CN115551847A - 用于调节核酸剪接的哒嗪衍生物 - Google Patents
用于调节核酸剪接的哒嗪衍生物 Download PDFInfo
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- CN115551847A CN115551847A CN202180030690.3A CN202180030690A CN115551847A CN 115551847 A CN115551847 A CN 115551847A CN 202180030690 A CN202180030690 A CN 202180030690A CN 115551847 A CN115551847 A CN 115551847A
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
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- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract
本披露的特征在于尤其调节核酸剪接,例如前mRNA的剪接的化合物和相关组合物及其使用方法。
Description
优先权要求
本申请要求以下申请的优先权:2020年2月28日提交的美国申请号62/983,537;2020年4月8日提交的美国申请号63/007,134;2020年6月17日提交的美国申请号63/040,474;2020年8月31日提交的美国申请号63/072,781;以及2020年12月16日提交的美国申请号63/126,491。前述申请中的每一个的披露内容通过引用以其全文并入本文。
背景技术
可变剪接是高等真核生物中蛋白质多样性的主要来源,并且经常以组织特异性或发育阶段特异性的方式进行调节。前mRNA中与疾病相关的可变剪接模式通常映射到剪接位点信号或序列基序和调节剪接因子的变化(Faustino和Cooper(2003),Genes Dev[基因与发育]17(4):419-37)。目前调节RNA表达的疗法包括寡核苷酸靶向和基因疗法;然而,这些方式中的每一种都呈现出目前提出的独特挑战。因此,需要新技术来调节RNA表达,包括开发靶向剪接的小分子化合物。
发明内容
本披露的特征在于尤其调节核酸剪接,例如前mRNA的剪接的化合物和相关组合物及其使用方法。在实施例中,本文描述的化合物是具有式(I)的化合物(例如,具有式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)以及其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体。本披露另外提供了使用本发明的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物以及其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体)及其组合物例如靶向,并且在实施例中与核酸(例如,核小核糖核蛋白(snRNP)或剪接体的前mRNA或核酸组分)、蛋白质(例如,snRNP或剪接体的蛋白质组分,例如剪接机制的成员,例如U1、U2、U4、U5、U6、U11、U12、U4atac、U6atac snRNP中的一个或多个)或其组合结合或形成复合物的方法。在另一方面,本文描述的化合物可用于通过增加或减少剪接位点的剪接来改变核酸(例如,前mRNA或mRNA(例如前mRNA和由前mRNA产生的mRNA))的组成或结构。在一些实施例中,增加或减少剪接导致调节产生的基因产物(例如,RNA或蛋白质)的水平。
在另一方面,本文描述的化合物可用于预防和/或治疗疾病、障碍或病症,例如与剪接(例如可变剪接)相关的疾病、障碍或病症。在一些实施例中,本文描述的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物以及其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体)及其组合物用于在受试者中预防和/或治疗增殖性疾病、障碍或病症(例如,以非意愿的细胞增殖为特征的疾病、障碍或病症,例如癌症或良性肿瘤)。在一些实施例中,本文描述的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物以及其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体)及其组合物用于预防和/或治疗非增殖性疾病、障碍或病症。在一些实施例中,本文描述的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物以及其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体)及其组合物用于在受试者中预防和/或治疗神经疾病或障碍、自身免疫性疾病或障碍、免疫缺陷性疾病或障碍、溶酶体贮积病或障碍、心血管疾病或障碍、代谢性疾病或障碍、呼吸疾病或障碍、肾脏疾病或障碍或传染性疾病。
在一方面,本披露提供了具有式(I)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-S(O)x-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;M和P各自独立地是C(R2)或N;X和Y各自独立地是C、C(R5a)、C(R5a)(R5b)、N或N(R5c),其中在化合价允许的情况下,X和Y之间的键可以是单键或双键,并且其中X和Y不能都是C(R5a)(R5b);每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;R5a是氢、C1-C6-烷基或-ORF;R5b是氢或C1-C6-烷基;或R5a和R5b与它们所附接的碳原子一起形成氧代基团;每个R5c是氢、C1-C6-烷基、C1-C6-卤代烷基或C(O)RD;每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;RF是氢或C1-C6烷基;R10是C1-C6-烷基或卤代;每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;n是0、1、2、3或4;并且x是0、1或2。
在另一方面,本发明提供了药物组合物,其包含具有式(I)的化合物(例如,具有式(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体和任选地药学上可接受的赋形剂。在实施例中,本文描述的药物组合物包括有效量(例如,治疗有效量)的具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体。
在另一方面,本披露提供了用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体调节剪接,例如核酸(例如,DNA或RNA,例如前mRNA)剪接的方法。在另一方面,本披露提供了用于在用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体调节剪接,例如核酸(例如,DNA或RNA,例如前mRNA)剪接中使用的组合物。调节剪接可以包括影响剪接中涉及的任何步骤并且可以包括剪接事件的上游事件或下游事件。例如,在一些实施例中,具有式(I)的化合物结合靶标,例如靶核酸(例如,DNA或RNA,例如前体RNA,例如前mRNA)、靶蛋白或其组合(例如,snRNP和前mRNA)。靶标可以包括前mRNA或剪接机制组分,例如U1snRNP中的剪接位点。在一些实施例中,具有式(I)的化合物改变靶核酸(例如,DNA或RNA,例如前体RNA,例如前mRNA)、靶蛋白或其组合。在一些实施例中,具有式(I)的化合物将靶核酸(例如,RNA,例如前体RNA,例如前mRNA)上剪接位点的剪接相对于参比(例如,不存在具有式(I)的化合物,例如在健康或患病的细胞或组织中)增加或减少约0.5%或更多(例如,约1%、2%、3%、4%、5%、10%、20%、30%、40%、50%、75%、90%、95%或更多)。在一些实施例中,存在具有式(I)的化合物导致靶核酸(例如,RNA)的转录相对于参比(例如,不存在具有式(I)的化合物,例如在健康或患病的细胞或组织中)增加或减少约0.5%或更多(例如,约1%、2%、3%、4%、5%、10%、20%、30%、40%、50%、75%、90%、95%或更多)。
在另一方面,本披露提供了用于在受试者中通过施用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或相关组合物预防和/或治疗疾病、障碍或病症的方法。在一些实施例中,疾病或障碍导致非意愿的或异常的剪接。在一些实施例中,疾病或障碍是增殖性疾病、障碍或病症。示例性增殖性疾病包括癌症、良性肿瘤或血管生成。在其他实施例中,本披露提供了用于治疗和/或预防非增殖性疾病、障碍或病症的方法。在其他实施例中,本披露提供了用于治疗和/或预防神经疾病或障碍、自身免疫性疾病或障碍、免疫缺陷性疾病或障碍、溶酶体贮积病或障碍、心血管疾病或障碍、代谢性疾病或障碍、呼吸疾病或障碍、肾脏疾病或障碍或传染性疾病的方法。
