TWI385174B - 作為酪胺酸激酶抑制劑之稠合雙環及多環嘧啶化合物 - Google Patents
作為酪胺酸激酶抑制劑之稠合雙環及多環嘧啶化合物 Download PDFInfo
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- TWI385174B TWI385174B TW098137894A TW98137894A TWI385174B TW I385174 B TWI385174 B TW I385174B TW 098137894 A TW098137894 A TW 098137894A TW 98137894 A TW98137894 A TW 98137894A TW I385174 B TWI385174 B TW I385174B
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- compound
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- heteroaryl
- aryl
- heterocycloalkenyl
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- C07D513/04—Ortho-condensed systems
Description
本發明係關於一種式(I)之稠合雙環或多環化合物,尤指一種適用於抑制EGFR激酶活性、治療癌症之稠合雙環或多環化合物。
本案根據主張2008年11月10日申請之美國臨時申請案第61/112,865號,其中全部內容合併於此以供參酌。
於細胞內調節各種不同功能(如分化、增生、遷移及凋亡)的訊息途徑中,蛋白質激酶扮演重要的角色。由於蛋白質激酶失去調節作用時牽涉許多疾病(包含癌症),因此蛋白質激酶在癌症治療上成為飽受注目的治療目標。
表皮生長因子受體(Epidermal growth factor receptor,EGFR)屬於四個關係相近的受體酪胺酸激酶(EGFR、HER2、HER3及HER4)其中一亞類,當EGF配位體與EGFR胞外區域結合時,會活化胞內蛋白質-酪胺酸激酶活性,因此在EGFR之C端區域會有幾個酪胺酸發生自體磷酸化。(Kamath,S.,Buolamwini,J.K.,Med. Res. Rev.
2006,26
,569-594)
已知EGFR訊息傳導的失調,牽涉許多癌症發展,例如膀胱癌、乳癌、結腸癌及肺癌,因此數個EGFR激酶抑制劑如吉非替尼(Gefitinib)及埃羅替尼(Erlotinib),已用於治療癌症,尤其是非小細胞肺癌(Non-Small Cell Lung cancer,NSCLC)。不過,大部分因為EGFR激酶中第790個蘇胺酸突變成甲硫胺酸(T790M),所以只有10至20%的NSCLC患者對於吉非替尼的治療有反應,也因此EGFR激酶抑制劑,尤其是可以抑制EGFR突變體(例如T790M突變體)活性的抑制劑,其作為抗癌藥物的發展受到高度關注。
本發明非預期的發現某種稠合雙環或多環化合物可用來抑制EGFR激酶(如RGFR T790M突變體),使得這些化合物能夠應用於治療癌症(例如NSCLC)。
在一態樣中,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;A為烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、矽烷基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為,其中p為0、1或2,q為1或2,Z為O、S或NH,W為CH2
或NR5
,其中R5
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Ra
、C(O)C(O)Ra
、C(O)ORa
、C(O)NRa
Rb
或SO2
Ra
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R6
、R7
、R8
、R9
、R10
及R11
各自為氫、烷基或鹵素。本發明尤其關於一種式(II)之稠合雙環或三環化合物:
上述化合物其中之一子集,包括以下化合物:W為NR5
,R5
為SO2
Ra
、,其中R6
及R7
分別為H、選擇性經烷胺基(如二烷胺)取代之烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
或CH2
NRc
Rd
,其中Rc
及Rd
分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc
及Rd
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R8
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。在這些化合物中,A可為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基,或者A可為C(O)OR3
;B可為苯基;m可為0或1;n可為0;X可為N;Y可為NH;或Z可為S。
上述化合物之另一子集,包括以下化合物:W為CH2
。在這些化合物中,A可為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基,或者A可為C(O)OR3
;B可為苯基;m可為0或1;n可為0;X可為N;Y可為NH;或Z可為S。
「烷基」一詞係指直鏈或支鏈之單價碳氫基團,其包含1-20個碳原子(如:C1
-C10
),烷基舉例包括但不限於:甲基、乙基、正丙基、異丙基、正丁基、異丁基及第三丁基。「烯基」一詞係指直鏈或支鏈之單價碳氫基團,其包含2-20個碳原子(如:C2
-C10
)及一個以上的雙鍵,烯基舉例包括但不限於:乙烯基、丙烯基及烯丙基(allyl)。「炔基」一詞係指直鏈或支鏈之單價碳氫基團,其包含2-20個碳原子(如:C2
-C10
)及一個以上的參鍵,炔基舉例包括但不限於:乙炔基、1-丙炔基、1-及2-丁炔基、及1-甲基-2-丁炔基。「烷胺基」一詞係指-N(R)-烷基,其中R可為H、烷基、烯基、炔基、環烷基、環烯基、雜環烷基、雜環烯基、芳基或雜芳基。
「環烷基」一詞係指單價飽和碳氫環結構,其具有3至30個碳原子(如:C3
-C12
),環烷基舉例包括但不限於:環丙基、環丁基、環戊基、環己基、環庚基及環辛基。「環烯基」一詞係指單價非芳香性碳氫環結構,其具有3至30個碳原子(如:C3
-C12
)及一個以上的雙鍵,舉例包括:環戊烯基、環己烯基及環庚烯基。「雜環烷基」一詞係指單價非芳香性5-8員單環結構、8-12員雙環結構或11-14員三環結構,其具有一個以上的雜原子(如O、N、S或Se),雜環烷基舉例包括但不限於:哌嗪基(piperazinyl)、吡咯烷基(pyrrolidinyl)、二噁烷基(dioxanyl)、嗎啉基(morpholinyl)及四氫呋喃基(tetrahydrofuranyl)。「雜環烯基」一詞係指單價非芳香性5-8員單環結構、8-12員雙環結構或11-14員三環結構,其具有一個以上的雜原子(如O、N、S或Se)及一個以上的雙鍵。
「芳基」一詞係指單價C6
單環狀、C10
雙環狀、C14
三環狀芳香環結構,芳基舉例包括但不限於:苯基、萘基及蒽基。「雜芳基」一詞係指單價芳香性5-8員單環、8-12員雙環或11-14員三環結構,其具有一個以上的雜原子(如O、N、S或Se),雜芳基舉例包括但不限於:吡啶基(pyridyl)、呋喃基(furyl)、咪唑基(imidazolyl)、苯並咪唑基(benzimidazolyl)、嘧啶基(pyrimidinyl)、噻吩基(thienyl)、喹啉基(quinolinyl)、吲哚基(indolyl)及噻唑基(thiazolyl)。
上述之烷基、烯基、炔基、環烷基、雜環烷基、環烯基、雜環烯基、烷胺基、芳基及雜芳基,包括經取代及未經取代之兩種基團。在烷胺基、環烷基、雜環烷基、環烯基、雜環烯基、芳基及雜芳基上之可能的取代基,舉例包括但不限於:C1
-C10
烷基、C2
-C10
烯基、C2
-C10
炔基、C3
-C20
環烷基、C3
-C20
環烯基、C1
-C20
雜環烷基、C1
-C20
雜環烯基、C1
-C10
烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1
-C10
烷胺基、芳胺基、羥基、鹵素、氧代(O=)、硫代(S=)、硫基(thio)、矽烷基(silyl)、C1
-C10
烷硫基、芳硫基、C1
-C10
烷磺醯基(alkylsulfonyl)、芳磺醯基(arylsulfonyl)、醯基胺(acylamino)、胺基醯(aminoacyl)、胺基硫醯(aminothioacyl)、脒基(amidino)、硫醇基(mercapto)、醯胺基(amido)、硫脲基(thioureido)、硫氰酸基(thiocyanato)、磺醯胺基(sulfonamido)、胍基(guanidine)、脲基(ureido)、氰基、硝基、醯基、硫醯基、醯氧基(acyloxy)、脲基(carbamido)、氨甲醯基(carbamyl)、羧基(carboxyl)及羧酸酯基。另一方面,在烷基、烯基或炔基上之可能取代基,包括C1
-C10
烷基除外之上述所有取代基。環烷基、環烯基、雜環烷基、雜環烯基、芳基及雜芳基亦可互相稠合。
在另一態樣中,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;A為烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、矽烷基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為 ,其中R’及R”各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、氰基、ORa
、ORa
O、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,Z為O或NH,但R’及R”中最多一者為H,且W為N或CR5
,其中R5
為烯基、炔基、經ORa
、ORa
O或NRb
C(O)Ra
取代之芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
。尤其,該化合物係如式(II)所示:
上述化合物其中之一子集,包括以下化合物:R’為,其中R6
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
或CH2
NRc
Rd
,其中Rc
及Rd
分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc
及Rd
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。這些化合物中,A可為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基;B可為苯基;m可為1;n可為0;X可為N;Y可為NH;或Z可為O。
該些化合物其中之另一子集,包括以下化合物:B為苯基且n為0。在些化合物中,A可為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基,或者A可為C(O)OR3
;m可為0或1;X可為N;Y可為NH;Z可為O,W可為CR5
,其中R5
為鹵素;或R’及R”各自可為ORa
。
於再一態樣中,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;A為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為
其中R’及R”各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、氰基、ORa
、ORa
O、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,Z為O或NH,且W為N或CR5
,其中R5
為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
。尤其,該化合物係如式(II)所示:
於再另一態樣中,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;當X為N時,A為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、矽烷基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;且當X為CR1
時,A為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為 ,其中R’及R”各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、氰基、ORa
、ORa
O、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,Z為S,且W為N或CR5
,其中R5
為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
。尤其,該化合物係如式(II)所示:
更進一步,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;A為烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、矽烷基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為,其中R’及R”各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、硝基、氰基、ORa
、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,但R’及R”中至少一者為NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
或NHSO2
Ra
。尤其,該化合物係如式(II)所示:
上述化合物其中之一子集,包括以下化合物:R’為,其中R6
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
或CH2
NRc
Rd
,其中Rc
及Rd
分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc
及Rd
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。在這些化合物中,A可為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基,或A可為C(O)OR3
;B可為苯基;m可為0或1;或n可為0。
於更佳另一態樣中,本發明關於一種式(I)之稠合雙環或多環化合物:
在式(I)中,X為N或CR1
,其中R1
為CN、CONH2
、鹵素或H;Y為O、S或NR2
,其中R2
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基;當X為N時,A為烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
,其中R3
及R4
各自為H、烷基、烯基、炔基、矽烷基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者R3
及R4
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基;且當X為CR1
時,A為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、氰基、硝基、OR3
、OC(O)R3
、C(O)R3
、C(O)OR3
、C(O)NR3
R4
、NR3
R4
、NHC(O)R3
、NHC(O)NR3
R4
、NHC(S)R3
、NHC(O)OR3
、SO2
R3
、SO3
R3
或SO2
NR3
R4
;B為芳基或雜芳基;m及n各自為0、1或2;以及C環為,其中R’為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、硝基、氰基、ORa
