CN108473499B - 新颖的吡唑并嘧啶衍生物 - Google Patents
新颖的吡唑并嘧啶衍生物 Download PDFInfo
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- CN108473499B CN108473499B CN201680078063.6A CN201680078063A CN108473499B CN 108473499 B CN108473499 B CN 108473499B CN 201680078063 A CN201680078063 A CN 201680078063A CN 108473499 B CN108473499 B CN 108473499B
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- chloro
- pyrazolo
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- stirred
- acid
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- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical class C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 title abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 17
- 102000057613 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Human genes 0.000 claims abstract description 10
- 108700026676 Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Proteins 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 128
- 239000000203 mixture Substances 0.000 claims description 85
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- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- ZMPUACZRXUZAJD-QMMMGPOBSA-N 1-[2-chloro-7-[(1S)-1-methoxyethyl]pyrazolo[1,5-a]pyrimidin-6-yl]-3-[2-(trifluoromethyl)pyridin-4-yl]urea Chemical compound ClC1=NN2C(N=CC(=C2[C@H](C)OC)NC(=O)NC2=CC(=NC=C2)C(F)(F)F)=C1 ZMPUACZRXUZAJD-QMMMGPOBSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- TWJGQZBSEMDPQP-UHFFFAOYSA-N 2-chloro-n-[4-[5-(3,4-dichlorophenyl)-3-(2-methoxyethoxy)-1,2,4-triazol-1-yl]phenyl]acetamide Chemical compound C=1C=C(NC(=O)CCl)C=CC=1N1N=C(OCCOC)N=C1C1=CC=C(Cl)C(Cl)=C1 TWJGQZBSEMDPQP-UHFFFAOYSA-N 0.000 claims 1
- 229940122339 MALT1 inhibitor Drugs 0.000 claims 1
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 56
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
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Abstract
本发明描述了新的吡唑并嘧啶衍生物,其一般与MALT1蛋白水解和/或自身蛋白水解活性相互作用,尤其是其可抑制所述活性。本发明还描述了所述新的吡唑并嘧啶衍生物的合成,其作为药剂的应用,尤其是通过与MALT1蛋白水解和/或自身蛋白水解活性相互作用。
Description
本发明描述新的吡唑并嘧啶衍生物,其一般与MALT1蛋白水解和/或自身蛋白水解活性相互作用,尤其是其能抑制所述活性。本发明还描述所述新的吡唑并嘧啶衍生物的合成,它们作为药剂的应用,尤其是通过与MALT1蛋白水解和/或自身蛋白水解活性相互作用。
发明领域
技术背景
许多出版物中描述了MALT1(黏膜相关性淋巴样组织淋巴瘤易位蛋白1)在影响免疫应答中的基本作用。例如Rudi Beyaert等(WO 2009/065897)描述某些化合物作为MALT1蛋白水解和/或自身蛋白水解活性的抑制剂。
在BCL10和MALT1缺陷小鼠中的研究似乎表明了它们在从抗原受体至转录因子NFkB的信号转导级联放大中的基本作用。而且,导致BCL10和MALT1过度表达的染色体易位、或产生组成型活性融合蛋白API2-MALT1似乎造成NFkB的不受控且不依赖于刺激的活化。已经通过临床前淋巴瘤模型中的活性描述了MALT1蛋白水解活性的抑制剂(Vincendeau等,Int.J.Hematol.Oncol.2013,2,409)。此外,某些出版物似乎表明了MALT1的重要作用及其在由先天细胞受体(如Dectin受体)所触发的信号转导级联放大中和在由多种细胞类型的G-蛋白偶联受体所触发的信号转导级联放大中的蛋白水解功能。
因此,似乎需要发现并开发潜在的包含有价值的药理学性质的MALT1抑制剂。
附图简要描述
图1显示实施例1的DSC和TGA
图2显示实施例2的DSC和TGA
图3显示实施例3的DSC和TGA
图4显示实施例4的TGA
图5显示实施例5的DSC
发明概述
发明详述
在实施方式1中,本发明提供式(I)化合物或其药学上可接受的盐,其中,
R1是氟、氯、甲基或氰基;
R2和R3各自独立选自任选被C1-C6烷氧基取代的C1-C6烷氧基;任选被卤素或C1-C6烷氧基取代的C1-C6烷基;任选被C1-C6烷基取代的氨基;苯二甲酰亚氨基;或任选被包含氮或氧杂原子的5元或6元杂环取代的羟基,其中所述环任选被C1-C3烷基羰基取代;
或R2和R3与其连接的碳原子一起形成3-5元碳环或包含1个选自N和O的杂原子的杂环;
R4是氢;任选被C1-C6烷氧基取代的C1-C6烷基;
X1是N、N-O或CR6;
X2是N或CR7;
R5是氯、氰基、或任选被卤素和/或羟基取代的C1-C6烷基;
R6是氢、氧代、甲氧基、1,2,3-***-2-基、或在氮原子处被R9和R10取代的氨基羰基;
R7是氢、任选被卤素和/或羟基取代的C1-C6烷基、或N,N-二甲基氨基羰基;
R8是氢、任选被甲氧基或氨基取代的C1-C6烷氧基;
R9和10各自独立选自氢;C1-C6烷基,其任选被如下基团取代:C1-C6烷氧基、N-单-C1-C6烷基氨基、或N,N-二-C1-C6烷基氨基;或
R9和10与其连接的氮原子一起形成5-7元杂环,其具有一个、两个或三个选自氧、氮和硫的环杂原子,该环任选被C1-C6烷基、羟基或氧代取代;
前提是X1和X2必须不同时为N,或当X2为N时X1必须不是N-O。
实施方式2涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2是任选被C1-C6烷氧基取代的C1-C6烷基;
R3是任选被C1-C6烷氧基取代的C1-C6烷氧基;
R4是氢;
X1是N;
X2是CR7;
R5是氯、氰基、二氟甲基、三氟甲基;
R7是氢;且
R8是氢。
实施方式3涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2是任选被C1-C6烷氧基取代的C1-C6烷基;
R3是任选被C1-C6烷氧基取代的C1-C6烷氧基;
R4是氢;
X1是CR6;
X2是N;
R5是氯、氰基、二氟甲基、三氟甲基;
R6是氢、氧代、甲氧基、1,2,3-***-2-基、N-甲基氨基羰基、N,N-二甲基氨基羰基、吡咯烷-1-基羰基,且
R8是氢。
实施方式4涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是甲基、氟或氯;
R2是C1-C6烷基;
R3是C1-C6烷氧基;
R4是氢;
X1是CR6;
X2是N;
R5是氯、氰基、二氟甲基、三氟甲基;
R6是氢、甲氧基、1,2,3-***-2-基、N-甲基氨基羰基、N,N-二甲基氨基羰基、吡咯烷-1-基羰基,且
R8是氢。
实施方式5涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是甲基、氟或氯;
R2是C1-C6烷基;
R3是C1-C6烷氧基;
R4是氢;
X1是N;
X2是CR7;
R5是氯、氰基、二氟甲基、三氟甲基;
R7是氢;且
R8是氢。
实施方式6涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2是C1-C6烷氧基;
R3是C1-C6烷基;
R4是氢;
X1是CR6;
X2是N;
R5是氯、氰基、二氟甲基、三氟甲基;
R6是氢、甲氧基、1,2,3-***-2-基、N-甲基氨基羰基、N,N-二甲基氨基羰基、吡咯烷-1-基羰基,且
R8是氢。
实施方式7涉及实施方式1的化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2是C1-C6烷氧基;
R3是C1-C6烷基;
R4是氢;
X1是N;
X2是CR7;
R5是氯、氰基、二氟甲基、三氟甲基;
R7是氢;且
R8是氢。
实施方式8涉及化合物,尤其是实施方式1的化合物或其药学上可接受的盐,其中该化合物选自,
(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(三氟甲基)吡啶-4-基)脲;
1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氰基-6-甲氧基吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-基)-3-(2-氯-7-(1-(2-甲氧基乙氧基)乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-基)-3-(2-氯-7-(1-甲氧基-2-甲基-丙基)吡唑并[1,5-a]嘧啶-6-基)脲;
1-(2-氯-7-(1-(甲氧基甲基)环丙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基吡啶-3-基)脲;
1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-((1R,2S)-1,2-二甲氧基丙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲;
(S)-1-(5-氰基吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
1-(7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-
基)-3-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲;
(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氟-7-(1-甲氧基-2-甲基丙基)-吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(7-(1-甲氧基-2-甲基丙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-甲氧基吡啶-3-基)脲;
1-(2-氟-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(1-羟乙基)-6-(三氟甲基)吡啶-4-基)脲;
(S)-1-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
1-(2-氯-7-(1,2-二甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲;
1-(2-氯-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(2,2,2-三氟-1-羟基-乙基)吡啶-4-基)脲;
(S)-1-(5-氯-2-(2-甲氧基乙氧基)吡啶-3-基)-3-(2-氯-7-(1-甲氧基乙基)-吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氰基-6-甲氧基吡啶-3-基)-3-(7-(1-甲氧基-2-甲基丙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-氰基吡啶-4-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氰基-6-甲氧基吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
1-(2-氯-7-((1R,2S)-1,2-二甲氧基丙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲;
1-(7-((S)-1-(((S)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-甲氧基吡啶-3-基)脲;
(S)-1-(5-氰基-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-6-氯-4-(3-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)-N,N-二甲基吡啶酰胺;
(S)-1-(5-二氟-甲基)吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)-吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-(三氟甲基)吡啶-3-基)脲;
(S)-3-氯-5-(3-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)-N,N-二甲基吡啶酰胺;
(S)-1-(5-氯-吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(5-氯-6-(吡咯烷-1-羰基)吡啶-3-基)-3-(2-氯-7-(1-甲氧基乙基)吡唑并-[1,5-a]嘧啶-6-基)脲;
(S)-3-氯-5-(3-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)-N-甲基吡啶酰胺;
(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氯吡啶-3-基)脲;
(S)-1-(7-(1-氨基乙基)-2-氯吡唑并[1,5-a]嘧啶-6-基)-3-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲;
(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-羟基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-羟基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
1-(2-((S)-2-氨基丙氧基)-5-氯吡啶-3-基)-3-(2-氯-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲;
(S)-2-(二氟甲基)-4-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡啶1-氧化物;
1-(2-氯-7-((1R,2S)-1,2-二甲氧基丙基)吡唑并[1,5-a]嘧啶-6-基)-3-(5-氰基-6-甲氧基吡啶-3-基)脲;
1-(2-氯-7-(1-(甲氧基甲基)环丙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-氰基吡啶-4-基)脲;和
(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡啶酰胺。
实施方式9涉及一种药物组合物,其包含治疗有效量的根据实施方式1-8中任一项的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载剂。
实施方式10涉及一种组合,其包含治疗有效量的根据实施方式1-8中任一项的化合物或其药学上可接受的盐以及一种或多种治疗活性助剂。
实施方式11涉及调控对象中的MALT1活性的方法,其中该方法包括向该对象给予治疗有效量的根据实施方式1-8中任一项的化合物或其药学上可接受的盐。
实施方式12涉及根据实施方式1-8中任一项的化合物或其药学上可接受的盐,用作药剂、尤其是用作起到MALT1抑制剂作用的药剂。
实施方式13涉及式(II)化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2和R3各自独立选自C1-C6烷基或C1-C6烷氧基;
