TWI733679B - Hpk1抑制劑及其使用方法 - Google Patents
Hpk1抑制劑及其使用方法 Download PDFInfo
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- TWI733679B TWI733679B TW105120043A TW105120043A TWI733679B TW I733679 B TWI733679 B TW I733679B TW 105120043 A TW105120043 A TW 105120043A TW 105120043 A TW105120043 A TW 105120043A TW I733679 B TWI733679 B TW I733679B
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- Prior art keywords
- compound
- pharmaceutically acceptable
- alkyl
- cancer
- acceptable salt
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Abstract
本發明係關於由式(I)表示之化合物:
或其醫藥學上可接受之鹽。本文中提供變數之值。亦包括包含由該式(I)表示之化合物及醫藥學上可接受之載劑或稀釋劑的藥物組合物及用該式(I)化合物治療患有疾病之個體的方法。
Description
本申請案主張2015年6月25日申請之美國臨時申請案第62/184,348號之權益。前述申請案之整個教示內容以引用的方式併入本文中。
造血祖細胞激酶1(HPK1)為造血細胞受限的Ste20絲胺酸/蘇胺酸激酶。可藉由活化信號來誘發HPK1激酶活性,該等活化信號在配位體接合後由在造血細胞中所發現之各種不同細胞表面受體產生。T細胞受體(TCR)、B細胞抗原受體(BCR)(Liou等人,2000,Immunity 12:399)、轉型生長因子β受體(TGF-βR)(Wang等人,1997.J.Biol.Chem.272:22771;Zhou等人,1999,J.Biol.Chem.274:13133)、紅血球生成素受體(EPOR)(Nagata等人,1999,Blood 93:3347)及Fas(Chen等人,1999,Oncogene 18:7370)之配位體接合或抗體介導交聯可誘發HPK1激酶活性。每一受體利用唯一(但有時利用重疊的)信號傳導機制來活化HPK1。HPK1經由AP-1、NFKB、Erk2及Fos路徑充當T及B細胞功能之向下調節劑;舉例而言,HPK1涉及經由T細胞受體接附蛋白質SLP-76之磷酸化及活化而在T細胞中作為信號轉導之負調控劑(Di Bartolo等人,2007,J.Exp.Med.204:681),此情形引起AP-1及Erk2路徑之隨後向下調節。在B細胞中,HPK1經由SLP-76旁系同源物BLINK之磷酸化向下調節B細胞受體(BCR)信號傳導(Wang等人,
2012,J.Biol.Chem.287:11037)。
因此,HPK1現被視為用於治療性干預之可能靶向物。舉例而言,據報導,HPK1可為用於癌症免疫療法之新穎靶向物(Sawasdikosol等人,Immunol Res.2012年12月;54(1-3):262-5)。具體言之,HPK1對偶基因之靶向破壞賦予T細胞回應於TCR接合之提高的Th1細胞激素生產。HPK1(-/-)T細胞比單倍型匹配的野生型對應體增殖得更快且對***素E2(PGE(2))介導之抑制具有抗性。最引人注目的是,接受HPK1(-/-)T細胞之授受性轉移的小鼠變得對肺腫瘤生長具有抗性。又,自樹突狀細胞(DC)損失HPK1賦予其優良的抗原呈遞能力,使得HPK1(-/-)DC在用作癌症疫苗時能夠誘發更強效的抗腫瘤免疫反應。
在評估HPK1之小分子抑制劑是否將俘獲基因靶向破壞之小鼠的表型時,考慮蛋白質之非催化作用係至關重要的。特定言之,雖然全長HPK1可促進經活化B細胞(NF-κB)路徑之核因子κ輕鏈強化子的TCR介導之活化,但催化無活性裂解產物HPK1-C可在TCR再刺激後抑制NF-κB活化,從而造成活化誘發之細胞死亡(AICD)(Brenner等人,EMBO J.2005,24:4279)。一併考慮HPK1之催化及非催化作用,有可能使用小分子抑制劑阻斷HPK1激酶活性可促進B細胞及T細胞之活化,從而產生優良的抗腫瘤免疫,同時亦促進AICD,從而有助於維持周邊免疫耐受性。HPK1抑制劑之確切效果將藉由在癌症(諸如同基因型腫瘤異種移植)小鼠模型中之測試加以證實。鑒於HPK1不在造血系統外之任何主要器官中表現,HPK1激酶活性之抑制劑將不大可能造成任何嚴重的副作用。
鑒於以上內容,在此項技術中需要可抑制HPK1的新穎化合物。
申請人現已發現某些噻吩并吡啶化合物為HPK1抑制劑(參見實例
B)。該等化合物亦具有對FLT3及LCK之抑制活性(參見實例C)。另外,已證實單獨作為HPK1抑制劑及與抗PD-1抗體組合之某些噻吩并吡啶化合物在具有某些癌細胞類型之臨床前模型中有效(參見實例E)。本文中揭示之特定組合療法展現具有顯著抗癌效果的出人意料的生物活性。具體言之,藉由HPK1抑制劑及抗PD-1抗體之組合,現已在CT26.WT結腸癌瘤中證實PD-1/PD-L1阻斷後之顯著反應。基於此等發現,本文中揭示噻吩并吡啶化合物、其醫藥組合物及其使用方法。
本發明之另一實施例為一種包含醫藥學上可接受之載劑或稀釋劑以及上文所描述之由結構式(I)表示之化合物或其醫藥學上可接受之鹽的醫藥組合物。
本發明之另一實施例為一種治療患有可藉由HPK1調節之疾病的個體之方法,該方法包含向該個體投與有效量之結構式(I)化合物或其醫藥學上可接受之鹽。
本發明之另一實施例為一種抑制需要抑制HPK1活性之個體的HPK1活性之方法,該方法包含向該個體投與有效量的由結構式(I)表示之化合物或其醫藥學上可接受之鹽。
本發明之另一實施例為一種用於療法的由結構式(I)表示之化合物或其醫藥學上可接受之鹽。在一些實施例中,該療法用於治療患有癌症之個體。替代地,該療法用於抑制需要抑制HPK1活性之個體的
HPK1活性。
本發明之另一實施例為由結構式(I)表示之化合物或其醫藥學上可接受之鹽的用途,其係用於製造用於治療患有癌症之個體的藥劑。
本發明之另一實施例為由結構式(I)表示之化合物或其醫藥學上可接受之鹽的用途,其係用於製造用於抑制需要抑制HPK1活性之個體的HPK1活性之藥劑。
本發明亦係針對一種治療患有癌症之個體的方法,該方法包含向該個體投與有效量之HPK1抑制劑(例如,由結構式(I)表示之化合物)或其醫藥學上可接受之鹽及有效的第二抗癌治療(例如,化學治療劑、靶向治療劑、輻射或手術)。在一個實例中,第二抗癌治療為PD-1抑制劑。
本發明亦係針對一種治療患有癌症之個體的方法,該方法包含向個體投與有效量之HPK1抑制劑(例如,由結構式(I)表示之化合物)或其醫藥學上可接受之鹽,及有效量之免疫調節劑,諸如檢查點抑制劑(例如,抗PD-1抗體、抗CTLA4抗體或抗PD-L1抗體)或色胺酸氧化之抑制劑(例如,IDO1、IDO2或TDO2抑制劑)。在一個實例中,免疫調節劑為抗PD-1抗體。
在一個實施例中,本發明進一步提供HPK1抑制劑(例如,由結構式(I)表示之化合物或其醫藥學上可接受之鹽)之用途,其係用於製造與諸如納武單抗(nivolumab)、派立珠單抗(pembrolizumab)、皮立珠單抗(pidilizumab)、BMS 936559、MPDL3280A、MSB0010718C或MEDI4736之PD-1抑制劑組合用於治療患有癌症之個體的藥劑。較佳地,PD-1抑制劑為納武單抗。替代地,PD-1抑制劑為派立珠單抗。在一個實施例中,PD-1抑制劑為抗PD1抗體。
在一個替代例中,HPK1抑制劑與有效量之一或多種其他抗癌療法一起投藥,且較佳地與PD-1抑制劑組合。
圖1展示化合物實例A30對α-CD3刺激之Jurkat E6.1細胞中之SLP-76絲胺酸376磷酸化的抑制效果。
圖2為說明在單獨且與抗PD1抗體組合地投予化合物A1後之腫瘤生長抑制百分比的圖表。
圖3展示化合物實例A30在EAE疾病進展模型中之效果。
在第一實施例中,本發明係針對由式(I)表示之化合物:
或其醫藥學上可接受之鹽,其中:X1、X2及X3中之一者為S,其他兩者各自獨立地為CR,其中R為-H、-F、-Cl、-Br、-CN、-NH2、-OH、視情況經取代之(C1-C6)烷基、視情況經取代之(C1-C6)烷氧基、視情況經取代之-(CH2)n(C3-C10)環烷基、視情況經取代之-(CH2)n-3至7員單環雜環基、視情況經取代之-(CH2)n苯基、視情況經取代之-(CH2)n-5至7員單環雜芳基、視情況經取代之-(CH2)n橋聯(C6-C12)環烷基、視情況經取代之-(CH2)n-6至12員橋聯雜環基、視情況經取代之-(CH2)n-7至12員雙環雜芳基或視情況經取代之-(CH2)n-7至12員雙環雜芳基;Y為鍵、-CH2-、-C(=O)-;R1為-NRaRb或-ORa1;Ra在每次出現時獨立地為-H、視情況經取代之(C1-C6)烷基、視情況經取代之-(CH2)n(C3-C10)環烷基、視情況經取代之-(CH2)n-3至10
員雜環基、視情況經取代之-(CH2)n(C6-C10)芳基、視情況經取代之-(CH2)n-5至10員雜芳基、視情況經取代之-(CH2)n橋聯(C6-C12)環烷基或視情況經取代之-(CH2)n-6至12員橋聯雜環基;Rb在每次出現時獨立地為-H或-(C1-C6)烷基;或,Ra及Rb與其所連接之氮一起形成視情況經取代之-(C3-C10)雜環基;Ra1在每次出現時獨立地為-H、視情況經取代之(C1-C6)烷基、視情況經取代之(C3-C10)環烷基、視情況經取代之3至10員雜環基、視情況經取代之(C6-C10)芳基或視情況經取代之3至10員雜芳基;或R2及R3各自獨立地為-H或-(C1-C6)烷基;R4及R5各自獨立地為-H、視情況經取代之(C1-C6)烷基、視情況經取代之(C3-C10)環烷基、視情況經取代之3至10員雜環基、視情況經取代之(C6-C10)芳基、視情況經取代之5至10員雜芳基、視情況經取代之橋聯(C6-C12)環烷基或視情況經取代之6至12員橋聯雜環基;或R4及R5與其所連接之氮一起形成視情況經取代之4至10員雜環基、視情況經取代之5至10員雜芳基或視情況經取代之6至12員橋聯雜環基;R6在每次出現時獨立地為-F、-Cl、-Br、-CN、-NH2、-OH、-(C1-C6)烷基、-(C1-C6)鹵烷基、-(C2-C6)烯基、-(C2-C6)炔基、(C3-C6)環烷基、-(C1-C6)烷氧基、-(C1-C6)鹵烷氧基、-(C1-C6)伸烷基-OH或-(C1-C6)伸烷基-NH2;m為0、1、2或3;且n為0、1或2。
在第二實施例中,本發明提供由結構式(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物:
或其醫藥學上可接受之鹽。結構式(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)中之變數的值如針對結構式(I)所描述。
在第三實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中R4及R5與其所連接之氮一起形成4至7員單環雜環基或6至12員橋聯雜環基,其中該4至7員單環雜環基或6至12員橋聯雜環基視情況經由1至3個選自-F、-Cl、-Br、-CN、-NH2、-OH、側氧基、-(C1-C4)烷基、-(C1-C4)鹵烷基、-(C1-C4)烷氧基、-(C1-C4)鹵烷氧基、-(C1-C4)伸烷基-OH或-(C1-C4)伸烷基-NH2之基團取代。變數之剩餘部分的值如針對結構式(I)所描述。
在第四實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中Ra在每次出現時獨立地為-H、-(C1-C6)烷基、-(CH2)n-(C3-C7)環烷基、-(CH2)n-4至7員單環雜環基、-(CH2)n橋聯(C6-C12)環烷基、視情況經取代之-(CH2)n-5至10員雜芳基或-(CH2)n-6至12員橋聯雜環基,其中-(C1-C6)烷基、-(CH2)n-(C3-C7)環烷基、-(CH2)n-4至7員單環雜環基、-(CH2)n橋聯(C6-C12)環烷基、-(CH2)n-5至10員雜芳基或-(CH2)n-6至12員橋聯雜環基視情況經由1至3個選自-F、-Cl、-Br、-CN、-NH2、-OH、側氧基、-(C1-C4)烷基、-(C1-C4)鹵烷基、-(C1-C4)烷氧基、-(C1-C4)鹵烷氧基、-(C1-C4)伸烷基-OH或-(C1-C4)伸烷基-NH2之基團取代,且變數之剩餘部分的值如上文針對結構式(I)或在第三實施例中所描述。
