CN116964050A - 可用作t细胞激活剂的化合物 - Google Patents
可用作t细胞激活剂的化合物 Download PDFInfo
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- CN116964050A CN116964050A CN202180093907.5A CN202180093907A CN116964050A CN 116964050 A CN116964050 A CN 116964050A CN 202180093907 A CN202180093907 A CN 202180093907A CN 116964050 A CN116964050 A CN 116964050A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
提供了具有结构(I)的化合物:或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,其中X、L、Y、R1、R2、R3和Cy如本文所定义。还提供了含有此类化合物的药物组合物以及这些化合物本身。提供了方法,其中该化合物是二酰甘油激酶α(DGKα)和二酰甘油激酶ζ(DGKζ)中的一者或两者的抑制剂或可用于治疗与DGKα和/或DGKζ活性相关的疾病、病症和病状。更具体地,提供了通过向有需要的受试者施用有效量的含有结构(I)的化合物的该药物组合物来治疗增殖性或病毒感染的方法。
Description
技术领域
本发明整体涉及激活T细胞、促进T细胞增殖和/或表现出抗肿瘤活性的化合物。本文提供了苯胺化合物、包含此类化合物的组合物以及它们的使用方法。本发明还涉及包含根据本发明的至少一种化合物的药物组合物,其可用于治疗增殖性病症,诸如癌症和病毒感染。
背景技术
人类癌症具有许多遗传和表观遗传改变,产生了潜在地可被免疫系统识别的新抗原(Sjoblom等人,Science,2006,314,268-74)。由T淋巴细胞和B淋巴细胞组成的适应性免疫系统具有强大的抗癌潜力,对多种肿瘤抗原的应答具有广泛的能力和精确的特异性。此外,免疫系统展现了相当大的可塑性和记忆组分。成功地利用适应性免疫系统的所有这些属性将使得免疫疗法在所有癌症治疗方式中是独特的。然而,尽管在临床前模型和患者中观察到对癌症的内源性免疫应答,但这种应答是无效的,并且已确立的癌症被视为“自身的”并且被免疫系统耐受。由于这种耐受状态,肿瘤可以利用若干种不同的机制来主动破坏抗肿瘤免疫。这些机制包括功能失调的T-细胞信号传导(Mizoguchi等人,Science,1992,258,1795-98),抑制性调节细胞(Facciabene等人,Cancer Res,2012,72,2162-71),以及内源性“免疫检查点”的增选,其用于下调适应性免疫应答的强度并保护正常组织免受肿瘤的附带损伤,以规避免疫破坏(Topalian等人,Curr.Opin.Immunol.,2012,24,1-6;Mellman等人,Nature,2011,480,480-489)。
二酰甘油激酶(DGK)是脂质激酶,其介导二酰基甘油向磷脂酸的转化,从而终止通过TCR信号传导途径传播的T细胞功能。因此,DGK用作细胞内检查点,并且预期DGK的抑制增强T细胞信号传导途径和T细胞激活。支持证据包括DGKα或DGKζ的敲除小鼠模型,其显示高应答性T细胞表型和改善的抗肿瘤免疫活性(Riese等人,Journal of BiologicalChemistry,2011,7,5254-5265;Zha等人,Nature Immunology,2006,12,1343)。
此外,观察到从人肾细胞癌患者中分离的肿瘤浸润性淋巴细胞过表达DGKα,这导致受抑制的T细胞功能(Prinz等人,J immunology,2012,12,5990-6000)。因此,DGKα和DGKζ被认为是癌症免疫疗法的靶标(Riese等人,Front Cell Dev Biol.,2016,4,108;Chen等人,Front Cell Dev Biol.,2016,4,130;Avila-Flores等人,Immunology and CellBiology,2017,95,549-563;Noessner,Front Cell Dev Biol.,2017,5,16;Krishna等人,Front Immunology,2013,4,178;Jing等人,Cancer Research,2017,77,5676-5686)。全长人二酰甘油激酶α同种型酶被公开为SEQ ID NO:1,并且全长人二酰甘油激酶ζ酶被公开为SEQ ID NO:2。
因此,仍然需要可用作DGKα和DGKζ中的一者或两者的抑制剂的化合物。另外,仍然需要可用作DGKα和DGKζ中的一者或两者的抑制剂的化合物,该化合物相对于其他二酰甘油激酶、蛋白激酶和/或其他脂质激酶具有选择性,以及需要用于治疗将从这样的调节中受益的疾病、病症和病状的相关组合物和方法。在恢复T细胞激活、降低抗原阈值、增强抗肿瘤功能性和/或克服一种或多种内源性免疫检查点(诸如PD-1、LAG-3和TGFβ)的抑制作用方面安全且有效的药剂对于治疗患有增殖性病症(诸如癌症)以及病毒感染的患者将具有重要意义。本发明满足了这些和其他需求,如在以下公开内容中完全提供的。
发明内容
本文描述了具有作为DGKα和DGKζ中的一者或两者的抑制剂的活性的化合物。此外,具有作为DGKα和DGKζ中的一者或两者的抑制剂的活性的化合物对其他二酰甘油激酶、蛋白激酶和/或其他脂质激酶具有选择性。提供这些化合物以用作药物,其具有对其可药性是重要的期望的稳定性、生物利用度、治疗指数和毒性值。
在一个实施方案中,提供了结构为(I)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,其中X、L、Y、R1、R2、R3和Cy如本文所定义。
在其他实施方案中,提供了具有如本文所定义的结构(I-A)、(I-B)、(I-B-顺式)或(I-B-反式)中的任一者的化合物,或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一些实施方案中,提供了具有如本文所定义的结构(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物,或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在又一些实施方案中,提供了药物组合物,该药物组合物包含载体或赋形剂和具有结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在具体实施方案中,提供了药物组合物,该药物组合物包含如本文所定义的具有结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)的结构(I)的化合物,或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一个实施方案中,提供了方法,其中化合物是二酰甘油激酶α(DGKα)和二酰甘油激酶ζ(DGKζ)中的一者或两者的抑制剂或可用于治疗与DGKα和/或DGKζ活性相关的疾病、病症和病状。
在更具体的实施方案中,二酰甘油激酶α(DGKα)或二酰甘油激酶ζ(DGKζ)依赖性病状是增殖性病症或病毒感染。
在一个实施方案中,提供了治疗二酰甘油激酶α(DGKα)或二酰甘油激酶ζ(DGKζ)依赖性病状的方法,该方法包括施用有效量的如本文所定义的结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在又一个实施方案中,提供了治疗增殖性病症或病毒感染的方法,该方法包括向有需要的受试者施用有效量的药物组合物,该药物组合物包含载体或赋形剂和具有结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在另一个实施方案中,提供了具有本文所公开的结构中的一种或多种结构的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
具体实施方式
如上所述,提供了具有作为DGKα和DGKζ中的一者或两者的抑制剂的活性的化合物。此外,具有作为DGKα和DGKζ中的一者或两者的抑制剂的活性的化合物对其他二酰甘油激酶、蛋白激酶和/或其他脂质激酶具有选择性。
除非另有定义,否则本文使用的所有技术和科学术语具有与要求保护的主题所属领域的技术人员通常理解的相同含义。应当理解,详细描述仅是示例性和说明性的,而不是对所要求保护的任何主题的限制。在本申请中,除非另外特别说明,否则单数的使用包括复数。必须注意的是,如在说明书中使用的,除非上下文另外清楚地指明,否则单数形式“一个”、“一种”和“该/所述”包括多个指代物。在本申请中,除非另有说明,否则“或”的使用是指“和/或”。此外,术语“包括”以及其他形式诸如“包含”、“含有”和“具有”的使用不是限制性的。
尽管可以在单个实施方案的上下文中描述本发明的各种特征,但是也可以单独地或以任何合适的组合来提供这些特征。相反地,尽管为了清楚起见,本发明可以在单独的实施方案的上下文中进行描述,但是本发明也可以在单个实施方案中实施。
说明书中对“一些实施方案”,“实施方案”,“一个实施方案”或“其他实施方案”的引用意味着结合这些实施方案描述的特定特征、结构或特性被包括在本发明的至少一些实施方案中,但不一定被包括在本发明的所有实施方案中。
在不脱离本发明的精神或本质属性的情况下,本发明可以其他特定形式实施。本发明包括本文所述的本发明的方面和/或实施方案的所有组合。应当理解,本发明的任何和所有实施方案可与任何其他实施方案或多个实施方案结合以描述附加实施方案。还应当理解,实施方案的每个单独要素意在与来自任何实施方案的任何和所有其他要素组合以描述附加实施方案。
如本文所用,范围和量可表示为“约”特定值或范围。约还包括确切的量。因此,“约100μL”意指“约100μL”以及“100μL”。在一些实施方案中,约意指在该值的5%以内。因此,“约100μL”意指95μL-105μL。在一些实施方案中,约意指在该值的4%以内。在一些实施方案中,约意指在该值的3%以内。在一些实施方案中,约意指在该值的2%以内。在一些实施方案中,约意指在该值的1%以内。一般来讲,术语“约”包括预期在实验误差内的量。
定义
“烷基”意指直链或支链饱和烃基团。“低级烷基”意指具有1至8个碳原子,在一些实施方案中1至6个碳原子,在一些实施方案中1至4个碳原子,以及在一些实施方案中1至2个碳原子的直链或支链烷基。直链低级烷基的示例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基。支链低级烷基的示例包括但不限于异丙基、异丁基、仲丁基、叔丁基、新戊基、异戊基和2,2-二甲基丙基。
“烯基”基团包括如上定义的直链、支链烷基基团,不同的是在两个碳原子之间存在至少一个双键。因此,烯基基团具有2至约20个碳原子,并且通常具有2至12个碳原子,或在一些实施方案中具有2至8个碳原子。示例包括但不限于-CH=CH2、-CH=CH(CH3)、-CH=C(CH3)2、-C(CH3)=CH2、-C(CH3)=CH(CH3)、-C(CH2CH3)=CH2、-CH=CHCH2CH3、-CH=CH(CH2)2CH3、-CH=CH(CH2)3CH3、-CH=CH(CH2)4CH3或乙烯基。
“炔基”包括直链和支链烷基,不同的是在两个碳原子之间存在至少一个三键。因此,炔基基团具有2至约20个碳原子,并且通常具有2至12个碳原子,或在一些实施方案中具有2至8个碳原子。示例包括但不限于-C≡CH、-C≡C(CH3)、-C≡C(CH2CH3)、-CH2C≡CH、-CH2C≡C(CH3)和-CH2C≡C(CH2CH3)等。
如本文所用,“亚烷基”意指二价烷基。直链低级亚烷基的示例包括但不限于亚甲基(即,-CH2-)、亚乙基(即,-CH2CH2-)、亚丙基(即,-CH2CH2CH2-)和亚丁基(即,-CH2CH2CH2CH2-)。如本文所用,“杂亚烷基”是其中一个或多个碳原子被杂原子替代的亚烷基,该杂原子诸如但不限于N、O、S或P。
“烷氧基”是指通过氧原子连接的如上定义的烷基(即,-O-烷基)。低级烷氧基的示例包括但不限于甲氧基、乙氧基、正丙氧基、正丁氧基、异丙氧基、仲丁氧基、叔丁氧基等。
“碳环”是指形成环结构的烷基,所述碳环可以是经取代的或未经取代的,其中环是完全饱和的、部分不饱和的或完全不饱和的,其中如果存在不饱和,环中π电子的共轭可以产生芳香性。
在一个实施方案中,碳环包含如上文所定义的环烷基。
在另一个实施方案中,碳环包含如上文所定义的芳基。
“环烷基”是指形成环结构的烷基,所述环烷基可以是经取代的或未经取代的,其中环是完全饱和的、部分不饱和的或完全不饱和的,其中如果存在不饱和,环中π电子的共轭不会产生芳香性。环烷基的示例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。在一些实施方案中,环烷基具有3个到8个环成员,然而在其他实施方案中,环碳原子的数量在3个到5个、3个到6个或3个到7个的范围内。环烷基进一步包含如但不限于降冰片基、金刚烷基、冰片基、莰稀基、异莰稀基和蒈稀基的多环环烷基和如但不限于十氢萘酯等的稠环。
代表性的取代环烷基基团可以是单取代的或多于一次取代的,诸如但不限于2,2-、2,3-、2,4-、2,5-或2,6-二取代的环己基基团或单、二或三-取代的降冰片基或环庚基基团,它们可被例如氨基、羟基、氰基、羧基、硝基、硫基、烷氧基和卤素基团取代。
“芳基”是不含杂原子的环状芳族烃。因此,芳基包括但不限于苯基、甘菊环基、庚搭烯基、联苯基、引达省基、芴基、菲基、三亚苯基、芘基、并四苯基、基、亚联苯基、蒽基和萘基。在一些实施方案中,芳基在基团的环部分中含有6个到14个碳。术语“芳基(aryl)”和“芳基(aryl groups)”包含稠环,其中至少一个环但不一定所有环是芳香族的,如稠合的芳香族-脂肪族环系统(例如,茚满基、四氢萘基等)。
“碳环烷基”是指一个或多个氢原子被碳环替代的如上定义的烷基。碳环烷基的示例包括但不限于苄基等。
如本文所用,“杂环”或“杂环基”基团包括含有3个或更多个环成员的芳族和非芳族环化合物(杂环),其中一个或多个为杂原子,诸如但不限于N、O、S或P。如本文所定义的杂环基团可为杂芳基基团或包含至少一个环杂原子的部分或完全饱和的环状基团。在一些实施方案中,杂环基团包括3至20个环成员,而其他这样的基团具有3至15个环成员。至少一个环含有杂原子,但多环体系中的每个环不需要含有杂原子。例如,二氧戊环基环和苯并二氧戊环基环体系(亚甲基二氧苯基环体系)均是本文含义内的杂环基团。被指定为C2杂环的杂环基团可以是具有两个碳原子和三个杂原子的5元环、具有两个碳原子和四个杂原子的6元环等。同样,C4杂环可以是具有一个杂原子的5元环、具有两个杂原子的6元环等。碳原子数加上杂原子数的总和等于环原子的总数。饱和杂环是指不含不饱和碳原子的杂环。
杂环基还包含稠环物质,包含具有稠合芳香族和非芳香族基团的那些。杂环基还包含含有杂原子如但不限于奎宁环基的多环体系,并且还包含具有取代基的杂环基,包括但不限于烷基、卤基、氨基、羟基、氰基、羧基、硝基、硫代基或烷氧基,与环成员之一键合。如本文所定义的杂环基可以是杂芳基或包含至少一个环杂原子的部分或完全饱和的环状基团。杂环基包括但不限于吡咯烷基、呋喃基、四氢呋喃基、二氧戊环基、哌啶基、哌嗪基、吗啉基、吡咯基、吡唑基、三唑基、四唑基、噁唑基、异噁唑基、噻唑基、吡啶基、噻吩基、苯并噻吩基、苯并呋喃基、二氢苯并呋喃基、吲哚基、二氢吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、噻萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟噪呤基、喹啉基、异喹啉基、四氢喹啉基、喹喔啉基和喹唑啉基。
在一个实施方案中,杂环基包括杂芳基。
“杂芳基”是指含有5个或更多个环成员的芳香族环部分,其中一个或多个是杂原子,诸如但不限于N、O和S。杂芳基包括但不限于基团,诸如吡咯基、吡唑基、吡啶基、哒嗪基、嘧啶基(pyrimidyl)、吡嗪基(pyrazyl)、吡嗪基(pyrazinyl)、嘧啶基(pyrimidinyl)、噻吩基、三唑基、四唑基、三嗪基、噻唑基、苯硫基、噁唑基、异噁唑基、苯并噻吩基、苯并呋喃基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、氮杂苯并咪唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、咪唑并吡啶基、异噁唑并吡啶基、噻萘基、嘌呤基、黄嘌呤基、腺嘌呤基、鸟嘌呤基、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、喹喔啉基和喹唑啉基。术语“杂芳基”和“杂芳基基团”包括稠环化合物,诸如其中至少一个环但不一定所有环是芳族的,包括四氢喹啉基、四氢异喹啉基、吲哚基和2,3-二氢吲哚基。
“杂环烷基”是指一个或多个氢原子被杂环替代的如上定义的烷基。杂环烷基的示例包括但不限于吗啉代乙基等。
“卤代”或“卤素”是指氟、氯、溴和碘。
“羟基”是指-OH。
“卤代烷基”是指一个或多个氢原子被卤素替代的如上定义的烷基。低级卤代烷基的示例包括但不限于-CF3、-CH2CF3等。
“卤代烷氧基”是指一个或多个氢原子被卤素替代的如上定义的烷氧基。低级卤代烷氧基的示例包括但不限于-OCF3、-OCH2CF3等。
“羟基烷基”是指一个或多个氢原子被-OH替代的如上定义的烷基。低级羟烷基的示例包括但不限于-CH2OH、-CH2CH2OH等。
如本文所用,术语“任选取代的”是指具有0、1或更多个取代基诸如0–25、0–20、0–10或0–5个取代基的基团(例如,烷基、碳环或杂环)。取代基包括但不限于–ORa、-NRaRb、-S(O)2Ra或-S(O)2ORa、卤素、氰基、烷基、卤代烷基、烷氧基、碳环、杂环、碳环烷基或杂环烷基,其中每个Ra和Rb独立地为H、烷基、卤代烷基、碳环或杂环,或者Ra和Rb与它们所连接的原子一起形成3-8元碳环或杂环。
“异构体”在本文中用于涵盖结构的所有手性形式、非对映异构体形式或外消旋形式,除非明确指出特定立体化学或异构形式。此类化合物可以在任何或所有不对称原子处以任何富集程度富集或解析光学异构体,如由图式可显而易见。外消旋混合物和非对映异构体混合物以及单独的光学异构体均可以被合成为基本上不含其对映异构体或非对映异构体配偶体,并且这些均在本公开的某些实施方案的范围内。由手性中心的存在产生的异构体包括一对称为“对映异构体”的不可重叠的异构体。纯化合物的单种对映异构体是旋光性的(即,它们可以旋转平面偏振光的平面并且指定为R或S)。该术语还涵盖由双键上的取代模式产生的异构体,特别是(E)-和(Z)-异构体,或顺式-和反式-异构体。E-Z构型描述了具有两个,三个或四个取代基的双键的绝对立体化学。遵循Cahn-Ingold-Prelog优先级规则(CIP规则),对双键上的每个取代基指定优先级,并且确定两个取代基中较高者在每个碳上的位置。如果较高优先级的两个基团在双键的同一侧上(彼此顺式),则将该键指定为Z(“zusammen”,德语为“一起”)。如果较高优先级的两个基团在双键的相对侧上(彼此反式),则将该键指定为E(“entgegen”,德语为“相反”)。
如本文所述,1,4-二取代环己烷可以作为顺式和反式异构体存在。每种异构体可以单独分离或作为混合物存在。混合物可以主要是一种异构体,例如99.9%或99%或90%,主要是另一种异构体,富含一种或另一种异构体(例如80/20混合物,或40/60混合物),或者是大致相等的混合物。顺式或反式的指派示于下图中。
“分离的光学异构体”是指已经从相同式的相应光学异构体基本上纯化的化合物。例如,分离的异构体可为至少约80%、至少80%或至少85%纯的。在其他实施方案中,分离的异构体为按重量计至少90%纯的或至少98%纯的、或至少99%纯的。
“基本上对映体或非对映体”纯意指一种对映体相对于另一种对映体或非对映体的对映体或非对映体富集水平为至少约80%,并且更具体地超过80%、85%、90%、95%、98%、99%、99.5%或99.9%。
术语“外消旋体”和“外消旋混合物”是指两种对映异构体的等量混合物。外消旋体被标记为“(±)”,因为它不是旋光性的(即,不会沿任一方向旋转平面偏振光,因为它的组成对映异构体彼此抵消)。
“水合物”是与水分子结合存在的化合物。结合可以包含化学计量量的水,如一水合物或二水合物,或者可以包含随机量的水。如本文所用的术语“水合物”是指固体形式;换句话说,水溶液中的化合物尽管可以是水合的,但不是如本文所用的术语的水合物。
“溶剂化物”类似于水合物,不同之处在于存在除水之外的溶剂。例如,甲醇或乙醇可以形成“醇化物”,其同样可以是化学计量的或非化学计量的。如本文所用的术语“溶剂化物”是指固体形式;换句话说,溶剂溶液中的化合物尽管可以是溶剂化的,但不是如本文所用的术语的溶剂化物。
“同位素”是指质子数相同但中子数不同的原子,并且结构(I)的化合物的同位素包括其中一个或多个原子被该原子的同位素替代的任何这样的化合物。例如,碳12是最常见的碳形式,具有六个质子和六个中子,而碳13具有六个质子和七个中子,并且碳14具有六个质子和八个中子。氢具有两种稳定同位素,氘(一个质子和一个中子)和氚(一个质子和两个中子)。虽然氟具有几种同位素,但氟19的寿命最长。因此,具有结构(I)的化合物的同位素包括但不限于结构(I)的化合物,其中一个或多个碳12原子被碳13和/或碳14原子替代,其中一个或多个氢原子被氘和/或氚替代,和/或其中一个或多个氟原子被氟19替代。
“盐”通常是指与抗衡离子结合的呈离子形式的有机化合物,如羧酸或胺。例如,在阴离子形式的酸与阳离子之间形成的盐被称为“酸加成盐”。相反地,在阳离子形式的碱与阴离子之间形成的盐被称为“碱加成盐”。
术语“药学上可接受的”是指已经批准用于人类消费并且通常是无毒的药剂。例如,术语“药学上可接受的盐”是指无毒的无机酸或有机酸和/或碱加成盐(参见例如Lit等人,Salt Selection for Basic Drugs,Int.J.Pharm.,33,201-217,1986)(以引用方式并入本文)。
本公开的化合物的药学上可接受的碱加成盐包括例如金属盐,包括碱金属盐、碱土金属盐和过渡金属盐,例如钙盐、镁盐、钾盐、钠盐和锌盐。药学上可接受的碱加成盐还包括由碱性胺例如N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制备的有机盐。
药学上可接受的酸加成盐可以由无机酸或有机酸制备。无机酸的示例包含盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸可选自脂族、脂环族、芳族、芳族脂族、杂环、羧酸和磺酸类有机酸,其示例包括甲酸、乙酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、4-羟基苯甲酸、苯乙酸、扁桃酸、马尿酸、丙二酸、草酸、扑酸(双羟萘酸)、甲磺酸、乙磺酸、苯磺酸、泛酸、三氟甲磺酸、2-羟基乙磺酸、对甲苯磺酸、磺胺酸、环己基氨基磺酸、硬脂酸、海藻酸、β羟基丁酸、水杨酸、半乳糖二酸和半乳糖醛酸。
尽管药学上不可接受的盐通常不能用作药物,但此类盐可以用作例如本文所述的化合物的合成中的中间体,例如在其通过重结晶的纯化中。
在一些实施方案中,化合物是药学上可接受的盐。在一些实施方案中,化合物是异构体。在一些实施方案中,化合物是外消旋体。在一些实施方案中,化合物是溶剂化物。在一些实施方案中,化合物是水合物。在一些实施方案中,化合物是同位素。在一些实施方案中,化合物是互变异构体。
“互变异构体”是指质子从分子的一个原子转移到同一分子的另一个原子。本文提供的化合物可以作为互变异构体存在。互变异构体是可通过氢原子的迁移、伴随单键和相邻双键的转换而相互转化的化合物。在可能发生互变异构的键合排列中,将存在互变异构体的化学平衡。
在一个实施方案中,结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物可包括互变异构体。
化合物
如上所详述,本公开提供具有作为DGKα和DGKζ中的一者或两者的抑制剂的活性的化合物。因此,一个实施方案提供了具有以下结构(I)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,其中:
R1是包含1-4个环氮原子并且被1、2、3或4个取代基取代的8-13元杂芳基,其中每个取代基独立地为OH、氧代、卤代、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基;
X为N或CH;
当X为N时,则L为键、CH2、C(O)或CHMe,并且
当X为CH时,则L为键、NH、NMe或NHC(O);
Y为N或CH;
R2每次出现时独立地为卤代、OH或OMe;
a为0、1或2;
n为0、1、2、3或4;
R3为H或C1-4烷基;并且
Cy是包含0或1个环氧原子的3-6元环烷基或杂环烷基。
在另一个实施方案中,提供了以下结构(I-A)、(I-B)、(I-B-顺式)或(I-B-反式)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在又一个实施方案中,提供了具有结构(I-A)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一些实施方案中,提供了具有结构(I-B)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一个实施方案中,提供了具有结构(I-B-顺式)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在又一个实施方案中,提供了具有结构(I-B-反式)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一些实施方案中,提供了异构体,其中具有结构(I-B-顺式)或(I-B-反式)的异构体作为混合物存在。在其他实施方案中,提供了异构体,其中混合物主要是一种异构体,即99.9%或99%或至少90%的(I-B-顺式)异构体。在其他实施方案中,提供了异构体,其中混合物是99.9%或99%或至少90%的(I-B-反式)异构体。
在又一些实施方案中,混合物富含(I-B-顺式)或(I-B-反式)异构体。在一些实施方案中,异构体是一种异构体相对于另一种异构体的80/20混合物。在又一些实施方案中,异构体是一种异构体相对于另一种异构体的60/40混合物。在一些实施方案中,异构体是一种异构体相对于另一种异构体的大致相等的混合物。在又一些实施方案中,(I-B-顺式)和(I-B-反式)作为50/50混合物存在。
在又一个实施方案中,提供了具有以下结构(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的一者的化合物:
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一个实施方案中,R1为9、10或13元杂芳基。在一些实施方案中,R1为9元杂芳基。在其他实施方案中,R1为10元杂芳基。在又一个实施方案中,R1为13元杂芳基。
在一个实施方案中,杂芳基包含1至3个环氮原子。在又一个实施方案中,杂芳基包含一个环氮原子。在一些其他实施方案中,杂芳基包含2个环氮原子。在一个实施方案中,杂芳基包含3个环氮原子。
在另一个实施方案中,R1是13元杂芳基,其中杂芳基环包含2、3或4个环氮原子。
在一个实施方案中,R1被1个取代基取代,其中取代基是OH、卤素、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基。在一些其他实施方案中,R1被2个取代基取代,其中每个取代基独立地为OH、卤代、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基;在又一些实施方案中,R1被3个取代基取代,其中每个取代基独立地为氧代、卤素、CN、NO2或C1-4烷基。在一些实施方案中,R1被4个取代基取代,其中每个取代基独立地为氧代、卤素、CN、NO2或C1-4烷基。
在另一个实施方案中,R1为:
在一个实施方案中,是未取代的。
在另一个实施方案中,-(R2)n中的n是1、2、3或4,并且其中R2每次出现时独立地为卤代、OH或OMe。在一些其他实施方案中,n为1并且其中R2为OH。在又一些实施方案中,n为1并且其中R2为OMe。在一个实施方案中,n为1或2并且其中R2为卤代。在一个实施方案中,卤代为氟。
在一个实施方案中,n为2并且其中每个R2独立地为OH和卤代。在另一个实施方案中,卤代为氟。
在又一个实施方案中,n为2并且其中每个R2独立地为OMe和卤代。
在一个实施方案中,Y为CH。
在另一个实施方案中,Y是N。
在另一个实施方案中,具有以下结构中的一者:/>
在一个实施方案中,a为0或1。
在另一个实施方案中,R3为H或甲基。在又一个实施方案中,R3为H。在又一个实施方案中,R3为甲基。
在一些实施方案中,a为0或1,并且其中R3为H。
在一个实施方案中,Cy为环丙基或包含1个氧原子的4或5元杂环烷基。在另一个实施方案中,Cy为环丙基。在又一个实施方案中,Cy为包含1个氧原子的4或5元杂环烷基。在一个实施方案中,Cy为氧杂环丁烷。
在一个实施方案中,Cy为环丙基并且其中R3为H。
在另一个实施方案中,Cy为包含1个氧原子的4或5元杂环烷基,并且其中R3为H。
在一个实施方案中,Cy为环丙基并且其中a为0。
在另一个实施方案中,Cy为环丙基并且其中a为1。
在一些实施方案中,Cy为包含1个氧原子的4或5元杂环烷基,并且其中a为0。
在又一个实施方案中,Cy为包含1个氧原子的4或5元杂环烷基,并且其中a为1。
在一些实施方案中,Cy为环丙基或氧杂环丁烷,其中a为0或1,并且其中R3为H。
结构(I)以及结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)的代表性化合物在适用的情况下包括但不限于以下表1中列出的化合物中的任一种化合物,或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
为此,代表性化合物在本文中通过其相应“化合物编号(Compound Number)”或“实施例编号(Example Number)”来鉴定,有时缩写为“化合物编号(Compound No.)”或“化合物编号(Cmpd.No.)”、“编号(No.)”、“实施例编号(Example No.)”、“实施例编号(Eg.No.)”或“实施例(Ex)”等。
表1:式(I)的化合物
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药物组合物
在某些实施方案中,提供了药物组合物,该药物组合物包含结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
在一些实施方案中,药物组合物还包含药学上可接受的载体、稀释剂或赋形剂。例如,活性化合物通常与载体混合或由载体稀释或封装在载体中,所述载体可以呈安瓿、胶囊、小药囊、纸或其他容器的形式。当活性化合物与载体混合时,或当载体用作稀释剂时,所述载体可以是充当活性化合物的媒剂、赋形剂或介质的固体、半固体或液体材料。活性化合物可以吸附在粒状固体载体上,例如含在小药囊中。合适载体的一些示例是水、盐溶液、醇、聚乙二醇、聚羟基乙氧基化蓖麻油、花生油、橄榄油、明胶、乳糖、白土、蔗糖、糊精、碳酸镁、糖、环糊精、直链淀粉、硬脂酸镁、滑石粉、明胶、琼脂、果胶、阿拉伯胶、硬脂酸或纤维素的低级烷基醚、硅酸、脂肪酸、脂肪酸胺、脂肪酸单甘油酯和甘油二酯、季戊四醇脂肪酸酯、聚氧乙烯、羟甲基纤维素和聚乙烯吡咯烷酮。类似地,载体或稀释剂可以包含如单硬脂酸甘油酯或二硬脂酸甘油酯等本领域已知的任何缓释材料,其单独或与蜡混合。