R4是氢;
R5和R7各自独立选自氢、氰基、卤素或任选被氟和/或羟基取代的C1-C6烷基。
实施方式14涉及式(III)化合物或其药学上可接受的盐,其中,
R1是氟或氯;
R2和R3各自独立选自C1-C6烷基或C1-C6烷氧基;
R4是氢;
R5是氢、氰基、卤素或任选被氟和/或羟基取代的C1-C6烷基;且
R6是氢、1,2,3-***-2-基、N,N-二甲基氨基羰基、N-单甲基氨基羰基、或吡咯烷-1-基羰基。
实施方式15涉及实施方式1的化合物或其药学上可接受的盐,其中X1是N且X2不是N,或X1不是N且X2是N。
定义
如本文所用,DSC代表差示扫描量热法,TGA代表热重分析。
如本文所用,术语“C1-C6烷基”是指具有最多6个碳原子的完全饱和的分支或不分支的烃部分。除非提供另外的说明,其是指具有1-6个碳原子、1-4个碳原子或1-2个碳原子的烃部分。烷基的代表性例子包括但并不限于:甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等。
如本文所用,术语“C1-C6烷氧基”是指烷基-O-,其中烷基是本文上述定义的。烷氧基的代表性例子包括但并不限于:甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基、环丙氧基、环己氧基等。通常,烷氧基基团具有约1-6个碳原子、1-4个碳原子或1-2个碳原子。
如本文所用,术语“任选被卤素取代的C1-C6烷基”是指可被一个或多个卤素取代的如以上定义的C1-C6烷基。例子包括但并不限于:三氟甲基、二氟甲基、氟甲基、三氯甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基、3-溴-2-氟丙基和1-溴甲基-2-溴乙基。
如本文所用,术语“任选被羟基取代的C1-C6烷基”是指可被一个或多个羟基取代的如以上定义的C1-C6烷基。例子包括但并不限于:羟甲基、羟乙基、1,2-二羟乙基、2,3-二羟丙基等。
如本文所用,术语“二C1-6烷基氨基”是指式-N(Ra)-Ra部分,其中各Ra是如以上定义的C1-6烷基,其可相同或不同。与其类似的术语“单C1-6烷基氨基”是指式-N(H)-Ra部分,其中Ra是如以上定义的C1-6烷基,其可相同或不同。
如本文所用,术语“卤素”或“卤代”是指氟、氯、溴和碘;可特指氯;也可特指氟。
如本文所用,术语“杂环基”或“杂环”是指,除非另外指明,饱和和部分饱和的,且优选为单环或多环的环(在多环的情况中具体是二环、三环或螺环的环)的杂环基团;其具有3-24个、更优选4-16个、最优选5-10个、最优选5或6个环原子;其中一个或多个、优选一至四个、尤其一或两个环原子是杂原子(因此其余环原子是碳)。连接环(即,与该分子相连的环)优选具有4-12个、尤其5-7个环原子。该杂环基团可在杂原子或碳原子处附连。杂环基可包括稠合或桥接的环以及螺环。杂环的例子包括:四氢呋喃(THF)、二氢呋喃、1,4-二氧杂环乙烷、吗啉、1,4-二噻烷、哌嗪、哌啶、1,3-二氧戊烷、四氢咪唑、咪唑啉、吡咯啉、吡咯烷、四氢吡喃、二氢吡喃、噁噻戊烷(oxathiolane)、二硫杂环戊环、1,3-二氧杂环己烷、1,3-二噻烷、氧硫杂环己烷、硫代吗啉等。取代的杂环基是被1-4个(例如一个、或两个、或三个、或四个)取代基独立取代的杂环基基团。
如本文所用,术语“芳基”是指在环部分中具有6-20个碳原子的芳香烃基团。通常,芳基是具有6-20个碳原子的单环、二环或三环芳基。而且,如本文所用的术语“芳基”是指可以是单芳香环、或稠合在一起的多芳香环的芳香取代基。非限制性例子包括:苯基、萘基或四氢萘基。
取代芳基是被1-5个(如一个、或两个、或三个)取代基取代的芳基基团,所述取代基独立选自:羟基、巯基、氰基、硝基、C1-C4烷基、C1-C4烯基、C1-C4炔基、C1-C4烷氧基、C1-C4硫烷基、C1-C4烯氧基、C1-C4炔氧基、卤素、C1-C4烷基羰基、羧基、C1-C4烷氧基羰基、氨基、C1-C4烷基氨基、二-C1-C4烷基氨基、C1-C4烷基氨基羰基、二-C1-C4烷基氨基羰基、C1-C4烷基羰基氨基、C1-C4烷基羰基(C1-C4烷基)氨基、磺酰基、氨磺酰基、烷基氨磺酰基、C1-C4烷基氨基磺酰基,上述各烃基团(例如烷基、烯基、炔基、烷氧基残基)可被一个或多个独立选自(每次出现时)卤素、羟基或C1-C4烷氧基基团的残基进一步取代。
如本文所用,术语“盐”是指本发明化合物的酸加成或碱加成盐。“盐”具体包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明化合物的生物有效性和性质的盐,且其通常在生物或其他方面符合需要。在许多情况中,本发明化合物可依靠氨基和/或羧基基团或类似基团的存在而形成酸式和/或碱式盐。
可用无机酸和有机酸形成药学上可接受的酸加成盐,例如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、氯茶碱盐(chlortheophyllonate)、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙磺酸盐、乳酸盐、乳糖醛酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可由其衍生得到盐的无机酸包括,例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可由其衍生得到盐的有机酸包括,例如乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
可用无机和有机碱形成药学上可接受的碱加成盐。
可由其衍生得到盐的无机碱包括,例如铵盐和来自周期表第I至XII族的金属。在一些实施方式中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌、和铜;特别合适的盐包括铵、钾、钠、钙和镁盐。
可由其衍生得到盐的有机碱包括,例如伯、仲、和叔胺,取代的胺包括天然产生的取代的胺,环胺,碱性离子交换树脂等。某些有机胺包括异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨基丁三醇。
本发明的药学上可接受的盐可通过常规化学方法从碱或酸部分合成。一般来说,这样的盐可通过使这些化合物的游离酸形式与化学计量量的合适碱(例如Na、Ca、Mg、或K的氢氧化物、碳酸盐、碳酸氢盐等)反应、或通过使这些化合物的游离碱形式与化学计量量的合适酸反应来制备。这样的反应通常在水中或在有机溶剂中、或在该两者的混合物中进行。一般来说,在可行情况下适宜使用非水性介质如醚、乙酸乙酯、乙醇、异丙醇、或乙腈。其他合适盐的列表可见于,例如,“雷明顿药物科学”,第20版,Mack出版公司,伊斯顿(Easton),Pa.(1985);和“药物盐手册:性质、选择、和应用”,Stahl和Wermuth(Wiley-VCH出版公司,韦恩(Weinheim,德国),2002)。
本文给出的任意化学式也意在代表该化合物的无标记形式和同位素标记形式。同位素标记化合物具有本文所给出化学式描绘的结构,但一个或多个原子被具有选择的原子质量或质量数的原子替换。可结合到本发明化合物中的同位素的例子包括:氢、碳、氮、氧、磷、氟、和氯的同位素,例如对应的2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本发明包括如本文定义的多种同位素标记化合物,例如其中存在放射性同位素例如3H和14C、或其中存在非放射性同位素例如2H和13C的那些化合物。这样的同位素标记化合物可用于代谢研究(用14C),反应动力学研究(用例如2H或3H),检测或成像技术,例如正电子发射断层成像术(PET)或单光子发射计算机断层成像术(SPECT),包括药物或基底组织分布化验,或在病人的放射性治疗中。具体来说,18F或标记的化合物可能特别适用于PET或SPECT研究。式(I)的同位素标记化合物可一般通过本领域技术人员已知的常规技术或通过与所附实施例和制备中所述那些类似的方法使用合适的同位素标记试剂代替之前所用的非标记试剂来制备。
此外,用更重的同位素、尤其是氘(即,2H或D)取代可提供因代谢稳定性更大而导致的某些治疗优势,例如增加体内半衰期或减小剂量要求或改善治疗指数。应理解,本上下文中的氘被认为是式(I)化合物的取代基。这样的更重同位素、尤其是氘的浓度,可通过同位素富集系数定义。本文所用术语“同位素富集系数”表示该同位素丰度与指定同位素天然丰度之间的比率。若本发明化合物中的取代基被指示为氘,此化合物对各指定氘原子的同位素丰度系数为至少3500(在各指定原子处纳入52.5%的氘),至少4000(纳入60%的氘),至少4500(纳入67.5%的氘),至少5000(纳入75%的氘),至少5500(纳入82.5%的氘),至少6000(纳入90%的氘),至少6333.3(纳入95%的氘),至少6466.7(纳入97%的氘),至少6600(纳入99%的氘),或至少6633.3(纳入99.5%的氘)。
根据本发明的药学上可接受的溶剂化物包括那些其中结晶溶剂可被同位素取代的那些,例如D2O、d6-丙酮、d6-DMSO。
包含能用作氢键的供体和/或受体的某些基团的本发明化合物即式(I)化合物可能能与合适的共晶形成剂形成共晶。这些共晶可通过已知的共晶形成过程从式(I)化合物制备。这些过程包括研磨、加热、共升华、共熔、或在溶液中使式(I)化合物在结晶条件下与共晶形成剂接触并分离由此形成的共晶。合适的共晶形成剂包括WO 2004/078163中所述的那些。因此本发明还提供包含式(I)化合物的共晶。
如本文所用,术语“药学上可接受的载剂”包括任意和全部溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等张剂、吸收延迟剂、盐、防腐剂、药物稳定剂、黏结剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染色剂等及其组合,如本领域技术人员已知的(参见例如“雷明顿药物科学”,第18版,Mack印刷公司,1990,1289-1329页)。除非任意常规载剂与活性成分不相容,已考虑其在治疗或药物组合物中的应用。
术语“治疗有效量”的本发明化合物是指将引起对象的生物或医学反应,例如减小或抑制酶或蛋白活性,或改善症状、减轻病症、减慢或延迟疾病进程、或预防疾病等的量的本发明化合物。在一种非限制性实施方式中,术语“治疗有效量”是指给予对象时有以下效果的本发明化合物的量:(1)至少部分减轻、抑制、预防和/或改善(i)由MALT1介导的病症、或失调或疾病、(ii)与MALT1活性相关的病症、或失调或疾病、或(iii)由MALT1活性(正常或不正常)表征的病症、或失调或疾病;或(2)减小或抑制MALT1活性;或(3)减小或抑制MALT1表达;或(4)改变MALT1蛋白水平。在另一种非限制性实施方式中,术语“治疗有效量”是指给予细胞、或组织、或非细胞生物材料、或介质时能有效地至少部分减小或抑制MALT1活性、或部分或完全地减小或抑制MALT1表达的本发明化合物量。
如本文所用,术语“对象”是指动物。通常,该动物是哺乳动物。对象还指例如灵长类(例如,人类,男性或女性)、牛、绵羊、山羊、马、狗、猫、兔、大鼠、小鼠、鱼、鸟等。在一些实施方式中,该对象是灵长类。在另一些实施方式中,该对象是人类。
如本文所用,术语“抑制”、“抑制作用”或“遏制”是指减小或遏制给定病症,症状,或失调,或疾病,或明显降低生物活性或过程的基线活性。
如本文所用,涉及任何疾病或病症的术语“治疗”、“处理”或“疗法”是指在一种实施方式中,改善疾病或病症(即,减慢或停止或减小该疾病或其至少一种临床症状的发展)。在另一种实施方式中,“治疗”、“处理”或“疗法”是指减轻或改善至少一种身体参数,包括该病人可能未描述的那些。在另一种实施方式中,“治疗”、“处理”或“疗法”是指在身体上(例如,稳定可辨别症状)、在生理上(例如,稳定身体参数)、或这两方面上调控疾病或病症。在另一种实施方式中,“治疗”、“处理”或“疗法”是指预防或延迟该疾病或病症的发作或发展或进程。
如本文所用,若对象将在生物学上、医学上、或生活质量上得益于某种治疗,则该对象是对该治疗“有需求的”对象。
如本文所用,术语“一个”、“一种”、“该”和类似术语用于本发明上下文(尤其是在权利要求的上下文中)时,应理解为涵盖单数和复数,除非本文另有指示或上下文中有清楚的相反指示。
本文所述的所有方法都可按任意合适顺序进行,除非本文另有指示或上下文中另有清楚的相反指示。本文提供的任意和全部实施例或示范性语言(例如,“例如”)的用途仅意在更好地说明本发明,而非对本发明范围作出不同于权利要求的限制。
本发明化合物的任意不对称原子(例如,碳等)可以外消旋或对映异构富集,例如(R)-、(S)-或(R,S)-构型存在。在一些实施方式中,各不对称原子具有至少50%对映异构过量,至少60%对映异构过量,至少70%对映异构过量,至少80%对映异构过量,至少90%对映异构过量,至少95%对映异构过量,或至少99%对映异构过量的(R)-或(S)-构型。在具有不饱和双键的原子处的取代基在可能情况下以顺-(Z)-或反-(E)-形式存在。
因此如本文所用,本发明化合物可以是一种可能的旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,或例如作为基本纯的几何(顺式或反式)异构体、非对映异构体、光学异构体(对映物)、外消旋物或其混合物。
所得异构体的任何混合物可按组成的物理化学差异分离成纯的或基本纯的几何或光学异构体、非对映异构体、外消旋物,例如通过色谱法和/或分级结晶。
所得最终产物或中间体的任何外消旋物可通过已知方法拆分成光学对映物,例如通过分离其非对映盐,获得光学活性的酸或碱,并释放该光学活性的酸性或碱性化合物。具体来说,由此可使用碱性部分将本发明化合物拆分成其光学对映物,例如通过对由光学活性酸形成的盐进行分级结晶,该光学活性酸是例如酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、二-O,O′-对-甲苯酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸。外消旋产物还可通过手性色谱法例如高压液相色谱(HPLC)使用手性固定相拆分。
此外,本发明化合物包括其盐还可以其水合物的形式获得,或包含其结晶所用的其他溶剂。本发明化合物可固有地或通过设计与药学上可接受的溶剂(包括水)形成溶剂化物;因此,预期本发明涵盖溶剂化和非溶剂化形式。术语“溶剂化物”是指本发明化合物(包括其药学上可接受的盐)与一种或多种溶剂分子的分子复合物。此类溶剂分子是常用于药物领域的已知其对接受者无害的那些,例如水、乙醇等。术语“水合物”是指其中的溶剂分子是水的复合物。
本发明化合物包括其盐、水合物和溶剂化物可固有地或通过设计形成多晶形物。
在另一个方面,本发明提供包含本发明化合物和药学上可接受载剂的药物组合物。该药物组合物可配制用于特定的给药途径,例如口服给药、肠胃外给药、和直肠给药等。另外,本发明的药物组合物可制成固体形式(包括但并不限于胶囊、片剂、丸剂、细粒、粉末或栓剂)、或液体形式(包括但并不限于溶液、悬浮液或乳剂)。可对药物组合物进行常规药学操作例如灭菌,和/或可包含常规惰性稀释剂、润滑剂、或缓冲剂、以及佐剂,例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
通常,药物组合物是片剂或明胶胶囊,其包含活性成分以及:
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁或钙盐和/或聚乙二醇;亦可用于片剂
c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄耆胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;需要时
d)崩解剂,例如淀粉、琼脂、藻酸或其钠盐,或泡腾混合物;和/或
e)吸收剂、着色剂、调味剂和甜味剂。
片剂可以根据本领域已知的方法经过薄膜包衣的或肠溶性包衣。
用于口服给药的合适组合物以片剂、锭剂、水性或油性悬浮液、分散性粉末或细粒、乳剂、硬质或软质胶囊、或糖浆剂或酏剂形式包含有效量的本发明化合物。意在口服应用的组合物根据药物组合物制造领域中已知的任意方法制备,这样的组合物可包含一种或多种选自甜味剂、调味剂、着色剂和防腐剂的物质以提供在制药上精致和适口的制剂。片剂可包含活性成分以及与之混合的适用于制造片剂的非毒性药学上可接受的赋形剂。这些赋形剂是,例如惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉、或藻酸;粘合剂,例如淀粉、明胶或***胶;和润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂未包衣,或通过已知技术包衣以延迟在胃肠道中的崩解和吸收并从而在更长时间段内提供持续作用。例如,可使用延时材料例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服应用的制剂可以是硬质明胶胶囊,其中的活性成分与惰性固体稀释剂混合,该稀释剂是例如碳酸钙、磷酸钙或高岭土,或者是软质明胶胶囊,其中的活性成分与水或油介质混合,该油介质是例如花生油、液体石蜡或橄榄油。
一些可注射组合物是水性等渗溶液或悬浮液,栓剂有利地由脂肪乳剂或悬浮液制备。所述组合物可以是灭菌的和/或包含佐剂,例如防腐剂、稳定剂、润湿剂或乳化剂、促溶剂、用于调节渗透压的盐和/或缓冲剂。另外,它们还可包含其他有治疗价值的物质。所述组合物按照相应的常规混合、造粒或包衣方法制备,包含约0.1-75%、或约1-50%的活性成分。
适用于透皮应用的组合物包含有效量的本发明化合物和合适的载剂。适合于透皮递送的载剂包括可吸收的药学上可接受的溶剂以帮助通过宿主皮肤。例如,透皮装置为绷带形式,其包含:背衬元件,包含该化合物和可选载剂的储库,可选的控速阻挡层从而在延长时间段中以受控和预定的速率向宿主皮肤递送该化合物,以及将该装置与皮肤固定的方式。