在第五實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中R為H、-F、-Cl、-Br、-OH、-(C1-C4)烷基、-(C1-C4)鹵烷基、-(C1-C4)烷氧基、-(C1-C4)伸烷基-OH或視情況經由1至3個選自-F、-Cl、-Br、-OH、-(C1-C4)烷基、-(C1-C4)鹵烷基或-(C1-C4)烷氧基之基團取代的4至7員單環雜環基,且變數之剩餘部分的值如上文針對結構式(I)或者在第三或第四實施例中所描述。
在第六實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中R4及R5與其所連接之氮一起形成-N-烷基-哌嗪基或嗎啉基,其中哌嗪基或嗎啉基視情況經由1至2個選自-F、-Cl、-Br、-OH、-(C1-C4)烷基、-(C1-C4)鹵烷基或-(C1-C4)烷氧基之基團取代,且變數之剩餘部分的值如上文針對結構式(I)或者在第三、第四或第五實施例中所描述。
在第七實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中Ra在每次出現時獨立地為-H、-(CH2)n-(C3-C6)環烷基、-(CH2)n-3至6員雜環基,其中-(CH2)n-(C3-C6)環烷基或-(CH2)n-3至6員雜環基視情況經由1至3個選自-F、-Cl、-Br、-CN、-NH2、-OH、-(C1-C4)烷基或-(C1-C4)烷氧基之基團取代;且n為0或1,且變數之剩餘部分的值如上文針對結構式(I)或者在第三、第四、第五或第六實施例中所描述。
在第八實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中R為H、-(C1-C4)烷基、-(C1-C4)烷氧基、視情況經由-CO2-(C1-C4)烷基取代之N-哌嗪基,且變數之剩餘部分的值如上文針對結構式(I)或者在第三、第四、第五、第六或第七實施例中所描述。替代地,R為H。
在第九實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)
至(II-C)或(III-A)至(III-C)表示之化合物,其中R4及R5與其所連接之氮一起形成-N-甲基-哌嗪基或嗎啉基,其兩者視情況經由一個或兩個甲基取代,且變數之剩餘部分的值如上文針對結構式(I)或者在第三、第四、第五、第六、第七或第八實施例中所描述。
在第十實施例中,本發明提供由結構式(I)、(I-A)至(I-C)、(II-A)至(II-C)或(III-A)至(III-C)表示之化合物,其中Ra在每次出現時獨立地為:-H;視情況經由-OH取代之-(C3-C6)環烷基;-(CH2)n-四氫-2H-哌喃;嗎啉基;視情況經由-F、-OH或甲基取代之哌啶基;或四氫呋喃;且n為0或1,且變數之剩餘部分的值如上文針對結構式(I)或者在第三、第四、第五、第六、第七、第八或第九實施例中所描述。
本發明亦包括在例證說明中藉由結構描繪及/或藉由名稱描述之化合物。本發明包括此等化合物之中性形式(游離鹼)以及其醫藥學上可接受之鹽兩者。藉由此等化合物之治療及/或此等化合物之用途包括此等化合物之中性形式以及其醫藥學上可接受之鹽。
單獨或作為較大部分(諸如「烷氧基」或「鹵烷基」及其類似物)之一部分使用的術語「烷基」意謂飽和脂族直鏈或分支鏈單價烴基。除非另外規定,否則烷基通常具有1至6個碳原子,亦即(C1-C6)烷基。如本文中所使用,「(C1-C6)烷基」意謂具有以直鏈或分支鏈排列之1至6個碳原子的基團。實例包括甲基、乙基、正丙基、異丙基等。
「烷氧基」意謂經由氧鍵聯原子連接之烷基,其由-O-烷基表示。舉例而言,「(C1-C4)烷氧基」包括甲氧基、乙氧基、丙氧基及丁氧基。
術語「鹵烷基」及「鹵烷氧基」視具體情況而定意謂經由一或多個鹵素原子取代之烷基或烷氧基。術語「鹵素」意謂F、Cl、Br或I。較佳地,鹵烷基或鹵烷氧基中之鹵素為F。
「烯基」意謂含有至少一個雙鍵之分支鏈或直鏈單價烴基。烯
基可為單不飽和或多不飽和的,且可以E或Z組態存在。除非另外規定,否則烯基通常具有2至6個碳原子,亦即(C2-C6)烯基。舉例而言,「(C2-C6)烯基」意謂具有以直鏈或分支鏈排列之2至6個碳原子的基團。
「炔基」意謂含有至少一個參鍵之分支鏈或直鏈單價烴基。除非另外規定,否則炔基通常具有2至6個碳原子,亦即(C2-C6)炔基。舉例而言,「(C2-C6)炔基」意謂具有以直鏈或分支鏈排列之2至6個碳原子的基團。
「環烷基」意謂飽和脂族環烴基,其通常含有3至8個環碳原子,亦即(C3-C8)環烷基。(C3-C8)環烷基包括(但不限於)環丙基、環丁基、環戊基、環己基、環庚基及環辛基。
如本文中所使用,如在「橋聯環烷基」或「橋聯雜環基」中單獨或作為較大部分之一部分使用的術語「橋聯」係指包括共用至少三個鄰接環原子之兩個環的環系統。橋聯環烷基通常含有6至12個環碳原子。橋聯雜環基通常具有選自碳及至少一個(典型地1至4個,更典型地1個或2個)雜原子(例如,氧、氮或硫)之6至12個環原子。
如在「芳基烷基」、「芳基烷氧基」或「芳氧基烷基」中單獨或作為較大部分之一部分使用的術語「芳基」意謂碳環芳環。其亦包括與環烷基稠合之苯環。術語「芳基」可與術語「芳環」、「碳環芳環」、「芳基」及「碳環芳族基」互換使用。芳基通常具有六至十四個環原子。實例包括苯基、萘基、蒽基、1,2-二氫萘基、1,2,3,4-四氫萘基、茀基、茚滿基、茚基及其類似基團。「經取代之芳基」在任何一或多個可取代環原子處被取代,該可取代環原子為鍵結至氫之環碳原子。
術語「雜芳基」、「雜芳族基」、「雜芳基環」、「雜芳基」、「雜芳環」及「雜芳族基」在本文中可互換使用。當如在「雜芳基烷基」或
「雜芳烷氧基」中單獨或作為較大部分之一部分使用時,「雜芳基」係指具有選自碳及至少一個(典型地1至4個,更典型地1個或2個)雜原子(例如,氧、氮或硫)之五至十四個環原子的芳環基。「雜芳基」包括單環雜芳環稠合至一或多個其他芳基、雜環基或雜芳環之單環及多環。由此,「5至14員雜芳基」包括單環、雙環或三環系統。
單環5至6員雜芳基之實例包括呋喃基(例如,2-呋喃基、3-呋喃基)、咪唑基(例如,N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基)、異噁唑基(例如,3-異噁唑基、4-異噁唑基、5-異噁唑基)、噁二唑基(例如,2-噁二唑基、5-噁二唑基)、噁唑基(例如,2-噁唑基、4-噁唑基、5-噁唑基)、吡唑基(例如,3-吡唑基、4-吡唑基)、吡咯基(例如,1-吡咯基、2-吡咯基、3-吡咯基)、吡啶基(例如,2-吡啶基、3-吡啶基、4-吡啶基)、嘧啶基(例如,2-嘧啶基、4-嘧啶基、5-嘧啶基)、噠嗪基(例如,3-噠嗪基)、噻唑基(例如,2-噻唑基、4-噻唑基、5-噻唑基)、異噻唑基、***基(例如,2-***基、5-***基)、四唑基(例如,四唑基)及噻吩基(例如,2-噻吩基、3-噻吩基)。多環芳族雜芳基之實例包括咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、異苯并呋喃基、吲哚基、苯并***基、苯并噻唑基、苯并噁唑基、喹啉基、異喹啉基、吲唑基、異吲哚基、吖啶基或苯并異噁唑基。「經取代之雜芳基」在任何一或多個可取代環原子處被取代,該可取代環原子為鍵結至氫之環碳或環氮原子。
「雜環基」意謂視情況含有一或多個雙鍵之飽和或不飽和非芳族3至12員環基。其可為單環、雙環、三環或稠合的。雜環烷基含有1至4個選自N、O或S之雜原子,其可相同或不同。雜環基環視情況含有一或多個雙鍵及/或視情況與一或多個芳環(例如,苯環)稠合。術語「雜環基」意欲包括所有可能之異構形式。雜環烷基之實例包括(但不限於)吖丁啶基、嗎啉基、硫代嗎啉基、吡咯啶酮基、吡咯啶基、
哌啶基、哌嗪基、內醯脲基、戊內醯胺基、環氧乙烷基、環氧丙烷基、二氫咪唑、二氫呋喃基、二氫哌喃基、二氫吡啶基、二氫嘧啶基、二氫噻吩基、二氫苯硫基、二氫噻喃基、四氫咪唑、四氫呋喃基、四氫哌喃基、四氫噻吩基、四氫吡啶基、四氫嘧啶基、四氫苯硫基及四氫硫代哌喃基。多環雜環烷基之實例包括二氫吲哚基、二氫異吲哚基、二氫苯并咪唑基、二氫苯并噻吩基、二氫苯并呋喃基、二氫異苯并呋喃基、二氫苯并***基、二氫苯并噻唑基、二氫苯并噁唑基、二氫喹啉基、四氫喹啉基、二氫異喹啉基、四氫異喹啉基、二氫吲唑基、二氫吖啶基、四氫吖啶基、二氫苯并異噁唑基、色滿、色烯、異色滿及異色烯。
本文中所描述之某些化合物可以各種立體異構或互變異構形式存在。立體異構體為僅在其空間排列方面不同的化合物。當所揭示化合物藉由不指示立體化學的結構指定或描繪時,應理解,該名稱或結構涵蓋所有可能的立體異構體、幾何異構體,包括基本上純的立體或幾何異構體以及其組合。
應理解,當本文中之化合物在本文中由結構式表示或由化學名稱指代時,針對該化合物可存在之所有其他互變異構形式由該結構式涵蓋。
某些所揭示之化合物可以各種立體異構形式存在。立體異構體為僅在其空間排列方面不同的化合物。對映異構體為鏡像不可重疊之立體異構體對,最常見的原因係其含有充當對掌性中心之不對稱取代的碳原子。「對映異構體」意謂為彼此之鏡像且不可重疊的分子對中之一者。非對映異構體為含有兩個或更多個不對稱取代之碳原子的立體異構體。「幾何異構體」為取代基原子關於碳碳雙鍵、碳環基環或橋聯雙環系統之定向不同的立體異構體。
當藉由名稱或結構描繪幾何異構體時,應理解,該經命名或經描繪之幾何異構體的幾何異構純度為至少60wt%、70wt%、80wt%、90wt%、99wt%或99.9wt%純。藉由將混合物中之經命名或經描繪幾何異構體之重量除以混合物中所有幾何異構體之總重量來測定幾何異構純度。
當藉由結構命名或描繪所揭示化合物之立體化學時,經命名或經描繪之立體異構體相對於所有其他立體異構體為至少60wt%、70wt%、80wt%、90wt%、99wt%或99.9wt%純。相對於所有其他立體異構體之重量百分比純度為一種立體異構體之重量相比於其他立體異構體之重量的比率。當藉由結構命名或描繪單一對映異構體時,經描繪或經命名對映異構體為至少60wt%、70wt%、80wt%、90wt%、99wt%或99.9wt%光學純(亦稱為「對映異構純」)。按重量計之光學純度百分比為對映異構體之重量相比於對映異構體之重量加其光學異構體之重量的比率。
當藉由結構命名或描繪所揭示化合物之立體化學,且經命名或經描繪結構涵蓋多於一種立體異構體(例如,如呈非對映異構對形式)時,應理解,所涵蓋立體異構體中之一者或所涵蓋立體異構體之任何混合物包括在內。應進一步理解,經命名或經描繪立體異構體之立體異構純度相對於所有其他立體異構體為至少60wt%、70wt%、80
wt%、90wt%、99wt%或99.9wt%純。在此情況下,藉由將名稱或結構涵蓋之立體異構體之混合物的總重量除以所有立體異構體之混合物的總重量來測定立體異構純度。
當藉由不指示立體化學之結構命名或描繪所揭示化合物,且該化合物具有一個對掌性中心時,應理解,該名稱或結構涵蓋化合物之不含對應光學異構體的一種對映異構體、化合物之外消旋混合物及相對於其對應光學異構體富集一種對映異構體之混合物。
當藉由不指示立體化學之結構命名或描繪所揭示化合物且(例如)該化合物具有至少兩個對掌性中心時,應理解,該名稱或結構涵蓋不含其他立體異構體之一種立體異構體、立體異構體之混合物及相對於其他立體異構體富集一或多種立體異構體之立體異構體的混合物。舉例而言,該名稱或結構可涵蓋不含其他非對映異構體之一種立體異構體、立體異構體之混合物及相對於其他非對映異構體富集一或多種非對映異構體之立體異構體的混合物。
可藉由熟知方法使對映異構及非對映異構混合物拆分為其組分對映異構體或立體異構體,該等方法諸如對掌性相氣相層析法、對掌性相高效液相層析法、使化合物結晶成對掌性鹽錯合物或使化合物在對掌性溶劑中結晶。亦可藉由熟知的不對稱合成方法自非對映異構性或對映異構性純中間物、試劑及觸媒獲得對映異構體及非對映異構體。
本教示內容包括本文中所揭示化合物之醫藥學上可接受之鹽。
所揭示化合物具有鹼性胺基,且因此可與醫藥學上可接受之酸形成醫藥學上可接受之鹽。本文中所描述化合物之合適的醫藥學上可接受之酸加成鹽包括無機酸(諸如氫氯酸、氫溴酸、磷酸、偏磷酸、硝酸及硫酸)及有機酸(諸如乙酸、苯磺酸、苯甲酸、乙磺酸、甲磺酸、丁二酸及三氟乙酸)之鹽。具有諸如羧酸之酸基的本教示化合物可與醫藥
