TW202222770A - 苄胺或苄醇衍生物及其用途 - Google Patents
苄胺或苄醇衍生物及其用途 Download PDFInfo
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- TW202222770A TW202222770A TW110143499A TW110143499A TW202222770A TW 202222770 A TW202222770 A TW 202222770A TW 110143499 A TW110143499 A TW 110143499A TW 110143499 A TW110143499 A TW 110143499A TW 202222770 A TW202222770 A TW 202222770A
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/22—Nitrogen and oxygen atoms
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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Abstract
本發明公開了一種作為鈉通道調節劑的化合物及其用途,該類化合物對電壓門控鈉離子通道亞型Nav1.8離子通道活性具有明顯的抑制、阻斷作用,可作為Nav1.8專一性抑制劑,可用以製備治療由Nav1.8介導的腸痛、神經性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原發性疼痛、多發性硬化症、恰克-馬利-杜斯氏症、失禁、心律失常等疾病的藥物,具有廣闊的應用前景。
Description
本發明涉及醫藥技術領域,特別是涉及一種用作電壓門控鈉離子通道亞型Nav1.8專一性抑制劑的化合物及其用途。
隨著全球老齡化社會的到來,慢性疼痛疾病影響的範圍已逐漸擴大,全球有三分之一以上的人患有慢性疼痛,中國關節炎患者數量高達1.2億;同時,中國至少還有八九千萬神經病理性慢疼痛患者,而且呈增長態勢;另外,癌症最終也將成為一種慢性病,癌痛將長期伴隨著患者,據報導,中國半數以上的癌症患者並未接受過癌痛治療。疼痛本是動物或人體自我保護的一種機制,然而許多持續疼痛卻超出了其有用性,給患者身體或身心健康帶來的極大的痛苦,疼痛治療是改善症患者生活質量的重要因素,市場前景也十分巨大。
2005年,全球止痛劑市場總量達800億美元以上,處方藥品銷售額約為200億美元。根據美國國家衛生研究院(National Institutes of Health,NIH)的統計估算,美國有多達2500萬人每天在於疼痛作鬥爭,其中有2300萬的成年人患有嚴重的疼痛。國內方面,隨著中國製造業大國地位的不斷提升,產業工人數量急劇膨脹,長期的勞作容易導致各種機體勞損和關節疼痛,該群體已成為疼痛藥物消費的另一個大群體。資料顯示:中國非處方藥市場上止痛藥增長迅速,其銷售額僅次於感冒藥,約占20%的比例。
但是,鴉片類止痛藥物的濫用給社會造成了驚人的影響,據WHO估計,全球每年有6.9萬人死于鴉片類藥物過量,1500萬人依賴鴉片類藥物(即鴉片類藥物成癮),開發新的安全有效的止痛藥物的重要性不言而喻。
電壓門控性鈉離子通道(Nav)的內向電流是中樞和外周神經元動作電位產生和傳導的重要環節,而神經元興奮性增高或對刺激的反應性增加是各種疼痛產生發展的重要機制。因此,電壓門控性鈉離子通道在疼痛傳導通路特別是在外周感覺神經元中的作用一直是疼痛研究的熱點。
人類鈉離子通道有9種,分別為Nav1.1~Nav1.9,Nav1.5、Nav1.8 和Nav1.9是河豚毒素(tetrodotoxin,TTX)不敏感性鈉通道,其中,Nav1.8是參與慢性疼痛、心房纖維性顫動、巴德- 吉亞利症候群的重要離子通道,是疼痛治療的高選擇性作用靶點。Nav1.8主要表達在小直徑痛覺感受神經元,參與感覺神經元的動作電位和節律放電。Nav1.8受炎症性介質的調控,同時在坐骨神經損傷模型中上調表達,Nav1.8的基因剔除和靜默研究表明,其參與神經性和炎症性疼痛的調節。由於Nav1.8主要侷限於感受疼痛的神經元,故選擇性Nav1.8阻斷劑不大可能誘導非選擇性Nav阻斷劑所常見的不良反應。因此,針對Nav1.8疼痛靶點進行專一性抑制劑篩選的研究已成為疼痛領域的熱點,但是,已知的Nav抑制劑主要存在治療窗帶較差等缺點,這可能是由於其缺乏亞型選擇性而導致。
目前已知的Nav1.8抑制劑有PF-01247324,A803467,PF-06305591以及VX150等。其中,前三個化合物都因為選擇性不夠好,藥代數據差,生物利用的低等問題終止於臨床前階段。VX-150目前處於臨床二期,在包括手術後急性疼痛、骨關節炎慢性疼痛和神經病理性疼痛等臨床研究中都達到主要臨床終點。VX-150耐受性良好,無嚴重不良反應發生。FDA已經授予VX-150突破性療法認定,用於治療中度至重度疼痛。不過VX-150臨床劑量較大,為1500毫克首服,隨後每12小時服用750毫克,其活性有待進一步的提高。同時,該化合物的溶解吸收也存在較大的問題,雖然以前藥的方法得到部分解決,但依然不夠理想。
因此,研發更高親和力、高專一性以及更好藥代動力學的Nav1.8抑制劑具有很大的社會價值和經濟價值。
本發明主要解決的技術問題是提供一種苄胺或苄醇衍生物,對Nav1.8具有強效的選擇性抑制作用。
為解決上述技術問題,本發明提供一種化合物,其特徵在於,具有式I所示結構或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽:
A
1、A
3分別獨立選自CR
1或N;
A
2選自NR
10R
11或OR
12;
R
1、R
2、R
3、R
4、R
5分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、取代或非取代的醯胺基、酯基、醯基、羧基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基;
R
10、R
11、R
12分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基;
或R
4與R
5及其相連的原子組成取代或非取代的3~10元環烷基、=O,或R
4與R
5及其相連的原子組成取代或非取代的3~10元雜環烷基,或R
5與R
11及其相連的原子組成取代或非取代的3~10元雜環烷基,或R
5與R
12及其相連的原子組成取代或非取代的3~10元雜環烷基;
其中,R
1、R
2、R
3、R
4、R
5、R
10、R
11、R
5與R
11及其相連的原子組成的雜環烷基中的取代基分別獨立選自氘、鹵素、羥基、氨基、烷基、雜烷基、環烷基、雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基;
z選自0、1、2、3、4、5,n選自0、1、2、3、4,m選自0、1、2、3、4、5。
本發明還提供了具有式III或III’所示結構或其異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽:
A
1選自CR
1或N;A
2選自NR
10R
11或OR
12;
R
1選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基;
R
6、R
7、R
8、R
9分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基;其中,取代基選自氘、鹵素、羥基、氨基、烷基、雜烷基、環烷基、雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基。
進一步地,n選自0、1、2。
進一步地,m選自0、1、2。
進一步地,z選自0、1、2、3。
其中,n、m、z三者的數值可以隨意組合。
R
1選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的醯胺基、酯基、醯基、羧基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基;其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基;
其中,R
1選自氫、鹵素、羥基、氰基、氨基、取代或非取代的C1~C6烷基、取代或非取代的3~6元環烷基、取代或非取代的2~7元雜烷基、取代或非取代的3~6元雜環烷基、取代或非取代的醯胺基、酯基、醯基;其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基;
進一步地,R
1選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的2~4元雜烷基;其中,取代基選自鹵素、羥基、氨基、C1~C3烷基、2~4元雜烷基、醯基。
進一步地,R
1選自氫、鹵素。
更進一步地,R
1選H,F。
一方面,n為1或2,每一個R
2獨立選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的環丙基。
進一步地,每一個R
2獨立選自氫、鹵素、三氟甲基、取代或非取代的環丙基;當n為1時,R
2不為H;n為2時,兩個R
2不同時為H。
一發明,m為2或3,每一個R
3分別獨立選自鹵素、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基,其中,取代基選自氘、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、鹵素、羥基、醯胺基;每個R
3不同。
進一步地,每一個R
3分別獨立選自氫、鹵素、取代或非取代C1~C6烷基、取代或非取代C1~C6烷氧基,其中,取代基選自氘、鹵素、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、羥基、醯胺基。
更進一步地,每一個R
3分別獨立選自鹵素、取代或非取代的C1~C3烷基、取代或非取代C1~C3烷氧基。
進一步地,R
4與R
5及其相連的原子組成環烷基或雜環烷基時,可以是相鄰兩個取代位點的R
4與R
5及其相連的原子組成環烷基或雜環烷基(如
組成
),或不相鄰兩個取代位點的R
4與R
5及其相連的原子組成環烷基或雜環烷基(如
組成
),或同一取代位點的R
4與R
5及其相連的原子組成環烷基或雜環烷基(如
組成
)。
一方面本發明還提供了具有式IV、IV’或IV’’所示結構或其異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽:
其中,
A
1選自N或-CR
1;R
15、R
16分別獨立選自氫、C1-C3烷基,進一步選自氫、甲基;
R
17選自C1-C5的醯胺基、含有內醯胺的四元或五元雜環,至少含有羥基或氨基取代的C1-C5烷基,或者R
15、R
16其中之一與R
17及其相連的原子組成
,Z
3選自0、1或2;R
17進一步選自C1-C3的醯胺基、含有內醯胺的四元或五元雜環,至少含有羥基或氨基取代的C1-C3烷基,或者R
15、R
16其中之一與R
17及其相連的原子組成
,Z
3選自0、1或2;
R
19選自
、
,R
13、R
14分別獨立選自氫、醯基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜環烷基、取代或非取代的雜芳基,Z
1、Z
2分別獨立為1-5。
另一方面,本發明還提供了具有式V或V’所示結構或其異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽:
其中,A
1 、A
3選自CR1;或者,A1選自N,A3選自N或CR1;
R
20分別獨立選自氫、醯基、
、C1-C5烷基或環烷基、噻唑。
本發明還提供一種藥用組合物,該藥用組合物活性成份選自請求項1~21任一請求項所述的化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶中的一種或兩種以上的組合。
本發明還提供了本發明化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備鈉離子通道調節劑中的用途。
進一步地,所述鈉離子通道調節劑為Nav1.8抑制劑。
本發明還提供了本發明化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備治療致使Nav1.8過度表達的疾病的藥物中的用途。
本發明還提供了本發明化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備治療Nav1.8過度表達所致疾病的藥物中的用途。
本發明還提供了本發明化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備用於治療慢性疼痛、腸痛、神經性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原發性疼痛、多發性硬化症、恰克-馬利-杜斯氏症、失禁和心律失常中的任意一種或多種疾病的藥物中的用途。
進一步地,所述神經性疼痛選自皰疹後神經痛、糖尿病性神經痛、痛性HIV相關性感覺神經病、三叉神經痛、口腔灼熱症候群、截肢術後疼痛、幻痛、痛性神經瘤、創傷性神經瘤、莫頓式神經瘤、神經擠壓損傷、脊管狹窄、腕隧道症候群、神經根痛、坐骨神經痛、神經撕脫傷、臂叢神經損傷、複雜性局部疼痛症候群、藥物療法引起的神經痛、癌症化學療法引起的神經痛、抗逆轉錄病毒療法引起的神經痛、脊髓損傷後疼痛、原發性小纖維神經病、原發性感覺神經病、三叉自主神經性頭痛中的一種或幾種;
所述肌肉骨骼痛選自骨關節炎疼痛、背痛、冷痛、燒傷疼痛、牙痛中的一種或幾種;
所述炎性疼痛痛選自類風濕性關節炎疼痛和/或外陰痛;
所述原發性疼痛選自纖維肌痛。
含有本發明化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶的藥物組合物中,可以含有藥學上可接受的輔料。
本發明中所述“藥學上可接受的”是指包括任意不干擾活性成分的生物活性的有效性且對它被給予的宿主無毒性的物質。
本發明所述藥學上可接受的輔料,是藥物中除主藥以外的一切附加材料的總稱,輔料應當具備如下性質:(1)對人體無毒害作用,幾無副作用;(2)化學性質穩定,不易受溫度、pH、保存時間等的影響;(3)與主藥無配伍禁忌,不影響主藥的療效和質量檢查;(4)不與包裝材料相互發生作用。本發明中輔料包括但不僅限於填充劑(稀釋劑)、潤滑劑(助流劑或抗粘著劑)、分散劑、濕潤劑、粘合劑、調節劑、增溶劑、抗氧劑、抑菌劑、乳化劑、崩解劑等。粘合劑包含糖漿、阿拉伯膠、明膠、山梨醇、黃芪膠、纖維素及其衍生物(如微晶纖維素、羧甲基纖維素鈉、乙基纖維素或羥丙甲基纖維素等)、明膠漿、糖漿、澱粉漿或聚乙烯吡咯烷酮等;填充劑包含乳糖、糖粉、糊精、澱粉及其衍生物、纖維素及其衍生物、無機鈣鹽(如硫酸鈣、磷酸鈣、磷酸氫鈣、沉降碳酸鈣等)、山梨醇或甘胺酸等;潤滑劑包含微粉矽膠、硬脂酸鎂、滑石粉、氫氧化鋁、硼酸、氫化植物油、聚乙二醇等;崩解劑包含澱粉及其衍生物(如羧甲基澱粉鈉、澱粉乙醇酸鈉、預膠化澱粉、改良澱粉、羥丙基澱粉、玉米澱粉等)、聚乙烯吡咯烷酮或微晶纖維素等;濕潤劑包含十二烷基硫酸鈉、水或醇等;抗氧劑包含亞硫酸鈉、亞硫酸氫鈉、焦亞硫酸鈉、二丁基苯酸等;抑菌劑包含0.5%苯酚、0.3%甲酚、0.5%三氯第三丁醇等;調節劑包含鹽酸、枸櫞酸、氫氧化鉀(鈉)、枸櫞酸鈉及緩衝劑(包括磷酸二氫鈉和磷酸氫二鈉)等;乳化劑包含聚山梨酯-80、沒酸山梨坦、普流羅尼克F-68,卵磷酯、豆磷脂等;增溶劑包含吐溫-80、膽汁、甘油等。
術語“藥學上可接受的鹽”指本發明化合物與酸或鹼所形成的適合用作藥物的鹽。上述酸鹼為廣義的路易斯酸鹼。適合形成鹽的酸包括但並不限於:鹽酸、氫溴酸、氫氟酸、硫酸、硝酸、磷酸等無機酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有機酸;以及天冬胺酸、谷胺酸等酸性胺基酸。
本發明化合物或藥物組合物的施用方式沒有特別限制,代表性的施用方式包括(但並不限於):口服、腸胃外(靜脈內、肌肉內或皮下)、和局部給藥。
用於口服給藥的固體劑型包括膠囊劑、片劑、丸劑、散劑和顆粒劑。在這些固體劑型中,活性化合物與至少一種常規惰性賦形劑(或載體)混合,如檸檬酸鈉或磷酸二鈣,或與下述成分混合:(a) 填料或增容劑,例如,澱粉、乳糖、蔗糖、葡萄糖、甘露醇和矽酸;(b) 粘合劑,例如,羥甲基纖維素、藻酸鹽、明膠、聚乙烯基吡咯烷酮、蔗糖和阿拉伯膠;(c) 保濕劑,例如,甘油;(d) 崩解劑,例如,瓊脂、碳酸鈣、馬鈴薯澱粉或木薯澱粉、藻酸、某些複合矽酸鹽、和碳酸鈉;(e) 緩溶劑,例如石蠟;(f) 吸收加速劑,例如,季胺化合物;(g) 潤濕劑,例如鯨蠟醇和單硬脂酸甘油酯;(h) 吸附劑,例如,高嶺土;和(i) 潤滑劑,例如,滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉,或其混合物。膠囊劑、片劑和丸劑中,劑型也可包含緩衝劑。
固體劑型如片劑、糖丸、膠囊劑、丸劑和顆粒劑可採用包衣和殼材製備,如腸衣和其它本領域公知的材料。它們可包含不透明劑,並且,這種組合物中活性化合物或化合物的釋放可以延遲的方式在消化道內的某一部分中釋放。可採用的包埋組分的實例是聚合物質和蠟類物質。必要時,活性化合物也可與上述賦形劑中的一種或多種形成微膠囊形式。
用於口服給藥的液體劑型包括藥學上可接受的乳液、溶液、懸浮液、糖漿或酊劑。除了活性化合物外,液體劑型可包含本領域中常規採用的惰性稀釋劑,如水或其它溶劑,增溶劑和乳化劑,例如,乙醇、異丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲醯胺以及油,特別是棉籽油、花生油、玉米胚油、橄欖油、蓖麻油和芝麻油或這些物質的混合物等。
除了這些惰性稀釋劑外,組合物也可包含助劑,如潤濕劑、乳化劑和懸浮劑、甜味劑、矯味劑和香料。
除了活性化合物外,懸浮液可包含懸浮劑,例如,乙氧基化異十八烷醇、聚氧乙烯山梨醇和脫水山梨醇酯、微晶纖維素、甲醇鋁和瓊脂或這些物質的混合物等。
用於腸胃外注射的組合物可包含生理上可接受的無菌含水或無水溶液、分散液、懸浮液或乳液,和用於重新溶解成無菌的可注射溶液或分散液的無菌粉末。適宜的含水和非水載體、稀釋劑、溶劑或賦形劑包括水、乙醇、多元醇及其適宜的混合物。
用於局部給藥的本發明化合物的劑型包括軟膏劑、散劑、貼劑、噴射劑和吸入劑。活性成分在無菌條件下與生理上可接受的載體及任何防腐劑、緩衝劑,或必要時可能需要的推進劑一起混合。
本發明化合物同樣可以用於注射製劑。其中,所述注射劑選自液體注射劑(水針)、注射用無菌粉末(粉針)或注射用片劑(是指藥物用無菌操作法製成的模印片或機壓片,臨用時用注射用水溶解,供皮下或肌肉注射之用)。
其中,所述注射用粉劑的中除含有上述化合物外,還至少含有賦形劑。本發明中所述賦形劑,為有意加到藥物中的成分,其在所用的量上不應具有藥理學特性,但是,賦形劑可以有助於藥物的加工、溶解或溶出、通過靶向給藥途徑遞藥或有助於穩定性。
因分子中某一原子在兩個位置迅速移動而產生的官能團異構體稱之為互變異構體。
內消旋體(mesomer)分子內含有不對稱性的原子,但具有對稱因素而使分子內總旋光度為零,即無旋光性。
外消旋體是一種具有旋光性(見旋光異構)的手性分子(見手征性)與其對映體的等莫耳混合物。
互為實物與鏡像而不可重疊的立體異構體,稱為對映異構體 (Enantiomer,簡稱為對映體),對映異構體都有旋光性,其中一個是左旋的,一個是右旋的,所以對映異構體又稱為旋光異構體。
非對映異構體(diastereoisomers)是指分子具有兩個或多個手性中心,並且分子間為非鏡像的關係的立體異構體。
“取代”是指分子中的氫原子被其它不同的原子或分子所替換。
“元”是表示構成環或雜烷基的骨架原子的個數。
本發明中所述“一鍵”,指該處僅為一個連接鍵,亦可理解為“無”。
“烷基”,是指脂肪族烴基團,指飽和烴基。烷基部分可以是直鏈烷基,亦可以是支鏈烷基。典型的烷基包括但不限於甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基、己基等等。
本發明中使用的C1~Cn包括C1~C2、C1~C3……C1~Cn,n為大於一的整數;作為取代基的前綴表示取代基中碳原子個數的最小值和最大值,例如,“C1~C6烷基”是指含有一個至6個碳原子的直鏈或支鏈的烷基。
“雜烷基”是指含有雜原子的烷基,包括烷氧基。
“烯基”,是指具有至少一個碳-碳雙鍵的脂肪族碳氫基團。所的烯基可以是直鏈或支鏈的。
“炔基”,是指具有至少一個碳-碳三鍵的脂肪族碳氫基團。所述炔基可以是直鏈或支鏈的。
“醯胺基”是具有式-C(O)NHR或-NHC(O)R的化學結構,其中R可選自烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基等。
“磺醯基”是具有式-S(=O)
2R的化學結構,包括磺醯胺基,其中R可選自烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基、氨基等;
“磷醯基”是具有式-P(=O)RR’的化學結構,其中R、R’可別獨立選自烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基、羥基、氨基等;
“酯基”是指具有式-COOR的化學結構,其中R選自烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基等。
“醯基”是指具有式-C(O)R的化學結構,其中R選自烷基、雜烷基、環烷基、雜環烷基、芳基、雜芳基等。
“環烷基”指飽和或不飽和的環狀烴取代基。
“雜環烷基”指環骨架上含有至少一個雜原子的環烷基。
雜原子包括但不限於O、S、N、P、Si等。
“環”是指任意的共價封閉結構,包括例如碳環(例如芳基或環烷基)、雜環(例如雜芳基或雜環烷基)、芳香基(如芳基或雜芳基)、非芳香基(如環烷基或雜環烷基)。本發明中所述“環”可以是單環也可以是多環,可以是並環、螺環或橋環。
“芳基”,是指平面環具有離域的π電子系統並且含有4n+2個π電子,其中n是整數。芳基環可以由五、六、七、八、九或多於九個原子構成。芳基包括但不限於苯基、萘基、菲基、蒽基、茀基和茚基等。
“鹵素”或“鹵”是指氟、氯、溴或碘。
“氘”是指氫(H)的同位素,也被稱為重氫,元素符號一般為D或
2H,可以使用氘替代本發明H的位置。
文中所述烷基、雜烷基、環基、雜環基、氨基、酯基、羰基、醯胺基、磺醯基、磷醯基、硼酸基、硼酸酯基、芳基、雜芳基等,可以是非取代的烷基、雜烷基、環基、雜環基、氨基、酯基、羰基、醯胺基、磺醯基、磷醯基、硼酸基、硼酸酯基、芳基、雜芳基,也可以是取代的烷基、雜烷基、環基、雜環基、氨基、酯基、羰基、醯胺基、磺醯基、磷醯基、硼酸基、硼酸酯基、芳基、雜芳基。
上文中,除已經指明的外,所述“取代”是指所提及的基團可以被一個或多個額外的基團取代,所述額外的基團各自並且獨立地選自烷基、環烷基、芳基、羧基、雜芳基、雜環烷基、羥基、烷氧基、烷硫基、芳氧基、O=、胍基、氰基、硝基、醯基、鹵素、鹵代烷基、氨基等等。
抑制劑,是指導致蛋白質生物活性降低的產品,如本發明化合物可以降低Nav1.8離子通道活性,即為Nav1.8抑制劑。
本發明的有益效果是:本發明提供了一系列對Nav1.8離子通道活性具有明顯的抑制作用的化合物,為以Nav1.8為治療的靶點的疾病如慢性疼痛、腸痛、神經性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原發性疼痛、多發性硬化症、恰克-馬利-杜斯氏症、失禁或心律失常疾病等的治療提供新的方案,可用於製備治療相關疾病的藥物,具有廣闊的應用前景。
下面對本發明的技術方案進行清楚、完整地描述,顯然,所描述的實施例是本發明一部分實施例,而不是全部的實施例。基於本發明中的實施例,本發明領域具通常知識者在沒有做出創造性勞動前提下所獲得的所有其他實施例,都屬於本發明保護的範圍。
本發明中,化合物的結構是通過質譜(MS)和/或核磁共振(1HNMR)設備來確定的。化學縮寫簡稱具有以下意義:
DMF:N,N-二甲基甲醯胺
THF:四氫呋喃
DIAD:偶氮二甲酸二異丙酯
DIPEA:N,N-二異丙基乙胺
PE:石油醚
EA:乙酸乙酯
DCM:二氯甲烷
HATU:O-(7-氮雜苯並三唑-1-基)-N,N,N′,N′-四甲基脲
DMSO:二甲基亞碸
DAST:二乙胺基三氟化硫
TBAF:四丁基氟化銨
NMP:N-甲基吡咯烷酮
CDI:N,N'-羰基二咪唑
LiHMDS:雙三甲基矽基胺基鋰
中間體合成
步驟1:2-氟-4-(三氟甲基)苯甲酸甲酯的合成
向反應瓶中加入2-氟-4-(三氟甲基)苯甲酸(2.08 g,10 mmol),碳酸鉀(2.76 g,20 mmol)和20 mL乙腈,室溫下加入碘甲烷(1.70 g,12 mmol),該反應混合物加熱至回流攪拌6小時,TLC顯示反應完全。反應體系降溫至室溫後過濾,濾液旋乾,得到2.10 g目標產物,收率:95%。
步驟2:2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸甲酯的合成
向反應瓶中加入2-氟-4-(三氟甲基)苯甲酸甲酯(1.11 g,5 mmol),4-氟-2-甲基苯酚(0.63 g,5 mmol),碳酸鉀(1.38 g,10 mmol)和10 mL N-甲基吡咯烷酮,該反應混合物加熱至120°C攪拌20小時,TLC顯示反應完全。反應體系降溫至室溫後倒入50 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(PE/EA=20/1),得到1.3 g目標產物,收率:79%。
步驟3:2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸甲酯(656 mg,2 mmol),氫氧化鈉(320 mg,8 mmol),10 mL水和10 mL 甲醇,該反應混合物於室溫下攪拌8小時,TLC顯示反應完全。反應體系倒入50 mL水中,用1M的鹽酸調節pH值至5,乙酸乙酯萃取,有機相乾燥並旋乾,得到620 mg目標產物,收率:99%。