、ORa
O、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
,其中Ra
及Rb
各自為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Ra
及Rb
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,Z為O或S,且W為N或CR5
,其中R5
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、鹵素、硝基、C(O)ORa
、C(O)NRa
Rb
、NRb
C(O)Ra
、NHC(O)NRa
Rb
、NRb
C(S)Ra
、NHSO2
Ra
或NRa
Rb
。尤其,該化合物係如式(II)所示:
上述化合物其中之一子集,包括以下化合物:m為1且A為OR3
,R3
為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3
烷基。在這些化合物中,R’為或,其中R6
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc
、C(O)ORc
、C(O)NRc
Rd
或CH2
NRc
Rd
,其中Rc
及Rd
分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc
及Rd
與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7
為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。
如果可以實施的話,上述稠合雙環或多環化合物不僅包括化合物本身,也包括其鹽類、其溶劑化物、以及其前驅藥。舉例而言,稠合雙環或多環化合物上帶有正電之基團(例如胺基),可與陰離子形成鹽類,而適合的陰離子包含氯離子、溴離子、碘離子、硫酸根、硫酸氫根、磺胺酸根、硝酸根、磷酸根、檸檬酸根、甲磺酸根、三氟乙酸根、穀胺酸根、醛糖酸根、戊二酸根、蘋果酸根、馬來酸根、琥珀酸根、延胡索酸根、酒石酸根、甲苯磺酸根、水楊酸根、乳酸根、萘磺酸根及乙酸根。同樣,稠合雙環或多環化合物上帶有負電之基團(例如羧酸根),可與陽離子形成鹽類,而適合的陽離子包含鈉離子、鉀離子、鎂離子、鈣離子及銨離子(如四甲基銨離子),而稠合雙環或多環化合物亦包含那些含有四級氮原子的鹽類。前驅藥形式舉例包含:酯類及其他醫藥上可接受之衍生物,根據給主體的投藥方式,其能夠提供活性稠合雙環或多環化合物。
本發明亦關於一種抑制EGFR激酶(或其他如ERBB2激酶之酪胺酸激酶)活性的方法,其經由將有效劑量之上述一種以上稠合雙環或多環化合物,與表現蛋白質激酶的細胞接觸,此細胞可為腫瘤細胞或過度表現蛋白質激酶的細胞。
此外,本發明涵蓋一種治療EGFR激酶引導的病症(或其他如ERBB2激酶之酪胺酸激酶引導的病症)如癌症之方法,透過將一有效劑量之一種以上前述稠合雙環或多環化合物,投予一所需之主體。
含上述一種上述稠合雙環或多環化合物且用於治療癌症(如NSCLC)的醫藥組成物、此治療用途、以及使用該些化合物製造治療癌症藥劑的用途,同樣在本發明的範疇中。
(S
)-2-(5,6-二甲基噻吩并[2,3-d
]嘧啶-4-基胺基)-2-苯基乙醇((S
)-2-(5,6-dimethylthieno[2,3-d
]pyrimidin-4-ylamino)-2-phenylethanol)、(S
)-2-(5-甲基噻吩并[2,3-d
]嘧啶-4-基胺基)-2-苯基乙醇((S
)-2-(5-methylthieno[2,3-d
]pyrimidin-4-ylamino)-2-phenylethanol)、(S
)-2-苯基2-(噻吩并[2,3-d
]嘧啶-4-基胺基)乙醇((S
)-2-phenyl-2-(thieno[2,3-d
]pyrimidin-4-ylamino)ethanol)及其類似物,以及如前述之治療用途,同樣在本發明範疇。
本發明於後文將提出一個以上的詳細實施例,由此描述及申請專利範圍將更為了解本發明的其他特徵、目的、以及優點。
以下所示為本發明示例性化合物。
本發明的稠合雙環或多環化合物,可使用已知化學轉變方法(包括保護基方法論)進行製備,例如R. Larock,Comprehensive Organic Transformations
,VCH Publishers (1989);T.W. Greene及P.G.M. Wuts,Protective Groups in Organic Synthesis
,3rd
Ed.,John Wiley and Sons(1999);L. Fieser及M. Fieser,Fieser and Fieser’s Reagents for Organic Synthesis
,John Wiley and Sons(1994);以及L. Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis
,John Wiley and Sons(1995)及其後續版本中所述。以下流程1至4表示合成本發明化合物的轉變過程。
流程1所示的途徑舉例出本發明噻吩并嘧啶化合物(VII)的合成。將三乙胺加入經適當取代的酮類(I)、丙二腈(II)及硫(S8
)之絕對酒精混合液中,所得的混合液迴流16小時後濃縮,殘餘物以水及乙酸乙酯分層萃取,濃縮有機層後所得的殘餘物以矽膠色層分析法純化,以獲得噻吩化合物(III)。而後,將HCl加入噻吩(III)及甲酸之混合液中,所得的混合液迴流16小時後,加入水並將所形成的沉澱物過濾,以得到噻吩并嘧啶酮(IV)。IV及POCl3
的混合物在55-65℃下加熱3小時,然後加入水,接著加入碳酸氫鈉中和酸,使用乙酸乙酯萃取混合液,濃縮經分離的有機層,殘餘物以管柱色層分析法純化,以獲得經氯取代之噻吩并嘧啶酮(V)。將V與適當的胺類(VI)於正丁醇中加熱16小時,則可獲得所需之經取代的噻吩并嘧啶(VII)。
本發明之噻吩并嘧啶(XVI)可如流程2所示,將途徑稍經修改來合成。在鹼性環境下以Boc保護哌啶-4-酮(VIII),產物與丙二腈及硫反應,以形成噻吩環。將X與乙酸甲脒在DMF、100℃下進行環化反應,可獲得噻吩并嘧啶酮XI,再將XI與POCl3
反應,以得到經氯取代之噻吩并嘧啶(XII),其經由與適當的胺類(VI)於熱正丁醇中反應則可轉換成經取代之噻吩并嘧啶(XIII),於二噁烷中持續16小時使用HCl移除XIII中之Boc保護基,則可獲得化合物XIV。在DMF中使用HOBt及EDC,將XIV與適當的酸類XV進行醯胺偶合反應,後續接著進行標準流程,則可得到所需的產物XVI。
流程3所示的途徑舉例出本發明呋喃并嘧啶化合物(XXI)的合成。在30分鐘內,於0℃下將二乙胺逐漸滴入經適當取代的安息香(XVII)及丙二腈(II)之DMF混合液中,所得的混合液持續攪拌16小時後,加入水並將所形成的沉澱物利用過濾收集,並在乙醇中結晶以得到經取代之呋喃(XVIII)。在30分鐘內,於0℃下將乙酸酐逐漸滴入XVIII及甲酸之混合液中,所得的混合液100℃下加熱16小時,然後加入水,沈澱物生成並過濾得呋喃并嘧啶酮(XIX)。將XIX與POCl3
的混合物在55-65℃下加熱3小時,然後加入水,接著加入碳酸氫鈉,再使用乙酸乙酯萃取所得的混合液,而後濃縮有機層,殘餘物以管柱色層分析法純化,以獲得經氯取代之呋喃并嘧啶(XX)。將XX與適當的胺類(VI)於熱正丁醇中加熱16小時,則可獲得所需之經胺基取代的呋喃并嘧啶(VII)。
本發明呋喃并嘧啶化合物可使用其他方法合成,以下流程4舉例出另一種合成途徑。於DMF中使用N
-溴琥珀醯亞胺(N
-bromosuccinimide,NBS),讓經氯取代之呋喃并嘧啶(XX)進行溴化反應,可獲得經溴、氯取代之呋喃并嘧啶(XXII),或者使用N
-氯琥珀醯亞胺(N
-chlorosuccinimide,NCS)獲得對應XXII的二氯衍生物。在正丁醇中加熱使XXII與適當的胺類(VI)進行反應,可獲得經溴、胺取代之呋喃并嘧啶(XXIII),然後將化合物XXIII與適當的硼酸在標準鈴木偶合條件(Pd(OAc)2
、PPh3
及碳酸鈉於水及二噁烷混合液中持續迴流2-3小時)下進行反應,則可合成本發明呋喃并嘧啶化合物(XXIV)。
本發明的稠合雙環或多環化合物,以類似於流程1至4所列出的方法,加上本領域通常知識者可得知之所需修飾則可合成。
如此合成所得之稠合雙環或多環化合物,更可經由快速管柱層析、高效液相層析、結晶或任何其他適合的方法來進行純化。
本文所述之化合物可含非芳香性雙鍵及一個以上不對稱中心,因此其能以外消旋物(racemates)及消旋混合物(racemic mixtures)、單一鏡像異構物、個別非鏡像異構物、非鏡像體混合物、以及順式或反式異構物的形式存在,所以所有異構物皆考慮其內。
在本發明範疇內,也包含(1)一種醫藥組成物,其含有效劑量之至少一種本發明稠合雙環或多環化合物、與醫藥可接受載體,以及(2)一種治療癌症之方法,其係透過將有效劑量之這種稠合雙環或多環化合物,投予須此治療之主體。
於此所使用之「治療」一詞,係指將稠合雙環或多環化合物,投予具有癌症、癌症之症狀或朝癌症發展之傾向的主體,以期達到治療、治癒、減輕、緩和、改變、補救、改良、改善或影響癌症、癌症之症狀或朝癌症之發展。「有效劑量」一詞係指活性藥劑能夠對於治療主體產生預期療效所需的劑量,對於有效劑量,本領域具有通常知識者可了解到其會根據投藥路徑、使用賦形劑、以及與其它藥劑共同使用的可能性而改變。
可經由本發明方法治療的癌症,包含各種器官的實體或血液腫瘤兩者,其中實體腫瘤舉例包含:胰腺癌;膀胱癌;大腸直腸癌;乳癌,包括轉移性乳腺癌;***癌,包含雄激素依賴性和非雄激素依賴性***癌症;腎癌,包括如轉移性腎細胞癌;肝癌;肺癌,包括如非小細胞肺癌(non-small cell lung cancer,NSCLC)、細支氣管肺泡癌(bronchioloalveolar carcinoma,BAC)、和肺腺癌;卵巢癌,包括如進行性上皮或原發性腹膜癌;子宮頸癌;胃癌;食道癌;頭頸部癌,包括如頭頸部之鱗狀細胞癌;黑色素瘤;神經內分泌癌,包括轉移性神經內分泌腫瘤;腦腫瘤,包括如神經膠瘤、退行性寡樹突神經膠瘤、多型性成人神經膠母細胞瘤及成人退化性星細胞瘤;骨癌;以及來自軟組織腫瘤。血液惡性腫瘤舉例包括:急性骨髓性白血病(AML);慢性骨髓性白血病(CML),包括加速性CML和爆發階段的CML(CML-BP);急性淋巴母細胞性白血病(ALL);慢性淋巴母細胞性白血病(CLL);霍奇金氏病(Hodgkin’s disease,HD);非霍奇金氏病(non-Hodgkin’s lymphoma,NHL),包括濾泡型淋巴瘤及外套細胞淋巴瘤;B細胞淋巴瘤;T細胞淋巴瘤;多發性骨髓瘤(multiple myeloma,MM);華爾登氏巨球蛋白血症(Waldenstrom’s macroglobulinemia);骨髓增生不良症候群(myelodysplastic syndromes,MDS),包括頑抗性貧血(refractory anemia,RA)、伴有環狀含鐵胚細胞之頑抗性貧血(refractory anemia with ringed siderblasts,RARS)、伴有過多胚細胞之頑抗性貧血(refractory anemia with excess blasts,RAEB)、及轉變中的RAEB(RAEB-T);以及骨髓增生性症候群。使EGFR激酶活性向上調節或調節異常的其他癌症種類,列於Exp. Mol. Pathol
.,2008,84(2):79-89以及Crit. Rev. Oncol. Hematol
.,1995,19,183。
本發明的化合物可與細胞毒性劑、放射性治療或免疫性治療劑所組群組之治療劑一起進行投藥,適合與本發明蛋白質激酶抑制劑一起使用的細胞毒性劑,其非限定舉例包括:抗代謝藥物(antimetabolites),包含如卡培他濱(capecitibine)、吉西他濱(gemcitabine)、5-氟尿嘧啶(5-fluorouracil)或5-氟尿嘧啶/白葉酸(leucovorin)、氟達拉濱(fludarabine)、***糖基胞嘧啶(cytarabine)、巰基嘌呤(mercaptopurine)、硫代鳥嘌呤(thioguanine)、噴司他丁(pentostatin)和胺甲葉酸(methotrexate);拓蹼異構酶(topoisomerase)抑製劑,包括如依妥普賽(etoposide)、坦尼坡賽(teniposide)、喜樹鹼(camptothecin)、拓蹼替康(topotecan)、伊立替康(irinotecan)、阿德力黴素(doxorubcin)和道諾魯比辛(daunorubicin);長春花生物鹼(vinca alkaloid),包括如長春新鹼(vincristine)和長春鹼(vinblastin);紫杉烷類(taxanes),包括如紫杉醇(paclitaxel)和多西紫杉醇(docetaxel);鉑劑(platinum agents),包括如順鉑(cisplatin)、卡鉑定(carboplatin)和奧沙利鉑(oxaliplatin);抗生素(antibiotics),包括如放線菌素D(actinomycin D)、博來黴素(bleomycin)、絲裂黴素C(mitomycin C)、阿黴素(adriamycin)、道諾魯比辛(daunorubicin)、艾達魯比辛(idarubicin)、阿德力黴素(doxorubicin)和聚乙二醇脂質體阿德力黴素(pegylated liposomal doxorubicin);烷基化劑(alkylating agents),如黴法蘭(melphalan)、氮芥苯丁酸(chlorambucil)、硫酸布他卡因(busulfan)、沙奧特帕(thiotepa)、依弗醯胺(ifosfamide)、卡氮芥(carmustine)、環己亞硝(lomustine)、司莫司汀(semustine)、鏈球黴素(streptozocin)、達卡巴仁(decarbazine)和環磷醯胺(cyclophosphamide);沙利竇邁(thalidomide)和相關類似物,包括如CC-5013和CC-4047;蛋白酪胺酸激酶抑製劑,包括如甲磺醯伊麻替尼普(imatinib mesylate)和吉非替尼(gefitinib);抗體,包括如曲妥珠單抗(trastuzumab)、利妥西單抗(rituximab)、西妥昔單抗(cetuximab)和貝伐珠單抗(bevacizumab);邁杜蔥酮(mitoxantrone);***(dexamethasone);普賴松(prednisone);以及替莫唑胺(temozolomide)。
為實行本發明所述之方法,上述醫藥組成物可經由口服、非口服、噴霧吸入、局部、經直腸、經鼻、舌下、***或經由植入型藥盒(implanted reservoir)等方式投藥。於此使用之「非口服」(“parenteral”)係指皮下注射、皮內注射、靜脈內注射、肌肉內注射、關節腔內注射、動脈內注射、關節液內注射、胸腔內注射、脊髓內注射、疾病部位內注射、及顱內注射或注入技術。
無菌可注射之組成物,例如無菌可注射水性或油性懸浮液,可根據本領域已知技術,使用適合的分散劑或濕潤劑(如Tween 80)及懸浮劑來配製。無菌可注射之配製液可為無菌可注射的溶液或是懸浮於無毒的非口服注射稀釋液或溶劑中,例如1,3-丁二醇的溶液。可使用之可接受載體及溶劑為甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)或等滲透之氯化鈉溶液。除此之外,非揮發油係習用之溶劑或是懸浮介質(例如:合成單甘油酯或雙甘油酯)。脂肪酸如油酸(oleic acid)與其甘油酯衍生物,亦可用於製備注射劑;天然醫藥可接受之用油,例如橄欖油或篦麻油,特別是其多氧乙基化之型態,同樣可用於製備。這些油酯溶液或懸浮液,可包含長鏈醇類稀釋液或分散劑、羧甲基纖維素或類似之分散劑。其他常用之界面活性劑,如Tween或Spans或其他類似乳化劑或一般醫藥製造業所使用於醫藥可接受之固態、液態或其他可用於劑型開發目的之劑量型式之生物可利用增強劑。
用於口服投藥之組成物可為任何一種口服可接受之劑型,包括膠囊、錠片、乳化液與水懸浮液、分散液與溶液,但不限於此。以錠片為例,一般所使用之載體為乳糖或是玉米澱粉,潤滑劑(如硬脂酸鎂)亦常被添入其中。以口服膠囊投藥型式而言,可用的稀釋劑包括乳糖與乾燥玉米澱粉。當以水懸浮液或乳化液經口投藥時,活性成分可懸浮或是溶解於混有乳化劑或懸浮劑之油狀界面中。如果需要,可添加適度的甜味劑、風味劑或是色素。鼻用氣化噴霧劑或吸入劑組成物,可根據醫藥劑型領域中已知技術進行製備。例如,此組成物可製備為鹽溶液,應用苯甲醇(benzyl alcohol)或其他適合的防腐劑、增強生物可利用性之促吸收劑、碳氟化合物、及/或該領域中其他技藝中已知之溶解劑或分散劑。含稠合雙環或多環化合物之組成物,亦可以栓劑方式進行直腸投藥。
