依次用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到0.79g的N-4-(3-炔基苯基)喹唑啉-4,6-二胺,黃色固體,産率89%。
在室溫下,向N-4-(3-炔基苯基)喹唑啉-4,6-二胺(100mg, 0.38mmol)的DMF(2mL)溶液中依次加入吡啶(37μL ,0.46mmol),氯甲酸苯酯(49μL, 0.38mmol)。攪拌10min後,加入(甲基氨基)乙二甲縮醛(45.2mg, 0.38mmol),並加熱至100oC攪拌1h,冷卻至室溫後,反應液倒入水中,以乙酸乙酯萃取,有機相用水洗滌,硫酸鈉乾燥,濃縮後用柱色譜分離得到目標産物,黃色固體,産率83%。
1
H NMR (CD3
OD, 400 MHz): 8.84 (s, 1H), 8.83~8.82 (d,J
=2.0Hz, 1H), 8.60~8.57 (dd,J
=2.0Hz, 9.6Hz, 1H), 7.98~7.96 (d,J
=9.2Hz, 1H), 7.95 (s, 1H), 7.81~7.79 (dd,J
=1.6Hz, 7.2Hz, 1H), 7.52~7.49 (m, 2H), 7.17~7.16 (d,J
=2.8Hz, 1H), 6.82~6.81 (d,J
=2.8Hz, 1H), 3.64 (s, 1H), 3.38 (s, 3H); MS (m/e
): 342.3 (M+1)。
採用類似於實施例126的方法合成。
1
H NMR (CD3
OD, 400 MHz): 8.55 (s, 2H), 8.24~8.22 (dd,J
=2.8Hz, 9.2Hz, 1H), 7.97 (s, 1H), 7.88~7.86 (d,J
=8.8Hz, 1H), 7.82-7.81 (d,J
=2.4Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.28~7.26 (d,J
=8.8Hz, 1H), 7.09~7.08 (d,J
=3.2Hz, 1H), 6.79~6.78 (d,J
=3.2Hz, 1H), 3.52 (s, 1H); MS (m/e
): 327.9 (M+1)。
在室溫下,向N-4-(3-炔基苯基)喹唑啉-4,6-二胺(100mg, 0.38mmol)的DMF(2mL)溶液中依次加入吡啶(37μL, 0.46mmol),氯甲酸苯酯(49μL, 0.38mmol),攪拌10min後,反應液倒入水中,以乙酸乙酯萃取,有機相用水洗滌,硫酸鈉乾燥,濃縮後用柱色譜分離得到苯基-4-(3-炔基苯氨基)喹唑啉-6-基甲酸胺,黃色固體,産率95%。
將碳酸鉀(276mg, 1.99mmol)和2-溴-1,1-二甲氧基乙烷(236mg, 1.39mmol)加入到2-甲氧基乙胺(100mg, 1.33mmol)的DMF(2mL)溶液中,加熱至80℃攪拌3h。冷卻至室溫後,反應液倒入水中,乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到2,2-二甲氧基-N-(2-甲氧基乙基)乙胺,黃色油狀液體,産率91%,可直接用於下一
步反應,無需分離。
將2,2-二甲氧基-N-(2-甲氧基乙基)乙胺(22.0mg, 0.13mmol)加入到苯基-4-(3-炔基苯氨基)喹唑啉-6-基甲酸胺(50mg, 0.13mmol)的DMF(2mL)溶液,加熱至80℃攪拌0.5h後,加入對甲苯磺酸(28.5mg, 0.15mmol),在此溫度下繼續攪拌1h。冷卻至室溫後,反應液倒入水中,乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後以柱色譜分離,得到目標産物,黃色固體,産率82%。
1
H NMR (CD3
OD, 400 MHz): 8.57 (s, 2H), 8.24~8.22 (dd,J
=2.8Hz, 9.2Hz, 1H), 7.98 (s, 1H), 7.89~7.87 (d,J
=8.8Hz, 1H), 7.82-7.81 (d,J
=2.4Hz, 1H), 7.40~7.36 (t,J
=8.0Hz, 1H), 7.29~7.27 (d,J
=8.8Hz, 1H), 7.09~7.08 (d,J
=3.2Hz, 1H), 6.79~6.78 (d,J
=3.2Hz, 1H), 3.92~3.90 (t,J
=5.2Hz, 2H), 3.68~3.66 (t,J
=5.2Hz, 2H), 3.52 (s, 1H), 3.40 (s, 3H); MS (m/e
): 386.4 (M+1)。
合成方法類似於實施例128中的方法。
1
H NMR (DMSO-d6
, 400 MHz): 10.06 (s, 1H), 8.71 (s, 1H), 8.7-0 (s, 1H), 8.51~8.48 (dd,J
=1.6Hz, 8.4Hz, 1H), 8.09 (s, 1H), 7.99~7.97 (d,J
=8.0Hz, 1H), 7.89-7.8 7 (d,J
=8.8Hz, 1H), 7.45~7.41 (t,J
=8.0Hz, 1H), 7.34~7.33 (d,J
=3.2Hz, 1H), 7.26~7.24 (d,J
=7.2Hz, 1H), 6.93~6.92 (d,J
=3.2Hz, 1H), 4.23 (s, 1H), 3.77~3.74 (t,J
=6.4Hz, 2H),
3.61~3.55 (m, 4H), 2.61~2.56 (t,J
=6.4Hz, 2H), 2.48~2.24 (m, 4H); MS (m/e
): 441.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 10.04 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.49~8.46 (dd,J
=1.6Hz, 8.4Hz, 1H), 8.08 (s, 1H), 7.99~7.97 (d,J
=8.0Hz, 1H), 7.89-7.8 7 (d,J
=8.8Hz, 1H), 7.45~7.41 (t,J
=8.0Hz, 1H), 7.34~7.33 (d,J
=3.2Hz, 1H), 7.26~7.24 (d,J
=7.2Hz, 1H), 6.96~6.95 (d,J
=3.2Hz, 1H), 4.23 (s, 1H), 3.86~3.83 (t,J
=6.8Hz, 2H), 2.84~2.80 (t,J
=6.8Hz, 2H), 2.12 (s, 3H); MS (m/e
): 402.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.74 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.45~8.43 (dd,J