适用于局部(例如向皮肤和眼睛)应用的组合物包括水溶液、悬浮液、油膏剂、乳膏剂、凝胶剂或可喷制剂,例如用于通过气溶胶等递送。这样的局部递送***将特别适合皮肤应用,例如用于治疗皮肤癌,例如在防晒霜、洗剂、喷剂等中的预防性应用。因此它们特别适于在本领域中众所周知的局部(包括美容)制剂中使用。其可包含增溶剂、稳定剂、张力增强剂、缓冲剂和防腐剂。
如本文所用,局部应用还可包括吸入或鼻内应用。其可方便地以干粉形式(单独的、作为混合物例如与乳糖的干掺混物、或混合成分颗粒例如与磷脂的混合组分颗粒)从干粉吸入器递送、或经由加压容器、泵、喷射器、雾化器或喷雾器在使用或不使用合适推进剂的情况下以气溶胶喷雾递呈的方式递送。
本发明还提供包含本发明化合物作为活性成分的无水药物组合物和剂型,因为水可能促进某些化合物降解。
本发明的无水药物组合物和剂型可使用无水或包含低水分的成分在低水分或低湿度条件下制备。可制备并储存无水药物组合物从而保持其无水性质。因此,使用已知能防止暴露于水的材料包装无水组合物从而使它们被容纳在合适的规定试剂盒中。合适包装的例子包括但并不限于气密密封的箔、塑料、单位剂量容器(例如小瓶)、泡罩包装、和条带包装。
本发明还提供包含一种或多种能减小作为活性成分的本发明化合物的分解速率的物质的药物组合物和剂型。此类物质在本文中被称为“稳定剂”,包括但并不限于抗氧化剂,例如抗坏血酸、pH缓冲剂、或盐缓冲剂等。
本发明化合物的合成
本发明化合物的合成如方案1概述进行:
R10是C(R2R3R4)
R代表取代的吡啶基
(方案1)
用丙二酸单酯的二价阴离子处理活化的酸(例如作为离子型咪唑(imidazolid)活化),处理后提供β-酮酯2。用C1等价物(例如二甲基甲酰胺-二甲基乙缩醛或正甲酸三乙酯)缩合,然后与氨基吡唑在有机溶剂(如乙醇)中在升高温度下环化缩合提供取代的吡唑并嘧啶3。在步骤1中使用手性酸时,根据取代模式,可能在反应顺序过程中发生部分外消旋作用。在这种情况下,可通过手性色谱法将最终产物纯化至高对映体纯度。
酯脱保护提供酸4。酸4的Curtius重排提供中间体异氰酸酯,其通常与合适的氨基吡啶衍生物在“一锅式”反应中反应形成最终产物。
氨基吡唑(如3-氨基-5-氯吡唑)的合成可如下进行(方案2):
(方案2)
在Sandmeyer条件下处理氨基吡唑提供3-氯吡唑。硝化提供N-硝基吡唑,其加热后重排成所需的3-氯-5-硝基吡唑。用铁、锡或氯化锡还原硝基基团最终提供所需的3-氨基-5-氯吡唑10。
本发明中使用的氨基吡啶可用以下途径制备:
(方案3)
用亲核试剂在惰性溶剂(如DMF)中处理取代的对硝基氯吡啶给出取代产物12。这种情况中的亲核试剂可以是脱质子化的醇、胺、内酰胺或杂环,例如1,2,3-***的阴离子(R6取代基)。最终用锡或铁在酸性介质中还原硝基取代基提供所需的氨基吡啶衍生物13。
或者,氨基吡啶可经由合适芳基酸的Curtius重排制备(方案4):
(方案4)
用二苯基磷酰基叠氮化物和碱在叔丁醇中处理酸14提供叔丁氧基-羰基保护的氨基化合物15,其可在酸性条件下使用HCl或TFA脱保护以给出所需的苯胺/氨基吡啶16。
一些氨基吡啶和苯胺可按照方案5通过钯催化的芳基卤与硼酸偶联来制备:
(方案5)
本发明的烷氧基吡啶或吡啶酮一般经由羟基吡啶的烷基化制备(方案6):
(方案6)
用碱(如碳酸钾)和烷基卤化物处理羟基吡啶19导致形成吡啶酮20和烷氧基吡啶22。根据反应物的取代模式可实现选择性朝向一种或另一种反应产物。产物分离后,可使用标准铁或锡介导的还原方法来还原各化合物以提供氨基吡啶酮21以及氨基烷氧基吡啶23。
在方案3-6中,使3-硝基-吡啶衍生物反应以产出针对方案1中所示羧酸4的合适反应伙伴。与其类似,可以完全类似的方式获得相应的4-硝基-吡啶衍生物。
此外,可从取代的苯胺和氨基吡啶的溴类似物通过Pd催化的胺化反应使用保护形式的胺来源(如氨基甲酸叔丁酯)、然后通过脱保护来获得取代的苯胺和氨基吡啶。
(方案7)
实验部分
缩写
Ac2O 乙酸酐
AcOEt 乙酸乙酯
AcOH 乙酸
Boc2O 二碳酸二叔丁酯
bs 宽单峰
n-BuLi 正丁基锂
CaCl2 氯化钙
CCl4 四氯化碳
CDI 羰基二咪唑
CHCl3 氯仿
CH3CN 乙腈
CO2 二氧化碳
Cs2CO3 碳酸铯
d 双峰
DAST 二乙基氨基三氟化硫
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DEAD (E)-二乙基二氮烯-1,2-二羧酸酯
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
DPPA 二苯基磷酰基叠氮化物
EDC N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺
Et2O 二***
Et3N 三乙胺
EtOH 乙醇
h 小时
HCl 盐酸
hept. 七重峰
H2O 水
H2SO4 硫酸
HCHO 甲醛
HCOOH 甲酸
HNO3 硝酸
HOBt 羟基苯并***
HPLC 高效液相色谱
HV 高真空
iPrOH 异丙醇
IST International Sorbent Technology公司(供应商)
K2CO3 碳酸钾
KNO3 硝酸钾
KOH 氢氧化钾
1 升
LDA 二异丙基氨基锂
LiAlH4 氢化铝锂
LiCl 氯化锂
LiOH 氢氧化锂
mCPBA 间氯过苯甲酸
Mel 碘甲烷
MeOH 甲醇
MnO2 二氧化锰
m 多重峰
M 摩尔
min 分钟
ml 毫升
N 正常
NaBH4 硼氢化钠
NaBH(OAc)3 三乙酰氧基硼氢化钠
Na2CO3 碳酸钠
Na2SO4 硫酸钠
NaH 氢化钠
NaHCO3 碳酸氢钠
NaIO4 高碘酸钠
NaOH 氢氧化钠
NH4Cl 氯化铵
NMR 核磁共振
p 五重峰
Pd/C 炭负载钯
PdCl2(PPh3)2 二(三苯基膦)二氯化钯(II)
Pd2(dba)3 三(二亚苄基丙酮)合二钯(0)
Pd(PPh3)4 四(三苯基膦)合钯(0)
pTsOH 对甲苯磺酸
q 四重峰
RT 室温
Rt 保留时间
s 单峰
SFC 超临界流体色谱
t 三重峰
TBME 叔丁基甲基醚
tBuOH 叔丁醇
TBAF 叔丁基氟化铵
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
UPLC 超高效液相色谱
XantPhos 4,5-二(二苯基膦基)-9,9-二甲基氧杂蒽
分析方法
UPLC方法
方法B1:Waters UPLC;柱:Acquity HSS T3 1.8μm,2.1*50mm,60℃,洗脱剂A:H2O+0.05%HCOOH+3.75mM乙酸铵,B:CH3CN+0.04%HCOOH,梯度:10-95%B,1.5分钟内,流速:1ml/分钟。
方法B2:Waters UPLC;柱:Acquity HSS T3 1.8μm,2.1*50mm,60℃,洗脱剂A:H2O+0.05%HCOOH+3.75mM乙酸铵,B:CH3CN+0.04%HCOOH,梯度:5%-98%B,1.4分钟内,流速:1ml/分钟。
方法B3:Waters UPLC;柱:Ascentis Expresse C18 2.1*30mm,2.7μm,60℃,洗脱剂A:H2O+0.05%TFA,B:CH3CN+0.04%TFA,梯度:2%-98%B,1.4分钟内,流速:1ml/分钟。
方法B4:Waters UPLC;柱:Acquity UPLC BEH C18,2.1x50mm,1.7μm,35℃,洗脱剂A:H2O+0.1%TFA,B:CH3CN+0.1%TFA,梯度:5%-100%B,1.5分钟内,流速:0.6ml/分钟。
方法B5:Waters UPLC;柱:Acquity HSS T3 1.8μm,2.1*50mm,50℃,洗脱剂A:H2O+0.05%HCOOH+3.75mM乙酸铵,B:CH3CN+0.04%HCOOH,梯度:2%-98%B,1.4分钟内,流速:1.2ml/分钟。
方法B6:Waters UPLC;柱:Acquity HSS T3 1.8μm,2.1*50mm,50℃,洗脱剂A:H2O+0.05%HCOOH+3.75mM乙酸铵,B:CH3CN+0.04%HCOOH,梯度:5%-98%B,1.4分钟内,流速:1.2ml/分钟。
方法B7:Waters UPLC Acquity;柱:Acquity HSS T3 1.8μm,2.1*50mm,60℃,洗脱剂A:H2O+0.05%HCOOH+3.75mM乙酸铵,B:CH3CN+0.04%HCOOH,梯度:5%-98%B,9.4分钟内,流速:1ml/分钟。
HPLC方法
方法C1:Waters X-Bridge C18,2.5μm,3*50mm,40℃,洗脱剂A:H2O+0.1%TFA;B:CH3CN+0.1%TFA。梯度10-98%B,在8.6分钟内,保持1.4分钟,流速:1.4ml/分钟。
方法C2:Waters X-Bridge C18,2.5μm,3*30mm,40℃,洗脱剂A:水+0.1%TFA;B:CH3CN+0.1%TFA。梯度10-98%B,在3分钟内,保持0.5分钟,流速:1.4ml/分钟。
GC/MS方法
方法D1:气相色谱Finnigan Focus GC(Thermo Electron公司)单四极质量分析仪,EI,柱Zebron ZB-5ms,15mm,0.25mm内径,0.25μm膜厚度,5%聚亚芳基硅(polysilarylene),95%聚二甲基硅氧烷。
制备性方法
方法A1:HPLC,Waters Sunfire C18OBD,5μm,30*100mm,洗脱剂A:H2O+0.1%TFA,B:CH3CN+0.1%TFA。
方法A2:HPLC,Waters X-Bridge C18OBD,5μm,30*100mm,洗脱剂A:H2O+7.3mMNH4OH,B:CH3CN+7.3mM NH4OH。
方法A3:Macherey-Nagel Nucleosil 100-10C18,5μm,40*250mm,洗脱剂A:H2O+0.1%TFA,B:CH3CN+0.1%TFA。
方法A4:HPLC,Waters X-Bridge C18OBD,10μm,19*150mm,洗脱剂A:H2O,B:CH3CN。
方法A5:Thar SFC 200,用CO2/MeOH用以下柱之一洗脱:
Waters Atlantis Hilic Silica 250*30mm,5μm。
部分A:氨基吡唑的合成
A1:5-氯-1H-吡唑-3-胺
a)5-氯-1H-吡唑
在氮气氛下在0℃向1H-吡唑-5-胺(23.6g,284mmol)在CH3CN(1L)中的溶液加入HCl(140ml,1420mmol,32%)和氯化亚铜(I)(56.3g,568mmol)。在0℃加入亚硝酸异戊酯(80ml,568mmol)并将该混合物在0℃搅拌2天。加入亚硝酸异戊酯(20ml,0.5当量)并将该混合物在RT再搅拌5.5天。将该反应混合物缓慢倒入氢氧化铵(1l,25%)中并用AcOEt萃取。分离有机相并用AcOEt萃取水相。用盐水洗涤合并的有机层,在Na2SO4上干燥并浓缩。通过硅胶柱色谱(己烷/TBME由1:0至4:6)纯化粗产物以提供5-氯-1H-吡唑。M/z=103/105[M+H]+,Rt=0.48分钟(UPLC方法B2),1H NMR(600MHz,DMSO-d6):δppm:13.00(bs,1H),7.79(t,1H),6.29(t,1H),异戊醇:4.28(t,1H),3.41(q,2H),1.30(q,2H),0.85(d,6H)。
b)5-氯-1-硝基-1H-吡唑
在0℃向5-氯-1H-吡唑(3.88g,35.2mmol)在AcOH(5.10ml,89mmol)中的溶液逐滴加入90%HNO3水溶液(5.10ml,35.2mmol)并将该反应混合物在0℃搅拌2小时。然后逐滴加入Ac2O(12.92ml,137mmol)。将该混合物在RT搅拌4小时。将该混合物倒入冰水中并加入AcOEt和Na2CO3(33.6g,317mmol)。分离有机相并用AcOEt萃取水相。用饱和的NaHCO3水溶液和盐水洗涤合并的有机层,在Na2SO4上干燥并浓缩以提供5-氯-1-硝基-1H-吡唑。M/z=146/148[M-H]-,Rt=0.71分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6):δppm:8.91(d,1H),6.90(d,1H)。
c)5-氯-3-硝基-1H-吡唑
在高压釜中将5-氯-1-硝基-1H-吡唑(5.44g,35.0mmol)溶解在干苯甲醚(70ml)中并密封该反应器。将该混合物在140℃加热16小时。将该混合物冷却,过滤并将滤液蒸发至干。向残余物加入己烷,并将该悬浮液超声处理并研磨。过滤沉淀并用己烷冲洗以提供5-氯-3-硝基-1H-吡唑。M/z=146/148[M-H]-,Rt=0.60分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6):δppm:7.29(s,1H)。
d)5-氯-1H-吡唑-3-胺
在RT向5-氯-3-硝基-1H-吡唑(4.35g,29.2mmol)在MeOH(389ml)中的溶液小心加入32%的HCl水溶液(57.3ml,583mmol)。冷却至0℃后,分批加入SnCl2(27.6g,146mmol)并将该反应混合物在RT搅拌过夜。将溶剂蒸发至干,用乙酸乙酯稀释残余物并加入30%的NaOH水溶液直到pH变成碱性。冷却至0℃过夜后,使盐通过硅藻土垫过滤,并用AcOEt和水冲洗滤饼。分离有机相并用AcOEt萃取水相。用盐水洗涤合并的有机层,在Na2SO4上干燥,在真空下过滤并浓缩至干以提供5-氯-1H-吡唑-3-胺。M/z=118/120[M+H]+,Rt=0.36分钟(UPLC方法B2),1H NMR(600MHz,DMSO-d6):δppm:11.54(s,1H),5.25(s,2H),5.20(s,1H)。
部分B:羧酸化合物的合成
B1:(S)-2-甲氧基-3-甲基丁酸
a)(S)-2-羟基-3-甲基丁酸苄酯
向L-α-羟基异戊酸(4.95g,41.9mmol)在DMF(50ml)中的溶液加入苄基溴(5.95ml,50.3mmol)和DBU(6.32ml,41.9mmol)并将该反应混合物在RT搅拌14小时。蒸发溶剂,并将残余物提取在AcOEt/水中。有机相在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至9/1)纯化粗产物以提供(S)-2-羟基-3-甲基丁酸苄酯。M/z=209[M+H]+,Rt=0.98分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:7.46-7.29(m,5H),5.35(d,1H),5.14(d,2H),3.87(dd,1H),2.00-1.90(m,1H),0.88(d,3H),0.82(d,3H)。
b)(S)-2-甲氧基-3-甲基丁酸苄酯
在-20℃向(S)-2-羟基-3-甲基丁酸苄酯(8.55g,41.1mmol)在THF(150ml)中的溶液加入NaH(1.97g,49.3mmol,60%油分散体)并在30分钟内将该混合物温热至RT。冷却至0℃后,加入硫酸二甲酯(4.67ml,49.3mmol)并将该反应混合物在RT搅拌15小时。用Et3N处理该混合物,用1N HCl酸化,用TBME萃取水相并用盐水洗涤有机相,在Na2SO4上干燥,过滤并蒸发溶剂。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至9/1)纯化残余物以提供(S)-2-甲氧基-3-甲基丁酸苄酯。M/z=223[M+H]+,Rt=1.14分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δ7.47-7.30(m,5H),5.26-5.10(m,2H),3.63(d,1H),3.27(s,3H),2.05-1.90(m,1H),0.88(d,3H),0.84(d,3H)。
c)(S)-2-甲氧基-3-甲基丁酸
向(S)-2-甲氧基-3-甲基丁酸苄酯(2.8g,12.8mmol)在AcOEt(80ml)中的溶液加入Pd/C(0.68g,10%Pd)。用H2气体吹扫该混合物,并将该悬浮液在RT搅拌4.5小时。过滤该反应混合物,用AcOEt洗涤并蒸发溶剂以提供(S)-2-甲氧基-3-甲基丁酸。M/z=133[M+H]+,Rt=0.54分钟(UPLC方法B2),1H NMR(400MHz,
DMSO-d6)δppm:12.6(s,1H),3.46(d,1H),3.27(s,3H),2.00-1.90(m,1H),0.91(d,3H),0.87(d,3H)。
B2:(S)-2-(2-甲氧基乙氧基)丙酸
在0℃向NaH(3.19g,80mmol,60%油分散体)在DMF(60ml)中的悬浮液加入2-甲氧基乙醇(2.75ml,34.8mmol)。30分钟后,加入(R)-2-溴丙酸(1.5ml,16.6mmol)并将该反应混合物在RT搅拌1小时。用水猝灭该混合物,浓缩并用AcOEt萃取。在Na2SO4上干燥有机相,过滤并浓缩以提供(S)-2-(2-甲氧基乙氧基)丙酸。1H NMR(400MHz,DMSO-d6)δppm:12.56(bs,1H),3.92(q,1H),3.66-3.40(m,4H),3.24(s,3H),1.26(d,3H)。
B3:(S)-2(((R)-1-(叔-丁氧羰基)吡咯烷-3-基)氧基)丙酸
在0℃在氩气氛下向NaH 60%(在矿物油中,1.26g,31.4mmol)在干DMF(20ml)中的分散体加入(R)-3-羟基吡咯烷-1-羧酸叔丁酯(2.57g,13.73mmol)。将该反应混合物在这个温度下搅拌30分钟然后加入(R)-2-溴丙酸(0.591ml,6.54mmol)并将该反应混合物在RT搅拌3小时,用水猝灭,浓缩,倒入1N NaOH水溶液中并用AcOEt洗涤。然后用1N柠檬酸水溶液酸化水层至pH为3-4并用AcOEt萃取数次。在Na2SO4上干燥合并的有机层,过滤并浓缩以提供(S)-2-(((R)-1-(叔-丁氧羰基)吡咯烷-3-基)氧基)丙酸,其不经进一步纯化用于下一步中。1H NMR(400MHz,DMSO-d6)δppm:12.27(bs,1H),4.11–4.06(m,1H),4.02(m,1H),3.39–3.14(m,4H),1.95–