醫藥組成物之載體必須為「可接受性」,即其必須與組成物之活性主成份相容(較佳係能穩定活性主成份),並且不能對被治療之試體造成傷害。例如,一種或多種能與稠合雙環或多環化合物形成溶解性更佳的複合物的溶解劑,也可用為傳遞活性稠合雙環或多環化合物之醫藥載體。其他載體舉例包括膠質氧化矽、硬脂酸鎂、纖維素、月桂硫酸鈉與D&C黃色10號。
對於本發明稠合雙環或多環化合物抑制EGFR激酶活性的效果,可使用適合的體外(in vitro
)分析初步進行評估,更可在體外(in vitro
)及/或體內(in vivo
)審查化合物對於癌症的治療效果。舉例而言,可測試化合物,以得知其對於癌細胞生長(如HCC827細胞株的生長抑制分析)的抑制效果,或者可在罹癌動物(如老鼠模式)中投遞化合物,然後評估其療效。基於這些結果,可同時決定適合的劑量範圍以及投藥途徑。
上述已經足以實施本發明,而無需更多的闡述,因此下列特定具體實施例僅解釋為說明性,無論以任何方式皆不限制本發明其餘揭示範圍,並將本文所引述之所有發表文獻及專利申請案全部併入本文以供參考。
2-胺基-(4,5,6,7-四氫-苯并[ b ]噻吩-3-基氰(2-amino-4,5,6,7-tetrahydrobenzo[ b ]thiophen-3-yl cyanide)
(步驟a):將三乙胺(2mL)加入環己酮(1.18g)、丙二腈(0.66g)及硫(0.40g)之絕對酒精(3ml)混合液中,迴流16小時後,濃縮反應混合液,殘餘物以水及乙酸乙酯分層萃取,濃縮有機層並以矽膠管柱色層分析法使用己烷:乙酸乙酯(4:1)之混合液純化粗萃化合物,則可得標題化合物(0.94g,44%)。
3,4,5,6,7,8-六氫苯并[4,5]噻吩并[2,3- d ]嘧啶-4-酮(3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3- d ]pyrimidin-4-one)
(步驟b):將0.1mL濃縮HCl加入2-胺基-(4,5,6,7-四氫-苯并[b
]噻吩-3-基氰(0.9g)及甲酸(10mL)之混合液中,迴流16小時後,冷卻反應混合液並加入水(20mL),透過過濾收集沉澱物,以水及己烷清洗完全後則得標題化合物(0.8g,77%)。1
H NMR(300MHz,CDCl3
):δ7.91(s,1H),3.03-3.00(m,2H),2.80-2.77(m,2H),1.89-1.83(m,4H)。
4-氯-5,6,7,8-四氫苯并[4,5]噻吩并[2,3- d ]嘧啶(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d ]pyrimidine)
(步驟c):將3,4,5,6,7,8-六氫苯并[4,5]噻吩[2,3-d
]嘧啶-4-酮(0.8g)及POCl3
(10ml)之混合液於55-65℃下加熱3小時,加入水後接著加入碳酸氫鈉,所得的混合液以乙酸乙酯萃取後,濃縮有機層並以矽膠管柱色層分析法使用己烷:乙酸乙酯(20:1)之混合液純化粗萃化合物,則可得標題化合物(0.52g,60%)。1
H NMR(300MHz,CDCl3
):δ8.69(s,1H),3.10-3.07(m,2H),2.88-2.86(m,2H),1.89-1.92(m,4H)。LC-MS(ESI)m/z
225.3(M+H)。
S -2-苯基-2-(5,6,7,8-四氫-苯并[4,5]噻吩并[2,3- d ]嘧啶-4-基胺基)-乙醇( S -2-phenyl-2-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3- d ]pyrimidin-4-ylamino)-ethanol)
(化合物1,步驟d):將4-氯-5,6,7,8-四氫苯并[4,5]噻吩并[2,3-d
]嘧啶(1g)及S
-2-胺基-2-苯基-乙醇(0.672g,1.1當量)之正丁醇(1ml)混合液於80℃下加熱16小時後,濃縮反應混合液,殘餘物以水及二氯甲烷分層萃取,有機層以食鹽水清洗,再以MgSO4
乾燥後濃縮,最後以矽膠管柱色層分析法使用二氯甲烷:甲醇(30:1)之混合液純化粗萃化合物,則可得標題化合物(0.88g)。1
H NMR(400MHz,CDCl3
):δ8.20(s,1H),7.25-7.36(m,5H),6.14(d,1H),5.36(dd,1H,J
=9.6,5.6Hz),3.93-4.02(m,2H),2.81-2.99(m,2H),2.74(s,2H),1.80-1.96(m,4H)。LC-MS(ESI)m/z
326.1(M+H)。
化合物2-8、17-24、29、30、245及246以類似實施例1的方法進行製備。這些化合物之1
H NMR及MS數據列舉如下。
化合物2:1
H-NMR(400MHz,CDCl3
):δ8.20(s,1H),7.25-7.34(m,5H),6.11(d,1H,J
=6.4Hz),5.35-5.38(m,1H),3.93-3.99(m,2H),2.88-2.93(m,2H),2.73-2.76(m,2H),1.82-1.88(m,4H)。LC-MS(ESI)m/z
326.1(M+1)。
化合物3:1
H-NMR(400MHz,CDCl3
)δ2.48-2.55(m,2H),2.93-3.06(m,4H),3.83(brs,1H),4.00(dd,2H,J
=5.2,5.2Hz),5.34(ddd,1H,J
=5.2,5.2,5.2Hz),5.80(d,1H,J
=6.0Hz),7.29-7.40(m,5H),8.31(s,1H)。13
C-NMR(75MHz,CDCl3
)δ27.9(CH2
),28.9(CH2
),29.4(CH2
),57.1(CH),67.2(CH2
),113.4(C),126.4(CH),127.8(CH),128.9(CH),134.3(C),139.1(C),139.6(C),152.5(CH),156.3(C)。HRMS(EI)C17
H17
N3
OS(M+
)計算值:311.1092,實驗值311.1096。
化合物4:LC-MS(ESI)m/z
300.0(M+H)+
。
化合物5:LC-MS(ESI)m/z
286.0(M+H)+
。
化合物6:LC-MS(ESI)m/z
272.0(M+H)+
。
化合物7:LC-MS(ESI)m/z
348.0(M+H)+
。
化合物8:LC-MS(ESI)m/z
382.3(M+H)+
。
化合物17:1
H NMR(400MHz,CDCl3
):δ8.30(s,1H),7.445-7.48(m,1H),7.31-7.37(m,4H),6.41(d,1H,J
=6.4Hz),5.90(d,1H,6.4Hz),3.74(s,3H),3.00-3.04(m,2H),2.77-2.80(m,2H),1.18-1.95(m,4H)。LC-MS(ESI)m/z
354.2(M+H)。
化合物18:1
H NMR(300MHz,CDCl3
):δ9.00(s,1H),7.22~7.31(m,5H),5.78(s,1H),2.78~3.07(m,4H),1.84~2.01(m,4H)。
化合物19:LC-MS(ESI)m/z
340.0(M+H)+
。
化合物20:LC-MS(ESI)m/z
326.0(M+H)+
。
化合物21:LC-MS(ESI)m/z
376.0(M+H)+
。
化合物22:LC-MS(ESI)m/z
362.0(M+H)+
。
化合物23:1
H-NMR(400MHz,CDCl3
)δ0.94(t,3H,J
=4.0Hz),1.85-2.01(m,6H),2.76-2.78(m,2H),2.91-2.96(m,2H),5.31(q,1H,J
=4.0Hz),5.56(d,1H,J
=7.6Hz),7.21-7.23(m,1H),7.24--7.34(m,4H),8.31(s,1H)。HRMS(EI)C19
H21
N3
S(M+
)計算值323.1456,實驗值323.1452。
化合物24:LC-MS(ESI)m/z
324.0(M+H)+
。
化合物29:1
H-NMR(300MHz,CDCl3
)δ0.93(t,3H,J
=7.2Hz),1.42(s,9H),1.87-2.00(m,2H),2.98-3.00(m,2H),3.77-3.78(m,2H),4.62(s,2H),5.29(td,1H,J
=7.2,7.2Hz),5.41(d,1H,J
=7.2Hz),7.22-7.33(m,5H),8.33(s,1H)。LCMS(ESI)m/z
425.1[M+H]+
。
化合物30:LC-MS(ESI)m/z
346.0(M+H)+
。
化合物245:1
H NMR(400MHz,CDCl3
):δ:8.17(s,1H),8.08(br,1H),7.61(s,1H),7.41-7.37(m,3H),7.32-7.20(m,6H),6.42(dd,J
=1.8,17.0Hz,1H),6.34(dd,J
=9.6,16.8Hz,1H),5.75(dd,J
=2.0,9.6Hz,1H),5.43(dd,J
=4.0,7.2Hz,1H),4.01(dd,J
=4.2,11.8Hz,1H),3.94(dd,J
=7.4,11.8Hz,1H)。LCMS:417.0(M+H)。
化合物246:1
H NMR(400MHz,CDCl3
):δ:8.39(s,1H),7.79(d,J
=8.4Hz,1H),7.71(s,1H),7.44(t,J
=8.0Hz,1H),7.32(s,1H),7.26-7.21(m,4H),7.16(s,1H),7.02(dd,J
=2.0,7.6Hz,1H),6.45(dd,J
=1.4,17.0Hz,1H),6.32(dd,J
=10.2,17.0Hz,1H),5.94(d,J
=6.8Hz,1H),5.78(dd,J
=1.6,10.0Hz,1H),5.32(br,1H),3.81(d,J
=8.0Hz,1H),3.63(d,J
=6.8Hz,1H)。LCMS:417.0(M+H)。
2-胺基-(4,7-二氫-5H-噻吩并[2,3- c ]嘧啶-3,6-二甲酸6-第三丁酯3-乙酯(2-Amino-4,7-dihydro-5H-thieno[2,3- c ]pyridine-3,6-dicarboxylic acid 6-tert-butyl ester 3-ethyl ester)
(步驟a):將三乙胺(9mL)加入4-氧代-哌啶-1甲酸第三丁酯(4-oxo-piperidine-1-carboxylic acid tert-butyl ester)(12.9g)、氰基乙酸乙酯(7.345g)及硫(2.080g)之絕對酒精(50ml)混合液中,攪拌16小時後,透過過濾收集沉澱物,以乙醇清洗後則得標題化合物(18.7g,88%)。1
H NMR(300MHz,CDCl3
):δ6.02(s,2H),4.31(s,2H),4.23(q,2H,J
=7.2Hz),3.58(t,2H,J
=6.0Hz),2.72-2.80(brs,2H),1.44(s,9H),1.30(t,3H,J
=7.2Hz)。LC-MS(ESI)m/z
327.0(M+H)。
4-氧代-3,5,6,8-四氫-4H-9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(4-oxo-3,5,6,8-tetrahydro-4H-9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester)
(步驟b):於100℃下,將2-胺基-(4,7-二氫-5H-噻吩并[2,3-c
]嘧啶-3,6-二甲酸6-第三丁酯3-乙酯(18.5g)及乙酸甲脒(8.85g)之DMF(100mL)混合液加熱16小時,冷卻反應混合液後濃縮,殘餘物以水及乙酸乙酯分層萃取,有機層以水清洗3次後進行濃縮,則可得標題化合物(15.8g,90%)。1
H NMR(400MHz,CDCl3
):δ7.88(s,1H),4.56-4.62(brs,2H),3.62-3.70(brs,2H),3.02-3.08(brs,2H),1.42(s,9H)。LC-MS(ESI)m/z
308.1(M+H)。
4-氯-5,8-二氫-6 H -9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(4-chloro-5,8-dihydro-6 H -9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester)
(步驟c):將4-氧代-3,5,6,8-四氫-4H-9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(10.0g)加入POCl3
(30mL)及三乙胺(50mL)之0℃混合液中,反應混合液於60℃下加熱3小時後,加入水後再加入碳酸氫鈉中和反應混合液,所得的混合液以二氯甲烷酯萃取後,濃縮有機層並以矽膠管柱色層分析法使用己烷:乙酸乙酯(10:1)之混合液純化粗萃化合物,則可得標題化合物(3.1g,25%)。1
H NMR(400MHz,CDCl3
):δ8.70(s,1H),4.69(s,2H),3.74(t,2H,J
=5.6Hz),3.14-3.18(brs,2H),1.46(s,9H)。LC-MS(ESI)m/z
326.0(M+H)。
4-(2-羥基-1-苯基-乙胺基)-5,8-二氫-6 H -9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(4-(2-Hydroxy-1-phenyl-ethylamino)-5,8-dihydro-6 H -9-thia-1,3,7-triaza-fluorene-7-carboxylic acid tert-butyl ester)
(化合物9,步驟d):將4-氯-5,8-二氫-6H
-9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(0.25g)及S
-2-胺基-2-苯基-乙醇(0.128g)之正丁醇(1ml)混合液迴流8小時後,濃縮反應混合液,殘餘物以水及二氯甲烷分層萃取,濃縮有機層後以矽膠管柱色層分析法使用二氯甲烷:甲醇(20:1)之混合液純化粗萃化合物,則可得標題化合物(0.309g,95%)。1
H NMR(300MHz,CDCl3
):δ8.25(s,1H),7.26-7.38(m,5H),6.04(d,1H,J
=6.6Hz),5.36-5.43(m,1H),4.62(s,2H),3.97-4.02(m,2H),3.72-3.81(m,2H),2.90-3.08(m,2H),1.46(s,9H)。LC-MS(ESI)m/z
427.0(M+H)。
2-苯基-2-(5,6,7,8-四氫-9-硫雜-1,3,7-三氮雜-茀-4-基胺基)-乙醇(2-Phenyl-2-(5,6,7,8-tetrahydro-9-thia-1,3,7-triaza-fluoren-4-ylamino)-ethanol)
(化合物11,步驟e):於室溫下,將TFA(1mL)加入4-(2-羥基-1-苯基-乙胺基)-5,8-二氫-6H
-9-硫雜-1,3,7-三氮雜-茀-7-甲酸第三丁酯(0.6g)之二氯甲烷(2ml)混合液中,攪拌4小時後,緩緩加入碳酸氫鈉溶液進行中和,透過過濾收集所形成的沉澱物,先以水後以二氯甲烷清洗則得標題化合物(0.350g,76%)。1
H NMR(400MHz,CDCl3
):δ8.28(s,1H),7.26-7.38(m,5H),6.04(d,1H,J
=6.4Hz),5.38(d,1H,J
=4.8Hz),4.01(d,2H,J
=7.6Hz),3.99(d,2H,J
=3.2Hz),3.20(t,2H,J
=4.4Hz),2.84-3.04(m,2H)。LC-MS(ESI)m
/z
327.1(M+H)。
1-[4-(2-羥基-1-苯基-乙胺基)-5,8-二氫-6H-9-硫雜-1,3,7-三氮雜-茀-7-基]-丙烯酮(1-[4-(2-Hydroxy-1-phenyl-ethylamino)-5,8-dihydro-6H-9-thia-1,3,7-triaza-fluoren-7-yl]-propenone)