學上可接受之鹼形成醫藥學上可接受之鹽。合適的醫藥學上可接受之鹼性鹽包括銨鹽、鹼金屬鹽(諸如鈉鹽及鉀鹽)及鹼土金屬鹽(諸如鎂鹽及鈣鹽)。具有四級銨基之化合物亦含有諸如氯離子、溴離子、碘離子、乙酸根、過氯酸根及其類似者之抗衡離子。此等鹽之其他實例包括氫氯酸鹽、氫溴酸鹽、硫酸鹽、甲磺酸鹽、硝酸鹽、乙酸鹽、丁二酸鹽、苯甲酸鹽及與諸如麩胺酸之胺基酸形成的鹽。
本文中所描述之化合物可抑制HPK1。因此,一般而言,本文中所描述之化合物適用於治療與該等激酶相關之疾病或病況。
在一個實施例中,本文中所描述之化合物為HPK1抑制劑,且適用於治療與該等激酶相關之疾病,諸如癌症。
本教示之另一態樣係關於一種治療患有癌症之個體的方法,該方法包含向該個體投與有效量之本文中所描述化合物。在一個實施例中,本文中所描述化合物抑制腫瘤生長。
可藉由本教示之方法治療(包括減少復發之可能性)的癌症包括乳癌、結腸直腸癌、肺癌、卵巢癌、子宮癌、***癌、白血病、淋巴瘤、腦癌(包括多形性膠質母細胞瘤及神經母細胞瘤)、頭頸癌、胰臟癌、黑素瘤、肝細胞癌、腎癌及軟組織肉瘤。在一個實施例中,癌症為乳癌、結腸癌及卵巢癌。在一個實施例中,癌症選自白血病、急性骨髓白血病、慢性骨髓性白血病、乳癌、腦癌、結腸癌、結腸直腸癌、頭頸癌、肝細胞癌、肺腺癌、轉移性黑素瘤、胰臟癌、***癌、卵巢癌及腎癌。在一個實施例中,癌症為肺癌、結腸癌、腦癌、神經母細胞瘤、***癌、黑素瘤、多形性膠質母細胞瘤或卵巢癌。在另一實施例中,癌症為肺癌、乳癌、結腸癌、腦癌、神經母細胞瘤、***癌、黑素瘤、多形性膠質母細胞瘤或卵巢癌。在又一實施例中,癌症為乳癌、結腸癌及肺癌。在另一實施例中,癌症為乳癌。在又一實施例中,癌症為基底亞型乳癌或魯米那(luminal)B亞型乳
癌。在又一實施例中,癌症為基底亞型乳癌。在又一實施例中,基底亞型乳癌為ER(***受體)、HER2及PR(孕酮受體)陰性乳癌。在又一實施例中,癌症為軟組織癌。「軟組織癌」為涵蓋自身體之任何軟組織衍生的腫瘤之此項技術中公認的術語。該等軟組織連接、支撐或圍繞身體之各種結構及器官,包括(但不限於)平滑肌、骨胳肌、肌腱、纖維組織、脂肪組織、血液及***、血管周組織、神經、間葉細胞及滑膜組織。由此,軟組織癌可為脂肪組織、肌肉組織、神經組織、關節組織、血管、***及纖維組織之癌症。軟組織癌可為良性或惡性的。通常,惡性軟組織癌被稱為肉瘤或軟組織肉瘤。存在多種類型之軟組織腫瘤,包括脂肪瘤、脂胚細胞瘤、蟄伏脂瘤、脂肪肉瘤、平滑肌瘤、平滑肌肉瘤、橫紋肌瘤、橫紋肌肉瘤、神經纖維瘤、神經鞘瘤(schwannoma/neurilemoma)、神經瘤、惡性神經鞘瘤、神經纖維肉瘤、神經性肉瘤、結節性腱鞘炎、滑膜肉瘤、血管瘤、血管球瘤、血管外皮瘤、血管內皮瘤、血管肉瘤、卡波西肉瘤(Kaposi sarcoma)、***瘤、纖維瘤、彈力纖維瘤、淺表性彈力纖維瘤、纖維組織細胞瘤、纖維肉瘤、纖維黏液瘤、隆凸性皮膚纖維肉瘤(DFSP)、惡性纖維組織細胞瘤(MFH)、黏液瘤、顆粒細胞瘤、惡性間質瘤、肺泡軟組織肉瘤、上皮樣肉瘤、透明細胞肉瘤及促結締組織增生小細胞瘤。在特定實施例中,軟組織癌為選自由以下各者組成之群的肉瘤:纖維肉瘤、胃腸肉瘤、平滑肌肉瘤、去分化脂肪肉瘤、多形性脂肪肉瘤、惡性纖維組織細胞瘤、圓細胞肉瘤及滑膜肉瘤。
本教示亦提供一種治療患有疾病之個體的方法,該方法包含與有效免疫調節療法(亦稱為免疫療法)組合地向個體投與有效量之由結構式(I)表示之化合物。免疫療法為藉由使用免疫調節劑以誘導、增強或抑止免疫反應來治療疾病。經設計以誘發或擴增免疫反應之免疫療法被分類為活化免疫療法,而減小或抑制免疫反應之免疫療法被分類
為抑制免疫療法。本文中所描述之疾病為癌症。
單獨或組合途徑使用之免疫調節療法包括:i)免疫檢查點阻斷抑制劑,包括(但不限於)抗CTLA4(細胞毒性T淋巴細胞相關蛋白質4)抗體(例如,伊派利單抗(Ipilimumab))、使PD-1/PD-L1及PD-L2相互作用中斷之藥劑(例如,納武單抗(Opdivo-Bristol Myers Squibb)、派立珠單抗(Keytruda,KM-3475,Merck)、皮立珠單抗(CT-011,Cure Tech)、BMS 936559(BMS)及MPDL328OA(Roche));及其他免疫反應抑制性受體(例如,抗CD47);ii)基於細胞之療法,包括(但不限於)樹突狀細胞療法(例如,西普魯塞(Sipuleucel)T(Provenge)及授受性T細胞療法);iii)接種疫苗策略;iv)授受性T細胞療法;v)防礙免疫反應之代謝抑制的藥劑,包括吲哚胺2,3-二加氧酶(例如,INCB024360(Incyte)、1-甲基-D-色胺酸、因多莫得(indoximod)(NewLink Genetics))或精胺酸酶之抑制劑;及vi)基於細胞激素之療法,例如干擾素(特定而言I型干擾素)及介白素(例如,介白素-2)。
在一個實施例中,用於免疫調節療法之免疫調節劑為PD-1抑制劑,例如抗PD1抗體。
亦稱為PD-1及CD279(分化簇279)之漸進式細胞死亡蛋白質1為在人體中由PDCD1基因編碼之蛋白質。PD-1為屬於免疫球蛋白總科之細胞表面受體且在T細胞及促B細胞上表現。PD-1結合PD-L1及PD-L2兩種配位體,此兩者都為B7族之成員。
PD-1及其配位體在向下調節免疫系統中起到重要作用,其阻止T細胞之活化,此情形繼而降低自體免疫性且促進自身耐受性。PD-1之抑制性效果經由促進淋巴結中之抗原特異性T細胞中之細胞凋亡(漸進式細胞死亡)且同時減少調節性T細胞(抑制T細胞)中之細胞凋亡的雙機制來實現。
本發明中使用之PD-1抑制劑包括(但不限於)納武單抗、派立珠單
抗、皮立珠單抗、BMS 936559、MPDL3280A、MSB0010718C或MEDI4736。其中,BMS 936559、MPDL3280A、MSB0010718C及MEDI4736結合配位體PD-L1,所有者皆為抗體。納武單抗及派立珠單抗兩者經食品與藥物管理局批准用於不再對其他藥物起反應之不可切除性或轉移性黑素瘤之治療。
接種疫苗策略包括抗微生物免疫療法,其包括接種疫苗,涉及使免疫系統活化以對感染劑起反應。
授受性T細胞療法使用基於T細胞之細胞毒性反應以攻擊癌細胞。在活體外產生對患者之癌症具有自然或基因工程改造反應性之T細胞且接著將其轉移回至癌症患者體內。一項使用自體腫瘤浸潤性淋巴細胞之研究為針對患有轉移性黑素瘤的患者之有效治療。此可藉由採用與患者之腫瘤一起發現、經訓練用以攻擊癌細胞之T細胞來實現。接著促進使用高濃度的IL-2、抗CD3及同種異體反應性飼養細胞使被稱為腫瘤浸潤性淋巴細胞(TIL)之此等T細胞在活體外倍增。接著將此等T細胞轉移回至患者體內,同時外源性地投與IL-2以進一步增強其抗癌活性。
本教示亦提供治療患有癌症之個體的方法,該等方法包含與有效抗癌療法組合地向該個體投與有效量之由結構式(I)表示之化合物。在一個實施例中,癌症為轉移性癌症。「轉移性癌症」為已自其原發部位擴散至身體其他部分之癌症。
本文中所描述之抗癌療法包括有效量之第二抗癌劑以及所揭示HPK-1抑制劑的共同投藥。「抗癌劑」為當以有效量投與至患有癌症之個體時可部分或實質上達成以下各者中之一或多者的化合物:阻滯癌症生長、減緩癌症程度(例如,減小腫瘤大小)、抑制癌症生長速率及減緩或改良與癌症(諸如組織或血清組分)相關的臨床征狀或指標或增加個體壽命。
適合用於本文中所描述方法之抗癌劑包括已經批准用於治療癌症之任何抗癌劑。在一個實施例中,抗癌劑包括(但不限於)靶向抗體、血管生成抑制劑、烷化劑、抗代謝物、長春花生物鹼、紫杉烷、鬼臼毒素、拓撲異構酶抑制劑、激素抗腫瘤劑及其他抗腫瘤劑。在一個實施例中,抗癌劑為PD-1抑制劑,例如抗PD1抗體。
在一個實施例中,可用於本文中所描述方法之抗癌劑包括(但不限於)太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、5-氟尿嘧啶、曲妥珠單抗(trastuzumab)、拉帕替尼(lapatinib)、貝伐單抗(bevacizumab)、來曲唑(letrozole)、戈舍瑞林(goserelin)、他莫昔芬(tamoxifen)、西妥昔單抗(cetuximab)、帕尼單抗(panitumumab)、吉西他濱(gemcitabine)、卡培他濱(capecitabine)、伊立替康(irinotecan)、奧沙利鉑(oxaliplatin)、卡鉑(carboplatin)、順鉑(cisplatin)、阿黴素(doxorubicin)、表柔比星(epirubicin)、環磷醯胺、甲胺喋呤、長春鹼、長春新鹼、美法侖(melphalan)、阿糖胞苷(cytarabine)、依託泊苷(etoposide)、道諾比星(daunorubicin)、博萊黴素(bleomycin)、絲裂黴素(mitomycin)及阿德力黴素(adriamycin)以及其組合。
在一個實施例中,同時投與抗癌劑及由結構式(I)表示之化合物。當同時投與時,可以同一調配物或不同調配物投與抗癌劑及該化合物。替代地,在不同時間分開地投與該化合物及額外抗癌劑。
如本文中所使用,「治療患有癌症之個體」包括部分或實質上達成以下各者中之一或多者:阻滯癌症生長、減緩癌症程度(例如,減小腫瘤大小)、抑制癌症生長速率、減緩或改善與癌症(諸如組織或血清組分)相關的臨床症狀或指標或增加個體壽命,及降低癌症復發之可能性。
術語「有效量」意謂當向個體投與時,相比於對照量在個體中產生有利或所要結果(包括臨床結果,例如抑制、遏止或減輕癌症(例
如,由臨床症狀或癌細胞之量判定))的量。
一般而言,本文中教示之化合物的有效量取決於各種因素而改變但仍然可由熟習此項技術者以常規方式測定,該等因素諸如給定藥物或化合物、醫藥調配物、投藥途徑、疾病或病症類型、正治療之個體或宿主的身分及其類似者。一般技術者藉由此項技術中已知之常規方法可容易地測定本教示之化合物的有效量。
在一個實施例中,本文中教示之化合物的有效量在約0.1毫克/公斤體重至約1000毫克/公斤體重,替代地約1毫克/公斤體重至約500毫克/公斤體重之範圍內。在另一實施例中,本文中教示之化合物的有效量在約0.5mg/m2至約5000mg/m2,替代地約5mg/m2至約2500mg/m2之範圍內,且在另一替代例中為約50mg/m2至約1000mg/m2之範圍內。熟習此項技術者應瞭解,某些因素可影響有效地治療遭受癌症之個體或降低癌症復發之可能性所需的劑量。此等因素包括(但不限於)疾病或病症之嚴重強度、先前治療、個體之一般健康狀況及/或年齡及其他存在疾病。
「個體」為哺乳動物,較佳為人類,但亦可為需要獸醫治療之動物,例如伴侶動物(例如,狗、貓及其類似動物)、農畜(例如,牛、羊、豬、馬及其類似動物)及實驗室動物(例如,大鼠、小鼠、天竺鼠及其類似動物)。
如熟習此項技術者將理解,取決於所選投藥途徑,可以多種形式向患者投與本文中教示之化合物。可例如藉由口服、非經腸、頰內、舌下、經鼻、經直腸、貼片、泵送或經皮投藥來投與本教示之化合物並相應地調配醫藥組合物。非經腸投藥包括靜脈內、腹膜內、皮下、肌肉內、經上皮、經鼻、肺內、鞘內、經直腸及局部投藥模式。可藉由在所選時段內連續輸液來進行非經腸投藥。
可將本文中教示之化合物適合地調配成向個體投與之醫藥組合
物。本教示之醫藥組合物視情況包括一或多種其醫藥學上可接受之載劑及/或稀釋劑,諸如乳糖、澱粉、纖維素及右旋糖。亦可包括其他賦形劑,諸如:調味劑;甜味劑;及防腐劑,諸如對羥基苯甲酸甲酯、乙酯、丙酯及丁酯。合適的賦形劑之更完整清單可見於Handbook of Pharmaceutical Excipients(第5版,Pharmaceutical Press(2005))中。熟習此項技術者將知曉如何製備適合於各種類型投藥途徑之調配物。供選擇及製備合適的調配物之習知程序及成份描述於(例如)Remington's Pharmaceutical Sciences(2003年,第20版)及1999年出版之The United States Pharmacopeia:The National Formulary(USP 24 NF19)中。載劑、稀釋劑及/或賦形劑在與醫藥組合物之其他成份相容且對其接受者無害之意義上係「可接受的」。
通常,對於口服治療投藥,本教示之化合物可併入有賦形劑且以可攝取錠劑、頰內錠劑、糖衣錠、膠囊、酏劑、懸浮液、糖漿、粉片及其類似物之形式使用。
通常,對於經腸投藥,通常可適當地與諸如羥基丙基纖維素之界面活性劑在水中混合來製備本教示之化合物的溶液。亦可在存在或不存在醇之情況下在甘油、液體聚乙二醇、DMSO及其混合物中以及在油中製備分散液。在普通的儲存及使用條件下,此等製劑含有防腐劑以防止微生物生長。
通常,對於注射用途,用於臨時製備無菌注射溶液或分散液的本文所描述化合物之無菌水溶液或分散液及無菌粉末係適當的。
