TWI767896B - 作為免疫調節劑之雜環化合物 - Google Patents
作為免疫調節劑之雜環化合物 Download PDFInfo
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- TWI767896B TWI767896B TW105142378A TW105142378A TWI767896B TW I767896 B TWI767896 B TW I767896B TW 105142378 A TW105142378 A TW 105142378A TW 105142378 A TW105142378 A TW 105142378A TW I767896 B TWI767896 B TW I767896B
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- alkyl
- cycloalkyl
- cancer
- aryl
- membered heterocycloalkyl
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- 229960004276 zoledronic acid Drugs 0.000 description 1
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Abstract
本發明揭示式(I’)化合物、使用該等化合物作為免疫調節劑之方法及包含該等化合物之醫藥組合物。該等化合物可用於治療、預防或改善諸如癌症或感染等疾病或病症。
Description
本申請案係關於醫藥活性化合物。本發明提供化合物以及其組合物及使用方法。該等化合物調節PD-1/PD-L1蛋白/蛋白相互作用且可用於治療多種疾病,包括傳染病及癌症。
免疫系統在控制及消除諸如癌症等疾病方面起著重要作用。然而,癌症細胞通常形成多項策略來避開或阻抑免疫系統以有利於其生長。一種此類機制改變在免疫細胞上表現之共刺激及共抑制分子之表現(Postow等人,J.Clinical Oncology 2015,1-9)。阻斷抑制性免疫檢查點(例如PD-1)之信號傳導已證實為有前景且有效之治療形式。
程序性細胞死亡受體-1(PD-1)(亦稱為CD279)為在活化T細胞、自然殺手T細胞、B細胞及巨噬細胞上表現之細胞表面受體(Greenwald等人,Annu.Rev.Immunol 2005,23:515-548;Okazaki及Honjo,Trends Immunol 2006,(4):195-201)。其充當固有負反饋系統以防止T細胞活化,進而降低自體免疫性且提高自我耐受性。此外,亦已知PD-1在阻抑如癌症及病毒感染等疾病中之抗原特異性T細胞反應方面起著關鍵作用(Sharpe等人,Nat Immunol 2007 8,239-245;Postow等人,J.Clinical Oncol 2015,1-9)。
PD-1之結構由以下各項組成:細胞外免疫球蛋白可變樣結構域,其後為跨膜區及細胞內結構域(Parry等人,Mol Cell Biol 2005,9543-9553)。細胞內結構域含有兩個位於基於免疫受體酪胺酸之抑制基序及基於免疫受體酪胺酸之切換基序中之磷酸化位點,此表明PD-1負調控T細胞受體介導之信號。PD-1具有兩個配位體,即PD-L1及PD-L2(Parry等人,Mol Cell Biol 2005,9543-9553;Latchman等人,Nat Immunol 2001,2,261-268),且其表現模式不同。PD-L1蛋白在巨噬細胞及樹突狀細胞上因應
脂多醣及GM-CSF處理以及在T細胞及B細胞上在T細胞受體及B細胞受體信號傳導時發生上調。PD-L1亦在幾乎所有的腫瘤細胞上高度表現,且該表現在IFN-γ處理後進一步增加(Iwai等人,PNAS2002,99(19):12293-7;Blank等人,Cancer Res 2004,64(3):1140-5)。實際上,已顯示腫瘤PD-L1表現狀況可預測多個腫瘤類型(Wang等人,Eur J Surg Oncol 2015;Huang等人,Oncol Rep 2015;Sabatier等人,Oncotarget 2015,6(7):5449-5464)。相比之下,PD-L2表現更受限且主要由樹突狀細胞表現(Nakae等人,J Immunol 2006,177:566-73)。PD-1與其在T細胞上之配位體PD-L1及PD-L2之接合遞送某一信號,該信號抑制IL-2及IFN-γ產生以及在T細胞受體活化時誘導之細胞增殖(Carter等人,Eur J Immunol 2002,32(3):634-43;Freeman等人,J Exp Med 2000,192(7):1027-34)。該機制涉及募集SHP-2或SHP-1磷酸酶以抑制T細胞受體信號傳導,例如Syk及Lck磷酸化(Sharpe等人,Nat Immunol 2007,8,239-245)。PD-1信號傳導軸之活化亦減弱PKC-θ活化圈磷酸化,該PKC-θ活化圈磷酸化為活化NF-κB及AP1路徑及諸如IL-2、IFN-γ及TNF等細胞介素產生所必需(Sharpe等人,Nat Immunol 2007,8,239-245;Carter等人,Eur J Immunol 2002,32(3):634-43;Freeman等人,J Exp Med 2000,192(7):1027-34)。
來自臨床前動物研究之若干證據線索指示,PD-1及其配位體負調控免疫反應。已顯示PD-1缺失小鼠罹患狼瘡樣腎小球性腎炎及擴張型心肌病變(Nishimura等人,Immunity 1999,11:141-151;Nishimura等人,Science 2001,291:319-322)。使用LCMV慢性感染模型已顯示,PD-1/PD-L1相互作用抑制病毒特異性CD8 T細胞之效應物功能之活化、擴大及獲取(Barber等人,Nature 2006,439,682-7)。總而言之,該等資料支持旨在阻斷PD-1介導之抑制性信號傳導級聯以增大或「挽救」T細胞反應的治療方式之研發。因此,業內需要能阻斷PD-1/PD-L1蛋白/蛋白相互作用之新穎化合物。
或其醫藥學上可接受之鹽或立體異構物,其中各組成變量定義於本文中。
或其醫藥學上可接受之鹽或立體異構物,其中各組成變量定義於本文中。
本發明另外提供醫藥組合物,其包含本發明化合物或其醫藥學上可接受之鹽或立體異構物及至少一種醫藥學上可接受之載劑或賦形劑。
本發明另外提供調節或抑制PD-1/PD-L1蛋白/蛋白相互作用之方法,其包括向個體投與本發明化合物或其醫藥學上可接受之鹽或立體異構物。
本發明另外提供治療患者之疾病或病症之方法,其包括向患者投與治療有效量之本發明化合物或其醫藥學上可接受之鹽或立體異構物。
I. 化合物
或其醫藥學上可接受之鹽或立體異構物,其中:X1為N或CR1;X2為N或CR2;X3為N或CR3;X4為N或CR4;X5為N或CR5;X6為N或CR6其中X1、X2及X3不會同時為N;其中X4、X5及X6不會同時為N;X7為N或CR8a;X8為N或CR8b;X9為N或CR8c;Cy為C6-10芳基、C3-10環烷基、5至14員雜芳基或4至10員雜環烷基,其各自視情況經1至4個經獨立選擇之R9取代基取代;R1、R2、R3、R4、R5、R6及R9各自獨立地選自H、鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R1、R2、R3、R4、R5、R6及R9之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代;
R7為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、OR11、SR11、NH2、NHR11、NR11R11、NHOR11、C(O)R11、C(O)NR11R11、C(O)OR11、OC(O)R11、OC(O)NR11R11、NR11C(O)R11、NR11C(O)OR11、NR11C(O)NR11R11、C(=NR11)R11、C(=NR11)NR11R11、NR11C(=NR11)NR11R11、NR11S(O)R11、NR11S(O)2R11、NR11S(O)2NR11R11、S(O)R11、S(O)NR11R11、S(O)2R11及S(O)2NR11R11,其中R9及R11之C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個或3個Rb取代基取代;每一R11獨立地選自H、C1-6烷基、C1-6鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中R11之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個或3個經獨立選擇之Rb取代基取代;R8a、R8b及R8c各自獨立地選自H、C1-4烷基、C3-6環烷基、C3-6環烷基-C1-4烷基-、C6-10芳基、C6-10芳基-C1-4烷基-、5-10員雜芳基、4-10員雜環烷基、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、C2-4烯基、C2-4炔基、鹵基、CN、OR10、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NHR10、-NR10R10、NHOR10、C(O)R10、C(O)NR10R10、C(O)OR10、OC(O)R10、OC(O)NR10R10、NR10C(O)R10、NR10C(O)OR10、NR10C(O)NR10R10、C(=NR10)R10、C(=NR10)NR10R10、NR10C(-=NR10)NR10R10、NR10S(O)R10、NR10S(O)2R10、NR10S(O)2NR10R10、S(O)R10、S(O)NR10R10、S(O)2R10及S(O)2NR10R10,其中每一R10獨立地選自H、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6環烷基、C3-6環烷基-C1-4烷基-、C6-10芳基、C6-10芳基-C1-4烷基、5-10員雜芳基、4-10員雜環烷基、(5-10員雜芳基)-C1-4烷基-及(4-10
員雜環烷基)-C1-4烷基-,其中R8a、R8b、R8c及R10之C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C3-6環烷基、C3-6環烷基-C1-4烷基-、C6-10芳基、C6-10芳基-C1-4烷基-、5-10員雜芳基、4-10員雜環烷基、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個或3個經獨立選擇之Rd取代基取代;或兩個毗鄰R9取代基與其所連接之原子一起形成稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環或稠合C3-10環烷基環,其中稠合5至7員雜環烷基環及稠合5員或6員雜芳基環各自具有1-4個選自N、O及S之雜原子作為環成員,且其中稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環及稠合C3-10環烷基環各自視情況經1個、2個或3個經獨立選擇之Rb取代基取代;每一Ra獨立地選自H、CN、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Ra之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個Rd取代基取代;每一Rd獨立地選自C1-6烷基、C1-6鹵烷基、鹵基、C6-10芳基、5-10員雜芳基、C3-10環烷基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NH2、NHORe、ORe、SRe、C(O)Re、C(O)NReRe、C(O)ORe、OC(O)Re、OC(O)NReRe、NHRe、NReRe、NReC(O)Re、NReC(O)NReRe、NReC(O)ORe、C(=NRe)NReRe、NReC(=NRe)NReRe、NReC(=NOH)NReRe、NReC(=NCN)NReRe、S(O)Re、S(O)NReRe、S(O)2Re、NReS(O)2Re、NReS(O)2NReRe及S(O)2NReRe,其中Rd之C1-6烷基、C1-6鹵烷基、C6-10芳基、5-10員雜芳基、C3-10環烷基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1-3個經獨立選擇之Rh取代基取代;
每一Rb取代基獨立地選自鹵基、C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、OH、NH2、NO2、NHORc、ORc、SRc、C(O)Rc、C(O)NRcRc、C(O)ORc、OC(O)Rc、OC(O)NRcRc、C(=NRc)NRcRc、NRcC(=NRc)NRcRc、NHRc、NRcRc、NRcC(O)Rc、NRcC(O)ORc、NRcC(O)NRcRc、NRcS(O)Rc、NRcS(O)2Rc、NRcS(O)2NRcRc、S(O)Rc、S(O)NRcRc、S(O)-2Rc或S(O)2NRcRc;其中Rb之C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自進一步視情況經1-3個經獨立選擇之Rd取代基取代;每一Rc獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rc之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rf取代基取代:C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、鹵基、CN、NHORg、ORg、SRg、C(O)Rg、C(O)NRgRg、C(O)ORg、OC(O)Rg、OC(O)NRgRg、NHRg、NRgRg、NRgC(O)Rg、NRgC(O)NRgRg、NRgC(O)ORg、C(=NRg)NRgRg、NRgC(=NRg)NRgRg、S(O)Rg、S(O)NRgRg、S(O)2Rg、NRgS(O)2Rg、NRgS(O)2NRgRg及S(O)2NRgRg;其中Rf之C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rn取代基取代:C1-4烷基、C1-4鹵烷基、鹵基、CN、Ro、NHORo、
ORo、SRo、C(O)Ro、C(O)NRoRo、C(O)ORo、OC(O)Ro、OC(O)NRoRo、NHRo、NRoRo、NRoC(O)Ro、NRoC(O)NRoRo、NRoC(O)ORo、C(=NRo)NRoRo、NRoC(=NRo)NRoRo、S(O)Ro、S(O)NRoRo、S(O)2Ro、NRoS(O)2Ro、NRoS(O)2NRoRo及S(O)2NRoRo;每一Rg獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rg之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1-3個獨立地選自以下之Rp取代基取代:C1-6烷基、C1-6鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、鹵基、CN、NHORr、ORr、SRr、C(O)Rr、C(O)NRrRr、C(O)ORr、OC(O)Rr、OC(O)NRrRr、NHRr、NRrRr、NRrC(O)Rr、NRrC(O)NRrRr、NRrC(O)ORr、C(=NRr)NRrRr、NRrC(=NRr)NRrRr、NRrC(=NOH)NRrRr、NRrC(=NCN)NRrRr、S(O)Rr、S(O)NRrRr、S(O)2Rr、NRrS(O)2Rr、NRrS(O)2NRrRr及S(O)2NRrRr,其中Rp之C1-6烷基、C1-6鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-視情況經1個、2個或3個Rq取代基取代;或任兩個Ra取代基與其所連接之氮原子一起形成4員、5員、6員、7員、8員、9員或10員雜環烷基,其視情況經1個、2個或3個獨立地選自以下之Rh取代基取代:C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-、(4-7員雜環烷基)-C1-4烷基-、C1-6鹵烷基、C2-6烯基、C2-6炔基、鹵基、CN、ORi、SRi、NHORi、C(O)Ri、C(O)NRiRi、C(O)ORi、OC(O)Ri、OC(O)NRiRi、NHRi、NRiRi、NRiC(O)Ri、NRiC(O)NRiRi、NRiC(O)ORi、
C(=NRi)NRiRi、NRiC(=NRi)NRiRi、S(O)Ri、S(O)NRiRi、S(O)2Ri、NRiS(O)2Ri、NRiS(O)2NRiRi及S(O)2NRiRi,其中Rh之C1-6烷基、C2-6烯基、C2-6炔基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-及(4-7員雜環烷基)-C1-4烷基-各自進一步視情況經1個、2個或3個獨立地選自以下之Rj取代基取代:C3-6環烷基、C6-10芳基、5或6員雜芳基、4-7員雜環烷基、C2-4烯基、C2-4炔基、鹵基、C1-4烷基、C1-4鹵烷基、CN、NHORk、ORk、SRk、C(O)Rk、C(O)NRkRk、C(O)ORk、OC(O)Rk、OC(O)NRkRk、NHRk、NRkRk、NRkC(O)Rk、NRkC(O)NRkRk、NRkC(O)ORk、C(=NRk)NRkRk、NRkC(=NRk)NRkRk、S(O)Rk、S(O)NRkRk、S(O)2Rk、NRkS(O)2Rk、NRkS(O)2NRkRk及S(O)2NRkRk,其中Rj之C1-4烷基、C3-6環烷基、C6-10芳基、5員或6員雜芳基、4-6員雜環烷基、C2-4烯基、C2-4炔基、C1-4鹵烷基及C1-4鹵烷氧基各自視情況經1個、2個或3個經獨立選擇之Rq取代基取代;或連接至4至10員雜環烷基之同一碳原子之兩個Rh基團與其所連接之碳原子一起形成C3-6環烷基或具有1-2個選自O、N或S之雜原子作為環成員之4至6員雜環烷基;或任兩個Rc取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Re取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rg取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ri取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rk取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ro取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;且每一Re、Ri、Rk、Ro或Rr獨立地選自H、C1-4烷基、C3-6環烷基、C6-10
芳基、5或6員雜芳基、4-7員雜環烷基、C1-4鹵烷基、C2-4烯基及C2-4炔基,其中Re、Ri、Rk、Ro或Rp之C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、4-7員雜環烷基、C2-4烯基及C2-4炔基各自視情況經1個、2個或3個Rq取代基取代;每一Rq獨立地選自OH、CN、-COOH、NH2、鹵基、C1-6鹵烷基、C1-6烷基、C1-6烷氧基、C1-6烷基硫基、苯基、5-6員雜芳基、4-6員雜環烷基、C3-6環烷基、NHR12、NR12R12及C1-4鹵烷氧基,其中Rq之C1-6烷基、苯基、C3-6環烷基、4-6員雜環烷基及5-6員雜芳基各自視情況經以下基團取代:鹵基、OH、CN、-COOH、NH2、C1-4烷基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、苯基、C3-10環烷基、5-6員雜芳基及4-6員雜環烷基,且每一R12獨立地為C1-6烷基;其限制條件為當X8為CR8b且X7及X9各自為N時,R7不為NH2;且化合物不為(1R,5S,6R)-5-(2,6-二氟-3-((2-甲氧基吡啶并[3,4-b]吡嗪-5-基)胺基)苯基)-5-(氟甲基)-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-3-胺或(1S,5R,6S)-5-(2,6-二氟-3-((2-甲氧基吡啶并[3,4-b]吡嗪-5-基)胺基)苯基)-5-(氟甲基)-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-3-胺。
本發明提供式(I’)化合物或其醫藥學上可接受之鹽或立體異構物,其中:X1為N或CR1;X2為N或CR2;X3為N或CR3;X4為N或CR4;X5為N或CR5;X6為N或CR6其中X1、X2及X3不會同時為N;其中X4、X5及X6不會同時為N;X7為N或CR8a;X8為N或CR8b;X9為N或CR8c;
Cy為C6-10芳基、C3-10環烷基、5至14員雜芳基或4至10員雜環烷基,其各自視情況經1至4個經獨立選擇之R9取代基取代;R1、R2、R3、R4、R5、R6及R9各自獨立地選自H、鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R1、R2、R3、R4、R5、R6及R9之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代;R7為C1-4烷基、鹵基、CN、OH、環丙基、C2-4炔基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR11、NHOR11、C(O)R11、C(O)NR11R11、C(O)OR11、OC(O)R11、OC(O)NR11R11、NR11C(O)R11、NR11C(O)OR11、NR11C(O)NR11R11、C(=NR11)R11、C(=NR11)NR11R11、NR11C(=NR11)NR11R11、NR11S(O)R11、NR11S(O)2R11、NR11S(O)2NR11R11、S(O)R11、S(O)NR11R11、S(O)2R11及S(O)2NR11R11,其中R7之C1-4烷基、環丙基、C2-4炔基及C1-4烷氧基各自視情況經1或2個鹵基、OH、CN或OCH3取代基取代,且每一R11獨立地選自H及視情況經1或2個鹵基、OH、CN或OCH3取代之C1-4烷基;R8a、R8b及R8c各自獨立地選自H、C1-4烷基、C3-6環烷基、C2-4烯基、C2-4炔基、鹵基、CN、OH、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR10、NHOR10、C(O)R10、C(O)NR10R10、C(O)OR10、OC(O)R10、OC(O)NR10R10、NR10C(O)R10、NR10C(O)OR10、NR10C(O)NR10R10、C(=NR10)R10、C(=NR10)NR10R10、NR10C(=NR10)NR10R10、NR10S(O)R10、NR10S(O)2R10、NR10S(O)2NR10R10、S(O)R10、S(O)NR10R10、
S(O)2R10及S(O)2NR10R10,其中每一R10獨立地為H或視情況經1或2個獨立地選自鹵基、OH、CN及C1-4烷氧基之基團取代之C1-4烷基,且其中R8之C1-4烷基、C3-6環烷基、C2-4烯基及C2-4炔基各自視情況經1或2個獨立地選自以下之取代基取代:鹵基、OH、CN、C1-4烷基及C1-4烷氧基;或兩個毗鄰R9取代基與其所連接之碳原子一起形成稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環或稠合C3-10環烷基環,其中稠合5至7員雜環烷基環及稠合5員或6員雜芳基環各自具有1-4個選自N、O及S之雜原子作為環成員,且其中稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環及稠合C3-10環烷基環各自視情況經1或2個經獨立選擇之Rb取代基或1或2個經獨立選擇之Rq取代基取代;每一Ra獨立地選自H、CN、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Ra之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個Rd取代基取代;每一Rd獨立地選自C1-4烷基、C1-4鹵烷基、鹵基、C3-10環烷基、4-10員雜環烷基、苯基、5員或6員雜芳基、CN、NH2、NHORe、ORe、SRe、C(O)Re、C(O)NReRe、C(O)ORe、OC(O)Re、OC(O)NReRe、NHRe、NReRe、NReC(O)Re、NReC(O)NReRe、NReC(O)ORe、C(=NRe)NReRe、NReC(=NRe)NReRe、S(O)Re、S(O)NReRe、S(O)2Re、NReS(O)2Re、NReS(O)2NReRe及S(O)2NReRe,其中Rd之C1-4烷基、C3-10環烷基、苯基、5員或6員雜芳基及4-10員雜環烷基各自進一步視情況經1-3個經獨立選擇之Rq取代基取代;每一Rb取代基獨立地選自鹵基、C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、OH、NH2、NO2、NHORc、ORc、SRc、C(O)Rc、C(O)NRcRc、