1.77(m,2H),1.39(s,9H),1.25(d,3H)。
B4:(S)-2-(((S)-1-(叔-丁氧羰基)吡咯烷-3-基)氧基)丙酸
如化合物B3所述使用(S)-3-羟基吡咯烷-1-羧酸叔丁酯代替(R)-3-羟基吡咯烷-1-羧酸叔丁酯来类似地制备(S)-2-(((S)-1-(叔-丁氧羰基)吡咯烷-3-基)氧基)丙酸。1HNMR(400MHz,DMSO-d6)δppm:12.61(bs,1H),4.13–4.05(m,1H),3.99(q,1H),3.38–3.18(m,4H),1.93–1.82(m,2H),1.39(s,9H),1.23(d,3H)。
B5:2,3-二甲氧基丙酸
a)2,3-二羟基丙酸甲酯
将2,2-二甲基-1,3-二氧戊烷-4-羧酸甲酯(3ml,20.7mmol)和1N HCl(25.9ml,25.9mmol)在MeOH(40ml)中的溶液在RT搅拌20小时。用AcOEt萃取该反应混合物,用2-甲基四氢呋喃萃取水相,在Na2SO4上干燥合并的有机相,过滤并浓缩以提供2,3-二羟基丙酸甲酯。1H NMR(400MHz,DMSO-d6)δppm:5.38(d,1H),4.82(t,1H),4.08-4.03(m,1H),3.62(s,3H),3.57-3.52(m,2H)。
b)2,3-二甲氧基丙酸甲酯
将2,3-二羟基丙酸甲酯(500mg,4.16mmol)、甲基碘(5.21ml,83mmol)和氧化银(9.65g,41.6mmol)在DCM(10ml)中的溶液在RT搅拌过夜。加入水并用AcOEt萃取该混合物,在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至0/1)纯化该残余物以提供2,3-二甲氧基丙酸甲酯。1H NMR(400MHz,DMSO-d6)δppm:4.02(dd,1H),3.67(s,3H),3.60-3.51(m,2H),3.30(s,3H),3.24(s,3H)。
c)2,3-二甲氧基丙酸
向2,3-二甲氧基丙酸甲酯(190mg,1.28mmol)在THF(3ml)中的溶液加入NaOH(0.96ml,1.92mmol)。将该反应混合物在RT搅拌过夜。加入1N HCl将pH调节至2-3。用AcOEt萃取该混合物,在Na2SO4上干燥,过滤并浓缩以提供2,3-二甲氧基丙酸。1H NMR(400MHz,DMSO-d6)δppm:12.74(bs,1H),3.89(dd,1H),3.58-3.50(m,2H),3.29(s,3H),3.24(s,3H)。
部分C:β-酮酯的合成
C1:(S)-4-甲氧基-3-氧代戊酸叔丁酯
在0℃向(S)-2-甲氧基丙酸(10.0g,96mmol)在THF(200ml)中的溶液加入CDI(17.1g,106mmol)并将该反应混合物在RT搅拌3小时。在独立烧瓶中,在0℃向3-(叔-丁氧基)-3-氧代丙酸(22.2ml,144mmol)在THF(200ml)中的溶液逐滴加入2M异丙基氯化镁的THF(139ml,279mmol)溶液并将该反应混合物在20℃搅拌3小时。然后,在0℃将该溶液逐滴加入酰基咪唑溶液中并将所得混合物在RT搅拌1小时。用10%的柠檬酸水溶液(25ml)猝灭该反应混合物,用AcOEt萃取,用饱和的NaHCO3水溶液洗涤,在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:100/0至70/30)纯化该残余物以提供(S)-4-甲氧基-3-氧代戊酸叔丁酯。M/z=203[M+H]+,Rt=0.91分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:3.85(q,1H),3.54-3.46(m,2H),3.27(s,3H),1.40(s,9H),1.19(d,3H)。
类似地制备以下酮酯:
C9:(4S,5S)-4,5-二甲氧基-3-氧代己酸叔丁酯
a)(2S,3S)-2,3-二羟基丁酸甲酯
在0℃向L-别-苏氨酸(5.0g,42.0mmol)在0.5M的H2SO4水溶液(91ml,45mmol)中的溶液逐滴加入亚硝酸钠(9.41g,136mmol)在水(34ml)中的溶液。使该反应混合物温热至RT并搅拌过夜。在0℃将该混合物提取到MeOH(139ml)中并逐滴加入SOCl2(7.60ml,104mmol)。使该反应混合物温热至RT并搅拌2小时。浓缩该混合物并通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至1/1)纯化该残余物以提供(2S,3S)-2,3-二羟基丁酸甲酯。1H NMR(400MHz,DMSO-d6)δppm:4.6(brs,2H),3.77(m,1H),3.73(p,1H),3.63(s,3H),1.07(d,3H)。
b)(2S,3S)-2,3-二甲氧基丁酸甲酯
将(2S,3S)-2,3-二羟基丁酸甲酯(3.0g,22.4mmol)、甲基碘(28.0ml,447mmol)和氧化银(31.1g,134mmol)在DCM(120ml)中的溶液在RT在暗处搅拌6天。将该混合物过滤并浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至1/1)纯化该粗产物以提供(2S,3S)-2,3-二甲氧基丁酸甲酯。1H NMR(400MHz,DMSO-d6)δppm:3.85(d,1H),3.69(s,3H),3.53(p,1H),3.30(s,3H),3.25(s,3H),1.09(d,3H)。
c)(4S,5S)-4,5-二甲氧基-3-氧代己酸叔丁酯
在-78℃,将乙酸叔丁酯(2.38ml,17.6mmol)在干THF(7.4ml)中的溶液逐滴加入干THF(7.4ml)和2M LDA在THF/庚烷/乙苯(7.72ml,15.4mmol)中的混合物中。在-78℃搅拌1小时后,将该溶液逐滴移入(2S,3S)-2,3-二甲氧基丁酸甲酯(1.10g,4.41mmol)在干THF(7.4ml)中的溶液中。所得混合物在-78℃搅拌2小时。将该反应混合物倒入1M的HCl水溶液中并用AcOEt萃取,在相分离筒(IST)上干燥并蒸发。通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至9/1)纯化粗材料以提供(4S,5S)-4,5-二甲氧基-3-氧代己酸叔丁酯。M/z=247[M+H]+,Rt=1.02分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:3.79(m,1H),3.64-3.57(m,1H),3.48-3.44(m,2H),3.35(s,3H),3.26(s,3H),1.42(s,9H),1.05(d,3H)。
部分D:C-取代的吡唑并[1,5-a]嘧啶-6-羧酸酯的合成
D1:(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸
a)(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯
将1,1-二甲氧基-N,N-二甲基甲胺(12.4ml,94mmol)和(S)-4-甲氧基-3-氧代戊酸叔丁酯(18.9g,94mmol)的混合物在120℃搅拌1.5小时。然后加入5-氯-1H-吡唑-3-胺(11.0g,94mmol)在EtOH(100ml)中的溶液并将所得混合物在85℃搅拌1小时。将该反应混合物浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:100/0至70/30)纯化该残余物以提供(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=312-314[M+H]+,Rt=1.31分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.65(s,1H),7.03(s,1H),5.26(q,1H),3.22(s,3H),1.62(d,3H),1.55(s,9H)。
b)(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸
在RT向(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(15.0g,48.1mmol)在DCM(75ml)中的溶液加入TFA(74ml)。将该反应混合物搅拌过夜并浓缩。向该残余物加入Et2O并将该悬浮液蒸发至干以提供(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸。M/z=256-258[M+H]+,Rt=0.57分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.72(s,1H),7.03(s,1H),5.40(q,1H),3.20(s,3H),1.64(d,3H)。
D2:(S)-2-氟-7-(1-甲氧基-2-甲基丙基)吡唑并[1,5-a]嘧啶-6-羧酸
如针对化合物D1所述,在步骤a)中使用(S)-4-甲氧基-5-甲基-3-氧代己酸叔丁酯和5-氟-1H-吡唑-3-胺类似地制备(S)-2-氟-7-(1-甲氧基-2-甲基丙基)吡唑并[1,5-a]嘧啶-6-羧酸。M/z=268[M+H]+,Rt=0.78分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:13.77(bs,1H),8.80(s,1H),6.67(d,1H),5.09(d,1H),3.17(s,3H),2.78(m,1H),1.10(d,3H),0.67(d,3H)。
类似地制备以下化合物:
[a]:在步骤b)中使用二氧杂环乙烷中的4M HCl代替TFA/DCM。
D10:(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸
a)(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯
将1,1-二甲氧基-N,N-二甲基甲胺(0.66ml,4.94mmol)和(S)-4-甲氧基-3-氧代戊酸叔丁酯(1.0g,4.94mmol)的混合物在120℃搅拌1小时。然后加入5-甲基-1H-吡唑-3-胺(0.48g,4.94mmol)在EtOH(5ml)中的溶液并将该反应混合物在80℃搅拌1.5小时。浓缩该混合物并通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至8/2)纯化粗产物以提供(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=292[M+H]+,Rt=1.19分钟(UPLC方法B1)。
b)(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸
向(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(1.07g,3.67mmol)在DCM(5ml)中的溶液加入TFA(5.66ml,73.5mmol)。将该反应混合物在RT搅拌2天。蒸发该混合物并将残余物提取到Et2O中。过滤固体,用Et2O洗涤并在HV下干燥以提供(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸。将滤液浓缩并用饱和NaHCO3水溶液碱化并用AcOEt萃取。有机层在Na2SO4上干燥,过滤并蒸发以提供另一批(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸。M/z=236[M+H]+,Rt=0.50分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:13.47(bs,1H),8.58(s,1H),6.65(s,1H),5.46(q,1H),3.19(s,3H),2.47(s,3H),1.65(d,3H)。
D11:(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸
a)(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯
在120℃将1,1-二甲氧基-N,N-二甲基甲胺(1.31ml,9.89mmol)和(S)-4-甲氧基-3-氧代戊酸叔丁酯(0.40g,1.98mmol)的混合物搅拌1小时。然后加入5-氟-1H-吡唑-3-胺(0.30mg,2.97mmol)在EtOH(6.6ml)中的溶液并将反应混合物在80℃搅拌过夜。用水稀释该混合物并用AcOEt萃取两次。用饱和的NaHCO3水溶液、水和盐水洗涤有机层,在相分离筒(IST)上干燥并蒸发。通过快速柱色谱在硅胶上(环己烷/AcOEt为1/0至9/1)纯化粗材料以提供(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=296[M+H]+,Rt=1.21分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:8.65(s,1H),6.67(d,1H),5.20(q,1H),3.21(s,3H),1.61(d,3H),1.55(s,9H)。
b)(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸
向(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(0.67g,2.25mmol)在DCM(5ml)中的溶液加入TFA(3.47ml,45.0mmol)。将反应混合物在RT搅拌过夜。将混合物浓缩并将残余物与甲苯共蒸发。将残余物提取到Et2O中,过滤固体,用Et2O洗涤并在HV下干燥以提供(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸。M/z=240[M+H]+,Rt=0.57分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:13.63(bs,1H),8.73(s,1H),6.67(d,1H),5.37(q,1H),3.19(s,3H),1.63(d,3H)。
D12:7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧
啶-6-羧酸
a)7-((S)-1-(((R)-1-(叔丁氧羰基)吡咯烷-3-基)氧基)乙基)-2-氯-吡唑并[1,
5-a]嘧啶-6-羧酸叔丁酯
如对于化合物D1的步骤a)所述使用(R)-3-(((S)-5-(叔丁氧基)-3,5-二氧代戊-2-基)氧基)-吡咯烷-1-羧酸叔丁酯代替(S)-4-甲氧基-3-氧代戊酸叔丁酯类似地制备7-((S)-1-(((R)-1-(叔丁氧羰基)吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=467-469[M+H]+,Rt=1.52分钟(UPLC方法B1)。
b)2-氯-7-((S)-1-((R)-吡咯烷-3-基氧基)乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔
丁酯
向7-((S)-1-(((R)-1-(叔丁氧羰基)吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(730mg,1.56mmol)在二氧杂环乙烷(2ml)中的溶液中加入二氧杂环乙烷(3.91ml,15.6mmol)中的4N HCl。在RT将反应混合物搅拌1小时,在0℃用饱和的NaHCO3水溶液处理并用AcOEt萃取。在Na2SO4上干燥有机层,过滤,浓缩并用快速柱色谱在硅胶上(DCM/MeOH:10/0至8/2)纯化以提供2-氯-7-((S)-1-((R)-吡咯烷-3-基氧基)乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=367-369[M+H]+,Rt=0.80分钟(UPLC方法B1)。
c)7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]-嘧
啶-6-羧酸叔丁酯
在0℃向2-氯-7-((S)-1-((R)-吡咯烷-3-基氧基)乙基)吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(310mg,0.85mmol)在DCM(5ml)中的溶液中加入TEA(0.353ml,2.54mmol),然后加入乙酰氯(0.090ml,1.27mmol)。反应混合物在RT搅拌1小时,在0℃用饱和的NaHCO3水溶液猝灭并用AcOEt萃取。在Na2SO4上干燥有机层,过滤,浓缩并通过快速柱色谱在硅胶上(DCM/MeOH:10/0至8/2)纯化以提供7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯。M/z=409-411[M+H]+,Rt=1.13分钟(UPLC方法B1)。
d)7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧
啶-6-羧酸
向7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸叔丁酯(300mg,0.734mmol)在MeOH(3ml)中的溶液中加入二氧杂环乙烷(3.67ml,14.67mmol)中的4N HCl。反应混合物在RT搅拌过夜并浓缩以提供7-((S)-1-(((R)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸。M/z=353-355[M+H]+,Rt=0.60分钟(UPLC方法B1)。