(化合物12,步驟f):將丙烯酸(3.6mg)及EDCI(9.4mg)之無水DMF混合液攪拌2小時後,加入2-苯基-2-(5,6,7,8-四氫-9-硫雜-1,3,7-三氮雜-茀-4-基胺基)-乙醇,所得的混合液持續攪拌16小時後,使用水及乙酸乙酯分層萃取,有機層以MgSO4
乾燥後濃縮,殘餘物以矽膠管柱色層分析法使用二氯甲烷:甲醇(5:1)之混合液純化粗萃化合物,則可得標題化合物(8mg,44%)。1
H NMR(300MHz,CD3
OD):δ8.18(s,1H),7.20-7.44(m,5H),6.78-6.98(m,1H),6.28(d,1H,J
=17.1Hz),5.78-5.84(m,1H),5.39(t,1H,J
=5.1Hz),4.80-4.98(m,2H),4.07(t,2H,J
=5.7Hz),3.82-3.98(m,2H),3.20-3.38(m,2H)。LC-MS(ESI)m
/z
381.0(M+H)。
化合物9-11、13-16、25-28、59-68、75、106、107、154、176、178、180、181、183-235及327以類似實施例3的方法進行製備。這些化合物之1
H NMR及MS數據列舉如下。
化合物10:1
H NMR(400MHz,CDCl3
):δ8.31(s,1H),7.29~7.39(m,5H),6.00(d,1H,J
=6.4Hz),5.38~5.40(m,1H),4.70(s,2H),4.17(q,2H,J
=7.2Hz),4.00(d,2H,J
=4.0Hz),3.79~3.84(m,2H),3.00~3.05(m,2H),1.27(t,3H,J
=7.2Hz)。
化合物13:1
H-NMR(400MHz,CD3
OD)δ8.15(s,1H),7.38-7.42(m,2H),7.24-7.33(m,2H),7.20-7.23(m,1H),5.38-5.40(m,1H),4.77-4.79(m,2H),3.87-3.98(m,4H),3.14-3.26(m,2H),2.55(q,1.2H,,J
=7.6Hz),2.48(q,0.8H,J
=7.6Hz),1.17(t,1.8H,J
=7.6Hz),1.12(t,1.2H,J
=7.6Hz);HRMS(EI)C20
H21
N4
O2
S(M+
)計算值382.1463,實驗值382.1466。
化合物14:1
H-NMR(300MHz,CDCl3
):δ8.23(s,1H),7.67(d,1H,J
=15.6Hz),7.47-7.52(m,2H),7.24-7.27(m,8H),6.91(d,1H,J
=15.6Hz),6.16(s,1H),5.41(s,1H),4.75-4.92(m,2H),3.92-4.04(m,4H),3.08(br,2H)。LC-MS(ESI)m/z
457.1(M+H)。
化合物15:1
H NMR(300MHz,CDCl3
):δ-0.16(s,3H),-0.06(s,3H),0.83(s,9H),3.16(m,2H),3.87~4.07(m,4H),4.80~4.89(m,2H),5.37~5.42(m,1H),5.77(d,1H,J
=12Hz),6.34(d,1H,J
=18Hz),6.56~6.60(m,1H),7.20~7.34(m,5H),8.29(s,1H)。LC-MS(ESI)m/z
495.2(M+H)。
化合物16:1
H-NMR(300MHz,CDCl3
):δ1.97~2.03(m,3H),2.96~3.24(m,2H),3.84~4.15(m,4H),4.67~4.82(m,1H),4.92(s,1H),5.35~5.45(m,1H),6.13~6.16(m,1H),7.23~7.36(m,5H),8.22(s,0.5H),8.24(s,0.5H);13
C-NMR(75MHz,CDCl3
)δ4.1(CH3
),25.7(CH2
),26.7(CH2
),29.6(C),38.4(CH2
),41.0(CH2
),43.7(CH2
),46.2(CH2
),56.5(CH),56.7(CH),66.4(CH2
),66.5(CH2
),72.4(C),72.5(C),90.1(C),91.3(C),115.3(C),115.4(C),124.0(C),124.9(C),126.4(CH),126.5(C),127.7(C),127.8(CH),128.6(CH),128.8(C),128.8(C),129.0(C),139.3(C),139.4(C),152.8(C),153.2(CH),153.3(CH),156.7(C),156.9(C),164.9(C),165.1(C);HRMS(EI)C21
H20
N4
O2
S(M+
)計算值392.1307,實驗值392.1311。
化合物25:1
H-NMR(300MHz,CDCl3
)δ0.93(t,3H,J
=7.2Hz),1.42(s,9H),1.87-2.00(m,2H),2.98-3.00(m,2H),3.77-3.78(m,2H),4.62(s,2H),5.29(td,1H,J
=7.2,7.2Hz),5.41(d,1H,J
=7.2Hz),7.22-7.33(m,5H),8.33(s,1H)。LCMS(ESI)m/z
425.1[M+H]+
。
化合物26:LC-MS(ESI)m/z
397.0(M+H)+
。
化合物27:1
H-NMR(400MHz,CDCl3
)δ0.93(t,3H,J
=7.6Hz),1.89-19.7(m,2H),2.90-3.00(m,2H),3.24(t,2H,5.6Hz),4.04(s,2H),5.30(td,1H,7.2,7.2Hz),5.46(d,1H,7.2Hz),7.22-7.33(m,5H),8.32(s,1H)。LCMS(ESI)m/z
325.0[M+H]+
。
化合物28:LC-MS(ESI)m/z
438.0(M+H)+
。
化合物59:1
H-NMR(400MHz,CD3
OD):δ7.39~7.41(m,2H),7.29~7.33(m,2H),7.20~7.24(m,1H),6.25~6.30(m,1H),5.79~5.84(m,1H),5.39(dd,1H,J
=5.2,5.2Hz),4.90(m,2H),3.94~4.04(m,2H),3.89(dd,2H,J
=6.0,11.2Hz),3.25~3.27(m,2H)。LC-MS(ESI)m/z
381.1(M+H)。
化合物60:1
H-NMR(400MHz,CDCl3
):δ-0.14(s,3H),-0.04(s,3H),0.85(s,9H),3.18~3.29(m,2H),3.88~4.12(m,4H),4.82~4.91(m,2H),5.39~5.40(m,1H),5.79(d,1H,J
=12Hz),6.36(d,1H,J
=18Hz),6.58~6.61(m,1H),7.23~7.37(m,5H),8.31(s,1H)。LC-MS(ESI)m/z
495.3(M+H)。
化合物61:1
H-NMR(400MHz,CD3
OD):δ8.12(s,1H),7.32~7.43(m,3H),7.28~7.30(m,2H),7.19~7.23(m,1H),6.16~6.32(m,2H),5.38(dd,1H,J
=5.6,5.6Hz),4.76~4.83(m,2H),3.86~4.02(m,4H),3.21~3.33(m,2H)。LC-MS(ESI)m/
z 425.2(M+H)。
化合物62:1
H NMR(400MHz,CDCl3
):δ8.30(s,1H),7.28-7.40(m,5H),6.80-6.98(brs,1H),6.38-6.57(m,1H),6.03(d,1H,J
=13.6Hz),5.39(s,1H),4.86(s,1H),4.78(s,1H),4.00-4.12(brs,2H),3.90-3.99(brs,2H),3.01-3.20(brs,4H),2.24(s,6H)。LC-MS(ESI)m/z
438.2(M+H)。
化合物63:1
H NMR(400MHz,CDCl3
):δ8.32(s,1H),7.28-7.39(m,5H),6.44(dd,1H,J
=16.4,9.6Hz),6.32(d,1H,J
=16.4Hz),6.02(d,1H,J
=4.8Hz),5.99(d,1H,J
=6.4Hz),5.41(dd,1H,J
=10.4,4.8Hz),4.47(s,2H),3.96-4.23(m,2H),3.63(t,2H,J
=4.8Hz),3.04-3.18(m,2H)。LC-MS(ESI)m/z
417.1(M+H)。
化合物64:1
H NMR(300MHz,CD3
OD):δ8.20(s,1H),7.43(d,2H,J
=7.8Hz),7.31(m,2H),7.21(t,1H,6.9Hz),6.75-6.93(m,1H),6.26(d,1H,J
=16.5Hz),5.81(d,1H,J
=10.8Hz),5.48(q,1H,J
=6.9Hz),4.78-5.01(m,2H),3.91-4.05(m,2H),3.01-3.22(m,2H),1.61(d,3H,J
=7.2Hz)。LC-MS(ESI)m/z
365.1(M+H)。
化合物65:1
H-NMR(400MHz,CDCl3
):δ8.25(s,0.5H),8.24(s,0.5H),7.23-7.33(m,5H),6.81(m,1H),6.35-6.46(m,1H),6.05-6.12(m,2H),5.37-5.38(m,1H),4.81(m,1H),4.74(m,1H),3.88-3.98(m,4H),3.07(m,4H),2.35(m,4H),1.54(m,4H),1.39(m,2H)。LC-MS(ESI)m/z
478.1(M+H)。
化合物66:1
H-NMR(400MHz,CDCl3
):δ8.23(s,1H),7.22-7.33(m,5H),6.84-6.88(m,1H),6.53(t,1H,J
=16.2Hz),6.04-6.09(m,1H),5.36-5.38(m,1H),4.81(m,1H),4.74(m,1H),4.79(m,1H),3.88-3.97(m,4H),3.60-3.67(m,4H),3.10-3.11(m,4H),2.42(m,4H)。LC-MS(ESI)m/z
480.2(M+H)。
化合物67:1
H-NMR(400MHz,CDCl3
):δ8.28(s,1H),7.25-7.37(m,5H),6.82-6.88(m,1H),6.40-6.50(m,1H),6.09(d,1H,J
=1.6Hz),5.35-5.40(m,1H),4.76-4.88(m,2H),3.89-4.03(m,4H),3.13-3.16(m,4H),2.60(m,8H),2.28(s,3H)。LC-MS(ESI)m/z
493.1(M+H)。
化合物68:1
H-NMR(300MHz,CDCl3
):δ8.33(s,1H),7.29-7.47(m,6H),6.81(dd,1H,J
=15.0,15.0Hz),5.99 dd,1H,J
=6.0,15.0Hz),5.39-5.42(m,1H),4.90(brs,1H),4.81(brs,1H),4.26(q,1H,J
=7.2Hz),4.25(q,1H,J
=7.2Hz),3.92-4.08(m,4H),3.05-3.16(m,2H),1.31(t,1.5H,J
=7.2Hz),1.30(t,1.5H,J
=7.2Hz)。LC-MS(ESI)m
/z
453.1[M+1]+
。
化合物75:1
H-NMR(300MHz,CDCl3
)δ0.96-1.06(m,6H),2.55-2.58(m,4H),3.11-3.28(m,4H),3.93-4.02(m,2H),4.08-4.13(m,2H),4.80-4.85(m,1H),4.85-4.92(m,1H),5.39-5.44(m,1H),6.08(s,1H),6.52(dd,1H,J
=14.7,15.6Hz),6.90-6.97(m,1H),7.27-7.41(m,5H),8.32(s,1H)。HRMS(EI)C25
H31
N5
O2
S(M+
)計算值465.2198,實驗值465.2195。
化合物106:1
H-NMR(400MHz,CDCl3
):δ0.86-0.91(t,3H),1.77-2.01(m,2H),2.97-3.11(m,2H),3.90-4.08(m,2H),4.79-4.89(m,2H),5.26-5.43(m,H),5.74-5.79(m,H),6.24-6.36(m,H),7.21-7.32(m,5H),8.33(s,H)。LCMS-ESI(m
/z
):[M+1]+
479.1。
化合物107:1
H-NMR(400MHz,CDCl3
):δ0.95(t,3H,J
=7.2Hz),1.85~2.04(m,2H),2.17(s,3H),2.37(s,3H),3.13~3.17(m,2H),3.84~4.03(m,2H),4.80~4.89(m,2H),5.30~5.46(m,2H),6.53(dd,1H,J
=4.8,14.4Hz),7.25~7.36(m,5H),8.37(s,1H)。LCMS LCMS-ESI(m
/z
):436.1(M+H)。
化合物154:1
H NMR(300MHz,CDCl3
):δ:8.45(s,1H),8.34(s,1H),7.86(d,J=7.8Hz,1H),7.74(br,2H),7.49-7.32(m,6H),6.75(br,1H),6.53(d,J=16.8Hz,1H),6.35(dd,J=1.5,26.1Hz,1H),5.85(d,J=10.2Hz,1H),4.11(m,3H)。LCMS:402.1(M+H)。
化合物176:1
H-NMR(400MHz,CDCl3
):δ1.97-2.02(m,H),2.23-2.31(m,H),2.96-3.03(m,H),3.10-3.16(m,H),3.68-3.91(m,4H),4.79-4.95(m,2H),5.58-5.63(m,H),5.75-5.78(m,H),6.30-6.42(m,H),6.55-6.66(m,H),7.27-7.33(m,5H),8.33(s,H)。LC-MS(ESI)m/z
395.1(M+H)。
化合物178:1
H-NMR(400MHz,CDCl3
):δ1.23-1.27(m,3H),2.17-2.27(m,6H),3.03-3.11(m,4H),3.93-4.05(m,2H),4.80-4.93(m,2H),5.32-5.40(m,H),5.52-5.53(m,H),6.43-6.54(m,H),7.27-7.38(m,5H),8.39(s,H)。LC-MS(ESI)m/z
422.5(M+H)。
化合物180:1
H-NMR(400MHz,CDCl3
):δ8.22(1H,s),7.36-7.24(5H,m),6.11(1H,s),5.41-5.37(1H,m),5.27(1H,s),5.10(1H,s),3.99-3.89(4H,m),3.14-3.02(2H,m),2.00-1.91(5H,m)。
化合物181:1
H-NMR(400MHz,CDCl3
):δ0.83(s,15H),2.17-2.18(m,6H),3.06-3.09(m,4H),3.89-4.11(m,4H),4.86(m,2H),5.41-5.43(m,H),5.43-5.44(m,H),6.37-6.41(m,H),7.23-7.36(m,5H),8.30(s,H)。
化合物183:1
H-NMR(400MHz,CDCl3
):δ1.25(m,3H),2.05-2.27(m,4H),3.03-3.11(m,4H),3.93-4.05(m,2H),4.80-4.94(m,2H),5.29-5.54(m,H),6.43-6.52(m,H),7.27-7.38(m,5H),8.37(s,H)。LC-MS(ESI)m/z
422.1(M+H)。
化合物184:1
H-NMR(400MHz,CDCl3
):δ1.05-1.16(m,6H),1.24-1.27(m,3H),2.56-2.57(m,4H),3.07(m,2H),3.93-3.99(m,2H),4.80-4.93(m,2H),5.33-5.53(m,2H),6.46-6.59(m,H),7.28-7.38(m,5H),8.39(s,H)。
化合物185:1
H-NMR(300MHz,CDCl3