在另一方面,本披露提供了在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体下调靶蛋白的表达(例如,水平或生产率)的方法。在另一方面,本披露提供了在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体上调靶蛋白的表达(例如,水平或生产率)的方法。在另一方面,本披露提供了在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体改变靶蛋白同种型的方法。本披露的另一方面涉及在生物样品或受试者中抑制靶蛋白活性的方法。在一些实施例中,向生物样品、细胞或受试者施用具有式(I)的化合物包括抑制细胞生长或诱导细胞死亡。
在另一方面,本披露提供了用于在受试者中通过施用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或相关组合物预防和/或治疗疾病、障碍或病症中使用的组合物。在一些实施例中,疾病或障碍导致非意愿的或异常的剪接。在一些实施例中,疾病或障碍是增殖性疾病、障碍或病症。示例性增殖性疾病包括癌症、良性肿瘤或血管生成。在其他实施例中,本披露提供了用于治疗和/或预防非增殖性疾病、障碍或病症的方法。在其他实施例中,本披露提供了用于在治疗和/或预防神经疾病或障碍、自身免疫性疾病或障碍、免疫缺陷性疾病或障碍、溶酶体贮积病或障碍、心血管疾病或障碍、代谢性疾病或障碍、呼吸疾病或障碍、肾脏疾病或障碍或传染性疾病中使用的组合物。
在另一方面,本披露提供了用于在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体下调靶蛋白的表达(例如,水平或生产率)中使用的组合物。在另一方面,本披露提供了用于在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体上调靶蛋白的表达(例如,水平或生产率)中使用的组合物。在另一方面,本披露提供了用于在生物样品或受试者中用具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体改变靶蛋白同种型中使用的组合物。本披露的另一方面涉及用于在生物样品或受试者中抑制靶蛋白活性中使用的组合物。在一些实施例中,向生物样品、细胞或受试者施用具有式(I)的化合物包括抑制细胞生长或诱导细胞死亡。
在另一方面,本披露的特征在于包含容器的试剂盒,该容器中有具有式(I)的化合物(例如,具有式(I)、(I-a)、(I-b)、(I-c)、(I-d)、(I-e)、(I-f)、(I-g)或(I-h)的化合物)或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或其药物组合物。在某些实施例中,本文描述的试剂盒进一步包括针对施用具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或其药物组合物的说明书。
在本披露的任何和所有方面,在一些实施例中,本文描述的化合物、靶核酸(例如,DNA、RNA,例如前mRNA)或靶蛋白是除了美国专利号8,729,263、美国公开号2015/0005289、WO 2014/028459、WO 2016/128343、WO 2016/196386、WO 2017/100726、WO 2018/232039、WO2018/098446、WO 2019/028440、WO 2019/060917和WO 2019/199972之一中描述的化合物、靶核酸(例如,DNA、RNA,例如前mRNA)或靶蛋白之外的化合物、靶核酸(例如,DNA、RNA,例如前mRNA)或靶蛋白。在一些实施例中,本文描述的化合物、靶核酸(例如,DNA、RNA,例如前mRNA)或靶蛋白是美国专利号8,729,263、美国公开号2015/0005289、WO 2014/028459、WO2016/128343、WO 2016/196386、WO 2017/100726、WO 2018/232039、WO 2018/098446、WO2019/028440、WO 2019/060917和WO 2019/199972(其中的每一个都通过引用以其全文并入本文)之一中描述的化合物、靶核酸(例如,DNA、RNA,例如前mRNA)或靶蛋白。
本文阐述了本发明的一个或多个实施例的细节。通过具体实施方式、实例和权利要求书,本发明的其他特征、目标和优点将是显而易见的。
具体实施方式
选择的化学定义
以下更详细地描述特定官能团和化学术语的定义。化学元素根据元素周期表,CAS版本,Handbook of Chemistry and Physics[化学和物理手册],第75版,内封面进行鉴定,并且特定官能团通常如其中所述被定义。此外,有机化学的一般原理以及特定功能性部分和反应性描述在以下中:Thomas Sorrell,Organic Chemistry[有机化学],UniversityScience Books[大学科学书籍出版社],Sausalito[索萨利托],1999;Smith和March,March’s Advanced Organic Chemistry[马奇氏高级有机化学],第5版,John Wiley&Sons,Inc.[约翰·威利父子出版社],纽约,2001;Larock,Comprehensive OrganicTransformations[综合有机转化],VCH Publishers,Inc.[VCH出版社有限公司],纽约,1989;以及Carruthers,Some Modern Methods of Organic Synthesis[有机合成的一些现代方法],第3版,Cambridge University Press[剑桥大学出版社],剑桥,1987。
本文使用的缩写在化学和生物学领域具有其常规含义。本文阐述的化学结构和化学式根据化学领域已知的化学价的标准规则构建。
当列出一系列值时,旨在涵盖该范围内的每个值和子范围。例如,“C1-C6烷基”旨在涵盖C1、C2、C3、C4、C5、C6、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5和C5-C6烷基。
以下术语旨在具有以下所呈现的含义并且有助于理解本发明的描述和预期范围。
如本文所用的,“烷基”是指具有从1至24个碳原子的直链或支链饱和烃基的基团(“C1-C24烷基”)。在一些实施例中,烷基基团具有1至12个碳原子(“C1-C12烷基”)。在一些实施例中,烷基基团具有1至8个碳原子(“C1-C8烷基”)。在一些实施例中,烷基基团具有1至6个碳原子(“C1-C6烷基”)。在一些实施例中,烷基基团具有2至6个碳原子(“C2-C6烷基”)。在一些实施例中,烷基基团具有1个碳原子(“C1烷基”)。C1-C6烷基基团的实例包括甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊烷基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁烷基(C5)、叔戊基(C5)和正己基(C6)。烷基基团的另外实例包括正庚基(C7)、正辛基(C8)等。烷基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的烷基”)或被以下取代(“取代的烷基”):一个或多个取代基;例如,从1至5个取代基、1至3个取代基或1个取代基。在某些实施例中,烷基基团是未取代的C1-C10烷基(例如,-CH3)。在某些实施例中,烷基基团是取代的C1-C6烷基。
如本文所用的,“烯基”是指具有从2至24个碳原子、一个或多个碳-碳双键且不具有三键的直链或支链烃基的基团(“C2-C24烯基”)。在一些实施例中,烯基基团具有2至10个碳原子(“C2-C10烯基”)。在一些实施例中,烯基基团具有2至8个碳原子(“C2-C8烯基”)。在一些实施例中,烯基基团具有2至6个碳原子(“C2-C6烯基”)。在一些实施例中,烯基基团具有2个碳原子(“C2烯基”)。一个或多个碳-碳双键可以是内部的(例如在2-丁烯基中)或末端的(例如在1-丁烯基中)。C2-C4烯基基团的实例包括乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁间二烯基(C4)等。C2-C6烯基基团的实例包括上述C2-4烯基基团以及戊烯基(C5)、戊二烯基(C5)、己烯基(C6)等。烯基的另外实例包括庚烯基(C7)、辛烯基(C8)、辛三烯基(C8)等。烯基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的烯基”)或被以下取代(“取代的烯基”):一个或多个取代基,例如,从1至5个取代基、1至3个取代基或1个取代基。在某些实施例中,烯基基团是未取代的C1-C10烯基。在某些实施例中,烯基基团是取代的C2-C6烯基。