步驟1:4-溴-2-氟-5-(三氟甲基)苯胺的合成
將2-氟-5-(三氟甲基)苯胺(3.58 g,20 mmol)溶於50 mL DMF,室溫下加入NBS (3.56 g,20 mmol),該反應混合物室溫攪拌過夜。反應體系倒入200 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(PE/EA=2/1),得到4.80 g目標產物,收率:93%。
步驟2:4-環丙基-2-氟-5-(三氟甲基)苯胺的合成
向反應瓶中加入4-溴-2-氟-5-(三氟甲基)苯胺(2.58 g,10 mmol),環丙基硼酸(3.44 g,40 mmol),碳酸鈉(5.30 g,50 mmol)和30 mL DMF,置換氮氣後加入Pd(dppf)Cl
2(220 mg,0.3 mmol),該反應混合物在氮氣保護下加熱至90°C攪拌過夜。反應體系降溫至室溫後倒入200 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(PE/EA=2/1),得到1.62 g目標產物,收率:74%。
步驟3:1-碘-4-環丙基-2-氟-5-(三氟甲基)苯的合成
將4-環丙基-2-氟-5-(三氟甲基)苯胺(1.10 g,5 mmol)溶於15 mL乙腈,0°C下滴加亞硝酸異戊酯(0.70 g,6 mmol),加畢後體系室溫攪拌1小時。加入碘化鉀(1.66 g,10 mmol)的5 mL水溶液,該反應混合物室溫攪拌6小時。反應體系倒入50 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M的碳酸鈉水溶液及飽和食鹽水反洗,乾燥並旋乾後得到1.05 g目標產物,收率:61%。
步驟4:4-環丙基-2-氟-5-(三氟甲基)苯甲酸的合成
將1-碘-4-環丙基-2-氟-5-(三氟甲基)苯(660 mg, 2 mmol)及三乙胺(404 mg,4 mmol)溶於DMF/H
2O(10 mL/1 mL),加入Pd(dppf)Cl
2(73 mg,0.1 mmol),用一氧化碳置換體系中的空氣後,該反應混合物在1M Pa壓力的一氧化碳下加熱至90°C攪拌過夜。反應體系降溫至室溫後倒入50 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(DCM/MeOH=10/1),得到190 mg目標產物,收率:38%。
步驟5:4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸的合成
以上步產物為底物,通過與中間體1一致的方法得到中間體3化合物
步驟1:4-溴-2-氟-5-(三氟甲基)苯胺的合成
將1-氯-4-氟-2-(三氟甲基)苯(2.0 g,10.1 mmol)溶於20 mL乾燥的THF,體系於氮氣保護下降溫至-70°C,滴加2,2,6,6-四甲基哌啶鋰(11.1 mL,1.0 M 正己烷溶液,11.1 mmol),反應液繼續於-70°C攪拌0.5小時後,加入過量乾冰。自然升至室溫,加入100 mL水,鹽酸調節體系至酸性,乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(DCM/MeOH=20/1),得到1.8 g目標產物,收率:75%。
步驟2:5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸的合成
以上步產物為底物,通過與中間體1一致的方法得到中間體3化合物
步驟1:3-氨基-3-(2-氟-5-硝基苯基)丙酸的合成
向反應瓶中加入2-氟-5-硝基苯甲醛(2000 mg,11.8 mmol),丙二酸(1477 mg,14.2 mmol),乙酸銨(1823 mg,10 mmol)和20 mL乙醇,該反應混合物加熱至80°C攪拌過夜,TLC顯示反應完全。反應體系降溫至室溫後過濾,濾餅用乙醇洗滌三次,所得固體旋乾,得到約3000 mg黃色固體,粗品直接用於下一步反應。
步驟2:3-((第三丁氧羰基)氨基)-3-(2-氟-5-硝基苯基)丙酸的合成
向反應瓶中加入3-氨基-3-(2-氟-5-硝基苯基)丙酸(3000 mg,粗品),(Boc)
2O(4716 mg,21.6 mmol)和30 mL水,加入氫氧化鈉(1154 mg,28.9 mmol),反應混合物室溫攪拌過夜,反應體系直接旋乾,經矽膠柱層析純化(DCM/MeOH=20/1),得到780 mg淡黃色固體,兩步收率:20%。
步驟3:(3-氨基-1-(2-氟-5-硝基苯基)-3-氧代丙基)氨基甲酸第三丁酯的合成
向反應瓶中加入3-((第三丁氧羰基)氨基)-3-(2-氟-5-硝基苯基)丙酸(100 mg,0.35 mmol),氯化銨(185 mg,3.5 mmol),DIPEA(89 mg,0.69 mmol)和2 mL 四氫呋喃,加入HBTU(261 mg,0.69 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到75 mg淡黃色固體,收率:75%。
步驟4:(3-氨基-1-(5-氨基-2-氟苯基)-3-氧代丙基)氨基甲酸第三丁酯的合成
向反應瓶中加入(3-氨基-1-(2-氟-5-硝基苯基)-3-氧代丙基)氨基甲酸第三丁酯(75 mg,0.23 mmol)和2mL 乙醇,加入10%的Pd/C(50 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,乙醇洗滌濾餅,濾液旋乾後得到70 mg白色固體,收率:103%。
步驟5:第三丁基(3-氨基-1-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3-氧代丙基)氨基甲酸酯的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(89 mg,0.28 mmol),(3-氨基-1-(5-氨基-2-氟苯基)-3-氧代丙基)氨基甲酸第三丁酯(70 mg,0.23 mmol),DIPEA(61 mg,0.47 mmol)和2 mL 四氫呋喃,加入HBTU(179 mg,0.47 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=50/1),得到50 mg淡黃色固體,收率:36%。
步驟6:N-(3-(1,3-二氨基-3-氧代丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯的合成
將第三丁基(3-氨基-1-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3-氧代丙基)氨基甲酸酯(50 mg,0.084 mmol)溶於2 mL二氯甲烷,室溫下加入三氟乙酸 (2 mL)後攪拌過夜。反應體系倒入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(DCM/MeOH=20/1),得到8 mg白色固體,收率:20%。
LC/MS: m/z=494.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.16 (3H, s), 2.53-2.55 (2H, m), 4.46 (1H, brs), 6.77 (1H, d,
J= 8.4 Hz), 7.10-7.24 (4H, m), 7.17-7.19 (1H, m), 7.27 (1H, d,
J= 8.8 Hz), 7.80-7.85 (1H, m), 7.95 (1H, s), 10.61 (1H, s).
步驟1:3-(5-氨基-2-氟苯基)-3-((第三丁氧基羰基)氨基)丙酸的合成
向反應瓶中加入3-((第三丁氧羰基)氨基)-3-(2-氟-5-硝基苯基)丙酸(100 mg,0.34 mmol)和5mL 乙醇,加入10%的Pd/C(70 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,乙醇洗滌濾餅,濾液旋乾後得到95 mg白色固體,收率:100%。
步驟2:3-((第三丁氧基羰基)氨基)-3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)丙酸的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(110 mg,0.0.35 mmol)和2 mL氯化亞碸,80°C攪拌2小時後旋乾,所得固體溶於2 mL四氫呋喃後室溫滴加到含有3-(5-氨基-2-氟苯基)-3-((第三丁氧基羰基)氨基)丙酸(95 mg,0.31 mmol)和DIPEA(82 mg,0.64 mmol)的1 mL 四氫呋喃溶液中,反應混合物室溫攪拌2小時。倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到100 mg淡黃色固體,收率:53%。
步驟3:(3-氨基-3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)丙酸的合成
將3-((第三丁氧基羰基)氨基)-3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)丙酸(100 mg,0.17 mmol)溶於1 mL二氯甲烷,室溫下加入三氟乙酸 (1 mL)後攪拌過夜。反應體系倒入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(DCM/MeOH=20/1),得到9 mg白色固體,收率:11%。
LC/MS: m/z=495.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.16 (3H, s), 2.47-2.49 (2H, m), 4.45 (1H, brs), 6.78 (1H, d,
J= 8.4 Hz), 7.10-7.24 (5H, m), 7.17-7.19 (1H, m), 7.25 (1H, d,
J= 8.4 Hz), 7.82-7.85 (1H, m), 7.95 (1H, s), 10.55 (1H, s), 13.08 (1H, brs).
步驟1:(1-(2-氟-5-硝基苯基)-3-羥丙基)氨基甲酸第三丁酯的合成
將3-((第三丁氧羰基)氨基)-3-(2-氟-5-硝基苯基)丙酸(50 mg,0.15 mmol)溶於1 mL四氫呋喃,0°C下加入硼烷四氫呋喃溶液(1 M,1 mL),該反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(DCM/MeOH=30/1),得到30 mg白色固體,收率:63%。
步驟2:(1-(5-氨基-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯的合成
向反應瓶中加入(1-(2-氟-5-硝基苯基)-3-羥丙基)氨基甲酸第三丁酯(30 mg,0.096 mmol)和2mL 乙醇,加入10%的Pd/C(20 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,乙醇洗滌濾餅,濾液旋乾後得到25 mg白色固體,收率:93%。
步驟3:(1-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸 (30 mg,0.085 mmol),1-(5-氨基-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯(25 mg,0.088 mmol),DIPEA(23 mg,0.18 mmol)和2 mL 四氫呋喃,加入HATU(67 mg,0.18 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=50/1),得到35 mg白色固體,收率:66%。
步驟4:N-(3-(1-氨基-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將(1-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯(35mg,0.056 mmol)溶於1 mL二氯甲烷,室溫下加入三氟乙酸 (1 mL)後攪拌過夜。反應體系倒入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(DCM/MeOH=20/1),得到18 mg白色固體,收率:62%。
LC/MS: m/z=521.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.57 (2H, m), 1.01-1.04 (2H, m), 1.79-1.82 (2H, m), 2.12-2.14 (1H, m), 2.16 (3H, s), 3.37-3.40 (2H, m), 4.14-4.17 (1H, m), 6.35 (1H, s), 7.02-7.12 (3H, m), 7.20 (1H, d,
J= 8.4 Hz), 7.49-7.52 (1H, m), 7.74-7.76 (1H, m), 7.90 (1H, s), 10.43 (1H, s).
步驟1:(3-氨基-3-(2-氟-5-硝基苯基)-2-甲基丙酸的合成
向反應瓶中加入2-氟-5-硝基苯甲醛(2000 mg,11.8 mmol),2-甲基丙二酸(1676 mg,14.2 mmol),乙酸銨(1823 mg,10 mmol)和20 mL乙醇,該反應混合物加熱至80°C攪拌過夜,TLC顯示反應完全。反應體系降溫至室溫後過濾,濾餅用乙醇洗滌三次,所得固體用Prep-HPLC純化,得到620 mg白色固體,收率:23%。
步驟2:N-(3-(1,3-二氨基-2-甲基-3-氧代丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
以上一步產物及其它試劑為原料,用與實施例1相同的方法可製備得到實施例4化合物。
LC/MS: m/z=508.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 1.04 (3H, d,
J= 7.2 Hz), 2.16 (3H, s), 2.48-2.53 (1H, m), 4.25 (1H, d,
J= 6.0 Hz), 6.70 (1H, s), 6.81 (1H, d,
J= 8.4 Hz), 7.07-7.30 (5H, m), 7.60-7.64 (1H, m), 7.76-7.79 (2H, m), 7.96 (1H, d,
J= 2.4 Hz), 10.51 (1H, s).
步驟1:(第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-甲氧基丙基)氨基甲酸酯的合成
向反應瓶中加入1-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯 (100 mg,0.16 mmol), DIPEA(41 mg,0.32 mmol)和5 mL 二氯甲烷,室溫滴加甲基黃醯氯(22 mg,0.19 mmol),反應混合物室溫攪拌1小時。反應體系旋乾,加入5mL甲醇鈉的甲醇溶液(7 M),體系升溫至70°C攪拌過夜。反應液倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾得到80 mg黃色油狀物,直接用於下一步反應。
步驟2:(N-(3-(1-氨基-3-甲氧基丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將(第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-甲氧基丙基)氨基甲酸酯(70 mg,上步粗品)的2 mL 氯化氫/二氧六環溶液(2 M)室溫攪拌2小時,體系旋乾加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到3 mg白色固體,兩步收率:4%。
LC/MS: m/z=535.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.57 (2H, m), 1.02-1.04 (2H, m), 1.74-1.76 (2H, m), 2.13-2.15 (1H, m), 2.16 (3H, s), 3.19 (3H, s), 3.20-3.30 (2H, m), 4.14-4.16 (1H, m), 6.35 (1H, s), 7.05-7.10 (3H, m), 7.20 (1H, d,
J= 8.8 Hz), 7.49-7.52 (1H, m), 7.74-7.76 (1H, m), 7.90 (1H, s), 10.37 (1H, s).
實施例6
N-(3-(1-乙醯氨基-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
向N-(3-(1-氨基-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(50 mg,0.096 mmol)及DIPEA(32 mg,0.29 mmol)的2 mL二氯甲烷溶液中滴加乙醯氯(9 mg,0.12 mmol),室溫攪拌1小時後體系加入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到8 mg白色固體,收率:15%。
LC/MS: m/z=563.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.57 (2H, m), 1.01-1.04 (2H, m), 1.75-1.80 (2H, m), 1.82 (3H, s), 2.07-2.10 (1H, m), 2.16 (3H, s), 3.37-3.39 (2H, m), 4.51-4.53 (1H, m), 5.04-5.09 (1H, m), 6.33 (1H, s), 7.06-7.10 (3H, m), 7.20 (1H, d,
J= 8.8 Hz), 7.49-7.52 (1H, m), 7.62-7.66 (1H, m), 7.90 (1H, s), 8.33 (1H, d,
J= 7.6 Hz), 10.40 (1H, s).
實施例7
4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(3-羥基-1-(甲基氨基)丙基)苯基)-5-(三氟甲基)苯甲醯胺
實施例8
4-環丙基-N-(3-(1-(二甲基氨基)-3-羥丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
向N-(3-(1-氨基-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(50 mg,0.096 mmol)及碳酸鉀(26 mg,0.19 mmol)的2 mL乙腈溶液中加入碘甲烷(13 mg,0.096 mmol),室溫攪拌6小時後體系加入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化得產品。
實施例7數據:5 mg白色固體,收率:10%
LC/MS: m/z=535.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 1.03-1.05 (2H, m), 1.74-1.77 (1H, m), 1.90-2.00 (1H, m), 2.13-2.15 (1H, m), 2.16 (3H, s), 2.24 (3H, s), 3.35-3.43 (2H, m), 4.08 (1H, brs), 6.36 (1H, s), 7.06-7.10 (2H, m), 7.15-7.22 (2H, m), 7.51-7.55 (1H, m), 7.83 (1H, d,
J= 4.4 Hz), 7.92 (1H, s), 10.45 (1H, s).
實施例8數據:6 mg白色固體,收率:12%
LC/MS: m/z=549.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 1.04-1.07 (2H, m), 1.74-1.83 (2H, m), 2.13-2.15 (1H, m), 2.16 (3H, s), 2.20 (6H, s), 3.35-3.43 (2H, m), 4.11 (1H, brs), 6.37 (1H, s), 7.06-7.10 (2H, m), 7.16-7.22 (2H, m), 7.51-7.55 (1H, m), 7.81-7.83 (1H, m), 7.91 (1H, s), 10.39 (1H, s).
實施例9
4-環丙基-N-(3-(1,2-二氨基-2-氧代乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
步驟1:N-(3-乙醯基-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸 (81 mg,0.23 mmol), 5-氨基-2-氟苯乙酮(70 mg,0.46 mmol)和DIPEA(89 mg,0.69 mmol)的3 mL DMF溶液中加入HATU(175 mg,0.46 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經TLC純化(PE/EA=10/1),得到125 mg白色固體。
步驟2:2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-2-氧代乙酸的合成
向N-(3-乙醯基-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺 (125 mg,0.26 mmol)的3 mL 吡啶溶液中加入二氧化硒(57 mg,0.51 mmol),反應混合物於100°C攪拌過夜。反應體系旋乾後加入10 mL水,用1 M稀鹽酸調節pH值至酸性,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到100 mg白色固體,收率:75%。
步驟3:N-(3-(2-氨基-2-氧代乙醯基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向4-環丙基-2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-2-氧代乙酸 (100 mg,0.19 mmol), 氯化銨(102 mg,1.9 mmol)和DIPEA(50 mg,0.38 mmol)的3 mL DMF溶液中加入HATU(144 mg,0.38 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=10/1),得到50 mg白色固體,收率:50%。
步驟4:4-環丙基-N-(3-(1,2-二氨基-2-氧代乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將N-(3-(2-氨基-2-氧代乙醯基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(50 mg,0.096 mmol)和鹽酸羥胺(27 mg,0.38 mmol)的3 mL 甲醇溶液於60°C攪拌20分鐘。加入乙酸鈉 (32 mg,0.38 mmol),反應混合物自然冷卻至室溫後加入2 mL甲酸以及100 mg鋅粉,室溫攪拌2小時。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到12 mg白色固體,收率:25%。
LC/MS: m/z=520.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.57 (2H, m), 1.01-1.04 (2H, m), 2.10-2.12 (1H, m), 2.14 (3H, s), 4.48 (1H, s), 6.33 (1H, s), 7.07-7.13 (3H, m), 7.18-7.22 (2H, m), 7.46 (1H, s), 7.55-7.58 (1H, m), 7.68-7.71 (1H, m), 7.89 (1H, s), 10.44 (1H, s).
步驟5:N-(3-(2-氨基-1-(甲基氨基)-2-氧代乙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向4-環丙基-N-(3-(1,2-二氨基-2-氧代乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(10 mg,0.019 mmol)及碳酸鉀(6 mg,0.043 mmol)的2 mL乙腈溶液中加入碘甲烷(2.6 mg,0.018 mmol),室溫攪拌6小時後體系加入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化得到4 mg白色固體,收率:33%。
LC/MS: m/z=534.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.57 (2H, m), 1.02-1.04 (2H, m), 2.10-2.12 (1H, m), 2.14 (3H, s), 2.22 (3H, s), 4.20 (1H, s), 6.33 (1H, s), 7.07-7.27 (5H, m), 7.47 (1H, s), 7.55-7.58 (1H, m), 7.68-7.71 (1H, m), 7.90 (1H, s), 10.42 (1H, s).