C(O)ORc、OC(O)Rc、OC(O)NRcRc、C(=NRc)NRcRc、NRcC(=NRc)NRcRc、NHRc、NRcRc、NRcC(O)Rc、NRcC(O)ORc、NRcC(O)NRcRc、NRcS(O)Rc、NRcS(O)2Rc、NRcS(O)2NRcRc、S(O)Rc、S(O)NRcRc、S(O)2Rc或S(O)2NRcRc;其中Rb之C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自進一步視情況經1-3個經獨立選擇之Rd取代基取代;每一Rc獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rc之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rf取代基取代:C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、鹵基、CN、NHORg、ORg、SRg、C(O)Rg、C(O)NRgRg、C(O)ORg、OC(O)Rg、OC(O)NRgRg、NHRg、NRgRg、NRgC(O)Rg、NRgC(O)NRgRg、NRgC(O)ORg、C(=NRg)NRgRg、NRgC(=NRg)NRgRg、S(O)Rg、S(O)NRgRg、S(O)2Rg、NRgS(O)2Rg、NRgS(O)2NRgRg及S(O)2NRgRg;其中Rf之C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rn取代基取代:C1-4烷基、C1-4鹵烷基、鹵基、CN、Ro、NHORo、ORo、SRo、C(O)Ro、C(O)NRoRo、C(O)ORo、OC(O)Ro、OC(O)NRoRo、NHRo、NRoRo、NRoC(O)Ro、NRoC(O)NRoRo、NRoC(O)ORo、C(=NRo)NRoRo、NRoC(=NRo)NRoRo、S(O)Ro、S(O)NRoRo、S(O)2Ro、NRoS(O)2Ro、NRoS(O)2NRoRo及S(O)2NRoRo;
每一Rg獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rg之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1-3個經獨立選擇之Rp取代基取代;或任兩個Ra取代基與其所連接之氮原子一起形成4員、5員、6員、7員、8員、9員或10員雜環烷基,其視情況經1個、2個或3個獨立地選自以下之Rh取代基取代:C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-、(4-7員雜環烷基)-C1-4烷基-、C1-6鹵烷基、C2-6烯基、C2-6炔基、鹵基、CN、ORi、SRi、NHORi、C(O)Ri、C(O)NRiRi、C(O)ORi、OC(O)Ri、OC(O)NRiRi、NHRi、NRiRi、NRiC(O)Ri、NRiC(O)NRiRi、NRiC(O)ORi、C(=NRi)NRiRi、NRiC(=NRi)NRiRi、S(O)Ri、S(O)NRiRi、S(O)2Ri、NRiS(O)2Ri、NRiS(O)2NRiRi及S(O)2NRiRi,其中Rh之C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-及(4-7員雜環烷基)-C1-4烷基-各自進一步視情況經1個、2個或3個獨立地選自以下之Rj取代基取代:C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基、C2-4炔基、鹵基、C1-4烷基、C1-4鹵烷基、CN、NHORk、ORk、SRk、C(O)Rk、C(O)NRkRk、C(O)ORk、OC(O)Rk、OC(O)NRkRk、NHRk、NRkRk、NRkC(O)Rk、NRkC(O)NRkRk、NRkC(O)ORk、C(=NRk)NRkRk、NRkC(=NRk)NRkRk、S(O)Rk、S(O)NRkRk、S(O)2Rk、NRkS(O)2Rk、NRkS(O)2NRkRk及S(O)2NRkRk;或連接至4至10員雜環烷基之同一碳原子之兩個Rh基團與其所連接之碳原子一起形成C3-6環烷基或具有1-2個選自O、N或S之雜原子作為環成員之4至6員雜環烷基;或任兩個Rc取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Re取代基與其所連接之氮原子一起形成4員、5員、6員或7
員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rg取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ri取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rk取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ro取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;且每一Re、Ri、Rk、Ro或Rp獨立地選自H、C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C1-4鹵烷基、C2-4烯基及C2-4炔基,其中Re、Ri、Rk、Ro或Rp之C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基及C2-4炔基各自視情況經1個、2個或3個Rq取代基取代;每一Rq獨立地選自OH、CN、-COOH、NH2、鹵基、C1-6鹵烷基、C1-6烷基、C1-6烷氧基、C1-6烷基硫基、苯基、5-6員雜芳基、4-6員雜環烷基、C3-6環烷基、NHR12、NR12R12及C1-4鹵烷氧基,其中Rq之C1-6烷基、苯基、C3-6環烷基、4-6員雜環烷基及5-6員雜芳基各自視情況經以下基團取代:鹵基、OH、CN、-COOH、NH2、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、苯基、C3-10環烷基及4-6員雜環烷基,且每一R12獨立地為C1-6烷基;其限制條件為當X8為CR8b且X7及X9各自為N時,R7不為NH2;且化合物不為(1R,5S,6R)-5-(2,6-二氟-3-((2-甲氧基吡啶并[3,4-b]吡嗪-5-基)胺基)苯基)-5-(氟甲基)-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-3-胺或(1S,5R,6S)-5-(2,6-二氟-3-((2-甲氧基吡啶并[3,4-b]吡嗪-5-基)胺基)苯基)-5-(氟甲基)-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-3-胺。
在式(I’)化合物之一些實施例中,Cy不為3-胺基-1-氟甲基-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-1-基。在一些情況下,當R8a、R8b或R8c中之任一者為F時,Cy不為3-胺基-1-氟甲基-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-1-基。在一些情況下,當R8a、R8b或R8c中之任一者為鹵基時,Cy不為3-胺
基-1-氟甲基-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-1-基。在一些情況下,當R7為F時,Cy不為3-胺基-1-氟甲基-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-1-基。在一些情況下,當R7為鹵基時,Cy不為3-胺基-1-氟甲基-2-氧雜-4-氮雜二環[4.1.0]庚-3-烯-1-基。
在式(I’)化合物之一些實施例中,Cy為C6-10芳基,其視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為苯基或萘基,其各自視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為苯基,其視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為未經取代之苯基。
在式(I’)化合物之一些實施例中,Cy為C3-10環烷基,其視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為環丙基、環丁基、環戊基、環己基、環庚基或環辛基,其各自視情況經1至4個經獨立選擇之R9取代基取代。
在式(I’)化合物之一些實施例中,Cy為5至14員雜芳基,其視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為吡啶基、嘧啶基、吡嗪基、嗒嗪基、三嗪基、吡咯基、吡唑基、吖唑基、噁唑基、噻唑基、咪唑基、呋喃基、苯硫基、喹啉基、異喹啉基、萘啶基、吲哚基、苯并苯硫基、苯并呋喃基、苯并異噁唑基、咪唑并[1,2-b]噻唑基、嘌呤基、噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、異噻唑基、異噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基及1,3,4-噁二唑基,其各自視情況經1至4個經獨立選擇之R9取代基取代。
在式(I’)化合物之一些實施例中,Cy為4至10員雜環烷基,其視情況經1至4個經獨立選擇之R9取代基取代。在某些實施例中,Cy為氮雜環丁基、氮雜環庚基、二氫苯并呋喃基、二氫呋喃基、二氫哌喃基、嗎啉基、3-氧雜-9-氮雜螺[5.5]十一烷基、1-氧雜-8-氮雜螺[4.5]癸烷基、哌啶基、哌嗪基、側氧基哌嗪基、哌喃基、吡咯啶基、奎寧環基、四氫呋喃基、四氫哌喃基、1,2,3,4-四氫喹啉基、莨菪烷基、2,3-二氫-1,4-苯并二氧雜環己
烯-6-基及硫嗎啉基,其各自視情況經1至4個經獨立選擇之R9取代基取代。在一些實施例中,Cy為2,3-二氫-1,4-苯并二氧雜環己烯-6-基,其視情況經1至4個經獨立選擇之R9取代基取代。在一些實施例中,Cy為未經取代之2,3-二氫-1,4-苯并二氧雜環己烯-6-基。
在式(I’)化合物之一些實施例中,X7為CR8a,X8為CR8b且X9為CR8c。在一些情況下,R8a、R8b及R8c各自為H。
在式(I’)化合物之一些實施例中,X7為CR8a,X8為N且X9為N。在一些情況下,R8a為H。
在式(I’)化合物之一些實施例中,X7為CR8a,X8為N且X9為CR8c。在一些情況下,R8a及R8c各自為H。
在式(I’)化合物之一些實施例中,X7為CR8a,X8為CR8b且X9為N。在一些情況下,R8a及R8c各自為H。
在式(I’)化合物之一些實施例中,X7為N,X8為CR8b且X9為CR8c。在一些情況下,R8a及R8c各自為H。
在式(I’)化合物之一些實施例中,X7為N,X8為N且X9為CR8c。在一些情況下,R8c為H。
在式(I’)化合物之一些實施例中,X7為N,X8為CR8b且X9為N。在一些情況下,R8b為H。
在式(I’)化合物之一些實施例中,X7、X8及X9各自為N。
或其醫藥學上可接受之鹽或立體異構物,其中:X1為N或CR1;X2為N或CR2;X3為N或CR3;X4為N或CR4;
X5為N或CR5;X6為N或CR6其中X1、X2及X3不會同時為N;其中X4、X5及X6不會同時為N;R1、R2、R3、R4、R5、R6及R9各自獨立地選自H、鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R1、R2、R3、R4、R5、R6及R9之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代;R7為C1-4烷基、鹵基、CN、OH、環丙基、C2-4炔基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR11、NHOR11、C(O)R11、C(O)NR11R11、C(O)OR11、OC(O)R11、OC(O)NR11R11、NR11C(O)R11、NR11C(O)OR11、NR11C(O)NR11R11、C(=NR11)R11、C(=NR11)NR11R11、NR11C(=NR11)NR11R11、NR11S(O)R11、NR11S(O)2R11、NR11S(O)2NR11R11、S(O)R11、S(O)NR11R11、S(O)2R11及S(O)2NR11R11,其中R7之C1-4烷基、環丙基、C2-4炔基及C1-4烷氧基各自視情況經1或2個鹵基、OH、CN或OCH3取代基取代,且每一R11獨立地選自H及視情況經1或2個鹵基、OH、CN或OCH3取代之C1-4烷基;每一R8獨立地選自H、C1-4烷基、C3-6環烷基、C2-4烯基、C2-4炔基、鹵基、CN、OH、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR10、NHOR10、C(O)R10、C(O)NR10R10、C(O)OR10、OC(O)R10、OC(O)NR10R10、NR10C(O)R10、NR10C(O)OR10、NR10C(O)NR10R10、
C(=NR10)R10、C(=NR10)NR10R10、NR10C(=NR10)NR10R10、NR10S(O)R10、NR10S(O)2R10、NR10S(O)2NR10R10、S(O)R10、S(O)NR10R10、S(O)2R10及S(O)2NR10R10,其中每一R10獨立地為H或視情況經1或2個獨立地選自鹵基、OH、CN及C1-4烷氧基之基團取代之C1-4烷基,且其中R8之C1-4烷基、C3-6環烷基、C2-4烯基及C2-4炔基各自視情況經1或2個獨立地選自以下之取代基取代:鹵基、OH、CN、C1-4烷基及C1-4烷氧基;或兩個毗鄰R9取代基與其所連接之碳原子一起形成稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環或稠合C3-10環烷基環,其中稠合5至7員雜環烷基環及稠合5員或6員雜芳基環各自具有1-4個選自N、O及S之雜原子作為環成員,且其中稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環及稠合C3-10環烷基環各自視情況經1或2個經獨立選擇之Rq取代基或1或2個經獨立選擇之Rb取代基取代;每一Ra獨立地選自H、CN、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Ra之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個Rd取代基取代;每一Rd獨立地選自C1-4烷基、C1-4鹵烷基、鹵基、C3-10環烷基、4-10員雜環烷基、苯基、5員或6員雜芳基、CN、NH2、NHORe、ORe、SRe、C(O)Re、C(O)NReRe、C(O)ORe、OC(O)Re、OC(O)NReRe、NHRe、NReRe、NReC(O)Re、NReC(O)NReRe、NReC(O)ORe、C(=NRe)NReRe、NReC(=NRe)NReRe、S(O)Re、S(O)NReRe、S(O)2Re、NReS(O)2Re、NReS(O)2NReRe及S(O)2NReRe,其中Rd之C1-4烷基、C3-10環烷基、苯基、5員或6員雜芳基及4-10員雜環烷基各自進一步視情況經1-3個經獨立選擇之Rq取代基取代;每一Rb取代基獨立地選自鹵基、C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4
烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、OH、NH2、NO2、NHORc、ORc、SRc、C(O)Rc、C(O)NRcRc、C(O)ORc、OC(O)Rc、OC(O)NRcRc、C(=NRc)NRcRc、NRcC(=NRc)NRcRc、NHRc、NRcRc、NRcC(O)Rc、NRcC(O)ORc、NRcC(O)NRcRc、NRcS(O)Rc、NRcS(O)2Rc、NRcS(O)2NRcRc、S(O)Rc、S(O)NRcRc、S(O)2Rc或S(O)2NRcRc;其中Rb之C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自進一步視情況經1-3個經獨立選擇之Rd取代基取代;每一Rc獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rc之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rf取代基取代:C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、鹵基、CN、NHORg、ORg、SRg、C(O)Rg、C(O)NRgRg、C(O)ORg、OC(O)Rg、OC(O)NRgRg、NHRg、NRgRg、NRgC(O)Rg、NRgC(O)NRgRg、NRgC(O)ORg、C(=NRg)NRgRg、NRgC(=NRg)NRgRg、S(O)Rg、S(O)NRgRg、S(O)2Rg、NRgS(O)2Rg、NRgS(O)2NRgRg及S(O)2NRgRg;其中Rf之C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rn取代基取代:C1-4烷基、C1-4鹵烷基、鹵基、CN、Ro、NHORo、ORo、SRo、C(O)Ro、C(O)NRoRo、C(O)ORo、OC(O)Ro、OC(O)NRoRo、NHRo、NRoRo、NRoC(O)Ro、NRoC(O)NRoRo、NRoC(O)ORo、C(=NRo)NRoRo、
NRoC(=NRo)NRoRo、S(O)Ro、S(O)NRoRo、S(O)2Ro、NRoS(O)2Ro、NRoS(O)2NRoRo及S(O)2NRoRo;每一Rg獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rg之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1-3個經獨立選擇之Rp取代基取代;或任兩個Ra取代基與其所連接之氮原子一起形成4員、5員、6員、7員、8員、9員或10員雜環烷基,其視情況經1個、2個或3個獨立地選自以下之Rh取代基取代:C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-、(4-7員雜環烷基)-C1-4烷基-、C1-6鹵烷基、C2-6烯基、C2-6炔基、鹵基、CN、ORi、SRi、NHORi、C(O)Ri、C(O)NRiRi、C(O)ORi、OC(O)Ri、OC(O)NRiRi、NHRi、NRiRi、NRiC(O)Ri、NRiC(O)NRiRi、NRiC(O)ORi、C(=NRi)NRiRi、NRiC(=NRi)NRiRi、S(O)Ri、S(O)NRiRi、S(O)2Ri、NRiS(O)2Ri、NRiS(O)2NRiRi及S(O)2NRiRi,其中Rh之C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-及(4-7員雜環烷基)-C1-4烷基-各自進一步視情況經1個、2個或3個獨立地選自以下之Rj取代基取代:C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基、C2-4炔基、鹵基、C1-4烷基、C1-4鹵烷基、CN、NHORk、ORk、SRk、C(O)Rk、C(O)NRkRk、C(O)ORk、OC(O)Rk、OC(O)NRkRk、NHRk、NRkRk、NRkC(O)Rk、NRkC(O)NRkRk、NRkC(O)ORk、C(=NRk)NRkRk、NRkC(=NRk)NRkRk、S(O)Rk、S(O)NRkRk、S(O)2Rk、NRkS(O)2Rk、NRkS(O)2NRkRk及S(O)2NRkRk;或連接至4至10員雜環烷基之同一碳原子之兩個Rh基團與其所連接之碳原子一起形成C3-6環烷基或具有1-2個選自O、N或S之雜原子作為環成員之4至6員雜環烷基;或任兩個Rc取代基與其所連接之氮原子一起形成4員、5員、6員或7
員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Re取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rg取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ri取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rk取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ro取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;且每一Re、Ri、Rk、Ro或Rp獨立地選自H、C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C1-4鹵烷基、C2-4烯基及C2-4炔基,其中Re、Ri、Rk、Ro或Rp之C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基及C2-4炔基各自視情況經1個、2個或3個Rq取代基取代;每一Rq獨立地選自OH、CN、-COOH、NH2、鹵基、C1-4烷基、C1-4烷氧基、C1-4烷基硫基、苯基、4至6員雜環烷基、5員或6員雜芳基、C3-6環烷基、NHR12、NR12R12及C1-4鹵烷氧基,其中Rq之C1-4烷基、苯基、4至6員雜環烷基及5員或6員雜芳基各自視情況經1或2個獨立地選自以下之取代基取代:鹵基、OH、CN、-COOH、NH2、C1-4烷基、C1-4烷氧基、C3-10環烷基及4員、5員或6員雜環烷基,且每一R12獨立地為C1-6烷基;下標n為整數1、2、3、4或5;且下標m為整數1、2或3。
或其醫藥學上可接受之鹽或立體異構物,其中:X1為N或CR1;X2為N或CR2;X3為N或CR3;X4為N或CR4;X5為N或CR5;X6為N或CR6其中X1、X2及X3不會同時為N;其中X4、X5及X6不會同時為N;R1、R2、R3、R4、R3、R6及R9各自獨立地選自H、鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R1、R2、R3、R4、R5、R6及R9之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代;R7為C1-4烷基、鹵基、CN、OH、環丙基、C2-4炔基、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR11、NHOR11、C(O)R11、C(O)NR11R11、C(O)OR11、OC(O)R11、OC(O)NR11R11、NR11C(O)R11、NR11C(O)OR11、NR11C(O)NR11R11、C(=NR11)R11、C(=NR11)NR11R11、NR11C(=NR11)NR11R11、NR11S(O)R11、NR11S(O)2R11、NR11S(O)2NR11R11、S(O)R11、S(O)NR11R11、S(O)2R11及S(O)2NR11R11,其中每一R11獨立地選自H及視情況經1或2個鹵基、OH、CN或OCH3取代之C1-4烷基;每一R8獨立地選自H、C1-4烷基、C3-6環烷基、C2-4烯基、C2-4炔基、
鹵基、CN、OH、C1-4烷氧基、C1-4鹵烷基、C1-4鹵烷氧基、NH2、-NH-C1-4烷基、-N(C1-4烷基)2、OR10、NHOR10、C(O)R10、C(O)NR10R10、C(O)OR10、OC(O)R10、OC(O)NR10R10、NR10C(O)R10、NR10C(O)OR10、NR10C(O)NR10R10、C(=NR10)R10、C(=NR10)NR10R10、NR10C(=NR10)NR10R10、NR10S(O)R10、NR10S(O)2R10、NR10S(O)2NR10R10、S(O)R10、S(O)NR10R10、S(O)2R10及S(O)2NR10R10,其中每一R10獨立地為H或視情況經1或2個獨立地選自鹵基、OH、CN及C1-4烷氧基之基團取代之C1-4烷基,且其中R8之C1-4烷基、C3-6環烷基、C2-4烯基及C2-4炔基各自視情況經1或2個獨立地選自以下之取代基取代:鹵基、OH、CN、C1-4烷基及C1-4烷氧基;或兩個毗鄰R9取代基與其所連接之碳原子一起形成稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環或稠合C3-10環烷基環,其中稠合5至7員雜環烷基環及稠合5員或6員雜芳基環各自具有1-4個選自N、O及S之雜原子作為環成員,且其中稠合苯基環、稠合5至7員雜環烷基環、稠合5員或6員雜芳基環及稠合C3-10環烷基環各自視情況經1或2個經獨立選擇之Rq取代基取代;每一Ra獨立地選自H、CN、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Ra之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個Rd取代基取代;每一Rd獨立地選自C1-4烷基、C1-4鹵烷基、鹵基、C3-10環烷基、4-10員雜環烷基、苯基、5員或6員雜芳基、CN、NH2、NHORe、ORe、SRe、C(O)Re、C(O)NReRe、C(O)ORe、OC(O)Re、OC(O)NReRe、NHRe、NReRe、NReC(O)Re、NReC(O)NReRe、NReC(O)ORe、C(=NRe)NReRe、NReC(=NRe)NReRe、S(O)Re、S(O)NReRe、S(O)2Re、NReS(O)2Re、NReS(O)2NReRe及S(O)2NReRe,其中Rd之C1-4烷基、C3-10環烷基、苯基、5員或6員雜芳基及4-10員雜環烷基各自進一步視情況經1-3個經獨立選擇