如本文所用,术语“药物组合物”是指含有与药学上可接受的载体一起配制的一种或多种本文所述的化合物或其药学上可接受的异构体、外消旋体、水合物、溶剂化物、同系物或盐的组合物,其还可包括其他添加剂,并且在政府管理机构批准下作为用于治疗哺乳动物疾病的治疗方案的一部分而制造或销售。药物组合物可以配制成例如以单位剂型(例如,片剂、胶囊、囊片、软胶囊或糖浆)口服施用;局部施用(例如,作为霜膏、凝胶、洗剂或软膏);静脉内施用(例如,作为不含颗粒栓子的无菌溶液和在适于静脉内使用的溶剂体系中);或以本文所述的任何其他制剂形式。用于选择和制备合适制剂的常规程序和成分描述于例如Remington:The Science and Practice of Pharmacy,第21版,Gennaro编辑,Lippencott Williams&Wilkins(2005年)和出版于2013年的The United StatesPharmacopeia:The National Formulary(USP 36NF31)中。
在其他实施方案中,提供了制备具有本文所述的化合物的组合物的方法,这些方法包括将本公开的化合物与药学上可接受的载体或稀释剂一起配制。在一些实施方案中,药学上可接受的载体或稀释剂适于口服施用。在一些此类实施方案中,方法可以进一步包含将组合物调配成片剂或胶囊的步骤。在其他实施方案中,药学上可接受的载体或稀释剂适于肠胃外施用。在一些此类实施方案中,方法进一步包含冻干组合物以形成冻干制剂的步骤。
如本文所用,术语“药学上可接受的载体”是指除所公开的化合物或其药学上可接受的异构体、外消旋体、水合物、溶剂化物、同系物或盐之外(例如,能够悬浮或溶解活性化合物的载体)并且在患者中具有无毒且非炎性特性的任何成分。赋形剂可以包含例如:抗粘剂、抗氧化剂、粘合剂、包衣、压缩助剂、崩解剂、染料(着色剂)、润肤剂、乳化剂、填充剂(稀释剂)、成膜剂或包衣、调味剂、香料、助流剂(流动增强剂)、润滑剂、防腐剂、印刷油墨、吸附剂、悬浮剂或分散剂、甜味剂或水合水。示例性赋形剂包括但不限于:丁基化羟基甲苯(BHT)、碳酸钙、磷酸钙(二元)、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交聚维酮、半胱氨酸、乙基纤维素、明胶、羟丙基纤维素、羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露醇、甲硫氨酸、甲基纤维素、对羟基苯甲酸甲酯、微晶纤维素、聚乙二醇、聚乙烯吡咯烷酮、聚维酮、预胶化淀粉、对羟基苯甲酸丙酯、棕榈酸视黄酯、虫胶、二氧化硅、羧甲基纤维素钠、柠檬酸钠、羧基乙酸淀粉钠、山梨糖醇、淀粉(玉米)、硬脂酸、硬脂酸、蔗糖、滑石粉、二氧化钛、维生素A、维生素E、维生素C和木糖醇。
调配物可以与不会与活性化合物发生有害反应的辅助试剂混合。此类添加剂可以包含润湿剂、乳化剂和悬浮剂、影响渗透压的盐、缓冲剂和/或着色物质、防腐剂、甜味剂或调味剂。如果期望的话,也可以对组合物进行灭菌。
施用途径可以是将本公开的活性化合物有效转运到适当的或期望的作用部位的任何途径,诸如口服、鼻、肺、颊、皮下、皮内、透皮或肠胃外,例如直肠、贮库、皮下、静脉内、尿道内、肌内、鼻内、眼用溶液或软膏,优选口服途径。
剂型可以每天施用一次,或每天施用多于一次,如每天两次或三次。另选地,如果处方医师认为合适的话,则剂型的施用频率可以低于每天,诸如每隔一天或每周。给药方案包括例如剂量滴定到对于待治疗的适应症必需或有用的程度,从而使患者的身体适应治疗和/或最小化或避免与治疗相关的不希望的副作用。其他剂型包含延迟或控释形式。合适的剂量方案和/或形式包括例如在Physicians’Desk Reference的最新版本中阐述的那些,该文献以引用方式并入本文。
抑制DGK活性和治疗与DGKα和/或DGKζ相关的疾病
在某些实施方案中,本文所述的是用于抑制至少一种二酰甘油激酶的活性的方法,该方法包括使二酰甘油激酶与如本文所述的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物接触。在一些实施方案中,二酰甘油激酶是二酰甘油激酶α(DGKa)或二酰甘油激酶ζ(DGKζ)。在某些实施方案中,公开了治疗患有与DGKα、DGKζ或DGKα和DGKζ两者的活性相关联的疾病或病症的受试者的方法,该方法包括向有需要的受试者施用药学有效量的结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物。
如本文所用,术语“施用”是指通过任何可接受的方式或途径(包括(例如)通过口服、肠胃外(例如静脉内)或局部施用)向受试者提供化合物、包含该化合物的药物组合物。
如本文所用,术语“治疗”是指改善疾病或病理状况的体征或症状的干预。如本文所用,关于疾病、病理状况或症状的术语“治疗”也是指治疗的任何可观察到的有益效果。有益效果可以通过例如以下来证明:易感受试者中疾病的临床症状的延迟发作、疾病的一些或所有临床症状的严重程度降低、疾病的进展减慢、疾病复发的次数降低、受试者的整体健康或福祉的改善或者通过本领域众所周知的对特定疾病具有特异性的其他参数来证明。预防性治疗是对未表现出疾病体征或仅表现出早期体征的受试者施用的治疗,目的是降低发生病理的风险。治疗性治疗是在疾病的体征和症状出现后给予受试者的治疗。该术语涵盖治疗哺乳动物、特别是人的疾病状态,并且包括:
(a)预防疾病状态在哺乳动物中发生,特别是当这样的哺乳动物易患疾病状态但尚未被诊断为患有该疾病状态时;
(b)抑制疾病状态,即阻止其发展;以及/或者
(c)缓解疾病状态,即引起疾病状态的消退。
如本文所用,术语“DGK介导的”或“DGK调节的”或“DGK依赖性”疾病或病症意指已知DGK或其突变体在其中起作用的任何疾病或其他有害病状。因此,本申请的另一个实施方案涉及治疗已知DGKα、DGKζ或DGKα和DGKζ两者或其突变体在其中起作用的一种或多种疾病或减轻其严重程度。具体地,本申请涉及一种治疗选自病毒感染或增殖性病症(诸如癌症)的疾病或病状或减轻其严重程度的方法,其中所述方法包括向有需要的患者施用根据本申请的结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物。
如本文所用,术语“受试者”是指动物(例如,哺乳动物,诸如人)。要根据本文所述的方法治疗的受试者可以是已被诊断患有病毒感染或增殖性病症(诸如癌症)的受试者。诊断可以通过本领域已知的任何方法或技术进行。本领域技术人员将理解,根据本公开内容要治疗的受试者可以已经接受标准测试,或者可以在未经检查的情况下被鉴定为由于存在一种或多种与疾病或病状相关联的风险因素而有风险。
如本文所用,术语“有效量”是指足以在用药剂治疗的受试者中实现期望作用的指定药剂的量。理想地,药剂的有效量是足以抑制或治疗疾病而不在受试者中引起显著毒性的量。药剂的有效量将取决于被治疗的受试者、病痛的严重程度和药物组合物的施用方式。根据本公开,本领域技术人员将理解确定足以在受试者中实现期望效果的所公开的化合物的有效量的方法。
如本文所用,术语“治疗有效量”或“药物有效量”旨在包括有效地充当DGKα和/或DGKζ的抑制剂或有效地治疗或预防病毒感染和增殖性病症(诸如癌症)的单独的本发明化合物的量或与其他活性成分组合的本发明化合物的量。
如本文所用,术语“调节(modulate)”或“调节(modulating)”是指提高或降低一种或多种激酶的活性的能力。因此,本发明的化合物可用于通过使激酶与本文所述的任何一种或多种化合物或组合物接触来调节激酶的方法中。在一些实施方案中,化合物可以充当一种或多种激酶的抑制剂。在一些实施方案中,化合物可用于刺激一种或多种激酶的活性。在其他实施方案中,本发明的化合物可用于通过施用调节量的如本文所述的化合物来调节需要调节受体的个体中的激酶的活性。
如本文所用,术语“接触”是指在体外系统或体内系统中将所指示的部分集合在一起。例如,使DGKα和DGKζ酶与结构(I)的化合物“接触”包括向患有DGKα和DGKζ的个体或患者(诸如人)施用本发明的化合物,以及例如将结构(I)的化合物引入包含含有DGKα和DGKζ酶的细胞或纯化制剂的样品中。
术语“DGKα和DGKζ抑制剂”是指能够抑制T细胞中的二酰甘油激酶α和/或二酰甘油激酶ζ(DGKα和DGKζ)的活性从而导致T细胞刺激的药剂。DGKα和DGKζ抑制剂可以是可逆或不可逆DGKα和DGKζ抑制剂。“可逆DGKα和DGKζ抑制剂”是在催化位点处或非催化位点处可逆地抑制DGKα和DGKζ酶活性的化合物,并且“不可逆DGKα和DGKζ抑制剂”是通过与酶形成共价键而不可逆地破坏DGKα和DGKζ酶活性的化合物。
如本文所用,术语“细胞”是指体外、离体或体内的细胞。在一些实施方案中,离体细胞可以是从生物体诸如哺乳动物切除的组织样品的一部分。在一些实施方案中,体外细胞可以是细胞培养物中的细胞。在一些实施方案中,体内细胞是生活在生物体诸如哺乳动物中的细胞。
结构(I)的化合物可以抑制二酰甘油激酶α(DGKα)和/或二酰甘油激酶ζ(DGKαζ)的活性。例如,通过施用抑制量的结构(I)的化合物或其盐,结构(I)的化合物可用于抑制需要调节DGKα和DGKζ的细胞或个体中的DGKα和DGKζ的活性。
结构(I)的化合物以及包含至少一种结构(I)的化合物的药物组合物可用于治疗或预防与T细胞中的DGK靶标抑制相关的任何疾病或病状。这些包括病毒和其他感染(例如,皮肤感染、GI感染、尿道感染、泌尿生殖感染、全身性感染)和增殖性病症(例如,癌症)。
在一些实施方案中,提供了抑制激酶的方法,该方法包括使该激酶与有效量的结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素、或其组合物接触,用于治疗增殖性病症或病毒感染。
在一些实施方案中,激酶是DGK。在一些实施方案中,激酶是DGKα。在一些实施方案中,激酶是DGKζ。
在一些实施方案中,描述了用于治疗DGK依赖性病状的方法,该方法包括向有需要的受试者施用有效量的结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或药物组合物。在一些实施方案中,DGK依赖性病状是DGKα依赖性病状。在一些实施方案中,DGK依赖性病状是DGKζ依赖性病状。在一些实施方案中,DGK依赖性病状是感染。在一些实施方案中,DGK依赖性病状是病毒感染。在一些实施方案中,DGK依赖性病症是癌症。
在一些实施方案中是结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、互变异构体、同位素或药物组合物在制造药物中的用途。
在一些实施方案中,药物用于治疗癌症。在一些实施方案中,药物用于治疗自身免疫性疾病。
在一些方面,本发明提供了治疗患有或易患与T细胞中DGK靶标抑制相关联的医学病状的患者的方法。可以治疗多种医学病状。该方法包括向患者施用治疗有效量的包含结构(l)的化合物和/或其药学上可接受的盐、其立体异构体或其互变异构体的组合物。例如,本文所述的化合物可用于治疗或预防病毒感染和增殖性疾病诸如癌症。
本发明还提供了通过以下方式治疗个体(例如,患者)中与DGKα和DGKζ的活性或表达(包括异常活性和/或过表达)相关联的疾病的方法:向需要这样的治疗的个体施用治疗有效量或剂量的结构(I)的化合物或其药物组合物。示例性疾病可包括与DGKα和DGKζ酶的表达或活性(诸如过表达或异常活性)直接或间接相关的任何疾病、病症或病状。DGKα和/或DGKζ相关联的疾病还可包括可以通过调节DGKα和DGKζ酶活性来预防、改善或治愈的任何疾病、病症或病状。DGKα和DGKζ相关联的疾病的示例包括癌症和病毒感染,诸如HIV感染、乙型肝炎和丙型肝炎。
结构(I)的化合物以及包含至少一种结构(I)的化合物的药物组合物可被施用于动物,优选地为哺乳动物(例如,驯养动物、猫、狗、小鼠、大鼠),更优选地为人。可使用任何施用方法将化合物或药物组合物递送至患者。在某些实施方案中,结构(I)的化合物或包含至少一种结构(I)的化合物的药物组合物口服施用。在其他实施方案中,结构(I)的化合物或包含至少一种结构(I)的化合物的药物组合物肠胃外施用。
本文描述了治疗患有增殖性病症或病毒感染的受试者的方法,该方法包括向有需要的受试者施用药学有效量的如本文所述的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、互变异构体、同位素或组合物。
在一个实施方案中,提供了治疗增殖性病症或病毒感染的方法,该方法包括向有需要的受试者施用有效量的药物组合物,该药物组合物包含载体或赋形剂和具有结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
本文还描述了结构(I)的化合物或其药学上可接受的盐类、溶剂化物、水合物、异构体、同位体或组合物用于抑制选自二酰甘油激酶α(DGKa)和二酰甘油激酶ζ(DGKζ)的二酰甘油激酶中的至少一种二酰甘油激酶的活性的用途。
在一个实施方案中,提供了结构(I)的化合物或其药学上可接受的盐类、溶剂化物、水合物、异构体、同位体或组合物用于抑制选自二酰甘油激酶α(DGKa)和二酰甘油激酶ζ(DGKζ)的二酰甘油激酶中的至少一种二酰甘油激酶的活性的用途。
本文还描述了结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物用于治疗与DGKα或DGKζ、或DGKα和DGKζ两者的活性相关联的疾病或病症的用途。
在一个实施方案中,提供了结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素、或组合物用于治疗与DGKα或DGKζ、或DGKα和DGKζ两者的活性相关联的疾病或病症的用途。
还提供了结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物用于治疗增殖性病症或病毒感染的用途。
在一个实施方案中,提供了结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物用于治疗增殖性病症或病毒感染的用途。
癌症
在一些实施方案中,增殖性病症是癌症。因此,在一些方面,本发明提供了通过以下方式治疗个体(例如,患者)中与DGKα和DGKζ的活性或表达(包括异常活性和/或过表达)相关联的癌症的方法:向需要这样的治疗的个体施用治疗有效量或剂量的结构(I)的化合物或其药物组合物。
可用结构(I)的化合物治疗的癌症类型包括但不限于脑癌、皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、血癌、肺癌和骨癌。此类癌症类型的示例包括成神经母细胞瘤、肠癌(诸如直肠癌、结肠癌、常见腺瘤性息肉病癌及遗传性非息肉病结肠直肠癌)、食道癌、唇癌、喉癌、咽癌、舌癌、唾腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒膜癌、胰腺癌、前列腺癌、睪丸癌、乳腺癌、尿道癌、黑色素瘤、脑瘤(诸如胶质母细胞瘤、星形细胞瘤、脑膜瘤、髓母细胞瘤及外周神经外胚层瘤)、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、伯基特氏淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-细胞白血病淋巴瘤、弥漫性大B-细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑色素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因氏肉瘤和浆细胞瘤。
在一些实施方案中,癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、肾癌、膀胱癌、头颈癌、淋巴瘤、白血病或黑色素瘤。在一些实施方案中,癌症是结肠癌。在一些实施方案中,癌症是胰腺癌。在一些实施方案中,癌症是乳腺癌。在一些实施方案中,癌症是前列腺癌。在一些实施方案中,癌症是肺癌。在一些实施方案中,癌症是卵巢癌。在一些实施方案中,癌症是宫颈癌。在一些实施方案中,癌症是肾癌。在一些实施方案中,癌症是肾癌。在一些实施方案中,癌症是头颈癌。在一些实施方案中,癌症是淋巴瘤。在一些实施方案中,癌症是白血病。在一些实施方案中,癌症是黑色素瘤。
在一个实施方案中,提供了结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素、或其组合物用于治疗增殖性病症的用途。
在一些实施方案中,增殖性病症是癌症。在一些实施方案中,癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、肾癌、头颈癌、淋巴瘤、白血病和黑色素瘤。
还提供了结构(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物用于制造药物的用途。
感染
在其他方面,本发明提供了通过以下方式治疗个体(例如,患者)中与DGKα和DGKζ的活性或表达(包括异常活性和/或过表达)相关联的感染的方法:向需要这样的治疗的个体施用治疗有效量或剂量的结构(I)的化合物或其药物组合物。在一些实施方案中,感染是病毒感染。在一些实施方案中,感染是慢性病毒感染。
在一个实施方案中,提供了结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素、或其组合物用于治疗病毒感染的用途。
可使用本发明的组合治疗来治疗的慢性病毒感染包括但不限于由以下引起的疾病:丙型肝炎病毒(HCV)、人乳头瘤病毒(HPV)、巨细胞病毒(CIVIV)、单纯疱疹病毒(HSV)、EB病毒(EBV)、水痘带状疱疹病毒、柯萨奇病毒、人免疫缺陷病毒(HIV)。值得注意的是,寄生虫感染(例如,疟疾)也可以通过上述方法进行治疗,其中任选地添加已知用于治疗寄生虫病状的化合物来代替抗病毒剂。
组合疗法
一种或多种附加药剂或治疗方法(诸如例如抗病毒剂、化疗剂或其他抗癌剂、免疫增强剂、免疫抑制剂、辐射、抗肿瘤和抗病毒疫苗、细胞因子疗法(例如,IL2和GM-CSF)和/或酪氨酸激酶抑制剂)可任选地与结构(I)的化合物组合使用以用于治疗与DGKα和DGKζ相关联的疾病、病症或病状。药剂可以与本发明的化合物以单一剂型组合,或者药剂可以作为单独剂型同时或顺序施用。
在一些实施方案中,包含结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,与至少一种药学上可接受的载体、稀释剂或赋形剂的药物组合物还包含第二治疗剂。
组合疗法旨在包括以顺序方式施用这些治疗剂,即其中每种治疗剂在不同时间施用,以及以基本上同时的方式施用这些治疗剂或治疗剂中的至少两种治疗剂。基本上同时施用可以例如通过向受试者施用具有固定比率的每种治疗剂的单一剂型或治疗剂中的每种治疗剂的多个单一剂型来实现。每种治疗剂的顺序或基本上同时施用可通过任何合适的途径实现,包括但不限于口服途径、静脉内途径、肌内途径以及通过粘膜组织直接吸收。治疗剂可以通过相同的途径或通过不同的途径施用。例如,所选择的组合的第一治疗剂可通过静脉内注射施用,而组合的其他治疗剂可口服施用。另选地,例如,所有治疗剂可口服施用,或者所有治疗剂可通过静脉内注射施用。组合疗法还可包括将上述治疗剂与其他生物活性成分和非药物疗法(例如,手术或放射治疗)进一步组合施用。在组合疗法还包括非药物治疗的情况下,非药物治疗可以在任何合适的时间进行,只要实现来自治疗剂和非药物治疗的组合的共同作用的有益效果即可。例如,在适当的情况下,当非药物治疗暂时从治疗剂的施用中移除时,可能数天或甚至数周,仍然实现有益效果。
在一些方面,本发明提供了结构(I)的化合物和/或其药学上可接受的盐、其立体异构体或其互变异构体以及附加治疗剂的组合制剂,以用于治疗和/或预防与T细胞中DGK靶标抑制相关联的多种疾病或病症的同时、分开或顺序使用。
在一个方面,T细胞应答可以通过结构(I)的化合物以及以下中的一者或多者的组合来刺激:
(i)抑制T细胞激活的蛋白质的拮抗剂(例如,免疫检查点抑制剂)诸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳凝素9、CEACAM-1、BTLA、CD69、半乳凝素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1和TIM-4;以及
(ii)刺激T细胞激活的蛋白质的激动剂,诸如B7-1、B7-2、CD28、4-1BB(CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3和CD28H。
与抗癌剂的组合
在另一个方面,结构(I)的化合物可以与抗癌剂组合施用。抗癌剂包括例如小分子药物、抗体或其他生物或小分子。生物免疫肿瘤剂的示例包括但不限于癌症疫苗、抗体和细胞因子。在一个方面,抗体是单克隆抗体。在另一个方面,单克隆抗体是人源化的或人的。
在一个方面,免疫肿瘤剂是刺激(包括共刺激)受体的激动剂;或T细胞上的抑制(包括共抑制)信号的拮抗剂,这两者均导致扩增抗原特异性T细胞应答(通常称为免疫检查点调节剂)。刺激和抑制分子中的一些是免疫球蛋白超家族(IgSF)的成员。与共刺激或共抑制受体结合的膜结合配体的一个重要家族是B7家族,其包括B7-l、B7-2、B7-HI(PD-L1)、B7-DC(PD-L2)、B7-H2(ICOS-L)、B7-H3、B7-H4、B7-H5(VISTA)和B7-H6。结合共同刺激或共抑制受体的另一个膜结合配体家族是结合同源TNF受体家族成员的TNF分子家族,其包括CD40和CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137(4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEG1/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1、淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
用于治疗癌症的组合疗法的又一些药剂包括NK细胞上的抑制受体的拮抗剂或NK细胞上的激活受体的激动剂。例如,KIR的拮抗剂,诸如利瑞鲁单抗。
用于治疗癌症的组合疗法的又一些药剂包括抑制或消除巨噬细胞或单核细胞的药剂,包括但不限于CSF-1R拮抗剂,诸如CSF-1R拮抗剂抗体,包括RG-7155或FPA-008。
用于治疗癌症的组合疗法的又一些药剂包括连接阳性共刺激受体的激动剂,减弱通过抑制受体的信号传导的阻断剂,拮抗剂,以及全身性地增加抗肿瘤T细胞频率的一种或多种药剂,克服肿瘤微环境中不同免疫抑制途径(例如阻断抑制性受体结合,诸如PD-L1/PD-1相互作用)的药剂;耗尽或抑制Tregs,诸如使用抗CD25单克隆抗体(例如,达利珠单抗);或通过离体抗-CD25珠耗尽;抑制代谢酶诸如IDO,或逆转/预防T细胞无反应性或耗竭;以及在肿瘤位点触发先天免疫激活和/或炎症的药剂。
用于治疗癌症的组合疗法的又一些药剂包括CTLA-4拮抗剂,诸如拮抗性CTLA-4抗体。合适的CTLA-4抗体包括例如YERVOY(伊匹单抗)或曲美木单抗。
用于治疗癌症的组合疗法的又一些药剂包括PD-1拮抗剂,诸如拮抗性PD-1抗体。合适的PD-1抗体包括例如OPDIVO(纳武单抗)、KEYTRUDA(派姆单抗)、MEDI-0680(AMP-514;WO2012/145493)或匹地利珠单抗(CT-011)。靶向PD-1受体的另一种方法是由PD-L2的细胞外结构域(B7-DC)与IgG1的Fe部分融合组成的重组蛋白,称为AMP-224。
用于治疗癌症的组合疗法的又一些药剂包括PD-L1拮抗剂,诸如拮抗性PD-L1抗体。合适的PD-L1抗体包括例如MPDL3280A(RG7446;WO2010/077634)、度伐鲁单抗(MEDI4736)、BMS-936559(WO2007/005874)以及MSB0010718C(WO2013/79174)。
用于治疗癌症的组合疗法的又一些药剂包括LAG-3拮抗剂,诸如拮抗性LAG-3抗体。合适的LAG3抗体包括例如BMS-986016(WO10/19570,WO14/08218)或IMP-731或IMP-321(WO08/132601,WO09/44273)。
用于治疗癌症的组合疗法的又一些药剂包括CD137(4-1BB)激动剂,诸如激动性CD137抗体。合适的CD137抗体包括例如乌瑞芦单抗和PF-05082566(WO12/32433)。
用于治疗癌症的组合疗法的又一些药剂包括GITR激动剂,诸如激动性GITR抗体。合适的GITR抗体包括例如BMS-986153、BMS-986156、TRX-518(WO06/105021、WO09/009116)和MK-4166(WO11/028683)。
用于治疗癌症的组合疗法的又一些药剂包括IDO拮抗剂。合适的IDO拮抗剂包括例如INCB-024360(WO2006/122150,WO07/75598,WO08/36653,WO08/36642)、吲哚莫德、BMS-986205或NLG-919(WO09/73620,WO09/1156652,WO11/56652,WO12/142237)。
用于治疗癌症的组合疗法的又一些药剂包括OX40激动剂,诸如激动性OX40抗体。合适的OX40抗体包括例如MEDI-6383或MEDI-6469。
用于治疗癌症的组合疗法的又一些药剂包括OX40L拮抗剂,诸如拮抗性OX40L抗体。合适的OX40L拮抗剂包括例如RG-7888(WO06/029879)。
用于治疗癌症的组合疗法的又一些药剂包括CD40激动剂,诸如激动性CD40抗体。
用于治疗癌症的组合疗法的又一些药剂包括CD40拮抗剂,诸如拮抗性CD40抗体。合适的CD40抗体包括例如卢卡木单抗或达西组单抗。
用于治疗癌症的组合疗法的又一些药剂包括CD27激动剂,诸如激动性CD27抗体。合适的CD27抗体包括例如伐立鲁单抗。
用于治疗癌症的组合疗法的又一些药剂包括例如烷化剂(包括但不限于氮芥、乙烯亚胺衍生物、烷基磺酸酯、亚硝基脲和三氮烯),诸如尿嘧啶氮芥、5氮芥、环磷酰胺(CYTOXAN)、异环磷酰胺、美法仑、苯丁酸氮芥哌泊溴烷、三亚乙基蜜胺、三亚乙基硫代磷酰胺、白消安、卡莫司汀、洛莫司汀、链佐星、达卡巴嗪和替莫唑胺。合适的化疗剂或其他抗癌剂还包括例如抗代谢剂(包括但不限于叶酸拮抗剂、嘧啶类似物、嘌呤类似物和腺苷脱氨酶抑制剂),诸如氨甲蝶呤、5-氟尿嘧啶、氟尿苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨。合适的化疗剂或其他抗癌剂还包括例如某些天然产物及其衍生物(例如,长春花生物碱、抗肿瘤抗生素、酶、淋巴因子和表鬼臼毒素),诸如长春花碱、长春新碱、长春地辛、博来霉素、更生霉素、道诺霉素、多柔比星、表柔比星、伊达比星、ara-c、紫杉醇(Taxol)、光神霉素、脱氧助间型霉素、丝裂霉素-C、L-天冬酰胺酶、干扰素(特别是IFN-α)、依托泊和替尼泊苷。合适的化疗剂或其他抗癌剂还包括例如表鬼臼毒素;抗肿瘤酶;拓扑异构酶抑制剂;丙卡巴肼;米托蒽醌;铂配位络合物,诸如顺铂和卡铂;生物反应调节剂;生长抑制剂;抗激素治疗剂;甲酰四氢叶酸;替加氟;造血生长因子;诺维本、CPT-11、阿那曲唑、来曲唑、卡培他滨、雷洛昔芬、屈洛昔芬;抗体治疗剂诸如曲妥珠单抗(HERCEPTIN),共刺激分子诸如CTLA-4、4-1BB和PD-1的抗体,或细胞因子(IL-1O或TGF-β)的抗体;以及阻断免疫细胞迁移的药剂,诸如趋化因子受体(包括CCR2和CCR4)的拮抗剂。
用于治疗癌症的组合疗法的又一些药剂包括抗癌疫苗,包括树突细胞、合成肽、DNA疫苗和重组病毒。
用于治疗癌症的组合疗法的又一些药剂包括信号转导抑制剂(STI)。“信号转导抑制剂”是在癌细胞的正常功能中选择性抑制信号传导途径中的一个或多个关键步骤从而导致细胞凋亡的药剂。合适的STI包括但不限于:
(i)bcr/abl激酶抑制剂,诸如例如STI 571(GLEEVEC);
(ii)表皮生长因子(EGF)受体抑制剂,诸如例如激酶抑制剂(IRESSA,SSI-774)和抗体(Imclone:C225[Goldstein等人,Clin.Cancer Res,1995,1,1311-1318;以及Abgenix:ABX-EGF);
(iii)her-2/neu受体抑制剂,诸如法呢基转移酶抑制剂(FTI),诸如例如L-744,832(Kohl等人,Nat.Med.,1995,1(8),792-797);
(iv)Akt家族激酶或Akt途径的抑制剂,诸如例如雷帕霉素;
(v)细胞周期激酶抑制剂,诸如例如夫拉平度和UCN-01;以及
(vi)磷脂酰肌醇激酶抑制剂,诸如例如LY294002。
在黑色素瘤的治疗中,用于与结构(I)的化合物组合使用的合适药剂包括:达卡巴嗪(DTIC),任选地连同其他化学疗法药物诸如卡氮芥(BCNU)和顺铂;“Dartmouth方案”,其由DTIC、BCNU、顺铂和他莫昔芬;顺铂、长春花碱和DTIC、替莫唑胺或YERVOYTM的组合组成。结构(I)的化合物也可以与免疫疗法药物(包括细胞因子诸如干扰素α、白介素2和肿瘤坏死因子(TNF))组合用于黑色素瘤的治疗中。
结构(I)的化合物也可与疫苗疗法组合用于黑色素瘤的治疗中。抗黑色素瘤疫苗在某些方面类似于用于预防由病毒如脊髓灰质炎、麻疹和腮腺炎引起的疾病的抗病毒疫苗。可将称作抗原的弱化黑色素瘤细胞或黑色素瘤细胞的部分注射至患者中以刺激身体的免疫系统以破坏黑色素瘤细胞。
局限于手臂或腿的黑色素瘤也可利用包含一种或多种结构(I)的化合物的药剂的组合,使用高温分离肢体灌注技术治疗。该治疗方案暂时将涉及肢体的循环与身体其余部分分开并且将高剂量的化学疗法注射到供养肢体的动脉,因此向肿瘤区提供高剂量而不将内部器官暴露于这些剂量,否则这些剂量可引起严重副作用。
与抗病毒剂的组合
预期与结构(I)的化合物组合使用的合适的抗病毒剂包括核苷和核苷酸逆转录酶抑制剂(NRTI)、非核苷逆转录酶抑制剂(NNRTi)、蛋白酶抑制剂和其他抗病毒药物。
合适的NRTI的示例包括齐多夫定(AZT);地达诺新(ddl);扎西他滨(ddC);司他夫定(d4T);拉米夫定(3TC):阿巴卡韦(1592U89);阿德福韦酯[双(POM)-PMEA];洛布卡韦(BMS-180194);BCH-I0652,恩曲他滨[(-)-FTC];β-L-FD4(也称为β-L-D4C,并命名为β-L-2',3'-双脱氧-5-氟胞苷);DAPD,((-)-β-D-2,6-二氨基-嘌呤二氧戊环);以及洛德腺苷(FddA)。
合适的NNRTI的示例包括奈韦拉平(BI-RG-587);地拉韦啶(BHAP,U-90152);依法韦仑(DMP-266);PNU-142721,AG-1549;MKC-442(l-(乙氧基-甲基)-5-(]-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶二酮);以及(+)-胡桐素A(NSC-675451)和B。
合适的蛋白酶抑制剂的示例包括沙奎那韦(Ro 31-8959);利托那韦(ABT-538);茚地那韦(MK-639);奈非那韦(AG-1343);安普那韦(141W94);拉西那韦(BMS-234475);DMP-450;BMS-2322623,ABT-378和AG-1549。
其他抗病毒剂包括羟基脲、利巴韦林、IL-2、IL-12、喷他夫西和Yissum项目编号11607。
本发明还提供药物组合物,其包含与一种结构(I)的化合物、药学上可接受的载体、任选至少一种化疗药物以及任选至少一种抗病毒剂。
施用途径
对于本文所述的用途中的任何用途,本发明的化合物可以通过任何合适的方式施用,例如口服,诸如片剂、胶囊剂(其各自包括持续释放或定时释放制剂)、丸剂、散剂、颗粒剂、酏剂、酊剂、混悬剂(包括纳米混悬剂、微混悬剂、喷雾干燥分散剂)、糖浆剂和乳剂;舌下;经颊;肠胃外,诸如通过皮下、静脉内、肌肉内或跗骨内注射或输注技术(例如,作为无菌可注射水性或非水性溶液或悬浮液);经鼻,包括向鼻膜施用,诸如通过吸入喷雾;经局部,诸如以乳霜或软膏的形式;或者经直肠,诸如以栓剂的形式。它们可以单独施用,但通常与基于所选择的施用途径和标准药物实践选择的药物载体一起施用。
在一个实施方案中,本发明提供了口服药物组合物,其包含结构(I)或结构(I-A)、(I-B)、(I-B-顺式)、(I-B-反式)、(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的任一者的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,连同至少一种药学上可接受的口服载体、稀释剂或赋形剂。
试剂盒
本发明还包括可用于例如治疗或预防DGKα和DGKζ相关联的疾病或病症以及本文提及的其他疾病的药物试剂盒,其包括一个或多个含有药物组合物的容器,该药物组合物包含治疗有效量的结构(I)的化合物。如果需要,此类试剂盒还包括各种常规药物试剂盒组分中的一者或多者,诸如例如,具有一种或多种药学上可接受的载体的容器,对本领域技术人员显而易见的附加容器。指示待施用的组分的量、施用指南和/或用于混合组分的指南的作为插入物或作为标签的说明书也可包括在试剂盒中。