如本文所用的,术语“炔基”是指具有从2至24个碳原子、一个或多个碳-碳三键的直链或支链烃基的基团(“C2-C24炔基”)。在一些实施例中,炔基基团具有2至10个碳原子(“C2-C10炔基”)。在一些实施例中,炔基基团具有2至8个碳原子(“C2-C8炔基”)。在一些实施例中,炔基基团具有2至6个碳原子(“C2-C6炔基”)。在一些实施例中,炔基基团具有2个碳原子(“C2炔基”)。一个或多个碳-碳三键可以是内部的(例如在2-丁炔基中)或末端的(例如在1-丁炔基中)。C2-C4炔基基团的实例包括乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)等。炔基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的炔基”)或被以下取代(“取代的炔基”):一个或多个取代基,例如,从1至5个取代基、1至3个取代基或1个取代基。在某些实施例中,炔基基团是未取代的C2-10炔基。在某些实施例中,炔基基团是取代的C2-6炔基。
如本文所用的,术语“卤代烷基”是指非环状稳定的直链或支链或其组合,包括至少一个碳原子和选自由F、Cl、Br和I组成的组的至少一个卤素。卤素F、Cl、Br和I可以位于卤代烷基基团的任何位置。示例性卤代烷基基团包括但不限于:-CF3、-CCl3、-CH2-CF3、-CH2-CCl3、-CH2-CBr3、-CH2-CI3、-CH2-CH2-CH(CF3)-CH3、-CH2-CH2-CH(Br)-CH3和-CH2-CH=CH-CH2-CF3。卤代烷基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的卤代烷基”)或被以下取代(“取代的卤代烷基”):一个或多个取代基,例如,从1至5个取代基、1至3个取代基或1个取代基。
如本文所用的,术语“杂烷基”是指非环状稳定的直链或支链或其组合,包括至少一个碳原子和选自由O、N、P、Si和S组成的组的至少一个杂原子,并且其中氮和硫原子可以任选地被氧化,并且氮杂原子可以任选地被季铵化。杂原子O、N、P、S和Si可以位于杂烷基基团的任何位置。示例性杂烷基基团包括但不限于:-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH=CH-O-CH3、-Si(CH3)3、-CH2-CH=N-OCH3、-CH=CH-N(CH3)-CH3、-O-CH3和-O-CH2-CH3。至多两个或三个杂原子可以是连续的,例如,如-CH2-NH-OCH3和-CH2-O-Si(CH3)3。当列举“杂烷基”,然后列举特定的杂烷基基团,例如-CH2O、-NRCRD等时,应理解术语杂烷基和-CH2O或-NRCRD不是多余的或相互排斥的。相反,列举特定的杂烷基基团以增加清晰度。因此,术语“杂烷基”在本文中不应解释为排除特定的杂烷基基团,例如-CH2O、-NRCRD等。杂烷基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的杂烷基”)或被以下取代(“取代的杂烷基”):一个或多个取代基,例如,从1至5个取代基、1至3个取代基或1个取代基。
如本文所用的,“芳基”是指单环或多环(例如,双环或三环)4n+2芳族环系统(例如,在环状阵列中共享6、10或14个π电子)的基团,该芳族环系统中提供有6-14个环碳原子和零个杂原子(“C6-C14芳基”)。在一些实施例中,芳基基团具有六个环碳原子(“C6芳基”;例如,苯基)。在一些实施例中,芳基基团具有十个环碳原子(“C10芳基”;例如,萘基例如1-萘基和2-萘基)。在一些实施例中,芳基基团具有十四个环碳原子(“C14芳基”;例如,蒽基)。芳基基团可以描述为,例如,C6-C10元芳基,其中术语“元”是指部分内的非氢环原子。芳基基团包括苯基、萘基、茚基和四氢萘基。芳基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的芳基”)或被以下取代(“取代的芳基”):一个或多个取代基。在某些实施例中,芳基基团是未取代的C6-C14芳基。在某些实施例中,芳基基团是取代的C6-C14芳基。
如本文所用的,“杂芳基”是指5-10元单环或双环4n+2芳族环系统(例如,在环状阵列中共享6或10个π电子)的基团,该芳族环系统中提供有环碳原子和1-4个环杂原子,其中每个杂原子独立地选自氮、氧和硫(“5-10元杂芳基”)。在含有一个或多个氮原子的杂芳基基团中,在化合价允许的情况下,附接点可以是碳原子或氮原子。杂芳基双环系统可以在一个或两个环中包含一个或多个杂原子。“杂芳基”还包括其中如上定义的杂芳基环与一个或多个芳基基团稠合的环系统,其中附接点在芳基或杂芳基环上,并且在这样的情况下,环成员的数目表示稠合的(芳基/杂芳基)环系统中环成员的数目。双环杂芳基基团,其中一个环不含杂原子(例如,吲哚基、喹啉基、咔唑基等),附接点可以在任一环上,即携带杂原子的环(例如,2-吲哚基)或不含杂原子的环(例如,5-吲哚基)。杂芳基基团可以描述为,例如,6-10元杂芳基,其中术语“元”是指部分内的非氢环原子。杂芳基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的杂芳基”)或被以下取代(“取代的杂芳基”):一个或多个取代基,例如,从1至5个取代基、1至3个取代基或1个取代基。
含有一个杂原子的示例性5元杂芳基基团包括但不限于:吡咯基、呋喃基和苯硫基。含有两个杂原子的示例性5元杂芳基基团包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。含有三个杂原子的示例性5元杂芳基基团包括但不限于:三唑基、噁二唑基和噻二唑基。含有四个杂原子的示例性5元杂芳基基团包括但不限于:四唑基。含有一个杂原子的示例性6元杂芳基基团包括但不限于:吡啶基。含有两个杂原子的示例性6元杂芳基基团包括但不限于:哒嗪基、嘧啶基和吡嗪基。含有三个或四个杂原子的示例性6元杂芳基基团分别包括但不限于:三嗪基和四嗪基。含有一个杂原子的示例性7元杂芳基基团包括但不限于:氮杂基(azepinyl)、氧杂基(oxepinyl)和硫杂基(thiepinyl)。示例性5,6-双环杂芳基基团包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并苯硫基、异苯并苯硫基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、吲哚嗪基和嘌呤基。示例性6,6-双环杂芳基基团包括但不限于:萘啶基、蝶啶基、喹啉基、异喹啉基、噌啉基、喹喔啉基、酞嗪基和喹唑啉基。其他示例性杂芳基基团包括血红素和血红素衍生物。
如本文所用的,“环烷基”是指在非芳族环系统中具有3至10个环碳原子(“C3-C10环烷基”)和零个杂原子的非芳族环烃基的基团。在一些实施例中,环烷基基团具有3至8个环碳原子(“C3-C8环烷基”)。在一些实施例中,环烷基基团具有3至6个环碳原子(“C3-C6环烷基”)。在一些实施例中,环烷基基团具有3至6个环碳原子(“C3-C6环烷基”)。在一些实施例中,环烷基基团具有5至10个环碳原子(“C5-C10环烷基”)。环烷基基团可以描述为,例如,C4-C7元环烷基,其中术语“元”是指部分内的非氢环原子。示例性C3-C6环烷基基团包括但不限于:环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环己二烯基(C6)等。示例性C3-C8环烷基基团包括但不限于:上述C3-C6环烷基基团以及环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)、立方烷基(cubanyl)(C8)、双环[1.1.1]戊烷基(C5)、双环[2.2.2]辛烷基(C8)、双环[2.1.1]己烷基(C6)、双环[3.1.1]庚烷基(C7)等。示例性C3-C10环烷基基团包括但不限于:上述C3-C8环烷基基团以及环壬基(C9)、环壬烯基(C9)、环癸基(C10)、环癸烯基(C10)、八氢-1H-茚基(C9)、十氢萘基(C10)、螺[4.5]癸烷基(C10)等。如前述实例所示,在某些实施例中,环烷基基团是单环(“单环环烷基”)或含有稠合、桥联或螺环系统,例如双环系统(“双环环烷基”),并且可以是饱和的或可以是部分不饱和的。“环烷基”还包括其中如上定义的环烷基环与一个或多个芳基基团稠合的环系统,其中附接点在环烷基环上,并且在这样的情况下,碳的数目继续表示环烷基环系统中碳的数目。环烷基基团的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的环烷基”)或被以下取代(“取代的环烷基”):一个或多个取代基。在某些实施例中,环烷基基团是未取代的C3-C10环烷基。在某些实施例中,环烷基基团是取代的C3-C10环烷基。