之Rq取代基取代;每一Rb取代基獨立地選自鹵基、C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、OH、NH2、NO2、NHORc、ORc、SRc、C(O)Rc、C(O)NRcRc、C(O)ORc、OC(O)Rc、OC(O)NRcRc、C(=NRc)NRcRc、NRcC(=NRc)NRcRc、NHRc、NRcRc、NRcC(O)Rc、NRcC(O)ORc、NRcC(O)NRcRc、NRcS(O)Rc、NRcS(O)2Rc、NRcS(O)2NRcRc、S(O)Rc、S(O)NRcRc、S(O)2Rc或S(O)2NRcRc;其中Rb之C1-4烷基、C1-4鹵烷基、C1-4鹵烷氧基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自進一步視情況經1-3個經獨立選擇之Rd取代基取代;每一Rc獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rc之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地選自以下之Rf取代基取代:C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、鹵基、CN、NHORg、ORg、SRg、C(O)Rg、C(O)NRgRg、C(O)ORg、OC(O)Rg、OC(O)NRgRg、NHRg、NRgRg、NRgC(O)Rg、NRgC(O)NRgRg、NRgC(O)ORg、C(=NRg)NRgRg、NRgC(=NRg)NRgRg、S(O)Rg、S(O)NRgRg、S(O)2Rg、NRgS(O)2Rg、NRgS(O)2NRgRg及S(O)2NRgRg;其中Rf之C1-4烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個、4個或5個獨立地
選自以下之Rn取代基取代:C1-4烷基、C1-4鹵烷基、鹵基、CN、Ro、NHORo、ORo、SRo、C(O)Ro、C(O)NRoRo、C(O)ORo、OC(O)Ro、OC(O)NRoRo、NHRo、NRoRo、NRoC(O)Ro、NRoC(O)NRoRo、NRoC(O)ORo、C(=NRo)NRoRo、NRoC(=NRo)NRoRo、S(O)Ro、S(O)NRoRo、S(O)2Ro、NRoS(O)2Ro、NRoS(O)2NRoRo及S(O)2NRoRo;每一Rg獨立地選自H、C1-6烷基、C1-4鹵烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-,其中Rg之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-10員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-10員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1-3個經獨立選擇之Rp取代基取代;或任兩個Ra取代基與其所連接之氮原子一起形成4員、5員、6員、7員、8員、9員或10員雜環烷基,其視情況經1個、2個或3個獨立地選自以下之Rh取代基取代:C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-、(4-7員雜環烷基)-C1-4烷基-、C1-6鹵烷基、C2-6烯基、C2-6炔基、鹵基、CN、ORi、SRi、NHORi、C(O)Ri、C(O)NRiRi、C(O)ORi、OC(O)Ri、OC(O)NRiRi、NHRi、NRiRi、NRiC(O)Ri、NRiC(O)NRiRi、NRiC(O)ORi、C(=NRi)NRiRi、NRiC(=NRi)NRiRi、S(O)Ri、S(O)NRiRi、S(O)2Ri、NRiS(O)2Ri、NRiS(O)2NRiRi及S(O)2NRiRi,其中Rh之C1-6烷基、C3-10環烷基、4-7員雜環烷基、C6-10芳基、5-6員雜芳基、C3-10環烷基-C1-4烷基-、(5-6員雜芳基)-C1-4烷基-及(4-7員雜環烷基)-C1-4烷基-各自進一步視情況經1個、2個或3個獨立地選自以下之Rj取代基取代:C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基、C2-4炔基、鹵基、C1-4烷基、C1-4鹵烷基、CN、NHORk、ORk、SRk、C(O)Rk、C(O)NRkRk、C(O)ORk、OC(O)Rk、OC(O)NRkRk、NHRk、NRkRk、NRkC(O)Rk、NRkC(O)NRkRk、NRkC(O)ORk、C(=NRk)NRkRk、NRkC(=NRk)NRkRk、S(O)Rk、S(O)NRkRk、S(O)2Rk、NRkS(O)2Rk、NRkS(O)2NRkRk及S(O)2NRkRk;或連接至4至10員雜環烷基之同一碳原子之兩個Rh基團與其所連接之碳原子
一起形成C3-6環烷基或具有1-2個選自O、N或S之雜原子作為環成員之4至6員雜環烷基;或任兩個Rc取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Re取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rg取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ri取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Rk取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;或任兩個Ro取代基與其所連接之氮原子一起形成4員、5員、6員或7員雜環烷基,其視情況經1個、2個或3個經獨立選擇之Rh取代基取代;且每一Re、Ri、Rk、Ro或Rp獨立地選自H、C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C1-4鹵烷基、C2-4烯基及C2-4炔基,其中Re、Ri、Rk、Ro或Rp之C1-4烷基、C3-6環烷基、C6-10芳基、5或6員雜芳基、C2-4烯基及C2-4炔基各自視情況經1個、2個或3個Rq取代基取代;每一Rq獨立地選自OH、CN、-COOH、NH2、鹵基、C1-4烷基、C1-4烷氧基、C1-4烷基硫基、苯基、4至6員雜環烷基、5員或6員雜芳基、C3-6環烷基、NHR12、NR12R12及C1-4鹵烷氧基,其中Rq之C1-4烷基、苯基、4至6員雜環烷基及5員或6員雜芳基各自視情況經1或2個獨立地選自以下之取代基取代:鹵基、OH、CN、-COOH、NH2、C1-4烷基、C1-4烷氧基、C3-10環烷基及4員、5員或6員雜環烷基,且每一R12獨立地為C1-6烷基;下標n為整數1、2、3、4或5;且下標m為整數1、2或3。
如本文所描述之化合物或其醫藥學上可接受之鹽或立體異構物可用作PD-1/PD-L1蛋白/蛋白相互作用之抑制劑。舉例而言,如本文所
描述之化合物或其醫藥學上可接受之鹽或立體異構物可破壞PD-1路徑中之PD-1/PD-L1蛋白/蛋白相互作用。
或其醫藥學上可接受之鹽或立體異構物。在式(II)化合物之某些實施例中,R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。式(II)之其他變量如本文所描述之式(I)或式(I)化合物之任一實施例中所定義。在式(II)化合物之一實施例中,R7為CN或視情況經Rq取代之C1-4烷基。在另一實施例中,R7為CH3或CN。
或其醫藥學上可接受之鹽或立體異構物。在式(III)化合物之某些實施例中,R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、
C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。式(III)之其他變量如本文所描述之式(I)或式(I)化合物之任一實施例中所定義。
或其醫藥學上可接受之鹽或立體異構物,其中式(IV)之變量如本文所描述之式(I)或式(I)化合物之任一實施例中所定義。在式(II)化合物之某些實施例中,R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
或其醫藥學上可接受之鹽或立體異構物,其中式(V)之變量如本文所描述之式(I)或式(I)化合物之任一實施例中所定義。在式(V)化合物之某些實施例中,R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
或其醫藥學上可接受之鹽或立體異構物,其中式(VI)之變量如本文所描述之式(I)或式(I)化合物之任一實施例中所定義。在式(VI)化合物之某些實施例中,R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、
C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
或其醫藥學上可接受之鹽或立體異構物,其中式(VII)之變量如本文所描述之式(I’)或(I)或式(I’)或(I)化合物之任一實施例中所定義。在式(VII)化合物之某些實施例中,為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-、(4-10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R1之C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5-14員雜芳基、4-10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5-14員雜芳基)-C1-4烷基-及(4-10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
或其醫藥學上可接受之鹽或立體異構物,其中式(VIII)之變量如本文所描述之式(I’)或(I)或式(I’)或(I)化合物之任一實施例中所定義。在一些情況下,R9為H,n為1,X7為CR8a,X8為CR8b且X9為CR8c。在一些情況下,X7、X8及X9各自為CH。
或其醫藥學上可接受之鹽或立體異構物,其中式(IX)之變量如本文所描述之式(I’)或(I)或式(I’)或(I)化合物之任一實施例中所定義。在一些情況下,R9為H,n為1,X7為CR8a,X8為CR8b且X9為CR8c。在一些情況下,X7、X8及X9各自為CH。
在式I’、I、II、III、IV、V或VI化合物或其醫藥學上可接
受之鹽或立體異構物之一些實施例中,部分或選
自:、、、、、
,其中取代基R1、R2、R3、R4、R5及R6如本文所描述之式(I’)、
(I)或式(I’)或(I)化合物之任一實施例中所定義。在某些實施例中,在每次出現時,R1、R3、R4、R5及R6各自為H。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之
鹽或立體異構物之一些實施例中,部分或選自:
,其中取代基R1、R2、R3、R4、R5及R6如本文所描述之式(I’)、
(I)或式(I’)、(I)化合物之任一實施例中所定義。在某些實施例中,在每次出現時,R1、R2、R4、R5及R6各自為H。
在式I’、I、II、III、IV、V或VI化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X3為CR3,X4為CR4,X5為CR5且X6為CR6。在一些情況下,X1、X3、X4、X5及X6各自為CH。在一實施例中,X2為CR2。
在式I’、I、II、III、IV、V或VI化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X3為CR3,X4為CR4,X5為CR5且X6為N。在一些情況下,X1、X3、X4及X5各自為CH。在一實施例中,X2為CR2。
在式I’、I、II、III、IV、V或VI化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X3為CR3,X4為N,X5為CR5且X6為N。在一些情況下,X1、X3及X5各自為CH。在一實施例中,X2為CR2。
在式I’、I、II、III、IV、V或VI化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X3為N,X4為CR4,X5為CR5且X6為N。在一些情況下,X1、X4及X5各自為CH。在一實施例中,X2為CR2。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X2為N,X4為CR4,X5為CR5且X6為CR6。在一些情況下,X1、X4、X5及X6各自為CH。在一實施例中,X2為CR2。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X2為CR2,X4為CR4,X5為CR5且X6為CR6。在一些情況下,X1、X2、X4、X5及X6各自為CH。在一實施例中,X3為CR3。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X2為CR2,X4為CR4,X5為CR5且X6為N。在一些情況下,X1、X2、X4及X5各自為CH。在一實施例中,X3為CR3。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X2為CR2,X4為N,X5為CR5且X6為N。在一些情況下,X1、X2及X5各自為CH。在一實施例中,X3為CR3。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之鹽或立體異構物之一些實施例中,X1為CR1,X2為N,X4為CR4,X5為CR5且X6為N。在一些情況下,X1、X4及X5各自為CH。在一實施例中,X3為CR3。
在式I’、I、VII、VIII或IX化合物或其醫藥學上可接受之
鹽或立體異構物之一些實施例中,X1為CR1,X2為N,X4為CR4,X5為CR5且X6為CR6。在一些情況下,X1、X4、X5及X6各自為CH。在一實施例中,X3為CR3。
在一些實施例中,R1、R3、R4、R5及R6各自獨立地選自H、C1-6烷基、CN、-N(C1-6烷基)2及鹵基。
在一些實施例中,R1、R3、R4、R5及R6各自獨立地選自H、CN、C1-6烷基及鹵基。
在一些實施例中,R1、R2、R4、R5及R6各自獨立地選自H、C1-6烷基、CN、-N(C1-6烷基)2及鹵基。
在一些實施例中,R1、R2、R4、R5及R6各自獨立地選自H、CN、C1-6烷基及鹵基。
在一些實施例中,R1、R2、R3、R4、R5、R8及R9各自為H。
在一些實施例中,R1、R3、R4、R5、R6、R8及R9各自為H。
在一些實施例中,R1、R2、R4、R5、R6、R8及R9各自為H。
在一些實施例中,R2為-CH2-Rb。
在一些實施例中,R3為-CH2-Rb。
在一些實施例中,R3為H、鹵基或C1-6烷基。
在一些實施例中,R3為H、Cl或OCH3。
在一些實施例中,苯基環上之兩個毗鄰R9取代基與其所連接之碳原子一起形成5員、6員或7員稠合雜環烷基,其視情況經1或2個Rq取代基取代。在一些情況下,稠合雜環烷基為稠合二氧雜環己基,其視情況經1或2個Rq取代基取代。在一些情況下,稠合雜環烷基具有碳及1或2個選自O、N或S之雜原子作為環成員,其中碳環原子視情況經氧化形成羰基,N環原子視情況經氧化形成NO且S環原子視情況經氧化形成SO或SO2。
在一些實施例中,下標n為2且下標m為1。
在一些實施例中,R7為C1-4烷基或CN。
在一些實施例中,R7為CH3或CN。
在一些實施例中,R8及R9各自為H。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合物之一些實施例中,R2為經Rb取代之C1-4烷基。在某些實施例中,Rb為NHRc或NRcRc。在某些實施例中,Rb為NRcRc。在其他實施例中,Rb為2-羥基乙基胺基、2-羥基乙基(甲基)胺基、2-羧基哌啶-1-基、(氰基甲基)胺基、(S)-2-羧基哌啶-1-基、(R)-2-羧基哌啶-1-基或2-羧基哌啶-1-基,其各自視情況經1個、2個或3個Rq取代基取代。在其他實施例中,Rb為2-羥基乙基胺基、2-羥基乙基(甲基)胺基、2-羧基哌啶-1-基、(氰基甲基)胺基、(S)-2-羧基哌啶-1-基、(R)-2-羧基哌啶-1-基或2-羧基哌啶-1-基。在其他實施例中,Rb為2-羥基乙基胺基。在其他實施例中,Rb為2-羧基哌啶-1-基。在其他實施例中,R2為經Rq取代之C1-4烷基。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合物之一些實施例中,R2為經Rd取代之C1-4烷氧基。在某些實施例中,Rd為苯基、3-氰基苯基、3-吡啶基、2-吡啶基、4-吡啶基,其各自視情況經1個、2個或3個Rq取代基取代。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合物之一些實施例中,R2為-OCH2Rd。在某些實施例中,Rd為苯基、3-氰基苯基、3-吡啶基、2-吡啶基、4-吡啶基,其各自視情況經1個、2個或3個Rq取代基取代。
在式I’、I、II、III、III、IV、V、或VI、VII、VIII或IX化合物之一些實施例中,R3為經Rb取代之C1-4烷基。在某些實施例中,Rb為NHRc或NRcRc。在某些實施例中,Rb為NRcRc。在其他實施例中,Rb為2-羥基乙基胺基、2-羥基乙基(甲基)胺基、2-羧基哌啶-1-基、(氰基甲基)胺基、(S)-2-羧基哌啶-1-基、(R)-2-羧基哌啶-1-基或2-羧基哌啶-1-基,其各自視情況經1個、2個或3個Rq取代基取代。在其他實施例中,Rb為2-羥基乙基胺基、2-羥基乙基(甲基)胺基、2-羧基哌啶-1-基、(氰基甲基)胺基、(S)-2-羧基哌啶-1-基、(R)-2-羧基哌啶-1-基或2-羧基哌啶-1-基。在其他實施例中,Rb為2-羥基乙基胺基。在其他實施例中,Rb為2-羧基哌啶-1-基。在其他實施例中,R3為經Rq取代之C1-4烷基。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合
物之一些實施例中,R3為經Rd取代之C1-4烷氧基。在某些實施例中,Rd為苯基、3-氰基苯基、3-吡啶基、2-吡啶基、4-吡啶基,其各自視情況經1個、2個或3個Rq取代基取代。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合物之一些實施例中,R3為-OCH2Rd。在某些實施例中,Rd為苯基、3-氰基苯基、3-吡啶基、2-吡啶基、4-吡啶基,其各自視情況經1個、2個或3個Rq取代基取代。
在式I’、I、II、III、III、IV、V、VI、VII、VIII或IX化合物之一些實施例中,R3為2-羥基乙基胺基甲基、2-羥基乙基(甲基)胺基甲基、2-羧基哌啶-1-基甲基、(氰基甲基)胺基甲基、(S)-2-羧基哌啶-1-基甲基、(R)-2-羧基哌啶-1-基甲基、2-羧基哌啶-1-基甲基、苄基氧基、2-氰基苄基氧基、3-氰基苄基氧基、4-氰基苄基氧基、2-吡啶基甲氧基、3-吡啶基甲氧基或4-吡啶基甲氧基,其各自視情況經1個、2個或3個Rq取代基取代。在某些實施例中,R3為2-羥基乙基胺基甲基、2-羧基哌啶-1-基甲基、(S)-2-羧基哌啶-1-基甲基、(R)-2-羧基哌啶-1-基甲基或(3-氰基苄基)氧基,其各自視情況經1個、2個或3個Rq取代基取代。
在式I、II、III、V或VII化合物之一些實施例中,R8為H、鹵基、CN、N(C1-6烷基)2、C1-6烷基或C1-6烷氧基,其中C1-6烷基及C1-6烷氧基各自視情況經1-3個Rq取代基取代。在式I’、VIII或IX化合物之一些實施例中,R8a、R8b及R8c各自獨立地選自H、鹵基、CN、N(C1-6烷基)2、C1-6烷基及C1-6烷氧基,其中C1-6烷基及C1-6烷氧基各自視情況經1-3個Rq取代基取代。
在式I、II、III、V或VII化合物之一些實施例中,R8為H、鹵基、CN、N(CH3)2或CH3。在式I’、VIII或IX化合物之一些實施例中,R8a、R8b及R8c各自獨立地選自H、鹵基、CN、N(CH3)2及CH3。
應進一步瞭解,為清晰起見描述於單獨實施例上下文中之某些本發明特徵亦可以組合形式提供於單一實施例中(儘管意欲組合該等實施例如同以多種附屬形式書寫一般)。反之,為簡便起見描述於單一實施例上下文中之多個本發明特徵亦可單獨提供或以任一適宜子組合提供。因此,
預期描述為式(I’)或(I)化合物之實施例之特徵可組合於任一適宜組合中。
在本說明書各處,某些化合物特徵以群或以範圍來揭示。此類揭示內容意欲明確包括此類群及範圍之成員之每一及每個個別子組合。舉例而言,術語「C1-6烷基」意欲明確個別地揭示(但不限於)甲基、乙基、C3烷基、C4烷基、C5烷基及C6烷基。
術語「n員」在n為整數時通常描述成環原子數為n之部分中之成環原子數。舉例而言,哌啶基為6員雜環烷基環之實例,吡唑基為5員雜芳基環之實例,吡啶基為6員雜芳基環之實例,且1,2,3,4-四氫-萘為10員環烷基之實例。
在本說明書各處,可描述定義二價連接基團之變量。每一連接取代基意欲明確包括該連接取代基之前置及後置形式二者。舉例而言,-NR(CR'R")n-包括-NR(CR'R")n-及-(CR'R")nNR-二者且意欲個別地揭示每一形式。當結構需要連接基團時,針對該基團列示之馬庫什變量(Markush variable)應理解為連接基團。舉例而言,若結構需要連接基團且該變量之馬庫什基團定義列示「烷基」或「芳基」,則應理解「烷基」或「芳基」分別代表伸烷基連接基團或伸芳基連接基團。
術語「經取代」意指原子或原子之基團在形式上替代氫作為連接至另一基團之「取代基」。除非另有指示,否則術語「經取代」指任一取代度,例如單取代、二取代、三取代、四取代或五取代,其中此類取代為容許的。取代基經獨立地選擇,且取代可處於任一化學上可及之位置。應理解,給定原子之取代受化合價之限制。應理解,給定原子之取代產生化學上穩定之分子。片語「視情況經取代」意指未經取代或經取代。術語「經取代」意指移除氫原子且由取代基替代。單一二價取代基(例如側氧基)可替代兩個氫原子。
術語「Cn-m」指示包括終點之範圍,其中n及m為整數且指示碳數。實例包括C1-4、C1-6及諸如此類。
術語「烷基」單獨或與其他術語組合使用且指可為直鏈或具支鏈之飽和烴基團。術語「Cn-m烷基」指具有n至m個碳原子之烷基。烷基在形式上對應於一個C-H鍵經烷基與化合物其餘部分之連接點替代之烷
烴。在一些實施例中,烷基含有1至6個碳原子、1至4個碳原子、1至3個碳原子或1至2個碳原子。烷基部分之實例包括(但不限於)化學基團,例如甲基、乙基、正丙基、異丙基、正丁基、第三丁基、異丁基、第二丁基;高碳數同系物,例如2-甲基-1-丁基、正戊基、3-戊基、正己基、1,2,2-三甲基丙基及諸如此類。
術語「烯基」單獨或與其他術語組合使用且指對應於具有一或多個碳-碳雙鍵之烷基之直鏈或具支鏈烴基團。烯基在形式上對應於一個C-H鍵經烯基與化合物其餘部分之連接點替代之烯烴。術語「Cn-m烯基」指具有n至m個碳之烯基。在一些實施例中,烯基部分含有2至6個、2至4個或2至3個碳原子。實例性烯基包括(但不限於)乙烯基、正丙烯基、異丙烯基、正丁烯基、第二丁烯基及諸如此類。
術語「炔基」單獨或與其他術語組合使用且指對應於具有一或多個碳-碳三鍵之烷基之直鏈或具支鏈烴基團。炔基在形式上對應於一個C-H鍵經烷基與化合物其餘部分之連接點替代之炔烴。術語「Cn-m炔基」指具有n至m個碳之炔基。實例性炔基包括(但不限於)乙炔基、丙炔-1-基、丙炔-2-基及諸如此類。在一些實施例中,炔基部分含有2至6個、2至4個或2至3個碳原子。
術語「伸烷基」單獨或與其他術語組合使用且指二價烷基連接基團。伸烷基在形式上對應於兩個C-H鍵經伸烷基與化合物其餘部分之連接點替代之烷烴。術語「Cn-m伸烷基」指具有n至m個碳原子之伸烷基。伸烷基之實例包括(但不限於)乙-1,2-二基、丙-1,3-二基、丙-1,2-二基、丁-1,4-二基、丁-1,3-二基、丁-1,2-二基、2-甲基-丙-1,3-二基及諸如此類。
術語「烷氧基」單獨或與其他術語組合使用且指式-O-烷基,其中烷基如上文所定義。術語「Cn-m烷氧基」指烷氧基,其中之烷基具有n至m個碳。實例性烷氧基包括甲氧基、乙氧基、丙氧基(例如正丙氧基及異丙氧基)、第三丁氧基及諸如此類。在一些實施例中,烷基具有1至6個、1至4個或1至3個碳原子。
術語「烷基硫基」單獨或與其他術語組合使用且指式-S-烷基,其中烷基如上文所定義。術語「Cn-m烷基硫基」指烷基硫基,其中之烷
基具有n至m個碳。實例性烷基硫基包括甲基硫基、乙基硫基等。在一些實施例中,烷基硫基之烷基具有1至6個、1至4個或1至3個碳原子。
術語「胺基」單獨或與其他術語組合使用且指式-NH2基團。
術語「羰基」單獨或與其他術語組合使用且指-C(=O)-基團,其亦可寫為C(O)。
術語「氰基」或「腈」指式-C≡N基團,其亦可寫為-CN。
術語「鹵基」或「鹵素」單獨或與其他術語組合使用且指氟、氯、溴及碘。在一些實施例中,「鹵基」指選自F、Cl或Br之鹵素原子。在一些實施例中,鹵基為F。
術語「鹵烷基」單獨或與其他術語組合使用且指其中一或多個氫原子已經鹵素原子替代之烷基。術語「Cn-m鹵烷基」指具有n至m個碳原子及至少一個至多達{2(n至m)+1}個鹵素原子之Cn-m烷基,該等鹵素原子可相同或不同。在一些實施例中,鹵素原子為氟原子。在一些實施例中,鹵烷基具有1至6個或1至4個碳原子。實例性鹵烷基包括CF3、C2F5、CHF2、CCl3、CHCl2、C2Cl5及諸如此類。在一些實施例中,鹵烷基為氟烷基。
術語「鹵烷氧基」單獨或與其他術語組合使用且指式-O-鹵烷基,其中鹵烷基如上文所定義。術語「Cn-m鹵烷氧基」指鹵烷氧基,其中之鹵烷基具有n至m個碳。實例性鹵烷氧基包括三氟甲氧基及諸如此類。在一些實施例中,鹵烷氧基具有1至6個、1至4個或1至3個碳原子。
術語「側氧基」指氧原子作為二價取代基在連接至碳時形成羰基,或在連接至雜原子時形成亞碸或碸基團,或N-氧化物基團。在一些實施例中,雜環基團可視情況經1或2個側氧基(=O)取代基取代。
術語「硫離子基」指硫原子作為二價取代基在連接至碳時形成硫代羰基(C=S)。
術語「芳族」指具有一或多個具有芳族特徵(即當n為整數時具有(4n+2)個非定域π(pi)電子)之多不飽和環之碳環或雜環。
術語「芳基」單獨或與其他術語組合使用且指芳族烴基團,其可為單環或多環(例如具有2個稠合環)。術語「Cn-m芳基」指具有n至m