=2.4Hz, 8.8Hz, 1H), 8.07 (s, 1H), 7.97~7.95 (d,J
=8.0Hz, 1H), 7.89-7.87 (d,J
=8.8Hz, 1H), 7.45~7.41 (t,J
=8.0Hz, 1H), 7.31~7.30 (d,J
=3.2Hz, 1H), 7.26~7.24 (d,J
=7.2Hz, 1H), 7.08~7.07 (d,J
=3.2Hz, 1H), 4.23 (s, 1H), 4.14~4.10 (m, 1H), 3.99~3.96 (m, 2H), 3.50~3.45 (t,J
=8.4Hz, 2H), 1.91~1.86 (m, 2H), 1.79~1.75 (m, 2H); MS (m/e
): 412.4(M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.74 (s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.45~8.43 (dd,J
=2.4Hz, 8.8Hz, 1H), 8.07 (s, 1H), 7.97~7.95 (d,J
=8.0Hz, 1H), 7.89-7.87 (d,J
=
8.8Hz, 1H), 7.45~7.41 (t,J
=8.0Hz, 1H), 7.31~7.30 (d,J
=3.2Hz, 1H), 7.26~7.24 (d,J
=7.2Hz, 1H), 7.08~7.07 (d,J
=3.2Hz, 1H), 4.23 (s, 1H), 3.98~3.97 (m, 1H), 3.25~3.24 (m, 2H), 3.03~2.99 (m, 2H), 2.29 (s, 3H), 1.95~1.80 (m, 4H); MS (m/e
): 425.2 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.93 (s, 1H), 8.63 (s, 2H), 8.46~8.43 (dd,J
=2.8Hz, 8.8Hz, 1H), 8.06 (s, 1H), 7.96~7.94 (d,J
=8.4Hz, 2H), 7.45~7.41 (t,J
=8.0Hz, 1H), 7.26~7.24 (m, 2H), 6.93 (s, 1H), 4.24 (s, 1H), 3.65~3.62 (t,J
=6.8Hz, 2H), 1.67~1.64 (m, 2H), 1.35~1.24 (m, 2H), 0.95~0.91 (t,J
=7.2Hz, 3H); MS (m/e
): 384.4 (M+1)。
MS (m/e
): 466.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.79 (s, 1H), 8.62 (s, 1H), 8.55~8.33 (d,J
=8.8Hz, 1H), 8.13 (s, 1H), 8.04~8.02 (d,J
=8.0Hz, 1H), 7.88~7.85 (d,J
=8.0Hz, 1H), 7.46~7.40 (m, 2H), 6.91~6.90 (d,J
=3.2Hz, 1H), 4.23 (s, 1H), 3.74~3.71 (t,J
=6.4Hz, 2H), 2.57~2.54 (t,J
=6.4Hz, 2H), 2.27 (s, 6H); MS (m/e
): 399.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 10.41 (s, 1H), 8.84 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H), 8.57~8.54 (dd,J
=2.4Hz,
8.8Hz, 1H), 8.17 (s, 1H), 8.07~8.05 (d,J
=8.8Hz, 1H), 7.87~7.85 (d,J
=9.2Hz, 1H), 7.58~7.57 (d,J
=3.6Hz, 1H), 7.42~7.39 (t,J
=8.0Hz, 1H), 7.24~7.18 (m, 2H), 6.90 (s, 1H), 6.61 (d,J
=3.2Hz, 1H), 4.35~4.32 (t,J
=6.0Hz, 2H), 4.24 (s, 1H), 4.02~3.99 (t,J
=6.0Hz, 2H); MS (m/e
): 422.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.66~8.53 (m, 4H), 8.27~8.24 (dd,J
=2.0Hz, 9.2Hz, 1H), 7.91~7.79 (m, 4H), 7.50 (m, 1H), 7.43~7.39 (t,J
=8.0Hz, 1H), 7.31~7.29 (d,J
=7.6Hz, 1H), 7.18~7.17 (d,J
=3.2Hz, 1H), 6.90~6.89 (d,J
=3.2Hz, 1H), 5.02 (s, 2H), 3.38 (s, 1H); MS (m/e
): 419.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.96 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.45~8.43 (d,J
=8.4Hz, 1H), 8.05 (s, 1H), 7.95~7.87 (m, 2H), 7.45~6.99 (m, 8H), 6.99 (s, 1H), 6.61 (d,J
=3.2Hz, 1H), 4.88 (s, 2H), 4.24 (s, 1H); MS (m/e
): 436.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 10.04 (s, 1H), 8.68 (s, 1H), 8.62 (s, 1H), 8.46~8.44 (d,J
=9.2Hz, 1H), 8.07 (s, 1H), 7.97~7.95 (d,J
=7.6Hz, 1H), 7.88-7.86 (d,J
=9.2Hz, 1H), 7.44~7.40 (t,J
=8.0Hz, 1H), 7.28 (s, 1H), 7.25~7.23
(d,J
=7.2Hz, 1H), 6.81 (s, 1H), 4.24 (s, 1H), 3.07 (s, 1H), 0.90 (bs, 4H); MS (m/e
): 368.4 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.60 (s, 1H), 8.58~8.57 (d,J
=2.4Hz, 1H), 8.25~8.22 (dd,J