D13:7-((S)-1-(((S)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]-
嘧啶-6-羧酸
如对于化合物D12所述在步骤a)中使用(S)-3-(((S)-5-(叔-丁氧基)-3,5-二氧代戊-2-基)氧基)吡咯烷-1-羧酸叔丁酯代替(R)-3-(((S)-5-(叔-丁氧基)-3,5-二氧代戊-2-基)氧基)吡咯烷-1-羧酸叔丁酯来类似地制备7-((S)-1-(((S)-1-乙酰基吡咯烷-3-基)氧基)乙基)-2-氯吡唑并[1,5-a]嘧啶-6-羧酸。M/z=353-355[M+H]+,Rt=0.59分钟(UPLC方法B1)。
D14:(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸
a)2-(乙氧基亚甲基)-4-甲基-3-氧代戊酸乙酯
将异丁酰基乙酸乙酯(9.0g,56.9mmol)、原甲酸三乙酯(18.9ml,114mmol)和Ac2O(10.7ml,114mmol)在135℃搅拌过夜。将该溶液浓缩(16毫巴/60℃)以提供作为顺/反混合物的2-(乙氧基亚甲基)-4-甲基-3-氧代戊酸乙酯。M/z=215[M+H]+,Rt=0.93和0.99分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)7.84和7.66(2s,1H),4.27-4.06(m,4H),3.12-3.05(m,1H),1.27-1.15(m,6H),1.03-0.98(m,6H)。
b)2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸乙酯
在80℃将在EtOH(130ml)中的2-(乙氧基亚甲基)-4-甲基-3-氧代戊酸乙酯(11.8g,55.1mmol)和5-氯-1H-吡唑-3-胺(6.15g,52.3mmol)搅拌过夜。向反应混合物中加入水并用AcOEt萃取水相。用饱和的NaHCO3水溶液、水和盐水洗涤有机相,在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至9/1)纯化粗产物以提供2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸乙酯。M/z=268-270[M+H]+,Rt=1.27分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),7.00(s,1H),4.40-4.33(m,1H),4.37(q,2H),1.31(d,6H),1.36(t,3H)。
c)2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸
将2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸乙酯(10.5g,39.3mmol)溶解在EtOH(100ml)中并加入2N NaOH(39.3ml,79mmol)。反应混合物在60℃搅拌3小时。蒸发EtOH,加入AcOEt并用1M的HCl水溶液酸化混合物以给出白色悬浮液。过滤固体,用水洗涤并在真空下干燥。所得残余物用AcOEt处理并用饱和的NaHCO3水溶液萃取。分离水相,酸化至pH=2并过滤沉淀并用冷的AcOEt洗涤以提供2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸。M/z=240-242[M+H]+,Rt=0.83分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:8.83(s,1H),6.98(s,1H),4.58-4.47(m,1H),1.51(d,6H)。
部分E:氨基-吡啶的合成
E1:6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-胺
a)5-硝基-2-(2H-1,2,3-***-2-基)-3-(三氟甲基)吡啶
向2-氯-5-硝基-3-(三氟甲基)吡啶(1.0g,4.41mmol)和K2CO3(1.22g,8.83mmol)在THF(5ml)中的溶液中加入2H-1,2,3-***(0.31ml,5.30mmol)。在RT将反应混合物搅拌1小时。加入水并用AcOEt萃取混合物。用盐水洗涤有机层,在Na2SO4上干燥,过滤并在真空下浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:100/0至50/50)纯化残余物以提供5-硝基-2-(2H-1,2,3-***-2-基)-3-(三氟甲基)吡啶。M/z=260[M+H]+,Rt=0.88分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:9.69(d,1H),9.17(d,1H),8.37(s,2H)。
b)6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-胺
在RT向5-硝基-2-(2H-1,2,3-***-2-基)-3-(三氟甲基)吡啶(770mg,2.97mmol)在1.25M HCl(MeOH(48ml,59mmol)溶液)中的溶液中分批加入氯化亚锡(II)(2.82g,14.9mmol)。反应在RT搅拌2小时。加入4N的NaOH水溶液并用DCM萃取该溶液。有机层在无水Na2SO4上干燥,过滤并在真空下浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:100/0至0/100)纯化粗产物以提供6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-胺。M/z=230[M+H]+,Rt=0.64分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.08(d,1H),8.05(s,2H),7.43(d,1H),6.39(s,2H)。
E2:5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺
a)3-氯-5-硝基-2-(2H-1,2,3-***-2-基)吡啶
向2,3-二氯-5-硝基吡啶(1.0g,5.18mmol)和K2CO3(1.43g,10.4mmol)在THF(5ml)中的溶液中加入2H-1,2,3-***(0.360ml,6.22mmol)。反应混合物在RT搅拌过夜。由于反应不完全,加入额外的2H-1,2,3-***(0.300ml,5.18mmol)并将反应混合物在RT再搅拌2天。加入水并用AcOEt萃取混合物。用盐水洗涤有机层,在Na2SO4上干燥,过滤并在真空下浓缩。将残余物提取到DCM中,过滤掉固体并浓缩滤液。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至7/3)纯化残余物以提供3-氯-5-硝基-2-(2H-1,2,3-***-2-基)吡啶。Rt=0.75分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:9.39(d,1H),9.15(d,1H),8.33(s,2H)。
b)5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺
在RT向3-氯-5-硝基-2-(2H-1,2,3-***-2-基)吡啶(500mg,2.22mmol)在MeOH(35.5ml,44mmol)中的1.25M的HCl中的溶液中分批加入氯化亚锡(II)(2.1g,11.1mmol)。反应在RT搅拌2小时。将混合物浓缩并用DCM稀释残余物。用1N的NaOH水溶液碱化混合物并将各相分离。有机层在无水Na2SO4上干燥,过滤并在真空下浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至0/1)纯化残余物以提供5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺。M/z=196-198[M+H]+,Rt=0.50分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.05(s,2H),7.81(s,1H),7.20(s,1H),6.20(d,2H)。
E3:5-氨基-2-(2H-1,2,3-***-2-基)烟酰腈
a)5-硝基-2-(2H-1,2,3-***-2-基)烟酰腈
如对于化合物E1所述在步骤a)中使用2-氯-5-烟酰腈代替2-氯-5-硝基-3-(三氟甲基)吡啶来类似地制备5-硝基-2-(2H-1,2,3-***-2-基)烟酰腈。Rt=0.62分钟(UPLC方法B2).1H NMR(400MHz,DMSO-d6)δppm:9.61(s,1H),9.46(s,1H),8.47(s,2H)。
b)5-氨基-2-(2H-1,2,3-***-2-基)烟酰腈
向5-硝基-2-(2H-1,2,3-***-2-基)烟酰腈(700mg,3.24mmol)在EtOH(50ml)中的溶液中加入Pd-C(10%)(517mg,0.486mmol)。该反应容器配备有H2-气球,抽真空并用氢气吹扫。在RT搅拌30分钟后,将反应容器抽真空并用氩气吹扫。过滤反应混合物并用EtOH彻底冲洗。浓缩滤液并在真空中干燥以提供5-氨基-2-(2H-1,2,3-***-2-基)烟酰腈。M/z=187[M+H]+,Rt=0.47分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:8.15(s,2H),8.11(s,1H),7.47(s,1H),6.29(s,2H)。
E4:5-氨基-2-甲氧基烟酰腈
在Radley管中装入Pd(OAc)2(15.81mg,0.07mmol)和呫吨膦(xantphos,81mg,0.14mmol)并用氩气吹扫。加入5-溴-2-甲氧基烟酰腈(500mg,2.35mmol)、二苯甲亚胺(0.471ml,2.82mmol)、Cs2CO3(1.53g,4.69mmol)和二氧杂环乙烷(20ml)并将该混合物在100℃加热15小时。冷却至RT后,过滤反应混合物,用***洗涤并将滤液浓缩以给出5-((二苯基亚甲基)氨基)-2-甲氧基烟酰腈作为中间体。将其溶解在THF(20ml)中,加入2N的HCl水溶液(1.43ml,46.9mmol)并将混合物搅拌10分钟。用水和环己烷/AcOEt(1:1;50ml)稀释反应混合物。将各相分离并用AcOEt(2×30ml)萃取水相。合并的有机层在Na2SO4上干燥,过滤并浓缩以给出粗产物与苯甲酮的混合物。通过加入1N的NaOH水溶液中和水相并用AcOEt(2×30ml)萃取。合并的有机层在Na2SO4上干燥,过滤并浓缩。合并两部分并通过快速柱色谱在硅胶上(环己烷/AcOEt:4/1至0/1)纯化以提供5-氨基-2-甲氧基烟酰腈。M/z=150[M+H]+,Rt=0.60分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:7.81(d,1H),7.35(d,1H),5.21(s,2H),3.84(s,3H)。
E5:2-(二氟甲基)吡啶-4-胺
a)(2-(二氟甲基)吡啶-4-基)氨基甲酸叔丁酯
在90℃将4-溴-2-(二氟甲基)吡啶(5.7g,27.4mmol)、氨甲酸叔丁酯(3.85g,32.9mmol)、xantphos(1.43g,2.47mmol)、三(二苯亚甲基丙酮)二钯(0)(0.75g,0.82mmol)和碳酸铯(17.9g,54.8mmol)在二氧杂环乙烷(120ml)中的混合物搅拌72小时。过滤反应混合物并浓缩。通过快速柱色谱在硅胶上(环己烷/EtOAc:100/0至50/50)纯化粗产物。M/z=245[M+H]+,Rt=0.98分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:10.1(s,1H),8.42(d,1H),7.81(s,1H),7.50(d,1H),6.85(t,1H),1.50(s,9H)。
b)2-(二氟甲基)吡啶-4-胺
向(2-(二氟甲基)吡啶-4-基)氨基甲酸叔丁酯(7.53g,27.4mmol)在MeOH(25ml)中的溶液中加入二氧杂环乙烷(137ml,549mmol)中的4N的HCl。该溶液在RT搅拌过夜。浓缩反应混合物,用饱和的NaHCO3水溶液猝灭,用EtOAc萃取,在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/EtOAc:100/0至0/100)纯化产出标题化合物。M/z=145[M+H]+,Rt=0.18分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.03(d,1H),6.75(s,1H),6.66(t,1H),6.56(d,1H),6.35(s,2H)。
E6:1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙醇
a)1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙酮
在30ml的ACE Glass(Sigma-Aldrich,8648-03)中装入2-氯-6-(三氟甲基)吡啶-4-胺(500mg,2.54mmol)、三丁基(1-乙氧基乙烯基)锡烷(1.09ml,3.05mmol)、PdCl2(PPh3)2(89mg,0.13mmol)和氟化铯(850mg,5.60mml)。用氩气吹扫该管并加入二氧杂环乙烷(12.5ml)。密封该容器并将反应混合物在100℃搅拌3小时。再次加入三丁基(1-乙氧基乙烯基)锡烷(1.09ml,3.05mmol)和PdCl2(PPh3)2(89mg,0.13mmol)并在100℃搅拌反应混合物5小时。浓缩反应混合物,用AcOEt稀释并过滤通过硅藻土塞。将滤液浓缩至干,溶解在THF(12.50ml)中并加入1N的HCl水溶液(6.36ml,6.36mmol)。反应混合物在RT搅拌过夜,浓缩并用AcOEt萃取。有机层在相分离筒(IST)上干燥,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:100/0至75/25)纯化以提供1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙酮。M/z=205[M+H]+,Rt=0.86分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:7.25(d,1H),7.08(d,1H),6.90(s,2H),2.54(s,3H)。
b)1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙醇
在0℃向1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙酮(430mg,1.20mmol)在MeOH(6.15)中的溶液中加入NaBH4(47.7mg,1.26mmol)。该反应在0℃搅拌1小时,倒入水中并用AcOEt萃取三次。合并的有机层用盐水和水洗涤,在相分离筒(IST)上干燥,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至8/2)纯化以提供1-(4-氨基-6-(三氟甲基)吡啶-2-基)乙醇。M/z=207[M+H]+,Rt=0.58分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:6.84(d,1H),6.74(d,1H),6.51(s,2H),5.28(d,1H),4.54(qd,1H),1.29(d,3H)。
E7:1-(4-氨基吡啶-2-基)-2,2,2-三氟乙醇
a)1-(4-溴吡啶-2-基)-2,2,2-三氟乙醇
在0℃在惰性气氛下向4-溴皮考啉醛(1g,5.38mmol)和三甲基(三氟甲基)-硅烷(0.92g,6.45mmol)在THF(10ml)中的溶液中加入THF中的1M TBAF(0.27ml,0.27mmol)。在0℃保持30分钟之后,使反应温热至RT保持2小时。向反应混合物加入1N的HCl水溶液(6ml)并在RT搅拌溶液30分钟。然后,加入1N的NaOH水溶液至pH 8并用AcOEt萃取混合物。有机层在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至5/5)纯化以提供1-(4-溴吡啶-2-基)-2,2,2-三氟乙醇。M/z=256-258[M+H]+,Rt=0.85分钟(UPLC方法B1),1H NMR(400MHz,DMSO-d6)δppm:8.49(d,1H),7.81(d,1H),7.77–7.70(m,1H),7.19(s,1H),5.17(m,1H)。
b)(2-(2,2,2-三氟-1-羟乙基)吡啶-4-基)氨基甲酸叔丁酯
在90℃在惰性气氛下将1-(4-溴吡啶-2-基)-2,2,2-三氟乙醇(1.18g,4.61mmol)、氨基甲酸叔丁酯(0.65g,5.53mmol)、呫吨膦(xantphos,0.24g,0.42mmol)、三(二苯亚甲基丙酮)二钯(0)(0.13g,0.14mmol)和碳酸铯(3.00g,9.22mmol)在二氧杂环乙烷(20ml)中的混合物搅拌过夜。冷却至RT后,过滤反应混合物,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至7/3)纯化以提供(2-(2,2,2-三氟-1-羟乙基)吡啶-4-基)氨基甲酸叔丁酯。M/z=293[M+H]+,Rt=0.90分钟(UPLC方法B1)。
c)1-(4-氨基吡啶-2-基)-2,2,2-三氟乙醇