如本文所用的“杂环基”是指具有环碳原子和1至4个环杂原子的3至10元非芳族环系统的基团,其中每个杂原子独立地选自氮、氧、硫、硼、磷和硅(“3-10元杂环基”)。在含有一个或多个氮原子的杂环基基团中,在化合价允许的情况下,附接点可以是碳原子或氮原子。杂环基基团可以是单环(“单环杂环基”)或稠合、桥联或螺环系统,例如双环系统(“双环杂环基”),并且可以是饱和的或可以是部分不饱和的。杂环基双环系统可以在一个或两个环中包含一个或多个杂原子。“杂环基”还包括其中如上定义的杂环基环与一个或多个环烷基基团稠合的环系统(其中附接点在环烷基或杂环基环上),或其中如上定义的杂环基环与一个或多个芳基或杂芳基基团稠合的环系统(其中附接点在杂环基环上),并且在这样的情况下,环成员的数目继续表示杂环基环系统中环成员的数目。杂环基基团可以描述为,例如,3-7元杂环基,其中术语“元”是指部分内的非氢环原子,即碳、氮、氧、硫、硼、磷和硅。杂环基的每个例子可以独立地任选地被以下取代,即可以是未取代的(“未取代的杂环基”)或被以下取代(“取代的杂环基”):一个或多个取代基。在某些实施例中,杂环基基团是未取代的3-10元杂环基。在某些实施例中,杂环基基团是取代的3-10元杂环基。
含有一个杂原子的示例性3元杂环基基团包括但不限于:氮丙啶基、环氧乙烷基、硫代烯基。含有一个杂原子的示例性4元杂环基基团包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。含有一个杂原子的示例性5元杂环基基团包括但不限于:四氢呋喃基、二氢呋喃基、四氢苯硫基、二氢苯硫基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。含有两个杂原子的示例性5元杂环基基团包括但不限于:二氧戊环基、氧杂硫呋喃基、二硫呋喃基和噁唑烷-2-酮。含有三个杂原子的示例性5元杂环基基团包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。含有一个杂原子的示例性6元杂环基基团包括但不限于:哌啶基(例如,2,2,6,6-四甲基哌啶基)、四氢吡喃基、二氢吡啶基、吡啶壬基(例如,1-甲基吡啶2-壬基)和噻烷基。含有两个杂原子的示例性6元杂环基基团包括但不限于:哌嗪基、吗啉基、哒嗪酮基(2-甲基哒嗪-3-酮基)、嘧啶酮基(例如,1-甲基嘧啶-2-酮基、3-甲基嘧啶-4-酮基)、二噻烷基、二噁烷基。含有两个杂原子的示例性6元杂环基基团包括但不限于:三嗪烷基。含有一个杂原子的示例性7元杂环基基团包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚基。含有一个杂原子的示例性8元杂环基基团包括但不限于:氮杂环辛基、氧杂环辛烷基(oxecanyl)和硫杂环辛烷基(thiocanyl)。稠合至C6芳基环的示例性5元杂环基基团(在本文中也称为5,6-双环杂环基环)包括但不限于:二氢吲哚基、异吲哚啉基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基等。稠合至杂环基环的示例性5元杂环基基团(在本文中也称为5,5-双环杂环基环)包括但不限于:八氢吡咯并吡咯基(例如,八氢吡咯并[3,4-c]吡咯基)等。稠合至杂环基环的示例性6元杂环基基团(也称为4,6元杂环基环)包括但不限于:二氮杂螺壬基(例如,2,7-二氮杂螺[3.5]壬烷基)。稠合至芳基环的示例性6元杂环基基团(在本文中也称为6,6-双环杂环基环)包括但不限于:四氢喹啉基、四氢异喹啉基等。稠合至环烷基环的示例性6元杂环基基团(在本文中也称为6,7-双环杂环基环)包括但不限于:氮杂双环辛烷基(例如,(1,5)-8-氮杂双环[3.2.1]辛烷基)。稠合至环烷基环的示例性6元杂环基基团(在本文中也称为6,8-双环杂环基环)包括但不限于:氮杂双环壬烷基(例如,9-氮杂双环[3.3.1]壬烷基)。
除非另有说明,否则术语“亚烷基”、“亚烯基”、“亚炔基”、“卤代亚烷基”、“杂亚烷基”、“环亚烷基”或“杂亚环基”单独或作为另一取代基的一部分是指分别衍生自烷基、烯基、炔基、卤代亚烷基、杂亚烷基、环烷基或杂环基的二价基团。例如,除非另有说明,否则术语“亚烯基”本身或作为另一取代基的一部分意指衍生自烯烃的二价基团。亚烷基、亚烯基、亚炔基、卤代亚烷基、杂亚烷基、环亚烷基或杂亚环基基团可以描述为例如C1-C6元亚烷基、C2-C6元亚烯基、C2-C6元亚炔基、C1-C6元卤代亚烷基、C1-C6元杂亚烷基、C3-C8元环亚烷基或C3-C8元杂亚环基,其中术语“元”是指部分内的非氢原子。在杂亚烷基和杂亚环基基团的情况下,杂原子也可以占据一个或两个链末端(例如,亚烷基氧基、亚烷基二氧基、亚烷基氨基、亚烷基二氨基等)。另外,连接基团的式的书写方向并不暗示连接基团的方向。例如,式-C(O)2R’-可以同时代表-C(O)2R’-和-R’C(O)2-。
如本文所用的,术语“氰基”或“-CN”是指具有通过三键(例如,C≡N)与氮原子连接的碳原子的取代基。
如本文所用的,术语“卤素”或“卤代”是指氟、氯、溴或碘。
如本文所用的,术语“羟基”是指-OH。
如本文所用的,术语“硝基”是指具有与氮原子结合的两个氧原子的取代基,例如-NO2。
如本文所用的,如本文所用的术语“核碱基”是发现与核苷内的糖连接的含氮生物化合物,核苷是脱氧核糖核酸(DNA)和核糖核酸(RNA)的基本构建单元。主要的或天然存在的核碱基是胞嘧啶(DNA和RNA)、鸟嘌呤(DNA和RNA)、腺嘌呤(DNA和RNA)、胸腺嘧啶(DNA)和尿嘧啶(RNA),缩写分别为C、G、A、T和U。因为A、G、C和T出现在DNA中,所以这些分子称为DNA碱基;A、G、C和U称为RNA碱基。腺嘌呤和鸟嘌呤属于称为嘌呤(缩写为R)的双环类分子。胞嘧啶、胸腺嘧啶和尿嘧啶都是嘧啶。不作为遗传密码的正常部分起作用的其他核碱基被称为非天然存在的。在实施例中,核碱基可以被化学修饰,例如用烷基(例如甲基)、卤素、-O-烷基或其他修饰。
如本文所用的,术语“核酸”是指单链或双链形式的脱氧核糖核酸(DNA)或核糖核酸(RNA)及其聚合物。术语“核酸”包括基因、cDNA、前mRNA或mRNA。在一个实施例中,核酸分子是合成的(例如,化学合成的)或重组的。除非特别限定,否则该术语涵盖含有天然核苷酸的类似物或衍生物的核酸,这些核酸具有与参比核酸类似的结合特性并且以与天然存在的核苷酸类似的方式进行代谢。除非另有说明,否则特定的核酸序列还隐含地涵盖其经保守修饰的变体(例如,简并密码子取代)等位基因、直向同源物、SNP和互补序列以及明确说明的序列。
如本文所用的,“氧代”是指羰基,即-C(O)-。
如本文所定义的,烷基、烯基、炔基、卤代烷基、杂烷基、环烷基、杂环基、芳基和杂芳基基团任选地被取代。通常,术语“取代”,无论前面是否有术语“任选地”,意指存在于基团(例如碳或氮原子)上的至少一个氢被允许的取代基(例如,在取代时产生稳定化合物的取代基,例如不自发地经历转化(例如通过重排,环化,消除或其他反应)的化合物)替换。除非另有说明,否则“取代的”基团在该基团的一个或多个可取代的位置具有取代基,并且当任何给定结构中的多于一个位置被取代时,取代基在每个位置上相同或不同。术语“取代”考虑包括用有机化合物的所有允许的取代基取代,例如导致形成稳定化合物的本文描述的任何取代基。本披露考虑了任何和所有这样的组合以获得稳定的化合物。出于本发明的目的,杂原子例如氮可以具有氢取代基和/或如本文描述的任何合适的取代基,该取代基满足杂原子的化合价并导致形成稳定的部分。
两个或更多个取代基可以任选地连接以形成芳基、杂芳基、环烷基或杂环基基团。这样所谓的成环取代基典型地(但不是必须的)被发现附接到环状基础结构上。在一个实施例中,成环取代基附接到基础结构的相邻成员上。例如,附接到环状基础结构的相邻成员的两个成环取代基产生稠环结构。在另一实施例中,成环取代基附接到基础结构的单个成员上。例如,附接到环状基础结构的单个成员的两个成环取代基产生螺环结构。在又一实施例中,成环取代基附接到基础结构的非相邻成员上。
本文提供的化合物能以一种或多种特定的几何、光学、对映异构、非对映异构、差向异构、立体异构、互变异构、构象或异头形式存在,包括但不限于:顺式和反式;E型和Z型;内型和外型;R型、S型和内消旋型;D型和L型;d型和l型;(+)和(-)形式;酮、烯醇和烯醇化物形式;顺形式和反形式;向斜和背斜形式;α和β形式;轴向和赤道形式;船式、椅式、扭船式、信封式和半椅式;及其组合,以下统称为“异构体”(或“异构形式”)。
本文描述的化合物可以包含一个或多个不对称中心,因此能以各种异构形式(例如对映异构体和/或非对映异构体)存在。例如,本文描述的化合物可以呈单独的对映异构体、非对映异构体或几何异构体的形式,可以呈立体异构体混合物(包括外消旋混合物和富含一个或多个立体异构体的混合物)的形式。在实施例中,化合物中描述的立体化学是相对的而不是绝对的。异构体可以通过本领域技术人员已知的方法从混合物中分离,这些方法包括手性高压液相色谱法(HPLC)和手性盐的形成和结晶;或优选的异构体可以通过不对称合成来制备。参见,例如Jacques等人.,Enantiomers,Racemates and Resolutions[对映异构体、外消旋体和分辨率](Wiley Interscience[威利国际科学出版社],纽约,1981);Wilen,等人.,Tetrahedron[四面体]33:2725(1977);Eliel,Stereochemistry of CarbonCompounds[碳化合物的立体化学](McGraw-Hill[麦格劳希尔出版社],纽约,1962);以及Wilen,Tables of Resolving Agents and Optical Resolutions[分辨剂和光学分辨率的表],第268页(E.L.Eliel编辑,Univ.of Notre Dame Press[圣母大学出版社],巴黎圣母院(Notre Dame),印第安纳州,1972)。本披露另外涵盖本文描述的化合物作为基本上不含其他异构体的单独异构体,并且可替代地作为各种异构体的混合物。