=2.0Hz, 9.2Hz, 1H), 8.01 (s, 1H), 7.90~7.88 (d,J
=9.2Hz, 1H), 7.86-7.84 (d,J
=8.4Hz, 1H), 7.43~7.39 (t,J
=8.0Hz, 1H), 7.31~7.29 (d,J
=7.6Hz, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 4.59~4.57 (m, 1H), 3.56 (s, 1H), 2.16~2.12 (m, 2H), 1.92~1.76 (m, 6H); MS (m/e
): 396.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.92 (s, 1H), 8.63 (s, 2H), 8.42~8.39 (dd,J
=2.4Hz, 9.2Hz, 1H), 8.01 (s, 1H), 7.95~7.93 (d,J
=9.2Hz, 1H), 7.88-7.86 (d,J
=9.2Hz, 1H), 7.44~7.40 (t,J
=8.0Hz, 1H), 7.25~7.23 (m, 2H), 7.03 (s, 1H), 4.23 (s, 1H), 4.10(bs, 1H), 3.04 (s, 2H), 1.88 (bs, 8H), 1.03 (bs, 3H); MS (m/e
): 439.4 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 9.88 (s, 1H), 8.64 (s, 1H), 8.61 (s, 1H), 8.42~8.40 (d,J
=8.8Hz, 1H), 8.04 (s, 1H), 7.93~7.88 (m, 2H), 7.50~7.49 (d,J
=4.8Hz, 1H), 7.45~7.41 (t,J
=7.6Hz, 1H), 7.26~7.24 (d,J
=7.6Hz, 1H), 7.23~7.22 (d,J
=2.8Hz, 1H), 7.15 (s, 1H), 7.04~7.02 (t,J
=4.0Hz, 1H), 6.97~6.96 (d,J
=2.8Hz, 1H), 5.04 (s, 2H), 4.24
(s, 1H); MS (m/e
): 424.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.93 (s, 1H), 8.64 (s, 1H), 8.63 (s, 1H), 8.44~8.42 (dd,J
=2.0Hz, 8.8Hz, 1H), 8.05 (s, 1H), 7.95~7.93 (d,J
=8.4Hz, 1H), 7.90~7.88 (d,J
=8.8Hz, 1H), 7.45~7.43 (t,J
=8.0Hz, 1H), 7.27~7.25 (m, 2H), 6.86~6.85 (d,J
=3.2Hz, 1H), 6.00~5.93 (m, 1H), 5.24~5.16 (m, 2H), 4.29~4.27 (d,J
=5.2Hz, 2H), 4.24 (s, 1H); MS (m/e
): 368.4 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.89 (s, 1H), 8.62 (bs, 2H), 8.42 (bs, 1H), 8.05 (s, 1H), 7.91~7.80 (m, 2H), 7.44 (bs, 1H), 7.25~7.14 (m, 2H), 6.99 (s, 1H), 4.25 (s, 1H), 3.61 (bs, 2H), 3.26 (bs, 2H), 3.04~2.90 (m, 2H), 2.08 (bs, 2H), 1.93~1.88 (m, 4H); MS (m/e
): 453.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 9.91 (s, 1H), 8.64 (s, 1H), 8.63~8.62 (d,J
=2.0Hz, 1H), 8.39~8.36 (dd,J
=1.6Hz, 9.2Hz, 1H), 8.04 (s, 1H), 7.93~7.89 (m, 2H), 7.46~7.42 (t,J
=8.0Hz, 1H), 7.27 (s, 1H), 7.25~7.24 (d,J
=3.2Hz, 1H), 6.97~6.96 (d,J
=3.2Hz, 1H), 4.52~4.51 (d,J
=2.0Hz, 2H), 4.25 (s, 1H), 3.44 (s, 1H); MS (m/e
): 366.4 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 9.88 (s, 1H), 8.63 (s, 1H),
8.60 (s, 1H), 8.43~8.41 (d,J
=8.8Hz, 1H), 8.03 (s, 1H), 7.93~7.87 (m, 2H), 7.46~7.42 (t,J
=7.6Hz, 1H), 7.26~7.24 (d,J
=8.0Hz, 1H), 7.21~7.20 (d,J
=3.2Hz, 1H), 6.94~6.93 (d,J
=2.8Hz, 1H), 4.25 (s, 1H), 3.66~3.63 (t,J
=6.8Hz, 2H), 2.48~2.39 (m, 6H), 1.79~1.76 (m, 2H), 0.96~0.93 (t,J
=7.2Hz, 6Hz); MS (m/e
): 441.5 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz):10.11 (s,1H), 8.72 (d,J
=2.0Hz, 1H), 8.63 (s,1H), 8.59 (dd,J
=2.0Hz,J
=2.0Hz, 1H),8.10 (s,1H), 7.99 (d,J
=8.0Hz,1H), 7.88 (d,J
=9.2Hz,1H),7.43 (t,J
=8.0Hz,1H), 7.35 (d,J
=2.8Hz,1H), 7.24 (d,J
=7.6Hz,1H), 6.88 (d,J
=2.8Hz,1H), 4.23 (s,1H), 3.80-3.78 (m, 2H), 3.65-3.62 (m, 2H), 3.51-3.48 (m, 2H), 1.14-1.08 (m, 3H); MS (m/e
): 400 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 9.88 (s, 1H), 8.62 (s, 1H), 8.60 (s, 1H), 8.03 (s, 1H), 7.93~7.91 (d,J
=8.0Hz, 1H), 7.89~7.87 (d,J