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基乙醯基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-2-氧代乙酸(52 mg,0.1 mmol)溶於1 mL四氫呋喃,0°C下加入硼烷四氫呋喃溶液(1 M,1 mL),該反應混合物室溫攪拌2 小時。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(DCM/MeOH=30/1),得到23 mg白色固體,收率:45%。
步驟2:N-(3-(1-氨基-2-羥乙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基乙醯基)苯基)-5-(三氟甲基)苯甲醯胺(25 mg,0.05 mmol)和鹽酸羥胺(14 mg,0.2 mmol)的2 mL 甲醇溶液於60°C攪拌20分鐘。加入乙酸鈉 (16 mg,0.2 mmol),反應混合物自然冷卻至室溫後加入2 mL甲酸以及100 mg鋅粉,室溫攪拌2小時。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到7 mg白色固體,收率:28%。
LC/MS: m/z=507.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.53-0.56 (2H, m), 1.01-1.05 (2H, m), 2.12-2.14 (1H, m), 2.15 (3H, s), 3.44-3.47 (2H, m), 4.19-4.21 (1H, m), 6.37 (1H, s), 7.03-7.12 (3H, m), 7.21 (1H, d,
J= 8.4 Hz), 7.50-7.52 (1H, m), 7.74-7.76 (1H, m), 7.90 (1H, s), 10.40 (1H, s).
實施例12
N-(3-(氨基甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
步驟1:N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(94 mg,0.3 mmol),5-氨基-2-氟苄腈(41 mg,0.3 mmol),DIPEA(77 mg,0.6 mmol)和2 mL 四氫呋喃,加入HATU(190 mg,0.5 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=3/1),得到110 mg白色固體,收率:85%。
步驟2:N-(3-(氨基甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(110 mg,0.25 mmol)和2mL 甲醇,加入10%的Pd/C(30 mg),反應體系於氫氣氛圍(1 MPa)下50°C攪拌過夜。抽濾,甲醇洗滌濾餅,濾液旋乾後得到100 mg白色固體,收率:91%。
LC/MS: m/z=437.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.15 (3H, s), 3.73 (2H, s), 6.81 (1H, d,
J= 8.4 Hz), 7.09-7.26 (4H, m), 7.57-7.59 (1H, m), 7.76-7.79 (2H, m), 7.97 (1H, d,
J= 1.6 Hz), 10.55 (1H, s).
步驟3:N-(3-((((2-氨基-2-氧代乙基)氨基)甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向N-(3-(氨基甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(44 mg,0.1 mmol)及碳酸鉀(28 mg,0.2 mmol)的2 mL 乙腈溶液中加入溴乙醯胺(14 mg,0.1 mmol),室溫攪拌過夜。抽濾,濾液旋乾後經Prep-TLC純化(PE/EA=1/1),得到15 mg白色固體,收率:31%。
LC/MS: m/z=494.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.15 (3H, s), 3.06 (2H, s), 3.70 (2H, s), 6.81 (1H, d,
J= 8.8 Hz), 7.08-7.27 (6H, m), 7.61-7.63 (1H, m), 7.76-7.78 (2H, m), 7.95 (1H, s), 10.55 (1H, s).
實施例14
N-(3-(1-氨基乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
將N-(3-乙醯基-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(45 mg,0.1 mmol,通過相應的原料,以與實施例9第一步類似的方法得到)及0.1 mL氨水的2 mL四氫呋喃溶液攪拌6小時,加入三乙醯氧基硼氫化鈉(42 mg,0.2 mmol)。該反應混合物攪拌2小時後直接旋乾,粗品經Prep-TLC純化(PE/EA=1/1),得到6 mg白色固體,收率:13%。
LC/MS: m/z=451.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 1.26 (3H, d,
J= 6.4 Hz), 2.15 (3H, s), 4.28 (1H, q,
J= 6.4 Hz), 6.82 (1H, d,
J= 8.8 Hz), 7.07-7.26 (4H, m), 7.56-7.60 (1H, m), 7.77 (1H, dd,
J= 8.4 Hz, 1.6 Hz), 7.88 (1H, dd,
J= 8.0 Hz, 2.4 Hz), 7.96 (1H, d,
J= 2.4 Hz), 10.52 (1H, s).
步驟1:N-(3-溴-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(94 mg,0.3 mmol),3-溴-4-氟苯胺(57 mg,0.3 mmol),DIPEA(77 mg,0.6 mmol)和2 mL 四氫呋喃,加入HATU(190 mg,0.5 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=10/1),得到120 mg白色固體,收率:82%。
步驟2:2-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)第三丁基-1-H-吡咯-1-甲酸第三丁酯的合成
向反應瓶中加入N-(3-溴-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(97 mg,0.2 mmol),(1-(第三丁氧羰基)-1H-吡咯-2-基)硼酸(42 mg,0.2 mmol),碳酸鉀(55 mg,0.4 mmol)和2 mL DMF,置換氮氣後加入Pd(dppf)Cl
2(7 mg,0.01 mmol),該反應混合物氮氣保護下加熱至90°C攪拌6小時。反應體系降溫至室溫後倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-TLC純化(PE/EA=4/1),得到90 mg白色固體,收率:79%。
步驟3:2-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)吡咯烷-1-羧酸第三丁酯的合成
向反應瓶中加入2-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)第三丁基-1-H-吡咯-1-甲酸第三丁酯(90 mg,0.16 mmol)和5 mL 甲醇,加入10%的Pd/C(20 mg),反應體系於氫氣氛圍(1 MPa)下室溫攪拌過夜。抽濾,甲醇洗滌濾餅,濾液旋乾後得到85 mg白色固體,收率:94%。
步驟4:2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(吡咯烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將2-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)吡咯烷-1-羧酸第三丁酯(58 mg,0.1 mmol)的2 mL 氯化氫/二氧六環溶液(2 M)室溫攪拌2小時,體系旋乾後加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到25 mg白色固體,收率:52%。
LC/MS: m/z=477.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 1.44-1.53 (1H, m), 1.74-1.78 (2H, m), 2.16 (3H, s), 2.17-2.20 (1H, m), 2.97-3.00 (2H, m), 4.33 (1H, t,
J= 7.6 Hz), 6.81 (1H, d,
J= 8.4 Hz), 7.09-7.26 (4H, m), 7.58-7.61 (1H, m), 7.77 (1H, dd,
J= 8.8 Hz, 2.4 Hz), 7.77 (1H, dd,
J= 8.4 Hz, 4.0 Hz), 7.96 (1H, d,
J= 2.8 Hz), 10.51 (1H, s).
步驟1:2-((第三丁氧基羰基)氨基)-5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-5-氧代戊酸甲酯的合成
-70°C下,向N-(3-溴-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(486 mg,1.0 mmol)的5 mL無水四氫呋喃溶液中滴加正丁基鋰(1.6 M,3.1 mL),該溫度下攪拌1小時後滴加N-第三丁氧羰基-DL-焦谷胺酸甲酯(1215 mg,5.0 mmol)的2 mL四氫呋喃溶液,繼續攪拌1小時後倒入20 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾後經矽膠柱層析純化(PE/EA=4/1),得到210 mg白色固體,收率:32%。
步驟2:5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3,4-二氫-2H-吡咯-2-羧酸甲酯的合成
將2-((第三丁氧基羰基)氨基)-5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-5-氧代戊酸甲酯(210 mg,0.32 mmol)溶於5 mL二氯甲烷,加入2 mL三氟乙酸後室溫攪拌過夜。反應體系直接旋乾得~200 mg粗品。
步驟3:5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3,4-二氫-2H-吡咯-2-羧酸的合成
將上步所得粗品溶於5 mL四氫呋喃,加入2 mL濃度為1 M的氫氧化鈉水溶液後室溫攪拌6小時。反應體系用稀鹽酸調節pH值至5後直接用Prep-HPLC純化,得到90 mg目標產物,兩步收率:54%。
步驟4:5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3,4-二氫-2H-吡咯-2-羧醯胺的合成
向反應瓶中加入5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3,4-二氫-2H-吡咯-2-羧酸(52 mg,0.1 mmol),氯化銨(53 mg,1.0 mmol),DIPEA(39 mg,0.3 mmol)和2 mL 四氫呋喃,加入HBTU(76 mg,0.2 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到30 mg白色固體,收率:58%。
步驟5:2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(吡咯烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
向5-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-3,4-二氫-2H-吡咯-2-羧醯胺(30 mg,0.058 mmol)的2mL 甲醇溶液中加入20 mg硼氫化鈉,室溫攪拌2小時後,反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到6 mg白色固體,收率:20%。
LC/MS: m/z=520.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 1.55-1.74 (2H, m), 1.87-2.00 (1H, m), 2.05 (3H, s), 2.16-2.22 (1H, m), 3.45-3.46 (0.6H, m), 3.65-3.66 (0.4H, m), 4.10-4.42 (1H, m), 6.57-6.64 (1H, m), 7.01-7.11 (2H, m), 7.18-7.22 (2H, m), 7.25-7.45 (1H, m), 7.50-7.69 (1H, m), 7.71-7.77 (3H, m), 7.98 (1H, s), 10.63-10.74 (1H, m).
步驟1:2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(羥甲基)苯基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(94 mg,0.3 mmol),(5-氨基-2-氟苯基)甲醇(42 mg,0.3 mmol),DIPEA(77 mg,0.6 mmol)和2 mL四氫呋喃,加入HATU(190 mg,0.5 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=10/1),得到95 mg白色固體,收率:73%。
步驟2:N-(3-(氯甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(羥甲基)苯基)-5-(三氟甲基)苯甲醯胺(95 mg,0.22 mmol)的三氯氧磷溶液60°C攪拌1小時,反應液直接旋乾,用三氯甲烷帶兩次殘留的三氯氧磷即得到100 mg黃色固體,收率:100%。
步驟3:3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-2-硝基丙酸甲酯的合成
將N-(3-(氯甲基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(100 mg,0.22 mmol),硝基乙酸甲酯(52 mg,0.44 mmol),苄基三乙基氯化銨(50 mg,0.22 mmol)及碳酸氫鉀(44 mg,0.44 mmol)的3 mL DMF溶液60°C攪拌過夜,反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=3/1),得到25 mg白色固體,收率:21%。
步驟4:N-(3-(3-氨基-2-硝基-3-氧代丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-2-硝基丙酸甲酯(25 mg,0.046 mmol)及4 mL氨甲醇溶液(1 M)室溫攪拌過夜,旋乾反應液,得到25 mg白色固體,收率:100%。
步驟5:N-(3-(2,3-二氨基-3-氧丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入N-(3-(3-氨基-2-硝基-3-氧代丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(25 mg,0.046 mmol)和5mL 甲醇,加入10%的Pd/C(10 mg),反應體系於氫氣氛圍(1 MPa)下室溫攪拌過夜。抽濾,甲醇洗滌濾餅,濾液旋乾後經Prep-HPLC純化,得到9 mg白色固體,收率:38%。
LC/MS: m/z=494.1 [M+H]
+.
實施例18
2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(3-氧代哌嗪-2-基)苯基)-5-(三氟甲基)苯甲醯胺
將(2-(2-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)-2-氧代乙醯胺基)乙基)氨基甲酸第三丁酯(45 mg,0.072 mmol,通過相應的原料,以與實施例9類似的方法製備得到)的3 mL HCl/EA(4 M)溶液室溫攪拌2小時,旋乾後加入5 mL甲醇及50 mg氰基硼氫化鈉。該反應混合物室溫攪拌過夜後倒入20 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到8 mg白色固體,收率:22%。
LC/MS: m/z=506.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.16 (3H, s), 2.78-2.82 (1H, m), 2.88-3.01 (2H, m), 3.15-3.19 (1H, m), 4.52 (1H, s), 6.78 (1H, d,
J= 8.0 Hz), 7.10-7.26 (4H, m), 7.63-7.66 (1H, m), 7.74-7.78 (2H, m), 7.81 (1H, s), 7.93 (1H, s), 10.52 (1H, s).
步驟1:N-(2-氟-5-硝基亞苄基)-2-甲基丙烷-2-亞磺醯胺的合成
將2-氟-5-硝基苯甲醛 (333 mg,2.0 mmol),第三丁基亞磺醯胺(268 mg,2.2 mmol)及碳酸銫(987 mg,3.0 mmol)的10 mL 二氯甲烷溶液室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾得到573 mg黃色固體。
步驟2:3-((((第三丁基亞磺醯基)氨基)(2-氟-5-硝基苯基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯的合成
-70°C及氮氣保護下,向N-BOC-2-吡咯烷酮 (545 mg,2.94 mmol)的5 mL無水四氫呋喃溶液中滴加正丁基鋰(2.5 M,0.9 mL),加畢後繼續攪拌0.5小時,再將N-(2-氟-5-硝基亞苄基)-2-甲基丙烷-2-亞磺醯胺(200 mg,0.73 mmol)的1 mL 四氫呋喃溶液滴加到反應體系中,控制體系溫度低於-60°C。繼續攪拌1.5小時後反應體系倒入20 mL氯化銨水溶液中,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱純化(DCM/MeOH=20/1),得到280 mg黃色油狀物,收率:83%。
步驟3:3-((5-氨基-2-氟苯基)((第三丁基亞硫醯基)氨基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯的合成
向反應瓶中加入3-((((第三丁基亞磺醯基)氨基)(2-氟-5-硝基苯基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯(110 mg,0.24 mmol)和5mL 乙醇,加入10%的Pd/C(20 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,乙醇洗滌濾餅,濾液旋乾後得到100 mg黃色固體,收率:97%。
步驟4: 3-(((第三丁基亞磺醯基)氨基)(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)甲基)-2 -氧代吡咯烷-1-羧酸第三丁酯的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸 (82 mg,0.23 mmol),3-((5-氨基-2-氟苯基)((第三丁基亞硫醯基)氨基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯(98 mg,0.23 mmol),DIPEA(106 mg,0.82 mmol)和5 mL 四氫呋喃,加入HATU(163 mg,0.42 mmol),反應混合物室溫攪拌過夜。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=15/1),得到25 mg白色固體,收率:14%。
步驟5:N-(3-(氨基(2-氧吡咯烷-3-基)甲基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將3-(((第三丁基亞磺醯基)氨基)(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)甲基)-2 -氧代吡咯烷-1-羧酸第三丁酯(25 mg,0.033 mmol)的2 mL 氯化氫/乙酸乙酯溶液(2 M)室溫攪拌過夜,體系旋乾後加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到12 mg白色固體,收率:67%。
LC/MS: m/z=560.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.54-0.60 (2H, m), 1.00-1.06 (2H, m), 1.61-1.71 (1H, m), 2.13-2.12 (2H, m), 2.15 (3H, s), 2.52-2.58 (1H, m), 3.07-3.13 (2H, m), 4.60 (1H, d,
J= 3.2 Hz), 6.37 (1H, s), 7.05-7.09 (3H, m), 7.20 (1H, dd,
J= 9.2 Hz, 2.7 Hz), 7.51-7.57 (1H, m), 7.69 (1H, s), 7.79 (1H, dd,
J= 6.6 Hz, 2.4 Hz), 7.90 (1H, s), 10.40 (1H, s).
步驟1:第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丁基)氨基甲酸酯的合成
0°C下,向3-((第三丁氧基羰基)氨基)-3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙酸(63 mg,0.10 mmol)的2mL 無水四氫呋喃溶液中加入甲基鋰(1 M,0.4 mL),室溫下攪拌1小時後體系倒入10 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=2/1),得到30 mg白色固體,收率:47%。
步驟2: 第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥基丁基)氨基甲酸酯的合成
室溫下,向第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丁基)氨基甲酸酯(30 mg,0.047 mmol)的2mL 甲醇溶液中加入5 mg硼氫化鈉,室溫下攪拌1小時後體系倒入10 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=1/1),得到18 mg白色固體,收率:60%。
步驟3:N-(3-(1-氨基-3-羥基丁基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將第三丁基(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥基丁基)氨基甲酸酯(18 mg,0.028 mmol)的2 mL 氯化氫/乙酸乙酯溶液(2 M)室溫攪拌過夜,體系旋乾後加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到10 mg白色固體,收率:67%。
LC/MS: m/z=535.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 1.00-1.07 (5H, m), 1.55-1.57 (1H, m), 2.12-2.14 (1H, m), 2.16 (3H, s), 3.68-3.76 (2H, m), 4.19-4.28 (1H, m), 6.35 (1H, s), 7.06-7.10 (3H, m), 7.22 (1H, dd,
J= 9.2 Hz, 2.0 Hz), 7.49-7.55 (1H, m), 7.73-7.80 (1H, m), 7.91 (1H, s), 10.39 (1H, s).
實施例21
N-(3-(1-氨基-3-氟丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
向N-(3-(1-氨基-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(52 mg,0.10 mmol)的2 mL二氯甲烷溶液中加入DAST(24 mg,0.15 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到20 mg白色固體,收率:38%。
LC/MS: m/z=521.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.53-0.60 (2H, m), 1.00-1.06 (2H, m), 1.94-2.16 (7H, m), 4.31-4.33 (1H, m), 4.40-4.68 (1H, m), 6.34 (1H, s), 7.03-7.10 (2H, m), 7.14-7.23 (2H, m), 7.49-7.56 (1H, m), 7.84-7.92 (2H, m), 10.45 (1H, s).
步驟1:3-((第三丁基亞磺醯基)氨基)-2-氟-3-(2-氟-5-硝基苯基)丙酸乙酯的合成
-70°C及氮氣保護下,向氟乙酸乙酯 (480 mg,4.53 mmol)的5 mL無水四氫呋喃溶液中滴加LiHMDS(1.3 M,3.2 mL),加畢後繼續攪拌0.5小時,再將N-(2-氟-5-硝基亞苄基)-2-甲基丙烷-2-亞磺醯胺(230 mg,0.85 mmol)的1 mL 四氫呋喃溶液滴加到反應體系中,控制體系溫度低於-60°C。繼續攪拌1.5小時後反應體系倒入20 mL氯化銨水溶液中,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱純化(PE/EA=2/1),得到216 mg黃色固體,收率:68%。
步驟2:3-(5-氨基-2-氟苯基)-3-((第三丁基亞磺醯基)氨基)-2-氟丙酸乙酯的合成
向反應瓶中加入3-((第三丁基亞磺醯基)氨基)-2-氟-3-(2-氟-5-硝基苯基)丙酸乙酯(216 mg,0.57 mmol)和5mL 乙醇,加入10%的Pd/C(30 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,乙醇洗滌濾餅,濾液旋乾後得到200 mg黃色固體,收率:100%。
步驟3:3-((第三丁基亞磺醯基)氨基)-3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-2-氟丙酸乙酯的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸 (82 mg,0.23 mmol),3-(5-氨基-2-氟苯基)-3-((第三丁基亞磺醯基)氨基)-2-氟丙酸乙酯(80 mg,0.23 mmol),DIPEA(106 mg,0.82 mmol)和5 mL 四氫呋喃,加入HATU(163 mg,0.42 mmol),反應混合物室溫攪拌過夜。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到35 mg白色固體,收率:29%。
步驟4: N-(3-(1-((第三丁基亞磺醯基)氨基)-2-氟-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-( 三氟甲基)苯甲醯胺的合成
室溫下,向3-((第三丁基亞磺醯基)氨基)-3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-2-氟丙酸乙酯(35 mg,0.051 mmol)及5 mg氯化鋰的2mL 甲醇溶液中加入10 mg硼氫化鈉,室溫下攪拌4小時後體系倒入10 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到15 mg白色固體,收率:43%。
步驟5:N-(3-(1-氨基-2-氟-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將N-(3-(1-((第三丁基亞磺醯基)氨基)-2-氟-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-( 三氟甲基)苯甲醯胺(15 mg,0.023 mmol)的2 mL 氯化氫/乙酸乙酯溶液(2 M)室溫攪拌過夜,體系旋乾加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到4 mg白色固體,收率:32%。
LC/MS: m/z=539.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 0.99-1.07 (2H, m), 2.11-2.14 (1H, m), 2.16 (3H, s), 3.50-3.72 (2H, m), 4.26-4.30 (1H, m), 4.37-4.45 (0.5H, m), 4.50-4.57 (0.5H, m), 4.95 (1H, brs), 6.35 (1H, s), 7.07-7.16 (3H, m), 7.22 (1H, d,
J= 8.1 Hz), 7.53-7.61 (1H, m), 7.77-7.83 (1H, m), 7.92 (1H, s), 10.40-10.42 (1H, m).
步驟1: 3-((第三丁基亞磺醯基)氨基)-2,2-二氟-3-(2-氟-5-硝基苯基)丙酸乙酯的合成
將鋅粉(195 mg,3.0 mmol)和2-溴-2,2-二氟乙酸乙酯(404 mg,2.0 mmol)的無水四氫呋喃溶液攪拌回流30分鐘。然後在該溫度下將N-(2-氟-5-硝基亞苄基)-2-甲基丙烷-2-亞磺醯胺(272 mg,1.0 mmol)的無水THF溶液緩慢加入到混合物中。回流攪拌1.5小時後,將反應混合物過濾並將濾液濃縮。粗品經Prep-TLC純化(DCM/MeOH=50/1),得到190 mg白色固體,收率:48%。
步驟2:N-(3-(1-氨基-2,2-二氟-3-羥丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
以相應的試劑為原料,用於實施例22相同的方法可得到實施例23
LC/MS: m/z=557.2 [M+H]
+.