如本文所用的,纯对映异构体化合物基本上不含化合物的其他对映异构体或立体异构体(即,对映异构体过量)。换言之,化合物的“S”型基本上不含化合物的“R”型,因此是“R”型的对映异构体过量。术语“对映异构纯的”或“纯对映异构体”表示化合物包含按重量计超过75%、按重量计超过80%、按重量计超过85%、按重量计超过90%、按重量计超过91%、按重量计超过92%、按重量计超过93%、按重量计超过94%、按重量计超过95%、按重量计超过96%、按重量计超过97%、按重量计超过98%、按重量计超过99%、按重量计超过99.5%或按重量计超过99.9%的对映异构体。在某些实施例中重量基于化合物的所有对映异构体或立体异构体的总重量。
在本文提供的组合物中,对映异构纯的化合物可以与其他活性成分或非活性成分一起存在。例如,包含对映异构纯的R-化合物的药物组合物可以包含例如约90%的赋形剂和约10%的对映异构纯的R-化合物。在某些实施例中,这样的组合物中的对映异构纯的R-化合物可以例如包含按化合物总重量计,按重量计至少约95%的R-化合物和按重量计至多约5%的S-化合物。例如,包含对映异构纯的S-化合物的药物组合物可以包含例如约90%的赋形剂和约10%的对映异构纯的S-化合物。在某些实施例中,这样的组合物中的对映异构纯的S-化合物可以例如包含按化合物总重量计,按重量计至少约95%的S-化合物和按重量计至多约5%的R-化合物。
在一些实施例中,非对映异构纯的化合物可以与其他活性成分或非活性成分一起存在。例如,包含非对映异构纯的外型化合物的药物组合物可以包含例如约90%的赋形剂和约10%的非对映异构纯的外型化合物。在某些实施例中,这样的组合物中的非对映异构纯的外型化合物可以例如包含按化合物总重量计,按重量计至少约95%的外型化合物和按重量计至多约5%的内型化合物。例如,包含非对映异构纯的内型化合物的药物组合物可以包含例如约90%的赋形剂和约10%的非对映异构纯的内型化合物。在某些实施例中,这样的组合物中的非对映异构纯的内型化合物可以例如包含按化合物总重量计,按重量计至少约95%的内型化合物和按重量计至多约5%的外型化合物。
在一些实施例中,异构纯的化合物可以与其他活性成分或非活性成分一起存在。例如,包含异构纯的外型化合物的药物组合物可以包含例如约90%的赋形剂和约10%的异构纯的外型化合物。在某些实施例中,这样的组合物中的异构纯的外型化合物可以例如包含按化合物总重量计,按重量计至少约95%的外型化合物和按重量计至多约5%的内型化合物。例如,包含异构纯的内型化合物的药物组合物可以包含例如约90%的赋形剂和约10%的异构纯的内型化合物。在某些实施例中,这样的组合物中的异构纯的内型化合物可以例如包含按化合物总重量计,按重量计至少约95%的内型化合物和按重量计至多约5%的外型化合物。
在某些实施例中,活性成分可以与很少或没有赋形剂或载体一起配制。
本文描述的化合物还可包含一个或多个同位素取代。例如,H可以呈任何同位素形式,包括1H、2H(D或氘)和3H(T或氚);C可以呈任何同位素形式,包括12C、13C和14C;O可以呈任何同位素形式,包括16O和18O;N可以呈任何同位素形式,包括14N和15N;F可以呈任何同位素形式,包括18F、19F等。
术语“药学上可接受的盐”意在包括用相对无毒的酸或碱(取决于在本文描述的化合物上发现的特定取代基)制备的活性化合物的盐。当本披露的化合物含有相对酸性的官能团时,碱加成盐可以通过使这样的化合物的中性形式与足量的所需碱(纯碱或在合适的惰性溶剂中)接触来获得。药学上可接受的碱加成盐的实例包括钠盐、钾盐、钙盐、铵盐、有机氨基盐或镁盐,或类似的盐。当本发明的化合物含有相对碱性的官能团时,酸加成盐可以通过使这样的化合物的中性形式与足量的所需酸(纯酸或在合适的惰性溶剂中)接触来获得。药学上可接受的酸加成盐的实例包括衍生自无机酸和有机酸的盐,这些无机酸是例如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等,这些有机酸是例如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等。还包括氨基酸的盐,例如精氨酸盐等,以及有机酸(例如葡糖醛酸或半乳糖醛酸等)的盐(参见,例如,Berge等人,Journal of Pharmaceutical Science[药物科学杂志]66:1-19(1977))。本发明的某些特定化合物既含有碱性官能团又含有酸性官能团,这使得化合物可以转化为碱加成盐或酸加成盐。这些盐可以通过本领域技术人员已知的方法制备。本领域技术人员已知的其他药学上可接受的载体适用于本发明。
除了盐形式之外,本披露还提供了前药形式的化合物。本文描述的化合物的前药是那些在生理条件下容易发生化学变化以提供本发明化合物的化合物。此外,前药可以在离体环境中通过化学方法或生化方法转化为本发明的化合物。例如,当将前药置于具有合适酶或化学试剂的透皮贴剂储库中时,前药可以缓慢地转化为本发明的化合物。
术语“溶剂化物”是指通常通过溶剂分解反应与溶剂缔合的化合物的形式。此物理缔合可以包括氢键合。常规的溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、二乙醚等。具有式(I)的化合物可以制备为例如结晶形式,并且可以是被溶剂化的。合适的溶剂化物包括药学上可接受的溶剂化物,并且进一步包括化学计量的溶剂化物和非化学计量的溶剂化物。在某些情况下,溶剂化物能够分离(例如当一种或多种溶剂分子掺入结晶固体的晶格中时)。“溶剂化物”涵盖溶液相和可分离的溶剂化物两者。代表性溶剂化物包括水合物、乙醇化物和甲醇化物。
术语“水合物”是指与水缔合的化合物。典型地,化合物的水合物中包含的水分子的数目与水合物中化合物分子的数目具有确定的比率。因此,化合物的水合物可以由例如通式R·x H2O代表,其中R是化合物,并且其中x是大于0的数字。给定的化合物可以形成多于一种类型的水合物,包括例如,一水合物(x是1)、低级水合物(x是大于0且小于1的数字,例如,半水合物(R·0.5H2O))和多水合物(x是大于1的数字,例如,二水合物(R·2H2O)和六水合物(R·6H2O))。
术语“互变异构体”是指具有可互换形式的特定化合物结构并且在氢原子和电子移位方面变化的化合物。因此,两种结构可以通过π电子和原子(通常是H)的运动处于平衡。例如,烯醇和酮是互变异构体,因为通过用酸或碱的处理它们快速地相互转化。互变异构的另一个实例是苯基硝基甲烷的酸-和硝基-形式,它们同样是通过用酸或碱处理而形成的。互变异构形式可以与获得目的化合物的最优化学反应性和生物活性相关。
其他定义
以下定义是贯穿本披露中使用的更一般的术语。
冠词“一个/种(a/an)”是指一个/种或多于一个/种(例如,至少一个/种)该冠词的语法宾语。通过举例,“一个要素”意指一个要素或多于一个要素。除非另有指示,否则术语“和/或”意指“和”或者“或”。
本文使用的术语“约”是指在本领域的典型公差范围内。例如,“约”可以理解为与平均值相差约2个标准差。在某些实施例中,约意指±10%。在某些实施例中,约意指±5%。当约出现在一系列数字或范围之前时,应理解“约”可以修饰系列或范围中的每个数字。
如本文所用的,“获取”(“acquire”或“acquiring”)是指通过“直接获取”或“间接获取”值或物理实体来获得值(例如,数值)或图像或物理实体(例如,样品)。“直接获取”意指执行一个过程(例如,执行分析方法或计划)来获得值或物理实体。“间接获取”是指从另一方或来源(例如,直接获取物理实体或值的第三方实验室)接收值或物理实体。直接获取值或物理实体包括执行一个过程,该过程包括物理物质的物理变化或机器或设备的使用。直接获取值的实例包括从人受试者获得样品。直接获取值包括执行使用机器或设备(例如质谱仪)来获取质谱数据的过程。
如本文所用的,术语“施用(administer、administering或administration)”是指植入、吸收、摄取、注射、吸入、或以其他方式引入本发明化合物或其药物组合物。
如本文所用的,术语“病症”、“疾病”和“障碍”可互换使用。
具有式(I)的化合物的“有效量”是指足以引发所需生物反应,即治疗病症的量。如本领域普通技术人员将理解的,具有式(I)的化合物的有效量可以根据所需的生物学终点、化合物的药代动力学、所治疗的病症、施用模式以及受试者的年龄和健康状况等因素而变化。有效量涵盖治疗性治疗和预防性治疗。例如,在治疗癌症时,有效量的本发明化合物可以减轻肿瘤负荷或阻止肿瘤的生长或扩散。
具有式(I)的化合物的治疗有效量是足以在病症的治疗中提供治疗益处或者延迟或最小化与病症相关的一种或多种症状的量。在一些实施例中,治疗有效量是足以在病症的治疗中提供治疗益处或最小化与病症相关的一种或多种症状的量。化合物的治疗有效量意指独自或与其他疗法组合,在病症的治疗方面提供治疗益处的治疗剂的量。术语“治疗有效量”可以涵盖改善整体疗法、减少或避免症状或病症起因、或增强另一治疗剂的治疗功效的量。