個環碳原子之芳基。芳基包括例如苯基、萘基、二氫茚基、茚基及諸如此類。在一些實施例中,芳基具有6至約10個碳原子。在一些實施例中,芳基具有6個碳原子。在一些實施例中,芳基具有10個碳原子。在一些實施例中,芳基為苯基。在一些實施例中,芳基為萘基。
術語「雜芳基」或「雜芳族」單獨或與其他術語組合使用且指具有至少一個選自硫、氧及氮之雜原子環成員之單環或多環芳族雜環。在一些實施例中,雜芳基環具有1個、2個、3個或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基部分中之任一成環N可為N-氧化物。在一些實施例中,雜芳基具有5-14個環原子,包括碳原子及1個、2個、3個或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基具有5-10個環原子,包括碳原子及1個、2個、3個或4個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基具有5-6個環原子及1或2個獨立地選自氮、硫及氧之雜原子環成員。在一些實施例中,雜芳基為5員或6員雜芳基環。在其他實施例中,雜芳基為8員、9員或10員稠合雙環雜芳基環。實例性雜芳基包括(但不限於)吡啶基(pyridinyl)(吡啶基(pyridyl))、嘧啶基、吡嗪基、嗒嗪基、吡咯基、吡唑基、吖唑基、噁唑基、噻唑基、咪唑基、呋喃基、硫苯基、喹啉基、異喹啉基、萘啶基(包括1,2-萘啶、1,3-萘啶、1,4-萘啶、1,5-萘啶、1,6-萘啶、1,7-萘啶、1,8-萘啶、2,3-萘啶及2,6-萘啶)、吲哚基、苯并硫苯基、苯并呋喃基、苯并異噁唑基、咪唑并[1,2-b]噻唑基、嘌呤基及諸如此類。
5員雜芳基環為具有5個環原子之雜芳基,其中一或多個(例如1個、2個或3個)環原子獨立地選自N、O及S。實例性5員環雜芳基包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、噁唑基、吡唑基、異噻唑基、異噁唑基、1,2,3-三唑基、四唑基、1,2,3-噻二唑基、1,2,3-噁二唑基、1,2,4-三唑基、1,2,4-噻二唑基、1,2,4-噁二唑基、1,3,4-三唑基、1,3,4-噻二唑基及1,3,4-噁二唑基。
6員雜芳基環為具有6個環原子之雜芳基,其中一或多個(例如1個、2個或3個)環原子獨立地選自N、O及S。實例性6員環雜芳基為吡啶基、吡嗪基、嘧啶基、三嗪基及嗒嗪基。
術語「環烷基」單獨或與其他術語組合使用且指非芳族烴環系統(單環、雙環或多環),包括環化烷基及烯基。術語「Cn-m環烷基」指具有n至m個環成員碳原子之環烷基。環烷基可包括單環或多環(例如具有2個、3個或4個稠合環)基團及螺環。環烷基可具有3個、4個、5個、6個或7個成環碳(C3-7)。在一些實施例中,環烷基具有3至6個環成員、3至5個環成員或3至4個環成員。在一些實施例中,環烷基為單環。在一些實施例中,環烷基為單環或雙環。在一些實施例中,環烷基為C3-6單環環烷基。環烷基之成環碳原子可視情況經氧化以形成側氧基或硫離子基。環烷基亦包括伸環烷基。在一些實施例中,環烷基為環丙基、環丁基、環戊基或環己基。具有一或多個稠合(即具有共同鍵)至環烷基環之芳族環(例如環戊烷、環己烷及諸如此類之苯并或噻吩基衍生物)之部分亦包括在環烷基之定義中。含有稠合芳族環之環烷基可經由任一成環原子(包括稠合芳族環之成環原子)連接。環烷基之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環戊烯基、環己烯基、環己二烯基、環庚三烯基、降莰基、降菔基、降蒈基、雙環[1.1.1]戊基、雙環[2.1.1]己基及諸如此類。在一些實施例中,環烷基為環丙基、環丁基、環戊基或環己基。
術語「雜環烷基」單獨或與其他術語組合使用且指非芳族環或環系統,其可視情況含有一或多個伸烯基作為環結構之一部分,其具有至少一個獨立地選自氮、硫氧及磷之雜原子環成員,且其具有4-10個環成員、4-7個環成員或4-6個環成員。單環4員、5員、6員及7員雜環烷基包括在術語「雜環烷基」內。雜環烷基可包括單環或雙環(例如具有兩個稠合或橋接環)環系統。在一些實施例中,雜環烷基為具有1個、2個或3個獨立地選自氮、硫及氧之雜原子之單環基團。雜環烷基之成環碳原子及雜原子可視情況經氧化以形成側氧基或硫離子基或其他氧化連接(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)或氮原子可經四級銨化。雜環烷基可經由成環碳原子或成環雜原子連接。在一些實施例中,雜環烷基含有0至3個雙鍵。在一些實施例中,雜環烷基含有0至2個雙鍵。具有一或多個稠合(即具有共同鍵)至雜環烷基環之芳族環(例如哌啶、嗎啉、氮呯等之苯并或噻吩基衍生物)之部分亦包括在雜環烷基之定義中。含有稠合芳族環
之雜環烷基可經由任一成環原子(包括稠合芳族環之成環原子)連接。雜環烷基之實例包括氮雜環丁基、氮雜環庚基、二氫苯并呋喃基、二氫呋喃基、二氫哌喃基、嗎啉基、3-氧雜-9-氮雜螺[5.5]十一烷基、1-氧雜-8-氮雜螺[4.5]癸基、哌啶基、哌嗪基、側氧基哌嗪基、哌喃基、吡咯啶基、奎寧環基、四氫呋喃基、四氫哌喃基、1,2,3,4-四氫喹啉基、莨菪烷基及硫嗎啉基。
術語「芳基烷基」單獨或與其他術語組合使用且指芳基-(伸烷基)-基團,其中芳基及伸烷基如本文所定義。實例性芳基烷基為苄基。
術語「雜芳基烷基」單獨或與其他術語組合使用且指雜芳基-(伸烷基)-基團,其中雜芳基及伸烷基如本文所定義。實例性雜芳基烷基為吡啶基甲基。
術語「環烷基烷基」單獨或與其他術語組合使用且指環烷基-(伸烷基)-基團,其中環烷基及伸烷基如本文所定義。實例性環烷基烷基為環丙基甲基。
術語「雜環烷基烷基」單獨或與其他術語組合使用且指雜環烷基-(伸烷基)-基團,其中雜環烷基及伸烷基如本文所定義。實例性雜環烷基烷基為氮雜環丁基甲基。
在某些地方,該等定義或實施例係關於特定環(例如氮雜環丁烷環、吡啶環等)。除非另有指示,否則該等環可連接至任一環成員,其限制條件為不超過該原子之化合價。舉例而言,氮雜環丁烷環可連接在環之任一位置,而氮雜環丁-3-基環連接在3位。
本文所述化合物可為不對稱的(例如具有一或多個立體中心)。除非另有指示,否則意欲針對所有立體異構物,例如鏡像異構物及非鏡像異構物。含有經不對稱取代之碳原子之本發明化合物可以光學活性或外消旋形式來分離。關於如何自光學無活性起始材料製備光學活性形式之方法為業內已知,例如藉由解析外消旋混合物或藉由立體選擇性合成。烯烴之許多幾何異構物、C=N雙鍵及諸如此類亦可存在於本文所述化合物中,且所有此類穩定異構物皆涵蓋於本發明中。本發明化合物之順式及反式幾何異構物描述為異構物混合物或分開的異構形式且可以該等形式來分離。
化合物之外消旋混合物之解析可藉由業內已知之多種方法中之任一者來實施。一方法包括使用手性解析酸分段再結晶,該酸為光學活性鹽形成有機酸。適用於分段再結晶方法之解析劑為例如光學活性酸,例如D及L形式之酒石酸、二乙醯基酒石酸、二苯甲醯基酒石酸、苦杏仁酸、蘋果酸、乳酸或各種光學活性樟腦磺酸(例如β-樟腦磺酸)。適於分段結晶方法之其他解析劑包括α-甲基-苄基-胺之立體異構純形式(例如S及R形式或非鏡像異構純形式)、2-苯基甘胺醇、降麻黃鹼、麻黃鹼、N-甲基麻黃鹼、環己基乙基胺、1,2-二胺基環己烷及諸如此類。
外消旋混合物之解析亦可藉由經光學活性解析劑(例如二硝基苯甲醯基苯基甘胺酸)封裝之管柱上之溶析來實施。適宜溶析溶劑組合物可藉由熟習此項技術者來確定。
在一些實施例中,本發明化合物具有(R)-構形。在其他實施例中,化合物具有(S)-構形。除非另有指示,否則在具有一個以上手性中心之化合物中,化合物中之每一手性中心可獨立地為(R)或(S)。
本發明化合物亦包括互變異構形式。互變異構形式源自單鍵與毗鄰雙鍵之交換以及質子之伴隨遷移。互變異構形式包括質子轉移互變異構物,其為具有相同經驗式及總電荷之異構質子化狀態。實例性質子轉移互變異構物包括酮-烯醇對、醯胺-醯亞胺酸對、內醯胺-內醯亞胺對、烯胺-亞胺對及質子可佔據雜環系統之兩個或更多個位置之環形式,例如1H-咪唑及3H-咪唑、1H-1,2,4-三唑、2H-1,2,4-三唑及4H-1,2,4-三唑、1H-異吲哚及2H-異吲哚及1H-吡唑及2H-吡唑。互變異構形式可處於平衡或藉由適當取代立體鎖定於一種形式。
本發明化合物亦可包括在中間體或最終化合物中出現之原子之所有同位素。同位素包括彼等具有相同原子序但不同質量數之原子。舉例而言,氫之同位素包括氚及氘。本發明化合物之一或多個構成原子可經原子之天然或非天然豐度之同位素替代或取代。在一些實施例中,化合物包括至少一個氘原子。舉例而言,本發明化合物中之一或多個氫原子可經氘替代或取代。在一些實施例中,化合物包括兩個或更多個氘原子。在一些實施例中,化合物包括1個、2個、3個、4個、5個、6個、7個、8
個、9個、10個、11個或12個氘原子。將同位素納入有機化合物中之合成方法為業內已知。
如本文所用術語「化合物」意欲包括所繪示結構之所有立體異構物、幾何異構物、互變異構物及同位素。該術語亦欲指本發明化合物而與其製備方式(例如合成、經由生物方法(例如代謝或酶轉化)或其組合)無關。
所有化合物及其醫藥學上可接受之鹽可與其他物質(例如水及溶劑)一起存在(例如水合物及溶劑合物)或可經分離。當呈固態時,本文所述化合物及其鹽可以多種形式存在且可例如呈溶劑合物(包括水合物)形式。化合物可呈任何固態形式,例如多形體或溶劑合物,因此除非另外明確指示,否則本說明書中對化合物及其鹽之提及應理解為涵蓋化合物之任何固態形式。
在一些實施例中,本發明化合物或其鹽實質上為經分離的。「實質上經分離」意指化合物至少部分地或實質上自形成或檢測到其之環境分離。部分分離物可包括例如富含本發明化合物之組合物。實質分離物可包括含有至少約50重量%、至少約60重量%、至少約70重量%、至少約80重量%、至少約90重量%、至少約95重量%、至少約97重量%或至少約99重量%之本發明化合物或其鹽之組合物。
片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範疇內適於與人類及動物之組織接觸使用且無過度毒性、刺激性、過敏反應或其他問題或併發症且與合理益處/風險比相當之彼等化合物、材料、組合物及/或劑型。
業內應理解如本文所用表述「環境溫度」及「室溫」通常指為實施反應之房間之大致溫度的溫度,例如反應溫度,例如約20℃至約30℃之溫度。
本發明亦包括本文所述化合物之醫藥學上可接受之鹽。術語「醫藥學上可接受之鹽」指所揭示化合物之衍生物,其中母體化合物藉由將現有酸或鹼部分轉化成其鹽形式而經修飾。醫藥學上可接受之鹽之實例包括(但不限於)鹼性殘基(例如胺)之礦物酸或有機酸鹽;酸性殘基(例如羧酸)
之鹼性或有機鹽;及諸如此類。本發明之醫藥學上可接受之鹽包括母體化合物之例如自無毒無機或有機酸形成之無毒鹽。本發明之醫藥學上可接受之鹽可藉由習用化學方法自含有鹼性或酸性部分之母體化合物合成。通常,此類鹽可藉由使該等化合物之游離酸或鹼形式與化學計量量之適宜鹼或酸於水中或於有機溶劑中或於兩者之混合物中反應來製備;通常,非水性介質(如醚、乙酸乙酯、醇(例如甲醇、乙醇、異丙醇或丁醇)或乙腈(MeCN))較佳。適宜鹽之列表參見Remington's Pharmaceutical Sciences,第17版(Mack Publishing Company,Easton,1985),第1418頁;Berge等人,J.Pharm.Sci.,1977,66(1),1-19及Stahl等人,Handbook of Pharmaceutical Salts:Properties,Selection,and Use,(Wiley,2002)。在一些實施例中,本文所述化合物包括N-氧化物形式。
II. 合成
本發明化合物(包括其鹽)可使用已知有機合成技術來製備且可根據多種可能合成途徑(例如下文方案中之彼等)中之任一者來合成。
用於製備本發明化合物之反應可在可由熟習有機合成技術者容易選擇之適宜溶劑中實施。適宜溶劑在實施反應之溫度(例如,可介於溶劑之冰點至溶劑之沸點之間的溫度)下可實質上不與起始材料(反應物)、中間體或產物反應。給定反應可在一種溶劑或一種以上溶劑之混合物中實施。端視具體反應步驟,可由熟習此項技術者選擇適用於具體反應步驟之溶劑。
本發明化合物之製備可涉及多個化學基團之保護及去保護。對保護及去保護之需要及適宜保護基團之選擇可容易地由熟習此項技術者確定。保護基團之化學法描述於例如以下文獻中:Kocienski,Protecting Groups,(Thieme,2007);Robertson,Protecting Groups Chemistry,(Oxford University Press,2000);Smith等人,March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第6版(Wiley,2007);Peturssion等人,「Protecting Groups in Carbohydrate Chemistry」,J.Chem.Educ.,1997,74(11),1297;及Wuts等人,Protective Groups in Organic Synthesis,第4版(Wiley,2006)。
可根據業內已知之任何適宜方法來監測反應。舉例而言,可藉由光譜手段(例如核磁共振光譜法(例如1H或13C)、紅外光譜法、分光亮度法(例如UV-可見光)、質譜法)或藉由層析方法(例如高效液相層析(HPLC)或薄層層析(TLC))來監測產物形成。
下文方案提供與製備本發明化合物相關之一般指導方針。熟習此項技術者應理解,方案中所顯示之製備可使用一般有機化學知識來修改或優化以製備各種本發明化合物。
本發明式8化合物可使用方案1中所顯示之方法來合成。在方案1中,在標準金屬催化之交叉偶合反應條件(例如鈴木(Suzuki)偶合反應,例如在鈀觸媒(例如1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II))及鹼(例如碳酸氫鹼或碳酸鹼)存在下)下,經鹵基(Hal1)取代之適宜族胺1可與適宜偶合試劑2(其中M為例如-B(OH)2)反應以產生化合物3。然後,在適宜SNAr條件(例如酸催化,例如在HCl存在下;或不經催化)或標準偶合反應條件(例如布赫瓦爾德-哈特維希(Buchwald-Hartwig)胺化,例如在鈀觸媒(例如[(2-二-環己基膦基-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)-2-(2'-胺基-1,1'-聯苯)]鈀(II)甲烷磺酸鹽)及鹼(例如碳酸鹼或丁醇鹼)存在下)下,芳族胺3可與化合物4之鹵基(Hal2)選擇性反應,形成化合物5。可藉由在標準偶合反應條件(例如鈴木偶合反應,例如在鈀觸媒(例如1,1'-雙(二環己基膦基)二茂鐵]二氯鈀(II))及鹼(例如碳酸氫鹼或碳酸鹼)存在下)下,偶合5之鹵基(Hal3)與乙烯基試劑(例如乙烯基硼酸頻哪醇酯)來合成式6化合物。可在適宜試劑(例如但不限於OsO4及NaIO4)存在下氧化裂解化合物6中之乙烯基以提供式7之醛。然後可藉由在適宜溶劑(例如THF或DCM)中使用還原劑(例如但不限於三乙氧基硼氫化鈉)、視情況在鹼(例如DIPEA)存在下式7化合物與胺HN(Rc)2之間之還原性胺化來獲得式8化合物。
或者,本發明式8化合物可使用方案2中所顯示之方法來合成。在標準偶合反應條件(例如布赫瓦爾德-哈特維希胺化,例如在鈀觸媒(例如[(2-二-環己基膦基-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)-2-(2'-胺基-1,1'-聯苯)]鈀(II)甲烷磺酸鹽)及鹼(例如碳酸鹼或丁醇鹼)存在下)下,芳族胺3可與式9之鹵基(Hal4)反應。隨後使用適宜還原劑(例如但不限於氫化鋰鋁)還原化合物10中之羧基可給出式11醇。可用適宜氧化劑(例如但不限於戴斯-馬丁過碘烷(Dess-Martin periodinane))氧化化合物11中之醇單元以獲得醛7。然後可使用與方案1中所顯示類似之條件自化合物7獲得式8化合物。
本發明式16化合物可使用方案3中所顯示之方法來合成。在方案3中,在適宜SNAr條件(酸催化,例如在HCl存在下;或不經催化)或標準偶合反應條件(例如布赫瓦爾德-哈特維希胺化,例如在鈀觸媒(例如[(2-二-環己基膦基-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)-2-(2'-胺基-1,1'-聯苯)]鈀(II)甲烷磺酸鹽)及鹼(例如碳酸鹼或丁醇鹼)存在下)下,芳族胺3可與化合物12之鹵基(Hal5)選擇性反應以獲得化合物13。式14化合物可藉由在標準偶合反應條件(例如鈴木偶合反應,例如在鈀觸媒(例如1,1'-雙(二環己基膦基)二茂鐵]二氯鈀(II))及鹼(例如碳酸氫鹼或碳酸鹼)存在下)下偶合13之鹵基(Hal6)與乙烯基試劑(例如乙烯基硼酸頻哪醇酯)來合成。可在適宜試劑(例如但不限於OsO4及NaIO4)存在下氧化裂解化合物14中之乙烯基以提供式15醛。然後可藉由在適當溶劑(例如THF或DCM)中使用還原劑(例如但不限於三乙氧基硼氫化鈉)、視情況在鹼(例如DIPEA)存在下式15化合物與胺HN(Rc)2之間之還原性胺化來獲得式16化合物。
式21化合物可使用如方案4中所概述之程序來製備。在適宜SNAr條件(酸催化,例如在HCl存在下;或不經催化)或適宜選擇性偶合反應條件(例如布赫瓦爾德-哈特維希胺化,例如在鈀觸媒(例如[(2-二-環己基膦基-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)-2-(2'-胺基-1,1'-聯苯)]鈀(II)甲烷磺酸鹽)及鹼(例如碳酸鹼或丁醇鹼)存在下)下,式17芳族胺可與化合物18之鹵基(Hal7)選擇性反應以獲得式19化合物。在鈴木偶合條件(例如在鈀觸媒及適宜鹼存在下)或施蒂勒(Stille)偶合條件(例如在鈀觸媒存在下)或根岸(Negishi)偶合條件(例如在鈀觸媒存在下)下,式19化合物中之鹵化物(Hal8)可偶合至式20化合物,其中M為硼酸、硼酸酯或經適當取代之金屬[例如M為B(OR)2、Sn(烷基)4或Zn-Hal],以獲得式21衍生物。或者,式20化合物可為環胺(其中M為H且連接至環Cy中之胺氮),且可在適宜布赫瓦爾德-哈特維希胺化條件(例如在鈀觸媒及鹼(例如第三丁醇鈉)存在下)下實施式19芳基鹵化物與式18環胺之偶合。
或者,式21化合物可使用如方案5中所概述之反應序列來製備。可使用與方案4中所述類似之條件(例如用於偶合式19化合物與式20化合物之條件)來達成式17芳族鹵化物與式20化合物之偶合,以獲得式22芳族胺,該芳族胺可在如方案4中所述之適宜SNAr條件或適宜選擇性偶合反應條件下與式18化合物之鹵基(Hal7)反應,以獲得式21化合物。
III
. 化合物之用途
本發明化合物可抑制PD-1/PD-L1蛋白/蛋白相互作用之活性,且因此可用於治療與PD-1活性相關之疾病及病症及與PD-L1(包括其與諸如PD-1及B7-1(CD80)等其他蛋白質之相互作用)相關之疾病及病症。
在某些實施例中,本發明化合物或其醫藥學上可接受之鹽或立體異構物可用於治療性投與以在癌症或慢性感染中增強免疫性,包括增強對疫苗接種之反應。在一些實施例中,本發明提供抑制PD-1/PD-L1蛋白/蛋白相互作用之方法。該方法包括向個體或患者投與式(I’)、(I)或如本文所述之任一式之化合物或如申請專利範圍中之任一者所列舉及本文所述之化合物或其醫藥學上可接受之鹽或立體異構物。本發明化合物可單獨使用、與其他藥劑或療法組合使用或作為輔助或新輔助療法使用來治療疾病或病症,包括癌症或傳染病。關於本文所述之用途,可使用任一本發明化合物,包括其任一實施例。
本發明化合物抑制PD-1/PD-L1蛋白/蛋白相互作用,從而阻斷PD-1路徑。阻斷PD-1可增強哺乳動物(包括人類)對癌性細胞及傳染病之免疫反應。在一些實施例中,本發明提供在活體內使用式(I’)、(I)化合物或其鹽或立體異構物治療個體或患者使得抑制癌性腫瘤之生長。可使用式(I’)、(I)或如本文所述任一式之化合物或如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽或立體異構物來抑制癌性腫瘤之生長。或者,式(I’)、(I)或如本文所述任一式之化合物或如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽或立體異構物可與其他藥劑或標準癌症治療結合使用,如下文所述。在一實施例中,本發明提供抑制活體內腫瘤細胞生長之方法。該方法包括使腫瘤細胞在活體內與式(I’)、(I)或如本文所述任一式之化合物或如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽或立體異構物接觸。在另一實施例中,本發明提供抑制個體或患者之腫瘤細胞生長之方法。該方法包括向有需要之個體或患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物或如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽或立體異構物。
在一些實施例中,本文提供治療癌症之方法。該方法包括向有需要之患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽。癌症之實例包括可使用本發明化合物抑制其生長之彼等及通常對免疫療法有反應之癌症。
可使用本發明化合物治療之癌症之實例包括(但不限於)骨癌、胰臟癌、皮膚癌、頭頸癌、皮膚或眼內惡性黑色素瘤、子宮癌、卵巢癌、直腸癌、肛區癌、胃癌、睪丸癌、子宮癌、輸卵管癌、子宮內膜之癌、子宮內膜癌、子宮頸癌、陰道癌、陰戶癌、霍奇金氏病(Hodgkin's Disease)、非霍奇金氏淋巴瘤、食道癌、小腸癌、內分泌系統癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、陰莖癌、慢性或急性白血病(包括急性骨髓樣白血病、慢性骨髓樣白血病、急性淋巴母細胞性白血病、慢性淋巴球性白血病)、兒童實體腫瘤、淋巴球性淋巴瘤、膀胱癌、腎或尿道癌、腎盂癌、中樞神經系統(CNS)贅瘤、原發性CNS淋巴瘤、腫瘤血管生成、脊軸腫瘤、腦幹膠質瘤、垂體腺瘤、卡波西氏肉瘤(Kaposi's sarcoma)、表皮樣癌、鱗狀細胞癌、T細胞淋巴瘤、環境誘導之癌症(包括由石棉誘導之彼等)及該等癌症之組合。本發明化合物亦可用於治療轉移性癌症、尤其表現PD-L1之轉移性癌症。
在一些實施例中,可使用本發明化合物治療之癌症包括黑色素瘤(例如轉移性惡性黑色素瘤)、腎癌(例如透明細胞癌)、前列腺癌(例如激素難治性前列腺腺癌)、乳癌、結腸癌及肺癌(例如非小細胞肺癌)。另外,本發明包括難治性或復發性惡性腫瘤,其生長可使用本發明化合物來抑制。
在一些實施例中,可使用本發明化合物治療之癌症包括(但不限於)實體腫瘤(例如,前列腺癌、結腸癌、食道癌、子宮內膜癌、卵巢癌、子宮癌、腎癌、肝癌、胰臟癌、胃癌、乳癌、肺癌、頭頸癌、甲狀腺癌、神經膠質母細胞瘤、肉瘤、膀胱癌等)、血液癌症(例如淋巴瘤、白血病,例如急性淋巴母細胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴球性白血病(CLL)、慢性髓性白血病(CML)、DLBCL、外膜細胞淋巴瘤、非霍奇金氏淋巴瘤(包括復發性或難治性NHL及復發性濾泡性淋巴瘤)、霍奇金氏淋巴瘤或多發性骨髓瘤)及該等癌症之組合。
用本發明化合物阻斷PD-1路徑亦可用於治療感染,例如病毒、細菌、真菌及寄生蟲感染。本發明提供治療感染(例如病毒感染)之方法。該方法包括向有需要之患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物、
其鹽。引起可藉由本發明方法治療之感染之病毒的實例包括(但不限於)人類免疫缺陷病毒、人類乳頭瘤病毒、流行性感冒病毒、A型、B型、C型或D型肝炎病毒、腺病毒、痘病毒、單純疱疹病毒、人類巨細胞病毒、嚴重急性呼吸道症候群病毒、伊波拉病毒(ebola virus)及麻疹病毒。在一些實施例中,引起可藉由本發明方法治療之感染之病毒包括(但不限於)肝炎(A型、B型或C型)病毒、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II及CMV、艾司坦-巴爾病毒(Epstein Barr virus))、腺病毒、流行性感冒病毒、黃病毒、埃柯病毒(echovirus)、鼻病毒、柯薩奇病毒(coxsackie virus)、冠狀病毒、呼吸道融合病毒、腮腺炎病毒、輪狀病毒、麻疹病毒、德國麻疹病毒、小病毒、痘瘡病毒、HTLV病毒、登革熱病毒(dengue virus)、乳頭瘤病毒、軟疣病毒、脊髓灰白質炎病毒、狂犬病病毒、JC病毒及蟲媒病毒性腦炎病毒。
本發明提供治療細菌感染之方法。該方法包括向有需要之患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽。引起可藉由本發明方法治療之感染之致病性細菌之非限制性實例包括披衣菌(chlamydia)、立克次體細菌、分枝桿菌(staphylococci)、葡萄球菌(staphylococci)、鏈球菌(streptococci)、肺炎球菌(pneumonococci)、腦膜炎球菌(meningococci)及淋球菌(conococci)、克留氏菌屬(klebsiella)、變形桿菌屬(proteus)、鋸桿菌屬(serratia)、假單胞菌屬(pseudomonas)、退伍軍人菌屬(legionella)、白喉、沙氏桿菌屬(salmonella)、桿菌、霍亂、破傷風、臘腸菌病、炭疽、瘟疫、鉤端螺旋體病及萊姆病(Lyme's disease)細菌。
本發明提供治療真菌感染之方法。該方法包括向有需要之患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽。引起可藉由本發明方法治療之感染之致病性真菌之非限制性實例包括念珠菌屬(Candida)(白色念珠菌(Candida albicans)、克魯斯念珠菌(Candida krusei)、光滑念珠菌(Candida glabrata)、熱帶念珠菌(Candida tropicalis)等)、新型隱球菌(Cryptococcus neoformans)、麴菌屬(Aspergillus)(熏煙色麴菌(Aspergillus fumigatus)、黑麴菌(Aspergillus niger)等)、毛黴屬(Genus Mucorales)(毛黴菌