一般方法
具有结构(I)的化合物可以使用本领域技术人员已知的标准合成技术合成。例如,本公开的化合物可使用下文描述并且在方案1-14中阐述的一般合成程序来合成。
对这些方法的修改对本领域技术人员来说是显而易见的。为此,本文所描述的反应、过程和合成方法不限于以下实验部分中描述的特定条件,而是旨在作为对本领域技术人员的指导。例如,反应可以在任何合适的溶剂或其他试剂中进行以进行必要的转化。通常,合适的溶剂是质子或非质子溶剂,其在反应进行的温度(即,可以在冷冻至沸腾温度范围内的温度)处基本上不与反应物、中间体或产物反应。给定的反应可以在一种溶剂或多于一种溶剂的混合物中进行。取决于具体的反应,可以采用用于反应后具体后处理的合适的溶剂。
除非另有说明,否则采用质谱(MS)、液相色谱-质谱(LCMS)、NMR、HPLC、蛋白质化学、生物化学、重组DNA技术和药理学的常规方法。化合物使用标准有机化学技术例如March’s Advanced Organic Chemistry,第7版,John Wiley and Sons,Inc.(2013)中描述的那些来制备。可以采用本文所描述的合成转化的替代反应条件,诸如改变溶剂、反应温度、反应时间以及不同的化学试剂和其他反应条件。必要时,可能需要使用适当的保护基团。这种基团的引入和裂解可使用Peter G.M.Wuts和Theodora W.Green,ProtectingGroups in Organic Synthesis,第4版,Wiley-Interscience.(2006)中描述的标准方法进行。所有的起始物质和试剂均是可商购获得的或容易制备的。
结构(I-A-1)的化合物
将1-受保护哌啶-4-酮与合适的苯胺偶联,得到1-受保护-N-芳基哌啶-4-胺中间体,如方案1所示。
环烷基或杂环烷基环(Cy)通过与环烷基或杂环烷基甲基溴、环烷基或杂环烷基-R3酮或环烷基或杂环烷基-醛反应而引入。去除哌啶保护基团并与R1氯化物偶联,得到最终期望化合物,如方案2所示。
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结构(I-A-2)的化合物
苯胺中间体可如上所述以及方案1和2所示来制备。通过与R1-COOH或R1-COCl反应引入R1-C(O)-基团以提供最终期望的化合物,如方案3所示。
结构(I-A-3)或结构(I-A-4)的化合物,
苯胺中间体可如上所述以及方案1和2所示来制备。通过与R1酮或R1-醛反应引入-CH2-R1或-CHMe-R1基团以提供最终期望的化合物,如方案4所示。
结构(I-B-1)的化合物
单保护的、单取代的二氨基环己烷中间体可通过以下方式制备:将芳基溴与单保护的二氨基环己烷偶联(方案5),或者另选地将苯胺与氨基保护的4-氨基环己烷-1-酮偶联(方案6),如下所示:
根据方案7通过与乙氧基-Cy-OTMS(a为0)或根据方案8通过与环甲醛(a为1或2)反应引入环烷基或杂环烷基环,然后将胺脱保护。
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然后根据本领域技术人员熟知的标准杂环化学合成R1杂芳基环。作为例示性示例,参见下面的方案9,制备R1作为取代的吡啶并吡嗪酮。
结构(I-B-2)或(I-B-3)的化合物
单保护的、单取代的二氨基环己烷中间体可以以与对于结构(I-B-1)的化合物相同的方式制备,如上文以及方案5和6中所述。环烷基或杂环烷基环可以与对于结构(I-B-1)的化合物相同的方式引入,如上文所述以及方案7和8所示。
苯胺胺被脱保护并与R1氯化物偶联以产生最终期望的产物(L是NH)。对于结构(I-B-3)的化合物,其中L是NMe,在与R1氯化物偶联之前或之后,与甲基碘的反应引入甲基基团,这取决于所采用的具体化合物和保护基团,如以下方案10和11所示。
以类似的方式,其中R2a是羟基的结构IB2或IB3的化合物可以根据如下所示的方案12,在适当的情况下使用羟基保护基团来制备。
结构(I-B-4)的化合物
然后根据方案13,将如上所述制备的1-受保护-N-芳基哌啶-4-胺中间体与环甲醛偶联,去保护并与R1羧酸偶联。另选地,根据方案14,首先将1-受保护-N-芳基哌啶-4-胺中间体脱保护,随后与R1羧酸反应以形成酰胺,然后将其与环烷基或杂环烷基环部分偶联。
实施例
提供以下实施例仅用于说明目的,而不是限制本文提供的权利要求的范围。虽然本文已经示出并描述了本发明的优选实施方案,但是对于本领域技术人员来说显而易见的是,这些实施方案仅作为示例提供。在不偏离本发明的情况下,本领域技术人员现在将想到许多变化、改变和替代。应理解的是,本文所述的本发明实施方案的各种替代方案可用于实施本发明。这意味着以下权利要求书限定本发明的范围并且因此涵盖这些权利要求及其等效物范围内的方法和结构。
化学合成
实施例1:
结构(I-A-1)的化合物
实施例1A:8-(4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-基)-5-甲基-6-氧代-
5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-羧酸叔丁酯
将4-氧代哌啶-1-羧酸叔丁酯(9.13g,45.8mmol)、2-氨基苯酚(5.0g,45.8mmol,3.76mL)、乙酸(50mL)和三乙酰氧基硼氢化钠(19.4g,91.6mmol)在DCM(100mL)中的溶液在室温下搅拌2小时。然后添加环丙烷甲醛(4.82g,68.7mmol,5.14mL)和三乙酰氧基硼氢化钠(14.6g,68.7mmol),并将所得混合物在室温下搅拌1.5小时。将混合物倒入水(200mL)中并用DCM(3×150mL)萃取。将合并的有机层用盐水(500mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法用石油醚/乙酸乙酯(10:1)纯化以得到标题化合物(12.0g,75%)作为黄色固体。
LCMS(ES,m/z):347.25[M+H]+。
步骤2:2-((环丙基甲基)(哌啶-4-基)氨基)苯酚水合三氟乙酸酯
将4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-羧酸叔丁酯(500mg,1.44mmol)在DCM(5mL)和TFA(2mL)中的溶液在室温下搅拌2小时。将混合物减压浓缩以得到标题化合物(800mg,假定定量)作为棕色油。
LCMS(ES,m/z):247.20[M+H]+。
步骤3:8-(4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-基)-5-甲基-6-氧代-5,
6-二氢-1,5-萘啶-2-腈
将2-((环丙基甲基)(哌啶-4-基)氨基)苯酚水合三氟乙酸酯(100mg,405μmol)、8-氯-5-甲基-6-氧代-1,5-萘啶-2-腈(89mg,406μmol)和DIPEA(1.05g,8.12mmol,1.41mL)在DMF(3mL)中的溶液在140℃下搅拌2小时。将混合物冷却至室温,用水(10mL)稀释并用乙酸乙酯(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反相色谱法纯化(柱:Xselect CSH OBD,30×150mm,5um;移动相,A:水(10mmol/L NH4HCO3+0.1%NH3·H2O)以及B:ACN(在7分钟内63%至83%);检测器:220nm)。将收集的级分冻干以得到标题化合物(28.2mg,16%)作为浅黄色固体。
1H-NMR(DMSO-d6,400MHz)δ(ppm):8.30(s,1H),8.16(d,J=8.8Hz,1H),8.06(d,J=8.9Hz,1H),7.23-7.21(m,1H),7.02-6.98(m,1H),6.83-6.77(m,2H),6.07(s,1H),4.03-3.99(m,2H),3.52(s,3H),3.18-3.12(m,1H),2.88-2.79(m,4H),1.92-1.89(m,2H),1.60-1.52(m,2H),0.78-0.63(m,1H),0.29-0.21(m,2H),0.00-0.08(m,2H)。
LCMS(ES,m/z):430.20[M+H]+。
实施例1B:8-(4-((环丙基甲基)(苯基)氨基)哌啶-1-基)-5-甲基-7-硝基-6-氧
代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:4-(苯基氨基)哌啶-1-羧酸叔丁酯
将4-氧代哌啶-1-羧酸叔丁酯(8.00g,40.2mmol)和苯胺(3.74g,40.2mmol,3.66mL)在甲苯(200mL)中的混合物在室温下搅拌1小时。将三乙酰氧基硼氢化钠(10.2g,48.2mmol)添加到所得溶液中并在室温下搅拌2.5小时。将反应用水(80mL)淬灭并用乙酸乙酯(3×100mL)萃取所得溶液。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-乙酸乙酯,1:10)纯化以得到标题化合物(7.00g,58%)作为黄色固体。
LCMS(ES,m/z):277.15[M+H]+。
步骤2:4-((环丙基甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯
将4-(苯基氨基)哌啶-1-羧酸叔丁酯(400mg,1.45mmol)和NaH(116mg,2.9mmol,60%)在DMF(10mL)中的混合物在0℃下搅拌0.5小时。将溴甲基环丙烷(195mg,1.45mmol,138μL)添加到所得溶液中并在室温下搅拌16小时。将混合物缓慢倒入水(25mL)中并用乙酸乙酯(3×25mL)萃取。将合并的有机层用盐水(25mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-乙酸乙酯,1:1)纯化以得到标题化合物(130mg,25%)作为无色油。
LCMS(ES,m/z):331.20[M+H]+。
步骤3:N-(环丙基甲基)-N-苯基-哌啶-4-胺盐酸盐
将HCl(4M在二噁烷中,983μL)添加到4-((环丙基甲基)-(苯基)氨基)哌啶-1-羧酸叔丁酯(130mg,393μmol)在乙酸乙酯(2.50mL)中的溶液中,并将所得混合物在室温下搅拌0.5小时。将所得溶液浓缩并用乙醚(5mL)洗涤。通过过滤收集固体以得到标题化合物(90mg,96%)。
LCMS(ES,m/z):231.20[M+H]+。
步骤4:8-(4-((环丙基甲基)(苯基)氨基)哌啶-1-基)-5-甲基-7-硝基-6-氧代-5,
6-二氢-1,5-萘啶-2-腈
将8-氯-5-甲基-7-硝基-6-氧代-1,5-萘啶-2-腈(97.7mg,369μmol)、N-(环丙基甲基)-N-苯基-哌啶-4-胺盐酸盐(85mg,369μmol)和DIPEA(238mg,1.85mmol,321μL)在DMF(2mL)中的溶液在室温下搅拌1小时。将粗产物通过反相色谱法纯化(柱:C18,30×250mm,5μm;移动相:A:水(0.05%TFA)以及B:ACN(在30分钟内0%至60%);检测器:UV254nm)。将收集的级分冻干以得到标题化合物(37.1mg,22%)作为黄色固体。
1H-NMR(DMSO-d6,400MHz)δ(ppm):8.29(d,J=8.8Hz,1H),8.20(d,J=8.8Hz,1H),7.21-7.17(m,2H),6.95-6.92(m,2H),6.66-6.63(m,1H),4.05-3.99(m,1H),3.81-3.77(m,2H),3.59(s,3H),3.29-3.23(m,2H),3.10(d,J=5.6Hz,2H),2.02-1.94(m,2H),1.87-1.84(m,2H),0.97-0.95(m,1H),0.52-0.50(m,2H),0.28-0.26(m,2H)。
LCMS(ES,m/z):459.25[M+H]+。
实施例1C:5-甲基-7-硝基-8-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)哌啶-1-
基)-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:4-((氧杂环丁烷-3-基甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯
将4-(苯基氨基)哌啶-1-羧酸叔丁酯(600mg,2.17mmol)、氧杂环丁烷-3-甲醛(374mg,4.34mmol)和乙酸(0.05mL)在DCM(5mL)中的溶液在室温下搅拌2小时。添加三乙酰氧基硼氢化钠(920mg,4.34mmol),并且将所得化合物在室温下搅拌16小时。将残余物通过反相快速色谱法纯化(柱:C18硅胶,80g;移动相,A:水(10mM NH4HCO3)以及ACN(在30分钟内5%至100%);检测器:UV 254nm)。将收集的级分浓缩以得到标题化合物(600mg,71%)作为黄色油。
LCMS(ES,m/z):347.20[M+H]+。
步骤2:N-(氧杂环丁烷-3-基甲基)-N-苯基哌啶-4-胺三氟乙酸酯
将4-((氧杂环丁烷-3-基甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯(300mg,865μmol)和TFA(0.5mL)在DCM(2.5mL)中的溶液在室温下搅拌16小时。将反应物浓缩以得到标题化合物(300mg,假定定量产率)作为黄色油。
LCMS(ES,m/z):247.10[M+H]+。
步骤3:5-甲基-7-硝基-8-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)哌啶-1-基)-
6-氧代-5,6-二氢-1,5-萘啶-2-腈
将甲基-7-硝基-6-氧代-1,5-萘啶-2-腈(100mg,378μmol)、N-(氧杂环丁烷-3-基甲基)-N-苯基哌啶-4-胺三氟乙酸酯(93.1mg,378μmol)和DIPEA(244mg,329μL,1.89mmol)在DMF(4mL)中的溶液在室温下搅拌2小时。将残余物通过反相快速色谱法纯化(柱:C18,80g;移动相,A:水(10Mm NH4HCO3)以及ACN(在30分钟内35%至70%梯度);检测器:UV254nm)。将收集的级分浓缩以得到标题化合物(51mg,27%)作为黄色固体。
1H NMR(400MHz,DMSO-d6)δ(ppm):8.30(d,J=8.8Hz,1H),8.21(d,J=9.2Hz,1H),7.21-7.17(m,2H),6.88(d,J=8.0Hz,2H),6.72(t,J=7.2Hz,1H),4.59-4.56(m,2H),4.35-4.32(m,2H),3.93-3.90(m,1H),3.80-3.76(m,2H),3.59(s,3H),3.47(d,J=6.8Hz,2H),3.32-3.09(m,3H),1.97-1.90(m,2H),1.89-1.80(m,2H)。
LCMS(ES,m/z):475.15[M+H]+。
实施例1D:5-甲基-8-(4-(((3-甲基氧杂环丁烷-3-基)甲基)(苯基)氨基)哌啶-1-
基)-7-硝基-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:4-(((3-甲基氧杂环丁烷-3-基)甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯
将4-(苯基氨基)哌啶-1-羧酸叔丁酯(552mg,2.00mmol)、3-甲基氧杂环丁烷-3-甲醛(200mg,2.00mmol)和乙酸(1滴)在DCM(4mL)中的混合物在室温下搅拌0.5小时,随后添加三乙酰氧基硼氢化钠(635mg,3.00mmol)。将所得溶液在室温下搅拌16小时。将所得混合物浓缩,并且将残余物通过硅胶色谱法(石油醚-乙酸乙酯,10:1)纯化以得到4-[N-[(3-甲基氧杂环丁烷-3-基)甲基]苯胺基]哌啶-1-羧酸叔丁酯(100mg,13%)作为白色固体。
LCMS(ES,m/z):361.15[M+H]+。
步骤2:N-((3-甲基氧杂环丁烷-3-基)甲基)-N-苯基哌啶-4-胺水合三氟乙酸酯
将4-(((3-甲基氧杂环丁烷-3-基)甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯(90.0mg,250μmol)在DCM(2.5mL)和TFA(0.5mL)中的溶液在室温下搅拌1小时。将所得溶液减压浓缩以得到标题化合物(65mg,假定定量)作为黄色固体。
LCMS(ES,m/z):261.15[M+H]+。
步骤3:5-甲基-8-(4-(((3-甲基氧杂环丁烷-3-基)甲基)(苯基)氨基)哌啶-1-
基)-7-硝基-6-氧代-5,6-二氢-1,5-萘啶-2-腈
将N-((3-甲基氧杂环丁烷-3-基)甲基)-N-苯基哌啶-4-胺水合三氟乙酸酯(55.0mg,211μmol)、8-氯-5-甲基-7-硝基-6-氧代-1,5-萘啶-2-腈(55.9mg,211μmol)和DIPEA(81.9mg,634μmol,110μL)在DMF(2mL)中的混合物在室温下搅拌1小时。将所得溶液通过反相快速色谱法纯化(柱:C18硅胶;移动相,A:水(含有10mM NH4HCO3)以及B:ACN(在30分钟内5%B至75%B);检测器:UV 254/220nm)。将收集的级分冻干以得到标题化合物(18.3mg,16%)作为黄色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):8.30(d,J=8.7Hz,1H),8.26(d,J=8.7Hz,1H),7.26(t,J=7.2Hz,8.4Hz,2H),6.96(d,J=8.1Hz,2H),6.82(t,J=7.2Hz,1H),4.39(d,J=5.7Hz,2H),3.98(d,J=5.7Hz,2H),3.85-3.68(m,3H),3.58(s,3H),3.34-3.14(m,4H),1.92-1.75(m,4H),1.34(s,3H)。
LCMS(ES,m/z):489.15[M+H]+。
实施例1E:6-氯-4-(4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-基)-1-甲基-2-
氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:4-((2-甲氧基苯基)氨基)哌啶-1-羧酸叔丁酯
将4-氧代哌啶-1-羧酸叔丁酯(8.20g,41.2mmol)、2-甲氧基苯胺(4.61g,37.4mmol,4.23mL)和乙酸(112mg,1.87mmol)在DCM(200mL)中的溶液在室温下搅拌0.5小时。添加三乙酰氧基硼氢化钠(15.8g,74.8mmol),并且将所得化合物在室温下搅拌12小时。将混合物倒入水(100mL)中并用DCM(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-乙酸乙酯,3:1)纯化以得到标题化合物(10.7g,93%)作为黄色固体。
LCMS(ES,m/z):307.20[M+H]+。
步骤2:4-((环丙基甲基)(2-甲氧基苯基)氨基)哌啶-1-羧酸叔丁酯
将4-((2-甲氧基苯基)氨基)哌啶-1-羧酸叔丁酯(5.00g,16.3mmol)和环丙烷甲醛(2.29g,32.6mmol,2.44mL)在DCM(40mL)和乙酸(80mL)中的溶液在室温下搅拌0.5小时。加入三乙酰氧基硼氢化钠(6.92g,32.6mmol),并将所得混合物在室温下搅拌1.5小时。将混合物倒入水(100mL)中并用DCM(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法用石油醚/乙酸乙酯(10:1)纯化以得到标题化合物(1.7g,9%)作为黄色固体。
LCMS(ES,m/z):361.30[M+H]+。
步骤3:2-((环丙基甲基)(哌啶-4-基)氨基)苯酚氢溴酸盐
将4-((环丙基甲基)(2-甲氧基苯基)氨基)哌啶-1-羧酸叔丁酯(500mg,1.39mmol)和BBr3(DCM中的1M,11.1mL)在DCM(5mL)中的溶液在室温下搅拌12小时。将混合物倒入甲醇(5mL)中,并且减压浓缩以得到标题化合物(580mg,假定定量产率)作为棕色油。
LCMS(ES,m/z):247.20[M+H]+。
步骤4:6-氯-4-(4-((环丙基甲基)(2-羟基苯基)氨基)哌啶-1-基)-1-甲基-2-氧
代-1,2-二氢-1,5-萘啶-3-腈
将2-((环丙基甲基)(哌啶-4-基)氨基)苯酚氢溴酸盐(87.0mg,353μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(116mg,455μmol)和Cs2CO3(445mg,1.37mmol)在DMF(3mL)中的溶液在80℃下搅拌2小时。将混合物冷却至室温,用水(10mL)稀释并用乙酸乙酯(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反相色谱法纯化(柱:Xselect CSH OBD,30×150mm,5um;移动相,A:水(10mmol/LNH4HCO3+0.1%NH3·H2O)以及B:ACN(在7分钟内55%至75%);检测器:220nm)。将收集的级分冻干以得到标题化合物(8.3mg,4%)作为浅黄色固体。1H-NMR(DMSO-d6,300MHz)δ(ppm):8.34(s,1H),8.04(d,J=9.0Hz,1H),7.77(d,J=8.7Hz,1H),7.21-7.19(m,1H),6.99-6.96(m,1H),6.83-6.75(m,2H),4.22-4.17(m,2H),3.50(s,3H),3.44-3.36(m,3H),2.87(d,J=6.6Hz,2H),2.00-1.96(m,2H),1.72-1.60(m,2H),0.78-0.65(m,1H),0.28-0.21(m,2H),0.00--0.09(m,2H)。
LCMS(ES,m/z):464.20[M+H]+。
实施例1F:N-(环丙基甲基)-1-(7-甲基-[1,2,4]三唑并[4,3-a]喹啉-5-基)-N-苯
基哌啶-4-胺的合成
步骤1:2,4-二氯-6-甲基喹啉
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将4-甲基苯胺(10.0g,93.3mmol,10.3mL)和丙二酸(9.71g,93.3mmol)在三氯氧化磷(200mL)中的溶液在100℃下搅拌5小时。将所得混合物减压浓缩并在连续搅拌下缓慢倒在冰上。过滤固体,并用乙酸乙酯(3×300mL)萃取。将合并的有机层用盐水(800mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法用石油醚/乙酸乙酯(20:1)纯化以得到标题化合物(9.4g,48%)作为白色固体。
LCMS(ES,m/z):212.00[M+H]+。
步骤2:4-氯-2-肼基-6-甲基喹啉
将2,4-二氯-6-甲基喹啉(21.0g,99.0mmol)和水合肼(282g,950mmol,275mL)在乙醇(400mL)中的溶液在30℃下搅拌16小时。将所得混合物冷却至室温并在减压下部分浓缩。将溶液用DCM(3×100mL)萃取,用盐水(100mL)洗涤,经无水硫酸钠干燥并在减压下浓缩以得到标题化合物(20.6g,假定定量)作为黄色固体。
LCMS(ES,m/z):208.05[M+H]+。
步骤3:5-氯-7-甲基-[1,2,4]三唑并[4,3-a]喹啉
将4-氯-2-肼基-6-甲基喹啉(4.60g,22.2mmol)、原甲酸三甲酯(63.9g,602mmol,66mL)和硫酸(2.17g,22.2mmol,1mL)在乙醇(400mL)中的溶液在45℃下搅拌12小时。将混合物减压浓缩,并用乙酸乙酯(3×200mL)萃取。将合并的有机层用盐水(500mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反向快速色谱法纯化(柱:C18硅胶,120g;移动相,A:水(0.1%NH4HCO3)以及B:ACN(在50分钟内5%至60%);检测器:UV 254nm)以得到标题化合物(450mg,假定定量)作为浅黄色固体。
LCMS(ES,m/z):218.00[M+H]+。
步骤4:4-((环丙基甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯
将4-(苯基氨基)哌啶-1-羧酸叔丁酯(2.79g,10.1mmol)和环丙烷甲醛(1.06g,15.1mmol,1.13mL)在乙酸(10mL)和DCM(20mL)中的溶液在室温下搅拌20分钟。添加三乙酰氧基硼氢化钠(4.28g,20.2mmol),并将所得混合物在室温下搅拌1小时。将混合物在减压下浓缩,并且通过反相快速色谱法纯化(柱:C18硅胶;移动相,A:水(10mM NH4HCO3)以及B:ACN(在30分钟内0%至80%);检测器:UV 254nm)。将收集的级分浓缩以得到标题化合物(2.76g,81%)。
LCMS(ES,m/z):331.45[M+H]+。
步骤5:N-(环丙基甲基)-N-苯基哌啶-4-胺盐酸盐
将4-((环丙基甲基)(苯基)氨基)哌啶-1-羧酸叔丁酯(1.30g,3.93mmol)和HCl(二噁烷中的4M,9.83mL)在乙酸乙酯(15mL)中的溶液在室温下搅拌0.5小时。将所得混合物减压浓缩,并用乙醚(15mL)洗涤。过滤固体以得到标题化合物(1.04g,96%)。
LCMS(ES,m/z):231.20[M+H]+。
步骤6:N-(环丙基甲基)-1-(7-甲基-[1,2,4]三唑并[4,3-a]喹啉-5-基)-N-苯基
哌啶-4-胺
将N-(环丙基甲基)-N-苯基哌啶-4-胺盐酸盐(160mg,695μmol)、5-氯-7-甲基[1,2,4]三唑并[4,3-a]喹啉(151mg,694μmol)、Pd2(dba)3.CHCl3(72.0mg,69.5μmol)、(5-二苯基膦基-9,9-二甲基-呫吨-4-基)-二苯基-膦(81.0mg,139μmol)和Cs2CO3(679mg,2.08mmol)在二噁烷(5mL)中的混合物在氮气氛下在110℃下搅拌12小时。将混合物冷却至室温,过滤出固体,并将滤液在减压下浓缩。将残余物通过反相色谱法纯化(柱:XBridge Shield RP18OBD,19×250mm,10um;移动相,A:水(10mmol/L NH4HCO3+0.1% NH3·H2O)以及B:ACN(在7分钟内67%至80%);检测器:220nm)。将收集的级分冻干以得到标题化合物(20.5mg,7%)。
1H-NMR(DMSO-d6,300MHz)δ(ppm):9.77(d,J=0.7Hz,1H),8.31(d,J=8.4Hz,1H),7.82(t,J=1.3Hz,1H),7.61(dd,J=8.5,1.9Hz,1H),7.27-7.15(m,2H),7.08(s,1H),6.94(d,J=8.0Hz,2H),6.66(t,J=7.2Hz,1H),3.92-3.79(m,1H),3.49(br d,J=11.7Hz,2H),3.21(d,J=5.8Hz,2H),2.94-2.86(m,2H),2.53(s,3H),2.02(dt,J=12.8,9.2Hz,2H),1.88(br d,J=12.0Hz,2H),1.05-0.95(m,1H),0.54-0.50(m,2H),0.36-0.31(m,2H)。
LCMS(ES,m/z):412.40[M+H]+。
实施例2:
结构(I-B-1)的化合物
实施例2A:反式-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1-甲基-2-氧代-3H-吡
啶并[2,3-b]吡嗪-6-腈
步骤1:反式-N-[4-[N-(环丙基甲基)苯胺基]环己基]氨基甲酸叔丁酯
以与实施例9,步骤2类似的方式使用反式-N-(4-苯胺基环己基)氨基甲酸叔丁酯(6.0g,20.7mmol)、环丙烷甲醛(2.17g,31mmol,2.32mL)、STAB(8.76g,41.32mmol)、AcOH(30mL)和DCM(60mL)制备以得到标题化合物(2.80g,8.13mmol,39%)作为浅黄色固体。
LCMS(ES,m/z):345.25[M+H]+
步骤2:反式-N4-(环丙基甲基)-N4-苯基-环己烷-1,4-二胺水合三氟乙酸酯
将反式-N-[4-[N-(环丙基甲基)苯胺基]环己基]氨基甲酸叔丁酯(2.8g,8.13mmol)在DCM(20mL)和TFA(5mL)中的溶液在室温下搅拌2小时。将混合物减压浓缩以得到标题化合物(3g,假定定量)作为棕色油。
LCMS(ES,m/z):245.20[M-TFA+H]+
步骤3:反式-2-[[4-[N-(环丙基甲基)苯胺基]环己基]氨基]乙酸酯
将反式-N4-(环丙基甲基)-N4-苯基-环己烷-1,4-二胺水合三氟乙酸酯(2g,5.86mmol)和TEA(8.28g,81.8mmol,11.41mL)、Cs2CO3(20.60g,24.55mmol)在DMF(25mL)中的溶液在50℃下搅拌48小时。将混合物倒入水(50mL)中,并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,2:3)纯化以得到标题化合物(1.1g,3.33mmol,41%)作为棕色油。
LCMS(ES,m/z):331.25[M+H]+
步骤4:反式-2-[(6-溴-3-硝基-2-吡啶基)-[4-[N-(环丙基甲基)苯胺基]环己基]
氨基]乙酸乙酯
将反式-2-[[4-[N-(环丙基甲基)苯胺基]环己基]氨基]乙酸乙酯(970mg,2.94mmol)、2,6-二溴-3-硝基-吡啶(993mg,3.52mmol)和DIEA(1.14g,8.81mmol)在ACN(15mL)中的溶液在80℃下搅拌2小时。然后将混合物冷却至室温,用水(50mL)稀释并用EtOAc(3×40mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,10:1)纯化以得到标题化合物(1.5g,2.82mmol,96%)作为黄色固体。LCMS(ES,m/z):531.20,533.20[M+H]+
步骤5:反式-6-溴-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1,3-二氢吡啶并[2,
3-b]吡嗪-2-酮
将反式-2-[(6-溴-3-硝基-2-吡啶基)-[4-[N-(环丙基甲基)苯胺基]-环己基]氨基]乙酸乙酯(1.5g,2.82mmol),Fe(788mg,14.11mmol)和NH4Cl(453mg,8.47mmol)在THF(6mL)、H2O(2mL)和EtOH(6mL)中的混合物在70℃下搅拌12小时。在冷却至室温后,过滤出固体并将滤液浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,1:1)纯化以得到标题化合物(970mg,2.13mmol,75%)作为白色固体。
LCMS(ES,m/z):455.20,457.20[M+H]+
步骤6:反式-6-溴-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1-甲基-3H-吡啶并
[2,3-b]吡嗪-2-酮
将反式-6-溴-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1,3-二氢吡啶并[2,3-b]吡嗪-2-酮(1g,2.20mmol)、Cs2CO3(2.13g,6.59mmol)和CH3I(3.12g,22.0mmol)在DMF(20mL)中的浆液搅拌3小时。将混合物用水(50mL)稀释并用EtOAc(3×40mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,1:1)纯化以得到标题化合物(970mg,2.07mmol,94%)作为白色固体。