=9.2Hz, 1H), 7.45~7.43 (t,J
=8.0Hz, 1H), 7.26~7.24 (d,J
=7.2Hz, 1H), 7.18~7.17 (d,J
=3.2Hz, 1H), 6.91~6.90 (d,J
=2.8Hz, 1H), 4.23 (s, 1H), 3.75~3.72 (t,J
=6.4Hz, 2H), 2.59~2.56 (t,J
=6.4Hz, 2H), 2.51~2.40 (m, 4H), 2.38~2.32 (m, 4H), 2.14 (s, 3H); MS (m/e
): 454.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 9.92 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.44~8.42 (d,J
=8.8Hz, 1H), 8.04 (s, 1H), 7.96~7.87 (m, 2H), 7.46~7.42 (t,J
=7.6Hz, 1H), 7.26~7.24 (d,J
= 7.6Hz, 1H), 7.18~7.17 (d,J
=2.8Hz, 1H), 6.91 ~6.90 (d,J
=2.4Hz, 1H), 4.25 (s, 1H), 3.37~3.69 (m, 1H), 3.52~3.47 (m, 1H), 2.30~2.26 (m, 2H), 2.19~2.06 (m, 2H), 1.78~1.71 (m, 2H), 1.65~1.59 (m, 2H), 1.42~1.45 (m, 1H), 1.07~1.10 (m, 3H); MS (m/e
): 439.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.57 (s, 1H), 8.53 (s, 1H), 8.22~8.20 (dd,J
=1.6Hz, 9.2Hz, 1H), 7.99 (s, 1H), 7.89~7.87 (d,J
=8.8Hz, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.39~7.37 (t,J
=7.6Hz, 1H), 7.29~7.27 (d,J
=7.2Hz, 1H), 7.03~7.02 (d,J
=2.8Hz, 1H), 6.82~6.81 (d,J
=3.2Hz, 1H), 4.16~4.12 (t,J
=6.8Hz, 2H), 3.56 (s, 1H), 2.59~2.56 (t,J
=6.4Hz, 2H); MS (m/e
): 400.4 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.58~8.57 (m, 2H), 8.25~8.22 (dd,J
=2.0Hz, 8.8Hz, 1H), 7.98 (s, 1H), 7.92~7.89 (d,J
=8.8Hz, 1H), 7.86~7.84 (d,J
=8.0Hz, 1H), 7.43~7.39 (t,J
=7.6Hz, 1H), 7.31~7.29 (d,J
=7.2Hz, 1H), 7.09~7.08 (d,J
=2.8Hz, 1H), 6.80~6.79 (d,J
=3.2Hz, 1H), 3.86~3.83 (t,J
=6.4Hz, 2H), 3.53 (s, 1H), 2.91~2.88 (t,J
=6.8Hz, 2H), 2.26~2.22 (m, 2H), 1.85~1.66 (m, 5H); MS
(m/e
): 425.1 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.61 (s, 1H), 8.53 (s, 1H), 8.22~8.20 (dd,J
=1.6Hz, 9.2Hz, 1H), 7.99 (s, 1H), 7.89~7.87 (d,J
=8.8Hz, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.39~7.37 (t,J
=7.6Hz, 1H), 7.29~7.27 (d,J
=7.2Hz, 1H), 7.03~7.02 (d,J
=2.8Hz, 1H), 6.83~6.82 (d,J
=2.8Hz, 1H), 4.08~4.05 (t,J
=6.8Hz, 2H), 3.55 (s, 1H), 3.52~3.40 (m, 4H), 2.85~2.82 (t,J
=6.8Hz, 2H), 2.00~1.89 (m, 4H); MS (m/e
): 453.4 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.59 (s, 1H), 8.57~8.56 (d,J
=2.0Hz, 1H), 8.24~8.21 (dd,J
=2.4Hz, 8.8Hz, 1H), 7.99 (s, 1H), 7.90~7.88 (d,J
=8.8Hz, 1H), 7.84~7.82 (d,J
=7.2Hz, 1H), 7.42~7.38 (t,J
=8.0Hz, 1H), 7.30~7.28 (d,J
=7.6Hz, 1H), 7.10~7.09 (d,J
=3.2Hz, 1H), 6.81~6.80 (d,J
=3.6Hz, 1H), 3.90~3.87 (t,J
=5.6Hz, 2H), 3.54 (s, 1H), 3.45~3.42 (t,J
=6.0Hz, 2H), 2.94 (s, 3H); MS (m/e
): 449.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.58 (s, 1H), 8.56~8.55 (d,J
=2.0Hz, 1H), 8.23~8.20 (dd,J
=2.4Hz, 8.8Hz, 1H), 7.99 (s, 1H), 7.89~7.87 (d,J
=8.8Hz, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.41~7.37 (t,J
=8.0Hz, 1H), 7.29~7.27 (d,J
=7.6Hz, 1H), 7.08~7.07 (d,J
=2.8Hz, 1H), 6.80~6.79 (d,J
=3.6Hz, 1H), 3.96~3.93 (t,J
=5.6Hz, 2H), 3.53 (s, 1H), 3.52~3.48 (t,J
=5.6Hz, 2H), 2.94 (s, 3H), 2.84 (s, 3H); MS (m/e
): 463.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.58 (s, 1H), 8.56~8.55 (d,J
=2.0Hz, 1H), 8.23~8.20 (dd,J