):δ8.31(s,1H),7.22~7.38(m,5H),6.54~6.66(m,1H),6.30~6.39(m,1H),5.99~6.11(m,1H),5.75~5,79(m,1H),5.52(m,1H),4.80~4.88(m,2H),3,76~4.13(m,4H),3.38(s,3H),3.03~3.04(m,2H)。LC-MS(ESI)m/z
395.1(M+H)。
化合物186:1
H-NMR(400MHz,CDCl3
):δ8.29(s,0.5H),8.28(s,0.5H),7.23-7.31(m,5H),6.88-6.92(m,1H),6.51-6.59(m,1H),6.29-6.36(m,1H),5.38-5.40(m,1H),4.81-4.88(m,2H),3.86-4.05(m,4H),3.17(m,4H),2.32(s,6H),0.83(s,9H),-0.11(s,3H),-0.20(s,3H):LC-MS(ESI)m/z
552.2(M+H)。
化合物187:1
H NMR(300MHz,CDCl3
):d 8.52(s,1H),7.82(br,1H),7.42(br,1H),7.17(m,1H),6.92(m,2H),6.52(m,1H),4.90(br d,2H),4.03(br,2H),3.17(br,4H),2.29(s,6H)。LC-MS(ESI)m/z
446.0(M+H)+
。
化合物188:1
H-NMR(400MHz,CDCl3
):δ1.97-2.05(m,H),2.24-2.30(m,H),2.97-3.01(m,H),3.09-3.15(m,H),3.65-3.99(m,4H),4.85-4.91(m,2H),5.58-5.62(m,H),5.76-5.79(m,H),6.30-6.38(m,H)7.26-7.39(m,5H),8.34(s,H)。LC-MS(ESI)m/z
395.1(M+H)。
化合物189:1
H-NMR(400MHz,CDCl3
):δ1.12-1.15(m,3H),1.61-1.64(m,3H),2.41-2.49(m,2H),2.94-3.08(m,2H),3.78-3.86(m,H),3.92-4.01(m,H),4.77-4.89(m,2H),5.50-5.55(m,H),7.27-7.41(m,5H),8.39(s,H)。
化合物190:1
H-NMR(400MHz,CDCl3
):δ1.13-1.20(m,6H),1.62-1.64(m,3H),2.54-2.68(m,4H),3.04-3.08(m,2H),3.28-3.29(m,2H),3.44-3.99(m,2H),4,80-4.89(m,2H),5.33-5.39(m,H),5.53(m,H),6.44-6.58(m,H),7.27-7.38(m,5H),8.40(s,H)。
化合物191:1
H-NMR(400MHz,CDCl3
):δ0.93-0.97(t,3H),1.13-1.16(m,6H),1.92-2.01(m,2H),2.16-2.56(m,4H),3.10-3.28(m,2H),3.46-3.47(m,2H),3.95-4.01(m,2H),4.79-4.92(m,2H),5.29-5.44(m,2H),6.46-6.60(m,H),7.25-7.30(m,5H),8.36(s,H)。
化合物192:1
H-NMR(400MHz,CDCl3
):δ2.05-2.17(m,6H),2.27-2.33(m,H),2.49-2.77(m,H),2.92-2.95(m,H),3.07-3.15(m,4H),3.74-3.88(m,4H),4.81-4.51(m,H),4.76-4.85(m,2H),5.36-5.39(m,H),6.42-6.52(m,H),7.26-7.36(m,4H),8.36(s,H)。LCMS-ESI(m/z
):452.1(M+H)。
化合物193:1
H-NMR(400MHz,CDCl3
):δ2.47-2.49(m,H),2.76-2.78(m,H),2.91-2.96(m,H),3.08-3.13(m,H),3.74-3.88(m,4H),4.48-4.49(m,H),4.76-4.85(m,2H),5.76-5.82(m,H),6.31-6.38(m,H),6.54-6.64(m,H),7.25-7.36(m,5H),8.38(s,H)。
化合物194:1
H-NMR(400MHz,CDCl3
):δ1.96-2.02(m,6H),3.03-3.16(m,4H),3.75-3.96(m,4H),4.74-4.95(m,2H),6.43-6.53(m,H),6.68-6.89(m,2H),7.25-7.35(m,5H),8.30(s,H)。LCMS-ESI(m/z
):452.1(M+H)。
化合物195:1
H-NMR(400MHz,CDCl3
):δ8.30(s,1H),7.22~7.31(m,10H),6.57(dd,1H,J
=10.8,17.8Hz),6.35(dd,1H,J
=8.0,17.6Hz),6.15(m,1H),5.77~5.79(m,1H),5.51~5.52(m,1H),4.78~4.88(m,2H),4.52(s,2H),3.77~3.95(m,4H),2.94~3.00(m,2H)。LC-MS(ESI)m/z
471.2(M+H)。
化合物196:1
H-NMR(400MHz,CDCl3
):δ 8.29(s,1H),7.22~7.37(m,10H),6.14(d,1H,J
=6.8Hz),5.52(m,1H),4.63(s,2H),4.52(s,2H),3.71~3.89(m,4H),2.93~2.94(m,2H),1.49(s,9H)。LC-MS(ESI)m/z
517.2(M+H)。
化合物197:1
H-NMR(300MHz,CDCl3
):δ8.28(s,1H),7.21~7.39(m,10H),6.22(d,1H,J
=6.6Hz),5.52~5.55(m,1H),4.52(s,2H),4.04(d,2H,J
=2.1Hz),3.91(dd,1H,J
=4.2,9.6Hz),3.82(dd,1H,J
=4.8,9.6Hz),3.16(dd,2H,J
=6.0,6.0Hz),2.88~2.90(m,2H)。LC-MS(ESI)m/z
417.1(M+H)。
化合物198:1
H-NMR(300MHz,CDCl3
):δ8.29(s,1H),7.22~7.35(m,10H),6.88(m,1H),6.43~6.49(m,1H),6.13(m,1H),5.52(m,1H),4.79~4.85(m,2H),4.53(s,2H),3.87~3.91(m,2H),3.79(m,2H),3.10~3.11(m,2H),2.99(m,2H),2.27(m,6H)。LC-MS(ESI)m/z
528.2(M+H)。
化合物199:1
H-NMR(400MHz,CDCl3
):δ0.87-0.94(m,6H),2.27-2.40(m,2H),2.56-2.57(m,4H),2.99-3.26(m,4H),3.64-4.16(m,4H),4.65(m,2H),5.53-5.59(m,2H),6.93-6.98(m,H),7.25-7.36(m,5H),8.36(s,H)。
化合物200:1
H NMR(300MHz,CDCl3
):δ8.32(s,1H),7.39-6.98(m,7H),6.99(m,2H),6.63(dd,1H,J 1
=9.3Hz,J 2
=16.2Hz),6.37(d,1H,J
=6.9Hz),6.12(d,NH),5.79(d,1H,J
=9.6Hz),5.57(br s,1H),4.84(br,2H),4.53(s,2H),3.89(m,2H),3.06(br,2H)。LC-MS(ESI)m/z
489.1(M+H)。
化合物201:1
H NMR(400MHz,CDCl3
):δ8.57(s,1H),7.30(m,7H),6.88(m,6H),5.18(m,1H),4.59(m,4H),4.42(br,2H),3.71(br,1H),3.54(br,1H),3.13(br,1H),3.00(br,1H)。LC-MS(ESI)m/z
643.2(M+H)。
化合物202:1
H NMR(300MHz,CDCl3
):δ8.34(s,1H),7.58(d,2H,J
=8.4Hz),7.37-7.25(m,7H),6.99(m,2H),6.59(dd,1H,J 1
=10.5Hz,J 2
=16.5Hz),6.36(d,1H,J
=16.5Hz),6.09(s,NH),5.79(dd,1H,J 1
=1.8Hz,J 2
=11.1Hz),5.60(br s,1H),4.85(m,2H),4.60(m,2H),3.79(m,4H),3.05(br,2H)。LC-MS(ESI)m/z
539.2(M+H)。
化合物203:1
H NMR(400MHz,CDCl3
):δ8.52(d,1H,J
=14.4Hz),8.31(s,1H),7.63(m,1H),7.19-7.39(m,2H),6.92(br,1H),6.48(br,1H),6.24(br,1H),5.58(s,1H),4.88(m,2H),4.67(s,1H),4.00(m,4H),3.11(m,4H)2.27(s,6H)。LC-MS(ESI)m/z
529.3(M+H)。
化合物204:1
H-NMR(400MHz,CDCl3
):δ1.60(s,6H),1.54-1.56(d,3H),2.94-2.96(m,3H),3.39-3.43(m,4H),3.77-3.87(m,H),4.70-4.85(m,2H),6.43-6.60(m,H),6.86-6.93(m,H),7.17-7.31(m,5H),8.46(s,H)。LC-MS(ESI)m/z
436.2(M+H)。
化合物205:1
H-NMR(400MHz,CDCl3
):δ1.52-1.54(d,3H),2.28(s,3H),3.21-3.48(m,4H),3.91(m,2H),5.39-5.44(m,H),6.46-6.48(m,H),6.65-6.72(m,H),7.16-7.43(m,5H),8.22(s,H)。
化合物206:1
H-NMR(400MHz,CDCl3
):δ1.34-1.38(m,3H),2.88-3.06(m,2H),3.72-3.73(m,2H),3.82-3.95(m,2H),4.58(m,H),4.76-4.88(m,H),5.49-5.50(m,H),6.87-6.97(m,H),7.03-7.09(m,H),7.14-7.35(m,8H),8.33(s,H)。
化合物207:1
H-NMR(400MHz,CDCl3
):δ0.80-0.82(m,2H),1.01-1.21(m,2H),1.61-1.74(m,3H),1.79-1.90(m,H),2.95-3.04(m,2H),3.94-4.06(m,2H),4.78-4.89(m,2H),5.31-5.38(m,H),7.24-7.35(m,5H),8.37(s,H)。LC-MS(ESI)m/z
379.1(M+H)。
化合物208:1
H-NMR(300MHz,CDCl3
):δ8.39(s,1H),7.27~7.36(m,5H),6.85(m,1H),6.54~6.61(m,1H),5.51~5.53(m,1H),5.28~5.37(m,1H),4.79~4.89(m,2H),3.92~4.05(m,4H),3.05(m,2H),1.61(d,3H,6.6Hz)。LC-MS(ESI)m/z
420.2(M+H)。
化合物209:1
H-NMR(300MHz,CDCl3
):δ8.35(s,1H),7.43~7.45(m,2H),7.24(m,2H),6.86~6.91(m,1H),6.40~6.53(m,1H),5.44(m,1H),5.22~5.29(m,1H),4.78~4.85(m,2H),3.91~4.10(m,2H),3.03~3.09(m,4H),2.25(s,6H),1.57(d,3H,J
=6.0Hz)。LC-MS(ESI)m/z
502.1(M+H)。
化合物210:1
H NMR(300MHz,CDCl3
):δ8.33(s,1H),7.31(m,6H),6.98(m,3H),6.49(br,m,1H),6.11(br,s,1H),5.58(s,1H),4.85(d,2H),6.22(s,2H),3.77(br,4H),3.08(m,4H),2.29(s,6H)。LC-MS(ESI)m/z
546.0(M+H)。
化合物211:1
H-NMR(400MHz,CDCl3
):δ0.35-0.44(m,4H),1.58-1.60(m,4H),3.0-3.02(m,2H),3.40-3.48(m,2H),3.88-3.94(m,2H),4.75-4.84(m,2H),5.48-5.50(m,H),6.37-6.47(m,H),6.94-6.95(m,H),7.24-7.34(m,5H),8.35(s,H)。LC-MS(ESI)m/z
434.2(M+H)。
化合物212:1
H-NMR(400MHz,CDCl3
):δ1.23-1.32(m,6H),1.43-1.60(m,4H),2.15-2.23(m,3H),2.89-2.98(m,2H),3.05-3.13(m,2H),3.91-3.97(m,2H),4.78-4.84(m,H),6.40-6.51(m,H),6.90-6.92(m,H),7.25-7.36(m,H),7.25-7.36(m,4H),8.38(s,H)。
化合物213:1
H-NMR(400MHz,CDCl3
):δ1.39-1.48(m,3H),2.15-2.25(m,3H),2.45-2.57(m,2H),2.85-2.89(m,2H),3.04-3.26(m,2H),3.74-3.91(m,2H),4.51-4.59(m,2H),6.64-6.56(m,H),6.86-6.91(m,H),7.17-7.36(m,5H),8.32(s,H)。
化合物214:1
H-NMR(300MHz,CDCl3
):δ8.38(s,1H),7.23~7.36(m,5H),6.85~6.88(m,1H),6.45~6.54(m,1H),5.50~5.51(m,1H),5.27~5.32(m,1H),4.73~4.88(m,4H),3.88~3.98(m,2H),3.01~3.90(m.2H),2.11(s,3H),1.60(d,3H,J
=5.2Hz)。LC-MS(ESI)m/z
437.2(M+H)。
化合物215:1
H-NMR(400MHz,CDCl3
):δ1.24-1.28(m,3H),2.70-2.73(m,4H),3.04-3.07(m,2H),3.40-3.47(m,2H),3.65-3.66(m,4H),3.86-3.99(m,2H),4.77-4.87(m,2H),5.49-5.55(m,H),6.64-6.70(m,H),6.88-6.92(m,H),7.26-7.40(m,5H),8.38(s,H)。
化合物216:1
H-NMR(300MHz,CDCl3
):δ1.05-1.07(m,3H),1.61-1.63(m,3H),2.52-2.64(m,3H),2.72-3.05(m,2H),3.33-3.46(m,2H),3.63-3.64(m,2H),3.91-3.98(m,2H),4.79-4.87(m,2H),5.51-5.53(m,H),6.44-6.57(m,H),6.92-7.24(m,H),7.27-7.37(m,5H)8.38(s,H)。
化合物217:1
H-NMR(400MHz,CDCl3
):δ0.92-0.94(m,3H),1.28-1.44(m,2H),1.85-1.92(m,2H),2.26-2.31(m,6H),3.10-3.13(m,3H),3.94-3.99(m,2H),4.78-4.86(m,2H),5.37-5.41(m,H),6.43-6.58(m,H),6.88-6.92(m,H),7.24-7.34(m,5H),8.34(s,H)。
化合物218:1
H NMR(300MHz,CDCl3
):δ8.28(s,1H),7.24(m,9H),6.92(m,1H),6.76(m,1H),6.45(m,1H),5.65(m,1H),4.81(m,2H),4.53(s,2H),6.63(m,4H),3.12(d,2H,J
=5.7Hz),2.95(br,2H),2.28(s,6h),2.06(br,2H)。LC-MS(ESI)m/z
560.3(M+H)。
化合物219:1
H NMR(300MHz,CDCl3