步驟1:第三丁基(3-氨基-1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙基)氨基甲酸酯的合成
向反應瓶中加入1-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥丙基)氨基甲酸第三丁酯 (100 mg,0.16 mmol), DIPEA(41 mg,0.32 mmol)和5 mL 二氯甲烷,室溫滴加甲基黃醯氯(22 mg,0.19 mmol),反應混合物室溫攪拌1小時。反應體系旋乾後溶於5 mL無水四氫呋喃中,加入~10 mg氨基鈉,室溫反應1小時。反應液倒入10 mL冰水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-HPLC純化,得到6 mg黃色油狀物,收率:6%。
步驟2:(4-環丙基-N-(3-(1,3-二氨基丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將(第三丁基(3-氨基-1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙基)氨基甲酸酯(6 mg,0.01 mmol)的2 mL 氯化氫/二氧六環溶液(2 M)室溫攪拌2小時,體系旋乾後加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到2 mg白色固體,收率:40%。
LC/MS: m/z=520.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 0.99-1.07 (2H, m), 1.62-1.65 (2H, m), 2.11-2.16 (4H, m), 2.60-2.70 (2H, m), 4.12-4.14 (1H, m), 6.35 (1H, s), 7.02-7.16 (3H, m), 7.20-7.23 (1H, m), 7.48-7.55 (1H, m), 7.76-7.78 (1H, m), 7.91 (1H, s), 10.38 (1H, s).
步驟1:2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲酸甲酯的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(314 mg,1.0 mmol),5-氨基-2-氟苯甲酸甲酯(169 mg,1.0 mmol),DIPEA(258 mg,2.0 mmol)和5 mL 四氫呋喃,加入HATU(456 mg,1.2 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱層析純化(PE/EA=3/1),得到330 mg淡黃色固體,收率:71%。
步驟2:2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲酸的合成
向反應瓶中加入2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲酸甲酯(330 mg,0.71 mmol),氫氧化鈉(114 mg,2.84 mmol),5 mL水和5 mL甲醇,該反應混合物於室溫下攪拌8小時,TLC顯示反應完全。反應體系倒入20 mL水中,用1M的鹽酸調節pH值至5,乙酸乙酯萃取,有機相乾燥並旋乾,得到320 mg目標產物,收率:100%。
步驟3:2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲醯氯的合成
將2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲酸(320 mg,0.71 mmol)的5 mL氯化亞碸溶液於80°C攪拌1小時,體系旋乾,用氯仿帶兩次,所得固體直接用於下一步反應。
步驟4:3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲醯基)-2-氧代吡咯烷-1-羧酸第三丁酯的合成
-70°C及氮氣保護下,向2-氧代吡咯烷-1-羧酸第三丁酯 (657 mg,3.55 mmol)的10 mL無水四氫呋喃溶液中滴加正丁基鋰(2.5 M,1.8 mL),加畢後繼續攪拌0.5小時,再將上步所得固體的2 mL 四氫呋喃溶液滴加到反應體系中,控制體系溫度低於-60°C。繼續攪拌1.5小時後反應體系倒入20 mL氯化銨水溶液中,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱純化(PE/EA=2/1),得到180 mg黃色固體,兩步收率:41%。
步驟5:3-((2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)(羥基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯的合成
室溫下,向3-(2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯甲醯基)-2-氧代吡咯烷-1-羧酸第三丁酯(62 mg,0.1 mmol)的2mL四氫呋喃溶液中加入10 mg硼氫化鈉,室溫下攪拌4小時後體系倒入10 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到40 mg白色固體,收率:65%。
步驟6:2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(羥基(2-氧代吡咯烷-3-基)甲基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將3-((2-氟-5-(2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)苯基)(羥基)甲基)-2-氧代吡咯烷-1-羧酸第三丁酯(40 mg,0.065 mmol)的2 mL 氯化氫/二氧六環溶液(2 M)室溫攪拌2小時,體系旋乾後加入10 mL水中,碳酸鈉調節pH值至鹼性,乙酸乙酯萃取,有機相乾燥並旋乾後經Prep-HPLC純化,得到25 mg白色固體,收率:74%。
LC/MS: m/z=521.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 1.62-1.72 (1H, m), 2.04-2.16 (4H, m), 3.10-3.18 (2H, m), 5.31 (1H, s), 5.59 (1H, d,
J= 7.2 Hz), 6.83 (1H, d,
J= 8.0 Hz), 7.10-7.25 (4H, m), 7.62-7.64 (2H, m), 7.78 (1H, d,
J= 8.4 Hz), 7.89 (1H, d,
J= 7.6 Hz), 7.97 (1H, s), 10.56 (1H, s).
實施例26
N-(3-(2-氨基-1-羥基-2-氧代乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
室溫下,向N-(3-(2-氨基-2-氧代乙醯基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(48 mg,0.10 mmol)的2mL 四氫呋喃溶液中加入10 mg硼氫化鈉,室溫下攪拌4小時後體系倒入10 mL水中。乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到25 mg白色固體,收率:52%。
LC/MS: m/z=481.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.14 (3H, s), 5.08 (1H, d,
J= 7.2 Hz), 6.24 (1H, d,
J= 7.2 Hz), 6.80 (1H, d,
J= 8.0 Hz), 7.12-7.26 (4H, m), 7.37 (1H, s), 7.45 (1H, s), 7.61-7.64 (1H, m), 7.75-7.80 (2H, m), 7.97 (1H, d,
J= 2.4 Hz), 10.54 (1H, s).
步驟1:2-(2-氟-5-硝基苯基)丙酸甲酯的合成
將2-(2-氟-5-硝基苯基)乙酸(199 mg,1.0 mmol),碳酸鉀(414 mg,3 mmol),及碘甲烷(284 mg,2.0 mmol)的5 mL四氫呋喃溶液室溫攪拌過夜,反應體系過濾,濾液旋乾,經矽膠柱層析純化(PE/EA=20/1),得到80 mg黃色固體,收率:35%。
步驟2:2-(2-氟-5-硝基苯基)丙醯胺的合成
將2-(2-氟-5-硝基苯基)丙酸甲酯(80 mg,0.35 mmol)的5 mL氨甲醇溶液50 °C攪拌過夜,反應體系旋乾,經Prep-TLC純化(PE/EA=5/1),得到60 mg黃色固體,收率:80%。
步驟3:2-(5-氨基-2-氟苯基)丙醯胺的合成
向反應瓶中加入2-(2-氟-5-硝基苯基)丙醯胺(60 mg,0.28 mmol)和5mL 甲醇,加入10%的Pd/C(10 mg),反應體系於氫氣氛圍下室溫攪拌過夜。抽濾,甲醇洗滌濾餅,濾液旋乾後得到50 mg淺黃色固體,收率:98%。
步驟4:N-(3-(1-氨基-1-氧代丙烷-2-基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(31 mg,0.10 mmol),2-(5-氨基-2-氟苯基)丙醯胺(18 mg,0.10 mmol),DIPEA(26 mg,0.20 mmol)和2 mL 四氫呋喃,加入HATU(57 mg,0.15 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=2/1),得到25 mg白色固體,收率:52%。
LC/MS: m/z=479.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.59 (2H, m), 1.02-1.04 (2H, m), 1.31 (3H, d,
J= 7.6 Hz), 2.10-2.14 (1H, m), 2.16 (3H, s), 3.82 (1H, q,
J= 7.6 Hz), 6.35 (1H, s), 6.94 (1H, s), 7.06-7.14 (3H, m), 7.21 (1H, d,
J= 8.4 Hz), 7.41 (1H, s), 7.56-7.59 (1H, m), 7.66-7.68 (1H, m), 77.90 (1H, s), 10.42 (1H, s).
步驟1:(E)-3-(2-氟-5-硝基苯基)丁-2-烯酸乙酯的合成
將含量為60%的鈉氫(308 mg,7.7 mmol)懸浮於乾燥的5 mL四氫呋喃,氮氣保護並降溫至0°C,緩慢滴加入磷醯基乙酸三乙酯(1.48 g,6.6 mmol),該混合物在冰浴下攪拌反應30分鐘後,冰浴下向反應體系滴加1-(2-氟-5-硝基苯基)乙-1-酮(1.0 g,5.5 mmol),反應溶液室溫攪拌2小時,反應體系用氯化銨溶液淬滅,乙酸乙酯萃取,有機相乾燥旋乾,經矽膠柱層析純化(PE/EA=5/1),得到900 mg灰色固體,收率:64%。
步驟2:3-(5-氨基-2-氟苯基)丁酸乙酯的合成
將E)-3-(2-氟-5-硝基苯基)丁-2-烯酸乙酯(900 mg,3.56 mmol)溶於25 mL甲醇,置換氫氣後,加入氫氧化鈀(90 mg,10%wt),反應在氫氣氛圍下攪拌反應4小時,反應體系直接過濾,濾液旋乾,得到750 mg灰色固體,收率:95%。
步驟3:3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丁酸乙酯的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(354 mg,1 mmol),3-(5-氨基-2-氟苯基)丁酸乙酯(268 mg,1.2 mmol),DIPEA(387 mg,3 mmol)和2 mL 四氫呋喃,加入HATU(456 mg,1.2 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱層析純化(PE/EA=2/1),得到450 mg白色固體,收率:80%。
步驟4:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(4-羥基丁烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丁酸乙酯(450 mg,0.8 mmol),無水氯化鋰(13 mg,0.3 mmol),和15 mL 甲醇,分批加入硼氫化鈉(152 mg,4 mmol),反應混合物室溫攪拌2小時。反應體系加稀鹽酸淬滅,乙酸乙酯萃取,有機相乾燥並旋乾,經矽膠柱層析純化(DCM/MeOH=30/1),得到370 mg白色固體,收率:90%。
LC/MS: m/z=520.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.54-0.60 (2H, m), 1.02-1.08 (2H, m), 1.16 (3H, d,
J= 6.8 Hz), 1.74-1.78 (2H, m), 2.07-2.19 (4H, m), 3.62-3.65 (2H, m), 4.42-4.44 (1H, m), 5.77 (1H, s), 6.39 (1H, s), 7.01-7.14 (3H, m), 7.20 (1H, dd,
J= 9.2 Hz, 2.8 Hz), 7.44-7.52 (1H, m), 7.56 (1H, dd,
J= 6.6 Hz, 2.4 Hz), 7.91 (1H, s), 10.36 (1H, s).
步驟1:4-環丙基-N-(3-(4-(1,3-二氧代異吲哚啉-2-基)丁烷-2-基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-( 三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(4-羥基丁烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺(104 mg,0.2 mmol),鄰苯二甲醯亞胺(44 mg,0.3 mmol),及三苯基磷(105 mg,0.4 mmol)溶於8 mL四氫呋喃,氮氣保護室溫下滴加DIAD(121 mg,0.6 mmol),反應溶液室溫攪拌3小時,反應體系加水,乙酸乙酯萃取,有機相乾燥旋乾,經矽膠柱層析純化(PE/EA=3/1),得到80 mg灰色固體,收率:62%。
步驟2:N-(3-(4-氨基丁烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-N-(3-(4-(1,3-二氧代異吲哚啉-2-基)丁烷-2-基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-( 三氟甲基)苯甲醯胺(80 mg,0.12 mmol)溶於8 mL乙醇和2 mL水合肼,反應體系加水,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=15/1),得到25 mg白色固體,收率:40%。
LC/MS: m/z=519.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.54-0.60 (2H, m), 1.02-1.08 (2H, m), 1.18 (3H, d,
J= 6.8 Hz), 1.65-1.75 (2H, m), 2.07-2.19 (4H, m), 2.55-2.59 (2H, m), 3.05-3.10 (1H, m), 6.39 (1H, s), 7.04-7.13 (3H, m), 7.19 (1H, dd,
J= 9.2 Hz, 2.8 Hz), 7.44-7.52 (1H, m), 7.61 (1H, dd,
J= 6.6 Hz, 2.4 Hz), 7.91 (1H, s), 10.38 (1H, s).
步驟1:(2-(2-氟-5-硝基苯基)丙基)氨基甲酸第三丁酯的合成
將2-(2-氟-5-硝基苯基)丙醯胺(212 mg,1.0 mmol),BH
3-THF(3 mL,3 mmol, 1.0 M)和10 mL四氫呋喃溶液於50°C攪拌2小時,加入15 mL甲醇淬滅反應,混合物攪拌30分鐘後,直接向反應體系加入(Boc)
2O(436 mg,2.0 mmol),室溫攪拌1小時。體系直接旋乾,經矽膠柱層析純化(PE/EA=3/1),得到180 mg灰白色固體,收率:60%。
步驟2: N-(3-(1-氨基丙-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
以相應底物為原料,根據實施例3相同的方案,得到實施例30
LC/MS: m/z=505.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.54-0.61 (2H, m), 1.00-1.08 (2H, m), 1.18 (3H, d,
J= 6.9 Hz), 2.07-2.19 (4H, m), 2.64-2.69 (1H, m), 2.72-2.77 (1H, m), 2.94-3.01 (1H, m), 6.39 (1H, s), 7.01-7.14 (3H, m), 7.20 (1H, dd,
J= 9.2 Hz, 2.8 Hz), 7.44-7.52 (1H, m), 7.57 (1H, dd,
J= 6.6 Hz, 2.4 Hz), 7.91 (1H, s), 10.37 (1H, s).
步驟1:3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丙酸甲酯的合成
將碳酸二甲酯(450 mg,5 mmol),及60%含量的鈉氫(100 mg,2.5 mmol)懸浮於15 mL乾燥四氫呋喃,室溫下加入N-(3-乙醯基-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(245 mg,0.5 mmol),溶液70°C攪拌6小時,反應體系冰浴降溫並加入氯化銨溶液淬滅反應,乙酸乙酯萃取,有機相乾燥濃縮乾,經矽膠柱層析純化(PE/EA=2/1),得到165 mg黃色固體,收率:60%。
步驟2:3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥基丙酸甲酯的合成
將3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丙酸甲酯(165 mg,0.3 mmol)和5 mL甲醇,分批加入硼氫化鈉(57 mg,1.5 mmol),室溫攪拌反應1小時後加入稀鹽酸淬滅反應,乙酸乙酯萃取,有機相乾燥並濃縮乾,經矽膠快速柱層析純化(PE/EA=1/1),得到125 mg黃色固體,收率:76%。
步驟3:3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氟丙酸甲酯的合成
向反應瓶中加入3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-羥基丙酸甲酯(125 mg,0.23 mmol)和5mL 二氯甲烷,在-45°C左右向反應體系加入DAST(74 mg,0.46 mmol), 反應體系於-45°C攪拌2小時。反應體系加水淬滅,乙酸乙酯萃取,有機相乾燥濃縮乾經矽膠柱層析純化(PE/EA=2/1)得到40 mg灰白色固體,收率:32%。
步驟4:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-氟-3-羥丙基)苯基)-5-(三氟甲基)苯甲醯胺的合成
向3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氟丙酸甲酯(40 mg,0.07 mmol),無水氯化鋰(4 mg,0.1 mmol)和3 mL甲醇的混合液中分批加入硼氫化鈉(27 mg,0.7 mmol),室溫攪拌反應1小時後加入稀鹽酸淬滅反應,乙酸乙酯萃取,有機相乾燥並濃縮乾,經矽膠Prep-TLC純化(DCM/MeOH=30/1),得到25 mg白色固體,收率:66%。
LC/MS: m/z=524.2 [M+H]
+.
步驟1:3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3,3-二氟丙酸甲酯的合成
向反應瓶中加入3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丙酸甲酯(200 mg,0.37 mmol)和15mL 二氯甲烷,在室溫下向反應體系加入DAST(119 mg,0.74 mmol), 反應體系於室溫攪拌2小時。反應體系加水淬滅,乙酸乙酯萃取,有機相乾燥濃縮乾經矽膠柱層析純化(PE/EA=2/1)得到45 mg灰白色固體,收率:21%。
步驟2:4-環丙基-N-(3-(1,1-二氟-3-羥丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
以相應底物為原料,根據實施例31相同的方案,得到實施例32
LC/MS: m/z=542.2 [M+H]
+.
步驟1:N-(3-(2-((2-((第三丁基二甲基甲矽烷基)氧基)乙基)氨基)-2-氧代乙醯基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基) -5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-(((2-羥乙基)氨基)-2-氧代乙醯基)苯基)-5-(三氟甲基)苯甲醯胺(100 mg,0.18 mmol),TEA(101 mg,1 mmol)溶於10 mL二氯甲烷,室溫下加入TBSOTf(95 mg,0.36 mmol),反應體系直接旋乾,經矽膠柱層析純化(PE/EA=5/1),得到90 mg,收率:74%。
步驟2:N-(3-(2-(((2-((第三丁基二甲基甲矽烷基)氧基)乙基)氨基)-1,1-二氟-2-氧乙基)-4-氟苯基)-4-環丙基-2-(4- 氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入N-(3-(2-((2-((第三丁基二甲基甲矽烷基)氧基)乙基)氨基)-2-氧代乙醯基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基) -5-(三氟甲基)苯甲醯胺(90 mg,0.13 mmol)和5mL 二氯甲烷,在室溫下向反應體系加入DAST(65 mg,0.4 mmol), 反應體系於室溫攪拌2小時。反應體系加水淬滅,乙酸乙酯萃取,有機相乾燥濃縮乾經矽膠柱層析純化(PE/EA=5/1)得到18 mg灰白色固體,收率:19%。
步驟3:4-環丙基-N-(3-(1,1-二氟-2-((2-羥乙基)氨基)-2-氧代乙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5 -(三氟甲基)苯甲醯胺的合成
向反應瓶中加入N-(3-(2-(((2-((第三丁基二甲基甲矽烷基)氧基)乙基)氨基)-1,1-二氟-2-氧乙基)-4-氟苯基)-4-環丙基-2-(4- 氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(18 mg),TBAF(0.2 mL,1M)和2mL 四氫呋喃,反應體系於室溫攪拌1小時。反應體系加水,乙酸乙酯萃取,有機相用稀鹽酸反洗2次,乾燥濃縮後經Prep-TLC純化(DCM/MeOH=20/1)得到5 mg灰白色固體,收率:31%。
LC/MS: m/z=585.2 [M+H]
+.
步驟1:(2-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙基)氨基甲酸第三丁酯的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(46 mg,0.1 mmol),碳酸鉀(41 mg,0.3 mmol),及(2-溴乙基)氨基甲酸第三丁酯(33 mg,0.15 mmol)的3 mL乙腈溶液100°C攪拌2小時,反應體系過濾,濾液旋乾,得到90 mg黃色固體,粗品未純化直接用於下步反應。
步驟2:N-(3-(2-氨基乙氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將(2-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙基)氨基甲酸第三丁酯(90 mg,粗品)的5 mL鹽酸乙酸乙酯溶液室溫攪拌反應1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,旋乾後經Prep-TLC純化(DCM/MeOH=12/1),得到20 mg白色固體,收率:39%(2步)。
LC/MS: m/z=507.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.61 (2H, m), 0.99-1.08 (2H, m), 2.11-2.13 (1H, m), 2.15 (3H, s), 2.91 (2H, d,
J= 5.8 Hz), 3.94 (2H, d,
J= 5.8 Hz), 6.38 (1H, s), 7.03-7.23 (5H, m), 7.52-7.61 (1H, m), 7.91 (1H, s), 10.41 (1H, s).