LCMS(ES,m/z):469.15,471.15[M+H]+
步骤7:反式-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1-甲基-2-氧代-3H-吡啶并
[2,3-b]吡嗪-6-腈
将反式-6-溴-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1-甲基-3H-吡啶并[2,3-b]吡嗪-2-酮(200mg,426μmol),Zn(CN)2(37.5mg,319.6μmol)和Pd(PPh3)4(15.7mg,42.6μmol)在DMF(3mL)中的溶液在N2气氛下加热至100℃持续2小时。冷却至室温后,用水(10mL)稀释并用EtOAc(3×10mL)萃取。将合并的有机层用盐水(20mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过HPLC纯化(柱:YMC-Actus Triart C18,30mm×150mm,5um;移动相,A:水(10mmol/L NH4HCO3+0.1%NH3·H2O)以及B:ACN(在7分钟内67%至87%);检测器:254nm)以得到标题化合物(45mg,108μmol,25%)作为白色固体。
1H NMR(400MHz,CDCl3)δ7.29-7.21(m,2H),7.08(d,J=7.9Hz,1H),6.99(d,J=7.9Hz,1H),6.88(d,J=8.4Hz,2H),6.73(t,J=7.2Hz,1H),4.67-4.54(m,1H),4.09(s,2H),3.64-3.53(m,1H),3.34(s,3H),3.12(d,J=5.7Hz,2H),2.05-1.98(m,2H),1.91-1.83(m,2H),1.76-1.59(m,4H),1.06-0.99(m,1H),0.59-0.52(m,2H),0.32-0.25(m,2H)。
LCMS(ES,m/z):469.15,471.15[M+H]+
实施例2B:4-(反式-4-(环丙基(2-羟基苯基)氨基)环己基)-1-甲基-2-氧代-1,2,
3,4-四氢吡啶并[3,2-b]吡嗪-6-腈
步骤1:反式-2-(4-环丙基(2-羟基苯基)氨基)环己基氨基)乙酸乙酯
向反式-2-[(4-氨基环己基)-环丙基-氨基]苯酚(9.0g,36.5mmol)和甲苯中的2-氧代乙酸乙酯(14.48mL,73.07mmol,50%)在EtOH(80mL)和AcOH(5mL)中的溶液中添加NaBH3CN(15.94g,36.53mmol)。在搅拌18小时后,将化合物用水(100mL)稀释并用EtOAc(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩以得到(9.43g,37%)作为浅黄色油。
LCMS(ES,m/z):333.16[M+H]+
步骤2:反式-2-((6-溴-3-硝基吡啶-2-基)(4-(环丙基(2-羟基苯基)氨基)-环己
基)氨基)乙酸乙酯
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将2,6-二溴-3-硝基-吡啶(8.0g,28.4mmol)、2-(反式-4-(环丙基(2-羟基苯基)氨基)环己基氨基)乙酸乙酯(9.43g,28.38mmol)和DIEA(18.34g,141.90mmol)在ACN(50mL)中的溶液在80℃下搅拌1小时,随之将混合物冷却至室温,用水(100mL)稀释并用EtOAc(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,2:1)纯化以得到标题化合物(1.3g,8%)作为黄色油。
LCMS(ES,m/z):533.12,535.12[M+H]+
步骤3:反式-2-((6-溴-3-硝基吡啶-2-基)(4-(环丙基(2-((2-(三甲基甲硅烷基)
乙氧基)甲氧基)苯基)氨基)环己基)氨基)乙酸乙酯
向反式-2-((6-溴-3-硝基吡啶-2-基)(4-(环丙基(2-羟基苯基)氨基)环己基)氨基)乙酸酯(1.07g,2.00mmol)在DMF(20mL)中的溶液中在0℃下添加NaH(150mg,3.75mmol,60%,以分钟计,油)。在0℃下30分钟后,添加SEM-Cl(625.1mg,3.75mmol),然后使其温热至室温。在室温下2小时后,将混合物用饱和NH4Cl(30mL)稀释并用EtOAc(3×30mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩以得到标题化合物(1.3g,97%)作为黑色油。LCMS(ES,m/z):663.15,665.15[M+H]+
步骤4:反式-6-溴-4-(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯
基)氨基)-环己基)-3,4-二氢吡啶并[2,3-b]吡嗪-2(1H)-酮
将反式-2-((6-溴-3-硝基吡啶-2-基)(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)环己基)氨基)乙酸乙酯(0.90g,1.37mmol)、Fe(383mg,6.86mmol)、NH4Cl(220mg,4.11mmol)在EtOH(10mL)、H2O(3mL)和THF(10mL)中的溶液在70℃下搅拌3小时。在冷却至室温后,过滤出固体并且将滤液用水(30mL)稀释,然后用EtOAc(3×30mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,2:1)纯化以得到标题化合物(300mg,33%)作为浅黄色固体。LCMS(ES,m/z):587.16,589.16[M+H]+
步骤5:反式-6-溴-4-(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯
基)-氨基)环己基)-1-甲基-3,4-二氢吡啶并[2,3-b]吡嗪-2(1H)-酮
向6-溴-4-(反式-4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-氨基)环己基)-3,4-二氢吡啶并[2,3-b]吡嗪-2(1H)-酮(290mg,493.5μmol)和Cs2CO3(320mg,987μmol)在DMF(8mL)中的浆液中添加CH3I(140mg,987μmol)。在搅拌2小时后,将其用饱和NH4Cl(水溶液,20mL)稀释然后用EtOAc(3×20mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩以得到标题化合物(280mg,88%)作为黑色油。LCMS(ES,m/z):601.16,603.16[M+H]+
步骤6:反式-4-(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨
基)-环己基)-1-甲基-2-氧代-1,2,3,4-四氢吡啶并[3,2-b]吡嗪-6-腈
将反式-6-溴-4-(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)-氨基)环己基)-1-甲基-3,4-二氢吡啶并[2,3-b]吡嗪-2(1H)-酮(280mg,465μmol),Zn(CN)2(110mg,931μmol),Pd(PPh3)4(108mg,93.08μmol)在DMF(10mL)中的溶液加热至100℃。在1小时后,将其冷却至室温,用水(30mL)稀释并用EtOAc(3×30mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物经由硅胶色谱法(石油醚-EtOAc,2:1)纯化以得到标题化合物(200mg,74%)作为黄色油。LCMS(ES,m/z):548.32[M+H]+
步骤7:反式-4-(4-(环丙基(2-羟基苯基)氨基)环己基)-1-甲基-2-氧代-1,2,3,
4-四氢吡啶并[3,2-b]吡嗪-6-腈
向反式-4-(4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)-环己基)-1-甲基-2-氧代-1,2,3,4-四氢吡啶并[3,2-b]吡嗪-6-腈(100mg,183μmol)在DCM(3mL)中的溶液中添加TFA(1mL)。搅拌1小时后,将其减压浓缩,并且将粗残余物通过HPLC纯化(柱:XBridge Prep Phenyl OBD,5um,19×250mm;移动相,A:水(0.05% TFA)以及B:ACN(在7分钟内40%至60%);检测器:220nm),从而得到标题化合物(6.7mg,8%)作为浅棕色固体。1H NMR(300MHz,CDCl3)δ7.14-7.02(m,2H),7.02-6.86(m,4H),4.57-4.45(m,1H),4.01(s,2H),3.32(s,3H),2.97-2.83(m,1H),1.83-1.75(m,2H),1.69-1.42(m,5H),0.91-0.79(m,3H),0.65-0.50(m,2H)。LCMS(ES,m/z):418.15[M+H]+
实施例2C:顺式-4-[4-[N-(环丙基甲基)苯胺基]环己基]-1-甲基-2-氧代-3H-吡
啶并[2,3-b]吡嗪-6-腈
以类似于实施例33的方式制备。将粗材料通过反向快速色谱法纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水与10% NH4HCO3,以及B:ACN,在50分钟内5%-100%),从而得到标题化合物(65.5mg,156μmol,24.44%)作为白色固体。
1H NMR(400MHz,CDCl3)δ7.32-7.26(m,2H),7.20-7.16(m,2H),7.07-7.02(m,2H),6.97(d,J=7.9Hz,1H),4.70-4.60(m,1H),4.15(s,2H),3.59-3.55(m,1H),3.34(s,3H),2.93(d,J=6.6Hz,2H),2.09-1.99(m,2H),1.98-1.90(m,2H),1.66-1.57(m,2H),1.42-1.35(m,2H),0.80-0.70(m,1H),0.35-0.30(m,2H),-0.07-(-)0.15(m,2H)。
LCMS(ES,m/z):416.20[M+H]+。
实施例3:
结构(I-B-2)或(I-B-3)的化合物
实施例3A:反式-6-氯-4-((4-(环丙基(苯基)氨基)环己基)氨基)-1-甲基-2-氧
代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-(4-(环丙基(苯基)氨基)环己基)氨基甲酸叔丁酯
将反式-(4-(苯基氨基)环己基)氨基甲酸叔丁酯(700mg,2.41mmol)、(1-乙氧基环丙氧基)三甲基硅烷(2.10g,12.1mmol,2.42mL)、氰基硼氢化钠(606mg,9.64mmol)和MS(487mg)在乙酸(20mL)中的溶液在氮气氛下在70℃下搅拌2小时。将混合物冷却至室温,用水(40mL)稀释并用乙酸乙酯(3×40mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法用石油醚/乙酸乙酯(5:1)纯化以得到标题化合物(220mg,27%)作为白色固体。
LCMS(ES,m/z):331.45[M+H]+。
步骤2:N-环丙基-N-苯基环己烷-1,4-二胺水合三氟乙酸酯
将反式-(4-(环丙基(苯基)氨基)环己基)氨基甲酸叔丁酯(200mg,605μmol)在DCM(2mL)和TFA(0.5mL)中的溶液在室温下搅拌2小时。将所得混合物减压浓缩以得到标题化合物(450mg,假定定量)作为棕色油。
LCMS(ES,m/z):231.55[M+H]+。
步骤3:反式-6-氯-4-((4-(环丙基(苯基)氨基)环己基)氨基)-1-甲基-2-氧代-1,
2-二氢-1,5-萘啶-3-腈
将N-环丙基-N-苯基环己烷-1,4-二胺水合三氟乙酸酯(60mg,260μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(68.0mg,268μmol)和DIPEA(180mg,1.39mmol,242mL)在DMF(3mL)中的溶液在室温下搅拌2小时。将所得混合物通过反相快速色谱法纯化(柱:C18硅胶,80g;移动相,A:水(0.05% NH4HCO3)以及B:ACN(在30分钟内0%至100%);检测器:UV254nm)。将收集的级分冻干以得到标题化合物(34.9mg,28%)作为浅黄色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):8.03(d,J=3.3Hz,1H),7.87(d,J=3.9Hz,1H),7.62(d,J=9Hz,1H),7.23-7.18(m,2H),7.03(d,J=7.5Hz,2H),6.79-6.75(m,1H),4.32-4.25(m,1H),3.57-3.52(m,1H),3.49(s,3H),2.49-2.33(m,1H),2.14-2.08(m,2H),1.87-1.65(m,6H),0.84-0.78(m,2H),0.40-0.35(m,2H)。
LCMS(ES,m/z):448.30[M+H]+。
实施例3B:反式-6-氯-4-((4-((环丙基甲基)(苯基)氨基)环己基)氨基)-1-甲基-
2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-(4-(苯基氨基)环己基)氨基甲酸叔丁酯
将反式-(4-氨基环己基)氨基甲酸叔丁酯(5.00g,23.3mmol)、溴苯(7.33g,46.7mmol)、BINAP(2.91g,4.67mmol)、碳酸二铯(15.2g,46.7mmol)和乙酸钯(524mg,2.33mmol)在甲苯(100mL)中的溶液在110℃下在氮气氛下搅拌24小时。将混合物冷却至室温,用水(200mL)稀释并用乙酸乙酯(3×150mL)萃取。将合并的有机层用盐水(400mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-乙酸乙酯,3:1)纯化以得到标题化合物(1.10g,16%)作为黄色固体。
LCMS(ES,m/z):291.20[M+H]+。
步骤2:反式-(4-((环丙基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯
将反式-(4-(苯基氨基)环己基)氨基甲酸叔丁酯(300mg,1.03mmol)和环丙烷甲醛(108mg,1.55mmol,116μL)在DCM(4mL)和乙酸(0.8mL)中的溶液在室温下搅拌0.5小时。添加三乙酰氧基硼氢化钠(438mg,2.07mmol),并且将所得化合物在室温下搅拌1.5小时。将混合物倒入冰/水(10mL)中并用DCM(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-乙酸乙酯,3:1)纯化以得到标题化合物(270mg,75%)作为黄色固体。
LCMS(ES,m/z):345.25[M+H]+。
步骤3:反式-N-(环丙基甲基)-N-苯基环己烷-1,4-二胺水合三氟乙酸酯
将反式-(4-((环丙基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯(260mg,754μmol)在TFA(1mL)和DCM(10mL)中的溶液在室温下搅拌2小时。将混合物减压浓缩以得到标题化合物(250mg,假定定量产率)作为棕色油。
LCMS(ES,m/z):245.20[M+H]+。
步骤4:反式-6-氯-4-((4-((环丙基甲基)(苯基)氨基)环己基)氨基)-1-甲基-2-
氧代-1,2-二氢-1,5-萘啶-3-腈
将反式-N-(环丙基甲基)-N-苯基环己烷-1,4-二胺三氟乙酸酯(96.2mg,393μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(100mg,393μmol)和DIPEA(254mg,1.97mmol)在DMF(3mL)中的溶液在室温下搅拌2小时。将混合物倒入冰/水(10mL)中并用乙酸乙酯(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反相色谱法纯化(柱:Xselect CSH OBD,30×150mm,5um;移动相,A:水(10mmol/L NH4HCO3+0.1% NH3·H2O)以及B:ACN(在7分钟内67%至87%);检测器:254nm)。将收集的级分冻干以得到标题化合物(21.7mg,12%)作为浅黄色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):8.04(d,J=9.0Hz,1H),7.85(d,J=9.0Hz,1H),7.61(d,J=8.7Hz,1H),7.21-7.16(m,2H),6.84(d,J=8.1Hz,2H),6.65-6.60(m,1H),4.40-4.15(m,1H),3.76-3.60(m,1H),3.39(s,3H),3.07(d,J=5.4Hz,2H),2.22-2.08(m,2H),1.96-1.70(m,4H),1.70-1.50(m,2H),1.02-0.82(m,1H),0.58-0.40(m,2H),0.36-0.13(m,2H)。
LCMS(ES,m/z):462.20[M+H]+。
实施例3C:反式-6-氯-4-((4-(环丙基(苯基)氨基)环己基)(甲基)氨基)-1-甲基-
2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-(4-(环丙基(苯基)氨基)环己基)(甲基)氨基甲酸叔丁酯
向反式-(4-(环丙基(苯基)氨基)环己基)氨基甲酸叔丁酯(440mg,1.33mmol)在DMF(10mL)中的搅拌溶液中添加NaH(96.0mg,2.40mmol,60%,以分钟计,油)并且将混合物在室温下搅拌0.5小时。添加甲基碘(378mg,2.66mmol),并且将所得化合物在室温下搅拌1小时。将其倒入冰/水(20mL)中并用乙酸乙酯(3×25mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法用石油醚/乙酸乙酯(10:1)纯化以得到标题化合物(378mg,82%)作为浅黄色油。
LCMS(ES,m/z):345.30[M+H]+。
步骤2:反式-(4-(环丙基(苯基)氨基)环己基)(甲基)胺水合三氟乙酸酯
将反式-(4-(环丙基(苯基)氨基)环己基)(甲基)氨基甲酸叔丁酯(360mg,1.05mmol)在TFA(3.60mL)和DCM(15mL)中的溶液在室温下搅拌0.5小时。将混合物减压浓缩以得到标题化合物(800mg,假定定量)作为棕色油。
LCMS(ES,m/z):245.20[M+H]+。
步骤3:反式-6-氯-4-((4-(环丙基(苯基)氨基)环己基)(甲基)氨基)-1-甲基-2-
氧代-1,2-二氢-1,5-萘啶-3-腈
将反式-(4-(环丙基(苯基)氨基)环己基)(甲基)胺水合三氟乙酸酯(100mg,409μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(104mg,409μmol)和DIPEA(528mg,4.09mmol)在DMF(2mL)中的溶液在室温下搅拌2小时。将混合物倒入水(10mL)中并用乙酸乙酯(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过反相色谱法纯化(柱:Xselect CSH OBD,30×150mm,5um;移动相,A:水(10mmol/L NH4HCO3+0.1% NH3·H2O)以及B:ACN(在7分钟内52%至72%);检测器:220nm)。将收集的级分冻干以得到标题化合物(32.9mg,17%)作为黄色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):8.05(d,J=9.0Hz,1H),7.80(d,J=9.0Hz,1H),7.22-7.17(m,2H),7.08-6.98(m,2H),6.75(t,J=7.2Hz,1H),4.38-4.34(m,1H),3.59-3.52(m,4H),3.24(s,3H),2.34-2.28(m,1H),2.04(br s,2H),2.01-1.73(m,6H),0.85-0.71(m,2H),0.42-0.30(m,2H)。
LCMS(ES,m/z):462.25[M+H]+。
实施例3D:6-氯-4-((反式-4-(环丙基(2-羟基苯基)氨基)环己基)(甲基)氨基)-
1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:(2-((2-溴苯氧基)甲氧基)乙基)三甲基硅烷
将DMF(20mL)中的2-溴苯酚(7.00g,40.5mmol)、SEM-Cl(8.09g,48.6mmol)和碳酸钾(8.39g,60.7mmol)在室温下搅拌1.5小时,然后用冰水(400mL)稀释并用EtOAc(3x)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(EtOAc-石油醚,10%)纯化以得到标题化合物(11g,81%)作为浅黄色油。
GCMS(ES,m/z):303.27
步骤2:(反式-4-((2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)-环己
基)氨基甲酸叔丁酯
将2-[(2-溴苯氧基)甲氧基]乙基-三甲基-硅烷(3.60g,11.9mmol)、反式-N-(4-氨基环己基)氨基甲酸叔丁酯(1.27g,5.94mmol)、二乙酰氧基钯(133mg,593μmol)、苄基-[1-[2-[苄基(苯基)膦烷基]-1-萘基]-2-萘基]-苯基-膦(386mg,593μmol)、碳酸二铯(3.87g,11.9mmol)和甲苯(20mL)在110℃下在氮气气氛下搅拌12小时。将混合物冷却至室温,用水稀释并用EtOAc(3x)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶柱色谱法(石油醚-EtOAc,5:1)纯化以得到标题化合物(1.3g,45%)作为浅黄色油。
LCMS(ES,m/z):437.47[M+H]+
步骤3:(反式-4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)-
环己基)氨基甲酸叔丁酯
以与实施例24,步骤3类似的方式制备
将N-[4-[2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯(1.30g,2.98mmol)、NaBH3CN(561mg,8.93mmol)和(1-乙氧基环丙氧基)-三甲基-硅烷(2.3g,13.2mmol)在乙酸(20mL)中的溶液在50℃下搅拌1.5小时。在冷却至室温后,将混合物用水稀释并用EtOAc(3)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶柱色谱法(石油醚-EtOAc,6:1)纯化以得到标题化合物(1.3g,82%)作为浅黄色油。
LCMS(ES,m/z):477.43[M+H]+
步骤4:(反式-4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)-
环己基)(甲基)氨基甲酸叔丁酯
向(反式-4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)环己基)氨基甲酸叔丁酯(200mg,419μmol)在DMF(8mL)中的溶液中在0℃下添加NaH(50mg,1.26mmol,60%,以分钟计,油)。在30分钟后,向混合物中逐滴添加碘甲烷(178mg,1.26mmol),然后将其在0℃下搅拌1.5小时,然后用饱和NH4Cl(水溶液)猝灭并用EtOAc(3x)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶柱色谱法(石油醚-EtOAc,8:1)纯化以得到标题化合物(200mg,86%)作为浅黄色油。
LCMS(ES,m/z):491.22[M+H]+
步骤5:2-(环丙基(反式-4-(甲基铵)环己基)氨基)苯酚三氟乙酸酯
向(反式-4-(环丙基(2-((2-(三甲基甲硅烷基)乙氧基)甲氧基)苯基)氨基)环己基)(甲基)氨基甲酸叔丁酯(200mg,407μmol)在DCM(8mL)中的溶液中添加2,2,2-三氟乙酸(1mL)。在室温下2小时后,将混合物减压浓缩,用饱和NaHCO3(水溶液)在0℃下碱化至pH 8并用EtOAc(3x)萃取。将合并的有机层用盐水洗涤,经无水硫酸钠干燥并减压浓缩以得到标题化合物(189mg,93%)作为棕色油。
LCMS(ES,m/z):261.22[M-TFA+H]+
步骤6:6-氯-4-((反式-4-(环丙基(2-羟基苯基)氨基)环己基)(甲基)氨基)-1-甲
基-2-氧代-1,2-二氢-1,5-萘啶-3-腈
将2-(环丙基(反式-4-(甲基铵)环己基)氨基)苯酚三氟乙酸酯(138mg,275μmol)、4,6-二氯-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈(70mg,275μmol)和DIPEA(178mg,1.38mmol)在DMF(5mL)中的溶液在室温下搅拌1小时。将混合物倒入水(10mL)中并用EtOAc(3×10mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过制备型HPLC(柱:Xselect CSH OBD柱,30×150mm,5um;移动相,A:水(10mmol/LNH4HCO3+0.1%NH3·H2O)以及B:ACN(在7分钟内52%至72%);检测器:220nm)以得到标题化合物(38.6mg,28%)作为浅黄色固体。
1H NMR(300MHz,DMSO-d6)δ8.26(s,1H),8.04(d,J=9.1Hz,1H),7.78(d,J=8.9Hz,1H),7.18-7.13(m,1H),6.94-6.87(m,1H),6.78-6.72(m,2H),4.29-4.16(m,1H),3.51(s,3H),3.19(s,3H),3.16-3.05(m,1H),2.07-1.93(m,4H),1.78(q,J=11.7Hz,2H),1.61-1.45(m,2H),0.52-0.45(m,2H),0.31(br s,2H)。
LCMS(ES,m/z):478.25,480.25[M+H]+
实施例3E:反式-6-氯-4-((4-(环丙基(4-甲氧基苯基)氨基)环己基)(甲基)氨
基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-N-[4-(4-甲氧基苯胺基)环己基]氨基甲酸叔丁酯
将反式-N-(4-氨基环己基)氨基甲酸叔丁酯(1.7g,7.93mmol)、1-溴-4-甲氧基-苯(1.0g,5.35mmol)、Cu2O(76mg,531.13μmol)、KOH(390mg,6.95mmol)和N1-(2-甲基-1-萘基)-N2-(苯基甲基)-乙二酰胺(170mg,535μmol)在乙醇(20mL)中的混合物加热至80℃持续16小时,随之将其浓缩,用水(50mL)稀释并用DCM(2×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物经由硅胶色谱法(石油醚-EtOAc,1:1)纯化以得到标题化合物(1.1g,3.1mmol,58%)作为白色固体。
LCMS(ES,m/z):321.20[M+H]+
步骤2-5:反式-6-氯-4-[[4-(N-环丙基-4-甲氧基-苯胺基)环己基]-甲基-氨基]-
1-甲基-2-氧代-1,5-萘啶-3-腈
以与如本文所述的实施例类似的方式进行。
将化合物通过反向快速色谱法纯化(柱,C18硅胶,80g,20um-35um;移动相,A:水与10mmol/L NH4HCO3以及B:ACN,在30分钟内0%-100%;检测器:UV 254nm),从而得到标题化合物(33.8mg,62.7μmol,13%)作为黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.04(d,J=9.0Hz,1H),7.80(d,J=8.9Hz,1H),6.99(d,J=8.6Hz,2H),6.80(d,J=8.8Hz,2H),4.32-4.23(m,1H),3.69(s,3H),3.52(s,3H),3.22(s,3H),2.34(br s,1H),2.09-2.00(m,2H),1.93-1.82(m,4H),1.72-1.61(m,2H),0.71-0.65(m,2H),0.31-0.26(m,2H)。
LCMS(ES,m/z):492.25[M+H]+。
实施例3F:反式-6-氯-4-((4-(环丙基(4-氟苯基)氨基)环己基)(甲基)氨基)-1-
甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
以类似于实施例3D的方式制备标题化合物。
将最终产物通过SFC纯化(柱:GreenSep萘基,3×25cm,5μm;移动相,A:CO2和B:ACN:MeOH,4:1与0.1%2M NH3-MeOH,在8分钟内保持42%;检测器:254nm),从而得到标题化合物(14.2mg,28.9μmol,7.8%)作为黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.05(d,J=9.0Hz,1H),7.80(d,J=9.0Hz,1H),7.03(d,J=6.7Hz,4H),4.37-4.28(m,1H),3.52(s,3H),3.50-3.41(m,1H),3.22(s,3H),2.35-2.29(m,1H),2.08-2.00(m,2H),1.97-1.85(m,4H),1.82-1.70(m,2H),0.77-0.72(m,2H),0.35-0.29(m,2H)。
LCMS(ES,m/z):480.15[M+H]+
实施例3G:反式-6-氯-4-((4-(环丙基(4-氟-2-羟基苯基)氨基)环己基)(甲基)氨
基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
将反式-2-[环丙基-[4-(甲基氨基)环己基]氨基]-5-氟-苯酚(200mg,718μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(182mg,718.48μmol)和DIEA(438mg,2.16mmol)在DMF(3mL)中的溶液在室温下搅拌1小时。将混合物通过HPLC纯化(柱:XBridge BEH C18OBD Prep柱,5μm,19×250mm;移动相,A:水(10mmol/L NH4HCO3+0.1%NH3·H2O)以及B:ACN(在9分钟内60%-80%);检测器:254nm),从而得到标题化合物(50.9mg,103μmol,14%)作为浅黄色固体。
1H NMR(400MHz,Methanol-d4)δ7.88(d,J=9.0Hz,1H),7.56(d,J=8.9Hz,1H),7.17-7.11(m,1H),6.48-6.42(m,2H),4.37-4.28(m,1H),3.51(s,3H),3.23(s,3H),2.99-2.91(m,1H),2.48-2.41(m,1H),2.04(br d,J=11.2Hz,4H),1.83-1.72(m,2H),1.48-1.37(m,2H),0.45-0.38(m,2H),0.35-0.27(m,2H)。
LCMS(ES,m/z):496.20[M+H]+
实施例3H:顺式-6-氯-4-((4-(环丙基(4-氟-2-甲氧基苯基)氨基)环己基)(甲基)
氨基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