术语“肽”、“多肽”和“蛋白质”可互换使用,并且是指包含由肽键共价连接的氨基酸残基的化合物。蛋白质或肽必须含有至少两个氨基酸,并且对其中可以包含的氨基酸的最大数量没有限制。多肽包括包含由肽键彼此相连的两个或更多个氨基酸的任何肽或蛋白质。如本文所用的,该术语是指短链,例如其在本领域中通常也称为肽、寡肽和寡聚体;并且还是指较长的链,其在本领域中通常称为蛋白质,存在有很多类型的蛋白质。
如本文所用的,“预防(prevention、prevent和preventing)”是指在疾病、障碍或病症发作之前治疗(包括施用疗法,例如施用本文描述的化合物(例如,具有式(I)的化合物)),以排除所述疾病、障碍或病症的身体表现。在一些实施例中,“预防(prevention、prevent和preventing)”需要尚未发展或尚未观察到疾病、障碍或病症的体征或症状。在一些实施例中,治疗包括预防,而在其他实施例中治疗不包括预防。
预期施用的“受试者”包括但不限于人(即任何年龄组的男性或女性,例如儿科受试者(例如婴儿、儿童、青少年)或成人受试者(例如,年轻人、中年人或老年人))和/或其他非人动物,例如哺乳动物(例如,灵长类动物(例如,食蟹猴、恒河猴);商业相关的哺乳动物,例如牛、猪、马、绵羊、山羊、猫和/或狗)和鸟类(例如,商业相关的鸟类,如鸡、鸭、鹅和/或火鸡)。在某些实施例中,动物是哺乳动物。动物可以是雄性或雌性并且处于任何发育阶段。非人动物可以是转基因动物。
如本文所用的,术语“治疗(treatment,treat和treating)”是指例如通过施用疗法,例如施用本文描述的化合物(例如,具有式(I)的化合物)将(例如,如本文描述的)疾病、障碍或病症的一种或多种症状、表现或根本原因逆转、减轻、延迟发作或抑制进展。在实施例中,治疗包括将疾病、障碍或病症的症状减少、逆转、减轻、延迟发作或抑制进展。在实施例中,治疗包括将疾病、障碍或病症的表现减少、逆转、减轻、延迟发作或抑制进展。在实施例中,治疗包括将疾病、障碍或病症的根本原因减少、逆转、减轻、减少或延迟发作。在一些实施例中,“治疗”需要已经发展或已经观察到疾病、障碍或病症的体征或症状。在其他实施例中,可以在没有疾病或病症的体征或症状的情况下,例如在预防性治疗中施用治疗。例如,可以在症状发作之前对易感个体施用治疗(例如,根据症状史和/或根据遗传或其他易感因素)。症状已经消退后也可以继续治疗,例如,以延迟或预防复发。症状已经消退后也可以继续治疗,例如,以延迟或预防复发。在一些实施例中,治疗包括预防,而在其他实施例中治疗不包括预防。
“增殖性疾病”是指由于细胞增殖引起的异常延伸而发生的疾病(Walker,Cambridge Dictionary of Biology[剑桥生物学词典];Cambridge University Press[剑桥大学出版社]:英国剑桥,1990)。增殖性疾病可能与以下有关:1)正常静止期细胞的病理增殖;2)细胞从其正常位置的病理迁移(例如,肿瘤细胞的转移);3)蛋白水解酶如基质金属蛋白酶(如胶原酶、明胶酶和弹性蛋白酶)的病理表达;4)增殖性视网膜病变和肿瘤转移中的病理性血管生成;或5)逃避宿主免疫监视和消除肿瘤细胞。示例性增殖性疾病包括癌症(即“恶性肿瘤”)、良性肿瘤和血管生成。
“非增殖性疾病”是指主要不通过细胞异常增殖而延伸的疾病。非增殖性疾病可能与受试者的任何细胞类型或组织类型相关。示例性非增殖性疾病包括神经疾病或障碍(例如,重复扩张疾病);自身免疫性疾病或障碍;免疫缺陷性疾病或障碍;溶酶体贮积病或障碍;炎性疾病或障碍;心血管病症、疾病或障碍;代谢性疾病或障碍;呼吸病症、疾病或障碍;肾脏疾病或障碍;和传染性疾病。
化合物
本披露的特征在于具有式(I)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-S(O)x-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;M和P各自独立地是C(R2)或N;X和Y各自独立地是C、C(R5a)、C(R5a)(R5b)、N或N(R5c),其中在化合价允许的情况下,X和Y之间的键可以是单键或双键,并且其中X和Y不能都是C(R5a)(R5b)或C(R5a);每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;每个R4独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基,其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;R5a是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、-NRBRC或-ORF;R5b是氢或C1-C6-烷基;或R5a和R5b与它们所附接的碳原子一起形成氧代基团;每个R5c是氢、C1-C6-烷基、C1-C6-卤代烷基或C(O)RD;每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、-ORA、-NRBRC、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;RF是氢、C1-C6烷基、环烷基、杂环基、芳基或杂芳基;R10是C1-C6-烷基或卤代;每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;每个R12独立地是氘、卤代、氰基、-ORA、-NRBRC、-NRBC(O)RD、-C(O)NRBRC、-C(O)RD、-C(O)ORD或-C(O)RD;n是0、1、2、3或4;并且x是0、1或2。
在另一方面,本披露的特征在于具有式(I-a)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-S(O)x-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;M和P各自独立地是C(R2)或N;X和Y各自独立地是C、C(R5a)、C(R5a)(R5b)、N或N(R5c),其中在化合价允许的情况下,X和Y之间的键可以是单键或双键,并且其中X和Y不能都是C(R5a)(R5b);每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;每个R3独立地是氢、C1-C6-烷基或C1-C6-卤代烷基;每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;R5a是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、-NRBRC或-ORF;R5b是氢或C1-C6-烷基;或R5a和R5b与它们所附接的碳原子一起形成氧代基团;每个R5c是氢、C1-C6-烷基、C1-C6-卤代烷基或C(O)RD;每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、-ORA、-NRBRC、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;RF是氢、C1-C6烷基、环烷基、杂环基、芳基或杂芳基;R10是C1-C6-烷基或卤代;每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;n是0、1、2、3或4;并且x是0、1或2。
如本文的一般描述,A或B中的每个独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代。
在一些实施例中,A和B中的每个独立地是单环,例如单环环烷基、单环杂环基、单环芳基或单环杂芳基。单环可以是饱和的、部分不饱和的或完全不饱和的(例如,芳族)。在一些实施例中,A或B独立地是包含3至10个环原子(例如,3、4、5、6、7、8、9或10个环原子)的单环。在一些实施例中,A是4元单环。在一些实施例中,B是4元单环。在一些实施例中,A是5元单环。在一些实施例中,B是5元单环。在一些实施例中,A是6元单环。在一些实施例中,B是6元单环。在一些实施例中,A是7元单环。在一些实施例中,B是7元单环。在一些实施例中,A是8元单环。在一些实施例中,B是8元单环。在一些实施例中,A或B独立地是任选地被一个或多个R1取代的单环。
在一些实施例中,A或B独立地是双环,例如双环环烷基、双环杂环基、双环芳基或双环杂芳基。双环可以是饱和的、部分不饱和的或完全不饱和的(例如,芳族)。在一些实施例中,A或B独立地是包含稠合、桥联或螺环系统的双环。在一些实施例中,A或B独立地是包含4至18个环原子(例如,4、5、6、7、8、9、10、11、12、13、14、15、16、17或18个环原子)的双环。在一些实施例中,A是6元双环。在一些实施例中,B是6元双环。在一些实施例中,A是7元双环。在一些实施例中,B是7元双环。在一些实施例中,A是8元双环。在一些实施例中,B是8元双环。在一些实施例中,A是9元双环。在一些实施例中,B是9元双环。在一些实施例中,A是10元双环。在一些实施例中,B是10元双环。在一些实施例中,A是11元双环。在一些实施例中,B是11元双环。在一些实施例中,A是12元双环。在一些实施例中,B是12元双环。在一些实施例中,A或B独立地是任选地被一个或多个R1取代的双环。