表一:按照與上述實施例所闡述操作類似的操作,以相應的試劑為原料製備以下化合物。
實施例 | 結構 | MS (ESI) m/z | 1H NMR | 合成參考實施例 |
35 | 517.2 | NA | 1 | |
36 | 480.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.15 (3H, s), 4.50 (1H, s), 6.81 (1H, d, J= 8.4 Hz), 7.12-7.26 (5H, m), 7.49 (1H, s), 7.63-7.65 (1H, m), 7.75-7.78 (2H, m), 7.96 (1H, s), 10.56 (1H, s). | 9 | |
37 | 534.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.54-0.58 (2H, m), 1.01-1.06 (2H, m), 2.10-2.13 (1H, m), 2.15 (3H, s), 2.45-2.47 (2H, m), 4.51-4.54 (1H, m), 6.34 (1H, s), 6.92 (1H, s), 7.01-7.07 (3H, m), 7.22 (1H, d, J= 8.4 Hz), 7.47 (1H, s), 7.54-7.56 (1H, m), 7.87 (1H, d, J= 8.8 Hz), 7.91 (1H, s), 10.43 (1H, s). | 1 | |
38 | 481.2 | 1H NMR (400 MHz, d 6-DMSO) δ 1.70-1.74 (2H, m), 2.15 (3H, s), 3.45-3.48 (2H, m), 4.20-4.24 (1H, m), 6.81 (1H, d, J= 8.4 Hz), 7.09-7.26 (5H, m), 7.54-7.58 (1H, m), 7.77 (1H, d, J= 8.4 Hz), 7.84 (1H, dd, J= 8.4 Hz, 2.8 Hz), 7.96 (1H, d, J= 2.4 Hz), 10.52 (1H, s). | 3 | |
39 | 494.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.17 (3H, s), 2.38 (2H, d, J= 6.4 Hz), 4.46 (1H, t, J= 6.4 Hz), 6.87 (1H, s), 6.94 (1H, s), 7.11-7.15 (3H, m), 7.23 (1H, d, J= 8.4 Hz), 7.43 (1H, s), 7.54-7.60 (2H, m), 7.83-7.88 (2H, m), 10.58 (1H, s). | 1 | |
40 | 420.1 | NA | 12 | |
41 | 480.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.16 (3H, s), 4.49 (1H, s), 6.92 (1H, s), 7.10-7.23 (5H, m), 7.47 (1H, s), 7.57-7.59 (2H, m), 7.73 (1H, dd, J= 8.0 Hz, 4.4 Hz), 7.83 (1H, d, J= 8.4 Hz), 10.55 (1H, s). | 9 | |
42 | 494.1 | NA | 9 | |
43 | 564.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.55-0.57 (2H, m), 1.01-1.03 (2H, m), 2.10-2.13 (1H, m), 2.14 (3H, s), 3.15-3.17 (2H, m), 3.35-3.40 (2H, m), 4.51 (1H, s), 4.70-4.73 (1H, m), 6.33 (1H, s), 7.07-7.11 (3H, m), 7.21 (1H, d, J= 8.4 Hz), 7.55-7.58 (1H, m), 7.63-7.65 (1H, m), 7.89 (1H, s), 8.10-8.13 (1H, m), 10.41 (1H, s). | 9 | |
44 | 578.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.55-0.57 (2H, m), 1.01-1.03 (2H, m), 2.10-2.13 (1H, m), 2.14 (3H, s), 3.22 (3H, s), 3.24-3.27 (2H, m), 3.34-3.36 (2H, m), 4.51 (1H, s), 6.33 (1H, s), 7.07-7.13 (3H, m), 7.21 (1H, d, J= 8.4 Hz), 7.55-7.58 (1H, m), 7.65 (1H, dd, J= 7.2 Hz, 2.4 Hz), 7.89 (1H, s), 8.14-8.17 (1H, m), 10.41 (1H, s). | 9 | |
45 | 521.2 | NA | 34 |
步驟1:第三丁基-(1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-(羥基亞氨基)丁基)氨基甲酸酯的合成
將(1-(5-(4-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丁基)氨基甲酸第三丁酯(63 mg,0.1 mmol),醋酸鈉(16 mg,0.2 mmol)及鹽酸羥胺(14 mg,0.2 mmol)的3 mL乙醇溶液室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥後旋乾,得到70 mg黃色固體。
步驟2:4-環丙基-N-(3-(1,3-二氨基丁基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將上一步反應所得粗品溶於5 mL甲醇,加入0.1 mL濃鹽酸及50 mg Pd/C(10%)。反應體系在0.2 MPa壓力的氫氣氛圍下攪拌6小時。過濾,濾液旋乾後經Prep-TLC純化(DCM/MeOH=10/1),得到3 mg白色固體,兩步收率:5%。
LC/MS: m/z=534.2 [M+H]
+.
步驟1:N-(3-(2-氨基-1-羥乙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將N-(3-(2-氨基-2-氧乙醯基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(104 mg,0.2 mmol)溶於3 mL四氫呋喃,0°C下加入四氫鋁鋰(23 mg,0.6 mmol),反應體系室溫攪拌過夜。反應液倒入10 mL水中,乙酸乙酯萃取,有機相乾燥後旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到25 mg黃色固體,收率:25%。
步驟2:N-(3-(2-氨基-1-氟乙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將N-(3-(2-氨基-1-羥乙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(25 mg,0.05 mmol)溶於3 mL二氯甲烷,體系冷卻至-20°C後加入二乙胺基三氟化硫(8 mg,0.05 mmol),0°C攪拌反應1小時。反應液倒入10 mL水中,乙酸乙酯萃取,有機相旋乾後經Prep-TLC純化(DCM/MeOH=15/1),得到8 mg類白色固體,收率:32%。
LC/MS: m/z=509.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.58-0.60 (2H, m), 1.02-1.07 (2H, m), 1.18 (3H, d,
J= 7.0 Hz), 2.13-2.17 (4H, m), 2.64-2.69 (1H, m), 2.72-2.77 (1H, m), 2.94-3.01 (1H, m), 6.28 (1H, s), 7.05-7.13 (3H, m), 7.20 (1H, dd,
J= 9.2 Hz, 2.8 Hz), 7.47-7.51 (1H, m), 7.57 (1H, dd,
J= 6.6 Hz, 2.4 Hz), 7.91 (1H, s), 10.37 (1H, s).
實施例48
N-(3-(4-氨基-4-氧代丁烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
將3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丁酸乙酯(56 mg,0.1 mmol)的5 mL氨甲醇溶液(7 M)室溫攪拌過夜,反應體系直接旋乾,粗品用少量乙酸乙酯打漿,得到35 mg白色固體,收率:66%。
LC/MS: m/z=533.2 [M+H]
+.
步驟1:4-環丙基-N-(3-(1,3-二羥丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)-3-氧代丙酸甲酯(55 mg,0.1 mmol)溶於3 mL甲醇,室溫下加入硼氫化鈉(38 mg,1.0 mmol)。反應體系室溫攪拌6小時後倒入10 mL水中,乙酸乙酯萃取,有機相旋乾後經Prep-TLC純化(DCM/MeOH=20/1),得到30 mg黃色固體,收率:58%。
步驟2:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(3-羥基-1-(1H-咪唑-1-基)丙基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-N-(3-(1,3-二羥丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(30 mg,0.06 mmol)溶於3 mL NMP,加入羰基二咪唑(16 mg,0.1 mmol)。反應體系於150°C攪拌兩天。直接用Prep-HPLC純化得8 mg白色固體,收率:24%。
LC/MS: m/z=572.2 [M+H]
+.
步驟1:第三丁基(3-(2-溴乙醯氨基)-1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙基)氨基甲酸酯的合成
將第三丁基(3-氨基-1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙基)氨基甲酸酯(62 mg,0.1 mmol)及三乙胺(20 mg,0.2 mmol)溶於5 mL二氯甲烷,體系冷卻至0°C後加入溴乙醯溴(20 mg,0.1 mmol)。反應液室溫攪拌1小時後旋乾,粗品經Prep-TLC純化(PE/EA=2/1),得到55 mg黃色固體,收率:74%。
步驟2:N-(3-(1-氨基-3-(2-溴乙醯氨基)丙基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將第三丁基(3-(2-溴乙醯氨基)-1-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丙基)氨基甲酸酯(55 mg,0.07 mmol)溶於5 mL鹽酸乙酸乙酯溶液攪拌反應1小時,反應體系旋乾後得目標產物的鹽酸鹽,直接用於下一步。
步驟3:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-氧代-1,4-二氮雜-5-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將上步產物溶於5 mL四氫呋喃,加入碳酸鉀(37 mg,0.2 mmol)後室溫攪拌過夜。過濾,濾液旋乾後經Prep-TLC純化(DCM/MeOH=10/1),得到16 mg類白色固體,兩步收率:39%。
LC/MS: m/z=560.2 [M+H]
+.
實施例51
4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-氧六氫嘧啶-4-基)苯基)-5-(三氟甲基)苯甲醯胺
將4-環丙基-N-(3-(1,3-二氨基丙基)-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(51 mg,0.1 mmol) 溶於3 mL四氫呋喃,加入碳酸鉀(37 mg,0.2 mmol)及三光氣(30 mg,0.1 mmol)後室溫攪拌6小時。過濾,濾液旋乾後經Prep-TLC純化(DCM/MeOH=30/1),得到20 mg白色固體,收率:36%。
LC/MS: m/z=546.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.57-0.60 (2H, m), 1.00-1.06 (2H, m), 1.70-1.77 (1H, m), 2.00-2.03 (1H, m), 2.12-2.16 (4H, m), 2.92-2.94 (1H, m), 3.09-3.11 (1H, m), 4.72-4.74 (1H, m), 6.34-6.37 (2H, m), 6.48 (1H, s), 7.05-7.23 (4H, m), 7.63-7.67 (2H, m), 7.89 (1H, s), 10.53 (1H, s).
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-硝基苯基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(35 mg,0.1 mmol),4-氟-3-硝基苯胺(16 mg,0.1 mmol),DIPEA(26 mg,0.2 mmol)和2 mL 四氫呋喃,再加入HATU(38 mg,0.1 mmol),反應混合物室溫攪拌過夜。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M氫氧化鈉水溶液及飽和食鹽水各反洗兩次,乾燥,旋乾,得到40 mg黃色固體,收率:82%。
步驟2:N-(3-氨基-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-硝基苯基)-5-(三氟甲基)苯甲醯胺(40 mg,0.08 mmol)溶於5 mL甲醇,加入10 mg Pd/C(10%)。反應體系在0.2 MPa壓力的氫氣氛圍下攪拌過夜。反應液過濾,濾液旋乾後經Prep-TLC純化(DCM/MeOH=30/1),得到26 mg白色固體,收率:68%。
LC/MS: m/z=463.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.58 (2H, m), 1.01-1.05 (2H, m), 2.08-2.15 (4H, m), 5.20 (2H, s), 6.34 (1H, s), 6.74-6.76 (1H, m), 6.90-6.92 (1H, m), 7.07-7.08 (2H, m), 7.19-7.21 (2H, m), 7.87 (1H, s), 10.13 (1H, s).
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(4-氧代丁烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯基)丁酸乙酯(281 mg,0.5 mmol)的5 mL四氫呋喃溶液在氮氣保護條件下冷卻至-70°C,滴加二異丁基氫化鋁(1M正己烷溶液,0.5 mL,0.5 mmol),加畢後反應體系於-70°C攪拌1小時。反應倒入20 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=3/1),得到140 mg黃色固體,收率:54%。
步驟2:N-(3-(4-((第三丁基亞磺醯基)亞氨基)丁烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5- (三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(4-氧代丁烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺(140 mg,0.27 mmol),碳酸銫(88 mg,0.27 mmol),及第三丁基亞磺醯胺(33 mg,0.27 mmol)的3 mL二氯甲烷溶液40°C攪拌過夜,反應體系過濾,濾液旋乾,得到165 mg黃色固體,粗品直接用於下步反應。
步驟3:N-(3-(4-((第三丁基亞磺醯基)氨基)-5,5,5-三氟戊烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基) -5-(三氟甲基)苯甲醯胺的合成
將N-(3-(4-((第三丁基亞磺醯基)亞氨基)丁烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5- (三氟甲基)苯甲醯胺(165 mg,0.27 mmol)及四丁基氟化銨(26 mg,0.1 mmol)的5 mL四氫呋喃溶液於氮氣保護下冷卻至0°C,加入(三氟甲基)三甲基矽烷(38 mg,0.27 mmol),反應液於0°C攪拌2小時,體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=1/1),得到30 mg黃色固體,兩步收率:16%。
步驟4:N-(3-(4-氨基-5,5,5-三氟戊烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將N-(3-(4-((第三丁基亞磺醯基)氨基)-5,5,5-三氟戊烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基) -5-(三氟甲基)苯甲醯胺(30 mg,0.04 mmol)的5 mL鹽酸乙酸乙酯溶液室溫攪拌1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到12 mg類白色固體,收率:48%。
LC/MS: m/z=587.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.57-0.59 (2H, m), 1.02-1.04 (2H, m), 1.16-1.22 (3H, m), 1.75-1.77 (1H, m), 1.90-1.98 (2H, m), 2.10-2.15 (4H, m), 2.70-2.75 (0.5H, m), 3.21-3.26 (0.5H, m), 6.39 (1H, s), 7.00-7.19 (4H, m), 7.45-7.51 (1H, m), 7.55-7.60 (1H, m), 7.90 (1H, s), 10.37-10.38 (1H, m).
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(環氧乙烷-2-基)丙-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(4-氧代丁烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺(45 mg,0.087 mmol)溶於2 mL DMSO,依次加入第三丁醇鉀(23 mg,0.20 mmol)及三甲基碘化亞碸(22 mg,0.10 mmol)反應液室溫攪拌4小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(PE/EA=2/1),得到20 mg白色固體,收率:43%。
步驟2:N-(3-(5-(第三丁基氨基)-4-羥基戊烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(環氧乙烷-2-基)丙-2-基)苯基)-5-(三氟甲基)苯甲醯胺(20 mg,0.038 mmol)溶於2 mL DMF,加入第三丁胺(15 mg,0.20 mmol)後升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到8 mg白色固體,收率:35%。
LC/MS: m/z=605.3 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 1.02-1.23 (14H, m), 1.60-1.68 (2H, m), 1.97-2.02 (1H, m), 2.10-2.14 (4H, m), 3.24-3.26 (2H, m), 3.60-3.62 (1H, m), 6.36-6.37 (1H, m), 7.06-7.12 (3H, m), 7.19-7.21 (1H, m), 7.41-7.44 (1H, m), 7.63-7.67 (1H, m), 7.89 (1H, s), 10.36-10.37 (1H, m).
步驟1:2-(2-氟-5-硝基苯基)-N-甲氧基-N-甲基乙醯胺的合成
向反應瓶中加入2-氟-5-硝基苯乙酸(3000 mg,15.1 mmol),N,O-二甲基羥胺鹽酸鹽(1510 mg,15.5 mmol),DIPEA(3870 mg,30.0 mmol)和50 mL 四氫呋喃,再加入HATU(7600 mg,20.0 mmol),反應混合物室溫攪拌4小時。反應體系倒入200 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M氫氧化鈉水溶液及飽和食鹽水各反洗兩次,乾燥,旋乾,得到2900 mg黃色固體,收率:79%。
步驟2:2-(2-氟-5-硝基苯基)-N-甲氧基-N-甲基丙醯胺的合成
將2-(2-氟-5-硝基苯基)-N-甲氧基-N-甲基乙醯胺(1000 mg,4.1 mmol)溶於10 mL DMF,依次加入碳酸銫(2608 mg,8.0 mmol)及碘甲烷(582 mg,4.1 mmol)。反應液室溫攪拌過夜。體系倒入100 mL水中,乙酸乙酯萃取,有機相用食鹽水反洗兩次,乾燥,旋乾,得到940 mg黃色固體,收率:89%。
步驟3:2-(5-氨基-2-氟苯基)-N-甲氧基-N-甲基丙醯胺的合成
將2-(2-氟-5-硝基苯基)-N-甲氧基-N-甲基丙醯胺(940 mg,3.7 mmol)溶於20 mL甲醇,加入100 mg Pd/C(10%)。反應體系在0.2 MPa壓力的氫氣氛圍下攪拌過夜。反應液過濾,濾液旋乾,得到700 mg黃色固體,收率:84%。
步驟4:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(甲氧基(甲基)氨基)-1-氧丙烷-2-基)苯基)-5-( 三氟甲基)苯甲醯胺的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(210 mg,0.6 mmol),2-(5-氨基-2-氟苯基)-N-甲氧基-N-甲基丙醯胺(130 mg,0.6 mmol),DIPEA(155 mg,1.2 mmol)和5 mL 四氫呋喃,再加入HATU(340 mg,0.9 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M氫氧化鈉水溶液及飽和食鹽水各反洗兩次,乾燥,旋乾,得到230 mg黃色固體,收率:71%。
步驟5:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-氧代丙烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(甲氧基(甲基)氨基)-1-氧丙烷-2-基)苯基)-5-( 三氟甲基)苯甲醯胺(230 mg,0.4 mmol)的5 mL四氫呋喃溶液在氮氣保護條件下冷卻至-70°C,滴加二異丁基氫化鋁(1M正己烷溶液,0.4 mL,0.4 mmol),加畢後反應體系於-70°C攪拌1.5小時。反應倒入20 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,得到200 mg黃色固體,收率:97%。
步驟6:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(環氧乙烷-2-基)乙基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-氧代丙烷-2-基)苯基)-5-(三氟甲基)苯甲醯胺(100 mg,0.20 mmol)溶於2 mL DMSO,依次加入第三丁醇鉀(34 mg,0.30 mmol)及三甲基碘化亞碸(44 mg,0.20 mmol)反應液室溫攪拌過夜,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=2/1),得到60 mg白色固體,收率:58%。
步驟7:N-(3-(4-(第三丁基氨基)-3-羥基丁烷-2-基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(1-(環氧乙烷-2-基)乙基)苯基)-5-(三氟甲基)苯甲醯胺(52 mg,0.10 mmol)溶於2 mL DMF,加入第三丁胺(37 mg,0.50 mmol)後升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到25 mg白色固體,收率:42%。
LC/MS: m/z=591.3 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.59 (2H, m), 0.96-1.05 (11H, m), 1.21-1.23 (3H, m), 2.10-2.14 (5H, m), 2.33-2.49 (2H, m), 3.00-3.04 (1H, m), 3.56 (1H, brs), 4.80 (1H, brs), 6.37 (1H, s), 7.04-7.09 (3H, m), 7.18-7.21 (1H, m), 7.49-7.52 (1H, m), 7.58-7.60 (1H, m), 7.89 (1H, s), 10.36 (1H, s).
實施例56
4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(210 mg,0.6 mmol),5-氨基-2-氟苯酚(76 mg,0.6 mmol),DIPEA(155 mg,1.2 mmol)和5 mL 四氫呋喃,再加入HATU(340 mg,0.9 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M氫氧化鈉水溶液及飽和食鹽水各反洗兩次,乾燥,旋乾,得到160 mg黃色固體,收率:58%。
LC/MS: m/z=464.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.59 (2H, m), 1.01-1.06 (2H, m), 2.10-2.15(4H, m), 6.37 (1H, s), 6.96-7.00 (1H, m), 7.03-7.10 (3H, m), 7.20 (1H, dd,
J= 9.2 Hz, 2.8 Hz), 7.45 (1H, dd,
J= 8.4 Hz, 2.4 Hz), 7.88 (1H, s), 9.92 (1H, s), 10.29 (1H, s).
步驟2:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(92 mg,0.2 mmol)溶於3 mL乙腈,加入碳酸鉀(55 mg,0.4 mmol)及環氧氯丙烷(37 mg,0.4 mmol)。反應液60°C攪拌過夜。過濾,濾液旋乾,經Prep-TLC純化(PE/EA=2/1),得到60 mg類白色固體,收率:58%。
步驟3:N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-5-(三氟甲基)苯甲醯胺(52 mg,0.10 mmol)溶於2 mL DMF,加入0.5 mL氨水後密封升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到30 mg白色固體,收率:56%。
LC/MS: m/z=537.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.55-0.59 (2H, m), 1.01-1.05 (2H, m), 2.10-2.14 (4H, m), 2.86-2.89 (1H, m), 3.03-3.06 (1H, m), 3.97-4.00 (2H, m), 4.04-4.08 (1H, m), 5.83 (1H, d,
J= 5.2 Hz), 6.36 (1H, s), 7.05-7.11 (3H, m), 7.17-7.22 (2H, m), 7.65-7.68 (1H, m), 7.89 (1H, s), 10.45 (1H, s).
步驟1:第三丁基(3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)環丁基)氨基甲酸酯的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(93 mg,0.2 mmol),(3-羥基環丁基)氨基甲酸第三丁酯(37 mg,0.2 mmol),及三苯基磷(105 mg,0.4 mmol)溶於3 mL四氫呋喃,氮氣保護室溫下滴加DIAD(80 mg,0.4 mmol),反應溶液室溫攪拌3小時。系倒入水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=1/1),得到85 mg類白色固體,收率:67%。
步驟2:N-(3-(3-氨基環丁氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將第三丁基(3-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)環丁基)氨基甲酸酯(63 mg,0.1 mmol)的5 mL鹽酸乙酸乙酯溶液室溫攪拌1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到40 mg類白色固體,收率:75%。
LC/MS: m/z=533.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.57-0.61 (2H, m), 1.01-1.06 (2H, m), 1.75-1.81 (1H, m), 1.90-2.15 (7H, m), 2.25-2.31 (1H, m), 2.71-2.76 (1H, m), 2.98-3.02 (0.5H, m), 3.56-3.58 (0.5H, m), 4.22-4.25 (0.5H, m), 4.79-4.81 (0.5H, m), 6.40 (1H, s), 7.00-7.21 (5H, m), 7.32-7.41 (1H, m), 7.89 (1H, s), 10.38-10.39 (1H, m).
實施例59
4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-(甲基磺醯胺基)乙氧基)苯基)-5-(三氟甲基)苯甲醯胺
將N-(3-(2-氨基乙氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(51 mg,0.1 mmol)及DIPEA(26 mg,0.2 mmol)溶於3 mL四氫呋喃,室溫下加入甲基磺醯氯(12 mg,0.1 mmol),反應溶液室溫攪拌3小時。體系倒入水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=1/1),得到45 mg白色固體,收率:78%。
LC/MS: m/z=585.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.60 (2H, m), 1.01-1.05 (2H, m), 2.10-2.15 (4H, m), 2.96 (3H, s), 3.37-3.40 (2H, m), 4.03-4.06 (2H, m), 6.37 (1H, s), 7.05-7.07 (2H, m), 7.16-7.22 (3H, m), 7.33-7.34 (1H, m), 7.55-7.57 (1H, m), 7.90 (1H, s), 10.41 (1H, s).
實施例60
4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(3,3,3-三氟-2-羥基丙氧基)苯基)-5-(三氟甲基)苯甲醯胺
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(46 mg,0.1 mmol),碳酸鉀(41 mg,0.3 mmol)及3-溴-1,1,1-三氟丙烷-2-醇(19 mg,0.1 mmol)的3 mL NMP溶液110°C攪拌過夜,反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(EA),得到35 mg白色固體,收率:52%。
LC/MS: m/z=576.1 [M+H]
+.