對於經鼻投藥,本教示之化合物可調配成霧劑、滴劑、凝膠及粉末。霧劑調配物通常包含活性物質於生理上可接受之水性或非水性溶劑中的溶液或精細懸浮液且通常以單劑量或多劑量的量以無菌形式於密封容器中呈現,該容器可呈筒狀形式或再填充以供霧化裝置使用。替代地,密封容器可為單式分配裝置,諸如單劑量經鼻吸入器或
霧劑分配器,其裝備有預期在使用之後進行處置之計量閥。當劑型包含霧劑分配器時,其將含有推進劑,該推進劑可為諸如壓縮空氣之壓縮氣體或諸如氟氯烴之有機推進劑。霧劑劑型亦可呈泵送霧化器之形式。
對於頰內或舌下投藥,本教示之化合物可與諸如糖、***膠、黃蓍膠或明膠及甘油之載劑一起經調配為錠劑、***錠或片劑。
對於經直腸投藥,本文中所描述之化合物可經調配成含有諸如可可脂之習知栓劑基質的栓劑形式。
可藉由熟習此項技術者已知之方法來製備本發明之化合物,如以下一般流程及程序以及隨後之製備性實例所說明。所有起始物質為市售或藉由熟習此項技術者已知之方法及下文所描述之程序製備。
申請專利範圍化合物之通用合成方法提供於以下例證說明中,如流程1及2中所說明。
例證說明
以原樣使用市售之起始物質、試劑及溶劑。一般而言,在諸如氮氣或氬氣之惰性氛圍下進行無水反應。PoraPak® Rxn CX係指購自Waters之商用陽離子交換樹脂。
藉由Biotage Initiator微波反應器進行微波反應。通常藉由LCMS(Bruker Exquire 4000或Waters Acquity UPLC系統)監測反應進程。使用具有KP-SIL或HP-SIL矽石濾筒或KP-NH鹼性改質之矽石及對應樣本之Biotage Isolera進行中間物或最終產物之急驟管柱層析純化。在40mL/min之流動速率下在40分鐘時間內使用10% MeOH/0.05% TFA-H2O至90% MeOH/0.05% TFA-H2O之梯度在具有Varian Monochrom 10μ C-18逆相管柱之Varian PreStar模型SD-1 HPLC系統上進行逆相HPLC
純化。亦使用裝備有KP-C18-H管柱之Biotage Isolera,使用10%至95%之間的MeOH或CH3CN/0.1% TFA-H2O進行逆相純化。在Bruker 400MHz光譜儀上記錄質子NMR,且使用Bruker Esquire 4000光譜儀或Waters Acquity UPLC系統獲得質譜。
使用寫入CambridgeSoft-PerkinElmer's ChemBioDraw Ultra版本12.0中之軟體產生化合物名稱。
用KHMDS、LiHMDS或LDA(3至5當量)處理芳基噁嗪-2,4-二酮(1當量)或胺基芳基腈及經取代之1H-苯并[d]咪唑-2-基)醋酸酯(1至1.2當量)於THF中之溶液。在45℃下攪拌反應物4至24小時。接著使反應物冷卻至室溫且用飽和的NH4Cl水溶液淬滅反應物。藉由EtOAc或DCM萃取水層,且經由MgSO4乾燥合併之有機萃取物、過濾及濃縮。藉由管柱層析法或製備性HPLC對粗產物進行純化,得到所要產物。
用KHMDS、LiHMDS、KOBut或LDA(3至5當量)在45℃下處理芳基噁嗪-2,4-二酮(1當量)或胺基芳基腈及經取代之1H-苯并[d]咪唑-2-基)醋酸酯(1至1.2當量)於THF中之溶液2至4h。接著使反應物冷卻至室溫且用飽和的NH4Cl水溶液淬滅反應物。藉由EtOAc或DCM萃取水層,且經由MgSO4乾燥、過濾及濃縮合併之有機萃取物。藉由管柱層析法分離出未環化的加成加合物,將其溶解於THF中且用KHMDS、LiHMDS或LDA(3至5當量)處理。在45℃下攪拌反應物1至4h。接著使
反應物冷卻至室溫且用飽和的NH4Cl水溶液淬滅反應物。藉由EtOAc或DCM萃取水層,且經由MgSO4乾燥合併之有機萃取物、過濾及濃縮。藉由管柱層析法或製備性HPLC對粗產物進行純化,得到所要產物。
用LiHMDS或LDA(5當量)處理胺基芳基腈及經取代之1H-苯并[d]咪唑-2-基)醋酸酯(1當量)於THF中之溶液(步驟1)。在35℃至40℃下攪拌反應物1至1.5h。接著使反應物冷卻至室溫且用飽和的NH4Cl水溶液淬滅反應物並進行濃縮。藉由製備性HPLC對粗產物進行純化,得到未環化中間物,經中和、乾燥且經受使用LiHMDS之通用方法A1中所描述之條件(步驟2)。
用Tf2O(8當量)處理苯并咪唑-2-基芳吡啶酮衍生物(1當量)及吡啶(20當量)於DCM中之溶液。在0℃下攪拌反應物2至8h。接著用飽和的NaHCO3水溶液淬滅反應物。用DCM萃取水層,且經由MgSO4乾燥合併之有機萃取物、過濾及濃縮。粗產物不經進一步純化即用於下一步驟中。
用胺(1.2至3當量)處理苯并咪唑-2-基芳吡啶酮雙三氟甲磺酸鹽衍生物(1當量)於MeCN、DCM或DMF中之溶液。在胺為鹽(例如,HCl)的情況下,使胺鹽溶解於MeOH或DMF中且穿過PoraPak Rxn CX離子交換管柱,得到游離鹼,其添加至反應混合物中。在室溫下或至多45℃下攪拌該反應混合物1至48h。移除溶劑,且藉由管柱層析法或製備性HPLC對粗產物進行純化,得到所要產物。
在80℃至100℃下加熱受保護的苯并咪唑-2-基芳基吡啶酮衍生物(1當量)於TFA/濃HCl(7:1 v/v)中之溶液3至24h。移除溶劑,且藉由管
柱層析法(游離鹼)或製備性HPLC(TFA鹽)對粗產物進行純化,得到所要產物。為產生呈HCl鹽形式之所要產物,在室溫下,使游離鹼溶解於MeOH中且添加1M HCl-Et2O(2至4當量)。攪拌溶液5分鐘並與MeOH共沸兩次。
在室溫下攪拌硫雜靛紅酸酐(1當量)、1-(氯甲基)-4-甲氧基苯(1至1.2當量)、K2CO3(1至1.2當量)及/或KI(1至1.2當量)於DMF中之溶液4至24h。接著將反應混合物緩慢地添加至H2O,藉由真空過濾收集沈澱,得到所要物。
在室溫下向4-第三丁氧羰基胺基-噻吩-3-甲酸(2.5g,10.2mmol)於PhMe(25mL)中之溶液添加乙二醯氯(1.29mL,15.3mmol)。將反應混合物逐漸加熱至95℃且在95℃下攪拌1小時。在反應完成之後,使反應物冷卻至室溫並過濾。用己烷(2×5mL)洗滌固體,且在真空下乾燥,得到呈膏狀固體狀之標題化合物(1.61g,93%)。1H NMR(400MHz,DMSO-d 6 )δ 11.57(s,1H),8.64(d,J=3.2Hz,1H),6.89(d,J=2.8Hz,1H);MS ESI[M+H]+ 170.0,[C6H3NO3S+H]+之計算值為169.9。
根據通用方法E,在室溫下,向1H-噻吩并[3,4-d][1,3]噁嗪-2,4-二
酮(1.6g,9.45mmol)於無水DMF(20mL)中之溶液中攪拌添加K2CO3(1.56g,11.3mmol),接著攪拌添加KI(0.62g,3.78mmol)。在10min內逐滴添加PMBCl(1.54mL,11.3mmol)且攪拌反應混合物另外2h。在反應完成之後,將反應混合物倒入至H2O(200mL)中以使經過濾之產物沈澱,用H2O洗滌且乾燥,得到呈灰白色固體狀之標題化合物(2.3g,84%)。1H NMR(400MHz,CDCl 3 )δ 8.35(d,J=3.2Hz,1H),7.31(d,J=8.8Hz,2H),6.89(d,J=8.8Hz,2H),6.62(d,J=3.2Hz,1H),5.08(s,2H),3.80(s,3H);MS ESI[M+H]+ 291.2,[C14H11NO4S+H]+之計算值為290.0。
根據通用方法A1,將2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯[J.Med.Chem.(2009),52,278-292](3.02g,10mmol)、LiHMDS(1M於THF中,4mL,4mmol)用於1-(4-甲氧基苯甲基)-1H-噻吩并[3,2-d][1,3]噁嗪-2,4-二酮[Tetrahedron(1999)55 6167-6174](2.89g,10mmol)之溶液以生成呈橙色固體狀之標題化合物(2.65g,51%)。1H NMR(400MHz,CDCl 3 )δ 13.68(br.s.,1H),12.57(s,1H),7.55(dd,J=5.2,2.0Hz,1H),7.40-7.32(m,1H),7.23(d,J=8.8Hz,2H),7.04-6.93(m,3H),6.85(d,J=8.8Hz,2H),5.37(s,2H),3.77(s,3H),3.30-3.19(m,4H),2.69-2.58(m,4H),2.39(s,3H);MS ESI[M+H]+ 502.1,[C27H27N5O3S+H]+之計算值為502.2。
根據通用方法A2,使用1-(4-甲氧基苯甲基)-1H-噻吩并[2,3-d][1,3]噁嗪-2,4-二酮(0.40g,1.4mmol)、2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(0.46g,1.5mmol)及LDA(1M於THF中,6.2mL,4.5mmol)之溶液來生成呈棕色固體狀之標題化合物(0.220g,32%)。1H NMR(400MHz,CDCl 3 )δ 13.87(br.s.,1H),12.52(s,1H),7.49(dd,J=14.9Hz,1H),7.40-7.24(m,3H),7.03-6.64(m,5H),5.28(d,J=13.8Hz,2H),3.76(s,3H),3.21(d,J=18.8Hz,4H),2.65(m,d,J=19.1Hz,4H),2.41(s,3H);MS ESI[M+H]+ 502.3,[C27H27N5O3S+H]+之計算值為502.2。
在Ar下,在40℃下向2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(2.58g,8.55mmol)及1-(4-甲氧基苯甲基)-1H-噻吩并[3,4-d][1,3]噁嗪-2,4-二酮(2.46g,8.55mmol)於無水THF(48mL)中之溶液逐滴添加1M LDA(34mL,1M於THF/己烷中,34mmol)。在40℃下攪拌所得棕色溶液1h且接著在室溫下用NH4Cl水溶液(50mL)淬滅。用H2O(50mL)稀釋反應混合物且用DCM(2×200mL)萃取。將合併之有機層用H2O洗滌一次,經由Na2SO4乾燥並濃縮,得到粗製酯。藉由急驟層析法(梯度:EtOAc/hex 0%至40%,接著MeOH/DCM 0%至25%)純化粗產物,得到呈淡棕色固體狀之標題化合物(3.05g,65%)。MS ESI[M+H]+ 548.2,[C29H33N5O4S+H]+之計算值為548.2。
在Ar條件下,在室溫下將上文所描述之3-(4-((4-甲氧基苯甲基)胺基)噻吩-3-基)-2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)-3-側氧基丙酸乙酯(3.05g,5.57mmol)溶解於無水THF(30mL)中。在40℃下逐滴添加LDA(16.8mL,1M於THF/己烷中,16.71mmol)之溶液。在40℃下攪拌所得棕色溶液1小時且接著在室溫下用NH4Cl水溶液(25mL)淬滅。用H2O(25mL)稀釋混合物且用DCM(2×250mL)萃取。將合併之有機層用H2O洗滌一次,經由Na2SO4乾燥並濃縮,得到粗產物。藉由急驟層析法(梯度:MeOH/DCM 0%至20%)純化粗產物,得到呈淡
棕色固體狀之標題化合物(1.81g,65%)。1H NMR(400MHz,DMSO-d 6 )δ 13.8-13.25(m,1H),8.13(d,J=3.6Hz,1H),7.58(d,J=8.8Hz,1H),7.36-7.29(m,3H),7.06-7.02(m,1H),6.97(d,J=3.6Hz,1H),6.86(d,J=8.4Hz,2H),5.19(s,2H),3.69(s,3H),3.16(br.s,4H),2.60(br.s,4H),2.31(s,3H);無法容易地偵測到因OH基團產生之信號。MS ESI 502.1[M+H]+,[C27H27N5O3S+H]+之計算值為502.2。
根據通用方法B使用4-羥基-7-(4-甲氧基苯甲基)-5-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(0.22g,0.44mmol)、Tf2O(0.60mL,3.5mmol)及吡啶(0.72mL,8.8mmol)進行合成。作為區位異構體之不確定混合物形式獲得之標題化合物不經純化即用於下一步驟中。MS ESI[M+H]+ 766.1,[C29H25F6N5O7S3+H]+之計算值為766.1。