=2.0Hz, 8.8Hz, 1H), 7.98 (s, 1H), 7.89~7.87 (d,J
=9.2Hz, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.41~7.37 (t,J
=7.6Hz, 1H), 7.29~7.27 (d,J
=8.0Hz, 1H), 7.07~7.06 (d,J
=2.8Hz, 1H), 6.73~6.72 (d,J
=2.8Hz, 1H), 3.85~3.82 (t,J
=5.6Hz, 2H), 3.55~3.52 (t,J
=6.0Hz, 2H), 3.52 (s, 1H), 1.56~1.52 (m, 1H), 0.83~0.81 (m, 2H), 074~0.71 (m, 2H); MS (m/e
): 439.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.61 (d,J
=2.0Hz, 1H), 8.60~8.56 (dd,J
=2.0Hz, 1H), 8.24~8.21 (dd,J
=2.0Hz, 9.2Hz, 1H), 8.01~7.99 (dd,J
=2.0Hz, 4.4Hz, 1H), 7.92~7.91 (dd,J
=2.4Hz, 9.2Hz, 1H), 7.86~7.84 (d,J
=8.0Hz, 1H), 7.43~7.39 (t,J
=8.0Hz, 1H), 7.32~7.30 (d,J
=8.0Hz, 1H), 4.05~4.02 (t,J
=5.6Hz, 1H), 3.98~3.96 (t,J
=5.6Hz, 1H), 3.94~3.92 (t,J
=5.6Hz, 1H), 3.78~3.75 (t,J
=5.6Hz, 1H), 3.55 (s, 1H), 3.27 (s, 1.5H), 3.05 (s, 1.5H), 1.92~1.85 (m, 1H), 0.82~0.77 (m, 3H), 0.69~0.65 (m, 1H); MS (m/e
): 453.5 (M+1)。
將醋酸脒(6.80g, 65.32mmol)加入到2-氨基-4-硝基苯甲酸(6.00g, 32.94mmol)的乙醇溶液中,加熱至回流,攪拌5h。冷卻至室溫後,有沈澱析出,過濾,濾餅用冷的乙醇洗滌2次,紅外乾燥,得到5.60g的7-硝基喹唑啉-4-羥基,黃色固體,産率89%。
7-硝基喹唑啉-4-羥基(3.4g, 17.79mmol)溶於氯化亞碸(20mL),加入0.5mL滴的DMF,反應液回流48h。減壓蒸餾除去溶劑,得到2.61g的4-氯-7-硝基喹唑啉,可直接用於下一步反應,無需進一步分離。
4-氯-7-硝基喹唑啉(2.0g, 9.54mmol)和3-炔基苯胺(1.2g, 10.00mmol)溶於異丙醇(30mL)後加熱回流5h。冷卻至室溫後,析出的固體過濾,濾餅用少量水洗滌,紅外乾燥後,得到2.6g的N-(3-炔基苯基)-7-硝基喹唑啉-4-胺,黃色固體,産率94%。
N-(3-炔基苯基)-7-硝基喹唑啉-4-胺(2.0g, 6.89mmol)和SnCl2
.2H2
O (5.0g, 26.37mmol)的乙酸乙酯溶液回流3h。反應液冷卻至室溫,用5%的碳酸氫鈉水溶液調節pH值至9-10後,以乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到1.6g的N-4-(3-炔基苯基)喹唑啉-4, 7-二胺,黃色固體,産率86%。
N-4-(3-炔基苯基)喹唑啉-4, 6-二胺(48mg, 0.18mmol)溶於DMF(2mL)後,在室溫下依次加入吡啶(32μL),氯甲酸苯酯(25.2μL, 0.18mmol),攪拌1.5h後,加入N1-(2,2-二甲氧基乙基)-N2,N2-二甲基乙烷-1,2-二胺(33.5mg, 0.19mmol),加熱至80℃攪拌1h。然後繼續加入對甲苯磺酸(35.6mg, 0.20mmol)並在次溫度下攪拌1h。冷卻至室溫後,反應液倒入水中,用乙酸乙酯萃取(20mL, 3次),有機相用飽和食鹽水洗滌,硫酸鈉乾燥,濃縮後得到的粗品用柱色譜分離,得到目標産物,黃色固體,産率75%。
1
H NMR (CD3
OD, 400 MHz): 8.57 (s, 1H), 8.48~8.47 (d,J
=3.6Hz, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.83~7.81 (d,J
=8.0Hz, 1H), 7.42~7.38 (t,J
=8.0Hz, 1H), 7.31~7.29 (d,J
=7.6Hz, 1H), 7.13~7.12 (d,J
=2.8Hz, 1H), 6.83~6.82 (d,J
=2.8Hz, 1H), 3.89~3.85 (t,J
=6.8Hz, 2H), 3.56 (s, 1H), 2.72~2.69 (t,J
=6.4Hz, 2H), 2.35 (s, 6H); MS (m/e
): 399.4 (M+1)。
採用的合成方法類似於實施例157中的方法。
1
H NMR (CD3
OD, 400 MHz): 8.59 (s, 1H), 8.52~8.49 (d,J
=8.8Hz, 1H), 8.11~8.08 (d,J
=2.4Hz, 1H), 8.09~8.08 (d,J
=2.4Hz, 1H), 7.98 (s, 1H), 7.83~7.81 (d,J
=8.0Hz, 1H), 7.43~7.39 (t,J
=7.6Hz, 1H), 7.32~7.30 (d,J
=7.6Hz, 1H), 7.18~7.17 (d,J
=2.8Hz, 1H), 6.85~6.84 (d,J
=3.2Hz, 1H), 3.81~3.77 (t,J
=6.8Hz, 2H), 3.56 (s, 1H), 2.74~2.67 (m, 6H), 2.02~1.95 (m, 2H), 1.14~1.10 (t,J
=7.2Hz, 6H); MS (m/e
): 441.5 (M+1)。
1
H NMR (MeOD, 400 MHz): 8.58 (s, 1H), 8.48~8.45 (dd,J
=1.6Hz, 8.0Hz, 1H), 8.09~8.08 (d,J
=2.4Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.83~7.81 (d,J
=8.0Hz, 1H), 7.42~7.38 (t,J
=8.0Hz, 1H), 7.31~7.29 (d,J
=7.2Hz, 1H), 7.12~7.11 (d,J
=2.8Hz, 1H), 6.84~6.83 (d,J