):δ8.32(s,1H),7.29(m,7H),7.99(m,3H),6.46(br,1H),6.10(br,NH),5.56(br,1H),4.52(d,2H,J
=3.9Hz),4.51(s,2H),3.83(m,4H),3.09(m,4H),2.34(s,6H)。LC-MS(ESI)m/z
546.1(M+H)。
化合物220:1
H NMR(300MHz,CDCl3
):δ8.32(s,1H),7.30(m,6H),6.99(m,3H),6.32(br,NH),6.12(d,1H),5.57(br,1H),4.86(m,2H),4.53(s,2H),3.88(br,4H),3.05(br,2H),1.93(d,3H,J
=4.8Hz)。LC-MS(ESI)m/z
503.2(M+H)。
化合物221:1
H NMR(300MHz,CDCl3
):δ8.33(s,1H),7.33(m,7H),6.95(m,3H),6.10(m,1H),5.57(m,1H),4.98(s,1H),4.84(s,1H),4.52(m,2H),4.09(m,1H),3.96(m,1H),3.87(m,2H),3.05(m,4H),2.07(s,3H)。LC-MS(ESI)m/z
501.2(M+H)。
化合物222:1
H NMR(300MHz,CDCl3
):δ8.48(s,1H),7.23(m,7H),8.87(m,6H),6.56(m,1H),6.35(d,1H,J
=16.8Hz),7.75(d,1H,J
=9.6Hz),5.15(m,1H),4.90(m,2H),4.65(br,2H),4.55(br,2H),4.36(br,2H),3.71(br,2H),3.06(br,2H)。LC-MS(ESI)m/z
598.3(M+H)。
化合物223:1
H-NMR(400MHz,CDCl3
):δ2.70-2.80(m,2H),3.63-3.69(m,2H),3.76(s,3H),3.77-3.91(m,2H),4.48(s,2H),4.79-4.87(m,2H),5.78-5.81(m,H),6.16-6.18(m,H),6.33-6.40(m,H),6.56-6.60(m,H),6.79-6.83(m,4H),7.24-7.37(m,5H),8.31(s,H)。
化合物224:1
H NMR(300MHz,CDCl3
):δ8.53(d,2H,J=5.4Hz),8.35(s,1H),7.32(m,5H),7.10(br,2H),6.94(br m,1H),6.55(br m,1H),6.04(br m,1H),5.63(br s,1H),4.86(br m,2H),4.57(m,4H),3.99(br m,4H),3.08(br,4H),2.129br s,6H)。LC-MS(ESI)m/z
529.2(M+H)。
化合物225:1
H-NMR(300MHz,CDCl3
):δ8.36(s,1H),7.23-7.30(m,1H),6.95-7.06(m,4H),6.56-6.59(m,1H),6.33(d,1H,J
=17.4Hz),5.73(d,1H,J
=10.2Hz),5.59(m,1H),4.72-4.85m,2H),4.49(s,2H),3.71-3.96(m,6H),2.97(t,2H,J
=5.7Hz)。
化合物226:LC-MS(ESI)m/z
516.0[M+1]+
。
化合物227:1
H-NMR(400MHz,CDCl3
):δ2.30(s,3H),3.02(m,2H),3.83-3.98(m,4H),4.53(s,2H),4.79-4.89(m,2H),5.54-5.78(m,H),5.80-6.16(m,H),6.33-6.39(m,H),6.59-6.63(m,H),7.02-7.38(m,9H),8.32(s,H)。LC-MS(ESI)m
/z
485.2(M+H)。
化合物228:1
H-NMR(400MHz,CDCl3
):δ2.27(s,6H),2.99-3.11(m,4H),3.71(s,3H),3.85-4.02(m,4H),4.52(s,H),4.80-4.87(m,2H),6.12-6.14(m,H),6.44-6.53(m,H),6.83-6.93(m,H),7.24-7.36(m,9H),8.31(s,H)。
化合物229:1
H-NMR(400MHz,CDCl3
)δ2.28(m,6H),3.13(m,4H),3.40(s,3H),3.79(m,2H),3.97~4.09(m,2H),4.82~4.89(m,2H),5.54(m,1H),6.04~6.13(m,1H),6.45~6.58(m,1H),6.91~6.95(m,1H),7.24~7.40(m,5H),8.33(s,1H);LCMS-ESI(m
/z
):452.0[M+H]+
。
化合物230:1
H-NMR(300MHz,CDCl3
)δ1.06(t,6H,J
=6.9Hz),2.53~2.57(m,4H),3.15(m,2H),3.30(m,2H),3.40(s,3H),3.72~3.80(m,2H),3.97~4.07(m,2H),4.82~4.88(m,2H),5.55(m,1H),6.05~6.14(m,1H),6.47~6.61(m,1H),6.95~7.00(m,1H),7.24~7.40(m,5H),8.33(s,1H);LCMS-ESI(m
/z
):480.0[M+H]+
。
化合物231:1
H NMR(300MHz,CDCl3
):δ8.54(m,2H),8.42(s,1H),7.53(d,1H,J
=7.5Hz),7.29(m,6H),6.91(br,1H),6.45(m,1H),6.06(br,NH),5.59(br,1H),4.84(m,2H),4.51(s,2H),3.83(m,4H),3.11(m,4H),2.29(s,6H)。LC-MS(ESI)m
/z
529.1(M+H)。
化合物232:1
H NMR(300MHz,CDCl3
):δ8.29(s,1H),7.25(m,9H),6.92(br m,1H),6.45(m,1H),6.19(br,1H),5.58(br s,1H),4.85(br m,2H),4.60(br s,2H),3.89(br m,4H),3.08(br m,4H),2.28(s,6h),2.28(br s,6H)。LC-MS(ESI)m
/z
546.1(M+H)。
化合物233:1
H-NMR(400MHz,CDCl3
):δ8.30(s,H)7.22-7.36(m,5H),6.45-6.47(d,1H),5.44-5.41(m,H),4.09-3.89(m,4H),3.26-3.29(t,2H),3.06-3.09(t,2H),0.82-0.84(m,15H)。
化合物234:1
H-NMR(400MHz,CDCl3
):δ8.26(1H,s),7.36-7.03(5H,m),6.10(1H,d,J
=6.4Hz),5.90(1H,t,J
=3.6Hz),5.41(1H,q,J
=4.0Hz),4.11-3.88(4H,m),3.15-3.01(2H,m)2.99-2.13(6H,m),1.69-1.57(4H,m)。
化合物235:H NMR(400MHz,CDCl3
):δ8.30(s,1H),7.28-7.38(m,5H),5.99(d,1H,J
=6.0Hz),5.41(t,1H,J
=4.8Hz),4.79(m,2H),3.96-4.02(m,2H),3.82-3.85(m,2H),3.09-3.16(m,2H),2.48(s,1.8H),2.45(s,1.2H)。LC-MS(ESI)m
/z
397.0[M+H]+
。
化合物327:1
H NMR(CDCl3
,400MHz)δ8.31(s,1H),7.38-7.28(m,5H),6.90(d,J
=10Hz,1H),6.62(t,J
=16.8Hz,1H),6.02(s,1H),5.39(d,J
=5.2Hz,1H),4.84(d,J
=16.8Hz,2H),4.00(s,3H),3.93(s,2H),3.62(s,1H),3.47(t,J
=5Hz,2H),3.34(d,J
=5Hz,4H),3.23(s,2H),2.57(s,2H),2.31(s,3H)。LCMS-ESI m/z 482.1(M+H)+
。
2-胺基-4,5-二苯基呋喃-3-甲腈(2-amino-4,5-diphenylfuran-3-carbonitrile)
(步驟a):將二乙胺(13.8g)在30分鐘內緩緩滴入安息香(10g)及丙二腈(3.8g)之0℃ DMF(30ml)混合液中(內溫不應超過40℃),所得的混合液在室溫下攪伴16小時後,加入水(100mL),過濾所形成的沉澱物,以足夠的水量清洗後再以己烷清洗,最後進行乾燥。乾燥固體使用乙醇再結晶,可得淡黃-褐色固體產物之標題化合物(6g,49%)。1
H NMR(300MHz,CDCl3
):δ7.47-7.34(m,8H),7.28-7.18(m,2H),4.94(br,2H)。LC-MS(ESI)m
/z
261.1(M+H)。
5,6-二苯基呋喃并[2,3- d ]嘧啶-4(3 H )-酮(5,6-Diphenylfuro[2,3- d ]pyrimidin-4(3 H )-one)
(步驟b):將2-胺基-4,5-二苯基呋喃-3-甲腈(2g)及甲酸(24mL)之混合液冷卻至0℃,然後緩緩滴入乙酸酐(24mL),所得的混合液再額外攪拌1小時後,於100℃下加熱16小時。冷卻反應混合液,加入水(40mL),透過過濾收集沉澱物並以水及己烷清洗完全,則得標題化合物(2.1g,95%)。1
H NMR(300MHz,CDCl3
):δ7.94(s,1H),7.56-7.52(m,4H),7.46-7.43(m,3H),7.32-7.28(m,3H),7.22(s,1H)。LC-MS(ESI)m
/z
289.1(M+H)。
4-氯-5,6-二苯基呋喃并[2,3- d ]嘧啶(4-Chloro-5,6-dipheny1furo[2,3- d ]pyrimidine)
(步驟c):於55-65℃下,將5,6-二苯基呋喃并[2,3-d
]嘧啶-4(3H
)-酮(3g)及POCl3
(30ml)之混合液加熱3小時,加入水後接著加入碳酸氫鈉,所得的混合液以乙酸乙酯萃取後,濃縮有機層並以矽膠管柱色層分析法使用己烷:乙酸乙酯(95:5)之混合液純化粗萃化合物,則可得白色固體狀之標題化合物(2g,63%)。1
H NMR(300MHz,CDCl3
):δ8.77(s,1H),7.61-7.58(m,2H),7.52-7.46(m,5H),7.35-7.32(m,3H). LC-MS(ESI)m
/z
307.0(M+H)。
S -2-(5,6-二苯基-呋喃并[2,3- d ]嘧啶-4-基胺基)-2-苯基-乙醇( S -2-(5,6-Diphenyl-furo[2,3- d ]pyrimidin-4-y1amino)-2-phenyl-ethanol)
(化合物31,步驟d):將4-氯-5,6-二苯基呋喃并[2,3-d
]嘧啶(0.160g)及S
-2-胺基-2-苯基-乙醇(0.137g,2當量)之正丁醇(5ml)混合液於80℃下加熱16小時後,濃縮反應混合液,殘餘物以水及乙酸乙酯分層萃取,濃縮有機層後,以矽膠管柱色層分析法使用二氯甲烷:甲醇(40:1)之混合液純化粗萃化合物,則可得標題化合物(0.140g,69%)。1
H NMR(300MHz,CDCl3
):δ8.31(s,1H),7.50-7.47(m,2H),7.45(br s,4H),7.47-7.40(m,7H),6.94(m,2H),5.24(d,1H,J
=5.6Hz),5.16(m,1H),3.72(m,2H)。LC-MS(ESI)m
/z
408.5(M+H)。
2-胺基-5-苯基-呋喃-3-甲腈(2-amino-5-phenyl-furan-3-carbonitrile)(2來自步驟a)
:類似於製備2-胺基-4,5-二苯基呋喃-3-甲腈之方法(見上述實施例5),使用2-溴苯乙酮(1
)製備出2
,產率為38%。1
H NMR(300MHz,CDCl3
)δ7.50-7.47(m,2H),7.39-7.33(m,2H),7.27-7.25(m,1H),6.54(s,1H),4.86(br,2H)。LCMS(ESI)m
/z
185.0(M+H)+
。
6-苯基-3H-呋喃并[2,3- d ]嘧啶-4-酮(6-Phenyl-3H-furo[2,3- d ]pyrimidin-4-one)(3來自步驟b)
:類似於製備5,6-二苯基呋喃并[2,3-d
]嘧啶-4(3H
)-酮之方法(見上述實施例5),使用2
製備出3
,產率為80%。1
H NMR(300MHz,CD3
OD)δ9.00(br,1H),8.36(br,1H),7.67(d,J
=7.5Hz,2H),7.44-7.38(m,2H),7.32-7.25(m,1H),7.10(s,1H)。LCMS(ESI)m
/z
235.0(M+Na)+
。
4-氯-6-苯基-呋喃并[2,3- d ]嘧啶(4-Chloro-6-phenyl- furo[2,3- d ]pyrimidine)(4來自步驟c)
:類似於製備4-氯-5,6-二苯基呋喃并[2,3-d
]嘧啶之方法(見上述實施例5),使用3
製備出4
,產率為94%。1
H NMR(300MHz,CDCl3
)δ8.75(s,1H),7.93-7.89(m,2H),7.55-7.26(m,3H),7.09(s,1H)。LCMS(ESI)m
/z
231.0(M+H)+
。
5-溴-4-氯-6-苯基-呋喃并[2,3- d ]嘧啶(5-Bromo-4-chloro-6-phenyl-furo[2,3- d ]pyrimidine)(5來自步驟d)
:將N
-溴琥珀醯亞胺(1.16g,6.50mmol)分批加入於DMF(20mL)之4-氯-6-苯基-呋喃并[2,3-d
]嘧啶(1.0g,4.33mmol),所得的混合液於室溫下攪拌3小時後,加入水(100mL),過濾所形成的沉澱物,以水清洗後,再以矽膠管柱色層分析法使用乙酸乙酯:正己烷(1:10)之混合液純化粗萃化合物,則可得5
(1.14g,85%)。1
H NMR(300MHz,CDCl3
):δ8.75(s,1H),8.20-8.16(m,2H),7.55-7.51(m,3H)。LCMS(ESI)m/z 308.9(M+H)+
,310.9(M+2+H)+
。
S -2-(5-溴-6-苯基-呋喃并[2,3- d ]嘧啶-4-基胺基)-2-苯基-乙醇( S -2-(5-Bromo-6-phenyl-furo[2,3- d ]pyrimidin-4-ylamino)-2-phenyl-ethanol)(6來自步驟e)
:將4-5-溴-4-氯-6-苯基-呋喃并[2,3-d
]嘧啶(5
)(0.2g,1當量)及(S
)-(+)-苯甘氨醇(1.5當量)於正丁醇(5mL)中在80℃加熱16小時,濃縮反應混合液,殘餘物以水(50mL)及乙酸乙酯(3×50mL)分層萃取,濃縮有機層後,以矽膠管柱色層分析法使用二氯甲烷:甲醇(40:1)之混合液純化粗萃化合物,則可得2-(5-溴-6-苯基-呋喃并[2,3-d
]嘧啶-4-基胺基)-2-苯基-乙醇(6),產率為69%。1
H NMR(300MHz,CDCl3
):δ8.30(s,1H),8.07-8.02(m,2H),7.51-7.30(m,8H),6.89(d,J
=6.9Hz,1H),5.50-5.45(m,1H),4.05(d,J
=4.8Hz,2H),3.39(brs,1H)。LCMS(ESI)m
/z
411.1(M+H+
)。
S -2-[5-(4-硝基-苯基)-6-苯基-呋喃并[2,3- d ]嘧啶-4-基胺基]-2-苯基-乙醇( S -2-[5-(4-Nitro-phenyl)-6-phenyl-furo[2,3- d ]pyrimidin-4-ylamino]-2-phenyl-ethanol)(7來自步驟f)
:於氮氣環境下,將6
(410mg,1.0mmol)及對硝基苯硼酸(195mg,1.2mmol)之混合物,溶解在二噁烷(2.0mL)中,於此混合液中加入Pd(dppf)2
Cl2
(4.2mg,0.05mmol)及Na2
CO3
溶液(2M,1.0mL),並於95℃、氮氣環境下加熱16小時,待完成後,將反應混合液冷卻至室溫,加入水並以乙酸乙酯(3×20mL)萃取,合併有機層並用NaSO4
乾燥後於真空下濃縮,所得的殘餘物以矽膠快速管柱層析法使用己烷:乙酸乙酯(1:1)進行純化,則可得7
(346mg,77%)。1
H NMR(300MHz,CDCl3