根據通用方法B,在-5℃下向4-羥基-1-(4-甲氧基苯甲基)-3-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[3,4-b]吡啶-2(1H)-酮(220mg,0.43mmol)及吡啶(708mL,8.76mmol)於DCM(12mL)中之溶液添加Tf2O(558mL,3.50mmol)。在-5℃與0℃之間攪拌反應物1h。用
飽和的NaHCO3水溶液淬滅反應物。用DCM萃取水層,經由Na2SO4乾燥合併之有機萃取物且在真空條件下濃縮,得到棕色油。作為區位異構體之不確定混合物形式獲得之粗產物不經進一步純化即直接用於下一步驟中。MS ESI[M+H]+ 766.0,[C29H25F6N5O7S3+H]+之計算值為766.1。
根據通用方法B,在0℃下向4-羥基-7-(4-甲氧基苯甲基)-5-(6-(N-嗎啉基)-1H-苯并[d]咪唑-2-基)-噻吩并[2,3-b]吡啶-6(7H)-酮(200mg,0.41mmol)及吡啶(0.66mL,8.2mmol)於DCM(20mL)中之溶液添加Tf2O(0.55mL,3.28mmol)。在0℃下攪拌反應混合物2h且接著用飽和的NaHCO3水溶液淬滅。用DCM萃取水層。經由Na2SO4乾燥合併之有機萃取物,且進行濃縮,得到呈棕色油狀之粗製標題化合物(兩種區位異構體之混合物),考慮到定量產率,粗製標題化合物不經進一步純化即直接用於後續步驟中。MS ESI[M+H]+ 753.0,[C28H22F6N4O8S3+H]+之計算值為752.9。
在室溫下向KOH(0.49g,8.76mmol)於H2O(20mL)中之溶液添加2-胺基-4-甲基-3-噻吩甲酸甲酯(1.0g,5.84mmol)。將所得反應物加熱至90℃持續2小時,且接著使其冷卻至0℃。在10分鐘內逐滴添加三光氣(0.866g,2.92mmol)於PhMe(12mL)中之溶液。將所得溶液逐
漸升溫至室溫並攪拌2小時。過濾所得固體,用H2O洗滌且進行乾燥,得到呈淺粉紅色固體狀之標題化合物(0.65g,61%)。1H NMR(400MHz,CD 3 OD)δ 6.65(d,J=1.2Hz,1H),2.42(d,J=1.2Hz,3H);MS ESI[M+H]+ 184.0,[C7H5NO3S+H]+之計算值為184.0。
在室溫下,向5-甲基-1H-噻吩并[2,3-d][1,3]噁嗪-2,4-二酮(0.625g,3.41mmol)於無水DMF(9mL)中之溶液攪拌添加K2CO3(0.566g,4.09mmol),接著攪拌添加KI(0.142g,0.85mmol)。在10分鐘內向反應物逐滴添加PMB-Cl(0.56mL,4.06mmol)且攪拌另外2h。將反應混合物倒入至H2O(100mL)中以使產物沈澱,其經過濾,用H2O洗滌並進行乾燥,得到呈淡棕色固體狀之標題化合物(0.935g,91%)。1H NMR(400MHz,CDCl 3 )δ 7.38(d,J=8.8Hz,2H),6.90-6.88(m,2H),6.46(d,J=1.2Hz,1H),5.05(s,2H),3.80(s,3H),2.42(d,J=1.2Hz,3H);MS ESI[M+H]+ 304.2,[C15H13NO4S+H]+之計算值為304.1。
在Ar條件下,在40℃下向2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(922mg,3.04mmol)及1-(4-甲氧基苯甲基)-5-甲基-1H-噻吩并[2,3-d][1,3]噁嗪-2,4-二酮(925mg,3.04mmol)溶於無水THF(28ml)中之溶液逐滴添加LDA(34mL,1M溶於THF/己烷中,34mmol)之溶液。在40℃下攪拌所得棕色溶液2h且接著在室溫下用
NH4Cl水溶液(25mL)淬滅。用H2O(25mL)稀釋反應混合物且用DCM(2×100mL)萃取。將合併之有機層用H2O洗滌一次,經由Na2SO4乾燥且進行濃縮,得到產物及未環化酯之混合物。藉由急驟層析法(梯度:EtOAc/hex 0%至40%,接著MeOH/DCM 0%至25%)純化粗物質,得到產物及未環化酯之混合物(900mg)。
在Ar條件下,在室溫下將上述產物及未環化酯之混合物(900mg)溶解於無水THF(9mL)中。在40℃下逐滴添加LDA(5mL,1M溶於THF/己烷中)之溶液。在40℃下攪拌所得棕色溶液1h且按照上文處理,得到粗產物。藉由急驟層析法(梯度:MeOH/DCM 0%至20%)純化粗產物,得到呈膏狀固體狀之標題化合物(325mg,21%)。1H NMR(400MHz,CDCl 3 )δ 12.54(s,1H),7.38(d,J=8.4Hz,1H),7.33(d,J=8.4Hz,2H),7.01-6.98(m,2H),6.85(d,J=8.8Hz,2H),6.40(s,1H),5.26(s,2H),3.80-3.61(m,6H),3.60-3.51(m,4H),2.89-2.88(m,4H),2.63(s,3H);無法容易地偵測到因OH基團產生之信號。MS ESI[M+H]+ 516.2,[C28H29N5O3S+H]+之計算值為516.2。
根據通用方法B,利用存於DCM(12mL)中之4-羥基-7-(4-甲氧基-苯甲基)-3-甲基-5-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(320mg,0.62mmol)、吡啶(1.0mL,12.4mmol)、Tf2O(0.833mL,4.96mmol)得到深棕色油來製備標題化合物。作為2種區位異構體之不確定混合物形式獲得之粗產物不經進一
步純化即直接用於下一步驟中。MS ESI[M+H]+ 780.0,[C30H27F6N5O7S3+H]+之計算值為780.1。
在140℃下用微波輻照5-氯-2-硝基苯胺(1.73g,10mmol)、(3r,5s)-rel-1,2,6-三甲基哌嗪(1.41g,11mmol)及K2CO3(2.72g,20mmol)之混合物4h。接著在攪拌下添加H2O(150mL),抽吸過濾,用H2O沖洗且乾燥,得到呈棕色固體狀之標題化合物(2.47g,94%)。1H NMR(400MHz,DMSO-d 6 )δ 7.79(d,J=10.0Hz,1H),7.23(s,2H,NH2),6.41(dd,J=9.6,1.6Hz,1H),6.20(d,J=2.4Hz,1H),3.77(d,J=12.4Hz,2H),2.59(t,J=11.8Hz,2H),2.19-2.11(m,2H),2.16(s,3H),1.05(d,J=6.0Hz,6H);MS ESI[M+H]+ 265.3,[C13H20N4O2+H]+之計算值為265.2。
向2-硝基-5-((3r,5s)-rel-3,4,5-三甲基哌嗪-1-基)苯胺(2.47g,9.4mmol)於MeOH(30mL)之懸浮液中添加10% Pd/C(247mg,10% wt.)。使所得混合物在H2氣囊下氫化O/N。在添加額外10% Pd/C(124mg,5% wt.)之後,使其在H2氣囊下氫化O/N,經過濾、濃縮及乾燥,得到呈深棕色固體狀之標題化合物(2.25g,定量)。1H NMR(400MHz,CD 3 OD)δ 6.66(d,J=8.4Hz,1H),6.47(d,J=2.4Hz,1H),6.31
(dd,J=8.4,2.8Hz,1H),3.35-3.25(m,2H),2.47-2.40(m,4H),2.34(s,3H),1.18(d,J=5.6Hz,6H);MS ESI[M+H]+ 235.3,[C13H22N4+H]+之計算值為235.2。
向4-((3r,5s)-rel-3,4,5-三甲基哌嗪-1-基)苯-1,2-二胺(2.25g,9.4mmol)於EtOH(40mL)之溶液中添加3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(2.93g,15mmol)。在80℃下加熱所得混合物2h。在移除溶劑之後,用DCM/MeOH(100mL/10mL)稀釋,用飽和的NaHCO3水溶液(30mL)鹼化且分離。用DCM(60mL×2)萃取水層,且藉由急驟層析法(梯度:100% EtOAc,接著MeOH/DCM 0%至20%)濃縮及純化合併之萃取物,得到呈深橙色固體狀之標題化合物(2.32g,73%)。1H NMR(400MHz,CDCl 3 )δ 10.13(br s,1H,NH),7.53-6.88(m,3H),4.25(q,J=7.2Hz,2H),4.03(s,2H),3.43(d,J=11.2Hz,2H),2.61(t,J=11.2Hz,2H),2.50-2.41(m,2H),2.35(s,3H),1.32(t,J=7.2Hz,3H),1.19(d,J=6.0 Hz,6H);MS ESI[M+H]+ 331.3,[C18H26N4O2+H]+之計算值為331.2。
在室溫下,向1-(4-甲氧基苯甲基)-1H-噻吩并[3,2-d][1,3]噁嗪-
2,4-二酮(1.16g,4mmol)及2-(6-((3r,5s)-rel-3,4,5-三甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(990mg,3mmol)於THF(20mL)之混合物中逐滴添加LDA(1.0M溶於THF/己烷中,10mL,10mmol)。在添加之後,在40℃下攪拌所得混合物1h,用DCM稀釋,用飽和的NH4Cl水溶液淬滅且用DCM萃取。藉由急驟層析法(梯度:20%至100% EtOAc/hex,接著MeOH(0.5% NH3)/DCM 0%至20%)濃縮及純化合併之萃取物,得到呈棕色泡沫狀的環化產物及未環化產物之混合物(1.10g)。在室溫下將混合物再溶解於THF(15mL)中,且逐滴添加LDA(1.0M溶於THF/己烷中,6mL,6mmol)。過程及處理兩者都與上文相同。獲得呈橙色固體狀之標題化合物(630mg,40%)。MS ESI[M+H]+ 530.3,[C29H31N5O3S+H]+之計算值為530.2。
根據通用方法B,在0℃下向7-羥基-4-(4-甲氧基苯甲基)-6-(6-((3r,5s)-rel-3,4,5-三甲基-哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(106mg,0.2mmol)於DCM(15mL)之溶液中添加吡啶(0.32mL,4mmol),接著添加Tf2O(0.27mL,1.2mmol)。在0℃下攪拌所得混合物1h,用DCM(10mL)稀釋,用飽和的NaHCO3水溶液(15mL)淬滅,用DCM(20mL×2)萃取且濃縮,得到呈棕色油狀之粗製標題化合物(兩種區位異構體之不確定混合物),將該粗製標題化合物直接用於後續步驟中。MS ESI[M+H]+ 794.1,[C31H29F6N5O7S3+H]+之計算值為794.11。
在65℃下攪拌MeC(OMe)3(2.26mL,12.3mmol)及CH2(CN)2(0.78mL,12.3mmol)之混合物3h,之後使其冷卻至室溫。添加THF(10mL)及硫(395mg),隨後逐滴添加Et3N(1.72mL,12.3mmol)。在60℃下攪拌所得反應混合物15min且在減壓下進行濃縮。將殘餘物分配於EtOAc與H2O之間,用EtOAc萃取,經由Na2SO4乾燥、過濾並濃縮至乾燥。用DCM濕磨殘餘物且過濾,得到呈棕色固體狀之標題化合物(1.23g,60%)。1H NMR(400MHz,CD 3 OD)δ 5.27(s,1H),3.99(q,J=7.0Hz,2H),1.38(t,J=7.0Hz,3H);MS ESI[M+H]+ 169.0,[C7H8N2OS+H]+之計算值為169.0。
在80℃下在封閉瓶中加熱MeC(OMe)3(1.3mL,10mmol)及CH2(CN)2(0.66g,10mmol)之混合物17h。使反應物冷卻至室溫,並添加哌嗪-1-甲酸第三丁酯(2.79g,15.0mmol)。在65℃下在攪拌下繼續加熱5h。接著在真空中濃縮反應混合物。添加S8(0.34g)及無水THF(10mL)。在40℃下在攪拌下加熱懸浮液。在15min內逐滴添加Et3N(1.3mL,9.3mmol)。使油浴溫度增加至60℃並繼續攪拌11h。接著在減壓下濃縮反應物且藉由急驟層析法(SiO2,己烷:EtOAc 5%至50%)純化,得到呈淺橙色固體狀之4-(5-胺基-4-氰基噻吩-3-基)哌嗪-1-甲酸第三丁酯(0.71g,23%)。1H NMR(400MHz,DMSO-d 6)δ 7.12(s,2H),5.46(s,1H),3.45-3.37(m,4H),2.90-2.81(m,4H),1.40(s,