=3.2Hz, 1H), 3.90~3.85 (m, 1H), 3.67~3.64 (m, 1H), 3.55 (s, 1H), 3.23~3.18 (m, 1H), 3.01~2.94 (m, 1H), 2.86~2.82 (m, 1H), 2.44~2.38 (m, 1H), 2.32~2.26 (m, 1H), 1.98~1.91 (m, 1H), 1.75~1.69 (m, 1H), 1.18 (s, 3H); MS (m/e
): 439.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.59 (s, 1H), 8.51~8.49 (dd,J
=2.0Hz, 7.6Hz, 1H), 8.13~8.12 (d,J
=2.0Hz, 1H), 8.11~8.10 (d,J
=2.0Hz, 1H), 7.98 (s, 1H), 7.83~7.81 (d,J
=8.0Hz, 1H), 7.43~7.39 (t,J
=8.4Hz, 1H), 7.32~7.30 (d,J
=8.0Hz, 1H), 7.16~7.15 (d,J
=3.6Hz, 1H), 6.82~6.81 (d,J
=3.2Hz, 1H), 3.82~3.78 (t,J
=7.2Hz, 2H), 3.61 (s, 1H), 2.73~2.33 (m, 10H), 2.28 (s, 3H), 2.00~1.93 (m, 2H); MS (m/e
): 468.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.59 (s, 1H), 8.51~8.49 (d,J
=9.6Hz, 1H), 8.11~8.08 (m, 2H), 7.98 (s, 1H), 7.83~7.81 (d,J
=8.0Hz, 1H), 7.43~7.39 (t,J
=7.6Hz, 1H), 7.32~7.30 (dd,J
=1.6Hz, 6.8Hz, 1H), 7.17~7.16 (d,J
=3.2Hz, 1H), 6.86~6.85 (d,J
=2.8Hz, 1H), 3.85~3.78 (t,J
=6.8Hz, 2H), 3.55 (s, 1H), 3.12~3.07 (m, 1H), 2.38 (s, 3H), 2.30~2.12 (m, 4H), 1.85~1.78 (m, 2H), 1.69~1.55 (m, 2H); MS (m/e
): 439.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.59 (s, 1H), 8.51~8.48 (d,J
=10.0Hz, 1H), 8.11~8.09 (m, 2H), 7.98 (s, 1H), 7.84~7.81 (d,J
=8.8Hz, 1H), 7.43~7.39 (t,J
=8.0Hz, 1H), 7.32~7.30 (d,J
=7.6Hz, 1H), 7.15~7.14 (d,J
=3.2Hz, 1H), 6.88~6.87 (d,J
=2.8Hz, 1H), 3.77~3.73 (t,J
=7.2Hz, 2H), 3.54 (s, 1H), 3.54~3.50 (t,J
=7.2Hz, 2H), 3.42~3.39 (t,J
=7.2Hz, 1H), 2.44~2.40 (t,J
=7.6Hz, 2H), 2.12~2.07 (m, 2H), 2.04~1.99 (m, 2H); MS (m/e
): 453.5 (M+1)。
1
H NMR (CD3
OD, 400 MHz): 8.60 (s, 1H), 8.53~8.50
(d,J
= 10.0Hz, 1H), 8.12~8.10 (m, 2H), 7.99 (s, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.84~7.82 (d,J
=8.0Hz, 1H), 7.44~7.41 (t,J
=7.6Hz, 1H), 7.33~7.31 (d,J
=7.2Hz, 1H), 7.19~7.18 (d,J
=2.8Hz, 1H), 6.86~6.85 (d,J
=3.6Hz, 1H), 3.94~3.91 (t,J
=6.8Hz, 2H), 3.56 (s, 1H), 3.26~3.23 (m, 2H), 3.03 (s, 3H), 2.30~2.26 (m, 2H); MS (m/e
): 448.4(M+1)。
合成方法及路線如下:
2-氨基-4-氟苯甲酸(1.55g, 10mmol)溶於甲醯胺(5mL)並加熱至150℃攪拌6h。反應液在攪拌下冷卻至室溫,析出的沈澱過濾,濾餅用乙酸乙酯洗滌,紅外工乾燥得到1.3g的7-氟喹唑啉-4-羥基,産率78%。
7-氟喹唑啉-4-羥基(1g, 6.0mmol)在0℃下溶於濃硫酸(3mL),然後在15min內緩慢滴入濃硝酸HNO3
(3mL),滴加完畢後,反應液加熱至100℃攪拌3h。冷卻至室溫後,反應液倒入攪拌中的冰水,有固體析出,過濾,粗品在冰乙酸
中進行重結晶,得到0.60g的7-氟-6-硝基喹唑啉-4-羥基,産率38%。
7-氟-6-硝基喹唑啉-4-羥基(518mg, 2mmol)溶於氯化亞碸(3mL),加入2-3滴的DMF,反應液回流3h。減壓蒸餾除去溶劑,剩餘的固體産物4-氯-7-氟-6-硝基喹唑啉可直接用於下一步反應,無需進一步分離。
4-氯-7-氟-6-硝基喹唑啉(458mg, 2.0mmol)和3-炔基苯胺(234mg, 2.0mmol)溶於異丙醇(5mL)後加熱回流3h。冷卻至室溫後,析出的固體過濾,濾餅用少量水洗滌,紅外乾燥後,得到0.59g的N-(3-炔基苯基)-7-氟-6-硝基喹唑啉-4-胺,産率95%。
N-(3-炔基苯基)-7-氟-6-硝基喹唑啉-4-胺(310mg, 1mmol)和SnCl2
.2H2
O (171mg, 4.5mmol)的乙酸乙酯溶液回流2h。反應液冷卻至室溫,用5%的碳酸氫鈉水溶液調節pH值至9-10後,以乙酸乙酯萃取,有機相用飽和食鹽水和水洗滌,硫酸鈉乾燥,濃縮後得到225mg的N-4-(3-炔基苯基)-7-氟喹唑啉-4, 6-二胺,黃色固體,産率81%。
N-4-(3-炔基苯基)-7-氟喹唑啉-4, 6-二胺(50mg, 0.18mmol)溶於DMF(2mL)後,在室溫下依次加入吡啶(17.5μL, 0.21mmol),氯甲酸苯酯(23μL, 0.18mmol),加熱至70℃攪拌1h,得到苯基-4-(3-炔基苯基胺)-7-氟喹唑啉-6-基-甲酸胺,可直接用於下一步反應,無需處理。此時,在同一溫度下繼續加入N1-(2,2-二乙氧基乙基)-N2,N2-二乙基乙烷-1,2-二胺(42mg, 0.18mmol)並攪拌2.5h。冷卻至室溫
後,反應液倒入水中,用乙酸乙酯萃取,有機相用飽和食鹽水洗滌,硫酸鈉乾燥,濃縮後得到的粗品用柱色譜分離,得到45mg的1-(2,2-二乙氧基乙基)-1-(2-(二乙氨基)乙基)-3-(4-(3-炔基苯基氨基)-7-氟喹唑啉-6-基)脲,産率70%。