向N4-环丙基-N4-(4-氟-2-甲氧基-苯基)-N1-甲基-环己烷-1,4-二胺水合三氟乙酸酯(300mg,738μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(188mg,738μmol)在DMF(3mL)中的溶液中添加DIEA(751mg,3.69mmol)。在1小时后,将溶液通过SFC直接纯化(柱:Viridis BEH 2-乙基吡啶Prep OBD,3×15cm,5μm;移动相,A:CO2和B:20%MeOH与0.5%2MNH3-MeOH,在10分钟内),从而得到标题化合物(46.5mg,83.6μmol,11%)作为黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.03(d,J=9.0Hz,1H),7.78(d,J=9.0Hz,1H),7.16-7.09(m,1H),6.89(dd,J=11.1,2.8Hz,1H),6.68(td,J=8.7,4.3Hz,1H),4.36-4.28(m,1H),3.79(s,3H),3.51(s,3H),3.47(s,1H),3.25(s,3H),2.42(br s,1H),2.14-2.01(m,2H),2.00-1.89(m,2H),1.61(bd,J=11.1Hz,2H),1.43(t,J=13.4Hz,2H),0.45-0.35(m,4H)。
LCMS(ES,m/z):510.25[M+H]+
实施例3I:反式-6-氯-4-[[4-[环丙基-(5-氟-2-吡啶基)氨基]环己基]-甲基-氨
基]-1-甲基-2-氧代-1,5-萘啶-3-腈的合成
根据以下方案,以与如本文所述实施例类似的方式制备
将最终产物通过反向快速色谱法纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水(0.5% TFA)以及B:ACN(在30分钟内30%至85%);检测器:UV 254nm)以得到标题化合物(61.2mg,116μmol,15%)作为灰白色固体。
1H NMR(300MHz,DMSO-d6)δ8.12(d,J=3.1Hz,1H),8.06(d,J=9.0Hz,1H),7.81(d,J=9.0Hz,1H),7.51(td,J=8.8,3.1Hz,1H),7.00(dd,J=9.3,3.6Hz,1H),4.39(br s,1H),4.26(br s,1H),3.53(s,3H),3.25(s,3H),2.41-2.34(m,1H),2.12-2.00(m,2H),2.00-1.82(m,6H),0.92-0.85(m,2H),0.56-0.49(m,2H)。
LCMS(ES,m/z):481.15,483.15[M+H]+
实施例3J:反式6-氯-4-((4-(环丙基(5-甲氧基吡啶-2-基)氨基)环己基)(甲基)
氨基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
以类似于实施例3D的方式制备标题化合物
将最终产物通过反向快速色谱法纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水(10mmol/L NH4HCO3)以及B:ACN(在50分钟内5%至80%);检测器:254nm),从而得到标题化合物(53.4mg,108μmol,19%)作为浅黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.06(d,J=9.0Hz,1H),7.91(d,J=3.1Hz,1H),7.81(d,J=8.8Hz,1H),7.26(dd,J=9.2,3.2Hz,1H),6.95(d,J=9.0Hz,1H),4.42-4.32(m,1H),4.29-4.20(m,1H),3.73(s,3H),3.52(s,3H),3.25(s,3H),2.34-2.28(m,1H),2.12-2.03(m,2H),1.99-1.76(m,6H),0.88-0.81(m,2H),0.52-0.44(m,2H)。
LCMS(ES,m/z):493.15[M+H]+
实施例3K:顺式-6-氯-4-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-1-
甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:顺式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯
根据如本文所述的类似方法,使用顺式-苄基(4-((4-氟苯基)氨基)环己基)氨基甲酸酯(250mg,730μmol)、环丙烷甲醛(768mg,11.0mmol,819μL)、DCM(3.4mL)、乙酸(11.0mg,183μmol,10.5μL)和三乙酰氧基硼氢化钠(1.91g,8.76mmol)制备化合物,以得到标题化合物(247mg,85%)作为油。
LCMS(ES,m/z):397.51[M+H]+。
步骤2:顺式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺
根据如本文所述的类似方法,使用顺式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯(245mg,618μmol)、钯(碳上的10%,65.8mg)、乙醇(3.1mL)和氢气制备化合物,以得到标题化合物(145mg,89%)作为油。
LCMS(ES,m/z):263.43[M+H]+。
步骤3:顺式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-6-氧
代-5,6-二氢-1,5-萘啶-2-腈
根据如本文所述的类似方法,使用顺式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺(58.1mg,222μmol)、DMA(953μL)、DIPEA(115mg,886μmol,154μL)和8-氯-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈(61.9mg,244μmol)制备化合物,并且通过硅胶色谱法用乙酸乙酯/庚烷(0%-100%)纯化以得到标题化合物(145mg,89%)作为油。
LCMS(ES,m/z):482.46[M+H]+。
步骤4:顺式-6-氯-4-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-1-甲
基-2-氧代-1,2-二氢-1,5-萘啶-3-腈
向顺式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈(59.2mg,123μmol)在DMF(2.4mL)中的溶液中添加NaH(3.00mg,130μmol,60%,以分钟计,油),并且将混合物在室温下搅拌0.3小时。添加甲基碘(19.1mg,135μmol),并且将所得化合物在室温下搅拌1小时。将混合物用HCl(1N,184uL)淬灭,过滤并在减压下浓缩。将残余物通过反相色谱法纯化(柱:SunFire Prep OBD C18,19×250mm,5μm;移动相,A:水(0.05%甲酸)以及B:ACN(0.05%甲酸,在10分钟内10%-50%);检测器:UV254/220nm)。将收集的级分冻干以得到标题化合物(26.9mg,45%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):8.09(d,J=9.1Hz,1H),7.82(d,J=8.9Hz,1H),7.26-7.18(m,2H),7.17-7.05(m,2H),4.47-4.30(m,1H),3.60-3.50(s,3H),3.28(s,3H),2.92(d,J=6.1Hz,2H),2.22-2.04(m,2H),1.87(br d,J=11.7Hz,2H),1.70(br d,J=8.8Hz,2H),1.49(br t,J=11.6Hz,2H),0.72(br s,1H),0.34(d,J=7.4Hz,2H),-0.04(d,J=4.3Hz,2H)。
LCMS(ES,m/z):494.56[M+H]+。
实施例3L:反式-6-氯-4-((4-((环丙基甲基)(5-氟吡啶-2-基)氨基)环己基)(甲
基)氨基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-N-[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]-氨基甲酸叔丁
酯
向反式-N-[4-[(5-氟-2-吡啶基)氨基]环己基]氨基甲酸叔丁酯(1.4g,4.53mmol)、环丙烷甲醛(349mg,4.98mmol)和TMS-Cl(1.23g,11.31mmol)在THF(20mL)中的混合物在0℃下添加BH3(THF中的1M,4.53mL)。在0℃下搅拌3小时后,将溶液倒入水(15mL)中并搅拌5分钟。添加饱和Na2CO3(水溶液,20mL)并搅拌混合物直至气体逸出停止。将混合物用EtOAc(3×30mL)萃取并且将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶柱色谱法(石油醚-EtOAc,2:1)纯化以得到标题化合物(800mg,2.09mmol,46%)作为白色固体。
LCMS(ES,m/z):364.20[M+H]+。
步骤2:反式-N-[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]-N-甲基-氨基甲
酸叔丁酯
向反式-N-[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]氨基甲酸叔丁酯(830mg,2.28mmol)在DMF(5mL)中的混合物中在0℃下分批添加NaH(274mg,6.85mmol,60%,以分钟计,油)。在0℃下30分钟后,添加MeI(1.62g,11.42mmol)。在0℃下再过1小时后,将混合物用饱和NH4Cl(水溶液,20mL)淬灭并用EtOAc(3×30mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,1:1)纯化以得到标题化合物(420mg,1.00mmol,44%)作为黄色油。
LCMS(ES,m/z):378.20[M+H]+。
步骤3:反式-N1-(环丙基甲基)-N1-(5-氟吡啶-2-基)-N4-甲基环己烷-1,4-二胺水
合三氟乙酸酯
将反式-N-[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]-N-甲基-氨基甲酸叔丁酯(420mg,1.11mmol)在DCM(3mL)和TFA(1mL)中的混合物搅拌1小时。将溶液浓缩以得到标题化合物(320mg,923μmol,59%,80%纯度)作为棕色油。
LCMS(ES,m/z):278.50[M-TFA+H]+
步骤4:反式-6-氯-4-[[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]-甲基-氨
基]-1-甲基-2-氧代-1,5-萘啶-3-腈
将反式-N1-(环丙基甲基)-N1-(5-氟吡啶-2-基)-N4-甲基环己烷-1,4-二胺水合三氟乙酸酯(150mg,306.6μmol,80%)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(77.9mg,306.6μmol)和DIPEA(118.9mg,919.8μmol)在DMF(3mL)中的混合物搅拌2小时。粗混合物通过反向快速色谱法直接纯化(柱,C18硅胶,80g,20um-35um;移动相,A:水(0.1% TFA)以及B:ACN(在20分钟内30%至80%);检测器:UV 254nm),从而得到标题化合物(39.1mg,74.3μmol,24%)作为黄色固体。
1H NMR(300MHz,DMSO-d6)δ8.08-8.03(m,2H),7.81(d,J=8.9Hz,1H),7.47(dt,J=8.8,5.3Hz,1H),6.74(dd,J=9.3,3.3Hz,1H),4.44-4.21(m,2H),3.52(s,3H),3.26(s,3H),3.19(d,J=6.0Hz,2H),2.13-1.92(m,4H),1.85-1.60(m,4H),1.01-0.89(m,1H),0.50-0.42(m,2H),0.31-0.23(m,2H)。
LCMS(ES,m/z):495.15[M+H]+。
实施例3M:顺式-6-氯-4-[[4-(N-4-氟苯基-N-氧杂环丁烷-3-基甲基苯胺基)环己
基]-甲基氨基]-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
以与如本文所述的实施例类似的方式制备。将粗材料通过HPLC纯化(柱:SunfireOBD,C18,19×250mm,5μm;移动相,A:水与0.1%甲酸,以及B:ACN与0.1%甲酸,在10分钟内25%-50%),从而得到标题化合物(8.2mg,35%)作为白色固体。
1H NMR(300MHz,DMSO-d6)δppm 8.06(d,J=9.2Hz,1H),7.79(d,J=8.6Hz,1H),7.25-7.08(m,4H),4.47-4.29(m,3H),4.10(t,J=6.1Hz,2H),3.53(s,3H),3.29-3.18(m,6H),2.91-2.78(m,1H),2.11(q,J=11.5Hz,2H),1.84(br d,J=13.2Hz,2H),1.66(br d,J=10.0Hz,2H),1.53-1.35(t,J=12.6Hz,2H)。
LCMS(ES,m/z):510.53[M+H]+。
实施例3N:反式-6-氯-4-[[4-(N-4-氟苯基-N-氧杂环丁烷-3-基甲基苯胺基)环己
基]-甲基氨基]-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
以与如本文所述的实施例类似的方式制备,对于最终步骤采用实施例3K中所述的甲基化。将粗材料通过HPLC纯化(柱:Sunfire OBD,C18,19×250mm,5μm;移动相,A:水与0.1%甲酸,以及B:ACN与0.1%甲酸,在10分钟内25%-50%),从而得到标题化合物(16.9mg,39%)作为白色固体。
LCMS(ES,m/z):510.53[M+H]+。
实施例3O:反式6-氯-4-((4-((4-氟-2-羟基苯基)(氧杂环丁烷-3-基甲基)氨基)
环己基)(甲基)氨基)-1-甲基-2-氧代-1,2-二氢-1,5-萘啶-3-腈的合成
步骤1:反式-6-氯-4-[[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷
基乙氧基甲氧基)苯胺基]环己基]-甲基-氨基]-1-甲基-2-氧代-1,5-萘啶-3-腈
向反式-N4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯基]-N1-甲基-N4-(氧杂环丁烷-3-基甲基)环己烷-1,4-二胺(300mg,684μmol)、4,6-二氯-1-甲基-2-氧代-1,5-萘啶-3-腈(174mg,684μmol)在DMF(5mL)中的溶液中添加TEA(208mg,2.05mmol)。在1小时后,将其通过反向快速色谱法直接纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水与10mmol/LNH4HCO3,以及B:ACN,在50分钟内5%-75%),从而得到标题化合物(250mg,381μmol,56%)作为黄色油。
LCMS(ES,m/z):656.45[M+H]+。
步骤2:反式-6-氯-4-[[4-[4-氟-2-羟基-N-(氧杂环丁烷-3-基甲基)苯胺基]环己
基]-甲基-氨基]-1-甲基-2-氧代-1,5-萘啶-3-腈
向装有反式-6-氯-4-[[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]-甲基-氨基]-1-甲基-2-氧代-1,5-萘啶-3-腈(250mg,381μmol)的小瓶中添加TBAF(THF中的1M,2mL),然后加热至50℃持续12小时。在冷却至室温后,将其用水(20mL)稀释并用EtOAc(3×20mL)萃取。将合并的有机层用盐水(30mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反向快速色谱法纯化(柱,C18硅胶,80g,20um-35um;移动相,A:水与10mmol/L NH4HCO3,以及B:ACN,在50分钟内5%-60%),从而得到标题化合物(79.1mg,135μmol,35%)作为浅黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.70(br s,1H),8.04(d,J=8.8Hz,1H),7.78(d,J=8.8Hz,1H),7.11(dd,J=8.7,6.4Hz,1H),6.61(dd,J=10.4,2.8Hz,1H)6.56(td,J=8.4,2.8Hz,1H),4.38(dd,J=7.8,5.9Hz,2H),4.22-4.15(m,1H),4.13(t,J=6.1Hz,2H),3.51(s,3H),3.26(d,J=7.6Hz,2H),3.19(s,3H),2.89-2.79(m,1H),2.77-2.68(m,1H),2.03-1.94(m,4H),1.86-1.72(m,2H),1.38-1.24(m,2H)。
LCMS(ES,m/z):526.15[M+H]+。
实施例3Q:顺式-5-甲基-8-((4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨
基)-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:顺式/反式-苄基(4-(苯基氨基)环己基)氨基甲酸酯
将苄基N-(4-氧代环己基)氨基甲酸酯(5.00g,20.2mmol)、苯胺(1.88g,20.2mmol,1.84mL)和乙酸(243mg,4.04mmol,231μL)在DCM(99.0mL)中的溶液在室温下搅拌0.25小时。向混合物中添加三乙酰氧基硼氢化钠(8.57g,40.4mmol),并将悬浮液搅拌1小时。将混合物用饱和碳酸氢钠(25mL)萃取并在减压下浓缩。将粗产物通过硅胶色谱法用乙酸乙酯/庚烷(0%-50%)纯化,从而得到顺式-苄基(4-(苯基氨基)环己基)氨基甲酸酯(2.54g,39%)和反式-苄基(4-(苯基氨基)环己基)氨基甲酸酯(1.95g,30%)作为白色固体(仅将顺式异构体用于步骤2)。
LCMS(ES,m/z):325.71[M+H]+。
步骤2:顺式-苄基(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨基甲酸酯
将顺式-苄基(4-(苯基氨基)环己基)氨基甲酸酯(80.0mg,247μmol)、氧杂环丁烷-3-甲醛(21.2mg,247μmol)和乙酸(3mg,49μmol,2.8μL)在DCM(1.23mL)中的溶液在室温下搅拌0.25小时。向混合物中添加三乙酰氧基硼氢化钠(105mg,493μmol),并将悬浮液搅拌16小时。将混合物用饱和碳酸氢钠(0.5mL)萃取并在减压下浓缩。将粗产物通过硅胶色谱法(乙酸乙酯-庚烷,0%-50%)纯化,从而得到标题化合物(58.1mg,60%)作为油。
LCMS(ES,m/z):395.38[M+H]+。
步骤3:顺式-N-(氧杂环丁烷-3-基甲基)-N-苯基环己烷-1,4-二胺
将顺式-苄基(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨基甲酸酯(57.0mg,144μmol)、钯(15.4mg,144μmol,碳上的10%)和乙醇(722μL)在氢气氛下在室温下搅拌16小时。将悬浮液过滤并减压浓缩以得到粗产物(37.2mg,99%)作为油。
LCMS(ES,m/z):261.40[M+H]+。
步骤4:顺式-5-甲基-8-((4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨
基)-6-氧代-5,6-二氢-1,5-萘啶-2-腈
将顺式-N-(氧杂环丁烷-3-基甲基)-N-苯基环己烷-1,4-二胺(37.2mg,143μmol)、8-氯-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈(31.4mg,143μmol,根据WO20202006016制备)和DIPEA(92.3mg,714μmol,124μL)在DMF(828μL)中的溶液在80℃下搅拌16小时。将混合物通过反相色谱法纯化(柱:SunFire Prep OBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内10%-40%);检测器:UV254/220nm)。将产物冻干以得到标题化合物(6.2mg,9.6%)作为白色固体。
1H-NMR(CDCl3,300MHz)δ(ppm):7.85(d,J=8.8Hz,1H),7.67(d,J=8.5Hz,1H),7.31-7.23(m,2H),6.96-6.87(m,3H),6.48(br d,J=7.2Hz,1H),5.82(s,1H),4.69(t,J=6.8Hz,2H),4.37(t,J=5.8Hz,2H),3.76-3.66(m,1H),3.62(s,3H),3.48(br d,J=7.1Hz,3H),3.21-3.09(m,1H),2.16-2.00(m,2H),1.82-1.69(m,6H)。
LCMS(ES,m/z):444.47[M+H]+。
实施例3R:反式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-
6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:反式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯
利用与实施例3Q相同的方法,使用反式-苄基(4-((4-氟苯基)氨基)环己基)氨基甲酸酯(337mg,983μmol)、环丙烷甲醛(138mg,1.97mmol,147μL)、DCM(4.3mL)、乙酸(11.8mg,197μmol,11.3μL)和三乙酰氧基硼氢化钠(463mg,1.97mmol)制备化合物,以得到标题化合物(332mg,85%)作为油。
LCMS(ES,m/z):397.46[M+H]+。
步骤2:反式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺
利用与实施例3Q相同的方法,使用反式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯(330mg,832μmol)、钯(碳上的10%,88.6mg)、乙醇(5.6mL)和氢气制备化合物,以得到标题化合物(199mg,91%)作为油。
LCMS(ES,m/z):263.43[M+H]+。
步骤3:反式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-6-氧
代-5,6-二氢-1,5-萘啶-2-腈
利用与实施例3Q相同的方法,使用反式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺(85.0mg,324μmol)、DMF(1.3mL)、DIPEA(209mg,1.62mmol,282μL)和8-氯-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈(71.2mg,324μmol)制备化合物,并且通过反相色谱法纯化(柱:SunFire Prep OBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内5%-40%);检测器:UV254/220nm)以得到标题化合物(9.7mg,6.6%)作为白色固体。
1H-NMR(CDCl3,300MHz)δ(ppm):7.81(d,J=8.7Hz,1H),7.64(d,J=8.9Hz,1H),7.01-6.91(m,2H),6.91-6.83(m,2H),6.23(d,J=7.6Hz,1H),5.81(s,1H),3.61(s,3H),3.54-3.43(m,1H),3.41-3.24(m,1H),3.03(d,J=5.9Hz,2H),2.28(br d,J=10.7Hz,2H),2.06-1.95(br d,J=10.7Hz,2H),1.58-1.37(m,4H),0.99-0.84(m,1H),0.57-0.48(m,2H),0.23-0.15(m,2H)。
LCMS(ES,m/z):446.54[M+H]+。
实施例3S:顺式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-
6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:顺式/反式-苄基(4-((4-氟苯基)氨基)环己基)氨基甲酸酯
利用与实施例3Q相同的方法,使用苄基N-(4-氧代环己基)氨基甲酸酯(5.01g,20.3mmol)、4-氟苯胺(2.25g,20.3mmol,1.94mL)、DCM(99mL)、乙酸(243mg,4.05mmol,232μL)和三乙酰氧基硼氢化钠(8.59g,40.5mmol)制备化合物以得到顺式-/反式-苄基(4-((4-氟苯基)氨基)环己基)-氨基甲酸酯(3.19g,46%)和反式-苄基(4-((4-氟苯基)氨基)环己基)氨基甲酸酯(1.90g,27%)作为白色固体(顺式-异构体用于步骤2)。
顺式:LCMS(ES,m/z):343.39[M+H]+。
反式:LCMS(ES,m/z):343.43[M+H]+。
步骤2:顺式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯
利用与实施例3Q相同的方法,使用顺式-苄基(4-((4-氟苯基)氨基)环己基)氨基甲酸酯(336mg,983μmol)、环丙烷甲醛(138mg,1.97mmol,147μL)、DCM(4.3mL)、乙酸(11.8mg,197μmol,11.3μL)和三乙酰氧基硼氢化钠(463mg,1.97mmol)制备化合物,以得到标题化合物(298mg,77%)作为油。
LCMS(ES,m/z):397.46[M+H]+。
步骤3:顺式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺
利用与实施例3Q相同的方法,使用顺式-苄基(4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基甲酸酯(295mg,744.02μmol)、钯(碳上的10%,79.2mg)、乙醇(5mL)和氢气制备化合物,以得到标题化合物(194mg,99%)作为油。
LCMS(ES,m/z):263.39[M+H]+。
步骤4:顺式-8-((4-((环丙基甲基)(4-氟苯基)氨基)环己基)氨基)-5-甲基-6-氧
代-5,6-二氢-1,5-萘啶-2-腈
利用与实施例3Q相同的方法,使用顺式-N-(环丙基甲基)-N-(4-氟苯基)环己烷-1,4-二胺(94.9mg,318μmol)、DMF(1.3mL)和DIPEA(205mg,1.59mmol,277μL)和8-氯-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈(69.8mg,318μmol)制备化合物,并且通过反相色谱法纯化(柱:SunFire Prep OBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内5%-40%);检测器:UV254/220nm)以得到标题化合物(1.2mg,8.3%)作为白色固体。
1H-NMR(CDCl3,300MHz)δ(ppm):7.83(d,J=8.3Hz,1H),7.65(d,J=8.6Hz,1H),7.01-6.89(m,4H),6.50(d,J=6.6Hz,1H),5.81(s,1H),3.76-3.66(m,1H),3.61(s,3H),3.53-3.43(m,1H),3.03(d,J=5.9Hz,2H),2.13-1.97(m,2H),1.81-1.68(m,6H),0.94-0.78(m,1H),0.55-0.45(m,2H),0.18-0.12(m,2H)。
LCMS(ES,m/z):446.50[M+H]+。
实施例3T:反式8-((4-(环丙基(苯基)氨基)环己基)(甲基)氨基)-5-甲基-6-氧
代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:反式-N1-环丙基-N1-苯基环己烷-1,4-二胺
将反式-N-[4-(N-环丙基苯胺基)环己基]氨基甲酸酯(1.3g,3.93mmol)在DCM(12mL)和TFA(3mL)中的溶液在室温下搅拌2小时。用饱和NaHCO3(水溶液)在0℃下将混合物碱化至pH 8并用DCM(3×40mL)萃取。将合并的有机层经无水硫酸钠干燥并减压浓缩以得到标题化合物(850mg,3.69mmol,94%)作为黄色固体。LCMS(ES,m/z):231.35[M+H]+
步骤2:反式-8-[[4-(N-环丙基苯胺基)环己基]氨基]-5-甲基-6-氧代-1,5-萘啶-
2-腈
将反式-N1-环丙基-N1-苯基环己烷-1,4-二胺(157mg,683μmol)、8-氯-5-甲基-6-氧代-1,5-萘啶-2-腈(150mg,683μmol)和DIEA(265mg,2.05mmol)在DMF(5mL)中的溶液在120℃下在氮气气氛下搅拌12小时。将混合物冷却至室温,用水(15mL)稀释并用EtOAc(3×15mL)萃取。将合并的有机层用盐水(20mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶色谱法(石油醚-EtOAc,2:1)纯化以得到标题化合物(90mg,218μmol,32%)作为浅黄色固体。
LCMS(ES,m/z):414.40[M+H]+
步骤3:反式-8-[[4-(N-环丙基苯胺基)环己基]-甲基-氨基]-5-甲基-6-氧代-1,
5-萘啶-2-腈
向反式-8-[[4-(N-环丙基苯胺基)环己基]氨基]-5-甲基-6-氧代-1,5-萘啶-2-腈(90mg,218μmol)在DMF(2mL)中的搅拌溶液中在0℃下添加NaH(17mg,435μmol,60%,以分钟计,油)。在30分钟后,逐滴添加碘甲烷(93mg,653μmol)。将所得混合物在0℃下搅拌1.5小时,用饱和NH4Cl(水溶液,10mL)淬灭并用EtOAc(3×10mL)萃取。将合并的有机层用盐水(10mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过反向快速色谱法纯化(柱,C18硅胶,40g,20um-35um;移动相,A:水(10mmol/L NH4HCO3)以及B:ACN(在30分钟内20%至75%);检测器:254nm),从而得到标题化合物(37.8mg,88.4μmol,41%)作为浅黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.16(d,J=8.8Hz,1H),8.04(d,J=8.9Hz,1H),7.22-7.14(m,2H),7.01(d,J=6.0Hz,2H),6.74(t,J=5.4Hz,1H),5.87(s,1H),4.43-4.35(m,1H),3.56-3.48(m,4H),2.85(s,3H),2.33-2.27(m,1H),1.96-1.71(m,8H),0.83-0.75(m,2H),0.39-0.33(m,2H)。
LCMS(ES,m/z):428.25[M+H]+
实施例3U:顺式-8-[[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-甲基-氨