9H)。MS ESI[M+H]+ 309.3,[C14H20N4O2S+H]+之計算值為309.1。
在Ar條件下,在室溫下將LiHMDS(1.0M溶於THF中,2.8mL,2.8mmol)逐滴添加至2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(0.170g,0.56mmol)及4-(5-胺基-4-氰基噻吩-3-基)哌嗪-1-甲酸第三丁酯(0.175g,0.56mmol)於無水THF(10mL)之經攪拌懸浮液中。在室溫下攪拌反應物另外5分鐘,且接著在40℃下在油浴中加熱1h。使反應物冷卻至室溫,用飽和的NH4Cl水溶液淬滅,在減壓下濃縮且藉由急驟層析法(MeOH/DCM 0%至20%)純化,得到呈淡茶色固體狀之標題化合物(83mg,26%)。1H NMR(400MHz,CD 3 OD)δ 7.45(d,J=8.8Hz,1H),7.10(d,J=2.3Hz,1H),7.03(dd,J=8.8,2.3Hz,1H),6.18(s,1H),3.62-3.50(m,4H),3.24-3.18(m,4H),3.05-2.98(m,4H),2.75-2.67(m,4H),2.41(s,3H),1.49(s,9H);MS ESI[M+H]+ 565.3,[C28H36N8O3S+H]+之計算值為565.4。
在室溫下,向3,4-二硝基苯甲酸(1.23g,5.8mmol)於無水DCM(20mL)之懸浮液中逐滴添加乙二醯氯(1.0mL,11.7mmol),隨後添加無水DMF(2滴)。攪拌反應物隔夜且隨後在室溫下進行濃縮。在0℃、Ar下將殘餘物溶解於無水THF(40mL)中。逐滴添加1-甲基哌
嗪(1.3mL,11.7mmol)(藉由間歇性搖晃攪拌黏稠的白色懸浮液)。在添加之後,持續冷卻10min,之後移除冷卻浴。在室溫下攪拌反應物3h之後,添加H2O。在減壓下移除THF且萃取殘餘物水溶液(CH2Cl2;2% MeOH溶於CH2Cl2.2x中)。經由Na2SO4乾燥合併之有機萃取物且在減壓下濃縮,得到呈淺橙色固體狀之(3,4-二硝基苯基)(4-甲基哌嗪-1-基)甲酮(1.77g,定量)。1H NMR(400MHz,DMSO-d 6 )δ 8.29(d,J=8.3Hz,1H),8.27(d,J=1.5Hz,1H),7.97(dd,J=8.3,1.8Hz,1H),3.59-3.68(m,2H),3.24-2.53(m,2H),2.42-2.35(m,2H),2.21-2.32(m,2H),2.20(s,3H)。MS ESI[M+H]+ 295.2,[C12H14N4O5+H]+之計算值為295.1。
藉由N2將(3,4-二硝基苯基)(4-甲基哌嗪-1-基)甲酮(0.53g,1.8mmol)於THF(25mL)及EtOH(50mL)中之溶液脫氣。添加Pd/C(191mg,0.18mmol)且在室溫下在H2(1atm)下攪拌反應物隔夜。接著經由矽藻土過濾反應混合物且在減壓下濃縮,得到呈紫色固體狀之(3,4-二胺基苯基)(4-甲基哌嗪-1-基)甲酮(0.44g,定量)。1H NMR(400MHz,DMSO-d6)δ 6.61-6.55(m,1H),6.47-6.45(m,2H),4.81(br.s,2H),4.58(br.s,2H),3.50-3.39(m,4H),2.34-2.22(m,4H),2.18(s,3H)。MS ESI[M+H]+ 235.1,[C12H18N4O+H]+之計算值為235.1。
在65℃,攪拌加熱在Ar下溶於無水EtOH(100mL)中之(3,4-二胺
基苯基)(4-甲基哌嗪-1-基)甲酮(0.44g,1.8mmol)及3-乙氧基-3-亞胺基丙酸鹽酸鹽(1.07g,5.5mmol)隔夜。接著在減壓下濃縮反應混合物。將殘餘物溶解於H2O(15mL)中,用10%Na2CO3水溶液中和,用CH2Cl2(2×)萃取,洗滌(鹽水)且經由Na2SO4乾燥。藉由急驟層析法(溶於CH2Cl2中之0%至50% MeOH)純化得到呈黃色泡沫狀之標題化合物(0.31g,52%)。1H NMR(400MHz,CD 3 OD)δ 7.71-7.57(m,2H),7.33(d,J=8.2Hz,1H),4.23(q,J=7.2Hz,2H),3.91-3.40(m,4H),2.62-2.38(m,4H),2.34(s,3H),1.28(t,J=7.1Hz,3H);CD3OD中不存在因CH2酯產生之信號。MS ESI[M+H]+ 331.2,[C17H22N4O3+H]+之計算值為331.2。
在室溫下,向3,4-二硝基苯甲酸(1.30g,6.1mmol)於無水DCM(50mL)之懸浮液中逐滴添加(COCl)2(1.0mL,11.7mmol),隨後添加無水DMF(2滴)。攪拌反應物隔夜且隨後在室溫下進行濃縮。在0℃、Ar下將殘餘物溶解於無水THF(24mL)中。逐滴添加嗎啉(1.0mL,11.6mmol)(藉由間歇性搖晃攪拌黏稠的白色懸浮液)。在添加之後,持續冷卻10min,之後移除冷卻浴。在室溫下攪拌反應物3h之後,添加H2O。在減壓下移除THF且萃取殘餘物水溶液(CH2Cl2.2x)。乾燥(Na2SO4)合併之有機萃取物且在減壓下濃縮,得到呈淺橙色固體狀之(3,4-二硝基苯基)((N-嗎啉基))甲酮(1.8g,定量)。1H NMR(400MHz,DMSO-d 6 )δ 8.28-8.31(m,2H),8.00(dd,J=8.28,1.76Hz,1H),3.39-3.80(m,8H)。
藉由N2使(3,4-二硝基苯基)((N-嗎啉基))甲酮(0.83g,2.9mmol)於THF(30mL)及EtOH(60mL)中之溶液脫氣。添加Pd/C(0.31mg,0.29mmol)且在室溫下在H2(1atm)氛圍下攪拌反應物隔夜。接著經由矽藻土過濾反應混合物且在減壓下濃縮,得到呈紫色泡沫之(3,4-二胺基苯基)((N-嗎啉基))甲酮。[C11H15N3O2+H]+之LCMS(ESI)m/z計算值為222.1;實驗值222.2。在65℃下,攪拌加熱在Ar下溶於無水EtOH(100mL)中之材料及3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(1.2g,6.2mmol)隔夜。接著在減壓下濃縮反應混合物。藉由急驟層析法(溶於CH2Cl2中之0%至20% MeOH)純化得到呈淡紅色泡沫狀之標題化合物(0.43g,47%)。1H NMR(400MHz,CD3OD)δ 7.52-7.76(m,2H),7.33(dd,J=8.28,1.51Hz,1H),4.22(q,J=7.19Hz,2H),4.00-4.05(m,2H),3.70(br.s.,8H),1.28(t,J=7.15Hz,3H);CD3OD中不存在因CH2酯產生之信號;MS ESI[M+H]+ 318.2,[C17H22N4O3+H]+之計算值為318.1。
在80℃下在密封試管中將5-氯-4-甲基-2-硝基苯胺(0.32g,1.7mmol)及1-甲基哌嗪(1.5mL,13.5mmol)加熱30min,隨後在105℃下加熱1d且在120℃下加熱2d。稍後使反應物冷卻,用H2O稀釋並過濾。用H2O沖洗所收集固體且在真空中乾燥,得到呈黃色固體狀之標
題化合物(0.36g,84%)。1H NMR(400MHz,DMSO-d 6)δ 7.72(s,1H),7.27(s,2H),6.44(s,1H),2.97-2.86(m 4H),2.49-2.39(m,4H),2.22(s,3H),2.11(s,3H)。[C12H18N4O2+H]+之LCMS(ESI)m/z之計算值為51.1;實驗值為235.3。
藉由N2使溶於EtOH(50mL)、THF(25mL)中之4-甲基-5-(4-甲基哌嗪-1-基)-2-硝基苯胺(0.36g,1.4mmol)及Pd/C(10%,81mg,0.08mmol)脫氣,且接著在H2(1atm)下攪拌5d。經由矽藻土過濾反應混合物,用EtOH沖洗襯墊。在減壓下濃縮濾過物,得到呈黃褐色固體狀之4-甲基-5-(4-甲基哌嗪-1-基)苯-1,2-二胺(0.35g,定量)。在65℃下,攪拌加熱在Ar下溶於無水EtOH(70mL)中之材料(0.35g)及3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(0.81g,4.1mmol)隔夜。接著在減壓下濃縮反應混合物,將其溶解於H2O(20mL)中且用2M Na2CO3水溶液鹼化至pH 9。用DCM(2×)萃取混合物;乾燥(Na2SO4)有機萃取物且在減壓下濃縮。藉由急驟層析法(溶於CH2Cl2中之0%至30% MeOH)純化得到呈黃色泡沫狀之標題化合物(0.36g,82%)。1H NMR(500MHz,CD3OD)δ7.35(s,1H),7.25(s,1H),4.22(q,J=7.09Hz,2H),2.95-3.03(m,4H),2.88-2.58(m,4H),2.43(s,3H),2.41(s,3H),1.28(t,J=7.09Hz,3H;CD3OD中不存在因CH2酯產生之信號;[C17H24N4O2+H]+之LCMS(ESI)m/z計算值為317.2;實驗值為317.3。
將5-氯-4-氟-2-硝基苯胺(1.0g,5.24mmol)、嗎啉(1.37mL,15.7mmol)及DMSO(5mL)之混合物在油浴140℃下加熱3h。接著在80℃下在攪拌下添加H2O(50mL)以使產物沈澱,且允許懸浮液達到室溫,抽吸過濾,用H2O洗滌且乾燥,得到呈黃色固體狀之標題化合物(1.25g,94%)。1H NMR(400MHz,CD 3 OD)δ 7.17(d,J=14.0Hz,1H),6.37(d,J=8.0Hz,1H),3.83(t,J=4.4Hz,4H),3.22(t,J=4.8Hz,4H);MS ESI[M+H]+ 242.1,[C10H12FN3O3+H]+之計算值為242.1。
在室溫、Ar層下,向100mL圓底燒瓶中裝入4-氟-5-(N-嗎啉基)-2-硝基苯胺(1.23g)及MeOH(37mL)。在室溫下在謹慎攪拌下添加雷尼鎳(Raney Nickel)(0.123g)。將反應物質緩慢加熱至60℃至65℃,且在約5分鐘內將水合肼(0.86mL)逐滴添加至反應物質中。在65℃至70℃下攪拌反應物2h。在反應完成之後,使其冷卻至室溫,且在Ar下經由矽藻土襯墊過濾觸媒並用MeOH(5mL * 2)洗滌矽藻土襯墊。濃縮合併之濾過物且藉由急驟層析法(梯度:MeOH/DCM 0%至25%)純化,得到呈淡棕色固體狀之標題化合物(0.615g,57%)。1H NMR(400MHz,CD 3 OD)δ 6.51-6.47(m,2H),3.81(t,J=4.8Hz,4H),2.93(t,J=4.8Hz,4H);MS ESI[M+H]+ 212.0,[C10H14FN3O+H]+之計算值為212.1。
在65℃下,以每5min之間隔分兩個等量批次向4-氟-5-(N-嗎啉基)苯-1,2-二胺(0.615g,2.91mmol)溶於EtOH(30mL)中之溶液添加3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(1.14g,5.82mmol)。接著在65℃下攪拌反應物質2h。在反應完成之後,在減壓下濃縮該反應物質以留下黏稠的棕色油。向所得油添加H2O(25mL),且使用2M Na2CO3水溶液將pH調整至約10。用DCM(30ML * 2)萃取所得混合物,且濃縮合併之萃取物並藉由急驟層析法(梯度:Hex/EtOAc 0%至40%,接著MeOH/DCM 0%至20%)純化,得到呈棕色固體狀之標題化合物(0.786g,88%)。1H NMR(400MHz,CD 3 OD)δ 7.26(d,J=12.4Hz,1H),7.19(d,J=7.6Hz,1H),4.25-4.20(m,2H),3.88(t,J=4.4Hz,4H),3.08(t,J=4.8Hz,4H),1.28(t,J=7.2Hz,3H);MS ESI[M+H]+ 308.1.0,[C15H18FN3O3+H]+之計算值為308.1。
將5-氯-2-硝基苯胺(8.63g,50mmol)、1-甲基-1,4-二氮雜環庚烷(6.85g,60mmol)及K2CO3(8.28g,60mmol)之混合物在90℃下加熱20h。在用H2O(500mL)稀釋之後,用EtOAc(60mL×3)萃取,濃縮且乾燥,得到呈深紅色油狀之粗製5-(4-甲基-1,4-二氮雜環庚烷-1-基)-2-硝基苯胺(12.50g)。NMR指示產物及5-氯-2-硝基苯胺(2:1)之混合物。1H NMR(400MHz,CD 3 OD)δ 7.72(d,J=10.0Hz,1H),6.26(dd,J=9.8,