步驟1:2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙酸乙酯的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(46 mg,0.1 mmol),碳酸鉀(28 mg,0.2 mmol),及溴乙酸乙酯(17 mg,0.1 mmol)的3 mL乙腈溶液60°C攪拌2小時,反應體系過濾,濾液旋乾,得到55 mg黃色固體,粗品直接用於下步反應。
步驟2:2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙酸的合成
將2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙酸乙酯(55 mg,0.1 mmol)溶於2 mL甲醇,加入1 mL水及一水合氫氧化鋰(17 mg,0.4 mmol),反應液室溫攪拌6小時,反應體系倒入10 mL水中,1M稀鹽酸調節pH值至酸性,乙酸乙酯萃取,有機相乾燥旋乾,得到45 mg白色固體,收率:87%。
步驟3:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-氧代-2-(((2,2,2-三氟乙基)氨基)乙氧基)苯基)-5 -(三氟甲基)苯甲醯胺的合成
向反應瓶中加入2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙酸(42 mg,0.08 mmol),2,2,2-三氟乙基胺(10 mg,0.1 mmol),DIPEA(26 mg,0.2 mmol)和3 mL 四氫呋喃,再加入HATU(38 mg,0.1 mmol),反應混合物室溫攪拌4小時。反應體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(PE/EA=1/1),得到35 mg白色固體,收率:73%。
LC/MS: m/z=603.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.58 (2H, m), 1.03-1.06 (2H, m), 2.10-2.14 (4H, m), 3.90-3.99 (2H, m), 4.65 (2H, s), 6.35 (1H, s), 7.04-7.11 (2H, m), 7.20-7.22 (2H, m), 7.48 (1H, d,
J= 7.6 Hz), 7.88 (1H, s), 7.17 (1H, t,
J= 6.4 Hz), 10.44 (1H, s).
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基乙氧基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(92 mg,0.2 mmol),碳酸鉀(41 mg,0.3 mmol),及溴乙醇(25 mg,0.2 mmol)的3 mL NMP溶液110°C攪拌5小時,反應體系倒入15 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,得到100 mg黃色固體。
步驟2:(2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙基)1H-咪唑-1-羧酸酯的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基乙氧基)苯基)-5-(三氟甲基)苯甲醯胺(80 mg,0.16 mmol)及CDI(32 mg,0.2 mmol)的4 mL四氫呋喃溶液50°C攪拌4小時。反應體系旋乾後得到的粗品直接用於下步反應。
步驟3:(2-(5-(4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺基)-2-氟苯氧基)乙基)氨基甲酸酯的合成
將上一步反應產物溶於5 mL氨-二氧六環溶液(1M)反應液於50°C攪拌4小時,旋乾,粗品經Prep-HPLC純化,得到20 mg白色固體,兩步收率:23%。
LC/MS: m/z=551.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.57-0.59 (2H, m), 1.03-1.06 (2H, m), 2.10-2.15 (4H, m), 4.16-4.17 (2H, m), 4.25-4.26 (2H, m), 6.38 (1H, s), 7.05-7.22 (5H, m), 7.55-7.57 (1H, m), 7.91 (1H, s), 10.41 (1H, s).
實施例63
4-環丙基-N-(2-(2,3-二羥基丙氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺
步驟1:2-(((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺的合成
稱取2-氯吡啶-4-胺(128 mg,1.0 mmol)及丙酮縮甘油(264 mg,2.0 mmol)於燒瓶,加入金屬鈉(46 mg,2.0 mmol),所得混合物於130°C攪拌2小時,反應體系冷卻後倒入15 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經柱層析純化(PE/EA=1/1)得到100 mg黃色油狀物,產率:44%。
步驟2:4-環丙基-N-(2-(((2,2-二甲基-1,3-二氧雜戊環-4-基)甲氧基)吡啶基-4-基)-2-(4-氟-2-甲基苯氧基)-5- (三氟甲基)苯甲醯胺的合成
向反應瓶中加入4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酸(142 mg,0.4 mmol),2-(((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺(100 mg,0.44 mmol),DIPEA(103 mg,0.8 mmol)和5 mL 四氫呋喃,再加入HATU(228 mg,0.6 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(PE/EA=3/1),得到130 mg白色固體,收率:58%。
步驟3:4-環丙基-N-(2-(2,3-二羥基丙氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-N-(2-(((2,2-二甲基-1,3-二氧雜戊環-4-基)甲氧基)吡啶基-4-基)-2-(4-氟-2-甲基苯氧基)-5- (三氟甲基)苯甲醯胺(130 mg,0.23 mmol)的5 mL鹽酸乙酸乙酯溶液室溫攪拌1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到105 mg白色固體,收率:87%。
LC/MS: m/z=521.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.58-0.60 (2H, m), 1.02-1.06 (2H, m), 2.10-2.13 (4H, m), 3.40-3.50 (2H, m), 3.74-3.79 (1H, m), 4.08-4.13 (1H, m), 4.22-4.26 (1H, m), 6.39 (1H, s), 7.04-7.16 (5H, m), 7.91 (1H, s), 8.02 (1H, d,
J= 5.6 Hz), 10.72 (1H, s).
步驟4:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(2-(環氧乙烷-2-基甲氧基)吡啶-4-基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-N-(2-(2,3-二羥基丙氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(104 mg,0.2 mmol),碳酸鉀(41 mg,0.3 mmol),及甲基黃醯氯(23 mg,0.2 mmol)的3 mL乙腈溶液室溫攪拌1小時,再升至60°C攪拌2小時,反應體系過濾,濾液旋乾,得到120 mg黃色固體,粗品直接用於下步反應。
步驟5:N-(2-(3-(第三丁基氨基)-2-羥基丙氧基)吡啶-4-基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將上一步所得產物溶於2 mL DMF,加入第三丁胺(73 mg,1.0 mmol)後升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到15 mg類白色固體,兩步收率:13%。
LC/MS: m/z=576.2 [M+H]
+.
步驟1:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-5-(三氟甲基)苯甲醯胺(92 mg,0.2 mmol)溶於3 mL DMF,加入碳酸鉀(55 mg,0.4 mmol)及間硝基苯磺酸縮水甘油酯(52 mg,0.2 mmol)。反應液60°C攪拌6小時。體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=3/1),得到100 mg類白色固體,收率:96%。
步驟2:N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺的合成
將4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-5-(三氟甲基)苯甲醯胺(52 mg,0.10 mmol)溶於2 mL DMF,加入0.5 mL氨水後密封升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到30 mg白色固體,收率:56%。
步驟3:4-環丙基-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基-3-(2-羥基乙醯氨基)丙氧基)苯基)-5-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入羥基乙酸(5 mg,0.06 mmol),N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-4-環丙基-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲醯胺(30 mg,0.06 mmol),DIPEA(26 mg,0.2 mmol)和3 mL 四氫呋喃,再加入HATU(38 mg,0.1 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到20 mg白色固體,收率:61%。
LC/MS: m/z=595.2 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 0.56-0.59 (2H, m), 1.01-1.06 (2H, m), 2.12-2.15 (4H, m), 3.18-3.23 (1H, m), 3.35-3.38 (1H, m), 3.81 (2H, d,
J= 6.0 Hz), 3.85-3.92 (3H, m), 5.31 (1H, d,
J= 4.8 Hz), 5.50 (1H, t,
J= 5.6 Hz), 6.37 (1H, s), 7.05-7.08 (2H, m), 7.15-7.21 (3H, m), 7.54 (1H, d,
J= 6.8 Hz), 7.70-7.73 (1H, m), 7.90 (1H, s), 10.40 (1H, s).
表二:按照與上述實施例所闡述操作類似的操作,以相應的試劑為原料製備以下化合物。
實施例 | 結構 | MS (ESI) m/z | 1H NMR | 合成參考實施例 |
66 | 576.3 | 1H NMR (400 MHz, d 6-DMSO) δ 0.54-0.58 (2H, m), 1.02-1.05 (2H, m), 1.10 (9H, s), 1.74-1.76 (2H, m), 2.12-2.15 (4H, m), 2.70-2.73 (2H, m), 4.17-4.20 (1H, m), 6.34 (1H, s), 7.07-7.13 (3H, m), 7.21 (1H, d, J= 8.8 Hz), 7.50-7.53 (1H, m), 7.81-7.82 (1H, m), 7.89 (1H, s), 10.42 (1H, s). | 24 | |
67 | 579.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.60 (2H, m), 0.96 (6H, d, J= 6.0 Hz), 1.01-1.06 (2H, m), 2.09-2.15 (4H, m), 2.55-2.58 (1H, m), 2.65-2.70 (2H, m), 3.88-3.91 (2H, m), 3.96-3.98 (1H, m), 5.04 (1H, brs), 6.38 (1H, s), 7.03-7.22 (5H, m), 7.53-7.55 (1H, m), 7.90 (1H, s), 10.39 (1H, s). | 57 | |
68 | 547.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.60 (2H, m), 1.01-1.06 (2H, m), 1.45-1.48 (1H, m), 1.62-1.71 (2H, m), 1.83-1.86 (1H, m), 2.10-2.15 (4H, m), 2.79-2.82 (2H, m), 3.40-3.45 (2H, m), 3.77-3.85 (2H, m), 6.38 (1H, s), 7.03-7.21 (5H, m), 7.54-7.56 (1H, m), 7.89 (1H, s), 10.38 (1H, s). | 58 | |
69 | 499.1 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.02-1.07 (2H, m), 1.97-2.02 (1H, m), 2.13 (3H, s), 6.40 (1H, s), 7.03-7.10 (2H, m), 7.17-7.20 (1H, m), 7.82-7.85 (1H, m), 7.98 (1H, s), 8.14-7.15 (1H, m), 8.65 (1H, d, J= 5.6 Hz), 11.19 (1H, s). | 56 | |
70 | 489.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.55-0.59 (2H, m), 1.01-1.06 (2H, m), 1.41 (6H, s), 2.10-2.14 (4H, m), 5.19 (1H, s), 6.34 (1H, s), 7.07-7.09 (2H, m), 7.19-7.21 (1H, m), 7.50-7.52 (1H, m), 7.90-7.92 (2H, m), 8.36 (1H, d, J= 5.2 Hz), 10.72 (1H, s). | 56 | |
71 | 534.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.02-1.07 (2H, m), 2.10-2.16 (4H, m), 2.28-2.38 (4H, m), 4.34-4.39 (1H, m), 4.80-4.83 (1H, m), 5.23 (1H, d, J= 5.2 Hz), 6.41 (1H, s), 7.03-7.22 (5H, m), 7.32-7.34 (1H, m), 7.90 (1H, s), 10.39 (1H, s). | 58 | |
72 | 575.8 | NA | 8 | |
73 | 599.2 | NA | 6 | |
74 | 544.2 | NA | 58 | |
75 | 561.1 | NA | 58 | |
76 | 521.2 | NA | 58 | |
77 | 593.2 | NA | 57 | |
78 | 577.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.20-0.22 (2H, m), 0.35-0.37 (2H, m), 0.58-0.61 (2H, m), 1.02-1.07 (2H, m), 2.10-2.13 (2H, m), 3.15 (3H, s), 2.64-2.69 (1H, m), 2.73-2.77 (1H, m), 3.86-3.99 (3H, m), 5.02 (1H, s), 6.38 (1H, s), 7.03-7.22 (5H, m), 7.52-7.55 (1H, m), 7.90 (1H, s), 10.40 (1H, s). | 57 | |
79 | 591.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.57-0.61 (2H, m), 1.02-1.07 (2H, m), 1.64-1.71 (4H, m), 2.13-2.15 (4H, m), 2.45-2.60 (5H, m), 2.64-2.68 (1H, m), 3.85-3.89 (1H, m), 3.96-4.04 (2H, m), 5.02 (1H, s), 6.39 (1H, s), 7.04-7.22 (5H, m), 7.54-7.56 (1H, m), 7.90 (1H, s), 10.40 (1H, s). | 57 | |
80 | 563.2 | NA | 58 | |
81 | 579.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.57-0.60 (2H, m), 1.02-1.06 (2H, m), 1.82 (3H, s), 2.10-2.16 (4H, m), 3.12-3.16 (1H, m), 3.24-3.29 (1H, m), 3.86-3.92 (3H, m), 5.25 (1H, d, J= 4.4 Hz), 6.38 (1H, s), 7.03-7.23 (5H, m), 7.54-7.58 (1H, m), 7.90 (1H, s), 7.93-7.96 (1H, m), 10.42 (1H, s). | 57 | |
82 | 561.2 | NA | 57 | |
83 | 579.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.60 (2H, m), 0.97 (6H, d, J= 6.0 Hz), 1.01-1.06 (2H, m), 2.09-2.15 (4H, m), 2.54-2.59 (1H, m), 2.65-2.70 (2H, m), 3.88-3.91 (2H, m), 3.96-3.98 (1H, m), 5.05 (1H, brs), 6.38 (1H, s), 7.04-7.21 (5H, m), 7.53-7.55 (1H, m), 7.90 (1H, s), 10.39 (1H, s). | 57 | |
84 | 578.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.61 (2H, m), 1.02-1.06 (2H, m), 1.32-1.40 (1H, m), 1.54-1.61 (1H, m), 1.76-1.80 (1H, m), 2.10-2.15 (4H, m), 2.21-2.24 (1H, m), 3.24-3.42 (4H, m), 4.08-4.10 (1H, m), 4.17-4.24 (1H, m), 4.70 (1H, d, J= 5.6 Hz), 6.41 (1H, s), 7.00-7.10 (2H, m), 7.16-7.22 (3H, m), 7.60 (1H, d, J= 8.0 Hz), 7.91 (1H, s), 10.39 (1H, s). | 58 | |
85 | 577.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.02-1.07 (2H, m), 1.32-1.38 (1H, m), 1.58-1.62 (1H, m), 1.81-1.84 (1H, m), 2.10-2.15 (4H, m), 2.21-2.24 (1H, m), 2.61-2.70 (2H, m), 3.25-3.40 (3H, m), 4.11-4.14 (1H, m), 4.20-4.24 (2H, m), 6.40 (1H, s), 7.03-7.08 (2H, m), 7.16-7.22 (3H, m), 7.62-7.65 (1H, m), 7.90 (1H, s), 10.43 (1H, s). | 58 | |
86 | 621.2 | NA | 57 | |
87 | 619.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.57-0.60 (2H, m), 1.02-1.05 (2H, m), 2.10-2.15 (4H, m), 2.33-2.39 (1H, m), 2.68-2.79 (2H, m), 3.27-3.31 (2H, m), 3.89-3.97 (3H, m), 5.15 (1H, d, J= 4.4 Hz), 6.38 (1H, s), 7.04-7.10 (2H, m), 7.15-7.22 (3H, m), 7.54-7.56 (1H, m), 7.90 (1H, s), 10.41 (1H, s). | 57 | |
88 | 561.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.46-0.47 (2H, m), 0.57-0.60 (4H, m), 1.00-1.05 (2H, m), 2.11-2.15 (4H, m), 2.62-2.65 (1H, m), 4.47 (2H, s), 6.34 (1H, s), 7.03-7.10 (2H, m), 7.17-7.22 (3H, m), 7.46 (1H, d, J= 8.0 Hz), 7.88 (1H, s), 8.20 (1H, d, J= 4.0 Hz), 10.43 (1H, s). | 61 | |
89 | 629.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.54-0.58 (2H, m), 1.00-1.07 (4H, m), 1.17-1.21 (2H, m), 2.10-2.14 (4H, m), 4.55 (2H, s), 6.34 (1H, s), 7.05-7.12 (3H, m), 7.16-7.22 (2H, m), 7.50 (1H, dd, J= 8.0 Hz, 2.4 Hz), 7.87 (1H, s), 8.99 (1H, s), 10.42 (1H, s). | 61 | |
90 | 538.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.60 (2H, m), 1.01-1.05 (2H, m), 2.10-2.15 (4H, m), 3.45 (2H, t, J= 5.6 Hz), 3.79-3.89 (2H, m), 4.00 (1H, dd, J= 9.2 Hz, 4.0 Hz), 4.72 (1H, t, J= 5.6 Hz), 5.03 (1H, d, J= 4.8 Hz), 6.37 (1H, s), 7.04-7.22 (5H, m), 7.56 (1H, dd, J= 8.0 Hz, 2.0 Hz), 7.90 (1H, s), 10.40 (1H, s). | 57 | |
91 | 633.2 | NA | 57 | |
92 | 613.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.55-0.59 (2H, m), 1.01-1.06 (2H, m), 2.08-2.14 (4H, m), 3.05-3.11 (1H, m), 3.21-3.27 (1H, m), 3.94-4.02 (3H, m), 5.26 (1H, d, J= 4.0 Hz), 5.58 (1H, t, J= 6.0 Hz), 6.37 (1H, s), 6.49-6.52 (1H, m), 6.59-6.62 (2H, m), 7.03-7.20 (7H, m), 7.50 (1H, dd, J= 8.0 Hz, 2.0 Hz), 7.90 (1H, s), 10.41 (1H, s). | 57 | |
93 | 603.2 | NA | 57 | |
94 | 671.3 | 1H NMR (400 MHz, d 6-DMSO) δ 0.57-0.59 (2H, m), 1.01-1.05 (2H, m), 1.50-1.62 (12H, m), 1.99 (3H, s), 2.10-2.14 (4H, m), 2.61-2.67 (2H, m), 3.81 (1H, brs), 3.88-3.92 (1H, m), 3.98-4.01 (1H, m), 5.00 (1H, brs), 6.38 (1H, s), 7.04-7.21 (5H, m), 7.53-7.56 (1H, m), 7.90 (1H, s), 10.38 (1H, s). | 57 | |
95 | 643.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.58 (2H, m), 1.01-1.06 (2H, m), 2.10-2.14 (4H, m), 3.02-3.05 (1H, m), 3.16-3.18 (1H, m), 3.62 (3H, s), 3.98-4.02 (3H, m), 5.22 (1H, d, J= 4.4 Hz), 5.32 (1H, t, J= 6.0 Hz), 6.37 (1H, s), 6.57 (2H, d, J= 8.8 Hz), 6.70 (2H, d, J= 8.8 Hz), 7.04-7.20 (6H, m), 7.56-7.59 (1H, m), 7.90 (1H, s), 10.38 (1H, s). | 57 | |
96 | 631.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.55-0.58 (2H, m), 1.02-1.06 (2H, m), 2.10-2.14 (4H, m), 3.02-3.05 (1H, m), 3.16-3.18 (1H, m), 3.98-4.03 (3H, m), 5.22 (1H, d, J= 4.4 Hz), 5.30 (1H, brs), 6.37 (1H, s), 6.85-6.88 (2H, m), 6.92-0.95 (2H, m), 7.05-7.22 (6H, m), 7.56-7.58 (1H, m), 7.91 (1H, s), 10.41 (1H, s). | 57 | |
97 | 617.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.57-0.59 (2H, m), 1.02-1.05 (2H, m), 2.10-2.14 (4H, m), 2.89-2.92 (1H, m), 3.00-3.03 (1H, m), 3.66 (3H, s), 3.92-4.01 (3H, m), 4.33 (1H, brs), 5.17 (1H, d, J= 4.8 Hz), 6.37 (1H, s), 6.95 (1H, s), 7.02-7.21 (6H, m), 7.57 (1H, dd, J= 7.6 Hz, 1.6 Hz), 7.90 (1H, s), 10.39 (1H, s). | 57 | |
98 | 620.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.59 (2H, m), 1.01-1.06 (2H, m), 2.10-2.15 (4H, m), 3.87-4.03 (4H, m), 4.17-4.19 (1H, m), 6.37 (1H, s), 6.39 (1H, brs), 7.05-7.21 (7H, m), 7.58-7.61 (1H, m), 7.90 (1H, s), 10.41 (1H, s). | 57 | |
99 | 603.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.59 (2H, m), 1.01-1.06 (2H, m), 2.10-2.14 (4H, m), 3.09-3.13 (1H, m), 3.21-25 (1H, m), 3.92-4.01 (3H, m), 5.10-5.30 (2H, m), 5.47 (1H, d, J= 1.6 Hz), 6.37 (1H, s), 7.04-7.20 (6H, m), 7.34 (1H, s), 7.54-7.56 (1H, m), 7.90 (1H, s), 10.38 (1H, s), 11.56 (1H, brs). | 57 | |
100 | 603.2 | NA | 57 | |
101 | 516.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.17 (3H, s), 3.44-3.47 (2H, m), 3.82-86 (1H, m), 4.28-4.33 (1H, m), 4.44-4.48 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 7.09-7.11 (2H, m), 7.15 (1H, s), 7.22 (1H, d, J= 9.2 Hz), 7.51 (1H, s), 8.13 (1H, s), 8.93 (1H, s), 11.29 (1H, s). | 63 | |
102 | 522.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.03-1.07 (2H, m), 2.10-2.14 (4H, m), 3.43-3.46 (2H, m), 3.81-85 (1H, m), 4.26-4.31 (1H, m), 4.42-4.45 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 6.41 (1H, s), 7.04-7.07 (2H, m), 7.20 (1H, dd, J= 9.2 Hz, 2.8 Hz), 7.50 (1H, d, J= 2.0 Hz), 7.97 (1H, s), 8.94 (1H, d, J= 2.0 Hz), 11.06 (1H, s). | 63 | |
103 | 515.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.16 (3H, s), 3.40-3.43 (2H, m), 3.75-3.79 (1H, m), 4.09-4.13 (1H, m), 4.23-4.27 (1H, m), 4.64 (1H, t, J= 5.6 Hz), 4.92 (1H, d, J= 5.2 Hz), 7.09-7.16 (5H, m), 7.21 (1H, d, J= 9.2 Hz), 8.05 (1H, d, J= 5.6 Hz), 8.08 (1H, s), 10.94 (1H, s). | 63 | |
106 | 573.2 | NA | 57 | |
107 | 555.2 | 1H NMR (400 MHz, d 6-DMSO) δ 2.18 (3H, s), 3.17-3.24 (1H, m), 3.33-3.39 (1H, m), 3.81-3.83 (2H, m), 3.88-3.93 (3H, m), 5.33 (1H, d, J= 4.8 Hz), 5.52 (1H, t, J= 5.6 Hz), 6.97 (1H, s), 7.09-7.14 (2H, m), 7.17-7.23 (3H, m), 7.57-7.61 (2H, m), 7.71-7.74 (1H, m), 7.85 (1H, d, J= 7.6 Hz), 10.56 (1H, s). | 65 | |
110 | 497.2 | NA | 57 |
步驟1:(R)-2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺的合成
稱取2-氯吡啶-4-胺(128 mg,1.0 mmol)及(R)-(-)-甘油醇縮丙酮(264 mg,2.0 mmol)於燒瓶,加入金屬鈉(46 mg,2.0 mmol),所得混合物於130°C攪拌2小時,反應體系冷卻後倒入15 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經柱層析純化(PE/EA=1/1)得到120 mg黃色油狀物,產率:54%。
步驟2:(R)-5-氯-N-(2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基) )-4-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(186 mg,0.54 mmol),(R)-2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺(120 mg,0.54 mmol),DIPEA(129 mg,1.00 mmol)和5 mL 四氫呋喃,再加入HATU(266 mg,0.7 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(PE/EA=3/1),得到180 mg白色固體,收率:60%。
步驟3:(S)-5-氯-N-(2-(2,3-二羥基丙氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺的合成
將(R)-5-氯-N-(2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基) )-4-(三氟甲基)苯甲醯胺(100 mg,0.18 mmol)的5 mL鹽酸乙酸乙酯溶液室溫攪拌1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到80 mg白色固體,收率:86%。
LC/MS: m/z=515.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.16 (3H, s), 3.40-3.43 (2H, m), 3.75-3.79 (1H, m), 4.09-4.13 (1H, m), 4.23-4.27 (1H, m), 4.64 (1H, t, J = 5.6 Hz), 4.92 (1H, d, J = 5.2 Hz), 7.09-7.16 (5H, m), 7.21 (1H, d, J = 9.2 Hz), 8.05 (1H, d, J = 5.6 Hz), 8.08 (1H, s), 10.94 (1H, s).