):δ8.41(s,1H),8.29(d,J
=8.4Hz,2H),7.67(d,J
=8.4Hz,2H),7.50-7.47(m,2H),7.34-7.26(m,6H),7.09-7.05(m,2H),5.23(dd,J
=10.2,5.4Hz,1H),5.16(d,J
=5.4Hz,1H),3.88-3.84(m,2H),3.31(t
,J
=5.4Hz,1H)。LC-MS(ESI)m
/z
453.1(M+H)+
。
S -2-[5-(3-硝基-苯基)-6-苯基-呋喃并[2,3- d ]嘧啶-4-基胺基]-2-苯基-乙醇( S -2-[5-(3-Nitro-phenyl)-6-phenyl-furo[2,3- d ]pyrimidin-4-ylamino]-2-phenyl-ethanol)(8來自步驟f)
:類似於使用對硝基苯硼酸製備7
之方法,使用6
合成8
,產率為75%。1
H NMR(300MHz,CDCl3
):δ8.41(s,2H),8.30(ddd,J
=8.1,1.2,1.2Hz,1H),7.82(dd,J
=7.8,1.2Hz,1H),7.65(dd,J
=8.1,7.8Hz,1H),7.50-7.47(m,2H),7.34-7.26(m,6H),7.11-7.07(m,2H),5.27-5.20(m,2H),3.88-3.84(m,2H),3.31(t
,J
=5.4Hz,1H)。LC-MS(ESI)m
/z
453.1(M+H)+
。
S -N-{4-[4-(2-羥基-1-苯基-乙胺基)-6-苯基-呋喃并[2,3-d]嘧啶-5-基胺基]-苯基}-丙烯醯胺( S -N-{4-[4-(2-hydroxy-1-phenyl-ethylamino)-6-phenyl-furo[2,3-d]pyrimidin-5-yl]-phenyl}-acrylamide)(化合物118來自步驟g)
:將7(136mg,0.3mmol)及5% Pd/C(10mg)之乙醇(3mL)混合液,於大氣壓力下進行氫化反應16小時,使用矽藻土過濾反應混合液後,真空移除溶劑則可獲得2-[5-(4-胺基-苯基)-6-苯基-呋喃并[2,3-d
]嘧啶-4-基胺基]-2-苯基-乙醇(2-[5-(4-amino-phenyl)-6-phenyl-furo[2,3-d
]pyrimidin-4-ylamino]-2-phenyl-ethanol),於此化合物及吡啶(0.05mL,0.6mmol)之***(3mL)混合液中,加入丙烯醯氯(0.03mL,0.33mmol),然後在室溫下攪拌16小時。加入水並以乙酸乙酯(3×20mL)萃取,合併有機層並用MgSO4
乾燥後於真空下濃縮,所得的殘餘物以矽膠快速管柱層析法使用己烷:乙酸乙酯(2:3)進行純化,則可得化合物118(29mg,20%)。1
H NMR(300MHz,CDCl3
)δ8.33(s,1H),8.00(brs,1H),7.80-7.71(m,2H),7.57(d,J
=8.4Hz,2H),7.47-7.44(m,3H),7.30-7.19(m,5H),7.07(d,J
=8.4Hz,2H),6.50(d,J
=16.8Hz,1H),6.32(dd,J
=16.8,10.2Hz,1H),5.83(d,J
=10.2Hz,1H),5.45(d,J
=6.3Hz,1H),5.20-5.18(m,1H),3.86-3.73(m,2H)。LCMS(ESI)m
/z
477.1(M+H)。
S -N-(3-(4-(2-羥基-1-苯基乙胺基)-6-苯基呋喃并[2,3-d]嘧啶-5-基)苯基)丙烯醯胺(化合物236來自步驟g)
:類似於製備化合物118之方法,使用8
合成化合物236,產率為25%。1
H NMR(300MHz,CDCl3
):δ8.58(brs,1H),8.27(s,1H),7.79-7.64(m,2H),7.49-7.46(m,2H),7.40(t,J
=7.5Hz,1H),7.27-7.20(m,8H),7.05-7.02(d,J
=7.5Hz,2H),6.46(d,J
=16.8Hz,1H),6.28(dd,J
=16.8,10.2Hz,1H),5.73(d,J
=10.2Hz,1H),5.64(d,J
=6.0Hz,1H),5.30(brs,1H),3.86(dd,J
=11.4,2.7Hz,1H),3.69(dd,J=11.4,6.9Hz,1H)。HRMS(EI)C29
H24
N4
O3
計算值476.1848,實驗值476.1843。
將8
(1g,0.002mmol,見上述實施例6)及5% Pd/C(10mg)之甲醇(10mL)混合液,於3個大氣壓力下進行氫化反應8小時,使用矽藻土過濾反應混合液後,真空移除溶劑則可獲得S
-2-[5-(3-胺基-苯基)-6-苯基-呋喃并[2,3-d
]嘧啶-4-基胺基]-2-苯基-乙醇(S
-2-[5-(3-amino-phenyl)-6-phenyl-furo[2,3-d
]pyrimidin-4-ylamino]-2-phenyl-ethanol),於此化合物之DCM(5mL)混合液中,加入4-溴巴豆酸(422mg,2.55mmol)、EDCI(490mg,2.55mmol),攪拌8小時後,加入N,N-二甲基胺(1.18ml,23.2mmol),於室溫下再持續攪拌8小時,之後將水加入反應混合液中並以二氯甲烷(3×20mL)萃取,合併有機層並用MgSO4
乾燥後於真空下濃縮,所得的殘餘物以矽膠快速管柱層析法使用二氯甲烷:甲醇(20:1)進行純化,則可得化合物243(370mg,30%)。
1
H NMR(300MHz,CDCl3
):δ8.32(s,1H),8.20(brs,1H),7.78-7.73(m,2H),7.54-7.51(m,2H),7.42(t,J
=7.8Hz,1H),7.27-7.18(m,7H),7.05-7.02(m,2H),6.94(dt,J
=15.9,6.0Hz,1H),6.14(d,J
=15.9,1H),5.67(d,J
=6.6Hz,1H),5.34(brs,1H),3.87(dd,J
=11.4,2.7Hz,1H),3.67(dd,J=11.4,6.9Hz,1H),2.71(brs,1H),2.25(s,6H)。LC-MS(ESI)m
/z
534.1(M+H)。
化合物32-58、237-242、244及247以類似實施例5、6或7的方法進行製備。這些化合物之1
H NMR及MS數據列舉如下。
化合物32:1
H NMR(300MHz,CDCl3
):δ8.39(s,1H),7.58-7.26(m,13H),6.99(m,2H),5.35(d,1H,J
=6.3Hz),5.26(m,1H),3.80(m,2H)。LC-MS(ESI)m
/z
408.1(M+H)。
化合物33:LC-MS(ESI)m
/z
422.1(M+H)+
。
化合物34:LC-MS(ESI)m
/z
422.2(M+H)+
。
化合物35:1
H NMR(300MHz,CDCl3
):δ8.37(s,1H),7.58(m,2H),7.35-7.26(m,8H),5.19(dd,1H,J 1
=5.7Hz,J 2
=10.5Hz),3.86(s,3H),3.80(dd,2H,J 1
=4.5Hz,J 2
=10.8Hz)。LC-MS(ESI)m
/z
438.7(M+H)。
化合物36:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),7.50(m,2H,),7.33-7.26(m,7H),7.03(m,2H),6.81(m,2H),5.31(d,1H,J
=5.7Hz),5.17(dd,1H,J 1
=5.4Hz,J 2
=10.2Hz),3.85(s,3H),3.81(m,2H),3.76(s,3H)。LC-MS(ESI)m
/z
468.4(M+H)。
化合物37:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),7.57(m,3H,),7.45(d,2H,J
=7.5Hz),7.32-7.26(m,6H),7.07(m,3H),5.41(d,1H,J
=6.3Hz),5.20(dd,1H,J 1
=6.3Hz,J 2
=9.3Hz),3.78(m,2H),2.25(s,3H)。LC-MS(ESI)m
/z
465.7(M+H)。
化合物38:1
H NMR(300MHz,CDCl3
):δ8.28(s,1H),7.65(m,2H),7.49(m,2H),7.40,(t,1H,J
=8.4Hz),7.26-7.15(m,7H),7.05(m,2H),5.61(d,1H,J
=6.0Hz),5.30(br,1H),3.84(m,1H),3.70(dd,1H,J 1
=6.3Hz,J 2
=10.8Hz),2.14(s,3H)。LC-MS(ESI)m
/z
465.7(M+H)。
化合物39:1
H NMR(300MHz,CDCl3
):δ8.36(s,1H),7.59(m,2H),7.49(m,2H),7.36-7.26(m,7H),7.10(m,2H),6.05(s,2H),5.46(d,1H,J
=5.1Hz),5.21(dd,1H,J 1
=5.4Hz,J 2
=10.5Hz),3.85(d,2H,J
=6.8Hz)。LC-MS(ESI)m
/z
452.6(M+H)。
化合物40:1
H NMR(300MHz,CDCl3
):δ8.38(s,1H),7.28(m,2H),7.42-7.26(m,8H),6.88(d,1H,J
=6.0Hz),6.49(m,2H),5.35(dd,1H,J 1
=3.9Hz,J 2
=15Hz),3.99(dd,2H,J 1
=7.5Hz,J 2
=11.4Hz)。LC-MS(ESI)m
/z
398.6(M+H)。
化合物41:1
H NMR(300MHz,CDCl3
):δ8.36(s,1H),7.68(m,2H),7.62m,(2H),7.38-7.28(m,6H),7.26(m,2H),6.54(m,1H),5.75(d,1H,J
=6.3Hz),5.30(q,1H,J
=5.4Hz),3.89(m,2H)。LC-MS(ESI)m
/z
398.7(M+H)。
化合物42:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),7.78(m,2H),7.46-7.33(m,8H),6.87(s,1H),5.38(d,1H,J
=5.7Hz),4.08(d,2H,J
=5.1Hz)。LC-MS(ESI)m
/z
332.6(M+H)。
化合物43:1
H NMR(300MHz,CDCl3
):δ8.32(s,1H),8.06(m,2H),7.52-7.26(m,8H),6.90(d,1H,J
=7.2Hz),5.48(m,1H),4.05(m,2H)。LC-MS(ESI)m
/z
411.1(M+H)。
化合物44:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),8.07(m,2H),7.52-7.26(m,8H),5.79(m,1H),4.57(dd,1H,J 1
=7.2Hz,J 2
=11.7Hz),4.45(dd,1H,J 1
=4.8Hz,J 2
=11.4Hz)。LC-MS(ESI)m
/z
452.0(M+H)。
化合物45:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),8.06(m,2H),7.53-7.26(m,8H),6.65(d,1H,J
=7.2Hz),5.48(m,1H),4.07(m,2H),3.03(br,1H)。LC-MS(ESI)m
/z
366.5(M+H)。
化合物46:1
H NMR(300MHz,CDCl3
):δ8.40(s,1H),7.60-7.57(m,6H),7.33-7.21(m,9H),5.84(d,1H,J
=9.0Hz),5.71(d,1H,J
=6.6Hz),3.68(s,3H)。LC-MS(ESI)m
/z
436.2(M+H)。
化合物47:LC-MS(ESI)m
/z
450.6(M+H)+
。
化合物48:LC-MS(ESI)m
/z
464.2(M+H)+
。
化合物49:LC-MS(ESI)m
/z
478.2(M+H)+
。
化合物50:1
H NMR(300MHz,CDCl3
+CD3
OD):δ8.19(s,1H),7.44-7.42(m,7H),7.24-7.17(m,8H),5.55(s,1H)。LC-MS(ESI)m
/z
422.1(M+H)。
化合物51:LC-MS(ESI)m
/z
421.2(M+H)+
。
化合物52:LC-MS(ESI)m
/z
480.0(M+H)+
。
化合物53:LC-MS(ESI)m
/z
424.0(M+H)+
。
化合物54:LC-MS(ESI)m
/z
406.5(M+H)+
。
化合物55:LC-MS(ESI)m
/z
406.6(M+H)+
。
化合物56:1
H NMR(300MHz,CDCl3
):δ8.36(s,1H),7.32(d,2H,J
=7.8Hz),7.42-7.24(m,8H),6.83(s,1H),5.73(br,1H),5.21(d,1H,J
=7.2Hz),1.99(m,2H),1.00(t,3H,J
=7.5Hz)。LC-MS(ESI)m
/z
330.1(M+H)+
。
化合物57:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),8.03(m,2H),7.51-7.44(m,2H),7.42-7.34(m,5H),7.31-7.34(m,1H),6.17(d,1H,J
=7.8Hz),6.35(q,1H,J
=7.8Hz),2.01(m,2H),0.99(t,3H,J
=7.5Hz)。LC-MS(ESI)m
/z
363.9(M+H)+
。
化合物58:LC-MS(ESI)m
/z
310.1(M+H)+
。
化合物237:1
H NMR(300MHz,CDCl3
,):δ8.34(s,1H),7.53(m,4H),7.41(m,3H),7.27(m,7H),7.15(m,2H),6.96(m,1H),6.85(d,1H,J
=7.5Hz),6.77(d,J
=9.6Hz),5.55(m,1H),5.46(m,1H),4.34(d,2H,J
=5.4Hz),3.67(m,1H),3.54(m,1H)。LC-MS(ESI)m
/z
516.2(M+H)。
化合物238:H NMR(300MHz,CDCl3
):δ8.38(s,1H),7.85-7.70(m,3H),7.75-7.44(m,3H),7.29-7.20(m,6H),7.12(d,J
=6.9Hz,2H),6.52(d,J
=16.8Hz,1H),6.34(dd,J
=16.8,9.9Hz,1H),5.85(d,J
=9.9Hz,1H),5.87-5.82(m,1H),4.99(d,J
=7.8Hz,1H),1.38(d,J
=6.9Hz,3H)。LC-MS(ESI)m
/z
461.2(M+H)。
化合物239:H NMR(300MHz,CDCl3
):δ8.38(s,1H),7.96-7.91(m,1H),7.55-7.47(m,5H),7.29-7.18(m,6H),7.12(d,J
=6.6Hz,2H),6.46(d,J
=16.8Hz,1H),6.23(dd,J
=16.8,10.2Hz,1H),5.80(d,J
=10.2Hz,1H),5.36-5.28(m,1H),5.04(d,J
=7.5Hz,1H),1.38(d,J
=6.6Hz,3H)。LC-MS(ESI)m
/z
461.2(M+H)。
化合物240:1
H NMR(300MHz,CDCl3
):δ8.36(s,1H),8.11(brs,1H),7.57-7.47(m,4H),7.30-7.21(m,8H),7.08-7.06(m,2H),6.47(d,J
=16.8Hz,1H),6.28(dd,J
=16.8,8.1Hz,2H),5.99(dd,J
=16.8,10.2Hz,1H),5.82-5.77(m,2H),5.33(d,J
=8.4Hz,1H),4.50(brs,1H),4.30-4.20(m,1H)。LC-MS(ESI)m
/z
531.0(M+H)。
化合物241:1
H NMR(300MHz,CDCl3
):δ8.37(s,1H),7.67-7.64(m,2H),7.56-7.52(m,3H),7.42(t,J