2.6Hz,1H),6.02(d,J=2.4Hz,1H),3.66-3.63(m,2H),3.58(t,J=6.4Hz,2H),2.77-2.74(m,2H),2.62-2.59(m,2H),2.39(s,3H),2.07-2.00(m,2H);MS ESI[M+H]+ 251.3,[C12H18N4O2+H]+之計算值為251.15。
在65℃下,在10min內向粗製5-(4-甲基-1,4-二氮雜環庚烷-1-基)-2-硝基苯胺(12.50g)及雷尼鎳(1.25g)溶於MeOH(150mL)中之混合物添加N2H4-H2O(12.0mL)。在添加之後,在70℃下攪拌所得混合物30min。在冷卻至室溫後,經由矽藻土過濾並用MeOH沖洗。濃縮並乾燥濾過物,得到呈深紅棕色油狀之粗製4-(4-甲基-1,4-二氮雜環庚烷-1-基)苯-1,2-二胺(10.57g)。1H NMR(400MHz,CD 3 OD)δ 6.63(d,J=8.0Hz,1H),6.53(dd,J=8.4,2.4Hz,1H),6.26(d,J=2.4Hz,1H),3.60-3.40(m,4H),2.75-2.71(m,2H),2.62-2.58(m,2H),2.37(s,3H),2.04-1.97(m,2H)。
將粗製4-(4-甲基-1,4-二氮雜環庚烷-1-基)苯-1,2-二胺(10.57g)及3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(19.50g,100mmol)溶於EtOH(200mL)中之混合物在90℃下加熱2h。在移除溶劑之後,用H2O(50mL)稀釋,用2M Na2CO3水溶液(40mL)鹼化且用DCM(60mL×3)萃取。濃縮合併之萃取物且藉由急驟層析法(梯度:EtOAc/己烷0%至100%,
接著MeOH/DCM 0%至25%)純化,得到呈深棕色油狀之標題化合物(經過3個步驟為7.31g,46%)。1H NMR(400MHz,CD 3 OD)δ 8.38(d,J=8.8Hz,1H),6.82-6.77(m,2H),4.22(q,J=6.8Hz,2H),3.66-3.61(m,2H),3.54(t,J=6.4Hz,2H),2.85-2.80(m,2H),2.68-2.64(m,2H),2.41(s,3H),2.12-2.05(m,2H),1.29(t,J=7.0Hz,3H);MS ESI[M+H]+ 317.3,[C17H24N4O2+H]+之計算值為317.20。
在Ar下,經15min向2-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(2.42g,8.05mmol)及2-胺基噻吩-3-甲腈(1.0g,8.05mmol)在40℃下溶於無水THF(40mL)中之溶液中逐滴添加LDA(40mL,1M溶於THF/己烷中,40mmol)。在40℃下攪拌所得棕色溶液2h,且接著在室溫下用NH4Cl水溶液(50mL)淬滅。用H2O(125mL)稀釋混合物且用乙酸乙酯(2×200ml)萃取。將合併之有機層用H2O洗滌一次,經由Na2SO4乾燥並濃縮,得到粗產物。用DCM(20mL)濕磨粗產物,隨後用MeOH(25mL)濕磨,得到呈淡棕色固體狀之標題化合物(1.95g,64%)。
使游離鹼(1.95g)懸浮於MeOH(50mL)中且在室溫下添加1M HCl-Et2O(13mL)。在室溫下攪拌懸浮液15min,且在真空下濃縮並與MeOH(2×25mL)共沸,得到呈深棕色固體狀之HCl鹽(2.28g,62%);1H NMR(400MHz,CD 3 OD)δ 7.69(d,J=9.2Hz,1H),7.52(d,J=5.6Hz,1H),7.36(dd,J=8.8,2.4Hz,1H),7.30(d,J=2.4Hz,1H),
7.19(d,J=5.6Hz,1H),3.97-3.93(m,2H),3.70-3.67(m,2H),3.39-3.35(m,2H),3.34-3.18(m,2H),3.01(s,3H);MS ESI[M+H]+ 381.2,[C19H20N6OS+H]+之計算值為381.1。
下列化合物係根據通用方法A3製備。
在室溫下,經15min將LDA(1.0M溶於THF/己烷中,2.3mL,2.3mmol)逐滴添加至2-(6-(4-甲基哌嗪-1-羰基)-1H-苯并[d]咪唑-2-基)醋酸乙酯(0.150g,0.45mmol)及2-胺基噻吩-3-甲腈(0.056g,0.45mmol)在Ar下溶於無水THF(20mL)中之經攪拌懸浮液。最初在室溫下進行添加,且5分鐘之後在35℃下進行添加。在35℃下繼續加熱1h,之後使反應混合物冷卻至室溫,用NH4Cl水溶液淬滅並在減壓下濃縮。藉由RP HPLC純化得到呈淺棕色固體狀之N-(3-氰基噻吩-2-基)-2-(5-(4-甲基哌嗪-1-羰基)-1H-苯并[d]咪唑-2-基)乙醯胺*TFA(82mg,35%)。1H NMR(400MHz,CD3OD)δ 7.96(s,1H),7.89(d,J=8.5Hz,1H),7.68(dd,J=8.4,1.4Hz,1H),7.09-7.14(m,2H),3.25-3.81(m,8H),2.97(s,3H)。
步驟2. 經由PoraPak(2g,使用MeOH,接著2M NH3溶於MeOH中)過濾前述反應之產物並乾燥。在室溫下經3分鐘用LiHMDS(1.0M溶於THF中,0.7mL,0.7mmol)處理材料(0.055g,0.13mmol)在Ar下之無水THF(12mL)溶液,攪拌10分鐘並在45℃下加熱95min。隨後使反應物冷卻至室溫,用NH4Cl水溶液淬滅,在減壓下濃縮並藉由製備性HPLC純化。經由PoraPak(2g)過濾並用CH2Cl2濕磨得到呈淺黃色固體狀之標題化合物(3.6mg,3%)。1H NMR(400MHz,CD3OD)δ 7.58-7.77(m,2H),7.51(d,J=5.80Hz,1H),7.30(dd,J=8.30,1.30Hz,
1H),7.14(d,J=5.80Hz,1H),3.53-3.92(m,4H),2.48-2.70(m,4H),2.43(s,3H)。MS ESI[M+H]+ 409.2,[C20H20N6O2S+H]+之計算值為409.2。
在室溫下向7-羥基-6-(6-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[3,2-b]吡啶-5(4H)-酮(58mg,0.152mmol)溶於無水DCM(1mL)中之懸浮液逐滴添加Tf2O(0.55mL,0.916mmol)。在室溫下攪拌所得反應混合物隔夜,之後在0℃下逐滴添加環丙胺(100mg,1.83mmol)。在40℃下攪拌所得反應混合物隔夜,並用DCM加以稀釋,接著用飽和的NaHCO3洗滌。經由Na2SO4乾燥有機層,過濾並濃縮至乾燥。將殘餘物溶解於MeOH中並使其流過PoraPak,接著在減壓下移除溶劑。藉由製備性HPLC純化粗產物,得到呈黃色固體狀之標題化合物(5mg,6%產率)。1H NMR(400MHz,CD 3 OD)δ 7.98(d,J=5.5Hz,1H),7.61(d,J=9.0Hz,1H),7.26(d,J=2.0Hz,1H),7.21(dd,J=8.4,2.0Hz,1H),7.10(d,J=5.5Hz,1H),3.92-3.84(m,2H),3.71-3.62(m,2H),3.41-3.36(m,2H),3.20-3.10(m,2H),3.09-3.03(m,1H),3.01(s,3H),1.04-0.96(m,2H),0.93-0.89(m,2H);MS ESI[M+H]+ 421.2,[C22H24N6OS+H]+之計算值為421.2。
將5-氯-2-硝基苯胺(2.5g,14.48mmol)、哌嗪-1-甲酸第三丁酯(3.24g,17.38mmol)及K2CO3(4.0g,28.96mmol)溶於DMSO(100mL)中之混合物在100℃下攪拌3天。接著在攪拌下添加H2O(150mL),抽吸過濾,用H2O沖洗且乾燥,得到呈棕色固體狀之標題化合
物(2.6g,57%)。1H NMR(400MHz,CDCl 3 )δ 8.04(d,J=9.79Hz,1H),6.27(dd,J=9.66,2.64Hz,1H),6.21-6.11(m,2H),5.95(d,J=2.51Hz,1H),3.61-3.54(m,4H),3.40-3.34(m,4H),1.50(s,9H);MS ESI[M+H]+ 323.2,[C15H22N4O4+H]+之計算值為323.2。
向4-(3-胺基-4-硝基苯基)哌嗪-1-甲酸第三丁酯(2.6g,8.04mmol)溶於MeOH(150mL)中之懸浮液中添加10% Pd/C(130mg,5% wt.)。使所得混合物在H2氣囊下氫化O/N。過濾所得反應混合物、濃縮並乾燥,得到呈深棕色固體狀之標題化合物(2.29g,97%)。1H NMR(400MHz,CDCl 3 )δ6.66(d,J=8.28Hz,1H),6.39(d,J=2.51Hz,1H),6.34(dd,J=8.28,2.51Hz,1H),3.60-3.53(m,4H),3.46-3.23(m,4H),3.02-2.95(m,4H),1.49(s,9H);MS ESI[M+H]+ 293.1,[C15H24N4O2+H]+之計算值為293.2。
向4-(3,4-二胺基苯基)哌嗪-1-甲酸第三丁酯(100mg,0.34mmol)溶於EtOH(3mL)中之溶液中添加3-乙氧基-3-亞胺基丙酸乙酯鹽酸鹽(190mg,0.68mmol)。在60℃下加熱所得混合物3h。在移除溶劑之後,用DCM(10mL)進行稀釋,藉由飽和的NaHCO3調整pH至約8且將其分離。用DCM(10mL×2)萃取水溶液且經由NaSO4乾燥合併之萃取物,接著濃縮並藉由急驟層析法(梯度:100% EtOAc,接著MeOH/DCM0%至20%)純化,得到呈深橙色固體狀之標題化合物(116mg,87%)。1H NMR(400MHz,CD 3 OD)δ 7.49-7.40(m,1H),7.15-7.10(m,2H),4.22(q,J=7.11Hz,2H),3.95(s,1H),3.61(br.s.,4H),
3.11(br.s.,4H),1.50(s,9H),1.28(t,J=7.15Hz,3H);MS ESI[M+H]+ 389.2,[C20H28N4O4+H]+之計算值為389.2。
根據通用方法A,使用2-胺基-4-乙氧基噻吩-3-甲腈(64mg,0.52mmol)、4-(2-(2-乙氧基-2-側氧基乙基)-1H-苯并[d]咪唑-6-基)哌嗪-1-甲酸第三丁酯(200mg,0.52mmol)、LiHMDS(1M溶於THF中,2.0mL,2.06mmol)之溶液產生呈淺棕色固體狀之標題化合物(88mg,35%)。1H NMR(500MHz,DMSO-d 6)δ 12.72-12.61(m,1H),12.13-12.02(m,1H),10.72-10.55(m,1H),8.01-7.93(m,1H),7.57(d,J=5.62Hz,1H),7.52-7.43(m,1H),7.24-7.10(m,2H),6.93-6.87(m,1H),3.52-3.44(m,4H),3.07-3.00(m,4H),1.45-1.40(m,9H);MS ESI[M+H]+ 467.2,[C23H26N6O3S+H]+之計算值為467.2。
在室溫下攪拌4-(2-(4-胺基-6-側氧基-6,7-二氫噻吩并[2,3-b]吡啶-5-基)-1H-苯并[d]咪唑-6-基)哌嗪-1-甲酸第三丁酯(83mg,0.178mmol)於TFA(1mL)中之混合物2h,之後進行濃縮。將殘餘物溶解於MeOH(20mL)中且使其流過PoraPak,接著濃縮,得到呈黃色固體狀之標題化合物(45mg,69%)。1H NMR(400MHz,DMSO-d 6)δ 12.65-12.58(m,1H),10.77-10.61(m,1H),8.03-7.94(m,1H),7.59(d,
J=5.77Hz,1H),7.54-7.42(m,1H),7.19-7.10(m,2H),6.92-6.86(m,1H),3.09-3.01(m,4H),2.94-2.88(m,4H);無法容易地偵測到因NH2產生之信號。MS ESI[M+H]+ 367.2,[C18H18N6OS+H]+之計算值為367.1。