基]-5-甲基-6-氧代-1,5-萘啶-2-腈的合成
步骤1:(2-((2-溴-5-氟苯氧基)甲氧基)乙基)三甲基硅烷
向2-溴-5-氟-苯酚(10g,52.4mmol,5.82mL)在DMF(207mL)中的搅拌溶液中在0℃下添加NaH(4.19g,104.8mmol,60%,以分钟计,油)。在0.5小时后,向混合物中添加SEM-Cl(10.47g,62.8mmol,11.1mL)。将反应混合物在室温下搅拌1.5小时,然后用冰水(400mL)稀释并用EtOAc(3×300mL)萃取。将合并的有机层用盐水(800mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(EtOAc-石油醚,10%)纯化以得到标题化合物(16g,95%)作为无色油。
步骤2:顺式-N-[4-[4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺基]环己基]
氨基甲酸叔丁酯
将顺式-N-(4-氨基环己基)氨基甲酸酯(7.0g,32.7mmol)、2-[(2-溴-5-氟-苯氧基)甲氧基]乙基-三甲基-硅烷(15.74g,49.0mmol)、BINAP(4.07g,6.53mmol)、Pd(OAc)2(1.10g,4.90mmol)和Cs2CO3(31.93g,97.99mmol)在甲苯(180mL)中的溶液在110℃下在氮气气氛下搅拌12小时。将混合物冷却至室温,用水(100mL)稀释并用EtOAc(3×100mL)萃取。将合并的有机层用盐水(100mL)洗涤,经无水硫酸钠干燥并减压浓缩。将残余物通过硅胶柱色谱法(石油醚-EtOAc,5:1)纯化以得到标题化合物(6g,13.20mmol,40%)作为黄色油。
LCMS(ES,m/z):455.30[M+H]+
步骤3:顺式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺
基]环己基]氨基甲酸叔丁酯
将顺式-N-[4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁基酯(4g,8.8mmol)、(1-甲氧基环丙氧基)-三甲基硅烷(7.05g,44.0mmol)和NaBH3CN(2.21g,35.2mmol)在AcOH(36mL)中的溶液在50℃下搅拌1.5小时。冷却至室温后,将混合物用水(50mL)稀释并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶柱色谱法(石油醚-EtOAc,6:1)纯化以得到标题化合物(3.15g,6.37mmol,72%)作为黄色油。
LCMS(ES,m/z):495.30[M+H]+
步骤4:顺式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺
基]环己基]-N-甲基-氨基甲酸叔丁酯
向顺式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯(3.15g,6.37mmol)在DMF(30mL)中的溶液中在0℃下添加NaH(1.02g,25.5mmol,60%,以分钟计,油)。在30分钟后向混合物中逐滴添加碘甲烷(4.52g,31.84mmol)。将所得混合物在0℃下搅拌1.5小时,然后用饱和NH4Cl(50mL,水溶液)淬灭并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶柱色谱法(石油醚-EtOAc,8:1)纯化以得到标题化合物(2.5g,4.9mmol,77%)作为无色油。
LCMS(ES,m/z):509.45[M+H]+
步骤5:顺式-2-[环丙基-[4-(甲基氨基)环己基]氨基]-5-氟-苯酚
向N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]-N-甲基-氨基甲酸叔丁酯(2.5g,4.91mmol)在DCM(30mL)中的溶液中添加TFA(5.5mL)。在室温下2小时后,将其减压浓缩,用饱和NaHCO3(水溶液)在0℃下碱化至pH 8并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩以得到标题化合物(830mg,2.98mmol,61%)作为黄色油。
LCMS(ES,m/z):279.20[M+H]+
步骤6:顺式-8-[[4-(N-环丙基-4-氟-2-羟基-苯胺基)环己基]-甲基-氨基]-5-甲
基-6-氧代-1,5-萘啶-2-腈
将顺式-2-[环丙基-[4-(甲基氨基)环己基]氨基]-5-氟-苯酚(200mg,718.48μmol)、(6-氰基-1-甲基-2-氧代-1,5-萘啶-4-基)三氟甲磺酸酯(239mg,718.5μmol,根据WO2020006018制备)和TEA(363mg,3.59mmol)在DMF(3mL)中的溶液在80℃下搅拌2小时。将化合物冷却并通过反向快速色谱法纯化(柱,C18硅胶,20um-35um;移动相,A:水与10mmol/LNH4HCO3以及B:ACN,在50分钟内5%-80%;检测器:254nm)。将收集的级分冻干以得到标题化合物(50.2mg,106.8μmol,15%)作为浅黄色固体。
1H NMR(300MHz,DMSO-d6)δ8.80(s,1H),8.13(d,J=8.8Hz,1H),8.02(d,J=8.9Hz,1H),7.18(dd,J=8.7,6.5Hz,1H),6.68–6.51(m,2H),5.85(s,1H),4.37-4.25(m,1H),3.50(s,3H),3.31(s,1H),2.89(s,3H),2.34(br s,1H),2.15-1.80(m,4H),1.52-1.33(m,4H),0.60-0.33(m,4H)。
LCMS(ES,m/z):462.25[M+H]+
实施例3V:反式-8-[[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-甲基-氨
基]-5-甲基-6-氧代-1,5-萘啶-2-腈的合成
以与本文所述的实施例类似的方式制备。将最终产物通过反向快速色谱法纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水(0.1%NH4CO3)以及B:ACN(在30分钟内10%至70%);检测器:UV 220nm)以得到标题化合物(28.6mg,8.8%)作为浅黄色固体。
1H NMR(300MHz,MeOH-d4)δ8.08-7.95(m,2H),7.10(dd,J=8.7,6.4Hz,1H),6.72(dd,J=10.8,2.8Hz,1H),6.59(td,J=8.4,2.8Hz,1H),5.93(s,1H),4.60-4.49(m,1H),3.84(s,3H),3.64(s,3H),3.26-3.17(m,1H),2.94(s,3H),2.60(tt,J=6.6,3.7Hz,1H),2.06-1.94(m,4H),1.81-1.60(m,4H),0.62-0.54(m,2H),0.36-0.28(m,2H)。LCMS(ES,m/z):476.30[M+H]+
实施例3W:顺式-8-[[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-甲基-氨
基]-5-甲基-6-氧代-1,5-萘啶-2-腈的合成
步骤1:顺式-N-[4-(4-氟-2-甲氧基-苯胺基)环己基]氨基甲酸叔丁酯
以类似于实施例1U的方式使用甲苯(100mL)中的顺式-N-(4-氨基环己基)氨基甲酸叔丁酯(4g,18.7mmol)、1-溴-4-氟-2-甲氧基-苯(9.95g,48.5mmol)、BINAP(2.32g,3.73mmol)、Pd(OAc)2(838mg,3.73mmol)和Cs2CO3(18.24g,56.0mmol)制备,从而得到标题化合物(1.9g,5.61mmol,30%)作为黄色固体。
LCMS(ES,m/z):339.40[M+H]+
步骤2:顺式-N-[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]氨基甲酸叔丁酯
以类似于实施例1U的方式使用AcOH(25mL)中的顺式-N-[4-(4-氟-2-甲氧基-苯胺基)环己基]氨基甲酸丁酯(1.9g,5.61mmol)、(1-甲氧环丙氧基)-三甲基硅烷(4.50g,28.1mmol)和NaBH3CN(1.41g,22.5mmol)制备,从而得到标题化合物(1.9g,5.02mmol,89%)作为白色固体。
LCMS(ES,m/z):379.25[M+H]+
步骤3:顺式-N-[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-N-甲基-氨基甲
酸叔丁酯
以类似于实施例1U的方式使用DMF(25mL)中的顺式-N-[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]氨基甲酸叔丁酯(1.9g,5.02mmol)、NaH(401mg,10.04mmol,60%,以分钟计,油)和MeI(2.85g,20.1mmol)制备,从而得到标题化合物(1.6g,4.08mmol,81%)作为白色固体。
LCMS(ES,m/z):393.25[M+H]+
步骤4:顺式-N-4-环丙基-N4-(4-氟-2-甲氧基-苯基)-N1-甲基-环己烷-1,4-二
胺;2,2,2-三氟乙酸
以类似于实施例1U的方式使用DCM(10mL)和TFA(2.5mL)中的顺式-N-[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-N-甲基-氨基甲酸叔丁酯(1.6g,4.08mmol)制备,从而得到标题化合物(1.6g,假定定量)作为棕色油。
LCMS(ES,m/z):293.20[M-TFA+H]+
步骤5:顺式-8-[[4-(N-环丙基-4-氟-2-甲氧基-苯胺基)环己基]-甲基-氨基]-5-
甲基-6-氧代-1,5-萘啶-2-腈
以类似于实施例1U类似的方式使用DMF(4mL)中的顺式-N4-环丙基-N4-(4-氟-2-甲氧基-苯基)-N1-甲基-环己烷-1,4-二胺(316mg,1.08mmol)、(6-氰基-1-甲基-2-氧代-1,5-萘啶-4-基)三氟甲磺酸酯(240mg,720μmol)和TEA(364mg,3.60mmol)制备。将残余物通过反向快速色谱法纯化(柱,C18硅胶,80g,20um-35um;移动相,A:水(10mmol/L NH4HCO3)以及B:ACN(在50分钟内5%至80%);检测器:254nm)。将收集的级分冻干以得到标题化合物(54mg,110μmol,15%,97.3纯度)作为灰白色固体。
1H NMR(400MHz,甲醇-d4)δ8.03(d,J=8.9Hz,1H),7.96(d,J=8.8Hz,1H),7.08(dd,J=8.5,6.6Hz,1H),6.76(dd,J=10.9,2.8Hz,1H),6.59(td,J=8.3,2.8Hz,1H),5.94(s,1H),4.63-4.50(m,1H),3.83(s,3H),3.63(s,3H),3.57-3.52(m,1H),3.01(s,3H),2.46(p,J=5.5Hz,1H),2.16-1.99(m,4H),1.58-1.43(m,4H),0.50-0.38(m,4H)。
LCMS(ES,m/z):476.20[M+H]+
实施例3X:反式8-((4-(环丙基(4-氟-2-羟基苯基)氨基)环己基)(甲基)氨基)-5-
甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:2-[(2-溴-5-氟-苯氧基)甲氧基]乙基-三甲基-硅烷
向2-溴-5-氟-苯酚(10g,52.3mmol,5.82mL)在DMF(150mL)中的搅拌溶液中在0℃下添加NaH(4.19g,105mmol,60%,以分钟计,油)。在0℃下搅拌0.5小时后,添加SEM-Cl(10.47g,62.8mmol)。在室温下再过1.5小时后,将混合物用饱和NH4Cl(水溶液,300mL)淬灭并用EtOAc(2×300mL)萃取。将合并的有机层用盐水(300mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,10:1)纯化以得到标题化合物(16g,49.8mmol,95%)作为无色油。
步骤2:反式-N-[4-[4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺基]环己基]
氨基甲酸叔丁酯
以类似于实施例1U的方式使用反式-N-(4-氨基环己基)氨基甲酸叔丁酯(7.83g,36.5mmol)、2-[(2-溴-5-氟-苯氧基)甲氧基]乙基-三甲基-硅烷(17.6g,54.8mmol)、BINAP(4.55g,7.30mmol)、Pd(OAc)2(1.65g,7.30mmol)和Cs2CO3(47.60g,146.1mmol)以及甲苯(100mL)制备以得到标题化合物(4g,8.8mmol,24%)作为无色油。
LCMS(ES,m/z):455.30[M+H]+
步骤3:反式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺
基]环己基]氨基甲酸叔丁酯
以类似于实施例1U的方式使用反式-N-[4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯(2g,4.40mmol)、(1-乙氧基环丙氧基)-三甲基-硅烷(3.53g,20.2mmol)、NaBH3CN(1.11g,17.6mmol)和AcOH(40mL)制备以得到标题化合物(1.8g,3.64mmol,83%)作为黄色油。
LCMS(ES,m/z):495.35[M+H]+
步骤4:反式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基甲氧基乙氧基)苯胺
基]环己基]-N-甲基-氨基甲酸叔丁酯
以类似于实施例1U的方式使用反式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯(1.8g,3.64mmol)、NaH(436mg,10.92mmol,60%)、CH3I(5.16g,36.38mmol)和DMF(20mL)制备以得到标题化合物(1.3g,2.56mmol,70%)作为白色固体。
LCMS(ES,m/z):509.35[M+H]+
步骤5:反式-2-[环丙基-[4-(甲基氨基)环己基]氨基]-5-氟-苯酚
以类似于实施例1U的方式使用反式-N-[4-[N-环丙基-4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]-N-甲基-氨基甲酸叔丁酯(1.3g,2.56mmol),DCM(10mL)和TFA(3mL)制备以得到标题化合物(700mg,假定定量)作为黄色固体。
LCMS(ES,m/z):279.15[M+H]+
步骤6:反式-8-[[4-(N-环丙基-4-氟-2-羟基-苯胺基)环己基]-甲基-氨基]-5-甲
基-6-氧代-1,5-萘啶-2-腈
以类似于实施例1U类似的方式使用反式-2-[环丙基-[4-(甲基氨基)环己基]氨基]-5-氟-苯酚(100mg,359.24μmol)、(6-氰基-1-甲基-2-氧代-1,5-萘啶-4-基)三氟甲磺酸酯(119mg,359μmol)、TEA(109mg,1.08mmol)和DMF(2mL)制备。将材料通过HPLC纯化(柱:YMC-Actus Triart C18,30mm×150mm,5um;移动相,A:水(10mmol/L NH4HCO3)以及B:ACN(在9分钟内52%至72%);检测器:254nm)以得到标题化合物(29.2mg,63.3μmol,18%)作为浅黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.14(d,J=8.8Hz,1H),8.03(d,J=8.9Hz,1H),7.15(dd,J=8.3,6.4Hz,1H),6.60-6.52(m,2H),5.86(s,1H),4.26-4.17(m,1H),3.51(s,3H),3.03-2.96(m,1H),2.80(s,3H),1.96(bd,J=12.6Hz,2H),1.85(bd,J=12.3Hz,2H),1.65(q,J=12.1Hz,2H),1.41(q,J=12.3Hz,2H),0.48-0.43(m,2H),0.10(br s,2H)。
LCMS(ES,m/z):462.25[M+H]+
实施例3Y:反式-8-[[4-(N-环丙基甲基-N-4-氟-2-甲氧基苯基-苯胺基)环己基]-
甲基-氨基]-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:顺式/反式-4-[(4-氟-2-甲氧基苯基-苯胺基)环己基]氨基甲酸叔丁酯
向N-(4-氧代环己基)氨基甲酸叔丁酯(5.00g,23.4mmol)、4-氟-2-甲氧基-苯胺(3.31g,2.76mL,23.4mmol)在DCM(114.19mL)中的混合物中添加乙酸(268.4μL,4.69mmol)。搅拌15分钟后,添加三乙酰氧基硼氢化钠(9.32g,35.2mmol,80.0%纯度)。将所得混合物搅拌16小时,随之添加饱和NaHCO3(20mL)和水(20mL)。在5分钟后,分离各层并且
将有机层真空浓缩。将粗残余物通过硅胶色谱法(EtOAc-庚烷,5%-20%)纯化,从而得到顺式-异构体(2.33g,29%)和反式-异构体(2.24g,28%)作为白色固体。
LCMS(ES,m/z):339.45[M+H]+。
步骤2:4-[(N-环丙基甲基-N-4-氟-2-甲氧基苯基-苯胺基)环己基]氨基甲酸叔丁
酯
向反式-4-[(4-氟-2-甲氧基苯基-苯胺基)环己基]氨基甲酸叔丁酯(260mg,768μmol)和环丙烷甲醛(74.6μL,999μmol)在DCM(3.53mL)中的溶液中添加乙酸(88μL,1.54mmol)。在15分钟后,添加三乙酰氧基硼氢化钠(244mg,1.15mmol)。在16小时后,再添加环丙烷甲醛(74.6μL,999μmol)和乙酸(88μL,1.54mmol),随后在30分钟后添加三乙酰氧基硼氢化钠(244.25mg,1.15mmol)。再过16小时后,将其用饱和NaHCO3淬灭,并在鼓泡平息后分离各层。将各层分离,并且将水性层用DCM(2x)萃取。将合并的有机层经无水Na2SO4干燥并真空浓缩。将粗残余物通过硅胶色谱法(EtOAc-庚烷,0%-30%)纯化,从而得到标题化合物(111.5mg,37%)。
LCMS(ES,m/z):393.41[M+H]+。
步骤3-5:反式-8-[[4-(N-环丙基甲基-N-4-氟-2-甲氧基苯基-苯胺基)环己基]-
甲基-氨基]-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈
以类似于实施例25,步骤3-5的方式进行。将粗材料通过HPLC纯化(柱:SunfireOBD,C18,19×250mm,5μm;移动相,A:水与0.1%甲酸,以及B:ACN与0.1%甲酸,10%-40%),从而得到标题化合物(6.4mg,13%)作为灰白色固体。
1H NMR(300MHz,DMSO-d6)δppm 8.19-8.11(m,1H),8.07-8.01(m,1H),7.10-7.02(m,1H),6.82(br d,J=10.5Hz,1H),6.69-6.60(m,1H),5.86(s,1H),4.29-4.16(m,1H),3.78(s,3H),3.51(s,3H),3.04-2.92(m,1H),2.87(br d,J=6.1Hz,2H),2.81(s,3H),2.73(br d,J=1.47Hz,1H),1.92-1.79(m,4H),1.76-1.58(m,2H),1.35-1.18(m,2H),0.70-0.58(m,1H),0.29-0.21(m,2H),0.04-(-)0.09(m,2H)。
LCMS(ES,m/z):490.48[M+H]+。
实施例3Z:顺式-8-[[4-(N-环丙基甲基-N-4-氟-2-甲氧基苯基-苯胺基)环己基]-
甲基-氨基]-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
以与实施例45类似的方式制备将粗材料通过硅胶色谱法(EtOAc-庚烷,0%-100%)纯化,从而得到标题化合物(17.3mg,12.8%)作为灰白色固体。
1H NMR(300MHz,DMSO-d6)δppm 8.13(d,J=8.7Hz,1H),8.03(d,J=8.9H,1H),7.23(t,J=7.6Hz,1H),6.92-6.85(m,1H),6.75-6.66(m,1H),5.87(s,1H),4.41-4.27(m,1H),3.80(s,3H),3.51(s,3H),2.90(s,3H),2.76(d,J=6.7H,2H),2.09-1.91(m,2H),1.83(br d,J=13.9,2H),1.52-1.30(m,4H),0.76-0.62(m,1H),0.32-0.22(m,2H),-0.10-(-)0.19(m,2H)。
LCMS(ES,m/z):490.54[M+H]+。
实施例3AA:反式-8-[[4-[环丙基甲基-(5-氟-2-吡啶基)氨基]环己基]-甲基-氨
基]-5-甲基-6-氧代-1,5-萘啶-2-腈的合成
将反式-N4-(环丙基甲基)-N4-(5-氟-2-吡啶基)-N1-甲基-环己烷-1,4-二胺(250mg,511μmol,80%)、(6-氰基-1-甲基-2-氧代-1,5-萘啶-4-基)三氟甲磺酸酯(170.3mg,511μmol)和TEA(155mg,1.53mmol)在DMF(2mL)中的混合物在80℃下搅拌1小时。在冷却至室温后,将溶液通过反向快速色谱法纯化(柱,C18硅胶,80g,20um-35um;移动相,A:水(0.5%TFA)和ACN(30分钟内30%-80%);检测器:UV 254nm),从而得到标题化合物(69.4mg,140.9μmol,28%、93.5%纯度)作为黄色固体。
1H NMR(300MHz,DMSO-d6)δ8.16(d,J=8.8Hz,1H),8.08-8.02(m,2H),7.46(td,J=8.8,3.2Hz,1H),6.72(dd,J=9.3,3.0Hz,1H),5.89(s,1H),4.46-4.32(m,1H),4.29-4.18(m,H),3.52(s,3H),3.19(d,J=6.0Hz,2H),2.89(s,3H),1.98-1.84(m,4H),1.84-1.56(m,4H),1.02-0.92(m,1H),0.49-0.42(m,2H),0.31-0.24(m,2H)。
LCMS(ES,m/z):461.15[M+H]+
实施例3BB:反式8-((4-((4-氟-2-羟基苯基)(氧杂环丁烷-3-基甲基)氨基)环己
基)(甲基)氨基)-5-甲基-6-氧代-5,6-二氢-1,5-萘啶-2-腈的合成
步骤1:反式-N-[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧
基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯
向反式-N-[4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)-苯胺基]环己基]氨基甲酸叔丁酯(2.8g,6.16mmol)、氧杂环丁烷-3-甲醛(1.06g,12.32mmol)在DCM(30mL)中的溶液中添加AcOH(6mL),然后添加STAB(1.96g,9.24mmol)。在1.5小时后,将混合物用饱和NH4Cl(水溶液,30mL)淬灭并用DCM(3×30mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,2:1)纯化,从而得到标题化合物(2.75g,5.24mmol,85%)作为黄色油。
LCMS(ES,m/z):525.35[M+H]+
步骤2:反式-N-[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧
基甲氧基)苯胺基]环己基]-N-甲基-氨基甲酸叔丁酯
向反式-N-[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]氨基甲酸叔丁酯(2.75g,5.24mmol)在DMF(25mL)中的溶液中在0℃下添加NaH(419mg,10.48mmol,60%,以分钟计,油)。在30分钟后,添加CH3I(2.98g,20.96mmol)。在0℃下再过1.5小时后,将混合物用饱和NH4Cl(水溶液,50mL)淬灭并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过硅胶色谱法(石油醚-EtOAc,3:1)纯化以得到标题化合物(2.7g,5.01mmol,96%)作为黄色油。
LCMS(ES,m/z):539.45[M+H]+
步骤3:反式-N4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯基]-N1-甲基-N4-
(氧杂环丁烷-3-基甲基)环己烷-1,4-二胺
向反式-N-[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]-N-甲基-氨基甲酸叔丁酯(2.5g,4.64mmol)在DCM(16mL)中的溶液中添加TFA(4mL)。在2小时后,将所得混合物减压浓缩,在0℃下用饱和NaHCO3中和并用EtOAc(3×50mL)萃取。将合并的有机层用盐水(50mL)洗涤,经无水硫酸钠干燥并减压浓缩以得到标题化合物(900mg,2.05mmol,44%)作为黄色油。
LCMS(ES,m/z):439.45[M+H]+
步骤4:反式-8-[[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙
氧基甲氧基)苯胺基]环己基]-甲基-氨基]-5-甲基-6-氧代-1,5-萘啶-2-腈
将反式-N4-[4-氟-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯基]-N1-甲基-N4-(氧杂环丁烷-3-基甲基)环己烷-1,4-二胺(200mg,456μmol)、(6-氰基-1-甲基-2-氧代-1,5-萘啶-4-基)三氟甲磺酸酯(152mg,455.94μmol)和TEA(92mg,911.88μmol)在DMF(3mL)的溶液加热至80℃持续1小时,随之将其冷却至室温并通过反向快速色谱法纯化(柱:C18硅胶,80g,20um-35um;移动相,A:水与10mmol/L NH4HCO3,以及B:ACN,在40分钟内5%-60%),从而得到标题化合物(160mg,257μmol,56%)作为黄色油。
LCMS(ES,m/z):622.50[M+H]+
步骤5:反式-8-[[4-[4-氟-2-羟基-N-(氧杂环丁烷-3-基甲基)苯胺基]环己基]-
甲基-氨基]-5-甲基-6-氧代-1,5-萘啶-2-腈
向装有反式-8-[[4-[4-氟-N-(氧杂环丁烷-3-基甲基)-2-(2-三甲基甲硅烷基乙氧基甲氧基)苯胺基]环己基]-甲基-氨基]-5-甲基-6-氧代-1,5-萘啶-2-腈(150mg,241μmol)的小瓶中添加TBAF(THF中的1M,2mL)。将溶液加热至50℃持续12小时。将混合物冷却至室温,用水(10mL)稀释并用EtOAc(3×10mL)萃取。将合并的有机层用盐水(10mL)洗涤,经无水硫酸钠干燥并减压浓缩。将粗残余物通过反向快速色谱法纯化(柱:C18硅胶,40g,20um-35um;移动相,A:水与10mmol/L NH4HCO3,以及B:ACN,在40分钟内5%-60%),从而得到标题化合物(37.5mg,69.6μmol,29%)作为浅黄色固体。
1H NMR(400MHz,DMSO-d6)δ8.68(br s,1H),8.13(d,J=8.8Hz,1H),8.03(d,J=8.9Hz,1H),7.10(dd,J=8.7,6.4Hz,1H),6.60(dd,J=10.4,2.8Hz,1H),6.55(td,J=8.8,2.8Hz,1H)5.87(s,1H),4.38(dd,J=7.6,6.0Hz,2H),4.22-4.12(m,1H),4.12(t,J=6.0Hz,2H),3.51(s,3H),3.25(d,J=7.5Hz,2H),2.80-2.67(m,5H),1.94(br d,J=11.6Hz,2H),1.85(br d,J=10.4Hz,2H),1.67(q,J=11.2Hz,2H),1.32-1.20(m,2H)。
LCMS(ES,m/z):492.15[M+H]+。
实施例3CC:顺式-6-氯-4-[[4-(N-环丙基-2,4-二氟-苯胺基)环己基]-甲基-氨
基]-1-甲基-2-氧代-1,5-萘啶-3-腈的合成
步骤1:顺式-N-[4-(2,4-二氟苯胺基)环己基]氨基甲酸叔丁酯
以与实施例38,步骤1类似的方式使用顺式-N-(4-氨基环己基)氨基甲酸叔丁酯(4.02g,18.7mmol)、2,4-二氟-1-碘-苯(3.0g,12.5mmol)、N1-(2-甲基-1-萘基)-N2-(苯基甲基)-乙二酰胺(199mg,625μmol)、Cu2O(89.4mg,625μmol)、KOH(911.8mg,16.25mmol)和乙醇(25mL)进行。将粗残余物通过硅胶色谱法(石油醚-EtOAc,5:1)纯化,从而得到标题化合物(380mg,1.16mmol,9.3%)作为白色固体。LCMS(ES,m/z):327.15[M+H]+
步骤2-5:顺式-6-氯-4-[[4-(N-环丙基-2,4-二氟-苯胺基)环己基]-甲基-氨基]-
1-甲基-2-氧代-1,5-萘啶-3-腈
以与实施例26,步骤3-6类似的方式进行。将粗材料通过HPLC纯化(柱:XBridgePrep OBD C18,30×150mm,5um;移动相,A:水与50mmol/L NH4HCO3,以及B:ACN,在7分钟内75%-95%),从而得到标题化合物(29.8mg,59.8μmol,9.9%)作为灰白色固体。
1H NMR(400MHz,DMSO-d6)δ8.04(d,J=9.2Hz,1H),7.78(d,J=8.8Hz,1H),7.38(td,J=8.8,6.4Hz,1H),7.22(ddd,J=9.1,8.8,2.8Hz,1H),7.07-6.99(m,1H),4.38-4.28(m,1H),3.51(s,3H),3.38-3.35(m,1H),3.24(s,3H),2.43-2.36(m,1H),2.11-1.92(m,4H),1.71-1.62(m,2H),1.51(t,J=13.2Hz,2H),0.55-0.49(m,2H),0.44-0.38(m,2H)。
LCMS(ES,m/z):498.15[M+H]+
实施例4:
结构(I-B-4)的化合物
实施例4A:顺式-N-4-((环丙基甲基)(苯基)氨基)环己基)-2-甲基-1H-吲哚-3-甲
酰胺的合成
步骤1.顺式-N1-(环丙基甲基)-N1-苯基环己烷-1,4-二胺盐酸盐
向顺式-4-((环丙基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯(18.9mg,54.9μmol)在二噁烷(200μL)中的溶液中添加HCl(二噁烷中的4M,200μL,800μmol)。在搅拌20小时后,将悬浮液减压浓缩以得到标题化合物作为白色固体(假定定量产率)。
LCMS(ES,m/z):245.10[M-HCl+H]+
步骤2.顺式-N-4-((环丙基甲基)(苯基)氨基)环己基)-2-甲基-1H-吲哚-3-甲酰
胺
向2-甲基-1H-吲哚-3-甲酸(35.0mg,200μmol)和HATU(76.5mg,200μmol)在DMF(1.0mL)中的溶液中在0℃下添加DIPEA(35μL,200μmol)。30分钟后,移除一半溶液并将其添加到顺式-N1-(环丙基甲基)-N1-苯基环己烷-1,4-二胺盐酸盐(13.4mg,54.9μmol)和DIPEA(38μL,219μmol)在DMF(236μL)中的溶液中。在18小时后,将粗材料通过HPLC纯化(柱:Xselect CSH OBD,C18,19×150mm,5μm;移动相,A:水与0.05%甲酸,以及B:ACN与0.05%甲酸,在15分钟内5%-40%),从而得到标题化合物(22mg,100%)作为白色固体。