在一些实施例中,A或B独立地是三环,例如三环烷基、三环杂环基、三环芳基或三环杂芳基。三环可以是饱和的、部分不饱和的或完全不饱和的(例如,芳族)。在一些实施例中,A或B独立地是包含稠合、桥联或螺环系统或其组合的三环。在一些实施例中,A或B独立地是包含6至24个环原子(例如,6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个环原子)的三环。在一些实施例中,A是8元三环。在一些实施例中,B是8元三环。在一些实施例中,A是9元三环。在一些实施例中,B是9元三环。在一些实施例中,A是10元三环。在一些实施例中,B是10元三环。在一些实施例中,A或B独立地是任选地被一个或多个R1取代的三环。
在一些实施例中,A或B独立地是单环环烷基、单环杂环基、单环芳基或单环杂芳基。在一些实施例中,A或B独立地是双环环烷基、双环杂环基、双环芳基或双环杂芳基。在一些实施例中,A或B独立地是三环烷基、三环杂环基、三环芳基或三环杂芳基。在一些实施例中,A是单环杂环基。在一些实施例中,B是单环杂环基。在一些实施例中,A是双环杂环基。在一些实施例中,B是双环杂环基。在一些实施例中,A是单环杂芳基。在一些实施例中,B是单环杂芳基。在一些实施例中,A是双环杂芳基。在一些实施例中,B是双环杂芳基。
在一些实施例中,A或B独立地是含氮杂环基,例如包含一个或多个氮原子的杂环基。含氮杂环基的一个或多个氮原子可以在环的任何位置。在一些实施例中,含氮杂环基是单环、双环或三环。在一些实施例中,A或B独立地是包含至少1个、至少2个、至少3个、至少4个、至少5个或至少6个氮原子的杂环基。在一些实施例中,A是包含1个氮原子的杂环基。在一些实施例中,B是包含1个氮原子的杂环基。在一些实施例中,A是包含2个氮原子的杂环基。在一些实施例中,B是包含2个氮原子的杂环基。在一些实施例中,A是包含3个氮原子的杂环基。在一些实施例中,B是包含3个氮原子的杂环基。在一些实施例中,A是包含4个氮原子的杂环基。在一些实施例中,B是包含4个氮原子的杂环基。在一些实施例中,A或B独立地是包含一个或多个另外杂原子,例如氧、硫、硼、硅或磷中的一个或多个的含氮杂环基。在一些实施例中,含氮杂环基的一个或多个氮被例如R1取代。
在一些实施例中,A或B独立地是含氮杂芳基,例如包含一个或多个氮原子的杂芳基。含氮杂芳基的一个或多个氮原子可以在环的任何位置。在一些实施例中,含氮杂芳基是单环、双环或三环。在一些实施例中,A或B独立地是包含至少1个、至少2个、至少3个、至少4个、至少5个或至少6个氮原子的杂芳基。在一些实施例中,A是包含1个氮原子的杂芳基。在一些实施例中,B是包含1个氮原子的杂芳基。在一些实施例中,A是包含2个氮原子的杂芳基。在一些实施例中,B是包含2个氮原子的杂芳基。在一些实施例中,A是包含3个氮原子的杂芳基。在一些实施例中,B是包含3个氮原子的杂芳基。在一些实施例中,A是包含4个氮原子的杂芳基。在一些实施例中,B是包含4个氮原子的杂芳基。在一些实施例中,A或B独立地是包含一个或多个另外杂原子,例如氧、硫、硼、硅或磷中的一个或多个的含氮杂芳基。在一些实施例中,含氮杂芳基的一个或多个氮被例如R1取代。
在一些实施例中,A是6元含氮杂环基,例如包含一个或多个氮的6元杂环基。在一些实施例中,A是包含1个氮原子的6元杂环基。在一些实施例中,A是包含2个氮原子的6元杂环基。在一些实施例中,A是包含3个氮原子的6元杂环基。在一些实施例中,A是包含4个氮原子的6元杂环基。6元含氮杂环基的一个或多个氮原子可以在环的任何位置。在一些实施例中,A是任选地被一个或多个R1取代的6元含氮杂环基。在一些实施例中,6元含氮杂环基的一个或多个氮被例如R1取代。在一些实施例中,A是包含一个或多个另外杂原子,例如氧、硫、硼、硅或磷中的一个或多个的6元含氮杂环基。
在一些实施例中,B是5元含氮杂环基或杂芳基,例如包含一个或多个氮的5元杂环基或杂芳基。在一些实施例中,B是包含1个氮原子的5元杂环基。在一些实施例中,B是包含1个氮原子的5元杂芳基。在一些实施例中,B是包含2个氮原子的5元杂环基。在一些实施例中,B是包含2个氮原子的5元杂芳基。在一些实施例中,B是包含3个氮原子的5元杂环基。在一些实施例中,B是包含3个氮原子的5元杂芳基。5元含氮杂环基或杂芳基的一个或多个氮原子可以在环的任何位置。在一些实施例中,B是任选地被一个或多个R1取代的5元含氮杂环基。在一些实施例中,B是任选地被一个或多个R1取代的5元含氮杂芳基。在一些实施例中,5元含氮杂环基或杂芳基的一个或多个氮被例如R1取代。在一些实施例中,B是包含一个或多个另外杂原子,例如氧、硫、硼、硅或磷中的一个或多个的5元含氮杂环基或杂芳基。
在一些实施例中,A和B中的每个独立地选自: 其中每个R1如本文所定义。在实施例中,A和B各自独立地是上述环中的一个的饱和、部分饱和或不饱和(例如,芳族)衍生物。在实施例中,A和B各自独立地是上述环中的一个的立体异构体。
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如本文的一般描述,L可以不存在或是指C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-S(O)x、-N(R3)C(O)-或-C(O)N(R3)-基团,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代。在一些实施例中,L可以不存在或是指C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-基团,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代。
在一些实施例中,L不存在。在一些实施例中,L是C1-C6-亚烷基(例如,C1-亚烷基、C2-亚烷基、C3-亚烷基、C4-亚烷基、C5-亚烷基或C6-亚烷基)。在一些实施例中,L是未取代的C1-C6亚烷基。在一些实施例中,L是取代的C1-C6-亚烷基,例如,被一个或多个R4取代的C1-C6亚烷基。在一些实施例中,L是被一个R4取代的C1-亚烷基。在一些实施例中,L是-CH2-(或亚甲基)。在一些实施例中,L是-C(O)-(或羰基)。
在一些实施例中,L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代。
在一些实施例中,L是C1-C6-杂亚烷基(例如,C1-杂亚烷基、C2-杂亚烷基、C3-杂亚烷基、C4-杂亚烷基、C5-杂亚烷基或C6-杂亚烷基)。在一些实施例中,L是未取代的C1-C6杂亚烷基。在一些实施例中,L是被一个或多个R4取代的C1-C6-杂亚烷基。在一些实施例中,杂亚烷基包含1个或多个杂原子。在一些实施例中,杂亚烷基包含氧、硫、氮、硼、硅或磷中的一个或多个。在一些实施例中,L是-N(R3)C(O)-。在一些实施例中,L是-C(O)N(R3)-。
在一些实施例中,L是氧。在一些实施例中,L是氮,其可以被R3取代。在一些实施例中,L是被一个R3取代的氮。在一些实施例中,L是-N(R3)-。在一些实施例中,L是-N(CH3)-。在一些实施例中,L是-NH-。在一些实施例中,L是-O-。
在一些实施例中,L是-S(O)x-。在一些实施例中,x是0、1或2。在一些实施例中,L是-S-或-S(O)2-。在一些实施例中,L是-S-。
如本文的一般描述,M和P中的每个独立地是指C(R2)或N。在一些实施例中,M和P中的每个独立地是C(R2)或N。在一些实施例中,M和P各自独立地是C(R2),例如,CH。在一些实施例中,M和P中的一个是C(R2),并且M和P中的另一个是N。在一些实施例中,M是C(R2)。在一些实施例中,M是N。在一些实施例中,P是C(R2)。在一些实施例中,P是N。在一些实施例中,M是C(R2)(例如,CH),并且P是N。在一些实施例中,M是N,并且P是C(R2)(例如,CH)。
如本文的一般描述,X和Y中的每个独立地是指C、C(R5a)、C(R5a)(R5b)、N或N(R5c)。在一些实施例中,X和Y中的每个独立地是C。在一些实施例中,X和Y中的每个是C(R5a)。在一些实施例中,X和Y不能都是C(R5a)。
在一些实施例中,当Y是N并且X是C(R5a)(例如,CH)时,L不是-N(R3)-(例如,-N(CH3)-)。在一些实施例中,当Y是N并且X是CH时,L不是-N(R3)-(例如,-N(CH3)-)。在一些实施例中,当Y是N并且X是C(R5a)(例如,CH)时,L不是-N(CH3)-。在一些实施例中,当Y是N并且X是CH时,L不是-N(CH3)-。在一些实施例中,当Y是N并且L是-N(R3)时,R3不是C1-C6-亚烷基。在一些实施例中,当Y是N并且L是-N(R3)时,R3不是CH3。在一些实施例中,当Y是N时,X也是N。在一些实施例中,当X是C(R5a)(例如,CH)时,Y不是N。在一些实施例中,当Y包含N时,X和Y之间的键不是双键。在一些实施例中,当Y包含N时,X和Y之间的键是单键。在一些实施例中,当Y是N时,B不是芳基或杂芳基。在一些实施例中,当Y是N时,B不是芳基。在一些实施例中,当Y是N时,B不是杂芳基。在一些实施例中,当Y是N时,B是环烷基或杂环基。在一些实施例中,当Y是N时,B是环烷基。在一些实施例中,当Y是N时,B是杂环基。