在室溫下攪拌4-胺基-5-(6-(哌嗪-1-基)-1H-苯并[d]咪唑-2-基)噻吩并[2,3-b]吡啶-6(7H)-酮(45mg,0.123mmol)、氧雜環丁-3-酮(8.8mg,0.123mmol)及NaBH(OAc)3(120mg,0.552mmol)於DCE(2mL)中之混合物隔夜,接著進行過濾。濃縮濾過物並藉由製備性HPLC純化,得到呈黃色固體狀TFA鹽形式之標題化合物(50mg,76%)。1H NMR(400MHz,CD 3 OD)δ 7.66(d,J=9.03Hz,1H),7.51(d,J=5.77Hz,1H),7.29(t,J=8.91Hz,2H),7.18(d,J=6.02Hz,1H),4.98-4.87(m,4H),4.54-4.45(m,1H),3.63-3.40(m,8H);MS ESI[M+H]+ 423.2,[C21H22N6O2S+H]+之計算值為423.2。
自Invitrogen(目錄號PV6355)購買活性HPK1(MAP4K1)作為人類HPK1(aa 1-346)之N端GST融合物。使用間接ELISA檢測系統量測HPK1活性。在12μM ATP(Sigma目錄號A7699)、5mM MOPS(pH 7.2)、2.5mM β-甘油磷酸酯、5mM MgCl2、0.4mM EDTA、1mM EGTA、0.05mM DTT存在下,在預塗覆有0.5μg/孔的牛髓鞘鹼性蛋白(MBP)(Millipore,目錄號13-110)之96孔微量滴定板中培育GST-HPK1(0.6nM)。使該反應進行30min,接著用洗滌緩衝液(補充有0.2%吐溫(Tween)20之磷酸鹽緩衝鹽水)將板洗滌5次,並藉由1:3000
稀釋之抗磷酸蘇胺酸兔多株抗體(Cell Signaling目錄號9381)培育30min。用洗滌緩衝液洗滌該板5次,在山羊抗兔辣根過氧化酶結合物(BioRad目錄號1721019,1:3000濃度)存在下培育30min,用洗滌緩衝液洗滌另外5次,並在TMB受質(Sigma目錄號T0440)存在下進行培育。使比色反應繼續5min,接著添加停止溶液(0.5N H2SO4),並藉由在450nm處用單色板讀取器(Molecular Devices M5)偵測來定量。
在固定濃度(10μM)或可變抑制劑濃度(在10點劑量反應滴定中典型地為50μM至0.1μM)兩者下測定化合物抑制。在酶存在下預培育化合物15min,隨後添加ATP並使用上文所描述之活性分析來定量剩餘活性。使用以下公式測定化合物之抑制%;抑制%=100×(1-(實驗值-背景值)/(高活性對照-背景值)。藉由公式(A+(B/(1+((x/C)^D))))使用非線性4點對數曲線擬合(XLfit4,IDBS)測定IC50值,其中A=背景值,B=範圍,C=反曲點,D=曲線擬合參數。
使用酪胺酸2肽作為受質(Invitrogen目錄號PV3191)之基於FRET之Z'-LYTE激酶分析套組來測定FLT3及LCK化合物抑制。根據用於LCK激酶反應之具有940μm之ATP濃度及1nM FLT3(Invitrogen目錄號PV3182)及180μM ATP及25nM LCK(Invitrogen目錄號P3043)的製造商推薦規格來進行FLT3激酶分析。根據製造商的說明測定抑制%值並使用非線性4點對數曲線擬合(XLfit4,IDBS)獲得IC50值。
在下表1中,提供例示性化合物的IC50值範圍。對於小於或等於0.05μM之值、大於0.05μm且小於或等於0.5μM之值及大於0.5μM之值,IC50範圍分別指示為「A」、「B」及「C」。
自美國菌種保藏中心(ATCC,Manassas,VA)獲得Jurket E6.1細胞,並根據供應商之指示維護。將細胞洗滌三次並在37℃下在補充有0.5%胎牛血清之RPMI 1640培養基中饑餓18h。用所指示濃度之抑制劑預處理血清饑餓之細胞4小時,之後在37℃下用10μg/mL α-CD3抗體(BioLegend,Inc.,San Diego,CA)刺激10min。在含有10mm焦磷酸鈉、10mm氟化鈉、10mm EDTA及1mm原釩酸鈉之磷酸鹽緩衝鹽水(pH 7.4)中洗滌細胞一次。使用冰冷的輻射免疫沈澱分析(RIPA)裂解緩衝液來製備蛋白質溶解產物。將總共100μg細胞溶解產物載入至具有全範圍分子量標號器作為大小參照之Bis-Tris凝膠(Life
Technologies,Carlsbad,CA)上,並藉由SDS-PAGE電泳分離。蛋白質轉移至PVDF膜(Millipore,Billerica,MA),藉由磷酸-SLP-76(Ser376)(兔多株編號13177;Cell Signaling Technology Inc.,Danvers,MA)、SLP-76(兔多株編號4958;Cell Signaling Technology Inc.,Danvers,MA)、磷酸-ERK(小鼠單株sc-7383;Santa Cruz BiotechnologyInc.,Santa Cruz,CA)及ERK1/2(兔多株06-182;Millipore,Billerica,MA)之抗體來阻斷及探測。以1比15000稀釋二次抗體並在室溫下培育1h。觀測蛋白質條帶並使用Odyssey近紅外成像劑(LI-COR,Lincoln,NE)來定量。
下表2列舉本發明之代表化合物針對α-CD3刺激之Jurkat E6.1細胞中之SLP-76絲胺酸376磷酸化及ERK1/2 T202/Y204磷酸化的作用。
*如藉由免疫墨點分析估算之>75%抑制
自美國菌種保藏中心(ATCC CRL-2638,Manassas,VA,DC,USA)獲得CT26 WT細胞株,其為源自小鼠之N-亞硝基-N-甲基胺基甲酸酯-(NNMU)誘發的未分化結腸癌瘤細胞株。細胞在含有4.5g/L葡萄糖、0.11g/L丙酮酸鈉、1.5g/L碳酸氫鈉、L-麩醯胺酸及2.385g/L
HEPES加10%胎牛血清之Roswell Park memorial Institute培養基(通常稱作RPMI 1640培養基)中生長。自傑克遜實驗室(Jackson Laboratories)購買六至八週齡雌性BALB/c小鼠,且在開始試驗之前在MaRS-TMDT動物資源中心接收並適應1週。向小鼠飼喂任意經熱壓處理過之水及由19%粗蛋白質、5%粗脂肪及5%粗纖維組成之嚙齒動物實驗室膳食(Rodent Lab Diet)(Harlan Teklad LM-485)。將小鼠圈養在微型隔離盒(microisolator)籠具中並維持在20℃至22℃及40%至60%濕度下12h照明循環之環境中。在移植當天,採集CT26細胞且用無血清RPMI1640重新懸浮至1×107/ml之濃度且在小鼠右背側中向每一小鼠皮下注射含有1×106個CT26細胞之0.1mL體積。6d之後,形成具有約65mm3之平均體積(使用公式計算:腫瘤體積=寬度2×長度/2)之可觸腫瘤。此時,將動物分成每組八隻動物之五個組以使得每一組包含之動物攜帶相似平均尺寸腫瘤並開始治療。對於給藥,將實例A1溶解於水中至7.5mg/mL或15mg/mL之濃度以分別用於75mg/kg及150mg/kg之給藥。作為陽性對照且為研究實例A1之組合活性,使用大鼠IgG2b抗PD1抗體(BioXcell(NH,USA))給藥。藉由以下各項處理五個組:i)藉由口服管飼(PO)投與10ml/kg水QD持續21天,加上在第0天、第3天、第6天及第10天藉由腹膜內(IP)注射給予150μg大鼠IgG2b同型對照抗體(對照組);ii)在第0天、第3天、第6天及第10天藉由腹膜內(IP)注射給予150μg抗PD-1抗體;iii)PO投與75mg/kg實例A1,QD持續21天;iv)PO投與150mg/kg實例A1 QD持續21天;v)PO投與150mg/kg實例A1 QD持續21天,加上在第0天、第3天、第6天及第10天藉由腹膜內(IP)注射給予150μg抗PD-1抗體。藉由體重量測及臨床觀測來評估毒性。每週三次採集腫瘤量測值及體重。藉由以下公式計算腫瘤生長抑制(TGI)百分比:%TGI=100×[1-(TVf,治療-TVi,治療)/(TVf,對照-TVi,對照)]
第21天之腫瘤生長抑制展示於圖2中。觀測回應於用實例A1之治療的劑量依賴性作用,其中75mg/kg及150mg/kg QD分別抑制腫瘤生長44%及64%。儘管抗PD-1抗體單獨產生34%之平均TGI,但當與150mg/kg QD實例A1組合時,TGI增加至86%。
根據大學健康網路(UHN)動物使用協定(Animal Use Protocols;AUP),當腫瘤大小超過1500mm3或動物之體重減小或動物呈現出於人文原因需要終止之臨床症狀時,應處死功效實驗中之小鼠。在此研究中,體重增加之所有動物在研究過程中充分耐受該化合物,且沒有動物由於臨床症狀而被終止。在第21天<1500mm3之腫瘤大小被用作表示存活之截止值。使用此截止值,在第21天處,對照組中沒有動物存活,抗PD-1組中8隻動物中有1隻(12.5%)存活,75mg/kg/天實例A1組中8隻動物中有2隻(25%)存活,150mg/kg/天實例A1組中8隻動物中有3隻(37.5%)存活,且150mg/kg/天實例A1及抗PD-1組中8隻動物中有7隻(87.5%)存活。此等結果顯示本發明化合物(如藉由化合物A1例示)具有活體內抗腫瘤活性且可有效地與其他免疫調節方法組合。
自傑克遜實驗室獲得C57/BL6小鼠。大學健康網路之機構動物護理及使用委員會(Institutional Animal Care and Use Committee of the University Health Network)審批通過所有動物程序。用在補充有結核分枝桿菌(Mycobacterium tuberculosis)之傳氏完全佐劑(Complete Freund's Adjuvant;CFA)中乳化的MOG35-55肽在皮下(SC)免疫小鼠。在免疫接種後之第0天及第2天,向小鼠腹膜內(IP)注射百日咳毒素(pertussis toxin)。根據下列指標,每天監測EAE之臨床症狀:0,無疾病;1,尾調降低;2,後肢虛弱或局部麻痹;3,整個後肢麻痹;4,前肢及後肢麻痹;5,死亡或由於瀕死的狀態而處死。在EAE誘導期間用化合物治療,向小鼠每日(QD)經口給予(PO)50mg/kg A30
(n=4)或水(媒劑對照;n=5)。資料為平均分值±SEM。測試結果展示於圖3中。
Claims (22)
- 一種由式(I)表示之化合物,
- 如請求項1之化合物,其中R4及R5與其所連接之氮一起形成-N-烷基-哌嗪基或嗎啉基,其中該哌嗪基或該嗎啉基視情況經由1至2個選自-F、-Cl、-Br、-OH、-(C1-C4)烷基、-(C1-C4)鹵烷基及-(C1-C4)烷氧基之基團取代。
- 如請求項11之化合物,其中Ra在每次出現時獨立地為-H、-(CH2)n-(C3-C6)環烷基、-(CH2)n-3至6員單環雜環基,其中該-(CH2)n-(C3-C6)環烷基或該-(CH2)n-3至6員單環雜環基視情況經由1至3個選自-F、-Cl、-Br、-CN、-NH2、-OH、-(C1-C4)烷基及-(C1-C4)烷氧基之基團取代;且n為0或1。
- 如請求項12之化合物,其中R為H、-(C1-C4)烷基、-(C1-C4)烷氧基、或N-哌嗪基。
- 如請求項13之化合物,其中R為H。
- 如請求項14之化合物,其中R4及R5與其所連接之氮一起形成-N-甲基-哌嗪基或嗎啉基,其兩者視情況經由一個或兩個甲基取代。
- 如請求項15之化合物,其中Ra在每次出現時獨立地為:-H;視情況經由-OH取代之-(C3-C6)環烷基;-(CH2)n-四氫-2H-哌喃;嗎啉基;視情況經由-F、-OH或甲基取代之哌啶基;或四氫呋喃;且n為0或1。
- 一種醫藥組合物,其包含如請求項1至17中任一項之化合物及醫藥學上可接受之載劑或稀釋劑。
- 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽的用途,其係用於製造用於治療癌症之藥劑。
- 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽的用途,其係用於製造用於治療癌症之藥劑,其中該藥劑為係用於伴隨第二抗癌治療之投藥。
- 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽的用途,其係用於製造用於治療癌症之藥劑,其中該藥劑係用於伴隨免疫調節劑之投藥,該免疫調節劑諸如檢查點抑制劑或色胺酸氧化之抑制劑。
- 如請求項21的用途,其中該藥劑係與有效量之抗PD-1抗體、抗CTLA4抗體或抗PD-L1抗體合併使用。
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