屬(mucor)、犁頭黴屬(absidia)、根黴菌屬(rhizopus))、申克氏孢子絲菌(Sporothrix schenkii)、皮炎芽生菌(Blastomyces dermatitidis)、巴西副球孢子菌(Paracoccidioides brasiliensis)、粗球黴菌(Coccidioides immitis)及莢膜組織漿菌(Histoplasma capsulatum)。
本發明提供治療寄生蟲感染之方法。該方法包括向有需要之患者投與治療有效量之式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽。引起可藉由本發明方法治療之感染之致病性寄生蟲之非限制性實例包括溶組織內阿米巴(Entamoeba histolytica)、大腸絨毛蟲(Balantidium coli)、福氏耐格里變形蟲(Naegleriafowleri)、棘狀變形蟲屬(Acanthamoeba sp.)、梨形鞭毛蟲(Giardia lamblia)、隱孢子蟲屬(Cryptosporidium sp.)、卡氏肺囊蟲(Pneumocystis carinii)、間日瘧原蟲(Plasmodium vivax)、小鼠焦蟲(Babesia microti)、布氏錐蟲(Trypanosoma brucei)、克氏錐蟲(Trypanosoma cruzi)、黑熱病利什曼原蟲(Leishmania donovani)、弓蟲(Toxoplasma gondii)及巴西鼠鉤蟲(Nippostrongylus brasiliensis)。
術語「個體」或「患者」可互換使用且指任何動物,包括哺乳動物,較佳小鼠、大鼠、其他囓齒類動物、兔、狗、貓、豬、牛、綿羊、馬或靈長類動物,且最佳人類。
片語「治療有效量」指活性化合物或醫藥劑在組織、系統、動物、個體或人類中引發研究者、獸醫師、醫師或其他臨床醫師所尋求之生物或醫學反應之量。
如本文所用,術語「治療(treating)」或「治療(treatment)」指以下中之一或多者:(1)抑制疾病;例如,抑制正經歷或顯示疾病、病況或病症之病理學或症狀學之個體之疾病、病況或病症(即阻止病理學及/或症狀學之進一步發展);及(2)改善疾病;例如,改善正經歷或顯示疾病、病況或病症之病理學或症狀學之個體之疾病、病況或病症(即逆轉病理學及/或症狀學),例如減輕疾病之嚴重程度。
在一些實施例中,本發明化合物可用於預防或降低罹患本文所提及之任一疾病之風險;例如,預防或降低可能易患疾病、病況或病症
但尚未經歷或顯示該疾病之病理學或症狀學之個體罹患該疾病、病況或病症之風險。
組合療法
癌症細胞生長及存活可受多個信號傳導路徑之影響。因此,組合不同的酶/蛋白質/受體抑制劑,從而在活性受其調節之靶中展現不同偏好可用於治療此類病況。靶向一個以上之信號傳導路徑(或一個以上之參與給定信號傳導路徑之生物分子)可降低細胞群中出現之抗藥性之可能性及/或降低治療之毒性。
本發明化合物可與一或多種其他酶/蛋白質/受體抑制劑組合使用來治療疾病,例如癌症或感染。癌症之實例包括實體腫瘤及液體腫瘤,例如血液癌症。感染之實例包括病毒感染、細菌感染、真菌感染或寄生蟲感染。舉例而言,本發明化合物可與一或多種以下激酶之抑制劑組合來治療癌症:Akt1、Akt2、Akt3、TGF-βR、PKA、PKG、PKC、CaM激酶、磷酸化酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IGF-1R、IR-R、PDGFαR、PDGFβR、CSFIR、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、Ron、Sea、TRKA、TRKB、TRKC、FLT3、VEGFR/Flt2、Flt4、EphA1、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK及B-Raf。在一些實施例中,本發明化合物可與以下抑制劑中之一或多者組合來治療癌症或感染。可與本發明化合物組合來治療癌症及感染之抑制劑之非限制性實例包括FGFR抑制劑(FGFR1、FGFR2、FGFR3或FGFR4,例如INCB54828、INCB62079及INCB63904)、JAK抑制劑(JAK1及/或JAK2,例如魯索替尼(ruxolitinib)、白瑞西替尼(baricitinib)或INCB39110)、IDO抑制劑(例如依波斯他(epacadostat)及NLG919)、LSD1抑制劑(例如INCB59872及INCB60003)、TDO抑制劑、PI3K-δ抑制劑、PI3K-γ抑制劑(例如PI3K-γ選擇性抑制劑,例如INCB50797)、Pim抑制劑、CSF1R抑制劑、TAM受體酪胺酸激酶(Tyro-3、Axl及Mer)、血管生成抑制劑、介白素受體抑制劑、含溴及額外末端結構域家族成員抑制劑(例如溴結構域抑制劑或BET抑制劑,例如
INCB54329及INCB57643)及三磷酸腺苷受體拮抗劑或其組合。
本發明化合物可與一或多種免疫檢查點抑制劑組合使用。實例性免疫檢查點抑制劑包括針對諸如以下等免疫檢查點分子之抑制劑:CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、CSF1R、JAK、PI3K δ、PI3K γ、TAM、精胺酸酶、CD137(亦稱為4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、PD-1、PD-L1及PD-L2。在一些實施例中,免疫檢查點分子為選自以下之刺激性檢查點分子:CD27、CD28、CD40、ICOS、OX40、GITR及CD137。在一些實施例中,免疫檢查點分子為選自以下之抑制性檢查點分子:A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3及VISTA。在一些實施例中,本文所提供之化合物可與一或多種選自以下之藥劑組合使用:KIR抑制劑、TIGIT抑制劑、LAIR1抑制劑、CD160抑制劑、2B4抑制劑及TGFR β抑制劑。
在一些實施例中,免疫檢查點分子之抑制劑為抗PD1抗體、抗PD-L1抗體或抗CTLA-4抗體。
在一些實施例中,免疫檢查點分子之抑制劑為PD-1之抑制劑,例如抗PD-1單株抗體。在一些實施例中,抗PD-1單株抗體為尼沃魯單抗(nivolumab)、派姆單抗(pembrolizumab)(亦稱為MK-3475)、皮地珠單抗(pidilizumab)、SHR-1210、PDR001或AMP-224。在一些實施例中,抗PD-1單株抗體為尼沃魯單抗或派姆單抗。在一些實施例中,抗PD1抗體為派姆單抗。在一些實施例中,抗PD-1抗體為SHR-1210。
在一些實施例中,免疫檢查點分子之抑制劑為PD-L1之抑制劑,例如抗PD-L1單株抗體。在一些實施例中,抗PD-L1單株抗體為BMS-935559、MEDI4736、MPDL3280A(亦稱為RG7446)或MSB0010718C。在一些實施例中,抗PD-L1單株抗體為MPDL3280A或MEDI4736。
在一些實施例中,免疫檢查點分子之抑制劑為CTLA-4之抑制劑,例如抗CTLA-4抗體。在一些實施例中,抗CTLA-4抗體為伊匹單抗(ipilimumab)。
在一些實施例中,免疫檢查點分子之抑制劑為LAG3之抑
制劑,例如抗LAG3抗體。在一些實施例中,抗LAG3抗體為BMS-986016或LAG525。
在一些實施例中,免疫檢查點分子之抑制劑為GITR之抑制劑,例如抗GITR抗體。在一些實施例中,抗GITR抗體為TRX518或MK-4166。
在一些實施例中,免疫檢查點分子之抑制劑為OX40之抑制劑,例如抗OX40抗體或OX40L融合蛋白。在一些實施例中,抗OX40抗體為MEDI0562。在一些實施例中,OX40L融合蛋白為MEDI6383。
本發明化合物可與一或多種治療諸如癌症等疾病之藥劑組合使用。在一些實施例中,藥劑為烷基化劑、蛋白酶體抑制劑、皮質類固醇或免疫調節劑。烷基化劑之實例包括環磷醯胺(CY)、美法侖(melphalan)(MEL)及苯達莫斯汀(bendamustine)。在一些實施例中,蛋白酶體抑制劑為卡非左米(carfilzomib)。在一些實施例中,皮質類固醇為地塞米松(dexamethasone)(DEX)。在一些實施例中,免疫調節劑為來那度胺(lenalidomide)(LEN)或泊馬度胺(pomalidomide)(POM)。
本發明化合物可另外與治療癌症之其他方法(例如藉由化學療法、照射療法、腫瘤靶向療法、輔助療法、免疫療法或手術)組合使用。免疫療法之實例包括細胞介素治療(例如干擾素、GM-CSF、G-CSF、IL-2)、CRS-207免疫療法、癌症疫苗、單株抗體、授受性T細胞轉移、溶瘤病毒療法及免疫調節小分子(包括沙利度胺(thalidomide)或JAK1/2抑制劑)及諸如此類。化合物可與一或多種抗癌藥物(例如化學治療劑)組合投與。實例性化學治療劑包括以下中之任一者:阿巴瑞克(abarelix)、阿地白介素(aldesleukin)、阿倫珠單抗(alemtuzumab)、阿利維A酸(alitretinoin)、異嘌呤醇(allopurinol)、六甲蜜胺(altretamine)、阿那曲唑(anastrozole)、三氧化砷、天冬醯胺酶、阿紮胞苷(azacitidine)、貝伐珠單抗(bevacizumab)、貝沙羅汀(bexarotene)、白瑞西替尼、博來黴素(bleomycin)、硼替佐米(bortezombi)、硼替佐米(bortezomib)、靜脈內白消安(busulfan)、口服白消安、卡普睪酮(calusterone)、卡培他濱(capecitabine)、卡鉑(carboplatin)、卡莫司汀(carboplatin)、西妥昔單抗(cetuximab)、苯丁酸氮芥(chlorambucil)、順鉑
(cisplatin)、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、環磷醯胺、阿糖胞苷(cytarabine)、達喀爾巴嗪(dacarbazine)、放線菌素D(dactinomycin)、達肝素鈉(dalteparin sodium)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地尼介白素(denileukin)、地尼介白素毒素連接物(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他賽(docetaxel)、多柔比星(doxorubicin)、丙酸屈他雄酮(dromostanolone propionate)、依庫珠單抗(eculizumab)、表柔比星(epirubicin)、厄洛替尼(erlotinib)、雌莫司汀(estramustine)、磷酸依託泊苷(etoposide phosphate)、依託泊苷、依西美坦(exemestane)、檸檬酸芬太尼(fentanylcitrate)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶、氟韋司群(fulvestrant)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥單抗奧佐米星(gemtuzumab ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸組胺瑞林(histrelin acetate)、替伊莫單抗(ibritumomab tiuxetan)、埃達黴素(idarubicin)、異環磷醯胺(ifosfamide)、甲磺酸伊馬替尼(imatinib mesylate)、干擾素α 2a、伊立替康(irinotecan)、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、來那度胺、來曲唑(letrozole)、若克瘤(leucovorin)、乙酸亮丙瑞林(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀(lomustine)、二氯甲基二乙胺(meclorethamine)、乙酸甲地孕酮(megestrol acetate)、美法侖、巰基嘌呤、胺甲喋呤(methotrexate)、甲氧沙林(methoxsalen)、絲裂黴素C(mitomycin C)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、苯丙酸諾龍(nandrolone phenpropionate)、奈拉濱(nelarabine)、諾非單抗(nofetumomab)、奧沙利鉑(oxaliplatin)、紫杉醇(paclitaxel)、帕米膦酸(pamidronate)、帕尼單抗(panitumumab)、培門冬酶(pegaspargase)、聚乙二醇化非格司亭(pegfilgrastim)、培美曲塞二鈉(pemetrexed disodium)、噴司他丁(pentostatin)、哌血生(pipobroman)、普卡黴素(plicamycin)、丙卡巴肼(procarbazine)、奎那克林(quinacrine)、拉布立酶(rasburicase)、利妥昔單抗(rituximab)、魯索替尼、索拉菲尼(sorafenib)、脲鏈黴素(streptozocin)、舒尼替尼(sunitinib)、馬來酸舒尼替尼、他莫昔芬(tamoxifen)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睪內酯(testolactone)、沙利度胺、硫鳥嘌呤、塞替派(thiotepa)、托泊替康(topotecan)、
托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、維A酸(tretinoin)、尿嘧啶氮芥、戊柔比星(valrubicin)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、弗利諾他(vorinostat)及唑來膦酸(zoledronate)。
其他抗癌劑包括抗體治療劑,例如曲妥珠單抗(Herceptin)、針對共刺激分子(例如CTLA-4)之抗體(例如伊匹單抗)、4-1BB、針對PD-1及PD-L1之抗體或針對細胞介素(IL-10、TGF-β等)之抗體。可與本發明化合物組合來治療癌症或感染(例如病毒、細菌、真菌及寄生蟲感染)之針對PD-1及/或PD-L1之抗體的實例包括(但不限於)尼沃魯單抗、派姆單抗、MPDL3280A、MEDI-4736及SHR-1210。
在一些實施例中,抗癌劑為烷基化劑、蛋白酶體抑制劑、皮質類固醇或免疫調節劑。烷基化劑之實例包括環磷醯胺(CY)、美法侖(MEL)及苯達莫斯汀。在一些實施例中,蛋白酶體抑制劑為卡非左米。在一些實施例中,皮質類固醇為地塞米松(DEX)。在一些實施例中,免疫調節劑為來那度胺(LEN)或泊馬度胺(POM)。
式(I’)或(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽、立體異構物可與免疫檢查點抑制劑組合使用來治療癌症及病毒感染。
實例性免疫檢查點抑制劑包括針對諸如以下等免疫檢查點分子之抑制劑:CD27、CD28、CD40、CD122、CD96、CD73、CD47、OX40、GITR、CSF1R、JAK、PI3K δ、PI3K γ、TAM、精胺酸酶、CD137(亦稱為4-1BB)、ICOS、A2AR、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、PD-1、PD-L1及PD-L2。在一些實施例中,免疫檢查點分子為選自以下之刺激性檢查點分子:CD27、CD28、CD40、ICOS、OX40、GITR及CD137。在一些實施例中,免疫檢查點分子為選自以下之抑制性檢查點分子:A2AR、B7-H3、B7-H4、BTLA、CTLA-4、IDO、KIR、LAG3、PD-1、TIM3及VISTA。在一些實施例中,本文所提供之化合物可與一或多種選自以下之藥劑組合使用:KIR抑制劑、TIGIT抑制劑、LAIR1抑制劑、CD160抑制劑、2B4抑制劑及TGFRβ抑制劑。
在一些實施例中,免疫檢查點分子之抑制劑為抗PD1抗體、抗PD-L1抗體或抗CTLA-4抗體。
在一些實施例中,免疫檢查點分子之抑制劑為PD-1之抑制劑,例如抗PD-1單株抗體。在一些實施例中,抗PD-1單株抗體為尼沃魯單抗、派姆單抗(亦稱為MK-3475)、皮地珠單抗、SHR-1210、PDR001或AMP-224。在一些實施例中,抗PD-1單株抗體為尼沃魯單抗或派姆單抗。在一些實施例中,抗PD1抗體為派姆單抗。
在一些實施例中,免疫檢查點分子之抑制劑為PD-L1之抑制劑,例如抗PD-L1單株抗體。在一些實施例中,抗PD-L1單株抗體為BMS-935559、MEDI4736、MPDL3280A(亦稱為RG7446)或MSB0010718C。在一些實施例中,抗PD-L1單株抗體為MPDL3280A或MEDI4736。
在一些實施例中,免疫檢查點分子之抑制劑為CTLA-4之抑制劑,例如抗CTLA-4抗體。在一些實施例中,抗CTLA-4抗體為伊匹單抗。
在一些實施例中,免疫檢查點分子之抑制劑為LAG3之抑制劑,例如抗LAG3抗體。在一些實施例中,抗LAG3抗體為BMS-986016或LAG525。
在一些實施例中,免疫檢查點分子之抑制劑為GITR之抑制劑,例如抗GITR抗體。在一些實施例中,抗GITR抗體為TRX518或MK-4166。
在一些實施例中,免疫檢查點分子之抑制劑為OX40之抑制劑,例如抗OX40抗體或OX40L融合蛋白。在一些實施例中,抗OX40抗體為MEDI0562。在一些實施例中,OX40L融合蛋白為MEDI6383。
本發明化合物可進一步與一或多種抗發炎劑、類固醇、免疫阻抑劑或治療性抗體組合使用。
式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽可與諸如以下等另一免疫原性劑組合:癌性細胞、經純化之腫瘤抗原(包括重組蛋白質、肽及碳水化合物分子)、細胞及經編碼免疫刺激性細胞介素之基因轉染之細胞。可用腫瘤疫苗之非限制性實例包括黑色素瘤抗原之肽,例如gp100、MAGE抗原、
Trp-2、MARTI及/或酪胺酸酶之肽或經轉染以表現細胞介素GM-CSF之腫瘤細胞。
式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽可與疫苗接種方案組合使用來治療癌症。在一些實施例中,腫瘤細胞經轉導以表現GM-CSF。在一些實施例中,腫瘤疫苗包括參與諸如以下等人類癌症之病毒之蛋白質:人類乳頭瘤病毒(HPV)、肝炎病毒(HBV及HCV)及卡波西氏疱疹肉瘤病毒(KHSV)。在一些實施例中,本發明化合物可與腫瘤特異性抗原(例如自腫瘤組織自身分離之熱休克蛋白)組合使用。在一些實施例中,式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽可與樹突狀細胞免疫組合來活化強效抗腫瘤反應。
本發明化合物可與使表現Fe α或Fe γ受體之效應細胞靶向腫瘤細胞之雙特異性大環肽組合使用。本發明化合物亦可與活化宿主免疫反應性之大環肽組合。
本發明化合物可與骨髓移植組合使用來治療多種造血來源之腫瘤。
式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其鹽可與疫苗組合使用來刺激針對病原體、毒素及自體抗原之免疫反應。此治療方法可尤其有用之病原體之實例包括當前無有效疫苗之病原體或習用疫苗不夠完全有效之病原體。該等病原體包括(但不限於)HIV、肝炎病毒(A型、B型及C型)、流行性感冒病毒、疱疹病毒、梨形鞭毛蟲屬(Giardia)、瘧疾、利什曼原蟲屬(Leishmania)、金黃色葡萄球菌(Staphylococcus aureus)、綠膿桿菌(Pseudomonas Aeruginosa)。
引起可藉由本發明方法治療之感染之病毒包括(但不限於)人類乳頭瘤病毒、流行性感冒病毒、A型、B型、C型或D型肝炎病毒、腺病毒、痘病毒、單純疱疹病毒、人類巨細胞病毒、嚴重急性呼吸道症候群病毒、伊波拉病毒、麻疹病毒、疱疹病毒(例如VZV、HSV-1、HAV-6、HSV-II及CMV、艾司坦-巴爾病毒)、黃病毒、埃柯病毒、鼻病毒、柯薩奇
病毒、冠狀病毒、呼吸道融合病毒、腮腺炎病毒、輪狀病毒、麻疹病毒、德國麻疹病毒、小病毒、痘瘡病毒、HTLV病毒、登革熱病毒、乳頭瘤病毒、軟疣病毒、脊髓灰白質炎病毒、狂犬病病毒、JC病毒及蟲媒病毒性腦炎病毒。
引起可藉由本發明方法治療之感染之致病性細菌包括(但不限於)披衣菌、立克次體細菌、分枝桿菌、葡萄球菌、鏈球菌、肺炎球菌、腦膜炎球菌及淋球菌、克留氏菌屬、變形桿菌屬、鋸桿菌屬、假單胞菌屬、退伍軍人菌屬、白喉、沙氏桿菌屬、桿菌、霍亂、破傷風、臘腸菌病、炭疽、瘟疫、鉤端螺旋體病及萊姆病細菌。
引起可藉由本發明方法治療之感染之致病性真菌包括(但不限於)念珠菌屬(白色念珠菌、克魯斯念珠菌、光滑念珠菌、熱帶念珠菌等)、新型隱球菌、麴菌屬(熏煙色麴菌、黑麴菌等)、毛黴屬(毛黴菌屬、犁頭黴屬、根黴菌屬)、申克氏孢子絲菌、皮炎芽生菌、巴西副球孢子菌、粗球黴菌及莢膜組織漿菌。
引起可藉由本發明方法治療之感染之致病性寄生蟲包括(但不限於)溶組織內阿米巴、大腸絨毛蟲、福氏耐格里變形蟲、棘狀變形蟲屬、梨形鞭毛蟲、隱孢子蟲屬、卡氏肺囊蟲、間日瘧原蟲、小鼠焦蟲、布氏錐蟲、克氏錐蟲、黑熱病利什曼原蟲、弓蟲及巴西鼠鉤蟲。
當向患者投與一種以上之醫藥劑時,其可同時、分開、依序或以組合形式(例如針對兩種以上之藥劑)投與。
IV. 調配物、劑型及投與
當用作醫藥時,本發明化合物可以醫藥組合物形式來投與。因此,本發明提供組合物,其包含式(I’)、(I)或如本文所述任一式之化合物、如申請專利範圍中之任一者中所列舉及本文所述之化合物或其醫藥學上可接受之鹽或其任一實施例,及至少一種醫藥學上可接受之載劑或賦形劑。該等組合物可以醫藥業內所熟知之方式製備,且可藉由多個途徑來投與,此端視指示局部抑或全身性治療及欲治療區域而定。投與可為局部(包括經皮、表皮、眼部及至黏膜,包括鼻內、陰道及直腸遞送)、肺(例如藉由吸入或吹入粉劑或氣溶膠,包括藉由噴霧器;氣管內或鼻內)、經口或非經腸。
非經腸投與包括靜脈內、動脈內、皮下、腹膜內、肌內或注射或輸注;或獻內,例如鞘內或心室內投與。非經腸投與可呈單次濃注劑量形式,或可例如藉由連續灌注幫浦。用於局部投與之醫藥組合物及調配物可包括經皮貼片、軟膏、洗劑、乳霜、凝膠、滴劑、栓劑、噴霧劑、液體及粉劑。可需要或期望習用醫藥載劑、水溶液、粉劑或油性基底、增稠劑及諸如此類。
本發明亦包括醫藥組合物,其含有本發明化合物或其醫藥學上可接受之鹽作為活性成份與一或多種醫藥學上可接受之載劑或賦形劑之組合。在一些實施例中,組合物適於局部投與。在製備本發明組合物時,活性成份通常與賦形劑混合、經賦形劑稀釋或裝入呈例如膠囊、藥囊、紙或其他容器形式之此類載劑內。當賦形劑充當稀釋劑時,其可為固體、半固體或液體材料,該等材料用作媒劑、載劑或活性成份之介質。因此,組合物可呈以下形式:錠劑、丸劑、粉劑、菱形錠劑、藥囊、藥丸、酏劑、懸浮液、乳液、溶液、糖漿、氣溶膠(呈固體形式或於液體介質中)、含有例如至多10重量%之活性化合物之軟膏、軟及硬明膠膠囊、栓劑、無菌可注射溶液及無菌包裝粉劑。
在製備調配物時,可將活性化合物研磨以在與其他成份組合之前提供適宜粒徑。若活性化合物實質上為不可溶的,則可將其研磨至小於200目之粒徑。若活性化合物實質上為水溶性的,則可藉由研磨調節粒徑以提供在調配物中實質上均勻之分佈,例如約40目。
本發明化合物可使用已知研磨程序(例如濕式研磨)來研磨以獲得適於錠劑形成及適於其他調配物類型之粒徑。本發明化合物之精細(奈米微粒)製劑可藉由業內已知之方法來製備,參見例如WO 2002/000196。
適宜賦形劑之一些實例包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、澱粉、阿拉伯樹膠、磷酸鈣、海藻酸鹽、黃蓍膠、明膠、矽酸鈣、微晶纖維素、聚乙烯基吡咯啶酮、纖維素、水、糖漿及甲基纖維素。調配物可另外包括:潤滑劑,例如滑石、硬脂酸鎂及礦物油;潤濕劑;乳化及懸浮劑;防腐劑,例如苯甲酸甲基酯及苯甲酸丙基羥基酯;甜味劑;及矯味劑。本發明組合物可經調配以在藉由採用業內已知之程序投與患者後提供活性成份之快速、持續或延遲釋放。
在一些實施例中,醫藥組合物包含矽化微晶纖維素(SMCC)及至少一種本文所述化合物或其醫藥學上可接受之鹽。在一些實施例中,矽化微晶纖維素包含約98%微晶纖維素及約2%二氧化矽w/w。
在一些實施例中,組合物為持續釋放組合物,其包含至少一種本文所述化合物或其醫藥學上可接受之鹽及至少一種醫藥學上可接受之載劑或賦形劑。在一些實施例中,組合物包含至少一種本文所述化合物或其醫藥學上可接受之鹽及至少一種選自微晶纖維素、乳糖單水合物、羥丙基甲基纖維素及聚氧化乙烯之組分。在一些實施例中,組合物包含至少一種本文所述化合物或其醫藥學上可接受之鹽及微晶纖維素、乳糖單水合物及羥丙基甲基纖維素。在一些實施例中,組合物包含至少一種本文所述化合物或其醫藥學上可接受之鹽及微晶纖維素、乳糖單水合物及聚氧化乙烯。在一些實施例中,組合物另外包含硬脂酸鎂或二氧化矽。在一些實施例中,微晶纖維素為Avicel PH102TM。在一些實施例中,乳糖單水合物為Fast-flo 316TM。在一些實施例中,羥丙基甲基纖維素為羥丙基甲基纖維素2208 K4M(例如Methocel K4 M PremierTM)及/或羥丙基甲基纖維素2208 K100LV(例如Methocel K00LVTM)。在一些實施例中,聚氧化乙烯為聚氧化乙烯WSR 1105(例如Polyox WSR 1105TM)。
在一些實施例中,使用濕式粒化方法來產生組合物。在一些實施例中,使用乾式粒化方法來產生組合物。
組合物可以單位劑型來調配,每一劑量含有約5mg至約1,000mg(1g)、更通常而言約100mg至約500mg活性成份。在一些實施例中,每一劑量含有約10mg活性成份。在一些實施例中,每一劑量含有約50mg活性成份。在一些實施例中,每一劑量含有約25mg活性成份。術語「單位劑型」指適於作為單一劑量用於人類個體及其他哺乳動物之物理離散單位,各單位含有經計算可產生期望治療效應之預定量的活性材料以及適宜醫藥賦形劑。
用於調配醫藥組合物之組分具有高質量且實質上不含可能有害之污染物(例如,至少國家食品級,通常至少分析級,且更通常至少醫藥級)。具體而言對於人類消耗,組合物較佳根據如美國食品藥品管理局(U.S.