步驟1:(S)-2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺的合成
稱取2-氯吡啶-4-胺(128 mg,1.0 mmol)及(S)-(+)-甘油醇縮丙酮(264 mg,2.0 mmol)於燒瓶,加入金屬鈉(46 mg,2.0 mmol),所得混合物於130°C攪拌2小時,反應體系冷卻後倒入15 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經柱層析純化(PE/EA=1/1)得到130 mg黃色油狀物,產率:58%。
步驟2:(S)-5-氯-N-(2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基) )-4-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(186 mg,0.54 mmol),(S)-2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-胺(120 mg,0.54 mmol),DIPEA(129 mg,1.00 mmol)和5 mL 四氫呋喃,再加入HATU(266 mg,0.7 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(PE/EA=3/1),得到205 mg白色固體,收率:68%。
步驟3:(R)-5-氯-N-(2-(2,3-二羥基丙氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺的合成
將(S)-5-氯-N-(2-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基) )-4-(三氟甲基)苯甲醯胺(100 mg,0.18 mmol)的5 mL鹽酸乙酸乙酯溶液室溫攪拌1小時,反應體系旋乾後加水,碳酸鈉調pH至鹼性,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到75 mg白色固體,收率:81%。
LC/MS: m/z=515.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.16 (3H, s), 3.40-3.43 (2H, m), 3.75-3.79 (1H, m), 4.09-4.13 (1H, m), 4.23-4.27 (1H, m), 4.64 (1H, t, J = 5.6 Hz), 4.92 (1H, d, J = 5.2 Hz), 7.09-7.16 (5H, m), 7.21 (1H, d, J = 9.2 Hz), 8.05 (1H, d, J = 5.6 Hz), 8.08 (1H, s), 10.94 (1H, s).
步驟1:5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-4-(三氟甲基)苯甲醯胺的合成
向反應瓶中加入5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(209 mg,0.6 mmol),5-氨基-2-氟苯酚(76 mg,0.6 mmol),DIPEA(155 mg,1.2 mmol)和5 mL 四氫呋喃,再加入HATU(340 mg,0.9 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相依次用1M的稀鹽酸,1M氫氧化鈉水溶液及飽和食鹽水各反洗兩次,乾燥,旋乾,得到185 mg黃色固體,收率:68%。
步驟2:(R)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-4-(三氟甲基)苯甲醯胺的合成
將5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-4-(三氟甲基)苯甲醯胺(91 mg,0.2 mmol)溶於3 mL DMF,加入碳酸鉀(55 mg,0.4 mmol)及(R)-(-)-間硝基苯磺酸縮水甘油酯(52 mg,0.2 mmol)。反應液60°C攪拌6小時。體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=3/1),得到100 mg類白色固體,收率:96%。
步驟3:(R)-N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺的合成
將(R)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-4-(三氟甲基)苯甲醯胺(100 mg,0.19 mmol)溶於2 mL DMF,加入0.5 mL氨水後密封升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到75 mg白色固體,收率:73%。
步驟4:(R)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基-3-(2-羥基乙醯氨基)丙氧基)苯基)-4-(三氟甲基) )苯甲醯胺的合成
向反應瓶中加入羥基乙酸(10 mg,0.12 mmol),(R)-N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺(64 mg,0.12 mmol),DIPEA(52 mg,0.4 mmol)和3 mL 四氫呋喃,再加入HATU(76 mg,0.2 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到45 mg白色固體,收率:63%。
LC/MS: m/z=589.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.18 (3H, s), 3.17-3.24 (1H, m), 3.34-3.39 (1H, m), 3.81-3.83 (2H, m), 3.88-3.93 (3H, m), 5.33 (1H, d, J = 4.8 Hz), 5.52 (1H, t, J = 5.6 Hz), 7.09-7.23 (6H, m), 7.53 (1H, dd, J = 7.6 Hz, 2.0 Hz), 7.72-7.75 (1H, m), 8.04 (1H, s), 10.63 (1H, s).
步驟1:(S)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-4-(三氟甲基)苯甲醯胺的合成
將5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-羥基苯基)-4-(三氟甲基)苯甲醯胺(91 mg,0.2 mmol)溶於3 mL DMF,加入碳酸鉀(55 mg,0.4 mmol)及(S)-(+)-間硝基苯磺酸縮水甘油酯(52 mg,0.2 mmol)。反應液60°C攪拌6小時。體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥旋乾,經Prep-TLC純化(PE/EA=3/1),得到95 mg類白色固體,收率:92%。
步驟2:(S)-N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺的合成
將(S)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(環氧乙烷-2-基甲氧基)苯基)-4-(三氟甲基)苯甲醯胺(95 mg,0.19 mmol)溶於2 mL DMF,加入0.5 mL氨水後密封升溫至100°C攪拌6小時,體系倒入10 mL水中,乙酸乙酯萃取,有機相乾燥並旋乾,經Prep-TLC純化(DCM/MeOH=10/1),得到80 mg白色固體,收率:82%。
步驟3:(S)-5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(2-羥基-3-(2-羥基乙醯氨基)丙氧基)苯基)-4-(三氟甲基) )苯甲醯胺的合成
向反應瓶中加入羥基乙酸(10 mg,0.12 mmol),(S)-N-(3-(3-氨基-2-羥基丙氧基)-4-氟苯基)-5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲醯胺(64 mg,0.12 mmol),DIPEA(52 mg,0.4 mmol)和3 mL 四氫呋喃,再加入HATU(76 mg,0.2 mmol),反應混合物室溫攪拌4小時。反應體系倒入20 mL水中,乙酸乙酯萃取,有機相乾燥,旋乾,經Prep-TLC純化(DCM/MeOH=20/1),得到50 mg白色固體,收率:70%。
LC/MS: m/z=589.1 [M+H]
+.
1H NMR (400 MHz, d
6-DMSO) δ 2.18 (3H, s), 3.17-3.24 (1H, m), 3.34-3.39 (1H, m), 3.81-3.83 (2H, m), 3.88-3.93 (3H, m), 5.33 (1H, d, J = 4.8 Hz), 5.52 (1H, t, J = 5.6 Hz), 7.09-7.23 (6H, m), 7.53 (1H, dd, J = 7.6 Hz, 2.0 Hz), 7.72-7.75 (1H, m), 8.04 (1H, s), 10.63 (1H, s).
表三:按照與上述實施例所闡述操作類似的操作,以相應的試劑為原料製備以下化合物。
實施例 | 結構 | MS (ESI) m/z | 1H NMR | 合成參考實施例 |
104 | 521.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.60 (2H, m), 1.02-1.06 (2H, m), 2.10-2.13 (4H, m), 3.40-3.50 (2H, m), 3.74-3.79 (1H, m), 4.08-4.13 (1H, m), 4.22-4.26 (1H, m), 4.63 (1H, t, J= 5.6 Hz), 4.91 (1H, d, J= 5.2 Hz), 6.39 (1H, s), 7.04-7.16 (5H, m), 7.91 (1H, s), 8.02 (1H, d, J = 5.6 Hz), 10.72 (1H, s). | 114 | |
105 | 521.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.60 (2H, m), 1.02-1.06 (2H, m), 2.10-2.13 (4H, m), 3.40-3.50 (2H, m), 3.74-3.79 (1H, m), 4.08-4.13 (1H, m), 4.22-4.26 (1H, m), 4.63 (1H, t, J= 5.6 Hz), 4.91 (1H, d, J= 5.2 Hz), 6.39 (1H, s), 7.04-7.16 (5H, m), 7.91 (1H, s), 8.02 (1H, d, J = 5.6 Hz), 10.72 (1H, s). | 113 | |
108 | 481.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.16 (3H, s), 3.41-3.44 (2H, m), 3.77-3.78 (1H, m), 4.10-4.14 (1H, m), 4.24-4.28 (1H, m), 4.63 (1H, t, J= 5.6 Hz), 4.90 (1H, d, J= 5.2 Hz), 6.99 (1H, s), 7.09-7.11 (2H, m), 7.16-7.18 (2H, m), 7.22 (1H, d, J= 8.8 Hz), 7.62 (1H, d, J= 8.0 Hz), 7.87 (1H, d, J= 7.6 Hz), 8.05 (1H, d, J= 5.6 Hz), 10.87 (1H, s). | 114 | |
109 | 482.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.16 (3H, s), 3.44-3.47 (2H, m), 3.82-3.86 (1H, m), 4.28-4.33 (1H, m), 4.44-4.48 (1H, m), 4.68 (1H, t, J= 5.6 Hz), 4.99 (1H, d, J= 5.2 Hz), 7.03 (1H, s), 7.09-7.11 (2H, m), 7.22 (1H, dd, J= 8.8 Hz, 0.6 Hz), 7.53 (1H, d, J= 1.6 Hz), 7.64 (1H, d, J= 8.0 Hz), 7.91 (1H, d, J= 7.6 Hz), 8.95 (1H, d, J= 2.0 Hz), 11.21 (1H, s). | 114 | |
111 | 522.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.03-1.07 (2H, m), 2.10-2.14 (4H, m), 3.43-3.46 (2H, m), 3.81-85 (1H, m), 4.26-4.31 (1H, m), 4.42-4.45 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 6.41 (1H, s), 7.04-7.07 (2H, m), 7.20 (1H, dd, J= 9.2 Hz, 2.8 Hz), 7.50 (1H, d, J= 2.0 Hz), 7.97 (1H, s), 8.94 (1H, d, J= 2.0 Hz), 11.06 (1H, s). | 113 | |
112 | 522.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.58-0.62 (2H, m), 1.03-1.07 (2H, m), 2.10-2.14 (4H, m), 3.43-3.46 (2H, m), 3.81-85 (1H, m), 4.26-4.31 (1H, m), 4.42-4.45 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 6.41 (1H, s), 7.04-7.07 (2H, m), 7.20 (1H, dd, J= 9.2 Hz, 2.8 Hz), 7.50 (1H, d, J= 2.0 Hz), 7.97 (1H, s), 8.94 (1H, d, J= 2.0 Hz), 11.06 (1H, s). | 114 | |
115 | 516.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.17 (3H, s), 3.44-3.47 (2H, m), 3.82-86 (1H, m), 4.28-4.33 (1H, m), 4.44-4.48 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 7.09-7.11 (2H, m), 7.15 (1H, s), 7.22 (1H, d, J= 9.2 Hz), 7.51 (1H, s), 8.13 (1H, s), 8.93 (1H, s), 11.29 (1H, s). | 113 | |
116 | 516.1 | 1H NMR (400 MHz, d 6-DMSO) δ 2.17 (3H, s), 3.44-3.47 (2H, m), 3.82-86 (1H, m), 4.28-4.33 (1H, m), 4.44-4.48 (1H, m), 4.69 (1H, t, J= 5.6 Hz), 5.00 (1H, d, J= 5.2 Hz), 7.09-7.11 (2H, m), 7.15 (1H, s), 7.22 (1H, d, J= 9.2 Hz), 7.51 (1H, s), 8.13 (1H, s), 8.93 (1H, s), 11.29 (1H, s). | 114 | |
119 | 595.2 | 1H NMR (400 MHz, d 6-DMSO) δ 0.56-0.59 (2H, m), 1.01-1.06 (2H, m), 2.12-2.15 (4H, m), 3.18-3.23 (1H, m), 3.35-3.38 (1H, m), 3.81 (2H, d, J = 6.0 Hz), 3.85-3.92 (3H, m), 5.31 (1H, d, J = 4.8 Hz), 5.50 (1H, t, J = 5.6 Hz), 6.37 (1H, s), 7.05-7.08 (2H, m), 7.15-7.21 (3H, m), 7.54 (1H, d, J = 6.8 Hz), 7.70-7.73 (1H, m), 7.90 (1H, s), 10.40 (1H, s). | 117 | |
120 | 531.1 | 1H NMR (400 MHz, d 6-DMSO) δ 3.41-3.44 (2H, m), 3.75 (3H, s), 3.77-3.79 (1H, m), 4.11-4.15 (1H, m), 4.25-4.29 (1H, m), 4.63 (1H, t, J= 5.6 Hz), 4.90 (1H, d, J= 5.2 Hz), 6.83-6.88 (1H, m), 6.99 (1H, s), 7.13-7.19 (3H, m), 7.28-7.31 (1H, m), 8.03 (1H, s), 8.07 (1H, d, J= 5.6 Hz), 10.88 (1H, s). | 114 | |
121 | 597.1 | NA | 114 | |
122 | 481.2 | 1H NMR (400 MHz, d 6-DMSO) δ 2.15 (3H, s), 3.41-3.44 (2H, m), 3.77-3.78 (1H, m), 4.10-4.14 (1H, m), 4.24-4.28 (1H, m), 4.63 (1H, t, J= 5.6 Hz), 4.90 (1H, d, J= 5.2 Hz), 6.85 (1H, d, J= 8.8 Hz), 7.11-7.26 (5H, m), 7.81 (1H, dd, J= 8.8 Hz, 2.0 Hz), 8.01 (1H, d, J= 1.6 Hz), 8.05 (1H, d, J= 6.0 Hz), 10.85 (1H, s). | 114 |
成藥性試驗
試驗例1:化合物對HEK293細胞的人類Na
V1.8離子通道的抑制活性試驗
1:測試化合物配方
試劑除用於酸鹼滴定的NaOH和KOH外,均從Sigma (St. Louis, MO) 公司購買。測試化合物的最終濃度均在當天配製,再溶於細胞外液。細胞外液(mM)為: NaCl,137;KCl,4;CaCl
2,1.8;MgCl
2,1;HEPES,10;glucose 10;pH 7.4 (NaOH滴定)。細胞內液(mM)為Aspartic acid,140;MgCl2,2;EGTA 11;HEPES,10;pH 7.2 (CsOH滴定)。所有測試化合物溶液均含 1μM TTX。
測試化合物的保存濃度為3mM。溶於二甲基亞碸( DMSO)。 測試當天再溶於細胞外液,配置成要求濃度。
測試化合物溶劑
2:測試方法
2.1:細胞
所有實驗都在室溫下進行。每個細胞都以自身為對照。
2.1.1:化合物的測試
化合物均採用利用自身重力的灌流系統進行灌流。每個濃度至少測試一個細胞。在電流穩定(或5分鐘)後,再比較化合物使用前後的電流大小變化來計算化合物的阻斷作用。
2.1.2:試驗細胞
NaV1.8離子通道穩態表達的HEK293細胞。
2.1.3:實驗儀器
膜片鉗放大器:patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instrument)
數模轉換器:Digidata 1440A(Axon CNS)/ Digidata 1550A(Axon instruments)
微操控儀:MP-225(SUTTER instrument)
倒置顯微鏡:TL4(Olympus)
玻璃微電極拉制儀:PC-10(NARISHIGE)
微電極玻璃毛細管:B12024F(武漢微探科學儀器有限公司)
2.2:電生理
將細胞轉移到灌流槽中,用細胞外液進行灌流。細胞內液(mM)為Aspartic acid, 140; MgCl2, 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH滴定)。細胞內液分批少量儲存於-80度冰箱,實驗當天融化。電極用PC-10(Narishige, Japan)拉制。全細胞膜片鉗記錄,噪音用採樣頻率的五分之一進行過濾。
2.3:測試電壓方程(resting)及結果
將細胞鉗制在–80 mV,然後用持續10毫秒方波去極化到10mV,以得到Na
V1.8電流。這一程序每5秒重複一次。檢測方波引發的最大電流,待其穩定後,灌流測試化合物,當反應穩定後,計算阻斷的強度。
名字 | 二甲基亞碸 (DMSO) |
來源 | Sigma |
分子量 | 78.1 g/mol |
純度 | 99.9% |
儲存 | 室溫 |
表四:化合物對Nav1.8的抑制率(100 nm濃度下的抑制率/%:A>=80, 80>B>=50, 50>C>=20, D<20)
實施例 | 抑制活性 | 實施例 | 抑制活性 | 實施例 | 抑制活性 |
1 | B | 2 | D | 3 | A |
4 | B | 5 | B | 6 | B |
7 | A | 8 | A | 9 | A |
10 | A | 11 | A | 12 | B |
13 | C | 14 | B | 15 | C |
16 | D | 17 | D | 18 | D |
19 | A | 20 | B | 21 | B |
22 | A | 23 | B | 24 | A |
25 | C | 26 | C | 27 | A |
28 | C | 29 | B | 30 | B |
31 | B | 32 | C | 33 | D |
34 | B | 35 | A | 36 | A |
37 | A | 38 | B | 39 | A |
40 | B | 41 | A | 42 | A |
43 | B | 44 | B | 45 | NA |
VX-150 | B |
表五(續表四):化合物對Nav1.8的抑制率(100 nm濃度下的抑制率/%:A>=80, 80>B>=50, 50>C>=20, D<20)
本專利多個實施例相對於VX-150(臨床二期)具有較為明顯的活性優勢,另有部分實施例的活性與之相當。
實施例 | 抑制活性 | 實施例 | 抑制活性 | 實施例 | 抑制活性 |
46 | A | 47 | B | 48 | A |
49 | B | 50 | C | 51 | A |
52 | B | 53 | D | 54 | B |
55 | A | 56 | B | 57 | A |
58 | B | 59 | C | 60 | D |
61 | C | 62 | B | 63 | B |
64 | C | 65 | A | 66 | A |
67 | A | 68 | C | 69 | C |
70 | C | 71 | B | 72 | B |
73 | C | 74 | B | 75 | B |
76 | A | 77 | A | 78 | A |
79 | C | 80 | B | 81 | B |
82 | A | 83 | A | 84 | C |
85 | C | 86 | C | 87 | B |
88 | B | 89 | B | 90 | B |
91 | C | 92 | C | 93 | B |
94 | B | 95 | C | 96 | C |
97 | B | 98 | A | 99 | B |
100 | B | 101 | B | 102 | B |
103 | A | 104 | A | 105 | B |
106 | A | 107 | B | 108 | B |
109 | C | 110 | B | 111 | B |
112 | C | 113 | A | 114 | A |
115 | B | 116 | B | 117 | A |
118 | B | 119 | A | 120 | A |
121 | A | 122 | B |
試驗例2:化合物對HEK293細胞hERG離子通道的抑制活性試驗
該實驗作為化合物心臟安全性實驗。
1:試驗儀器
膜片鉗儀器:PC-505B、MC-700A
微操控儀器:MP—225
拉制電極儀器:PC-10(Narishige, Japan)
2:藥物配製
化合物除用於酸鹼滴定的NaOH和KOH外,均從Sigma (St. Louis, MO) 公司購買。 測試化合物的最終濃度均在當天配製,再溶於細胞外液。細胞外液(mM)為: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH滴定)。 所有測試化合物和對照化合物溶液均含 0.3% DMSO。細胞內液(mM)為:K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH滴定)。
3:試驗方法
細胞:所有實驗都在室溫下進行。每個細胞都以自身為對照。
化合物的測試:化合物均採用利用自身重力的灌流系統進行灌流。每個濃度至少測試兩個細胞。在電流穩定(或5分鐘)後,再比較化合物使用前後的電流大小變化來計算化合物的阻斷作用。