向(2-(2,2,2-三氟-1-羟乙基)吡啶-4-基)氨基甲酸叔丁酯(610mg,2.09mmol)在MeOH(2ml)中的溶液中加入二氧杂环乙烷中的4N的HCl(10.44ml,41.7mmol)。反应混合物在RT搅拌过夜,浓缩,在饱和的NaHCO3水溶液和AcOEt之间分配。有机层在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至0/10)纯化以提供1-(4-氨基吡啶-2-基)-2,2,2-三氟乙醇。1H NMR(400MHz,DMSO-d6)δppm:7.94(m,1H),6.72(d,1H),6.63(d,1H),6.45(m,1H),6.16(s,2H),4.96–4.77(m,1H)。
E8:5-氯-2-(2-甲氧基乙氧基)吡啶-3-胺
a)5-氯-2-(2-甲氧基乙氧基)-3-硝基吡啶
在0℃向5-氯-2-羟基-3-硝基吡啶(1.23g,6.92mmol)、3-甲氧基丙-1-醇(0.71ml,7.62mmol)和PPh3(2.04g,7.62mmol)在THF(10ml)中的溶液中逐滴加入DEAD(1.24ml,7.62mmol)。反应混合物在RT搅拌过夜。浓缩反应混合物并通过快速柱色谱在硅胶上(庚烷/AcOEt:10/0至0/10)纯化以提供5-氯-2-(2-甲氧基乙氧基)-3-硝基吡啶。M/z=233-235[M+H]+,Rt=0.95(UPLC方法B2),1H NMR(600MHz,DMSO-d6)δppm:8.63(d,1H),8.58(d,1H),4.56(m,2H),3.69(m,2H),3.32(s,3H)。
b)5-氯-2-(2-甲氧基乙氧基)吡啶-3-胺
向5-氯-2-(2-甲氧基乙氧基)-3-硝基吡啶(740mg,3.18mmol)在乙酸(15ml)中的溶液中加入铁粉(1.78g,31.8mmol)并将反应混合物在RT搅拌2.5小时。将反应混合物浓缩,加入DCM(50ml)并将混合物搅拌10分钟。过滤混合物并用饱和的NaHCO3水溶液、水和盐水洗涤滤液。在Na2SO4上干燥有机相,过滤并蒸发溶剂以提供5-氯-2-(2-甲氧基乙氧基)吡啶-3-胺。M/z=203-205[M+H]+,Rt=0.78(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:7.31(d,1H),6.90(d,1H),5.25(s,2H),4.36(t,2H),3.67(t,2H),3.30(s,3H)。
E9:4-氨基-6-氯-N,N-二甲基吡啶酰胺
a)6-氯-N,N-二甲基-4-硝基吡啶酰胺
向6-氯-4-硝基-2-吡啶羧酸(500mg,2.47mmol)在DMF(10ml)中的溶液中加入HOBt(454mg,2.96mmol)并在RT搅拌反应混合物1小时。加入二甲基胺氯化氢(200mg,2.47mmol)和盐酸EDC(568mg,2.96mmol)并在RT搅拌反应混合物3天。将粗混合物倒入饱和的NaHCO3水溶液中并用AcOEt萃取三次。合并的有机层用水、盐水洗涤,在Na2SO4上干燥,过滤并浓缩以提供6-氯-N,N-二甲基-4-硝基吡啶酰胺,其不需进一步纯化就用于下一步骤中。M/z=230-232[M+H]+,Rt=0.73(UPLC方法B2)。
b)4-氨基-6-氯-N,N-二甲基吡啶酰胺
向6-氯-N,N-二甲基-4-硝基吡啶酰胺(380mg,1.66mmol)在AcOH(10ml)中的溶液中加入铁(924mg,16.6mmol)并在RT搅拌反应混合物1.5小时。浓缩反应混合物,加入DCM(50ml)并将混合物搅拌10分钟。过滤混合物并用饱和的NaHCO3水溶液、水和盐水洗涤滤液。在Na2SO4上干燥有机相,过滤并蒸发溶剂以提供4-氨基-6-氯-N,N-二甲基吡啶酰胺。M/z=200-202[M+H]+,Rt=0.48(UPLC方法B2)。
E10:5-氨基-3-氯-N,N-二甲基吡啶酰胺
a)5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸乙酯
在惰性气氛下向5-氯-6-(乙氧基羰基)烟酸(920mg,4.01mmol)在干二氧杂环乙烷中的溶液中加入DPPA(951ml,4.21mmol)和TEA(2.78ml,20.0mmol)。反应混合物在RT搅拌30分钟然后加入2-甲基丙-2-醇(7.7ml,80mmol)在干二氧杂环乙烷(10ml)中的溶液。反应混合物在80℃搅拌2小时。将反应混合物倒入盐水中并用AcOEt萃取三次。合并的有机层在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(庚烷/AcOEt:9/1至0/10)纯化以提供5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸乙酯。M/z=301-303[M+H]+,Rt=1.10(UPLC方法B2)。
b)5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸
向5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸乙酯(562mg,1.87mmol)在EtOH(5ml)中的溶液中加入2N的NaOH水溶液(2.80ml,5.61mmol)并在RT搅拌反应混合物2小时。将混合物浓缩,倒入水中,用2N的HCl水溶液酸化并用AcOEt萃取。有机层用水、盐水洗涤,在Na2SO4上干燥,过滤并浓缩以提供5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸。M/z=273-275[M+H]+,Rt=0.77(UPLC方法B2)。
c)(5-氯-6-(二甲基氨甲酰基)吡啶-3-基)氨基甲酸叔丁酯
向5-((叔丁氧羰基)氨基)-3-氯吡啶羧酸(170mg,0.62mmol)在DMF(5ml)中的溶液中加入HOBt(143mg,0.93mmol)并在RT搅拌反应混合物1小时。然后加入THF(0.94ml,1.87mmol)中的2M的二甲基胺和盐酸EDC(179mg,0.93mmol)并在RT搅拌反应混合物4小时。为了完成反应,再次加入THF(0.94ml,1.87mmol)中的2M的二甲基胺并在RT搅拌反应混合物过夜。将粗反应混合物倒入饱和的NaHCO3水溶液中并用AcOEt萃取三次。合并的有机层用水、盐水洗涤,在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(庚烷/AcOEt:8/2至0/10)纯化以提供(5-氯-6-(二甲基氨甲酰基)-吡啶-3-基)氨基甲酸叔丁酯。M/z=300-302[M+H]+,Rt=0.88(UPLC方法B2)。
d)5-氨基-3-氯-N,N-二甲基吡啶酰胺
向(5-氯-6-(二甲基氨甲酰基)吡啶-3-基)氨基甲酸叔丁酯(65mg,0.217mmol)中加入二氧杂环乙烷(0.1ml,0.434mmol)中的4N的HCl并在RT搅拌反应混合物过夜。为了完成反应,加入TFA(2ml)并在RT搅拌反应混合物过夜。浓缩反应混合物以提供作为相应的TFA盐的5-氨基-3-氯-N,N-二甲基吡啶酰胺。M/z=200-202[M+H]+,Rt=0.45(UPLC方法B2)。
E11:(5-氨基-3-氯吡啶-2-基)(吡咯烷-1-基)甲酮
a)(3-氯-5-硝基吡啶-2-基)(吡咯烷-1-基)甲酮
向3-氯-5-硝基吡啶羧酸(250mg,1.23mmol)在DMF(5ml)中的溶液中加入HOBt(284mg,1.85mmol),然后加入吡咯烷(132mg,1.85mmol)和EDC(355mg,1.85mmol)。反应混合物在RT搅拌16小时。加入饱和的NaHCO3溶液,混合物用AcOEt萃取3次并用水和盐水洗涤有机相。干燥有机相并蒸发溶剂以产出标题化合物,其不需进一步纯化就用于下一步中。M/z=256-258[M+H]+,Rt=0.74分钟(UPLC方法B1)。
b)(5-氨基-3-氯吡啶-2-基)(吡咯烷-1-基)甲酮
向(3-氯-5-硝基吡啶-2-基)(吡咯烷-1-基)甲酮(218mg,0.85mmol)在EtOH(10ml)和饱和的NH4Cl水溶液(5ml)中的溶液中加入铁粉(473mg,8.53mmol)。混合物在回流下搅拌2.5小时。冷却至RT后用2:1(100ml)的AcOEt/水处理反应混合物并在硅藻土上过滤混合物。用水和盐水洗涤有机相,在Na2SO4上干燥并蒸发溶剂。快速柱色谱(庚烷,AcOEt:100/0至0/100,然后用MeOH洗脱)提供标题化合物。M/z=226-228[M+H]+,Rt=0.55分钟(UPLC方法B1)。
E12:5-氨基-3-氯-N-甲基吡啶酰胺
如对于化合物E10所述在步骤a)中使用5-氯-6-(乙氧基羰基)烟酸和甲基胺代替二甲胺来制备5-氨基-3-氯-N-甲基吡啶酰胺。M/z=186-188[M+H]+,Rt=0.39分钟(UPLC方法B1)。
E13:(S)-(1-((3-氨基-5-氯吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯
a)(S)-(1-((5-氯-3-硝基吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯
在0℃在5分钟时间内向5-氯-3-硝基吡啶-2-酚(1.02g,5.86mmol)、N-Boc-L-氨基丙醇(1.14g,6.45mmol)和PPh3(1.72g,6.45mmol)在THF(10ml)中的悬浮液中逐滴加入DEAD(1.02ml,6.45mmol)。反应混合物在RT搅拌过夜。为了完成反应,加入N-Boc-L-氨基丙醇(550mg)、PPh3(850mg)和DEAD(0.5ml)并在RT搅拌反应混合物3小时,倒入水中并用AcOEt萃取三次。合并的有机层用饱和的NaHCO3水溶液和盐水洗涤,在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(庚烷/AcOEt:10/0至3/7)纯化以提供(S)-(1-((5-氯-3-硝基吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯。M/z=332-334[M+H]+,Rt=1.17分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:8.63(s,1H),8.59(s,1H),6.86(d,1H),4.42(dd,1H),4.22(dd,1H),3.89(m,1H),1.34(s,9H),1.11(d,3H)。
b)(S)-(1-((3-氨基-5-氯吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯
向(S)-(1-((5-氯-3-硝基吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯(1.09g,3.29mmol)在EtOH(15ml)和饱和的NH4Cl(5ml)水溶液中的悬浮液中加入铁粉(1.84g,32.9mmol)。悬浮液在80℃搅拌2小时,浓缩并通过快速柱色谱在硅胶上(DCM/MeOH+1%NH3:10/0至7/3)纯化以提供(S)-(1-((3-氨基-5-氯吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯。M/z=302-304[M+H]+,Rt=1.07分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:7.28(d,1H),6.95(d,1H),6.86(d,1H),5.39(s,2H),4.13(dd,1H),3.99(dd,1H),3.95-3.85(m,1H),1.39(s,9H),1.12(d,3H)。
关于最终产物的一般评论:
如以上在一般合成路径的说明中所示,如下获得下列化合物:通过使如部分D1- D14中所述的吡唑并[1,5-a]嘧啶-6-羧酸与合适的如部分E1-E13中所述的氨基-吡啶衍生物在Curtius重排反应中经由相应异氰酸酯作为中间体来反应以产出下示脲衍生物从而获得。
实施例1:(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-
a]嘧啶-6-基)脲
向(S)-7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-羧酸(100mg,0.43mmol)在二氧杂环乙烷(2.8ml)中的溶液中加入DPPA(113μl,0.51mmol)和Et3N(178μl,1.28mmol)。反应混合物在RT搅拌30分钟。然后加入5-氨基烟酰腈(152mg,1.28mmol)并在100℃搅拌反应混合物10分钟。将混合物冷却至RT,蒸发并将残余物溶解在AcOEt中。有机层用饱和的NaHCO3水溶液洗涤并在相分离筒(IST)上干燥,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至0/10)纯化以获得(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲。M/z=352[M+H]+,Rt=2.87分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:10.02(s,1H),8.83(t,1H),8.74(d,1H),8.63(d,1H),8.42(s,1H),8.39(s,1H),6.56(s,1H),5.50(q,1H),3.33(s,3H),2.44(s,3H),1.57(d,3H)。
为了除去会在合成过程中形成差向异构的任何材料,可通过制备型手性SFC将该化合物纯化至>98%对映异构过量。仪器:Thar SuperPure200,柱:Chiralpak IA 5μM,250×30mm,40℃,流动相:CO2/EtOH,60/40。
通过在回流下将该化合物溶解在乙腈(10ml/g)中来获得晶体材料。关闭加热并使溶液在搅拌下缓慢冷却至23℃过夜。过滤收集所得固体并用少量乙腈洗涤并在高真空下在50℃干燥过夜。
实施例1的粉末X射线衍射峰
溶解性
实施例2:(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并
[1,5-a]嘧啶-6-基)脲
向2-(二氟甲基)异烟酸(48.4mg,0.280mmol)在二氧杂环乙烷(1ml)中的溶液中加入DPPA(90mg,0.326mmol)和Et3N(0.1ml,0.699mmol)并在RT搅拌反应混合物1小时。然后加入(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸(70mg,0.233mmol)并在100℃搅拌反应混合物1小时。将混合物冷却至室温,倒入盐水中并用AcOEt萃取。合并的有机层在相分离筒(IST)上干燥,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至5/5)纯化以提供(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲。M/z=381[M+H]+,Rt=2.74分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:10.19(bs,1H),8.88(s,1H),8.47(m,2H),7.87(d,1H),7.54-7.50(m,1H),6.89(t,1H),6.56(d,1H),5.33(q,1H),3.30(s,3H),1.56(d,3H)。
为了除去会在合成过程中差向异构的任何材料,可通过制备型手性SFC将该化合物纯化至>98%对映异构过量。仪器:Thar SuperPure200,柱:Chiralpak AD-H5μM,250×30mm,40℃,流动相:CO2/EtOH,85/15。
对于实施例2的化合物,获得晶体水合形式,并描述了制备该形式的过程。
在室温下向100mg的(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲中加入1ml的4:1(体积/体积)的甲醇/水以形成悬浮液。该悬浮液在环境条件下搅拌12小时。通过真空过滤收集所得固体并在40℃在真空下干燥12小时。
实施例2的溶解性比较
实施例2水合物的粉末X射线衍射峰
实施例3:(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(三
氟甲基)吡啶-4-基)脲
向(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸(1.3g,4.78mmol)(在D1中获得)在1,4-二氧杂环乙烷(10ml)中的溶液中加入DPPA(1.24ml,5.74mmol)和Et3N(3.33ml,23.9mmol)。反应混合物在RT搅拌30分钟。然后加入2-(三氟甲基)吡啶-4-胺(1.55g,9.56mmol)并在100℃搅拌反应混合物2小时。混合物在AcOEt和饱和的NaHCO3水溶液之间分配并分离各相。有机层在Na2SO4上干燥,过滤并浓缩。通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至0/1)纯化粗材料。然后将残余物提取到MeOH中并加热直到溶解。冷却至RT后,通过过滤收集沉淀,用MeOH洗涤并干燥以提供(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(三氟甲基)吡啶-4-基)脲。M/z=415-417[M+H]+,Rt=4.18分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:10.38(s,1H),8.92(s,1H),8.57(s,1H),8.56(s,1H),8.06(d,1H),7.61(dd,1H),6.94(s,1H),5.41(q,1H),3.32(s,3H),1.57(d,3H)。