Food and Drug Administration)之適用規則所定義之良好製造實踐(Good Manufacturing Practice)標準來製造或調配。舉例而言,適宜調配物可為無菌及/或實質上等滲及/或完全順從美國食品藥品管理局之所有良好製造實踐規則。
活性化合物可在寬劑量範圍內有效且通常以治療有效量來投與。然而,應理解,實際上投與之化合物之量通常將由醫師根據相關情況來確定,該等情況包括欲治療病況、所選投與途徑、所投與之實際化合物、個體患者之年齡、體重及反應、患者症狀之嚴重程度及諸如此類)。
本發明化合物之治療劑量可根據例如以下等因素而變化:進行治療之具體使用、化合物之投與方式、患者之健康狀況及病況以及主治醫師之判斷。醫藥組合物中本發明化合物之比例或濃度可端視多個因素而變化,包括劑量、化學特徵(例如疏水性)及投與途徑。舉例而言,本發明化合物可以含有約0.1%至約10% w/v化合物之生理緩衝水溶液形式提供用於非經腸投與。一些典型劑量範圍為約1μg/kg至約1g/kg體重/天。在一些實施例中,劑量範圍為約0.01mg/kg至約100mg/kg體重/天。劑量可能端視諸如以下等變量而定:疾病或病症之類型及其進展程度、特定患者之總體健康狀況、所選化合物之相對生物效能、賦形劑之調配及其投與途徑。可根據得自活體外或動物模型測試系統之劑量-反應曲線來推斷有效劑量。
為製備諸如錠劑等固體組合物,將主要活性成份與醫藥賦形劑混合以形成含有本發明化合物之均質混合物之固體預調配組合物。當提及該等均質預調配組合物時,活性成份通常均勻分散於整個組合物中,以使得可容易地將組合物細分成同樣有效之單位劑型,例如錠劑、丸劑及膠囊。然後將此固體預調配物細分成含有例如約0.1mg至約1000mg本發明活性成份之上述類型之單位劑型。
本發明之錠劑或丸劑可經塗覆或以其他方式化合以提供提供延長作用的優點之劑型。舉例而言,錠劑或丸劑可包含內部劑量組分及外部劑量組分,後者呈前者上之包膜形式。兩種組分可藉由用於抵抗胃中之崩解且容許內部組分完整進入十二指腸中或容許延遲釋放之腸溶層分離。多種材料可用於此類腸溶層或包衣,此類材料包括多種聚合酸及聚合
酸與諸如蟲膠、鯨蠟醇及乙酸纖維素等材料之混合物。
可納入本發明化合物及組合物以經口或藉由注射投與之液體形式包括水溶液、經適宜矯味之糖漿、水性或油性懸浮液及經食用油(例如棉籽油、芝麻油、椰子油或花生油)矯味之乳液以及酏劑及類似醫藥媒劑。
用於吸入或吹入之組合物包括醫藥學上可接受之水性或有機溶劑中之溶液及懸浮液或其混合物及粉劑。液體或固體組合物可含有如上文所述之適宜醫藥學上可接受之賦形劑。在一些實施例中,組合物藉由經口或鼻呼吸途徑來投與用於局部或全身效應。組合物可藉由使用惰性氣體來霧化。霧化溶液可直接自霧化裝置來呼吸或霧化裝置可連接至面罩、塞條或間歇性正壓呼吸機。溶液、懸浮液或粉劑組合物可自以適當方式遞送調配物之裝置經口或經鼻投與。
局部調配物可含有一或多種習用載劑。在一些實施例中,軟膏可含有水及一或多種選自例如以下等疏水性載劑:液體石蠟、聚氧乙烯烷基醚、丙二醇、白凡士林及諸如此類。乳霜之載劑組合物可基於水與甘油及一或多種其他組分(例如甘油單硬脂酸酯、PEG-甘油單硬脂酸酯及鯨蠟硬脂醇)之組合。凝膠可使用異丙基醇及水適宜地與其他組分(例如甘油、經乙基纖維素及諸如此類)之組合來調配。在一些實施例中,局部調配物含有至少約0.1wt%、至少約0.25wt%、至少約0.5wt%、至少約1wt%、至少約2wt%或至少約5wt%之本發明化合物。局部調配物可適宜地包裝於例如100g管中,該等管視情況附有用於治療所選適應症(例如牛皮癬或其他皮膚病況)之說明書。
投與患者之化合物或組合物之量將端視以下因素而變化:被投與者、投與目的(例如預防或治療)、患者之狀態、投與方式及諸如此類。在治療應用中,組合物可以足以治癒或至少部分地阻止疾病之症狀及其併發症之量投與已患有疾病之患者。有效劑量將端視所治療之疾病病況以及主治醫師端視諸如疾病之嚴重程度、患者之年齡、體重及一般狀況及諸如此類等因素之判斷而定。
投與患者之組合物可呈上述醫藥組合物形式。該等組合物可藉由習用除菌技術來除菌,或可經過濾除菌。水溶液可經包裝以原樣或凍
乾形式使用,在投與之前將凍乾製劑與無菌水性載劑組合。化合物製劑之pH通常將介於3與11之間,更佳為5至9且最佳為7至8。應理解,使用某些前述賦形劑、載劑或穩定劑將可形成醫藥鹽。
本發明化合物之治療劑量可根據例如以下等因素而變化:進行治療之具體使用、化合物之投與方式、患者之健康狀況及病況以及主治醫師之判斷。醫藥組合物中本發明化合物之比例或濃度可端視多種因素而變化,包括劑量、化學特徵(例如疏水性)及投與途徑。舉例而言,本發明化合物可以含有約0.1%至約10% w/v化合物之生理緩衝水溶液形式提供用於非經腸投與。一些典型劑量範圍為約1μg/kg至約1g/kg體重/天。在一些實施例中,劑量範圍為約0.01mg/kg至約100mg/kg體重/天。劑量可能端視諸如以下等變量而定:疾病或病症之類型及其進展程度、特定患者之總體健康狀況、所選化合物之相對生物效能、賦形劑之調配及其投與途徑。可根據得自活體外或動物模型測試系統之劑量-反應曲線來推斷有效劑量。
V. 經標記化合物及分析方法
本發明化合物可進一步用於研究正常及異常組織中之生物過程。因此,本發明之另一態樣係關於本發明之經標記化合物(經放射性標記、經螢光標記等),其不僅可用於成像技術中亦可用於活體外及活體內分析中,用於定位及量化組織樣品(包括人類)中之PD-1或PD-L1蛋白,及用於藉由抑制經標記化合物之結合鑑別PD-L1配位體。因此,本發明包括含有此類經標記化合物之PD-1/PD-L1結合分析。
本發明另外包括本發明之經同位素取代之化合物。「經同位素取代」之化合物為其中一或多個原子經原子質量或質量數不同於通常在自然界中發現(即天然)之原子質量或質量數之原子替代或取代的本發明化合物。應理解,「經放射性標記」之化合物為納入至少一種放射活性同位素(例如放射性核種)之化合物。可納入本發明化合物中之適宜放射性核種包括(但不限於)3H(對於氚亦寫為T)、11C、13C、14C、13N、15N、15O、17O、18O、18F、35S、36Cl、82Br、75Br、76Br、77Br、123I、124I、125I及131I。納入本發明放射性標記化合物中之放射性核種將端視該放射性標記化合物之特定應用而定。舉例而言,對於活體外PD-L1蛋白標記及競爭分析,納入3H、14C、
82Br、125I、131I、35S或之化合物通常將最有用。對於放射性成像應用,11C、18F、125I、123I、124I、131I、75Br、76Br或77Br通常將最有用。在一些實施例中,放射性核種選自由3H、14C、125I、35S及82Br組成之群。將放射性同位素納入有機化合物中之合成方法為業內已知。
特定而言,本發明之經標記化合物可於篩選分析中用以鑑別及/或評估化合物。舉例而言,經標記之新合成或鑑別之化合物(即測試化合物)結合PD-L1蛋白之能力可經由追蹤標記監測其與PD-L1蛋白接觸時之濃度變化來評估。舉例而言,可評估測試化合物(經標記)減少已知結合至PD-L1蛋白之另一化合物(即標準化合物)之結合之能力。因此,測試化合物與標準化合物競爭結合至PD-L1蛋白之能力與其結合親和力直接相關。相反,在一些其他篩選分析中,標準化合物經標記且測試化合物未經標記。因此,監測經標記標準化合物之濃度以評估標準化合物與測試化合物之間之競爭,且因此確定測試化合物之相對結合親和力。
VI. 套組
本發明亦包括醫藥套組,其可用於例如治療或預防與PD-L1活性(包括其與諸如PD-1及B7-1(CD80)等其他蛋白質之相互作用)相關之疾病或病症(例如癌症或感染),該等套組包括一或多個容器,該等容器含有包含治療有效量之式(I’)、(I)化合物或其任一實施例之醫藥組合物。此類套組可另外包括多種習用醫藥套組組分中之一或多者,例如含有一或多種醫藥學上可接受之載劑之容器、其他容器等,如熟習此項技術者將容易明瞭。在套組中亦可包括呈插頁或呈標記形式指示欲投與組分之量、投與指南及/或混合組分指南之說明書。
本發明將藉助特定實例進行更詳細描述。以下實例出於說明性目的提供,且不欲以任何方式限制本發明。熟習此項技術者將容易地認識到,可改變或修改多個非關鍵參數以產生基本上相同之結果。已發現根據本文所述之至少一個分析,各實例之化合物抑制PD-1/PD-L1蛋白/蛋白相互作用之活性。
實例
本發明化合物之實驗程序提供於下文中。所製備之一些化合
物之開放式存取製備型LCMS純化在Waters質量導向分級系統上實施。用於操作該等系統之基本設備設定、方案及控制軟件已詳細描述於文獻中。參見例如Blom,「Two-Pump At Column Dilution Configuration for Preparative LC-MS」,K.Blom,J.Combi.Chem.,2002,4,295-301;Blom等人,「Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification」,J.Combi.Chem.,2003,5,670-83;及Blom等人,「Preparative LC-MS Purification:Improved Compound Specific Method Optimization」,J.Combi.Chem.,2004,6,874-883。
實例1
2-[({8-[(2-甲基聯苯-3-基)胺基]喹啉-3-基}甲基)胺基]乙醇
步驟1:2-甲基聯苯-3-胺
向3-溴-2-甲基苯胺(Aldrich,目錄號530018:0.39mL,3.2mmol)、苯基硼酸(Aldrich,目錄號P20009:0.50g,4.1mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(Aldrich,目錄號697230:0.13g,0.16mmol)及碳酸鉀(1.32g,9.57mmol)於1,4-二噁烷(20.0mL)及水(7mL)中之混合物通氮氣5min。然後將混合物加熱且在110℃下攪拌1.5h。將反應混合物冷卻至室溫,用飽和NaHCO3水溶液驟冷,且用乙酸乙酯(3×10mL)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾並在減壓下濃縮。藉由矽膠管柱上之急速層析用己烷中之乙酸乙酯(0→15%)溶析來純化殘餘物,以提供期望產物。C13H14N(M+H)+之LC-MS計算值:m/z=184.1;實驗值184.1。1H NMR(400MHz,DMSO)δ 7.40(dd,J=7.6,6.8Hz,2H),7.32(dd,J=7.6,7.2Hz,1H),7.29-7.14(m,2H),6.92(dd,J=7.6,7.6Hz,1H),6.64(d,J=7.2Hz,1H),6.40(d,J=7.2Hz,1H),4.89(s,2H),1.92(s,3H)。
步驟2:8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲酸
向小瓶中添加外消旋2,2'-雙(二苯基膦基)-1,1'-聯萘(Aldrich,目錄號481084:30mg,0.05mmol)、2-甲基聯苯-3-胺(262mg,1.43mmol)、8-溴喹啉-3-甲酸乙酯(Ark Pharm,目錄號AK-47201:0.200g,0.714mmol)、雙(二亞苄基丙酮)鈀(0)(Aldrich,目錄號227994:0.012g,0.021mmol)及第三丁醇鈉(Aldrich,目錄號359270:96.7mg,1.01mmol)。添加甲苯(3.6mL)且向反應混合物通氮氣5min,然後密封並在130℃下加熱18h。將反應混合物冷卻,且在真空中濃縮。所得殘餘物不經進一步純化即直接用於下一步驟中。C23H19N2O2(M+H)+之LC-MS計算值:m/z=355.1;實驗值355.4。
步驟3:{8-[(2-甲基聯苯-3-基)胺基]喹啉-3-基}甲醇
在-78℃下,向8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲酸(253mg,0.714mmol)於THF(3.6mL)中之溶液中添加THF中之1.0M四氫鋁酸鋰(2.14mL,2.14mmol)。將所得混合物升溫至室溫,且攪拌18h。將混合物冷卻至0℃且使用費雪處理(Fieser workup)驟冷:添加水(80μL),然後添加1N NaOH(240μL),且然後再添加水(80μL),且然後在室溫下將混合物攪拌1h。用乙酸乙酯(10mL)稀釋所得漿液,經矽藻土過濾,且用水洗滌。然後用鹽水洗滌有機萃取物,經硫酸鈉乾燥,過濾,然後在真空中濃縮。藉由矽膠層析(0→40%乙酸乙酯/己烷)純化所得殘餘物。C23H21N2O(M+H)+之LC-MS計算值:m/z=341.1;實驗值341.2。
步驟4:8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲醛
在0℃下,向{8-[(2-甲基聯苯-3-基)胺基]喹啉-3-基}甲醇(83.0
mg,0.244mmol)於二氯甲烷(1.0mL)中之溶液中添加戴斯-馬丁過碘烷(Aldrich,目錄號274623:103mg,0.244mmol)。在0℃下將混合物攪拌10min,然後在0℃下用飽和硫代硫酸鈉水溶液驟冷。用二氯甲烷(3×10mL)萃取混合物。然後用飽和碳酸氫鈉水溶液、水、然後鹽水洗滌有機萃取物。經硫酸鈉乾燥有機萃取物且在真空中濃縮。藉由管柱層析(0至20% EtOAc/己烷)純化期望醛。C23H19N2O(M+H)+之LC-MS計算值:m/z=339.1;實驗值339.3。
步驟5:2-[({8-[(2-甲基聯苯-3-基)胺基]喹啉-3-基}甲基)胺基]乙醇
在室溫下,將8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲醛(19mg,0.056mmol)及乙醇胺(Aldrich,目錄號398136:10μL,0.167mmol)於二氯甲烷(0.4mL)及N,N-二異丙基乙基胺(58.1μL,0.333mmol)中之混合物攪拌1h,然後小心地添加三乙氧基硼氫化鈉(0.0353g,0.167mmol)。在室溫下將反應混合物攪拌24h。將混合物濃縮,溶解於甲醇中,然後藉由製備型HPLC(pH=2,乙腈/水+TFA)純化,以獲得呈TFA鹽形式之期望產物。C25H26N3O(M+H)+之LC-MS計算值:m/z=384.2;實驗值384.2。1H NMR(400MHz,DMSO)δ 9.06(s,2H),8.94(d,J=2.0Hz,1H),8.43(d,J=2.0Hz,1H),8.33(s,1H),7.54-7.22(m,8H),7.06(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1 H),5.18(brs,1H),4.43(t,J=5.2Hz,2H),3.70(t,J=5.2Hz,2H),3.08(brs,2H),2.14(s,3H)。
實例2
2-[({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
步驟1:3-溴-N-(2-甲基聯苯-3-基)-1,7-萘啶-8-胺
向微波小瓶中添加2-甲基聯苯-3-胺(實例1、步驟1:0.1g,
0.546mmol)、3-溴-8-氯-1,7-萘啶(PharmaBlock,目錄號PBLJ2743:140mg,0.55mmol)、第三丁醇(2.5mL)及二噁烷中之4.0M氯化氫(0.136mL,0.546mmol)。在微波中將所得混合物照射至100℃並保持1h。濃縮所得混合物,且期望產物直接用於下一步驟中。C21H17N3Br(M+H)+之LC-MS計算值:m/z=390.1;實驗值390.1。
步驟2:N-(2-甲基聯苯-3-基)-3-乙烯基-1,7-萘啶-8-胺
向3-溴-N-(2-甲基聯苯-3-基)-1,7-萘啶-8-胺(213mg,0.546mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(Aldrich,目錄號633348:0.185mL,1.09mmol)及[1,1'-雙(二-環己基膦基)二茂鐵]二氯鈀(II)(Aldrich,目錄號701998:4mg,0.005mmol)於第三丁醇(3.93mL)及水(4mL)中之混合物通氮氣,然後密封。在110℃下將其攪拌2h。將反應混合物冷卻,然後用乙酸乙酯(3×10mL)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾並在減壓下濃縮。粗產物不經純化即直接用於下一步驟中。C23H20N3(M+H)+之LC-MS計算值:m/z=338.2;實驗值338.1。
步驟3:8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛
向N-(2-甲基聯苯-3-基)-3-乙烯基-1,7-萘啶-8-胺(184mg,0.55mmol)於1,4-二噁烷(11mL)及水(11mL)中之溶液中添加四氧化鋨於水中之4wt%溶液(0.52mL,0.082mmol)。將混合物攪拌5min,然後添加高碘酸鈉(467mg,2.18mmol)且攪拌1h。用乙酸乙酯(10mL)稀釋混合物,且分離各相。用乙酸乙酯(10mL)萃取水層且用水、然後用鹽水洗滌合併之有機層並經硫酸鈉乾燥。過濾萃取物,然後在真空中濃縮。藉由矽膠層析(0→40% EtOAc/己烷)純化期望醛。C22H18N3O(M+H)+之LC-MS計算值:m/z=340.1;實驗值340.1。
步驟4:2-[({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
此化合物係使用與針對實例1、步驟5所述類似之程序、用8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛(步驟3)替代8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲醛來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化反應混合物,以獲得呈TFA鹽形式之期望產物。C24H25N4O(M+H)+之LC-MS計算值:m/z=385.2;實驗值385.2。1H NMR(400MHz,DMSO)δ 9.24(s,2H),9.10(s,1H),8.50(s,1H),7.88(d,J=2.8Hz,2H),7.52-7.35(m,6H),7.28-7.18(m,2H),5.02(brs,1H),4.49(s,2H),3.71(t,J=5.2Hz,2H),3.11(s,2H),2.18(s,3H)。
實例3
1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸
步驟1:1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-3-基)甲基)哌啶-2-甲酸甲酯
在室溫下,將8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛(實例2、步驟3:65mg,0.19mmol)及哌啶甲酸甲酯鹽酸鹽(Aldrich,目錄號391204:100mg,0.574mmol)於二氯甲烷(2mL)及N,N-二異丙基乙胺(200μL,1.15mmol)中之混合物攪拌1h。小心地添加三乙氧基硼氫化鈉(0.0353g,0.167mmol)且在室溫下將混合物攪拌24h。用飽和碳酸氫鈉溶液驟冷反應混合物,且分離出有機層。用二氯甲烷(2×10mL)再萃取水層。經硫酸鈉乾燥合併之有機層,過濾,且在真空中濃縮。獲得油狀期望產物且其不經進一步純化即用於下一步驟中。C29H31N4O2(M+H)+之LC-MS計算值:m/z=467.2;實驗值467.2。
步驟2:1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸
向1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-3-基)甲基)哌啶-2-
甲酸甲酯(88mg,0.19mmol)、四氫呋喃(0.66mL)、甲醇(0.66mL)及水(0.33mL)中之混合物中添加氫氧化鋰(275mg,11.5mmol)。在65℃下將所得混合物加熱過夜。將混合物冷卻至室溫,然後用1N HCl調節至pH=1-2且藉由製備型HPLC(pH=2,乙腈/水+TFA)純化,以獲得呈TFA鹽形式之期望產物。C28H29N4O2(M+H)+之LC-MS計算值:m/z=453.2;實驗值453.2。1H NMR(400MHz,MeOD)δ 9.21(d,J=1.8Hz,1H),8.55(d,J=1.8Hz,1H),7.61(d,J=7.0Hz,1H),7.57-7.36(m,8H),7.33(d,J=7.0Hz,1H),4.80(m,1H),4.39(d,J=13.4Hz,1H),3.90(d,J=10.4Hz,1H),3.48(m,1H),3.16-3.00(m,1H),2.34(d,J=13.4Hz,1H),2.22(s,3H),1.96-1.55(m,6H)。
實例4
1-({4-[(2-甲基聯苯-3-基)胺基]吡啶并[3,2-d]嘧啶-7-基}甲基)哌啶-2-甲酸
步驟1:7-溴-N-(2-甲基聯苯-3-基)吡啶并[3,2-d]嘧啶-4-胺
向小瓶中添加2-甲基聯苯-3-胺(實例1、步驟1:0.4g,2.18mmol)、7-溴-4-氯吡啶并[3,2-d]嘧啶(Ark Pharm,目錄號AK-27560:540mg,2.2mmol)及異丙醇(10.mL)。將混合物加熱至110℃並保持4h。將混合物冷卻至室溫,濃縮,且粗產物不經進一步純化即直接用於下一步驟中。C20H16BrN4(M+1)+之LC-MS計算值:m/z=391.1;實驗值391.1。
步驟2:N-(2-甲基聯苯-3-基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺
此化合物係使用與針對實例2、步驟2所述類似之程序、用7-溴-N-(2-甲基聯苯-3-基)吡啶并[3,2-d]嘧啶-4-胺(步驟1)替代3-溴-N-(2-甲
基聯苯-3-基)-1,7-萘啶-8-胺來製備。粗產物不經進一步純化即直接用於下一步驟中。C22H19N4(M+1)+之LC-MS計算值:m/z=339.2;實驗值339.2。
步驟3:4-[(2-甲基聯苯-3-基)胺基]吡啶并[3,2-d]嘧啶-7-甲醛
此化合物係使用與針對實例2、步驟3所述類似之程序、用N-(2-甲基聯苯-3-基)-7-乙烯基吡啶并[3,2-d]嘧啶-4-胺替代N-(2-甲基聯苯-3-基)-3-乙烯基-1,7-萘啶-8-胺來製備。在室溫下將反應混合物攪拌18h,且然後用乙酸乙酯(10mL)稀釋。分離出有機層且用乙酸乙酯(2×10mL)再萃取水層。用鹽水洗滌合併之有機層,經硫酸鈉乾燥,過濾,且在真空中濃縮。粗產物不經進一步純化即直接用於下一步驟中。C21H17N4O(M+1)+之LC-MS計算值:m/z=341.1;實驗值341.1。
步驟4:1-((4-(2-甲基聯苯-3-基胺基)吡啶并[3,2-d]嘧啶-7-基)甲基)哌啶-2-甲酸甲酯
此化合物係使用與針對實例3、步驟1所述類似之程序、用4-[(2-甲基聯苯-3-基)胺基]吡啶并[3,2-d]嘧啶-7-甲醛(步驟3)替代8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。粗產物不經進一步純化即直接用於下一步驟中。C28H30N5O2(M+1)+之LC-MS計算值:m/z=468.2;實驗值468.2。
步驟5:1-({4-[(2-甲基聯苯-3-基)胺基]吡啶并[3,2-d]嘧啶-7-基}甲基)哌啶-2-甲酸
此化合物係使用與針對實例3、步驟2所述類似之程序、用1-((4-(2-甲基聯苯-3-基胺基)吡啶并[3,2-d]嘧啶-7-基)甲基)哌啶-2-甲酸甲酯(步驟4)替代1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-3-基)甲基)哌啶-2-甲酸甲酯來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化粗產物,以獲得
呈TFA鹽形式之期望產物。C27H28N5O2(M+H)+之LC-MS計算值:m/z=454.2;實驗值454.3。
實例5
1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-基}甲基)哌啶-2-甲酸
步驟1:4-氯-N-(2-甲基聯苯-3-基)-1,7-萘啶-8-胺
向小瓶中添加2-甲基聯苯-3-胺(實例1、步驟1:0.2g,1.09mmol)、4,8-二氯-1,7-萘啶(Synthonix,目錄號D7291:180mg,0.91mmol)及異丙醇(4mL)。將混合物加熱至100℃並保持4h。將混合物濃縮,且粗產物直接用於下一步驟中。C21H17ClN3(M+1)+之LC-MS計算值:m/z=346.1;實驗值346.1。
步驟2:N-(2-甲基聯苯-3-基)-4-乙烯基-1,7-萘啶-8-胺
此化合物係使用與針對實例2、步驟2所述類似之程序、用4-氯-N-(2-甲基聯苯-3-基)-1,7-萘啶-8-胺(步驟1)替代3-溴-N-(2-甲基聯苯-3-基)-1,7-萘啶-8-胺來製備。粗產物不經進一步純化即直接用於下一步驟中。C23H20N3(M+1)+之LC-MS計算值:m/z=338.2;實驗值338.2。
步驟3:8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-甲醛
此化合物係使用與針對實例2、步驟3所述類似之程序、用N-(2-甲基聯苯-3-基)-4-乙烯基-1,7-萘啶-8-胺(步驟2)替代N-(2-甲基聯苯-3-基)-3-乙烯基-1,7-萘啶-8-胺來製備。在室溫下將反應混合物攪拌18h,且然後用乙酸乙酯(10mL)稀釋。分離出有機層且用乙酸乙酯(2×10mL)再萃取
水層。用鹽水洗滌合併之有機層,經硫酸鈉乾燥,過濾,且在真空中濃縮。藉由矽膠層析(0→50% EtOAc/己烷)純化粗產物。C22H18N3O(M+1)+之LC-MS計算值:m/z=340.1;實驗值340.2。
步驟4:1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-4-基)甲基)哌啶-2-甲酸甲酯