陽性對照:陽性對照Cisapride濃度選擇是根據它對細胞敏感性測試,阻斷率90%左右的濃度為陽性對照最佳濃度。經測試Cisapride為100nM時,阻斷率為90%左右,故陽性對照Cisapride 定為100 nM。方法和測試化合物一樣。
電生理:將細胞轉移到灌流槽中,用細胞外液進行灌流。細胞內液(mM)為:K Aspartate, 130; MgCl2, 5; EGTA 5; HEPES, 10; Tris-ATP 4; pH 7.2 (KOH滴定)。細胞內液分批少量儲存於-80度冰箱,實驗當天融化。電極用PC-10(Narishige, Japan)拉制。全細胞膜片鉗記錄,噪音用 採樣頻率的五分之一進行過濾。
測試過程和結果:將細胞鉗制在–80 mV,然後用持續4秒方波去極化到40 mV,再用持續2秒方波超極化到-40 mV,以得到hERG尾電流 (Tail current見附圖)。這一程序每20秒重複一次。 hERG尾電流是純hERG電流。檢測第二個方波引發的最大尾電流,待其穩定後,灌流測試化合物,當反應穩定後,計算阻斷的強度。
表六:化合物對hERG抑制的IC50測試結果
化合物對hERG的強抑制會產生心臟QT間期延長等嚴重的心臟安全風險。從表9數據可見:本專利部分化合物對hERG的抑制明顯弱於VX-150(臨床二期),因此很可能會表現出更好的心臟安全性。
實施例 | IC50 (uM) | 實施例 | IC50 (uM) |
1 | 3.2 | 36 | 10.5 |
38 | 3.0 | 104 | 3.8 |
114 | 22.3 | 116 | 15.6 |
117 | 6.0 | 119 | 4.2 |
VX-150 | 7.0 |
試驗例3:化合物對Nav離子通道亞型選擇性測試
實驗的目的是為了調查化合物對穩態表達的人類Na離子通道細胞(NaV1.1,NaV1.3,NaV1.4,NaV1.5,NaV1.6,NaV1.7)的作用。在Na 離子電流穩定後,比較化合物應用前後Na 通道電流的大小,可以得到化合物對Na 離子通道的影響。
1:測試化合物配方
化合物除用於酸鹼滴定的NaOH 和KOH 外,均從Sigma (St. Louis, MO) 公司購買。 測試化合物的最終濃度均在當天配製,再溶於細胞外液。細胞外液(mM)為: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH 滴定)。
測試化合物的保存濃度為9 mM。溶於二甲基亞碸( DMSO)。 測試當天再溶於細胞外液,配置成1 uM的篩選濃度。
2:測試方法
2.1:細胞
所有實驗都在室溫下進行。每個細胞都以自身為對照。
2.1.1 化合物的測試
化合物均採用利用自身重力的灌流系統進行灌流。每個濃度至少測試1個細胞。在電流穩定(或5分鐘)後,再比較化合物使用前後的電流大小變化來計算化合物的阻斷作用。
2.1.2 實驗細胞/試劑
NaV1.1,NaV1.3,NaV1.4,NaV1.5,NaV1.6離子通道穩態表達的HEK293細胞。NaV1.7離子通道穩態表達的CHO細胞。
2.1.3 實驗儀器
膜片鉗放大器:patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instrument)
數模轉換器:Digidata 1440A(Axon CNS)/ Digidata 1550A(Axon instruments)
微操控儀:MP-225(SUTTER instrument)
倒置顯微鏡:TL4(Olympus)
玻璃微電極拉制儀:PC-10(NARISHIGE)
微電極玻璃毛細管:B12024F(武漢微探科學儀器有限公司)
2.2 電生理
將細胞轉移到灌流槽中,用細胞外液進行灌流。細胞內液(mM)為Aspartic acid, 140; MgCl2, 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH滴定)。細胞內液分批少量儲存於-80度冰箱,實驗當天融化。電極用PC-10(Narishige, Japan)拉制。全細胞膜片鉗記錄,噪音用 採樣頻率的五分之一進行過濾。
2.3 測試電壓方程(resting)及結果
將細胞鉗制在–80 mV,然後用持續10毫秒方波去極化到-10 mV,以得到Na離子通道電流(見圖)。這一程序每5秒重複一次。檢測方波引發的最大電流,待其穩定後,灌流測試化合物,當反應穩定後,計算阻斷的強度。
表七:化合物在1 uM濃度下對Nav亞型的抑制率
可見,本專利部分化合物對Nav離子通道具有良好的亞型選擇性。特別是對於可能引起心臟副作用的Nav1.5,本專利部分化合物抑制作用明顯弱於VX-150(臨床二期),因此很可能會表現出更好的安全性。
實施例 | Nav1.1 | Nav1.3 | Nav1.4 | Nav1.5 | Nav1.6 | Nav1.7 |
1 | <1% | 13.4% | <1% | 7.4% | <1% | 9.5% |
104 | 1.5% | 4.3% | <1% | <1% | 2.8% | 1.3% |
114 | 4.8% | 4.4% | 2.7% | 5.9% | 8.3% | <1% |
116 | 1.2% | 3.7% | <1% | <1% | 2.6% | <1% |
117 | <1% | 1.2% | <1% | 5.0% | <1% | <1% |
119 | <1% | <1% | 1.4% | 2.8% | 5.1% | <1% |
VX-150 | <1% | 2.2% | 3.6% | 15.4% | 1.7% | 8.7% |
試驗例4:化合物大鼠體內藥代動力學測試
SD 大鼠,雄性(購於上海西普爾-必凱實驗動物有限公司)。各受試化合物以口服(100 mg/kg,每組3只)給藥方式單次給予SD大鼠進行藥代動力學研究。受試化合物給藥當天配製,採用5%DMSO+95%saline對受試化合物進行混懸,並經渦旋2 min,超聲5min之後配製成給藥體系。口服給藥前動物需禁食10-14小時,並於給藥4小時後恢復給食。SD大鼠經灌胃口服給藥後,經頸靜脈採集藥代動力學樣本,採集時間點為:給藥前、給藥後15 min、30 min、1 h、2 h、4 h、6 h、8 h和24 h,每個時間點採集3個全血樣本,採集量約0.2 mL,並經肝素鈉抗凝。血液樣本採集後立即置於冰上,於1小時之內離心分離血漿(離心條件:6800轉/分鐘,6分鐘,2-8℃)。收集的血漿分析前存放於–80℃冰箱內。
表八:部分化合物在100mg/kg劑量下的藥代動力學測試結果
實施例 | T1/2(h) | Cmax(ng/ml) | AUC(ng/ml*h) |
104 | 5.1 | 5145 | 58002 |
112 | 6.3 | 8266 | 114951 |
114 | 11.7 | 7635 | 153626 |
116 | 8.7 | 2566 | 42454 |
117 | 3.0 | 9567 | 113972 |
119 | 1.9 | 5192 | 44501 |
VX-150 | 2.2 | 1176 | 13859 |
本次大鼠藥代實驗中,對比化合物VX-150是一個前藥(WO2015089361,化合物9),給藥後檢測的是其原藥(WO2014120808,化合物10)的血藥濃度。前述體外成藥性實驗均採用原藥(WO2014120808,化合物10)進行。
VX-150原藥溶解性極低,固體給藥吸收效果非常差,因此被開發成前藥以解決溶解性問題。而本專利部分化合物在不進行前藥修飾的情況下,其大鼠藥代動力學的表現即可大幅優於VX-150。
從以上成藥性研究數據可以看出,本發明化合物對Nav1.8離子通道活性具有明顯的抑制作用,部分化合物的細胞活性,離子通道選擇性,hERG安全性,大鼠藥代動力學等成藥性參數與臨床二期的VX-150相比具有明顯的優勢,可用作Nav1.8抑制劑,在鎮痛、心房纖維性顫動、巴德- 吉亞利症候群等領域具有廣闊的應用前景。
雖然本發明已以實施例揭露如上,然其並非用以限定本發明,本發明所屬技術領域中具有通常知識者,在不脫離本發明之精神和範圍內,當可作些許之更動與潤飾,因此本發明之保護範圍當視後附之申請專利範圍所界定者為準。
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Claims (29)
- 一種化合物,其特徵在於,具有式I所示結構或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽: , A 1、A 3分別獨立選自CR 1或N; A 2選自NR 10R 11或OR 12; R 1、R 2、R 3、R 4、R 5分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、取代或非取代的醯胺基、酯基、醯基、羧基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基; R 10、R 11、R 12分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基; 或R 4與R 5及其相連的原子組成取代或非取代的3~10元環烷基、=O,或R 4與R 5及其相連的原子組成取代或非取代的3~10元雜環烷基,或R 5與R 11及其相連的原子組成取代或非取代的3~10元雜環烷基,或R 5與R 12及其相連的原子組成取代或非取代的3~10元雜環烷基; 其中,R 1、R 2、R 3、R 4、R 5、R 10、R 11、R 5與R 11及其相連的原子組成的雜環烷基中的取代基分別獨立選自氘、鹵素、羥基、氨基、烷基、雜烷基、環烷基、雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基; z選自0、1、2、3、4、5,n選自0、1、2、3、4,m選自0、1、2、3、4、5; 進一步地,n選自0、1、2,m選自0、1、2;進一步地,z選自0、1、2、3。
- 根據請求項1所述的化合物,其特徵在於,具有式III或III’所示結構或其異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽: 、 , A 1選自CR 1或N;A 2選自NR 10R 11或OR 12; R 1選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基; R 6、R 7、R 8、R 9分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的芳基、取代或非取代的雜芳基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基;其中,取代基選自氘、鹵素、羥基、氨基、烷基、雜烷基、環烷基、雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基。
- 根據請求項2所述的化合物,其特徵在於, R 4、R 5每次出現時獨立地選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的醯胺基、酯基、醯基、羧基、磺醯基、磺醯胺基,或R 4與R 5及其相連的原子組成取代或非取代的3~6元環烷基,或R 4與R 5及其相連的原子組成取代或非取代的3~6元雜環烷基,或R 5與R 11及其相連的原子組成取代或非取代的3~6元雜環烷基,或R 4與R 5及其相連的原子組成=O,或R 5與R 12及其相連的原子組成取代或非取代的3~6元雜環烷基;其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基;R 4、R 5至少有一個為H; 進一步地,R 4、R 5每次出現時獨立地選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、取代或非取代的醯胺基,或R 4與R 5及其相連的原子組成取代或非取代的3~6元環烷基、=O,或R 4與R 5及其相連的原子組成取代或非取代的3~6元雜環烷基,或R 5與R 11及其相連的原子組成取代或非取代的3~6元雜環烷基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基;R 4、R 5至少有一個為H。
- 根據請求項4所述的化合物,其特徵在於,R 4、R 5每次出現時獨立地選自氫、鹵素、取代或非取代的C1~C6烷基、取代或非取代的3~6元環烷基、取代或非取代的2~7元雜烷基、取代或非取代的3~6元雜環烷基、取代或非取代的醯胺基,或R 4與R 5及其相連的原子組成=O,或R 5與R 11及其相連的原子組成取代或非取代的3~6元雜環烷基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、醯基、羧基、醯胺基; 進一步地,R 4、R 5每次出現時獨立地選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的2~4元雜烷基、取代或非取代的5元雜環烷基、取代或非取代的醯胺基,或R 4與R 5及其相連的原子組成=O,或R 5與R 11及其相連的原子組成取代或非取代的5元或6元雜環烷基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元烷氧基、3~6元雜環烷基、醯基、羧基、醯胺基;R 4、R 5至少有一個為H。
- 根據請求項5所述的化合物,其特徵在於,R 4、R 5每次出現時獨立地選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的2~4元氧雜烷基、取代或非取代的醯胺基、 ,或R 4與R 5及其相連的原子組成=O,或R 5與R 11及其相連的原子組成取代或非取代的 、 、 或 ,其中,取代基選自鹵素、羥基、氨基、C1~C3烷基、2~4元烷氧基、羧基、醯胺基;R 4、R 5至少有一個為H; 進一步地,R 4、R 5每次出現時獨立地選自氫、鹵素、甲基、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ,或R 4與R 5及其相連的原子組成=O,或R 5與R 11及其相連的原子組成 、 、 或 ,其中,取代基選自鹵素、羥基、氨基、C1~C3烷基、2~4元烷氧基、3~6元雜環烷基、醯基、羧基、醯胺基; 進一步地,R 4、R 5每次出現時獨立地選自氫、甲基、 、 、 、 、 、 、 、 、 、 、 、 、 ,或R 4與R 5及其相連的原子組成=O;,其中,取代基選自鹵素、羥基、氨基、C1~C3烷基、2~4元烷氧基、醯基、醯胺基;R 4、R 5至少有一個為H; 進一步地,R 4、R 5每次出現時獨立地選自氫、甲基、 、 、 、 、 、 、 、 、 ,或R 4與R 5及其相連的原子組成=O;R 4、R 5至少有一個為H。
- 根據請求項3所述的化合物,其特徵在於,當A 2選自NR 10R 11時,z選自1、2、3,優選1或2; 當A 2選自OR 12時,z選自0、1、2、3,優選0。
- 根據請求項3所述的化合物,其特徵在於,R 10、R 11、R 12獨立地選自氫、鹵素、羥基、氰基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、酯基、醯基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基; 或R 11與R 5及其相連的原子組成環取代或非取代的雜環烷基,從其引用的請求項中的限定範圍。
- 根據請求項8所述的化合物,其特徵在於,R 10、R 11、R 12獨立地選自氫、鹵素、羥基、氰基、取代或非取代的C1~C6烷基、取代或非取代的3~6元環烷基、取代或非取代的2~7元雜烷基、取代或非取代的3~6元雜環烷基、酯基、醯基、醯胺基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基; 或R 11與R 5及其相連的原子組成環取代或非取代的雜環烷基,從其引用的請求項中的限定範圍。
- 根據請求項9所述的化合物,其特徵在於,R 10、R 11、R 12獨立地選自氫、取代或非取代的C1~C3烷基、取代或非取代的2~4元雜烷基、醯基、醯胺基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、醯胺基、磺醯基、磺醯胺基; 或R 11與R 5及其相連的原子組成環取代或非取代的雜環烷基,從其引用的請求項中的限定範圍; 進一步地,R 10、R 11獨立地選自氫、取代或非取代的C1~C3烷基、醯基,其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、酯基、醯基、醯胺基; 或R 11與R 5及其相連的原子組成環取代或非取代的雜環烷基,從其引用的請求項中的限定範圍; R 12選自氫、取代或非取代的C1~C3烷基; R 10、R 11、R 12中的取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、酯基、醯基、醯胺基; 更進一步地,R 10、R 11獨立地選自氫、甲基、 、 ,優選氫、甲基、 ,更優選氫、甲基;R 12選自氫、 、 、 ;其中,R13、R14分別獨立選自氫、醯基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜環烷基、取代或非取代的雜芳基,Z1、Z2分別獨立為1-5;進一步地,R13、R14分別獨立選自氫、醯基、 、C1-C5烷基或環烷基、噻唑。
- 根據請求項3所述的化合物,其特徵在於,R 10、R 11中至少有一個為H。
- 根據請求項1所述的化合物,其特徵在於,具有式IV、IV’或IV’’所示結構或其異構體、互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式、藥學上可接受的水合物、溶劑化物或鹽: 、 、 其中, A 1選自N或-CR 1;R 15、R 16分別獨立選自氫、C1-C3烷基,進一步選自氫、甲基; R 17選自C1-C5的醯胺基、含有內醯胺的四元或五元雜環,至少含有羥基或氨基取代的C1-C5烷基,或者R 15、R 16其中之一與R 17及其相連的原子組成 ,Z 3選自0、1或2;R 17進一步選自C1-C3的醯胺基、含有內醯胺的四元或五元雜環,至少含有羥基或氨基取代的C1-C3烷基,或者R 15、R 16其中之一與R 17及其相連的原子組成 ,Z 3選自0、1或2; R 19選自 、 ,R 13、R 14分別獨立選自氫、醯基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜環烷基、取代或非取代的雜芳基,Z 1、Z 2分別獨立為1-5;進一步地,R 13、R 14分別獨立選自氫、醯基、 、C1-C5烷基或環烷基、噻唑。
- 根據請求項3所述的化合物,其特徵在於,R 6、R 7分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、酯基、醯基、羧基、醯胺基、磺醯基、磺醯胺基、硼酸基、硼酸酯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基; 其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、3~6元環烷基、2~7元雜烷基、3~6元雜環烷基、氰基、酯基、醯基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基。
- 根據請求項13所述的化合物,其特徵在於,R 6、R 7分別獨立選自氫、鹵素、羥基、氰基、氨基、取代或非取代的C1~C6烷基、取代或非取代的3~10元環烷基、取代或非取代的2~7元雜烷基、取代或非取代的3~10元雜環烷基、酯基、醯基、磷醯基、取代或非取代的烯基、取代或非取代的炔基; 其中,取代基選自鹵素、羥基、氨基、C1~C6烷基、2~7元雜烷基、氰基、酯基、醯基、醯胺基、芳基、雜芳基、磺醯基、磺醯胺基; 進一步地,R 6、R 7分別獨立選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的環丙基,R 6、R 7不同時為H; 更進一步地,R 6、R 7分別獨立選自氫、鹵素、三氟甲基、取代或非取代的環丙基,R 6、R 7不同時為H。
- 根據請求項3任意一項所述的化合物,其特徵在於,R 8、R 9分別獨立選自氫、鹵素、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基、羥基、氰基、氨基、酯基、醯基、醯胺基、磺醯胺基,其中,取代基選自氘、烷基、雜烷基、環烷基、雜環烷基、鹵素、羥基、氰基、氨基、醯基、磺醯胺基。
- 根據請求項15所述的化合物,其特徵在於,R 8、R 9分別獨立選自氫、鹵素、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基,其中,取代基選自氘、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、鹵素、羥基、醯胺基; 進一步地,R 8、R 9分別獨立選自氫、鹵素、取代或非取代C1~C6烷基、取代或非取代C1~C6烷氧基,其中,取代基選自氘、鹵素、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、羥基、醯胺基。
- 根據請求項16所述的化合物,其特徵在於,R 8選自鹵素、取代或非取代的C1~C3烷基、取代或非取代C1~C3烷氧基;優選取代或非取代的C1~C3烷基;更優選甲基; R 9選自鹵素、甲基、三氟甲基、取代或非取代烷氧基;優選F、Cl、Br、甲基、三氟甲基、甲氧基、三氟甲氧基;更優選F。
- 根據請求項18所述的化合物,其特徵在於,R 1選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的2~4元雜烷基;其中,取代基選自鹵素、羥基、氨基、C1~C3烷基、2~4元雜烷基、醯基; 進一步地,R 1選自氫、鹵素,優選H,F。
- 根據請求項1、2或18任意一項所述的化合物,其特徵在於:n為1或2,每一個R 2獨立選自氫、鹵素、取代或非取代的C1~C3烷基、取代或非取代的環丙基;進一步地,每一個R 2獨立選自氫、鹵素、三氟甲基、取代或非取代的環丙基;當n為1時,R 2不為H;n為2時,兩個R 2不同時為H。
- 根據請求項1、2或18任意一項所述的化合物,其特徵在於:m為2或3,每一個R 3分別獨立選自鹵素、取代或非取代的烷基、取代或非取代的環烷基、取代或非取代的雜烷基、取代或非取代的雜環烷基,其中,取代基選自氘、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、鹵素、羥基、醯胺基;每個R 3不同。 進一步地,每一個R 3分別獨立選自氫、鹵素、取代或非取代C1~C6烷基、取代或非取代C1~C6烷氧基,其中,取代基選自氘、鹵素、C1~C6烷基、2~7元雜烷基、3~6元環烷基、3~6元雜環烷基、羥基、醯胺基; 更進一步地,每一個R 3分別獨立選自鹵素、取代或非取代的C1~C3烷基、取代或非取代C1~C3烷氧基。
- 根據請求項3所述的化合物,其特徵在於:所述鹵素選自F、Cl、Br;取代或非取代的C1~C3烷基選自甲基、三氟甲基;取代或非取代C1~C3烷氧基選自甲氧基、三氟甲氧基。
- 一種藥用組合物,其特徵在於,該藥用組合物活性成份選自請求項1~25任一請求項所述的化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶中的一種或兩種以上的組合。
- 請求項1~23任意一項所述化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備鈉離子通道調節劑中的用途;進一步地,所述鈉離子通道調節劑為Nav1.8抑制劑。
- 請求項1~23任意一項所述化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備治療致使Nav1.8過度表達的疾病的藥物中的用途。
- 請求項1~23任意一項所述化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備治療Nav1.8過度表達所致疾病的藥物中的用途。
- 請求項1~23任意一項所述化合物或其立體異構體、溶劑化物、水合物、藥學上可接受的鹽或共晶在製備用於治療慢性疼痛、腸痛、神經性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原發性疼痛、多發性硬化症、恰克-馬利-杜斯氏症、失禁和心律失常中的任意一種或多種疾病的藥物中的用途。
- 根據請求項28所述的用途,其特徵在於,所述神經性疼痛選自皰疹後神經痛、糖尿病性神經痛、痛性HIV相關性感覺神經病、三叉神經痛、口腔灼熱症候群、截肢術後疼痛、幻痛、痛性神經瘤、創傷性神經瘤、莫頓氏神經瘤、神經擠壓損傷、脊管狹窄、腕隧道症候群、神經根痛、坐骨神經痛、神經撕脫傷、臂叢神經損傷、複雜性局部疼痛症候群、藥物療法引起的神經痛、癌症化學療法引起的神經痛、抗逆轉錄病毒療法引起的神經痛、脊髓損傷後疼痛、原發性小纖維神經病、原發性感覺神經病、三叉自主神經性頭痛中的一種或幾種; 所述肌肉骨骼痛選自骨關節炎疼痛、背痛、冷痛、燒傷疼痛、牙痛中的一種或幾種; 所述炎性疼痛痛選自類風濕性關節炎疼痛和/或外陰痛; 所述原發性疼痛選自纖維肌痛
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