对于实施例3的化合物获得晶体水合形式:将(S)-1-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)-3-(2-(三氟甲基)吡啶-4-基)脲溶解在乙腈(5ml/g)中,然后加热至50-60℃。在1-2小时内向溶液中加入水(5ml/g)同时保持内部温度为50-60℃。在1小时内将混合物冷却至RT并在该温度再保持1小时。过滤之后滤饼在55-60℃在真空下干燥。
实施例3半水合物的粉末X射线衍射峰
实施例3半水合物的溶解性
实施例4:1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-异丙基吡唑
并[1,5-a]嘧啶-6-基)脲
向2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-羧酸(1.6g,6.01mmol)在1,4-二氧杂环乙烷(9ml)中的溶液中加入DPPA(1.42ml,6.61mmol)和Et3N(3.35ml,24.0mmol)。反应混合物在RT搅拌30分钟。然后加入5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺(1.65g,8.41mmol)并在100℃搅拌反应混合物2小时。使混合物冷却至RT,用盐水稀释并用AcOEt萃取。合并的有机层在相分离筒上干燥并浓缩。通过快速柱色谱在硅胶上(DCM/MeOH:1/0至9/1)纯化粗材料,然后进行制备型HPLC纯化(方法A)。合并的馏分用NaHCO3溶液洗涤,将有机相干燥并浓缩至80ml体积。溶液在冰浴中冷却3小时并通过过滤收集沉淀并干燥以提供1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-异丙基吡唑并[1,5-a]嘧啶-6-基)脲。M/z=432-434[M+H]+,Rt=4.31分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:9.71(bs,1H),8.76(bs,1H),8.58(d,1H),8.56(s,1H),8.44(d,1H),8.15(s,2H),6.92(s,1H),3.81(m,1H),1.49(d,6H)。
实施例4的粉末X射线衍射峰
实施例5:(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-甲
氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲
向(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸(2.0g,7.35mmol)(D1)在1,4-二氧杂环乙烷(16ml)中的溶液中加入DPPA(1.90ml,8.82mmol)和Et3N(5.12ml,36.8mmol)。反应混合物在RT搅拌30分钟。然后加入5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺(1.87g,9.56mmol)并在100℃搅拌反应混合物2小时。混合物在AcOEt和饱和的NaHCO3水溶液之间分配并分离各相。有机层在Na2SO4上干燥,过滤并浓缩。粗材料通过快速柱色谱在硅胶上(环己烷/AcOEt:1/0至0/1)、然后通过反向HPLC(方法A)纯化。然后将产物提取到乙腈中并加热直到溶解。冷却至RT后通过过滤收集沉淀,洗涤并干燥以提供(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲。M/z=448-450[M+H]+,Rt=3.99分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:10.33(bs,1H),8.95(s,1H),8.60(bs,1H),8.54(d,1H),8.49(d,1H),8.16(s,2H),6.94(s,1H),5.42(q,1H),3.33(s,3H),1.59(d,3H)。
实施例5的粉末X射线衍射峰:
实施例5的溶解性:
实施例6:(S)-1-(5-氰基-6-甲氧基吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑
并[1,5-a]嘧啶-6-基)脲
向(S)-2-氟-7-(1-甲氧乙基)吡唑并[1,5-a]嘧啶-6-羧酸(50mg,0.199mmol)在二氧杂环乙烷(0.8ml)中的溶液中加入DPPA(0.053ml,0.238mmol)和Et3N(0.083ml,0.596mmol)。反应混合物在RT搅拌30分钟。然后加入5-氨基-2-甲氧基烟酰腈(35.5mg,0.238mmol)并在100℃搅拌反应混合物20分钟。将混合物冷却至RT,用AcOEt稀释并用饱和的NaHCO3水溶液和盐水洗涤。有机层在Na2SO4上干燥,过滤,浓缩并通过快速柱色谱在硅胶上(环己烷/AcOEt:10/0至5/5)纯化从而在ACN中重结晶后提供(S)-1-(5-氰基-6-甲氧基吡啶-3-基)-3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲。M/z=386[M+H]+,Rt=3.81分钟(HPLC方法C1),1H NMR(600MHz,DMSO-d6)δppm:9.71(s,1H),8.87(s,1H),8.41(m,3H),6.53(d,1H),5.33(q,1H),3.97(s,3H),3.30(s,3H),1.56(d,3H)。
与实施例1类似地制备以下实施例:
[d]:加入苯胺后在80℃搅拌反应混合物。
实施例38:(S)-1-(7-(1-氨基乙基)-2-氯吡唑并[1,5-a]嘧啶-6-基)-3-(5-氯-6-
(2H-1,2,3-***-2-基)吡啶-3-基)脲
a)(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-(1,3-二氧
代异二氢吲哚-2-基)乙基)吡唑并[1,5-a]嘧啶-6-基)脲
如实施例1中所述使用(S)-2-氯-7-(1-(1,3-二氧代异二氢吲哚-2-基)乙基)吡唑并[1,5-a]嘧啶-6-羧酸代替(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸、并使用5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-胺代替6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-胺来类似地制备(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-(1,3-二氧代异二氢吲哚-2-基)乙基)吡唑并[1,5-a]嘧啶-6-基)脲。M/z=563-565[M+H]+,Rt=1.09分钟(UPLC方法B1)。
b)(S)-1-(7-(1-氨基乙基)-2-氯吡唑并[1,5-a]嘧啶-6-基)-3-(5-氯-6-(2H-1,
2,3-***-2-基)吡啶-3-基)脲
在RT将(S)-1-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)-3-(2-氯-7-(1-(1,3-二氧代异二氢吲哚-2-基)乙基)吡唑并[1,5-a]嘧啶-6-基)脲(86mg,0.15mmol)在THF(763μl,0.76mmol)中的1M的肼中的溶液搅拌过夜。然后过滤反应,浓缩并通过制备型HPLC(方法A1)纯化,将各级分合并并用AcOEt和饱和的NaHCO3水溶液萃取。有机层在Na2SO4上干燥,过滤,浓缩并在HV下干燥以提供(S)-1-(7-(1-氨基乙基)-2-氯吡唑并[1,5-a]嘧啶-6-基)-3-(5-氯-6-(2H-1,2,3-***-2-基)吡啶-3-基)脲。M/z=433-435[M+H]+,Rt=2.40分钟(HPLC方法C1),1H NMR(400MHz,DMSO-d6)δppm:8.95(s,1H),8.59(d,1H),8.48(s,1H),8.15(s,2H),6.88(s,1H),5.49(bs,2H),5.06(q,1H),1.47(d,3H)。
实施例39:(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-羟乙基)-2-甲基吡唑并[1,5-a]
嘧啶-6-基)脲
实施例1
将(S)-1-(5-氰基吡啶-3-基)-3-(7-(1-甲氧基乙基)-2-甲基吡唑并[1,5-a]嘧啶-6-基)脲(50.0mg,0.14mmol)在DCM(2.0ml)中的悬浮液冷却至0℃并逐滴加入三溴化硼(DCM中的1M溶液,0.85ml)。所得悬浮液在0℃搅拌5小时并在RT再搅拌16小时。将反应混合物倒在冰水上并用乙酸乙酯萃取。用1N的HCl水溶液和盐水洗涤有机萃取物,干燥并浓缩。经制备型HPLC(方法A2)、随后SFC纯化(方法A5)产出标题化合物。M/z=338[M+H]+,Rt=2.21分钟(UPLC方法B7),1H NMR(400MHz,DMSO-d6)δppm:
实施例40:(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-羟乙基)吡唑并[1,
5-a]嘧啶-6-基)脲
实施例2
按照实施例39中的程序,将(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-羟乙基)吡唑并[1,5-a]嘧啶-6-基)脲转化成标题化合物。M/z=367[M+H]+,Rt=0.79分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:10.4(s,1H),8.95(s,1H),8.47(d,1H),7.89(s,1H),7.53(dd,1H),6.89(t,1H),6.52(d,1H),5.68(q,1H),1.50(d,3H)。
实施例41:1-(2-((S)-2-氨基丙氧基)-5-氯吡啶-3-基)-3-(2-氯-7-((S)-1-甲氧
基乙基)吡唑并[1,5-a]嘧啶-6-基)脲
a)((S)-1-((5-氯-3-(3-(2-氯-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]-嘧啶-6-
基)脲基)吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯
如实施例1中所述使用(S)-(1-((3-氨基-5-氯吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯代替(S)-2-氯-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸并使用(S)-(1-((3-氨基-5-氯吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯代替6-(2H-1,2,3-***-2-基)-5-(三氟甲基)吡啶-3-胺来类似地制备((S)-1-((5-氯-3-(3-(2-氯-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯。M/z=554-556[M+H]+,Rt=1.34分钟(UPLC方法B2),1H NMR(400MHz,甲醇-d4)δppm:8.79(s,1H),8.47(s,1H),7.75(s,1H),6.70(s,1H),5.53(q,1H),4.41–4.30(m,2H),4.16(m,1H),3.41(s,3H),1.65(d,3H),1.43(s,9H),1.25(d,3H)。
b)1-(2-((S)-2-氨基丙氧基)-5-氯吡啶-3-基)-3-(2-氯-7-((S)-1-甲氧基乙基)
吡唑并[1,5-a]嘧啶-6-基)脲
向((S)-1-((5-氯-3-(3-(2-氯-7-((S)-1-甲氧基乙基)吡唑并[1,5-a]-嘧啶-6-基)脲基)吡啶-2-基)氧基)丙-2-基)氨基甲酸叔丁酯(56mg,0.10mmol)中加入二氧杂环乙烷(0.5ml)中的4N的HCl并在RT搅拌反应混合物过夜。过滤反应混合物并在HV下干燥滤饼以获得1-(2-((S)-2-氨基丙氧基)-5-氯吡啶-3-基)-3-(2-氯-7-((S)-1-甲氧基乙基)-吡唑并[1,5-a]嘧啶-6-基)脲HCl盐。M/z=454-456[M+H]+,Rt=0.86分钟(UPLC方法B2),1H NMR(400MHz,甲醇-d4)δppm:8.75(s,1H),8.52(s,1H),7.80(s,1H),6.71(s,1H),5.54-5.48(m,1H),4.68–4.59(m,1H),4.53-4.46(m,1H),3.89–3.84(m,1H),3.40(s,3H),1.68(d,3H),1.47(d,3H)。
实施例42:(S)-2-(二氟甲基)-4-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧
啶-6-基)脲基)吡啶1-氧化物
实施例2
向10升一次性生物反应袋中加入1.35升OD100的解冻的细胞悬浮液(表达狗cypd3A12的大肠杆菌),4.1升PSE缓冲液和270ml柠檬酸钠50%(m/m)。最后加入504mg(1.33mmol)的(S)-1-(2-(二氟甲基)吡啶-4-基)-3-(2-氟-7-(1-羟乙基)吡唑并[1,5-a]嘧啶-6-基)脲。肉汤在30℃和3升/分钟的气流下以42摇/分钟振摇。23小时后,不再检测到进一步的反应进程。收集肉汤,离心,用ACN/MeOH升/升萃取团块3次并用相同体积的乙酸乙酯萃取上清液两次。汇合有机层,浓缩,在MgSO4上干燥,浓缩并通过RP-HPLC纯化。通过SFC(方法A5)再纯化提供标题化合物。M/z=397[M+H]+,Rt=0.75分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:10.2(s,1H),8.88(s,1H),8.46(b rs,1H),8.26(d,1H),7.94(d,1H),7.58(dd,1H),7.23(t,1H),6.56(d,1H),5.33(q,1H),1.57(d,3H)。
实施例43:(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)
脲基)吡啶酰胺
a)(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡
啶羧酸甲酯
向(S)-2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-羧酸(230mg,0.96mmol)在1,4-二氧杂环乙烷(1ml)中的溶液中加入DPPA(0.249ml,1.15mmol)和三乙胺(0.469ml,3.37mmol)。反应混合物在RT搅拌30分钟,然后加热到100℃保持15分钟。将反应混合物倒在饱和的NaHCO3水溶液上并用乙酸乙酯萃取。有机相用盐水洗涤,在Na2SO4上干燥,过滤并蒸发溶剂。粗产物通过快速色谱(乙酸乙酯/庚烷)纯化以产出标题化合物。M/z=422[M+H]+,Rt=0.97分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:10.2(bs,1H),8.88(s,1H),8.56(d,1H),8.53(bs,1H),8.32(d,1H),6.56(d,1H),5.33(q,1H),3.87(s,3H),1.57(d,3H),一个CH3O信号被溶剂峰遮掩。
b)(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡
啶羧酸
将(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡啶羧酸甲酯(200mg,0.47mmol)悬浮在甲醇(10ml)中。加入水(1ml)和氢氧化钠(0.47ml的2N水溶液,0.95mmol)并在室温搅拌反应混合物72小时。蒸发溶剂并用1N的HCl水溶液酸化残余物,导致产物沉淀。过滤沉淀,用水洗涤并干燥。M/z=409[M+H]+,Rt=0.74分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:13.4(bs,1H),10.16(s,1H),8.89(s,1H),8.56(d,1H),8,53(s,1H),8.28(d,1H),6.56(d,1H),5.34(q,1H),1.58(d,3H),CH3O信号被溶剂峰遮蔽。
c)(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡
啶酰胺
在RT向(S)-3-氯-5-(3-(2-氟-7-(1-甲氧基乙基)吡唑并[1,5-a]嘧啶-6-基)脲基)吡啶羧酸(100mg,0.245mmol)在DMF(5ml)中的溶液中加入HATU(112mg,0.489mmol),然后加入二氧杂环乙烷中的氨(0.98ml,0.5M溶液,0.489mmol)。反应在RT搅拌16小时。加入水并用乙酸乙酯萃取混合物。有机相用水和盐水洗涤,在Na2SO4上干燥,过滤并蒸发溶剂。通过制备型SFC(方法A5)纯化粗产物以产出标题化合物。M/z=408[M+H]+,Rt=0.77分钟(UPLC方法B2),1H NMR(400MHz,DMSO-d6)δppm:10.08(s,1H),8.89(s,1H),8.53(d,1H),8.51(s,1H),8.23(d,1H),7.90(bs,1H),7.54(bs,1H),6.56(d,1H),5.35(q,1H),1.57(d,3H),CH3O信号被溶剂峰遮蔽。
生物学/药理学部分