將對甲苯磺酸(28.5mg, 0.15mmol)加入到1-(2,2-二乙氧基乙基)-1-(2-(二乙氨基)乙基)-3-(4-(3-炔基苯基氨基)-7-氟喹唑啉-6-基)脲(45mg, 0.08mmol)的DMF (2mL)溶液,加熱至80℃攪拌1h。冷卻至室溫後,反應液倒入水中,用乙酸乙酯萃取,有機相用飽和食鹽水洗滌,硫酸鈉乾燥,濃縮後得到的粗品用柱色譜分離,得到目標産物,黃色固體,産率90%。
1
H NMR (DMSO-d6
, 400 MHz): 10.18 (s,1H), 8.89 (d,J
=8.0Hz, 1H), 8.67 (s,1H), 8.06 (s,1H),7.93(d,J
=7.6Hz,1H), 7.65(d,J
=11.2Hz,1H), 7.42 (t,J
=8.0Hz,1H), 7.25 (d,J
=7.2Hz, 1H),6.88 (s, 1H) 6.87 (d,J
=2.8Hz, 1H), 4.24 (s,1H), 3.66 (t,J
=2.8Hz, 2H), 2.66 (t,J
=6.4Hz, 2H), 2.49-2.53 (m,4H), 0.98-0.93 (m,6H); MS (m/e
): 445 (M+1)。
合成方法及路線如下:
在0℃下將金屬鈉(92mg, 4mmol)溶於甲醇(4mL),同時用氮氣保護,然後將7-氟-6-硝基喹唑啉-4-羥基(418mg, 2mmol)加入,回流3h。冷卻至室溫,用2N HCl將pH值調至3-4後,減壓蒸餾除去溶劑,剩餘物用乙酸乙酯溶解後,用水洗滌2次,硫酸鈉乾燥,濃縮後得到405mg的7-甲氧基-6-硝基喹唑啉-4-羥基,産率92%。
接下來的合成方法與實施例160相同。
1
H NMR (DMSO-d6
, 400 MHz):9.98 (s,1H), 8.69 (s,1H), 8.63 (s,1H), 8.05 (s,1H),7.92 (d,J
=7.2Hz,1H), 7.35-7.29 (m, 2H), 7.21 (d,J
=7.6Hz, 1H), 6.75 (d,J
=2.0Hz, 1H), 6.58 (d,J
=2.8Hz, 1H), 4.15 (s,1H), 3.91 (s,3H), 3.64 (t,J
=7.6Hz, 2H), 2.65 (t,J
=7.2Hz, 2H),2.58 (m,4H), 0.97 (m,6H); MS (m/e
): 457 (M+1)。
化合物166-170的合成採用實施例165的方法。
1
H NMR (DMSO-d6
, 400 MHz): 9.90 (s,1H), 8.67 (s,1H),
8.62 (s,1H), 8.08 (s,1H),7.92 (d,J
=8.4Hz,1H), 7.42-7.37 (m, 2H), 7.21 (d,J
=7.6Hz, 1H), 6.72 (s,2H), 4.22 (s,1H), 3.95 (s,3H), 3.77 (t,J
=2.8Hz, 2H), 3.59 (t,J
=4.8Hz, 2H), 3.31 (s,3H); MS (m/e
): 416 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.94 (s,1H), 8.69 (s,1H), 8.62 (s,1H), 8.09 (s,1H),7.93 (d.J
=7.6Hz,1H), 7.42-7.37 (m, 2H), 7.21 (d,J
=7.6Hz, 1H), 6.79 (d,J
=2.4Hz, 1H), 6.73 (d,J
=2.4Hz, 1H), 4.22 (s,1H), 3.94 (s,3H), 3.75 (t,J
=2.8Hz, 2H), 3.68-3.57 (m,4H), 3.59 (t,J
=4.8Hz, 2H), 2.51-2.48 (m, 4H); MS (m/e
): 471 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.90 (s,1H), 8.66 (s,1H), 8.62 (s,1H), 8.08 (s,1H),7.92 (d,J
=8.0Hz,1H), 7.42-7.37 (m, 2H), 7.21 (d,J
=7.2Hz, 1H), 6.76 (d,J
=2.8Hz, 1H), 6.70 (d,J
=2.8Hz, 1H), 4.24 (s,1H), 3.94 (s,3H), 3.71 (t,J
=6.0Hz, 2H), 2.56 (t,J
=8.4Hz, 2H), 2.42 (s,8H), 2.34 (s,3H); MS (m/e
): 484 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.94 (s,1H), 8.69 (s,1H), 8.62 (s,1H), 8.08 (s,1H),7.92 (d,J
=8.0Hz,1H), 7.41-7.35 (m, 2H), 7.21 (d,J
=7.6Hz, 1H), 6.76 (d,J
=2.4Hz, 1H), 6.72 (d,J
=2.4Hz, 1H), 4.24 (s,1H), 3.93 (s,3H), 3.72 (t,J
=6.8Hz, 2H), 2.46-2.50 (m, 6H), 1.80 (t,J
=7.2Hz, 2H), 1.00-0.96 (m,
6H); MS (m/e
): 471 (M+1)。
1
H NMR (DMSO-d6
, 400 MHz): 9.92 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.07 (s, 1H),7.91 (d,J
=8.8Hz, 1H), 7.43-7.39 (m, 2H), 7.22 (d,J
=7.2Hz, 1H), 6.78 (s, 2H), 4.49 (d,J
=2.0Hz, 2H), 4.23 (s, 1H), 3.95 (s, 3H); MS (m/e
): 396 (M+1)。
․細胞裂解液:50mM Tris-Cl/pH8.0,0.5M NaCl和0.2mM EDTA,0.1% Triton X-100,1μg/ml Aprotinin,0.75μg/ml Leupeptin,1μg/ml Pepstatin,1mM DTT,500μM Sodium Vanadate,1mM PMSF。使用前加入蛋白酶抑制劑,置於冰上。
․樣品稀釋液:20mM Tris-Cl/pH7.3,150mM NaCl,0.1% BSA,0.05% Tween-20。
․1xPBS緩衝液:NaCl 0.137M,KCl 0.0027M,Na2
PO4
-12H2
O 0.01M,KH2
PO4
0.0015M,pH7.4。
․洗滌緩衝液:含有0.05% Tween-20的PBS緩衝液。
․封閉液:含有1%BSA的PBS緩衝液。
․將A431細胞(中科院上海生化細胞所細胞庫)以2.5×104