此化合物係使用與針對實例3、步驟1所述類似之程序、用8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-甲醛(步驟3)替代8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。粗產物不經進一步純化即直接用於下一步驟中。C29H31N4 O2(M+1)+之LC-MS計算值:m/z=467.2;實驗值467.2。
步驟5:1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-基}甲基)哌啶-2-甲酸
此化合物係使用與針對實例3、步驟2所述類似之程序、用1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-4-基)甲基)哌啶-2-甲酸甲酯替代1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-3-基)甲基)哌啶-2-甲酸甲酯來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化粗產物,以獲得呈TFA鹽形式之期望產物。C28H29N4O2(M+H)+之LC-MS計算值:m/z=453.2;實驗值453.2。1H NMR(400MHz,MeOD)δ 9.11(d,J=4.4Hz,1H),8.09(d,J=4.4Hz,1H),7.94(d,J=7.2Hz,1H),7.62(d,J=7.2Hz,1H),7.55-7.37(m,8H),4.73(d,J=13.8Hz,1H),4.16(d,J=13.8Hz,1H),3.66-3.48(m,1H),3.12(m,1H),2.71(m,1H),2.24(s,3H),2.20(m,1H)1.94-1.52(m,6H)。
實例6
2-[({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-基}甲基)胺基]乙醇
在50℃下,將8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-甲醛(實例5、步驟3:0.022g,0.065mmol)及乙醇胺於二氯甲烷(1.00mL)及N,N-二異丙基乙胺(67.7μL,0.389mmol)中之混合物攪拌1h,然後小心地添加三乙
氧基硼氫化鈉(0.0412g,0.194mmol)。在50℃下將反應物攪拌12h。將混合物冷卻至室溫,且然後在真空中濃縮。將殘餘物溶解於甲醇中且藉由製備型HPLC(pH=2,乙腈/水+TFA)純化,以獲得呈TFA鹽形式之期望產物。C24H25N4O(M+H)+之LC-MS計算值:m/z=385.2;實驗值385.2。1H NMR(400MHz,DMSO)δ 9.19(s,2H),9.05(d,J=4.8Hz,1H),8.20-8.02(m,2H),7.97(d,J=3.6Hz,1H),7.48(dd,J=7.6,7.2Hz,2H),7.44-7.32(m,4H),7.09(m,1H),5.32(brs,1H),4.69(m,2H),3.86-3.67(m,2H),3.19(m,2H),2.21(s,3H)。
實例7
2-[({8-[(2-甲基聯苯-3-基)胺基]喹啉-4-基}甲基)胺基]乙醇
步驟1:8-[(2-甲基聯苯-3-基)胺基]喹啉-4-甲醛
用氮吹掃8-溴喹啉-4-甲醛(Oakwood Chemical,目錄號042977:100.0mg,0.4236mmol)、2-甲基聯苯-3-胺(實例1、步驟1:77.6mg,0.424mmol)、[(2-二-環己基膦基-3,6-二甲氧基-2',4',6'-三異丙基-1,1'-聯苯)-2-(2'-胺基-1,1'-聯苯)]鈀(II)甲烷磺酸鹽(Aldrich,目錄號761605:58mg,0.064mmol)及碳酸銫(0.690g,2.12mmol)於第三丁醇(10.0mL)中之混合物,且然後在100℃下攪拌2h。將混合物冷卻至室溫,用乙酸乙酯及水稀釋。分離各層且用鹽水洗滌有機層,經硫酸鈉乾燥,過濾,且在真空中濃縮。藉由管柱層析(0→50% EtOAc/己烷)純化殘餘物。C23H19N2O(M+H)+之LC-MS計算值:m/z=339.1;實驗值339.2。
步驟2:2-[({8-[(2-甲基聯苯-3-基)胺基]喹啉-4-基}甲基)胺基]乙醇
此化合物係使用與針對實例1、步驟5所述類似之程序、用8-[(2-甲基聯苯-3-基)胺基]喹啉-4-甲醛(步驟1)替代8-[(2-甲基聯苯-3-基)胺基]喹啉-3-甲醛來製備。藉由製備型HPLC(pH=2、乙腈/水+TFA)純化反應混合物,以獲得呈TFA鹽形式之期望產物。C25H26N3O(M+H)+之LC-MS計
算值:m/z=384.2;實驗值384.2。1H NMR(400MHz,DMSO)δ 9.13(s,2H),8.94(d,J=4.4Hz,1H),8.43(s,1H),7.73(d,J=4.4Hz,1H),7.60-7.43(m,4H),7.44-7.23(m,4H),7.10-6.99(m,2H),5.32(brs,1H),4.73(m,2H),3.76(t,J=5.2Hz,2H),3.21(s,2H),2.15(s,3H)。
實例8
1-({8-[(2-甲基聯苯-3-基)胺基]喹啉-4-基}甲基)哌啶-2-甲酸
步驟1:1-((8-(2-甲基聯苯-3-基胺基)喹啉-4-基)甲基)哌啶-2-甲酸甲酯
此化合物係使用與針對實例3、步驟1所述類似之程序、用8-[(2-甲基聯苯-3-基)胺基]喹啉-4-甲醛(實例7、步驟1)替代8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。粗產物不經進一步純化即直接用於下一步驟中。C30H32N3O2(M+H)+之LC-MS計算值:m/z=466.2;實驗值466.2。
步驟2:1-({8-[(2-甲基聯苯-3-基)胺基]喹啉-4-基}甲基)哌啶-2-甲酸
此化合物係使用與針對實例3、步驟2所述類似之程序、用1-((8-(2-甲基聯苯-3-基胺基)喹啉-4-基)甲基)哌啶-2-甲酸甲酯(步驟1)替代1-((8-(2-甲基聯苯-3-基胺基)-1,7-萘啶-3-基)甲基)哌啶-2-甲酸甲酯來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化粗產物,以獲得呈TFA鹽形式之期望產物。C29H30N3O2(M+H)+之LC-MS計算值:m/z=452.2;實驗值452.3。1H NMR(400MHz,MeOD)δ 8.93(d,J=4.4Hz,1H),7.77(d,J=4.4Hz,1H),7.71(d,J=8.4Hz,1H),7.58(dd,J=8.0,7.8Hz,1H),7.50-7.43(m,4H),7.40-7.30(m,4H),7.11(dd,J=15.2,7.8Hz,2H),5.14(d,J=12.8Hz,1H),4.65(m,1H),4.16(d,J=11.2Hz,1H),3.25-3.13(m,1H),2.42(d,J=11.2Hz,1H),2.20(s,3H),2.02-1.62(m,6H)。
實例9
2-[({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
步驟1:{[(2-氯吡啶-3-基)胺基]亞甲基}丙二酸二乙酯
將3-胺基-2-氯吡啶(Aldrich,目錄號A46900:5.71g,44.4mmol)及(乙氧基亞甲基)丙二酸二乙酯(Alfa Aesar,目錄號A13776:9.013mL,44.6mmol)合併於具有攪拌棒之小瓶中且在120℃下加熱5h。濃縮所得混合物且用己烷洗滌以提供米色固體狀期望化合物。C13H16ClN2O4(M+H)+之LC-MS計算值:m/z=299.1;實驗值299.1。
步驟2:8-氯-4-側氧基1,4-二氫-1,7-萘啶-3-甲酸乙酯
向三頸燒瓶中裝填{[(2-氯吡啶-3-基)胺基]亞甲基}丙二酸二乙酯(6.39g,21.4mmol)、攪拌棒及二苯基醚(Aldrich,目錄號240834:102mL)。藉由使氮鼓泡通過溶液將混合物脫氣10min。然後配備Vigreux回流冷凝器及溫度探針且將反應物之內部溫度加熱至240℃-250℃並保持1h。然後將反應物冷卻,且添加己烷以使產物沈澱。然後過濾混合物並用己烷洗滌沈澱。使用高真空再乾燥固體且其不經進一步純化即直接用於下一步驟中。C11H10ClN2O3(M+H)+之LC-MS計算值:m/z=253.0;實驗值253.1。
步驟3:8-(2-甲基聯苯-3-基胺基)-4-側氧基-1,4-二氫-1,7-萘啶-3-甲酸乙酯
向小瓶中添加2-甲基聯苯-3-胺(實例1、步驟1:0.457g,2.49mmol)、8-氯-4-羥基-1,7-萘啶-3-甲酸乙酯(630mg,2.5mmol)、碳酸銫(2.44g,7.48mmol)、Brettphos-Pd-G3前觸媒(Aldrich,目錄號761605:339mg,0.374mmol),然後添加第三丁醇(21mL)。向混合物通氮氣2min,然後密封且在100℃下加熱2h。冷卻至室溫後,過濾混合物並用乙酸乙酯洗滌固體。在真空中濃縮濾液且藉由管柱層析(0→20% MeOH/DCM)純化。C24H22N3O3(M+H)+之LC-MS計算值:m/z=400.2;實驗值400.2。
步驟4:4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲酸乙酯
向配備有Vigreux回流冷凝器之燒瓶中裝填8-(2-甲基聯苯-3-基胺基)-4-側氧基-1,4-二氫-1,7-萘啶-3-甲酸乙酯(0.480g,1.20mmol)、攪拌棒及磷醯氯(13mL,140mmol)。在110℃下將混合物攪拌1h。在真空中濃縮混合物且用冰驟冷剩餘磷醯氯並緩慢添加飽和碳酸氫鈉溶液。將DCM添加至混合物中,且分離各層。用DCM再萃取水層,且經硫酸鈉乾燥合併之有機萃取物,過濾,且在真空中濃縮。藉由管柱層析(0→40% EtOAc/己烷)純化粗殘餘物。C24H21ClN3O2(M+H)+之LC-MS計算值:m/z=418.1;實驗值418.2。
步驟5:{4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲醇
在-78℃下,向4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲酸乙酯(0.550g,1.32mmol)於四氫呋喃(13.8mL,1.70E2mmol)中之溶液中逐滴添加THF中之1.0M四氫鋁酸鋰(1.32mL,1.32mmol)。添加後,在此溫度下將反應物攪拌30min。藉由添加飽和氯化銨水溶液小心地驟冷反應物,然後添加飽和羅謝爾鹽(Rochelle's salt)水溶液且攪拌1h。用EtOAc稀釋混合物,且分離各層。用EtOAc再萃取水層,且經硫酸鈉乾燥合併之
有機萃取物,過濾,且在真空中濃縮。粗固體以標題化合物及相應醛之混合物形式直接用於下一步驟中。C22H19ClN3O(M+H)+之LC-MS計算值:m/z=376.1;實驗值376.2。
步驟6:4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛
在0℃下,向{4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲醇(464.0mg,1.234mmol)於二氯甲烷(11mL)中之溶液中添加戴斯-馬丁過碘烷(549.8mg,1.296mmol)。在0℃下將混合物攪拌1h。在此溫度下用飽和硫代硫酸鈉水溶液驟冷反應物,且分離各層。用二氯甲烷再萃取水層。用碳酸氫鈉、水及鹽水洗滌合併之有機層並經硫酸鈉乾燥,過濾,且在真空中濃縮。藉由層析使用矽膠墊(0→1:1 EtOAc/己烷)純化粗殘餘物。C22H17ClN3O(M+H)+之LC-MS計算值:m/z=374.1;實驗值374.2。
步驟7:2-[({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
在室溫下,將4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛(0.008g,0.02mmol)及乙醇胺(Aldrich,目錄號398136:3.87μL,0.0642mmol)於二氯甲烷(0.2mL)及N,N-二異丙基乙胺(22.4μL,0.128mmol)中之混合物攪拌1h。小心地逐份添加三乙氧基硼氫化鈉(0.0136g,0.0642mmol)。在室溫下將反應物攪拌12h。使用LC-MS(pH=10,水+NH4OH)觀察亞胺,且向混合物中添加硼氫化鈉(4.05mg,0.107mmol)及幾滴甲醇。在室溫下將反應物攪拌2h,然後用甲醇稀釋且藉由製備型HPLC(pH=2,水+TFA)純化,以提供呈TFA鹽形式之期望產物。C24H24ClN4O(M+H)+之LC-MS計算值:m/z=419.2;實驗值419.1。
實例10
2-[({4-甲氧基-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
步驟1:4-甲氧基-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛
將4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛(實例9、步驟6:20.0mg,0.0535mmol)、甲醇(1.0mL)及碳酸鉀(8.87mg,0.0642mmol)合併於小瓶中且在攪拌的同時在60℃下加熱1h。用乙酸乙酯稀釋混合物,過濾,且在真空中濃縮。所得黃色殘餘物直接用於下一步驟中。C23H20N3O2(M+H)+之LC-MS計算值:m/z=370.1;實驗值370.2。
步驟2:2-[({4-甲氧基-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
此化合物係使用與針對實例9、步驟7所述類似之程序、用4-甲氧基-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛替代4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化反應混合物,以獲得呈TFA鹽形式之期望產物。C25H27N4C2(M+H)+之LC-MS計算值:m/z=415.2;實驗值415.2。
實例11
1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸
步驟1:1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-.2-甲酸甲酯
在室溫下,將4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛(實例9、步驟6:0.020g,0.053mmol)及甲基哌啶-2-甲酸酯鹽酸鹽(Aldrich,目錄號391204:28.8mg,0.160mmol)於二氯甲烷(0.4mL)及N,N-二異丙基乙胺(55.9μL,0.321mmol)中之混合物攪拌1h。小心地逐份添加三
乙氧基硼氫化鈉(0.0340g,0.160mmol)。在室溫下將反應物攪拌2h。藉由LC-MS(pH=10,水+NH4OH)觀察所得亞胺且向反應混合物中添加幾滴甲醇及四氫硼酸鈉(10.1mg,0.267mmol)。將混合物攪拌1h,然後用飽和碳酸氫鈉水溶液驟冷。分離出有機層且用DCM再萃取水層。經Na2SO4乾燥合併之有機層,過濾,且在真空中濃縮。粗殘餘物直接用於下一步驟中。C29H30ClN4O2(M+H)+之LC-MS計算值:m/z=501.2;實驗值501.2。
步驟2:1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸
向裝填1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸甲酯(26.8mg,0.0535mmol)之小瓶中添加氫氧化鋰(12.81mg,0.5350mmol)、甲醇(0.5mL)、THF(0.5mL)及水(0.5mL)。在攪拌的同時將混合物加熱至60℃並保持2h。冷卻至室溫後,使用1N HCl水溶液酸化混合物,用甲醇稀釋,且藉由製備型HPLC(pH=2,水+TFA)純化,以提供呈TFA鹽形式之期望化合物。C28H28ClN4O2(M+H)+之LC-MS計算值:m/z=487.2;實驗值487.2。
實例12
2-{[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]胺基}乙醇
步驟1:3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯胺
將3-溴-2-甲基苯胺(Aldrich,目錄號530018:1.00mL,8.12mmol)、2,3-二氫-1,4-苯并二氧雜環己烯-6-基硼酸(Combi-Blocks,目錄號BB-8311:1.9g,10.mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1:1)(Aldrich,目錄號379670:0.05g,0.06mmol)及碳酸鉀(2.72g,
19.7mmol)於1,4-二噁烷(41.2mL)及水(20mL)中之混合物脫氣且再裝填氮三次。然後將混合物加熱且在110℃下攪拌1.5h。用飽和NaHCO3水溶液驟冷反應混合物,且用乙酸乙酯(3×10mL)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾並在減壓下濃縮。藉由管柱層析(0→30% EtOAc/己烷)純化所得殘餘物。C15H16NO2(M+H)+之LC-MS計算值:m/z=242.1;實驗值242.2。
步驟2:4-氯-N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-1,7-萘啶-8-胺
向小瓶中添加3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯胺(0.263g,1.09mmol)、4,8-二氯-1,7-萘啶(Synthonix,目錄號D7291:180mg,0.91mmol)及乙腈(10.0mL)。將反應物加熱至100℃並保持4h。冷卻至室溫後,添加碳酸銫(0.296g,0.910mmol)且然後將混合物回流4h。冷卻至室溫後,用乙酸乙酯稀釋混合物,過濾,且在真空中濃縮。C23H19ClN3O2(M+H)+之LC-MS計算值:m/z=404.1;實驗值404.1。
步驟3:N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-4-乙烯基-1,7-萘啶-8-胺
將N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-4-乙烯基-1,7-萘啶-8-胺(0.370g,0.936mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(Aldrich,目錄號633348:1.59mL,9.36mmol)、碳酸鈉(0.198g,1.87mmol)及[1,1'-雙(二-環己基膦基)二茂鐵]二氯鈀(II)(Aldrich,目錄號701998:7.1mg,0.0094mmol)於第三丁醇(6.73mL)及水(6mL)中之混合物脫氣且密封。在110℃下將混合物攪拌2h。將反應混合物冷卻,然後用乙酸乙酯(3×20mL)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,
過濾並在減壓下濃縮。粗殘餘物不經進一步純化即直接用於下一步驟中。C25H22N3O2(M+1)+之LC-MS計算值:m/z=396.2;實驗值396.2。
步驟4:8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-甲醛
向燒瓶中裝填N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-4-乙烯基-1,7-萘啶-8-胺(370.mg,0.936mmol)、1,4-二噁烷(20.mL)、攪拌棒及水(20.mL)。向此懸浮液中添加四氧化鋨於水中之4% w/w混合物(0.89mL,0.14mmol)。將反應物攪拌5min,然後添加高碘酸鈉(2001mg,9.356mmol)。在室溫下攪拌1h後,用飽和硫代硫酸鈉水溶液驟冷反應物。然後用乙酸乙酯(2×10mL)萃取混合物,且分離合併之有機層,用鹽水洗滌,經Na2SO4乾燥,過濾,且在真空中濃縮。藉由管柱層析(0→60% EtOAc/己烷)純化粗殘餘物。C24H20N3O3(M+H)+之LC-MS計算值:m/z=398.1;實驗值398.2。
步驟5:2-{[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]胺基}乙醇
此化合物係使用與針對實例9、步驟7所述類似之程序、用8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-甲醛替代4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化反應混合物,以獲得呈TFA鹽形式之期望產物。C26H27N4O3(M+H)+之LC-MS計算值:m/z=443.2;實驗值443.3。
實例13
1-[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]哌啶-2-甲酸
步驟1:1-((8-(3-(2,3-二氫苯并[b][1,4]二噁烷-6-基)-2-甲基苯基胺基)-1,7-萘啶-4-基)甲基)哌啶-2-甲酸甲酯
此化合物係使用與針對實例11、步驟1所述類似之程序、用8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-甲醛(實例12,步驟4)替代4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-甲醛來製備。粗化合物不經進一步純化即直接用於下一步驟中。C31H33N4O4(M+H)+之LC-MS計算值:m/z=525.2;實驗值525.2。
步驟2:1-[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]哌啶-2-甲酸
此化合物係使用與針對實例11、步驟2所述類似之程序、用1-((8-(3-(2,3-二氫苯并[b][1,4]二噁烷-6-基)-2-甲基苯基胺基)-1,7-萘啶-4-基)甲基)哌啶-2-甲酸甲酯替代1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸甲酯來製備。藉由製備型HPLC(pH=2,乙腈/水+TFA)純化反應混合物,以獲得呈TFA鹽形式之期望產物。C30H31N4O4(M+H)+之LC-MS計算值:m/z=511.2;實驗值511.3。
實例14
2-[({5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-基}甲基)胺基]乙醇
步驟1:5-氯吡啶并[3,4-b]吡嗪-2(1H)-酮
在90℃下,將2-氯吡啶-3,4-二胺(Aldrich,目錄號736376:0.5g,3mmol)及乙醛酸乙酯(1:1w/v於甲苯中,Alfa Aesar,目錄號L19207:0.73mL,3.6mmol)於乙醇(5.0mL)中之懸浮液加熱過夜。然後在-20℃下將混合
物冷卻2天。過濾沈澱,用冷乙醇洗滌,收集,且不經進一步純化即直接用於下一步驟中。C7H5ClN3O(M+H)+之LC-MS計算值:m/z=182.0;實驗值182.1。
步驟2:5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-醇
在100℃下,將2-甲基聯苯-3-胺(實例1、步驟1:0.020g,0.11mmol)、5-氯吡啶并[3,4-b]吡嗪-2(1H)-酮(0.020g,0.11mmol)、碳酸銫(0.107g,0.327mmol)及Brettphos Pd G3前觸媒(Aldrich,目錄號761605:7.9mg,0.0087mmol)於第三丁醇(0.3mL)中之脫氣混合物加熱2h。添加水中之1.0M氯化氫直至pH為約5。攪拌過夜後,過濾沈澱,且將固體乾燥並直接用於下一步驟中。C20H17N4O(M+H)+之LC-MS計算值:m/z=329.1;實驗值329.2。
步驟3:2-氯-N-(2-甲基聯苯-3-基)吡啶并[3,4-b]吡嗪-5-胺
在120℃下在密封瓶中,將5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-醇(0.25g,0.76mmol)於磷醯氯(2.5mL,27mmol)中之混合物加熱1.5h。冷卻反應物且在真空中濃縮。將所得黑色殘餘物溶解於1,2-二氯乙烷中且冷卻至0℃。添加飽和碳酸氫鈉水溶液且在室溫下攪拌1h。過濾沈澱並用鹽水洗滌濾液,經硫酸鈉乾燥,過濾,且濃縮。然後將黑色固體與第三丁基甲基醚(3mL)一起研磨,且過濾所得沈澱並洗滌,以獲得深棕色固體狀期望產物。然後使用管柱層析(0→30% EtOAc/己烷)純化濾液,以提供深棕色固體狀期望產物。C20H16ClN4(M+H)+之LC-MS計算值:m/z=347.1;實驗值347.1。
步驟4:N-(2-甲基聯苯-3-基)-2-乙烯基吡啶并[3,4-b]吡嗪-5-胺
在120℃下,將2-氯-N-(2-甲基聯苯-3-基)吡啶并[3,4-b]吡嗪-5-胺(0.25g,0.72mmol)、二環己基(2',4',6'-三異丙基聯苯-2-基)膦-(2'-胺基聯苯-2-基)(氯)鈀(1:1)(Aldrich,目錄號741825:0.063g,0.080mmol)、磷酸鉀(0.47g,2.2mmol)及4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(Aldrich,目錄號663348:0.18mL,1.1mmol)於1,4-二噁烷(2.5mL)及水(0.8mL)中之脫氣混合物回流2.5h。將混合物冷卻至室溫,且添加乙酸乙酯及水。將所得混合物攪拌1h,且過濾沈澱並洗滌。用鹽水洗滌有機濾液,經硫酸鈉乾燥,過濾並在真空中濃縮。使用急速層析(0→30% EtOAc/己烷)純化粗殘餘物,以提供橙色固體狀期望化合物。C22H19N4(M+H)+之LC-MS計算值:m/z=339.2;實驗值339.2。