1H NMR(300MHz,DMSO-d6)δppm 11.38(s,1H),7.70(br d,J=7.8Hz,1H),7.41-7.28(m,2H),7.18(t,J=7.8Hz,2H),7.12-7.00(m,2H),6.86(d,J=8.4Hz,2H),6.62(t,J=7.0,1H),4.13(br s,1H),3.73-3.55(m,1H),3.15(d,J=5.5Hz,2H),2.59(s,3H),1.99(brd,J=12.2Hz,2H),1.91-1.54(m,6H),1.04-0.91(m,1H),0.55-0.45(m,2H),0.29-0.23(m,2H)。
LCMS(ES,m/z):402.05[M+H]+。
实施例4B:反式-N-4-((环丙基甲基)(苯基)氨基)环己基)-2-甲基-1H-吲哚-3-甲
酰胺的合成
以与如本文所述的实施例类似的方式制备。将粗材料通过HPLC纯化(柱:XselectCSH OBD,C18,19×150mm,5μm;移动相,A:水与0.05%甲酸,以及B:ACN与0.05%甲酸,在15分钟内5%-40%),从而得到标题化合物(13.4mg,51%)作为白色固体。
1H NMR(300MHz,DMSO-d6)δppm 11.36(s,1H),7.73-7.62(m,1H),7.36-7.28(m,2H),7.24-7.14(m,2H),7.12-7.00(m,2H),6.86(d,J=8.4Hz,2H),6.62(t,J=7.0,1H),3.89-3.75(m,1H),3.65-3.55(m,1H),3.11(d,J=5.0Hz,2H),2.56(s,3H),2.05-1.95(m,2H),1.83-1.74(m,2H),1.68-1.47(m,6H),1.01-0.89(m,1H),0.55-0.44(m,2H),0.32-0.24(m,2H)。
LCMS(ES,m/z):402.25[M+H]+。
实施例4C:反式-2-甲基-N-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)-
1H-吲哚-3-甲酰胺的合成
以与本文所述实施例类似的方式使用氧杂环丁烷-3-甲醛(61.9mg,720μmol)制备以得到标题化合物(14.5mg,25%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):11.36(s,1H),7.72-7.65(m,1H),7.36-7.27(m,1H),7.18(t,J=8.0Hz,3H),7.11-7.00(m,2H),6.79(d,J=8.3Hz,2H),6.69(t,J=7.2Hz,1H),4.58(dd,J=7.8,5.9Hz,2H),4.35(t,J=6.1Hz,2H),3.92-3.75(m,1H),3.56-3.45(m,3H),3.21-3.05(m,2H),2.56(s,3H),2.00(br d,J=11.3Hz,2H),1.78-1.67(m,2H),1.67-1.43(m,4H)。
LCMS(ES,m/z):417.93[M+H]+。
实施例4D:顺式2-甲基-N-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)-1H-
吲哚-3-甲酰胺的合成
步骤1:顺式-(4-(苯基氨基)环己基)氨基甲酸叔丁酯
将N-(4-氧代环己基)氨基甲酸叔丁酯(2.50g,11.7mmol)、苯胺(2.18g,23.4mmol,2.14mL)和乙酸(1.41g,23.4mmol,1.34mL)在DCM(34.7mL)中的溶液在室温下搅拌0.25小时。向混合物中添加三乙酰氧基硼氢化钠(5.52g,23.4mmol),并将悬浮液搅拌16小时。将混合物用饱和碳酸氢钠(30mL)淬灭并且将有机层在减压下浓缩。将粗产物通过硅胶色谱法用乙酸乙酯/庚烷(0%-50%)纯化,从而得到标题化合物(618mg,18%)作为白色固体。
LCMS(ES,m/z):290.82[M+H]+。
步骤2:顺式-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯
将顺式-(4-(苯基氨基)环己基)氨基甲酸叔丁酯(200mg,689μmol)、氧杂环丁烷-3-甲醛(119mg,1.38mmol)和乙酸(41.4mg,689μmol,39.4μL)在DCM(2.72mL)中的溶液在室温下搅拌0.25小时。向混合物中添加三乙酰氧基硼氢化钠(438mg,2.07mmol),并将悬浮液搅拌16小时。将混合物用饱和碳酸氢钠(2mL)淬灭并且将有机层在减压下浓缩。将粗产物通过硅胶色谱法用乙酸乙酯/庚烷(0%-100%)纯化,从而得到标题化合物(205mg,83%)作为白色固体。
LCMS(ES,m/z):360.71[M+H]+。
步骤3:顺式-N-(氧杂环丁烷-3-基甲基)-N-苯基环己烷-1,4-二胺三氟乙酸酯
将顺式-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯(160mg,444μmol)和DCM(2.96mL)的溶液在0℃下搅拌0.25小时。将TFA(911mg,7.99mmol,615μL)逐滴添加,并且将混合物在0℃下搅拌2小时。添加碳酸氢钠(746mg,8.88mmol)和水(800μL),并且将混合物在减压下浓缩。将粗产物通过反相色谱法纯化(柱:SunFire PrepOBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内5%-45%);检测器:UV254/220nm)。将产物冻干以得到标题化合物(44.0mg,33%)作为白色固体。
LCMS(ES,m/z):260.91[M+H]+。
步骤4:顺式2-甲基-N-(4-((氧杂环丁烷-3-基甲基)(苯基)氨基)环己基)-1H-吲
哚-3-甲酰胺
将2-甲基-1H-吲哚-3-羧酸(7.99mg,45.6μmol)、HATU(17.4mg,45.6μmol)和DIPEA(23.6mg,183μmol,31.8μL)在DMF(212μL)中的溶液在室温下搅拌5分钟,并且添加顺式-N-(氧杂环丁烷-3-基甲基)-N-苯基环己烷-1,4-二胺三氟乙酸酯(22.0mg,45.63μmol)在DMF(212μL)中的溶液。将混合物在室温下搅拌16小时,并且通过反相色谱法纯化(柱:SunFirePrep OBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内10%-45%);检测器:UV254/220nm)。将产物冻干以得到标题化合物(3.4mg,17%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):11.39(s,1H),7.76-7.68(m,1H),7.42(br d,J=6.1Hz,1H),7.38-7.29(m,1H),7.19(t,J=8.2Hz,2H),7.13-7.03(m,2H),6.83(d,J=8.2Hz,2H),6.71(t,J=7.2Hz,1H),4.59(dd,J=7.8,5.9Hz,2H),4.34(t,J=6.1Hz,2H),4.11(br s,1H),3.62-3.46(m,3H),3.20-3.07(m,1H),2.60(s,3H),1.98(br d,J=11.7Hz,2H),1.92-1.78(m,2H),1.74-1.60(m,2H),1.54(br d,J=10.6Hz,2H)。
LCMS(ES,m/z):418.02[M+H]+。
实施例4E:反式2-甲基-N-(4-(((3-甲基氧杂环丁烷-3-基)甲基)(苯基)氨基)环
己基)-1H-吲哚-3-甲酰胺的合成
将反式-2-甲基-N-(4-(苯基氨基)环己基)-1H-吲哚-3-甲酰胺(40.0mg,115μmol)、3-甲基氧杂环丁烷-3-甲醛(115mg,1.15mmol)和乙酸(6.9mg,115μmol,6.6μL)在DCM(1.15mL)中的溶液在室温下搅拌0.25小时。向混合物中添加三乙酰氧基硼氢化钠(97.6mg,460μmol),并将悬浮液搅拌16小时。将混合物用饱和碳酸氢钠(2mL)萃取并在减压下浓缩。将粗产物通过反相色谱法纯化(柱:SunFire Prep OBD C18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内5%-50%);检测器:UV254/220nm)。将产物冻干以得到标题化合物(3.9mg,7.7%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):11.35(s,1H),7.72-7.65(m,1H),7.33-7.28(m,1H),7.25-7.16(m,3H),7.11-7.00(m,2H),6.85(d,J=8.1Hz,2H),6.78(t,J=7.2Hz,1H),4.41(d,J=5.5Hz,2H),3.97(d,J=5.6Hz,2H),3.24(s,2H),2.55(s,3H),1.98(br d,J=7.7Hz,2H),1.86-1.77(m,2H),1.63-1.40(m,4H),1.33(s,3H)。
LCMS(ES,m/z):432.62[M+H]+。
实施例4F:顺式-N-(4-((环丙基甲基)(苯基)氨基)环己基)-1H-吡咯并[3,2-b]吡
啶-3-甲酰胺的合成
步骤1:顺式-N-(环丙基甲基)-N-苯基环己烷-1,4-二胺盐酸盐
向顺式-(4-((环丙基甲基)(苯基)氨基)环己基)氨基甲酸叔丁酯(70.0mg,203μmol)和二噁烷(1.52mL)的溶液中添加氯化氢(二噁烷中的4M,1.02mL)。在室温下搅拌4小时后,将混合物减压浓缩,从而得到标题化合物(假定定量产率)作为白色固体。
LCMS(ES,m/z):245.51[M+H]+。
步骤2:顺式-N-(4-((环丙基甲基)(苯基)氨基)环己基)-1H-吡咯并[3,2-b]吡啶-
3-甲酰胺
将1H-吡咯并[3,2-b]吡啶-3-羧酸(16.2mg,99.7μmol)、HATU(37.9mg,99.7μmol)和DIPEA(64.4mg,499μmol,86.8μL)在DMF(412μL)中的溶液在0℃下搅拌5分钟。添加顺式-N-(环丙基甲基)-N-苯基环己烷-1,4-二胺盐酸盐(28.0mg,99.7μmol)在DMF(412μL)的溶液,并且将混合物在0℃下搅拌2小时。将溶液通过反相色谱法纯化(柱:SunFire Prep OBDC18,19×250mm,5μm;移动相,A:水(0.1%甲酸)以及B:ACN(0.1%甲酸,在10分钟内10%-40%);检测器:UV254/220nm)。将产物冻干以得到标题化合物(1.5mg,3.8%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):11.97(br s,1H),9.32(d,J=8.5Hz,1H),8.46(dd,J=4.7,1.1Hz,1H),8.18(d,J=3.0Hz,1H),7.96(dd,J=8.2,1.2Hz,1H),7.31(dd,J=8.2,4.7Hz,1H),7.18(t,J=7.9Hz,2H),6.87(d,J=8.3Hz,2H),6.61(t,J=7.1Hz,1H),4.34-4.24(m,1H),3.74(m,1H),3.22(d,J=5.7Hz,2H),1.93-1.63(m,8H),1.07-0.92(m,1H),0.56-0.44(m,2H),0.27(m,J=4.8Hz,2H)。
LCMS(ES,m/z):389.53[M+H]+。
实施例4G:顺式-N-(4-((环丙基甲基)(苯基)氨基)环己基)吡唑并[1,5-a]嘧啶-
3-甲酰胺的合成
以类似于实施例4F,步骤2的方式使用吡唑并[1,5-a]嘧啶-3-羧酸(16.3mg,99.7μmol)制备以得到标题化合物(10.5mg,27%)作为白色固体。
1H-NMR(DMSO-d6,300MHz)δ(ppm):9.36(d,J=7.0Hz,1H),8.79(d,J=3.9Hz,1H),8.59(s,1H),8.29(br d,J=8.0Hz,1H),7.33(dd,J=7.0,4.2Hz,1H),7.18(t,J=7.8Hz,2H),6.87(br d,J=8.3Hz,2H),6.62(t,J=7.2Hz,1H),4.31-4.20(m,1H),3.72(br s,1H),3.17(d,J=5.6Hz,2H),1.97-1.64(m,8H),1.06-0.90(m,1H),0.45-0.56(m,2H),0.27(q,J=5.0Hz,2H)。
LCMS(ES,m/z):389.93[M+H]+。
实施例5-214:
如表2中所示,实施例5-214的化合物根据与实施例1-4中所述那些类似的程序来制备。表2中的LCMS是(ES,m/z)[M+H]+。
表2:化合物5-214
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生物测定
实施例215:
DGKα和DGKζ生化测定
将本发明的化合物制备成10mM DMSO溶液,并使用Echo550将10nL原液转移到384板(Optiplate 384板)中。DMSO用作高对照,ATP底物缓冲液用作低对照。制备1x酶测定缓冲液(Hepes,pH 7.0 25mM,BSA 0.05%,Triton-X100 0.002%,CaCl2 1μM,MgCl2 10mM,DTT2mM)。通过使用1X测定缓冲液稀释酶DGKα(1μg/μL DGKα,Carna12-101,SEQ ID NO:3)或DGKζ(1μ/μL DGKζ,Carna 12-110,SEQ ID NO:4)来进行酶测定。将OAG(1-油酰基-2-乙酰基-sn-甘油,25mg/ml,Avanti 800100)和PS(10mg/ml,Avanti 840032P)以1:2的比率混合。用1X测定缓冲液通过100倍稀释制备1X底物溶液。将底物溶液在冰上超声处理1分钟。将纯ATP添加到底物溶液(DGKa:400μM)。将5μL酶溶液添加到384孔板,并将板在1000rpm下旋转1分钟,并在室温下温育30分钟。将5μL 1X底物溶液添加到384孔板,旋转该板,然后在室温下温育45分钟。添加10μL ADP-Glo洗涤剂以停止测定。在室温下60分钟后,添加20μL ADP-Glo检测缓冲液作为最后步骤。在室温下温育45分钟后读取板。
通过使用下式计算%抑制来进行数据分析:
高对照(Hc):DMSO/DGKα(DGKζ)/底物/ATP/ADP-Glo
低对照(Lc):ATP/ADP-Glo
本发明化合物的活性呈现于表3中,其中:
“A”表示小于10nM的IC50;
“B”表示10nM至小于100nM的IC50;
“C”表示100nM至小于1000nM的IC50;并且
“D”表示1000nM或更大的IC50。
表3:化合物活性
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可以组合上述各种实施方案来提供另外的实施方案。本说明书中提到的和/或专利申请数据表中所列的所有美国专利、美国专利申请公布、美国专利申请、外国专利、外国专利申请和非专利公布均全文以引用方式并入本文。如果需要,可以修改实施方案的各个方面以采用各专利、申请和出版物的概念来提供进一步的实施方案。
鉴于上文的详细说明,可以对这些实施方案作出这些和其他改变。一般来说,在随后的权利要求中,使用的术语不应解释成将权利要求书限制在本说明书和权利要求书中披露的具体实施方案中,而应解释成包括所有可能的实施方案以及这类权利要求书赋予的等效物的全部范围。因此,权利要求并不受本公开内容所限定。
优先权
本申请要求2020年12月16日提交的美国临时申请号63/126,433的优先权权益,该申请据此全文以引用方式并入。
关于序列表的声明
与本申请相关的序列表以文本格式提供以代替纸件拷贝,并据此以引用方式并入本说明书中。包含序列表的文本文件的名称是360474_402WO_SEQUENCE_LISTING.txt。该文本文件是33KB,在2021年12月16日创建,并通过EFS-Web以电子形式提交。
序列表
<110> 戈萨默生物服务公司
安东尼·卡萨雷斯
特里·凯勒
<120> 可用作T细胞激活剂的化合物
<130> 360474.402WO
<150> US 63/126,433
<151> 2020-12-16
<160> 4
<170> PatentIn version 3.5
<210> 1
<211> 735
<212> PRT
<213> 智人(Homo sapiens)
<300>
<308> RefSeq | NP_958852.1
<309> 2004-09-14
<313> (1)..(735)
<400> 1
Met Ala Lys Glu Arg Gly Leu Ile Ser Pro Ser Asp Phe Ala Gln Leu
1 5 10 15
Gln Lys Tyr Met Glu Tyr Ser Thr Lys Lys Val Ser Asp Val Leu Lys
20 25 30
Leu Phe Glu Asp Gly Glu Met Ala Lys Tyr Val Gln Gly Asp Ala Ile
35 40 45
Gly Tyr Glu Gly Phe Gln Gln Phe Leu Lys Ile Tyr Leu Glu Val Asp
50 55 60
Asn Val Pro Arg His Leu Ser Leu Ala Leu Phe Gln Ser Phe Glu Thr
65 70 75 80
Gly His Cys Leu Asn Glu Thr Asn Val Thr Lys Asp Val Val Cys Leu
85 90 95
Asn Asp Val Ser Cys Tyr Phe Ser Leu Leu Glu Gly Gly Arg Pro Glu
100 105 110
Asp Lys Leu Glu Phe Thr Phe Lys Leu Tyr Asp Thr Asp Arg Asn Gly
115 120 125
Ile Leu Asp Ser Ser Glu Val Asp Lys Ile Ile Leu Gln Met Met Arg
130 135 140
Val Ala Glu Tyr Leu Asp Trp Asp Val Ser Glu Leu Arg Pro Ile Leu
145 150 155 160
Gln Glu Met Met Lys Glu Ile Asp Tyr Asp Gly Ser Gly Ser Val Ser
165 170 175
Gln Ala Glu Trp Val Arg Ala Gly Ala Thr Thr Val Pro Leu Leu Val
180 185 190
Leu Leu Gly Leu Glu Met Thr Leu Lys Asp Asp Gly Gln His Met Trp
195 200 205
Arg Pro Lys Arg Phe Pro Arg Pro Val Tyr Cys Asn Leu Cys Glu Ser
210 215 220
Ser Ile Gly Leu Gly Lys Gln Gly Leu Ser Cys Asn Leu Cys Lys Tyr
225 230 235 240
Thr Val His Asp Gln Cys Ala Met Lys Ala Leu Pro Cys Glu Val Ser
245 250 255
Thr Tyr Ala Lys Ser Arg Lys Asp Ile Gly Val Gln Ser His Val Trp
260 265 270
Val Arg Gly Gly Cys Glu Ser Gly Arg Cys Asp Arg Cys Gln Lys Lys
275 280 285
Ile Arg Ile Tyr His Ser Leu Thr Gly Leu His Cys Val Trp Cys His
290 295 300
Leu Glu Ile His Asp Asp Cys Leu Gln Ala Val Gly His Glu Cys Asp
305 310 315 320
Cys Gly Leu Leu Arg Asp His Ile Leu Pro Pro Ser Ser Ile Tyr Pro
325 330 335
Ser Val Leu Ala Ser Gly Pro Asp Arg Lys Asn Ser Lys Thr Ser Gln
340 345 350
Lys Thr Met Asp Asp Leu Asn Leu Ser Thr Ser Glu Ala Leu Arg Ile
355 360 365
Asp Pro Val Pro Asn Thr His Pro Leu Leu Val Phe Val Asn Pro Lys
370 375 380
Ser Gly Gly Lys Gln Gly Gln Arg Val Leu Trp Lys Phe Gln Tyr Ile
385 390 395 400
Leu Asn Pro Arg Gln Val Phe Asn Leu Leu Lys Asp Gly Pro Glu Ile
405 410 415
Gly Leu Arg Leu Phe Lys Asp Val Pro Asp Ser Arg Ile Leu Val Cys
420 425 430
Gly Gly Asp Gly Thr Val Gly Trp Ile Leu Glu Thr Ile Asp Lys Ala
435 440 445
Asn Leu Pro Val Leu Pro Pro Val Ala Val Leu Pro Leu Gly Thr Gly
450 455 460
Asn Asp Leu Ala Arg Cys Leu Arg Trp Gly Gly Gly Tyr Glu Gly Gln
465 470 475 480
Asn Leu Ala Lys Ile Leu Lys Asp Leu Glu Met Ser Lys Val Val His
485 490 495
Met Asp Arg Trp Ser Val Glu Val Ile Pro Gln Gln Thr Glu Glu Lys
500 505 510
Ser Asp Pro Val Pro Phe Gln Ile Ile Asn Asn Tyr Phe Ser Ile Gly
515 520 525
Val Asp Ala Ser Ile Ala His Arg Phe His Ile Met Arg Glu Lys Tyr
530 535 540
Pro Glu Lys Phe Asn Ser Arg Met Lys Asn Lys Leu Trp Tyr Phe Glu
545 550 555 560
Phe Ala Thr Ser Glu Ser Ile Phe Ser Thr Cys Lys Lys Leu Glu Glu
565 570 575
Ser Leu Thr Val Glu Ile Cys Gly Lys Pro Leu Asp Leu Ser Asn Leu
580 585 590
Ser Leu Glu Gly Ile Ala Val Leu Asn Ile Pro Ser Met His Gly Gly
595 600 605
Ser Asn Leu Trp Gly Asp Thr Arg Arg Pro His Gly Asp Ile Tyr Gly
610 615 620
Ile Asn Gln Ala Leu Gly Ala Thr Ala Lys Val Ile Thr Asp Pro Asp
625 630 635 640
Ile Leu Lys Thr Cys Val Pro Asp Leu Ser Asp Lys Arg Leu Glu Val
645 650 655
Val Gly Leu Glu Gly Ala Ile Glu Met Gly Gln Ile Tyr Thr Lys Leu
660 665 670
Lys Asn Ala Gly Arg Arg Leu Ala Lys Cys Ser Glu Ile Thr Phe His
675 680 685
Thr Thr Lys Thr Leu Pro Met Gln Ile Asp Gly Glu Pro Trp Met Gln
690 695 700
Thr Pro Cys Thr Ile Lys Ile Thr His Lys Asn Gln Met Pro Met Leu
705 710 715 720
Met Gly Pro Pro Pro Arg Ser Thr Asn Phe Phe Gly Phe Leu Ser
725 730 735
<210> 2
<211> 929
<212> PRT
<213> 智人(Homo sapiens)
<300>
<308> RefSeq | NP_003637.2
<309> 2004-09-14
<313> (1)..(929)
<400> 2
Met Glu Pro Arg Asp Gly Ser Pro Glu Ala Arg Ser Ser Asp Ser Glu
1 5 10 15
Ser Ala Ser Ala Ser Ser Ser Gly Ser Glu Arg Asp Ala Gly Pro Glu
20 25 30
Pro Asp Lys Ala Pro Arg Arg Leu Asn Lys Arg Arg Phe Pro Gly Leu
35 40 45
Arg Leu Phe Gly His Arg Lys Ala Ile Thr Lys Ser Gly Leu Gln His
50 55 60
Leu Ala Pro Pro Pro Pro Thr Pro Gly Ala Pro Cys Ser Glu Ser Glu
65 70 75 80
Arg Gln Ile Arg Ser Thr Val Asp Trp Ser Glu Ser Ala Thr Tyr Gly
85 90 95
Glu His Ile Trp Phe Glu Thr Asn Val Ser Gly Asp Phe Cys Tyr Val
100 105 110
Gly Glu Gln Tyr Cys Val Ala Arg Met Leu Gln Lys Ser Val Ser Arg
115 120 125
Arg Lys Cys Ala Ala Cys Lys Ile Val Val His Thr Pro Cys Ile Glu
130 135 140
Gln Leu Glu Lys Ile Asn Phe Arg Cys Lys Pro Ser Phe Arg Glu Ser
145 150 155 160
Gly Ser Arg Asn Val Arg Glu Pro Thr Phe Val Arg His His Trp Val
165 170 175
His Arg Arg Arg Gln Asp Gly Lys Cys Arg His Cys Gly Lys Gly Phe
180 185 190
Gln Gln Lys Phe Thr Phe His Ser Lys Glu Ile Val Ala Ile Ser Cys
195 200 205
Ser Trp Cys Lys Gln Ala Tyr His Ser Lys Val Ser Cys Phe Met Leu
210 215 220
Gln Gln Ile Glu Glu Pro Cys Ser Leu Gly Val His Ala Ala Val Val
225 230 235 240
Ile Pro Pro Thr Trp Ile Leu Arg Ala Arg Arg Pro Gln Asn Thr Leu
245 250 255
Lys Ala Ser Lys Lys Lys Lys Arg Ala Ser Phe Lys Arg Lys Ser Ser
260 265 270
Lys Lys Gly Pro Glu Glu Gly Arg Trp Arg Pro Phe Ile Ile Arg Pro
275 280 285
Thr Pro Ser Pro Leu Met Lys Pro Leu Leu Val Phe Val Asn Pro Lys
290 295 300
Ser Gly Gly Asn Gln Gly Ala Lys Ile Ile Gln Ser Phe Leu Trp Tyr
305 310 315 320
Leu Asn Pro Arg Gln Val Phe Asp Leu Ser Gln Gly Gly Pro Lys Glu
325 330 335
Ala Leu Glu Met Tyr Arg Lys Val His Asn Leu Arg Ile Leu Ala Cys
340 345 350
Gly Gly Asp Gly Thr Val Gly Trp Ile Leu Ser Thr Leu Asp Gln Leu
355 360 365
Arg Leu Lys Pro Pro Pro Pro Val Ala Ile Leu Pro Leu Gly Thr Gly
370 375 380
Asn Asp Leu Ala Arg Thr Leu Asn Trp Gly Gly Gly Tyr Thr Asp Glu
385 390 395 400
Pro Val Ser Lys Ile Leu Ser His Val Glu Glu Gly Asn Val Val Gln
405 410 415
Leu Asp Arg Trp Asp Leu His Ala Glu Pro Asn Pro Glu Ala Gly Pro
420 425 430
Glu Asp Arg Asp Glu Gly Ala Thr Asp Arg Leu Pro Leu Asp Val Phe
435 440 445
Asn Asn Tyr Phe Ser Leu Gly Phe Asp Ala His Val Thr Leu Glu Phe
450 455 460
His Glu Ser Arg Glu Ala Asn Pro Glu Lys Phe Asn Ser Arg Phe Arg
465 470 475 480
Asn Lys Met Phe Tyr Ala Gly Thr Ala Phe Ser Asp Phe Leu Met Gly
485 490 495
Ser Ser Lys Asp Leu Ala Lys His Ile Arg Val Val Cys Asp Gly Met
500 505 510
Asp Leu Thr Pro Lys Ile Gln Asp Leu Lys Pro Gln Cys Val Val Phe
515 520 525
Leu Asn Ile Pro Arg Tyr Cys Ala Gly Thr Met Pro Trp Gly His Pro
530 535 540
Gly Glu His His Asp Phe Glu Pro Gln Arg His Asp Asp Gly Tyr Leu
545 550 555 560
Glu Val Ile Gly Phe Thr Met Thr Ser Leu Ala Ala Leu Gln Val Gly
565 570 575
Gly His Gly Glu Arg Leu Thr Gln Cys Arg Glu Val Val Leu Thr Thr
580 585 590
Ser Lys Ala Ile Pro Val Gln Val Asp Gly Glu Pro Cys Lys Leu Ala
595 600 605
Ala Ser Arg Ile Arg Ile Ala Leu Arg Asn Gln Ala Thr Met Val Gln