/孔的密度種到96孔板中,於5% CO2
,37℃的細胞培養箱中過夜培養。
․真空吸掉培養基,用200μL無血清DMEM培養基清
洗細胞後加入90μL/孔無血清DMEM培養基,於5% CO2
,37℃的細胞培養箱中饑餓過夜。
․將待測化合物以無血清DMEM培養基稀釋至10,3.3,1.1,0.37,0.12,0.04,0.013,0.004μM,將10μL稀釋後的化合物加入到90μL細胞培養體系中,DMSO終濃度爲0.5%,於5% CO2
,37℃的細胞培養箱中培養1小時。以不加入待測化合物的10μL無血清DMEM培養基加入到90μL細胞培養體系中,DMSO終濃度爲0.5%,其他處理或培養條件相同的處理組作爲對照孔。
․向藥物處理孔和對照孔分別加入10μL 200ng/ml EGF(Biosource,PHG0064),混合,培養45分鐘。
․吸掉培養基後加入100μL細胞裂解液,放於-80℃冰箱中過夜。
․在DELFIA Yellow Plate (Perkin Elmer,AAAND-0001)中加入100μL/孔用PBS稀釋至0.5μg/ml的anti-EGFR antibody (R&D,AF231),25℃搖床包被過夜。
․用200μL DELFIA洗滌緩衝液洗3次。
․加入200μL封閉液,25℃搖床孵育1小時。
․用200μL DELFIA洗滌緩衝液洗3次。
․加入80μL樣品稀釋液和20μL細胞裂解液,25℃搖床孵育1小時。
․加入100μL用DELFIA assay buffer (Perkin Elmer,1244-106)稀釋至0.5μg/ml的Eu-PT66抗體(Perkin Elmer,
AD0040),25℃搖床孵育1小時。
․用200μL DELFIA洗滌緩衝液洗3次。
․加入100μL DELFIA enhancement (Perkin Elmer,4001-0010),25℃搖床孵育30分鐘。
․在Victor3
Wallec 1420 (Perkin Elmer)檢測熒光信號(340nm激發光/620nm發射光)。
․背景讀值:表示未受任何刺激的細胞的熒光信號。
․對照孔讀值:表示只受EGF刺激的細胞的熒光信號。
結果顯示,化合物1-170均有抑制EGFR活性的作用,其IC50
的數值範圍爲0.001-10μM。
所有於本說明書中所揭示之特徵均可能以任何形式加以組合。於本說明書中所揭示的每個特徵,可能被提供相同的、均等或相似功能之變化的特徵所替換。因此,除非特別聲明,所揭示的每個特徵僅爲一般性均等或相似特徵之例示。
由上述可知,熟悉此項技術的人員可輕易掌握本發明之特徵,在不脫離本發明之精神和範圍內,可做不同更動
與潤飾,以符合不同之使用與條件。例如,可製備結構上與本發明化合物相似的化合物,應用其實施本發明。因此,其他的實施例亦在本發明之申請專利範圍內。
Claims (15)
- 一種如下結構式的化合物:
- 如申請專利範圍第1項所述的化合物及/或其藥學上可接受之鹽類,其中Z為N。
- 如申請專利範圍第1項所述的化合物及/或其藥學上可接受之鹽類,其中X為O、NH或N-CH3 。
- 如申請專利範圍第1項所述的化合物及/或其藥學上可接受之鹽類,其中Y為。
- 如申請專利範圍第4項所述的化合物及/或其藥學上可接受之鹽類,其中X為O、NH或N-CH3 ,且Z為N。
- 如申請專利範圍第1或5項所述的化合物及/或其藥學上可接受之鹽類,其中R3 或R4 之一為,其中n為1,且Ra 、Rb 和Rc 各獨立的選自H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基。
- 如申請專利範圍第1或5項所述的化合物及/或其藥學上 可接受之鹽類,其中R3 或R4 之一為,其中n為1或2;Ra 為H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基;Rb 和Rc 和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,其中雜原子為N、O或S。
- 如申請專利範圍第7項所述的化合物及/或其藥學上可接受之鹽類,其中Rb 和Rc 和與它們連接的N原子一起組成如下的雙環結構:
- 如申請專利範圍第1或5項所述的化合物及/或其藥學上可接受之鹽類,其中R3 或R4 之一為,其中Ra 為H、烷基、烯基、炔基、環烷基、雜環烷基、芳基或雜芳基。
- 如申請專利範圍第1或5項所述的化合物及/或其藥學上可接受之鹽類,其中R3 或R4 之一為,其中Ra 為 H、烷基、烯基、炔基、環烷基、雜環烷基、芳基、或雜芳基;Rd 和Re ,獨立地選自H、烷基、烯基或炔基。
- 如申請專利範圍第1或5項所述的化合物及/或其藥學上可接受之鹽類,其中R3 或R4 之一為,其中Ra 為H、烷基、烯基或炔基;Rd 和Re ,和與它們連接的N原子一起組成一個3-12員的碳環或雜環,其中包括芳香環,所述的環上包括1-3個雜原子,所述的雜原子為N、O或S。
- 如申請專利範圍第1項所述的化合物及/或其藥學上可接受之鹽類,其中該化合物為化合物1-80、84-91、93-101、103、104及106-170之任一者:
- 一種藥學組合物,包含申請專利範圍第1項的化合物及/或其藥學上可接受之鹽類,以及其藥學上可接受的載體。
- 一種如申請專利範圍第1項所述的化合物及/或其藥學上可接受之鹽類於製備治療腫瘤藥物之用途。
- 如申請專利範圍第14項所述的用途,其中所述的腫瘤為肺癌、頭頸癌、結腸癌或胰腺癌。
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CN102702115A (zh) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | 一种4-氯-7-氟-6-硝基喹唑啉的合成方法 |
CN102775315A (zh) * | 2012-07-31 | 2012-11-14 | 上海应用技术学院 | 一种间氨基苯乙炔的制备方法 |
CN103275018B (zh) * | 2013-04-26 | 2016-03-02 | 浙江工业大学 | 4-[3-氯-4-取代苯胺基]-6-取代甲酰氨基喹唑啉类化合物及制备和应用 |
CN108863951A (zh) * | 2017-05-16 | 2018-11-23 | 和记黄埔医药(上海)有限公司 | 化合物的盐及其晶型 |
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CN110903253B (zh) * | 2019-12-13 | 2020-12-25 | 西安交通大学医学院第一附属医院 | 一种喹唑啉酮类化合物及其制备方法和应用 |
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