本发明的化合物表现出有价值的药理学性质,例如易受MALT1影响的性质,例如MALT1蛋白水解和/或自身蛋白水解活性的抑制,例如如以下测试化验中所示并因此指示用于医疗。
试验:
MALT1生化试验-版本1:
采用酶活性试验使用MALT1的C-结构域(氨基酸329-824)确定测试化合物(即实施例1-42)和参比化合物的IC50值。读出参数是与酶活性成正比的荧光寿命随时间的增大。
该试验使用标记有单荧光团PT14的短肽底物作为对底物的裂解状态敏感的荧光寿命探针(PT14:6-(9-氧代-9H-吖啶-10-基)-己酸酯,AssayMetrics公司,UK)。肽底物具有以下序列:Ac-Trp-Leu-Arg-Ser-Arg^Cys(PT14)-NH2(产品号BS-9117,Biosyntan,德国,从左到右为N-端至C-端的三字母编码,Ac:乙酰基基团,Cys(PT14):具有经由马来酰亚胺基团与半胱氨酸巯基基团偶联的荧光团PT14的半胱氨酸残基;肽的C-端是酰胺化的;在上文写出的底物序列之内,^表示易断裂键)。试验缓冲剂包含pH 7.5的200mM Tris/HCl,0.8M柠檬酸钠,100μM EGTA,100μM DTT和0.05%(w/v)CHAPS。酶反应的动力学表征确定了米氏(Michaelis)常数(KM)为40μM且Kcat值为34s-1。该试验为使用黑色微滴定圆孔板(产品号95040020,Thermo Electron Oy公司,芬兰)的384孔板形式建立。将测试化合物溶解在100%(v/v)DMSO或包含90%(v/v)DMSO和10%(v/v)H2O的混合物中(储备浓度为100mM)。使用100%(v/v)DMSO或包含90%(v/v)DMSO和10%(v/v)H2O的混合物来制备测试化合物的系列稀释液。
为了测定化合物的抑制作用,在384孔板的孔中将0.25μl的测试化合物与12.5μl的酶混合,并在室温(22℃)孵育60分钟。其后,加入12.5μl底物,使酶反应在室温(22℃)进行60分钟。总试验体积为25.25μl,酶和底物的最终试验浓度分别为2.5nM和1μM。试验信号随时间的增大在所报告的试验条件下保持线性至少60分钟,并直接与最高达至少2.5nM的活性酶浓度成正比。DMSO含量在0.9和1%(v/v)之间。在稀释因子为3.16的系列稀释系列中(即,半对数稀释步骤),测试化合物的最终试验浓度通常为100μM至1nM。作为对照,在多个孔中仅以通过加入DMSO代替测试化合物进行反应,导致未抑制的酶反应(即0%抑制),或通过加入试验缓冲剂而没有与DMSO混合的酶进行反应,这等同于完全抑制的反应(即100%抑制)。使用微量滴定板酶标仪例如TECAN Ultra Evolution FLT仪器记录荧光寿命,荧光激发为405nm,发射记录为450nm。可使用上述对照作为参比(用于0和100%抑制)将荧光寿命转化成抑制百分比。使用非线性回归分析软件(Origin,OriginLab公司,美国)从抑制百分比相对于抑制剂浓度的图计算IC50值。使用4参数逻辑模型拟合数据,通过下式表征:
y=A2+(A1-A2)/(1+(x/IC50)^p)
其中y是某抑制剂浓度x时的抑制%。A1是最低抑制值,A2是最大抑制值。指数p是Hill系数。
或者通过如下所述测定荧光强度确定一些实施例(即实施例43和参比化合物)的生化活性:
MALT1生化试验-版本2:
通过酶活性试验使用MALT1的C-结构域(氨基酸329-824)确定测试化合物的IC50值。读出参数是与酶活性成正比的荧光强度增大。
该试验使用标记有荧光团若丹明110(Rh110)的短肽底物作为对底物的裂解状态敏感的荧光探针。该肽底物具有以下序列:Ac-Leu-Arg-Ser-Arg^Rh110-dPro(产品名BS-3027,Biosyntan公司,德国;在底物序列之内,^表示易断裂键)。该试验缓冲剂包含pH 7.5的200mM Tris/HCl,0.8M柠檬酸钠,100μM EGTA,100μM DTT和0.05%(w/v)CHAPS。酶反应的动力学表征确定了米氏常数(KM)为40μM且kcat值为34s-1。该试验为使用黑色微量滴定孔板的384孔板形式建立。将测试化合物溶解在100%(v/v)DMSO或包含90%(v/v)DMSO和10%(v/v)H2O的混合物中(储备浓度为100mM)。使用100%(v/v)DMSO或包含90%(v/v)DMSO和10%(v/v)H2O的混合物制备测试化合物的系列稀释剂。
为了测定化合物的抑制作用,在384孔板的孔中将0.1μl测试化合物与5μl酶混合,并在室温(22℃)孵育60分钟。其后,加入5μl底物,使酶反应在室温(22℃)进行60分钟。总试验体积为10μl,酶和底物的最终试验浓度分别为2nM和1μM。DMSO含量在0.9和1%(v/v)之间。在使用3.16的稀释因子的系列稀释系列中(即半对数稀释步骤),测试化合物的最终试验浓度通常为100μM至0.007nM。作为对照,在多个孔中通过仅加入DMSO代替测试化合物来进行反应,导致未受抑制的酶反应(即0%抑制),或通过加入试验缓冲剂而没有与DMSO混合的酶来进行反应,其等同于完全抑制的反应(即100%抑制)。使用微量滴定板酶标仪例如Wallac EnVision仪器(Perkin Elmer公司)记录荧光强度,荧光激发为485nm,发射记录为535nm。使用非线性回归分析软件(Origin,OriginLab公司,美国)从抑制百分比相对于抑制剂浓度的图计算IC50值。使用4参数逻辑模型拟合数据,通过下式表征:y=A2+(A1-A2)/(1+(x/IC50)^p)
其中y是某抑制剂浓度x时的抑制%。A1是最低抑制值,A2是最大抑制值。指数p是Hill系数。
Jurkat细胞中的人IL2促进剂报告基因试验(RGA)
使转染的Jurkat克隆K22 290_H23在RPMI 1640中增殖,其中补充有10%热灭活胎牛血清、50μM的2-巯基乙醇和1mg/ml遗传霉素。在培养过程中细胞浓度应不超过1×10e6个/ml。细胞应不超过通道30。在试验之前,洗涤细胞并制备至2×10e6细胞/ml的浓度。
制备作为2倍浓度溶液的化合物稀释液,然后通过加到细胞中稀释到1/2。在96深孔板的孔中将250μl化合物稀释液和250μl细胞混合在一起。直接在深孔板中将细胞/化合物预混物在37℃、5%CO2孵育30分钟。
用化合物预孵育细胞之后,用3μg/ml抗CD28mAb(克隆15E8)+1μg/ml的PMA刺激细胞。两种共刺激剂都以10倍浓缩的溶液在培养基中稀释。将10μl共刺激剂吸取到白色96孔板中并立即加入100μl细胞/化合物混合物,一式两份。细胞在37℃和5%CO2条件下刺激5.5小时。
细胞刺激之后,向每个孔加入50μl的BriteLitePlus试剂(Perkin Elmer公司)并用Wallac EnVision读数器(Perkin Elmer公司)测定生物发光。
使用上述试验测得以下IC50:
以上采用的参比**化合物见述于WO 93/09135(实施例49),其结构如下所示:
功用
根据在以上提供的测试试验中获得的结果,考虑本发明化合物可用于治疗选自以下的疾病或病症(指征):以NF-kB活化失调为特征的病情和病症,尤其是自身免疫/免疫学和炎性病症,过敏性病症,呼吸病症和肿瘤学病症。
所述自身免疫和炎性病症可尤其选自关节炎,强直性脊柱炎,炎性肠病,溃疡性结肠炎,胃炎,胰腺炎,克罗恩氏病,乳糜泻,多发性硬化,全身性红斑狼疮,类风湿性关节炎,风湿热,痛风,器官或移植排斥,急性或慢性移植物抗宿主病,慢性同种异体移植物排斥,贝切特氏病,葡萄膜炎,牛皮癣,皮炎,特异性皮炎,皮肌炎,重症肌无力,格雷夫氏病,桥本甲状腺炎,斯耶格伦综合征,和起泡病症(例如寻常天疱疮),抗体介导的脉管炎综合征,包括ANCA-相关的血管炎,紫癜,和免疫复合血管炎(癌症或感染一期或二期)。
所述肿瘤学病症可尤其选自癌,肉瘤,淋巴瘤,白血病和胚细胞肿瘤,例如腺癌,膀胱癌,透明细胞癌,皮肤癌,脑癌,***,结肠癌,结直肠癌,子宫内膜癌,膀胱癌,脑肿瘤,乳癌,胃癌,胚细胞肿瘤,成胶质细胞瘤,肝腺瘤,霍奇金淋巴瘤,肝癌,肾癌,肺癌,卵巢癌,皮肤肿瘤,***癌,肾细胞癌,胃癌,成神经管细胞瘤,非霍奇金淋巴瘤,扩散性大B细胞淋巴瘤,套细胞淋巴瘤,边缘区淋巴瘤,T细胞淋巴瘤,尤其是塞扎里综合征(Sézarysyndrome),蕈样真菌病,皮肤T细胞淋巴瘤,T细胞急性成淋巴细胞性白血病,黑素瘤,黏膜相关的淋巴组织(MALT)淋巴瘤,多发性骨髓瘤,浆细胞赘生物,痣性恶性黑素瘤,肢端痣性黑素瘤,和鳞状细胞癌。
所述过敏性病症可尤其选自接触性皮炎,乳糜泻,哮喘,对屋尘螨的超敏性,花粉和相关的过敏原,铍中毒。所述呼吸病症可尤其选自哮喘,支气管炎,慢性阻塞性肺病(COPD),囊性纤维化,肺水肿,肺栓塞,肺炎,肺肉瘤病,硅肺病,肺纤维化,呼吸衰竭,急性呼吸窘迫综合征,原发性肺动脉高压和肺气肿。
在另一种实施方式中,本发明化合物可用于治疗类风湿性关节炎,全身性红斑狼疮,脉管病症,过敏性疾病,哮喘,慢性阻塞性肺病(COPD),急性或慢性移植排斥,移植物抗宿主病,造血来源癌症或实体瘤,慢性骨髓性白血病,骨髓性白血病,非霍奇金淋巴瘤或其他B细胞淋巴瘤。
在另一种实施方式中,本发明化合物可用于治疗BENTA疾病,铍中毒,类风湿性关节炎,全身性红斑狼疮,狼疮肾炎,多发性硬化,多肌炎,牛皮癣,ABC-DLBCL,例如在Card11中具有活化突变,MALT淋巴瘤。
除了所指出的以NF-kB失调为特征的病情和病症以外,以IL-17分泌失调为特征(除了NF-kB失调以外或独立于NF-kB失调)的病情和病症包括牛皮癣,牛皮癣关节炎,寻常痤疮,化脓性汗腺炎,特异性皮炎。
组合/联用
本发明化合物可与一种或多种其他的治疗剂同时给予,或在它们之前或之后给予。本发明化合物可通过相同或不同的给予途径独立给予,或与其他试剂在同一药物组合物中一起给予。
本发明化合物可作为唯一的活性成分给予,或者与其他药物一起给予,例如作为其他药物的助剂联合给予,所述其他药物是例如免疫抑制或免疫调节剂或其他抗炎剂,例如用于治疗或防止同种异体-或异种移植物的急性或慢性排斥或炎性或自身免疫病症,或者所述其他药物是化疗剂,例如恶性细胞抗增殖剂。
例如,本发明化合物可与以下组合使用:钙调磷酸酶抑制剂,例如环孢菌素A或FK506;mTOR抑制剂,例如雷帕霉素,40-O-(2-羟乙基)-雷帕霉素,派尔莫司-7(biolimus-7)或派尔莫司-9(biolimus-9);具有免疫抑制性质的子囊霉素,例如ABT-281,ASM981;皮质类固醇;环磷酰胺;咪唑硫嘌呤(azathioprene);甲氨蝶呤;来氟米特;咪唑立宾;霉酚酸或盐;麦考酚酸吗乙酯;IL-1β抑制剂。
在另一种实施方式中,本发明化合物与属于PI3激酶抑制剂的助剂组合。
在另一种实施方式中,本发明化合物与影响BTK(Bruton酪氨酸激酶)的助剂组合。
为了***学疾病,本发明化合物可用于与B细胞调制剂组合,例如利妥昔单抗,奥法木单抗,Btk或Syk抑制剂,PKC、PI3激酶、PDK、PIM、JAK和mTOR的抑制剂,和BH3模拟物。
本文所用术语“共同给予”或“组合给予”等表示包括向单独病人给予选择的治疗剂,意在包括其中的试剂不一定通过相同的给予途径或同时给予的治疗方案。
本文所用术语“药物组合”表示得自混合或组合超过一种活性成分并包括固定和非固定的活性成分组合的产品。术语“固定组合”表示这些活性成分例如式(I)化合物和助剂都以单一实体或剂量形式同时给予病人。术语“非固定组合”表示这些活性成分例如式(I)化合物和助剂都作为独立实体同时、并行或相继以无特定时间限制的方式给予病人,其中这样的给予方式在病人体内提供2种化合物的治疗有效水平。后者还用于鸡尾酒疗法,例如给予3种或更多种活性成分。
在一种实施方式中,本发明提供一种产品,其包含式(I)化合物和至少一种另外的治疗剂作为组合的制剂在疗法中用于同时、独立或相继应用。在一种实施方式中,该疗法是治疗由MALT1介导的疾病或病状。作为组合制剂提供的产品包括一种组合物,其在同一药物组合物中包含式(I)化合物和另外的治疗剂,或式(I)化合物和另外的治疗剂为独立形式,例如试剂盒形式。
在一种实施方式中,本发明提供包含式(I)化合物和另外的治疗剂的药物组合物。任选该药物组合物可包含如上所述的药学上可接受的赋形剂。
在一种实施方式中,本发明提供包括两种或更多种独立的药物组合物的试剂盒,所述药物组合物中的至少一种包含式(I)化合物。在一种实施方式中,该试剂盒包括独立保持所述组合物的装置,例如容器、分开的瓶、或分开的箔包。这种试剂盒的一个例子是泡罩包装,其常用于药片、胶囊等的包装。
本发明的试剂盒可用于给予不同的剂型,例如口服和胃肠外,用于以不同的剂量间隔给予独立组合物,或用于彼此相对地滴定独立组合物。为了促进顺应性,本发明的试剂盒通常包括给药指导。
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WO2023148501A1 (en) | 2022-02-03 | 2023-08-10 | C4X Discovery Limited | Heterocyclic derivatives as malt1 inhibitors |
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GB9123326D0 (en) | 1991-11-04 | 1991-12-18 | Sandoz Ltd | Improvements in or relating to organic compounds |
BR0309475A (pt) * | 2002-04-23 | 2005-03-01 | Shionogi & Co | Derivados de pirazolo-[1,5-a]-pirimidina e inibidores de nad(p)h oxidase que contêm os mesmos |
CA2514733A1 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
CA2705694C (en) | 2007-11-21 | 2015-02-24 | Katholieke Universiteit Leuven, K.U.Leuven R & D | Inhibitors of malt1 proteolytic activity and uses thereof |
SG11201607895PA (en) * | 2014-05-28 | 2016-12-29 | Novartis Ag | Novel pyrazolo pyrimidine derivatives and their use as malt1 inhibitors |
WO2018085247A1 (en) * | 2016-11-01 | 2018-05-11 | Cornell University | Compounds for malt1 degradation |
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- 2016-11-11 BR BR112018009511A patent/BR112018009511A2/pt not_active Application Discontinuation
- 2016-11-11 CA CA3003820A patent/CA3003820A1/en not_active Abandoned
- 2016-11-11 US US15/775,060 patent/US20200289514A1/en not_active Abandoned
- 2016-11-11 SG SG11201803480WA patent/SG11201803480WA/en unknown
- 2016-11-11 CN CN201680078063.6A patent/CN108473499B/zh not_active Expired - Fee Related
- 2016-11-11 WO PCT/IB2016/056787 patent/WO2017081641A1/en active Application Filing
- 2016-11-11 KR KR1020187016267A patent/KR20180080311A/ko unknown
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- 2016-11-11 MX MX2018005390A patent/MX2018005390A/es unknown
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2018
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MX2018005390A (es) | 2018-08-16 |
JP2018533610A (ja) | 2018-11-15 |
HK1252752A1 (zh) | 2019-05-31 |
PH12018500932A1 (en) | 2019-01-28 |
SG11201803480WA (en) | 2018-05-30 |
IL259169A (en) | 2018-07-31 |
AU2016352813B2 (en) | 2019-09-19 |
EP3374361A1 (en) | 2018-09-19 |
US20200289514A1 (en) | 2020-09-17 |
CA3003820A1 (en) | 2017-05-18 |
WO2017081641A1 (en) | 2017-05-18 |
KR20180080311A (ko) | 2018-07-11 |
CN108473499A (zh) | 2018-08-31 |
ZA201802743B (en) | 2019-01-30 |
BR112018009511A2 (pt) | 2018-11-06 |
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