步驟5:5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-甲醛
此化合物係使用與針對實例12、步驟4所述類似之程序、用N-(2-甲基聯苯-3-基)-2-乙烯基吡啶并[3,4-b]吡嗪-5-胺替代N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-4-乙烯基-1,7-萘啶-8-胺來製備。粗化合物不經進一步純化即直接用於下一步驟中。C21H17N4O2(M+H2O)+之LC-MS計算值:m/z=359.1;實驗值359.2。
步驟6:2-[({5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-基}甲基)胺基]乙醇
向5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-甲醛(3.0mg,0.0088mmol)於二氯甲烷(1mL)中之溶液中添加乙醇胺(Aldrich,目錄號398136:10.0μL,0.166mmol)及乙酸(10.0μL,0.176mmol)。在室溫下將混合物攪拌20min,然後添加三乙氧基硼氫化鈉(31mg,0.15mmol)且在室溫下攪拌1h。添加水及飽和NaHCO3溶液。分離各層且濃縮有機層並溶解於THF/MeOH中。藉由製備型HPLC(pH=10,水+NH4OH,然後使用pH=2,水+TFA進行第二次純化)純化期望產物,以提供呈TFA鹽形式之化合物。
C23H24N5O(M+H)+之LC-MS計算值:m/z=386.2;實驗值386.2。
實例15
(2S)-1-({5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-基}甲基)哌啶-2-甲酸
將5-[(2-甲基聯苯-3-基)胺基]吡啶并[3,4-b]吡嗪-2-甲醛(實例14、步驟5:0.022g,0.065mmol)、(2S)-哌啶-2-甲酸(Alfa Aesar,目錄號L15373:15mg,0.12mmol)及乙酸(10.0μL,0.176mmol)於甲醇(1mL)及四氫呋喃(1mL)中之懸浮液攪拌2min。添加氰基硼氫化鈉(9.0mg,0.14mmol)且在室溫下攪拌4.5h。用甲醇稀釋混合物且藉由製備型HPLC(pH=10,水+NH4OH,然後使用pH=2,水+TFA進行第二次純化)純化,以提供呈TFA鹽形式之期望化合物。C27H28N5O2(M+H)+之LC-MS計算值:m/z=454.2;實驗值454.3。
實例16
2-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈
步驟1:2-胺基-6-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)苯甲腈
將2-胺基-6-溴苯甲腈(Combi-blocks,目錄號SS-7081:3.0g,15mmol)、2,3-二氫-1,4-苯并二氧雜環己烯-6-基硼酸(Combi-Blocks,目錄號BB-8311:3.6g,20.mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷之複合物(1:1)(Aldrich,目錄號379670:0.1g,0.1mmol)及碳酸鉀(5.11g,36.9mmol)於1,4-二噁烷(77mL)及水(30mL)中之混合物脫氣且再裝填氮三
次。然後將混合物加熱且在120℃下攪拌1.5h。用飽和NaHCO3水溶液驟冷反應混合物,且用乙酸乙酯(3×10mL)萃取。用鹽水洗滌合併之有機層,經Na2SO4乾燥,過濾並在減壓下濃縮。米色固體直接用於下一步驟中。C15H13N2O2(M+H)+之LC-MS計算值:m/z=253.1;實驗值253.2。
步驟2:8-氯-3-乙烯基-1,7-萘啶
將3-溴-8-氯-1,7-萘啶(PharmaBlock,目錄號PBLJ2743:0.200g,0.821mmol)、4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(Aldrich,目錄號663348:153μL,0.904mmol)、碳酸鈉(0.174g,1.64mmol)及[1,1'-雙(二-環己基膦基)二茂鐵]二氯鈀(II)(Aldrich,目錄號701998:6.2mg,0.0082mmol)於第三丁醇(5.91mL)及水(6mL)中之混合物脫氣且密封。在110℃下將其攪拌2h。將反應混合物冷卻,然後用乙酸乙酯(3×20mL)萃取。用鹽水洗滌合併之有機層,經MgSO4乾燥,過濾並在減壓下濃縮。粗殘餘物不經進一步純化即直接用於下一步驟中。C10H8ClN2(M+H)+之LC-MS計算值:m/z=191.0;實驗值191.0。
步驟3:8-氯-1,7-萘啶-3-甲醛
此化合物係使用與針對實例12、步驟4所述類似之程序、用8-氯-3-乙烯基-1,7-萘啶替代N-[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]-4-乙烯基-1,7-萘啶-8-胺來製備。粗化合物不經進一步純化即直接用於下一步驟中。C9H6ClN2O(M+H)+之LC-MS計算值:m/z=193.0;實驗值192.9。
步驟4:2-{[(8-氯-1,7-萘啶-3-基)甲基]胺基}乙醇
在室溫下,將8-氯-1,7-萘啶-3-甲醛(0.160g,0.831mmol)及乙醇胺(Aldrich,目錄號398136:251μL,4.15mmol)於二氯甲烷(6mL)及
N,N-二異丙基乙胺(868μL,4.98mmol)中之混合物攪拌1h。小心地逐份添加三乙氧基硼氫化鈉(0.528g,2.49mmol)。在室溫下將反應物攪拌2h。然後向混合物中小心地添加四氫硼酸鈉(157mg,4.15mmol)及甲醇(1mL),且在氮下將反應混合物攪拌過夜。用飽和碳酸氫鈉水溶液驟冷反應物。然後用氯仿/異丙醇之3:1混合物萃取混合物。用鹽水洗滌合併之有機層,經硫酸鈉乾燥,然後在真空中濃縮。藉由管柱層析(0→50%甲醇/DCM)純化粗殘餘物且獲得灰白色固體。C11H13CIN3O(M+H)+之LC-MS計算值:m/z=238.1;實驗值238.1。
步驟5:2-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈
向小瓶中添加2-胺基-6-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)苯甲腈(0.0106g,0.0421mmol)、2-{[(8-氯-1,7-萘啶-3-基)甲基]胺基}乙醇(10.00mg,0.04207mmol)、碳酸銫(0.0274g,0.0841mmol)、1,4-二噁烷(1mL)、(9,9-二甲基-9H-呫噸-4,5-二基)雙(二苯基膦)(Aldrich,目錄號526460:4.9mg,0.0084mmol)及叁(二亞苄基丙酮)二鈀(0)(Aldrich,目錄號328774:4.4mg,0.0042mmol)。向混合物通氮氣20s,然後將小瓶密封且在攪拌的同時加熱至110℃並保持2h。將混合物冷卻至室溫,用甲醇稀釋,且藉由製備型HPLC(pH=2,水+TFA)純化,以提供呈TFA鹽形式之化合物。C26H24N5O3(M+H)+之LC-MS計算值:m/z=454.2;實驗值454.2。
實例17
2-{[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-3-基)甲基]胺基}乙醇
向小瓶中添加3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯胺(實例12、步驟1:0.0102g,0.0421mmol)、2-{[(8-氯-1,7-萘啶-3-基)甲基]胺基}乙醇(實例16、步驟4:10.00mg,0.04207mmol)、碳酸銫(0.0274g,0.0841mmol)、1,4-二噁烷(1.00mL)、(9,9-二甲基-9H-呫噸-4,5-二基)雙(二
苯基膦)(Aldrich,目錄號526460:4.9mg,0.0084mmol)及叁(二亞苄基丙酮)二鈀(0)(Aldrich,目錄號328774:4.4mg,0.0042mmol)。向混合物通氮氣20s且將小瓶密封且在攪拌的同時加熱至110℃並保持2h。冷卻反應物,用甲醇稀釋,然後藉由製備型HPLC(pH=2,水+TFA)純化,以提供呈TFA鹽形式之化合物。C26H27N4O3(M+H)+之LC-MS計算值:m/z=443.2;實驗值443.2。
實例18
2-[({8-[(3-環己-1-烯-1-基-2-甲基苯基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
步驟1:2-[({8-[(3-溴-2-甲基苯基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
向微波瓶中添加3-溴-2-甲基苯胺(Aldrich,目錄號530018:29.5μL,0.240mmol)、2-{[(8-氯-1,7-萘啶-3-基)甲基]胺基}乙醇(實例16、步驟4:57.00mg,0.2398mmol)、第三丁醇(1.1mL)及二噁烷中之4.0M氯化氫(59.0μL,0.236mmol)。在微波中將反應物照射至100℃並保持1h。冷卻至室溫後,在真空中濃縮混合物,且藉由管柱層析(0→50%甲醇/DCM)純化期望化合物。C18H20BrN4O(M+H)+之LC-MS計算值:m/z=387.1;實驗值387.1。
步驟2:2-[({8-[(3-環己-1-烯-1-基2-甲基苯基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇
將2-[({8-[(3-溴-2-甲基苯基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇(0.0150g,0.0387mmol)、2-環己-1-烯-1-基-4,4,5,5-四甲基-1,3,2-二氧硼戊環(Aldrich,目錄號650277:0.0242g,0.116mmol)、碳酸鈉(0.00821g,0.0775mmol)及[1,1'-雙(二-環己基膦基)二茂鐵]二氯鈀(II)(Aldrich,目錄號 701998:0.29mg,0.00039mmol)於第三丁醇(0.279mL)及水(0.3mL)中之混合物脫氣且密封。在90℃下將混合物攪拌2h。冷卻反應物,用甲醇稀釋,然後藉由製備型HPLC(pH=10,水+NH4OH)純化。C24H29N4O(M+H)+之LC-MS計算值:m/z=389.2;實驗值389.3。
實例19
3-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]聯苯-2-甲腈
步驟1:3-胺基聯苯-2-甲腈
此化合物係使用與針對實例16、步驟1所述類似之程序、用苯基硼酸(Aldrich,目錄號P20009)替代2,3-二氫-1,4-苯并二氧雜環己烯-6-基硼酸來製備。使用管柱層析(0→50% EtOAc/己烷)純化粗化合物。C13H11N2(M+H)+之LC-MS計算值:m/z=195.1;實驗值195.2。
步驟2:3-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]聯苯-2-甲腈
此化合物係使用與針對實例16、步驟5所述類似之程序、用3-胺基聯苯-2-甲腈替代2-胺基-6-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)苯甲腈來製備。使用製備型HPLC(pH=2,水+TFA)純化反應混合物,以提供呈TFA鹽形式之化合物。C24H22N5O(M+H)+之LC-MS計算值:m/z=396.2;實驗值396.3。
實例20
2-環己-1-烯-1-基-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈
步驟1:2-胺基-6-環己-1-烯-1-基苯甲腈
此化合物係使用與針對實例16、步驟1所述類似之程序、用2-環己-1-烯-1-基-4,4,5,5-四甲基-1,3,2-二氧硼戊環(Aldrich,目錄號650277)替代2,3-二氫-1,4-苯并二氧雜環己烯-6-基硼酸來製備。使用管柱層析(0→50% EtOAc/己烷)純化粗化合物。C13H15N2(M+H)+之LC-MS計算值:m/z=199.1;實驗值199.1。
步驟2:2-環己-1-烯-1-基6-[(3-{[(2-羥基乙基)胺基]甲.基}-1,7-萘啶-8-基)胺基]苯甲腈
此化合物係使用與針對實例16、步驟5所述類似之程序、用2-胺基-6-環己-1-烯-1-基苯甲腈替代2-胺基-6-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)苯甲腈來製備。使用製備型HPLC(pH=2,水+TFA)純化反應混合物,以提供呈TFA鹽形式之化合物。C24H26N5O(M+H)+之LC-MS計算值:m/z=400.2;實驗值400.3。
實例21
2-環己基-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈
步驟1:2-胺基-6-環己基苯甲腈
在氫氣氛圍下在室溫下,將2-胺基-6-環己-1-烯-1-基苯甲腈(實例20、步驟1:100mg,0.5mmol)及碳載10%鈀(53mg,0.050mmol)於甲醇(5mL)中之混合物攪拌1.5h。經由矽藻土過濾反應混合物且在真空中濃縮濾液。期望化合物不經進一步純化即直接用於下一步驟中。C13H17N2(M+H)+之LC-MS計算值:m/z=201.1;實驗值201.2。
步驟2:2-環己基-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈
此化合物係使用與針對實例16、步驟5所述類似之程序、用2-胺基-6-環己基苯甲腈替代2-胺基-6-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)苯甲腈來製備。使用製備型HPLC(pH=2,水+TFA)純化反應混合物,以提供呈TFA鹽形式之化合物。C24H28N5O(M+H)+之LC-MS計算值:m/z=402.2;實驗值402.3。
實例A. PD-1/PD-L1同質時間解析螢光(HTRF)結合分析
在標準黑色384孔聚苯乙烯板中以20μL之最終體積來實施該等分析。首先將抑制劑連續稀釋於DMSO中,且然後添加至板孔中,隨後添加其他反應組分。分析中DMSO之最終濃度為1%。在25℃下在含有0.05% Tween-20及0.1% BSA之PBS緩衝液(pH 7.4)中實施分析。在C末端帶有His標籤之重組人類PD-L1蛋白(19-238)購自AcroBiosystems(PD1-H5229)。在C末端帶有Fc標籤之重組人類PD-1蛋白(25-167)亦購自AcroBiosystems(PD1-H5257)。將PD-L1及PD-1蛋白稀釋於分析緩衝液中且將10μL添加至板孔中。將板離心且將蛋白質與抑制劑一起預培育40分鐘。培育後添加10μL HTRF檢測緩衝液,其補充有特異性針對Fc之經銪穴狀化合物標記之抗人類IgG(PerkinElmer-AD0212)及結合至SureLight®-別藻藍蛋白(APC,PerkinElmer-AD0059H)之抗His抗體。離心後,在25℃下將板培育60min.,然後在PHERAstar FS板讀數器(665nm/620nm比率)上讀數。分析中之最終濃度為3nM PD1、10nM PD-L1、1nM銪抗人類IgG及20nM抗His-別藻藍蛋白。藉由使用GraphPad Prism 5.0軟件擬合控制活性%與抑制劑濃度對數之關係曲線來實施IC50測定。
使用實例A中所述之PD-1/PD-L1同質時間解析螢光(HTRF)結合分析對實例性化合物獲得之資料提供於表1中。
除本文所述者外,熟習此項技術者根據前述描述將明瞭本發明之多種修改。此類修改亦意欲屬於隨附申請專利範圍之範疇。本申請案中所引用之每一參考文獻(包括但不限於所有專利、專利申請案及公開案)皆以全文引用方式併入本文中。
Claims (45)
- 一種式(I)化合物或其醫藥學上可接受之鹽或立體異構物,
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R2為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5至14員雜芳基、4至10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5至14員雜芳基)-C1-4烷基-、(4至10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R2之該C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5至14員雜芳基、4至10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5至14員雜芳基)-C1-4烷基-及(4至10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R3為鹵基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵烷基、C1-6鹵烷氧基、C6-10芳基、C3-10環烷基、5至14員雜芳基、4至10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5至14員雜芳基)-C1-4烷基-、(4至10員雜環烷基)-C1-4烷基-、CN、NO2、ORa、SRa、NHORa、C(O)Ra、C(O)NRaRa、C(O)ORa、OC(O)Ra、OC(O)NRaRa、NHRa、NRaRa、NRaC(O)Ra、NRaC(O)ORa、NRaC(O)NRaRa、C(=NRa)Ra、C(=NRa)NRaRa、NRaC(=NRa)NRaRa、NRaS(O)Ra、NRaS(O)2Ra、NRaS(O)2NRaRa、S(O)Ra、S(O)NRaRa、S(O)2Ra及S(O)2NRaRa,其中R3之該C1-6烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-10環烷基、5至14員雜芳基、4至10員雜環烷基、C6-10芳基-C1-4烷基-、C3-10環烷基-C1-4烷基-、(5至14員雜芳基)-C1-4烷基-及(4至10員雜環烷基)-C1-4烷基-各自視情況經1個、2個、3個或4個Rb取代基取代。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R1、R3、R4及R5各自獨立地選自H、CN、C1-6烷基及鹵基。
- 如請求項7之化合物或其醫藥學上可接受之鹽或立體異構物,其中R1、R2、R4及R5各自獨立地選自H、CN、C1-6烷基及鹵基。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R2為-CH2-Rb。
- 如請求項10之化合物或其醫藥學上可接受之鹽或立體異構物,其中Rb為-NRcRc。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R3為-CH2-Rb。
- 如請求項12之化合物或其醫藥學上可接受之鹽或立體異構物,其中Rb為-NRcRc。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R2為2-羥基乙基胺基甲基、2-羧基哌啶-1-基甲基、(S)-2-羧基哌啶-1-基甲基、(R)-2-羧基哌啶-1-基甲基或(3-氰基苄基)氧基。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其中R3為2-羥基乙基胺基甲基、2-羧基哌啶-1-基甲基、(S)-2-羧基哌啶-1-基甲基、(R)-2-羧基哌啶-1-基甲基或(3-氰基苄基)氧基。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其係:2-[({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇;1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸;1-({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-基}甲基)哌啶-2-甲酸;2-[({8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-4-基}甲基)胺基]乙醇;或其醫藥學上可接受之鹽。
- 如請求項1之化合物或其醫藥學上可接受之鹽或立體異構物,其係:2-[({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇; 2-[({4-甲氧基-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)胺基]乙醇;1-({4-氯-8-[(2-甲基聯苯-3-基)胺基]-1,7-萘啶-3-基}甲基)哌啶-2-甲酸;2-{[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]胺基}乙醇;1-[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-4-基)甲基]哌啶-2-甲酸;2-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-6-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]苯甲腈;2-{[(8-{[3-(2,3-二氫-1,4-苯并二氧雜環己烯-6-基)-2-甲基苯基]胺基}-1,7-萘啶-3-基)甲基]胺基}乙醇;及3-[(3-{[(2-羥基乙基)胺基]甲基}-1,7-萘啶-8-基)胺基]聯苯-2-甲腈;或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至18中任一項之化合物或其醫藥學上可接受之鹽或立體異構物,及醫藥學上可接受之載劑或賦形劑。
- 一種如請求項1至18中任一項之化合物或其醫藥學上可接受之鹽或立體異構物之用途,其係用於製備用於體外抑制PD-1/PD-L1相互作用之藥劑。
- 一種如請求項1至18中任一項之化合物或其醫藥學上可接受之鹽或立體異構物或如請求項19之醫藥組合物之用途,其係用於製備用於治療與PD-1/PD-L1相互作用相關之疾病或病症之藥劑。
- 如請求項21之用途,其中該疾病或病症為癌症。
- 如請求項21之用途,其中該疾病或病症為病毒感染。
- 如請求項22之用途,其中該癌症係選自實體腫瘤、皮膚癌、鱗狀細胞癌、腎癌、黑色素瘤、肝癌、及肺癌。
- 如請求項22之用途,其中該癌症係選自骨癌、胰臟癌、皮膚癌、頭頸癌、子宮癌、卵巢癌、直腸癌、肛區癌、胃癌、睪丸癌、輸卵管癌、子宮內膜癌、子宮頸癌、陰道癌、陰戶癌、食道癌、小腸癌、內分泌系統癌、尿道癌、陰莖癌、兒童實體腫瘤、膀胱癌、、腎盂癌、中樞神經系統(CNS)贅瘤、脊軸腫瘤、腦幹膠質瘤、垂體腺瘤、表皮樣癌、鱗狀細 胞癌、腎癌(renal cancer)、透明細胞癌、前列腺癌、乳癌、結腸癌、肺癌、實體腫瘤、肝癌、神經膠質母細胞瘤、肉瘤、血液癌症、淋巴瘤、白血病及多發性骨髓瘤。
- 如請求項22之用途,其中該癌症為子宮內膜癌。
- 如請求項22之用途,其中該癌症係選自甲狀腺癌、副甲狀腺癌及腎上腺癌。
- 如請求項22之用途,其中該癌症係選自慢性白血病及急性白血病。
- 如請求項22之用途,其中該癌症係選自急性淋巴母細胞性白血病(ALL)、急性髓性白血病(AML)、慢性淋巴球性白血病(CLL)及慢性髓性白血病(CML)。
- 如請求項22之用途,其中該癌症係選自非霍奇金氏淋巴瘤、霍奇金氏淋巴瘤、淋巴球性淋巴瘤、原發性中樞神經系統(CNS)淋巴瘤、T細胞淋巴瘤、外膜細胞淋巴瘤、復發性濾泡性淋巴瘤及瀰漫性大B細胞淋巴瘤(DLBCL)。
- 如請求項30之用途,其中該非霍奇金氏淋巴瘤係復發性非霍奇金氏淋巴瘤(NHL)或難治性非霍奇金氏淋巴瘤(NHL)。
- 如請求項22之用途,其中該癌症係激素難治性前列腺腺癌。
- 如請求項22之用途,其中該癌症係選自皮膚黑色素瘤、轉移性惡性黑色素瘤、皮膚惡性黑色素瘤及眼內惡性黑色素瘤。
- 如請求項22之用途,其中該癌症係選自軟組織肉瘤及卡波西氏肉瘤(Kaposi's sarcoma)。
- 如請求項22之用途,其中該癌症為表現PD-L1之轉移性癌症。
- 如請求項22之用途,其中該癌症為肺癌。
- 如請求項36之用途,其中該肺癌為非小細胞肺癌(NSCLC)。
- 如請求項22之用途,其中該癌症為肝癌。
- 如請求項22之用途,其中該癌症為黑色素瘤。
- 如請求項22之用途,其中該癌症為膀胱癌。
- 如請求項22之用途,其中該癌症為尿道癌。
- 如請求項22之用途,其中該癌症為腎癌(renal cancer)。
- 如請求項42之用途,其中該腎癌為透明細胞癌。
- 一種如請求項1至18中任一項之化合物或其醫藥學上可接受之鹽或立體異構物或如請求項19之醫藥組合物之用途,其係用於製備用於增強、刺激、調節及/或增加患者之免疫反應之藥劑。
- 一種如請求項1至18中任一項之化合物或其醫藥學上可接受之鹽或立體異構物或如請求項19之醫藥組合物之用途,其係用於製備用於抑制患者中癌症細胞之生長、增殖或轉移之藥劑。
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- 2016-12-21 SG SG11201805300QA patent/SG11201805300QA/en unknown
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WO2015034820A1 (en) * | 2013-09-04 | 2015-03-12 | Bristol-Myers Squibb Company | Compounds useful as immunomodulators |
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