610 615 620
Lys Ala Lys Arg Arg Ser Ala Ala Pro Leu His Ser Asp Gln Gln Pro
625 630 635 640
Val Pro Glu Gln Leu Arg Ile Gln Val Ser Arg Val Ser Met His Asp
645 650 655
Tyr Glu Ala Leu His Tyr Asp Lys Glu Gln Leu Lys Glu Ala Ser Val
660 665 670
Pro Leu Gly Thr Val Val Val Pro Gly Asp Ser Asp Leu Glu Leu Cys
675 680 685
Arg Ala His Ile Glu Arg Leu Gln Gln Glu Pro Asp Gly Ala Gly Ala
690 695 700
Lys Ser Pro Thr Cys Gln Lys Leu Ser Pro Lys Trp Cys Phe Leu Asp
705 710 715 720
Ala Thr Thr Ala Ser Arg Phe Tyr Arg Ile Asp Arg Ala Gln Glu His
725 730 735
Leu Asn Tyr Val Thr Glu Ile Ala Gln Asp Glu Ile Tyr Ile Leu Asp
740 745 750
Pro Glu Leu Leu Gly Ala Ser Ala Arg Pro Asp Leu Pro Thr Pro Thr
755 760 765
Ser Pro Leu Pro Thr Ser Pro Cys Ser Pro Thr Pro Arg Ser Leu Gln
770 775 780
Gly Asp Ala Ala Pro Pro Gln Gly Glu Glu Leu Ile Glu Ala Ala Lys
785 790 795 800
Arg Asn Asp Phe Cys Lys Leu Gln Glu Leu His Arg Ala Gly Gly Asp
805 810 815
Leu Met His Arg Asp Glu Gln Ser Arg Thr Leu Leu His His Ala Val
820 825 830
Ser Thr Gly Ser Lys Asp Val Val Arg Tyr Leu Leu Asp His Ala Pro
835 840 845
Pro Glu Ile Leu Asp Ala Val Glu Glu Asn Gly Glu Thr Cys Leu His
850 855 860
Gln Ala Ala Ala Leu Gly Gln Arg Thr Ile Cys His Tyr Ile Val Glu
865 870 875 880
Ala Gly Ala Ser Leu Met Lys Thr Asp Gln Gln Gly Asp Thr Pro Arg
885 890 895
Gln Arg Ala Glu Lys Ala Gln Asp Thr Glu Leu Ala Ala Tyr Leu Glu
900 905 910
Asn Arg Gln His Tyr Gln Met Ile Gln Arg Glu Asp Gln Glu Thr Ala
915 920 925
Val
<210> 3
<211> 977
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GST-DGKA融合蛋白
<220>
<221> MISC_FEATURE
<222> (1)..(977)
<223> GST-DGKA, 全长人DGKA表达为N-末端GST-融合蛋白
<400> 3
Met Ala Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu
210 215 220
Phe Gln Gly Pro Leu Gly Ala Met Gly Ser Gly Ile Gln Arg Pro Thr
225 230 235 240
Ser Thr Met Ala Lys Glu Arg Gly Leu Ile Ser Pro Ser Asp Phe Ala
245 250 255
Gln Leu Gln Lys Tyr Met Glu Tyr Ser Thr Lys Lys Val Ser Asp Val
260 265 270
Leu Lys Leu Phe Glu Asp Gly Glu Met Ala Lys Tyr Val Gln Gly Asp
275 280 285
Ala Ile Gly Tyr Glu Gly Phe Gln Gln Phe Leu Lys Ile Tyr Leu Glu
290 295 300
Val Asp Asn Val Pro Arg His Leu Ser Leu Ala Leu Phe Gln Ser Phe
305 310 315 320
Glu Thr Gly His Cys Leu Asn Glu Thr Asn Val Thr Lys Asp Val Val
325 330 335
Cys Leu Asn Asp Val Ser Cys Tyr Phe Ser Leu Leu Glu Gly Gly Arg
340 345 350
Pro Glu Asp Lys Leu Glu Phe Thr Phe Lys Leu Tyr Asp Thr Asp Arg
355 360 365
Asn Gly Ile Leu Asp Ser Ser Glu Val Asp Lys Ile Ile Leu Gln Met
370 375 380
Met Arg Val Ala Glu Tyr Leu Asp Trp Asp Val Ser Glu Leu Arg Pro
385 390 395 400
Ile Leu Gln Glu Met Met Lys Glu Ile Asp Tyr Asp Gly Ser Gly Ser
405 410 415
Val Ser Gln Ala Glu Trp Val Arg Ala Gly Ala Thr Thr Val Pro Leu
420 425 430
Leu Val Leu Leu Gly Leu Glu Met Thr Leu Lys Asp Asp Gly Gln His
435 440 445
Met Trp Arg Pro Lys Arg Phe Pro Arg Pro Val Tyr Cys Asn Leu Cys
450 455 460
Glu Ser Ser Ile Gly Leu Gly Lys Gln Gly Leu Ser Cys Asn Leu Cys
465 470 475 480
Lys Tyr Thr Val His Asp Gln Cys Ala Met Lys Ala Leu Pro Cys Glu
485 490 495
Val Ser Thr Tyr Ala Lys Ser Arg Lys Asp Ile Gly Val Gln Ser His
500 505 510
Val Trp Val Arg Gly Gly Cys Glu Ser Gly Arg Cys Asp Arg Cys Gln
515 520 525
Lys Lys Ile Arg Ile Tyr His Ser Leu Thr Gly Leu His Cys Val Trp
530 535 540
Cys His Leu Glu Ile His Asp Asp Cys Leu Gln Ala Val Gly His Glu
545 550 555 560
Cys Asp Cys Gly Leu Leu Arg Asp His Ile Leu Pro Pro Ser Ser Ile
565 570 575
Tyr Pro Ser Val Leu Ala Ser Gly Pro Asp Arg Lys Asn Ser Lys Thr
580 585 590
Ser Gln Lys Thr Met Asp Asp Leu Asn Leu Ser Thr Ser Glu Ala Leu
595 600 605
Arg Ile Asp Pro Val Pro Asn Thr His Pro Leu Leu Val Phe Val Asn
610 615 620
Pro Lys Ser Gly Gly Lys Gln Gly Gln Arg Val Leu Trp Lys Phe Gln
625 630 635 640
Tyr Ile Leu Asn Pro Arg Gln Val Phe Asn Leu Leu Lys Asp Gly Pro
645 650 655
Glu Ile Gly Leu Arg Leu Phe Lys Asp Val Pro Asp Ser Arg Ile Leu
660 665 670
Val Cys Gly Gly Asp Gly Thr Val Gly Trp Ile Leu Glu Thr Ile Asp
675 680 685
Lys Ala Asn Leu Pro Val Leu Pro Pro Val Ala Val Leu Pro Leu Gly
690 695 700
Thr Gly Asn Asp Leu Ala Arg Cys Leu Arg Trp Gly Gly Gly Tyr Glu
705 710 715 720
Gly Gln Asn Leu Ala Lys Ile Leu Lys Asp Leu Glu Met Ser Lys Val
725 730 735
Val His Met Asp Arg Trp Ser Val Glu Val Ile Pro Gln Gln Thr Glu
740 745 750
Glu Lys Ser Asp Pro Val Pro Phe Gln Ile Ile Asn Asn Tyr Phe Ser
755 760 765
Ile Gly Val Asp Ala Ser Ile Ala His Arg Phe His Ile Met Arg Glu
770 775 780
Lys Tyr Pro Glu Lys Phe Asn Ser Arg Met Lys Asn Lys Leu Trp Tyr
785 790 795 800
Phe Glu Phe Ala Thr Ser Glu Ser Ile Phe Ser Thr Cys Lys Lys Leu
805 810 815
Glu Glu Ser Leu Thr Val Glu Ile Cys Gly Lys Pro Leu Asp Leu Ser
820 825 830
Asn Leu Ser Leu Glu Gly Ile Ala Val Leu Asn Ile Pro Ser Met His
835 840 845
Gly Gly Ser Asn Leu Trp Gly Asp Thr Arg Arg Pro His Gly Asp Ile
850 855 860
Tyr Gly Ile Asn Gln Ala Leu Gly Ala Thr Ala Lys Val Ile Thr Asp
865 870 875 880
Pro Asp Ile Leu Lys Thr Cys Val Pro Asp Leu Ser Asp Lys Arg Leu
885 890 895
Glu Val Val Gly Leu Glu Gly Ala Ile Glu Met Gly Gln Ile Tyr Thr
900 905 910
Lys Leu Lys Asn Ala Gly Arg Arg Leu Ala Lys Cys Ser Glu Ile Thr
915 920 925
Phe His Thr Thr Lys Thr Leu Pro Met Gln Ile Asp Gly Glu Pro Trp
930 935 940
Met Gln Thr Pro Cys Thr Ile Lys Ile Thr His Lys Asn Gln Met Pro
945 950 955 960
Met Leu Met Gly Pro Pro Pro Arg Ser Thr Asn Phe Phe Gly Phe Leu
965 970 975
Ser
<210> 4
<211> 1171
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> GST-DGKZ融合蛋白
<220>
<221> MISC_FEATURE
<222> (1)..(1171)
<223> GST-DKGZ, 全长人DGKZ表达为N-末端GST-融合蛋白
<400> 4
Met Ala Pro Ile Leu Gly Tyr Trp Lys Ile Lys Gly Leu Val Gln Pro
1 5 10 15
Thr Arg Leu Leu Leu Glu Tyr Leu Glu Glu Lys Tyr Glu Glu His Leu
20 25 30
Tyr Glu Arg Asp Glu Gly Asp Lys Trp Arg Asn Lys Lys Phe Glu Leu
35 40 45
Gly Leu Glu Phe Pro Asn Leu Pro Tyr Tyr Ile Asp Gly Asp Val Lys
50 55 60
Leu Thr Gln Ser Met Ala Ile Ile Arg Tyr Ile Ala Asp Lys His Asn
65 70 75 80
Met Leu Gly Gly Cys Pro Lys Glu Arg Ala Glu Ile Ser Met Leu Glu
85 90 95
Gly Ala Val Leu Asp Ile Arg Tyr Gly Val Ser Arg Ile Ala Tyr Ser
100 105 110
Lys Asp Phe Glu Thr Leu Lys Val Asp Phe Leu Ser Lys Leu Pro Glu
115 120 125
Met Leu Lys Met Phe Glu Asp Arg Leu Cys His Lys Thr Tyr Leu Asn
130 135 140
Gly Asp His Val Thr His Pro Asp Phe Met Leu Tyr Asp Ala Leu Asp
145 150 155 160
Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Glu Val Leu
210 215 220
Phe Gln Gly Pro Leu Gly Ala Met Gly Ser Gly Ile Gln Arg Pro Thr
225 230 235 240
Ser Thr Met Glu Pro Arg Asp Gly Ser Pro Glu Ala Arg Ser Ser Asp
245 250 255
Ser Glu Ser Ala Ser Ala Ser Ser Ser Gly Ser Glu Arg Asp Ala Gly
260 265 270
Pro Glu Pro Asp Lys Ala Pro Arg Arg Leu Asn Lys Arg Arg Phe Pro
275 280 285
Gly Leu Arg Leu Phe Gly His Arg Lys Ala Ile Thr Lys Ser Gly Leu
290 295 300
Gln His Leu Ala Pro Pro Pro Pro Thr Pro Gly Ala Pro Cys Ser Glu
305 310 315 320
Ser Glu Arg Gln Ile Arg Ser Thr Val Asp Trp Ser Glu Ser Ala Thr
325 330 335
Tyr Gly Glu His Ile Trp Phe Glu Thr Asn Val Ser Gly Asp Phe Cys
340 345 350
Tyr Val Gly Glu Gln Tyr Cys Val Ala Arg Met Leu Gln Lys Ser Val
355 360 365
Ser Arg Arg Lys Cys Ala Ala Cys Lys Ile Val Val His Thr Pro Cys
370 375 380
Ile Glu Gln Leu Glu Lys Ile Asn Phe Arg Cys Lys Pro Ser Phe Arg
385 390 395 400
Glu Ser Gly Ser Arg Asn Val Arg Glu Pro Thr Phe Val Arg His His
405 410 415
Trp Val His Arg Arg Arg Gln Asp Gly Lys Cys Arg His Cys Gly Lys
420 425 430
Gly Phe Gln Gln Lys Phe Thr Phe His Ser Lys Glu Ile Val Ala Ile
435 440 445
Ser Cys Ser Trp Cys Lys Gln Ala Tyr His Ser Lys Val Ser Cys Phe
450 455 460
Met Leu Gln Gln Ile Glu Glu Pro Cys Ser Leu Gly Val His Ala Ala
465 470 475 480
Val Val Ile Pro Pro Thr Trp Ile Leu Arg Ala Arg Arg Pro Gln Asn
485 490 495
Thr Leu Lys Ala Ser Lys Lys Lys Lys Arg Ala Ser Phe Lys Arg Lys
500 505 510
Ser Ser Lys Lys Gly Pro Glu Glu Gly Arg Trp Arg Pro Phe Ile Ile
515 520 525
Arg Pro Thr Pro Ser Pro Leu Met Lys Pro Leu Leu Val Phe Val Asn
530 535 540
Pro Lys Ser Gly Gly Asn Gln Gly Ala Lys Ile Ile Gln Ser Phe Leu
545 550 555 560
Trp Tyr Leu Asn Pro Arg Gln Val Phe Asp Leu Ser Gln Gly Gly Pro
565 570 575
Lys Glu Ala Leu Glu Met Tyr Arg Lys Val His Asn Leu Arg Ile Leu
580 585 590
Ala Cys Gly Gly Asp Gly Thr Val Gly Trp Ile Leu Ser Thr Leu Asp
595 600 605
Gln Leu Arg Leu Lys Pro Pro Pro Pro Val Ala Ile Leu Pro Leu Gly
610 615 620
Thr Gly Asn Asp Leu Ala Arg Thr Leu Asn Trp Gly Gly Gly Tyr Thr
625 630 635 640
Asp Glu Pro Val Ser Lys Ile Leu Ser His Val Glu Glu Gly Asn Val
645 650 655
Val Gln Leu Asp Arg Trp Asp Leu His Ala Glu Pro Asn Pro Glu Ala
660 665 670
Gly Pro Glu Asp Arg Asp Glu Gly Ala Thr Asp Arg Leu Pro Leu Asp
675 680 685
Val Phe Asn Asn Tyr Phe Ser Leu Gly Phe Asp Ala His Val Thr Leu
690 695 700
Glu Phe His Glu Ser Arg Glu Ala Asn Pro Glu Lys Phe Asn Ser Arg
705 710 715 720
Phe Arg Asn Lys Met Phe Tyr Ala Gly Thr Ala Phe Ser Asp Phe Leu
725 730 735
Met Gly Ser Ser Lys Asp Leu Ala Lys His Ile Arg Val Val Cys Asp
740 745 750
Gly Met Asp Leu Thr Pro Lys Ile Gln Asp Leu Lys Pro Gln Cys Val
755 760 765
Val Phe Leu Asn Ile Pro Arg Tyr Cys Ala Gly Thr Met Pro Trp Gly
770 775 780
His Pro Gly Glu His His Asp Phe Glu Pro Gln Arg His Asp Asp Gly
785 790 795 800
Tyr Leu Glu Val Ile Gly Phe Thr Met Thr Ser Leu Ala Ala Leu Gln
805 810 815
Val Gly Gly His Gly Glu Arg Leu Thr Gln Cys Arg Glu Val Val Leu
820 825 830
Thr Thr Ser Lys Ala Ile Pro Val Gln Val Asp Gly Glu Pro Cys Lys
835 840 845
Leu Ala Ala Ser Arg Ile Arg Ile Ala Leu Arg Asn Gln Ala Thr Met
850 855 860
Val Gln Lys Ala Lys Arg Arg Ser Ala Ala Pro Leu His Ser Asp Gln
865 870 875 880
Gln Pro Val Pro Glu Gln Leu Arg Ile Gln Val Ser Arg Val Ser Met
885 890 895
His Asp Tyr Glu Ala Leu His Tyr Asp Lys Glu Gln Leu Lys Glu Ala
900 905 910
Ser Val Pro Leu Gly Thr Val Val Val Pro Gly Asp Ser Asp Leu Glu
915 920 925
Leu Cys Arg Ala His Ile Glu Arg Leu Gln Gln Glu Pro Asp Gly Ala
930 935 940
Gly Ala Lys Ser Pro Thr Cys Gln Lys Leu Ser Pro Lys Trp Cys Phe
945 950 955 960
Leu Asp Ala Thr Thr Ala Ser Arg Phe Tyr Arg Ile Asp Arg Ala Gln
965 970 975
Glu His Leu Asn Tyr Val Thr Glu Ile Ala Gln Asp Glu Ile Tyr Ile
980 985 990
Leu Asp Pro Glu Leu Leu Gly Ala Ser Ala Arg Pro Asp Leu Pro Thr
995 1000 1005
Pro Thr Ser Pro Leu Pro Thr Ser Pro Cys Ser Pro Thr Pro Arg
1010 1015 1020
Ser Leu Gln Gly Asp Ala Ala Pro Pro Gln Gly Glu Glu Leu Ile
1025 1030 1035
Glu Ala Ala Lys Arg Asn Asp Phe Cys Lys Leu Gln Glu Leu His
1040 1045 1050
Arg Ala Gly Gly Asp Leu Met His Arg Asp Glu Gln Ser Arg Thr
1055 1060 1065
Leu Leu His His Ala Val Ser Thr Gly Ser Lys Asp Val Val Arg
1070 1075 1080
Tyr Leu Leu Asp His Ala Pro Pro Glu Ile Leu Asp Ala Val Glu
1085 1090 1095
Glu Asn Gly Glu Thr Cys Leu His Gln Ala Ala Ala Leu Gly Gln
1100 1105 1110
Arg Thr Ile Cys His Tyr Ile Val Glu Ala Gly Ala Ser Leu Met
1115 1120 1125
Lys Thr Asp Gln Gln Gly Asp Thr Pro Arg Gln Arg Ala Glu Lys
1130 1135 1140
Ala Gln Asp Thr Glu Leu Ala Ala Tyr Leu Glu Asn Arg Gln His
1145 1150 1155
Tyr Gln Met Ile Gln Arg Glu Asp Gln Glu Thr Ala Val
1160 1165 1170
Claims (52)
1.一种化合物,所述化合物具有结构(I):
或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,其中:
R1是包含1-4个环氮原子并且被1、2、3或4个取代基取代的8-13元杂芳基,其中每个取代基独立地为OH、氧代、卤代、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基;
X为N或CH;
当X为N时,则L为键、CH2、C(O)或CHMe,并且
当X为CH时,则L为键、NH、NMe或NHC(O);
Y为N或CH;
R2每次出现时独立地为卤代、OH或OMe;
a为0、1或2;
n为0、1、2、3或4;
R3为H或C1-4烷基;并且
Cy是包含0或1个环氧原子的3-6元环烷基或杂环烷基。
2.根据权利要求1所述的化合物,其中所述化合物具有以下结构(I-A)、
(I-B)、(I-B-顺式)或(I-B-反式)中的一者:
3.根据权利要求1所述的化合物,其中所述化合物具有以下结构(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-B-1)、(I-B-2)、(I-B-3)或(I-B-4)中的一者:
4.根据权利要求1至3中任一项所述的化合物,其中R1为9、10或13元杂芳基。
5.根据权利要求4所述的化合物,其中R1为9元杂芳基。
6.根据权利要求4所述的化合物,其中R1为10元杂芳基。
7.根据权利要求4所述的化合物,其中R1为13元杂芳基。
8.根据权利要求4至7中任一项所述的化合物,其中所述杂芳基包含1至3个环氮原子。
9.根据权利要求8所述的化合物,其中所述杂芳基包含一个环氮原子。
10.根据权利要求8所述的化合物,其中所述杂芳基包含2个环氮原子。
11.根据权利要求8所述的化合物,其中所述杂芳基包含3个环氮原子。
12.根据权利要求1至11中任一项所述的化合物,其中R1被1个取代基取代,其中所述取代基是OH、卤素、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基。
13.根据权利要求1至11中任一项所述的化合物,其中R1被2个取代基取代,其中每个取代基独立地为OH、卤代、CN、NO2、C1-4烷基、O-C1-4烷基、C1-4烯基或C3-6环烷基。
14.根据权利要求1至11中任一项所述的化合物,其中R1被3个取代基取代,其中每个取代基独立地为氧代、卤素、CN、NO2或C1-4烷基。
15.根据权利要求1至11中任一项所述的化合物,其中R1被4个取代基取代,其中每个取代基独立地为氧代、卤素、CN、NO2或C1-4烷基。
16.根据权利要求12至15中任一项所述的化合物,其中R1为:
17.根据权利要求1至16中任一项所述的化合物,其中未被取代。
18.根据权利要求1至16中任一项所述的化合物,其中-(R2)n中的n是1、2、3或4,并且其中R2每次出现时独立地为卤代、OH或OMe。
19.根据权利要求18所述的化合物,其中n为1并且其中R2为OH。
20.根据权利要求18所述的化合物,其中n为1并且其中R2为OMe。
21.根据权利要求18所述的化合物,其中n为1或2并且其中R2为卤代。
22.根据权利要求21所述的化合物,其中卤代为氟。
23.根据权利要求18所述的化合物,其中n为2并且其中每个R2独立地为OH和卤代。
24.根据权利要求23所述的化合物,其中卤代为氟。
25.根据权利要求18所述的化合物,其中n为2并且其中每个R2独立地为OMe和卤代。
26.根据权利要求1至25中任一项所述的化合物,其中Y为CH。
27.根据权利要求1至25中任一项所述的化合物,其中Y为N。
28.根据权利要求1至27所述的化合物,其中具有以下结构中的一者:
29.根据权利要求1至28中任一项所述的化合物,其中a为0或1。
30.根据权利要求1至29中任一项所述的化合物,其中R3为H或甲基。
31.根据权利要求30所述的化合物,其中R3为H。
32.根据权利要求30所述的化合物,其中R3为甲基。
33.根据权利要求1至32中任一项所述的化合物,其中Cy为环丙基或包含1个氧原子的4或5元杂环烷基。
34.根据权利要求33所述的化合物,其中Cy为环丙基。
35.根据权利要求33所述的化合物,其中Cy为包含1个氧原子的4或5元杂环烷基。
36.根据权利要求35所述的化合物,其中Cy为氧杂环丁烷。
37.根据权利要求34或35中任一项所述的化合物,其中R3为H。
38.根据权利要求34或35中任一项所述的化合物,其中a为0或1。
39.根据权利要求1所述的化合物,其中所述化合物为表1中所列化合物中的任一者,或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素。
40.一种药物组合物,所述药物组合物包含根据权利要求1至39中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素,以及至少一种药学上可接受的赋形剂。
41.一种用于抑制至少一种二酰甘油激酶的活性的方法,所述方法包括使所述二酰甘油激酶与根据权利要求1至39中任一项所述的化合物或根据权利要求40所述的药物组合物接触。
42.根据权利要求41所述的方法,其中所述二酰甘油激酶是二酰甘油激酶α(DGKa)或二酰甘油激酶ζ(DGKζ)。
43.一种治疗与DGKα、DGKζ、或DGKα和DGKζ两者的活性相关联的疾病或病症的方法,所述方法包括向有需要的受试者施用有效量的根据权利要求40所述的药物组合物。
44.一种治疗增殖性病症或病毒感染的方法,所述方法包括向有需要的受试者施用有效量的根据权利要求40所述的药物组合物。
45.根据权利要求44所述的方法,其中所述增殖性病症是癌症。
46.根据权利要求45所述的方法,其中所述癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、肾癌、头颈癌、淋巴瘤、白血病或黑色素瘤。
47.根据权利要求1至39中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体、同位素或组合物用于抑制二酰甘油激酶中的至少一种二酰甘油激酶的活性的用途,其中所述二酰甘油激酶是二酰甘油激酶α(DGKa)或二酰甘油激酶ζ(DGKζ)。
48.根据权利要求40所述的药物组合物用于治疗与DGKα或DGKζ、或DGKα和DGKζ两者的活性相关联的疾病或病症的用途。
49.根据权利要求40所述的药物组合物用于治疗增殖性病症或病毒感染的用途。
50.根据权利要求49所述的用途,其中所述增殖性病症是癌症。
51.根据权利要求50所述的用途,其中所述癌症是结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、卵巢癌、宫颈癌、肾癌、头颈癌、淋巴瘤、白血病和黑色素瘤。
52.根据权利要求1至39中任一项所述的化合物或其药学上可接受的盐、溶剂化物、水合物、异构体或同位素用于制造药物的用途。
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