=7.8Hz,1H),7.29-7.22(m,7H),7.07-7.04(m,2H),5.48-5.47(m,1H),5.30-5.29(m,1H),3.88-3.75(m,3H),2.01(s,3H)。LC-MS(ESI)m
/z
489.1(M+H)。
化合物242:1
H NMR(300MHz,CDCl3
):δ8.35(s,1H),7.76-7.73(m,2H),7.61-7.21(m,11H),7.06-7.03(m,2H),5.54-5.53(m,1H),5.00-4.97(m,1H),4.04-4.02(m,2H),3.49(s,3H),2.28(s,3H)。LC-MS(ESI)m
/z
503.1(M+H)。
化合物244:1
H NMR(300MHz,CDCl3
):δ8.24(s,1H),8.04(s,1H),7.65(d,J
=8.4Hz,1H),7.50-7.29(m,9H),7.00(brs,1H),6.48(d,J
=16.8Hz,1H),6.38(dd,J
=16.8,9.6Hz,1H),5.78(d,J
=9.6Hz,1H),5.38(brs,1H),4.03-3.97(m,2H),2.32(s,1H)。LC-MS(ESI)m
/z
401.0(M+H)。
化合物247:1
H-NMR(400MHz,CDCl3
):δ2.24(s,3H),3.44(s,3H),3.79-3.83(m,H),3.99-4.01(m,H),5.77-5.80(d,H),6.19-6.30(m,H),6.39-6.47(d,2H),7.03-7.48(m,10H),8.46(s,H)。
EGFR激酶分析係於96孔盤中在37℃下進行60分鐘,其中使用50μl的混合液,此混合液含有以下成分:50ng GST-EGFR-KDWT
蛋白質、25mM Tris-HCl pH 7.5、4mM MnCl2
、2mM DTT、10mM MgCl2
、0.1mg/ml牛血清白蛋白、10μM poly(Glu,Tyr)4:1、0.5mM Na3
VO4
、5μM ATP及待測化合物。接著,進行培養,其中添加50μl Kinase-Glo Plus Reagent(Promega),然後將混合液置於25℃下再額外培養20分鐘。每個反應混合液中吸取70μl,轉換至黑色微量盤中,於多重標定冷光偵測技術儀(Wallac Vector 1420 multilabel counter,PerkinElmer)上測量冷光。
GST-EGFR-KDWT
蛋白質之表現及純化,如Analytical Biochemistry 377(2008)89-94所述之方法。
此分析中測試化合物1-68、75、106、107、118、154、176、178、180、181、183-247及327。出乎預期之外,化合物1、7、8、15、18、20、22、23、31、35、38-43、45、61、154、181、188、192、204、206、238-240、242及247展現出介於101nM及0.9μM之間的IC50
值(亦即EGFR的活性受到50%抑制時之待測化合物的濃度):化合物36、37、63、118、186、220、230及244顯示介於60及100nM之間的IC50
值;且化合物12、50、53、62、64-67、75、106、107、176、178、185、187、190、191、193-195、198-200、202、203、205、208-219、223、224、226-229、231-233、236、241、243、245、246及327展現出低於59nM的IC50
值。
使用MTS分析(Promega,Madison,WI,USA)檢查HCC827細胞的存活性。在96孔盤的每個孔中,將1000個HCC827細胞植入100μL含10% FBS之RPMI1640培養基中,與待測化合物培養96小時後,在37℃下於通有5% CO2
的潮濕培養箱中,將細胞與20μL的MTS/PMS混合液(MTS/PMS比例為20:1)培養2小時,使存活的細胞得以將四唑鹽類(tetrazolium salt(MTS))轉換成甲臢(formazan),而存活細胞數目指標的甲臢含量/濃度,則使用微量盤分析儀(PerkinElmer Victor2 plate reader,PerkinElmer,Shelton,CT,USA)測定490nm的吸光值來決定。
根據實施例9中的實驗數據,本分析中僅測試化合物1、3-5、7-8、12、15、23、31、35、37-51、53、54、56、62-68、75、106、107、118、176、178、181、185-188、190-195、198、200、202-206、208-219、223、224、226-232、236、238、239、241及243-246。意外發現化合物3、4、15、23、31、40、42、44、46、47、54、56、118、186、188、193、206及244的IC50
值(亦即造成細胞50%死亡的測化合物濃度),介於301nM及999nM之間;而化合物1、35、37-39、41、63、202及245的IC50
值,介於100nM及300nM之間;且化合物12、62、64-68、75、106、107、176、178、181、185、187、190-192、194、195、198、200、203-205及208-219、223、224、226-232、236、238、239、241、243及246的IC50
值,介於1nM及99nM之間。
將含EGFR激酶催化區域(第696至1022個胺基酸且具有L858R/T790M)之GST-EGFR-KDL858RT/790M
,利用含pBac-PAK8-GST-EGFR-KDL858RT/790M
質體之桿狀病毒,轉染至Sf9昆蟲細胞中進行表現,GST-EGFR-KDL858RT/790M
蛋白質之表現及純化,如上述Analytical Biochemistry 377(2008)89-94所述之方法。
EGFRL858RT790M
Kinase-Glo分析係於96孔盤中,以最終體積為50μl在37℃下進行60分鐘,此體積中含有以下成分:200ng GST-EGFR-KDL858R/T790M
蛋白質、25mM HEPES pH 7.4、4mM MnCl2
、2mM DTT、10mM MgCl2
、0.1mg/ml牛血清白蛋白、10μM poly(Glu,Tyr)4:1、0.5mM Na3
VO4
、1μM ATP及待測化合物。接著,進行培養,其中添加50μl Kinase-Glo Plus Reagent(Promega),然後將混合液置於25℃下培養20分鐘。每個反應混合液中吸取70μl,轉換至黑色微量盤中,於多重標定冷光偵測技術儀(Wallac Vector 1420 multilabel counter,PerkinElmer)上測量冷光。
此分析中測試化合物9、11-16、36、59-68、75、106、107、118、154、176、178、180、181及183-236、238-241、243、245-247及327。出乎預期之外,化合物63-67、75、106、178、188、190、191、193、198、203、205、211、215、228、232、239及241之IC50
值(亦即EGFR突變體的活性受到50%抑制時之待測化合物的濃度),介於500nM及2.5μM之間;且化合物12、62、176、185、187、195、200、202、210、223、226、227、236、240及243之IC50
值介於10nM及499nM之間。
使用肺癌異種移植小鼠(注入有HCC827),評估本發明化合物的體內效率,如Cancer Research 2004,64,4621-4628所述。
HCC827細胞藉由皮下注射裸鼠,以形成肺癌異植小鼠。帶有腫瘤大小約100mm3
的小鼠,隨機分派成兩個群組:空白控制組(10隻小鼠)及處理組(21隻小鼠)。在受處理的小鼠中,21隻由小鼠尾巴靜脈以靜脈注射投藥,每日接受5mg/kg及15mg/kg劑量之化合物62,1星期5天並持續2星期(第1-5日及第8-12日)。
出乎意料之外,化合物62在5及15 mg/kg劑量下明顯抑制腫瘤生長(p
<0.05),此表示其具有體內抗癌的潛力。在觀察期間的最後,處理後的第22天,經過化合物62處理所得的腫瘤大小為空白控制組腫瘤大小的39%(5 mg/kg)或23%(15 mg/kg)。
本說明書中所揭示之全部特徵可以任何方式組合。本說明書中所揭示之特徵可被相同、相當或類似目的之另一種特徵所取代。因此,除非另有指明,否則所揭示之各特徵僅為一般性之相當或類似特徵之實例。
藉由上述說明,本發明可輕易的由熟習本項技藝者瞭解本發明必要之特徵,且在不悖離本發明之範疇下,能夠對本發明有種種改變及修飾,以適用於種種用途與情況,因此其他具體實施例亦在本申請專利範圍內。
Claims (37)
- 一種式(II)之化合物:
- 如申請專利範圍第1項所述之化合物,其中,R’為或,其中R6 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc 、C(O)ORc 、C(O)NRc Rd 或CH2 NRc Rd ,其中Rc 及Rd 分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc 及Rd 與其兩者所鍵結 之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。
- 如申請專利範圍第2項所述之化合物,其中,B為苯基且n為0。
- 如申請專利範圍第3項所述之化合物,其中,m為1且A為OR3 ,R3 為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3 烷基。
- 如申請專利範圍第4項所述之化合物,其中,X為N,Y為NH且Z為O。
- 如申請專利範圍第1項所述之化合物,其中,B為苯基且n為0。
- 如申請專利範圍第6項所述之化合物,其中,A為C(O)OR3 且m為0。
- 如申請專利範圍第7項所述之化合物,其中,X為N,Y為NH且Z為O。
- 如申請專利範圍第8項所述之化合物,其中,W為CR5 ,其中R5 為鹵素。
- 如申請專利範圍第6項所述之化合物,其中,R’及R”各自為ORa 。
- 如申請專利範圍第10項所述之化合物,其中,m為1且A為OR3 ,R3 為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3 烷基。
- 如申請專利範圍第11項所述之化合物,其中,X為N,Y為NH且Z為O。
- 如申請專利範圍第1項所述之化合物,其中,該化合物為或
- 一種式(II)之化合物:
- 一種式(II)之化合物:
- 如申請專利範圍第15項所述之化合物,其中,m為1且A為OR3 ,R3 為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3 烷基。
- 如申請專利範圍第15項所述之化合物,其中,該化合物為化合物
- 一種式(II)之化合物:
- 如申請專利範圍第18項所述之化合物,其中,R’為或,其中R6 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc 、C(O)ORc 、C(O)NRc Rd 或CH2 NRc Rd ,其中Rc 及Rd 分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環 烯基、雜環烷基或雜環烯基,或者Rc 及Rd 與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。
- 如申請專利範圍第19項所述之化合物,其中,B為苯基且n為0。
- 如申請專利範圍第20項所述之化合物,其中,A為C(O)OR3 或烷基,且m為0。
- 如申請專利範圍第18項所述之化合物,其中,m為1且A為OR3 ,R3 為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3 烷基。
- 如申請專利範圍第18項所述之化合物,其中,該化合物為或
- 一種式(II)之化合物:
- 如申請專利範圍第24項所述之化合物,其中,m為1且A為OR3 ,R3 為H、芳基、雜芳基或選擇性經芳基或雜芳基取代之C1-3 烷基。
- 如申請專利範圍第24項所述之化合物,其中,R’為或,其中R6 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基、雜環烯基、C(O)Rc 、C(O)ORc 、C(O)NRc Rd 或CH2 NRc Rd ,其中Rc 及Rd 分別為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基,或者Rc 及Rd 與其兩者所鍵結之氮原子形成為雜環烷基、雜環烯基或雜芳基,且R7 為H、烷基、烯基、炔基、芳基、雜芳基、環烷基、環烯基、雜環烷基或雜環烯基。
- 如申請專利範圍第24項所述之化合物,其中,該化合物為或
- 一種使用一化合物製造治療癌症的藥物之用途,其中該化合物為有效劑量之申請專利範圍第1項所述的化合物。
- 一種使用一化合物製造治療癌症的藥物之用途,其中該化合物為有效劑量之申請專利範圍第14項所述的化合物。
- 一種使用一化合物製造治療癌症的藥物之用途,其中該化合物為有效劑量之申請專利範圍第15項所述的化合物。
- 一種使用一化合物製造治療癌症的藥物之用途,其中該化合物為有效劑量之申請專利範圍第18項所述的化合物。
- 一種使用一化合物製造治療癌症的藥物之用途,其中該化合物為有效劑量之申請專利範圍第24項所述的化合物。
- 一種醫藥組成物,包括:一申請專利範圍第1項所述之化合物以及一醫藥可接受載體。
- 一種醫藥組成物,包括:一申請專利範圍第14項所述之化合物以及一醫藥可接受載體。
- 一種醫藥組成物,包括:一申請專利範圍第15項所述之化合物以及一醫藥可接受載體。
- 一種醫藥組成物,包括:一申請專利範圍第1R項所述之化合物以及一醫藥可接受載體。
- 一種醫藥組成物,包括:一申請專利範圍第24項所述之化合物以及一醫藥可接受載體。
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JP (1) | JP5781934B2 (zh) |
KR (1) | KR101703941B1 (zh) |
CN (1) | CN102264745B (zh) |
HK (1) | HK1162509A1 (zh) |
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CN103360407B (zh) * | 2012-04-10 | 2016-06-22 | 上海希迈医药科技有限公司 | 一种噻吩并嘧啶类衍生物、其制备方法及其在医药上的应用 |
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- 2009-11-09 KR KR1020117011218A patent/KR101703941B1/ko active IP Right Grant
- 2009-11-09 TW TW098137894A patent/TWI385174B/zh active
- 2009-11-09 US US12/614,584 patent/US8507502B2/en active Active
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JP2012508252A (ja) | 2012-04-05 |
WO2010054285A3 (en) | 2010-09-16 |
HK1162509A1 (zh) | 2012-08-31 |
CN102264745B (zh) | 2015-07-22 |
TW201018696A (en) | 2010-05-16 |
KR20110103937A (ko) | 2011-09-21 |
US20100120805A1 (en) | 2010-05-13 |
JP5781934B2 (ja) | 2015-09-24 |
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US8507502B2 (en) | 2013-08-13 |
KR101703941B1 (ko) | 2017-02-07 |
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