在一些实施例中,X和Y中的每个独立地是任选地被R7取代的C。在一些实施例中,两个R7基团与它们所附接的原子一起形成环烷基、杂环基、芳基或杂芳基。在一些实施例中,X和Y各自独立地是被R7取代的C,其中两个R7基团与X和Y一起形成环烷基、杂环基、芳基或杂芳基(例如,3-7元环烷基、杂环基、芳基或杂芳基)。在一些实施例中,R7基团与X和Y一起形成4-7元杂环基。在一些实施例中,R7基团与X和Y一起形成4-7元杂芳基。在一些实施例中,R7基团与X和Y一起形成5元杂环基。在一些实施例中,R7基团与X和Y一起形成5元杂芳基。环烷基、杂环基、芳基或杂芳基可以被一个或多个R9取代。
在一些实施例中,选自 其中D、E、F、G、和H各自独立地是C、C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O;R5d、R5e、和R5f各自独立地是氢、卤代或C1-C6烷基,或R5d和R5e一起形成氧代基团;R7如本文所定义;并且n是0、1或2的整数。
在一些实施例中,D、E、F、G、和H中的一个是N(R5f)或N,并且D、E、F、G、和H中的其他各自独立地是C(R5d)。在一些实施例中,D、E、F、G、和H中的两个各自独立地是N(R5f)或N,并且D、E、F、G、和H中的其他各自独立地是C(R5d)。在一些实施例中,D、E、F、G、和H中的三个各自独立地是N(R5f)或N,并且D、E、F、G、和H中的其他各自独立地是C(R5d)。在一些实施例中,D、E、F、G、和H中的一个是N(R5f),并且D、E、F、G、H中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、F、G、和H中的两个各自独立地是N(R5f),并且D、E、F、G、H中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、F、G、和H中的三个各自独立地是N(R5f),并且D、E、F、G、H中的其他各自独立地是C(R5d)(R5e)。
在一些实施例中,D、E、F、G、和H中的一个是N(R5f),并且D、E、F、G、和H中的其他独立地是O或C(R5d)(R5e)。在一些实施例中,D、E、F、G、和H中的一个是S,并且D、E、F、G、和H中的其他各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D、E、F、G、和H中的一个是S,并且D、E、F、G、和H中的其他各自独立地是C(R5d)(例如,CH)。
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f)或N,并且D、E、和F中的另一个是C(R5d)。在一些实施例中,D、E、和F中的三个各自独立地是N(R5f)或N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)。在一些实施例中,D是N(R5f)、E是C(R5d)、并且F是N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是N。在一些实施例中,D、E、和F中的一个是NH,并且D、E、和F中的其他独立地是CH或N。
在一些实施例中,D、E、和F中的一个是N(R5f)(例如,NH),并且D、E、和F中的其他独立地是O或C(R5d)(R5e)(例如,C(O))。在一些实施例中,D是N(R5f)(例如,CH),E是C(R5d)(R5e)(例如,C(O))、并且F是O。在一些实施例中,D是O、E是C(R5d)(R5e)(例如,C(O))、并且F是N(R5f)(例如,NH)。在一些实施例中,D是NH、E是C(O)、并且F是O。在一些实施例中,D是O、E是C(O)、并且F是NH。
在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S,并且E和F各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D是S、E是C(R5d)(例如,CH)、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S、E是CH、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是CH。
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f),并且D、E、和F中的另一个是C(R5d)(R5e)。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,E是N(R5f),并且D和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,F是N(R5f),并且D和E中的每个独立地是C(R5d)(R5e)。在一些实施例中,D是NH、E是C(O)、并且F是CH2。在一些实施例中,D是CH2、E是NH、并且F是C(O)。在一些实施例中,D是NH、E是CH、并且F是C(O)。
在一些实施例中,R1是氢。在一些实施例中,R1是C1-C6-烷基。在一些实施例中,R1是C2-C6-烯基。在一些实施例中,R1是C2-C6-炔基。在一些实施例中,R1是C1-C6-杂烷基。在一些实施例中,R1是C1-C6-卤代烷基(例如,-CF3)。在一些实施例中,R1是C1-烷基(例如,甲基)。在一些实施例中,R1是未取代的C1-C6-烷基、未取代的C2-C6-烯基、未取代的C2-C6-炔基、未取代的C1-C6-杂烷基或未取代的C1-C6-卤代烷基。在一些实施例中,R1是被一个或多个R8取代的C1-C6-烷基。在一些实施例中,R1是被一个或多个R8取代的C2-C6-烯基。在一些实施例中,R1是被一个或多个R8取代的C2-C6-炔基。在一些实施例中,R1是被一个或多个R8取代的C1-C6-杂烷基。在一些实施例中,R1是被一个或多个R8取代的C1-C6-卤代烷基。在一些实施例中,R1是甲基。
在一些实施例中,R1是环烷基(例如,3-7元环烷基)。在一些实施例中,R1是杂环基(例如,3-7元杂环基)。在一些实施例中,R1是芳基。在一些实施例中,R1是C1-C6亚烷基-芳基(例如,苄基)。在一些实施例中,R1是C1-C6亚烯基-芳基。在一些实施例中,R1是C1-C6亚烷基-杂芳基。在一些实施例中,R1是杂芳基。在一些实施例中,R1是未取代的环烷基、未取代的杂环基、未取代的芳基、未取代的C1-C6亚烷基-芳基、未取代的C1-C6亚烯基-芳基、未取代的C1-C6亚烷基-杂芳基或未取代的杂芳基。在一些实施例中,R1是被一个或多个R8取代的环烷基。在一些实施例中,R1是被一个或多个R8取代的杂环基。在一些实施例中,R1是被一个或多个R8取代的芳基。在一些实施例中,R1是被一个或多个R8取代的C1-C6亚烷基-芳基。在一些实施例中,R1是被一个或多个R8取代的C1-C6亚烯基-芳基。在一些实施例中,R1是被一个或多个R8取代的C1-C6亚烷基-杂芳基。在一些实施例中,R1是被一个或多个R8取代的杂芳基。
在一些实施例中,R1是-ORA。在一些实施例中,R1是-NRBRC(例如,NH2或NMe2)。在一些实施例中,R1是-NRBC(O)RD。在一些实施例中,R1是-C(O)NRBRC。在一些实施例中,R1是-C(O)RD。在一些实施例中,R1是-C(O)ORD。在一些实施例中,R1是-SRE。在一些实施例中,R1是-S(O)xRD。在一些实施例中,R1是卤代,例如,氟、氯、溴或碘。在一些实施例中,R1是氰基。在一些实施例中,R1是硝基(-NO2)。在一些实施例中,R1是氧代。
在一些实施例中,两个R1基团与它们所附接的原子一起形成3-7元环烷基。在一些实施例中,两个R1基团与它们所附接的原子一起形成3-7元杂环基。在一些实施例中,两个R1基团与它们所附接的原子一起形成5或6元芳基。在一些实施例中,两个R1基团与它们所附接的原子一起形成5或6元杂芳基。环烷基、杂环基、芳基或杂芳基可以被一个或多个R8取代。
在一些实施例中,R2是氢。在一些实施例中,R2是C1-C6烷基。在一些实施例中,R2是C2-C6-烯基。在一些实施例中,R2是C2-C6-炔基。在一些实施例中,R2是C1-烷基(例如,甲基)。在一些实施例中,R2是甲基。在一些实施例中,R2是-ORA。在一些实施例中,R2是卤代(例如,氟、氯、溴或碘)。在一些实施例中,R2是氟。在一些实施例中,R2是氰基。
在一些实施例中,R3是氢。在一些实施例中,R3是C1-C6烷基。在一些实施例中,R3是C1-C6卤代烷基。在一些实施例中,R3是C1-烷基(例如,甲基)。在一些实施例中,R3是甲基。在一些实施例中,R3被一个或多个R12修饰。在一些实施例中,R12是氘。在一些实施例中,R3是CD3。
在一些实施例中,R4是C1-C6-烷基。在一些实施例中,R4是C1-C6-杂烷基。在一些实施例中,R4是C1-C6-卤代烷基。在一些实施例中,R4是环烷基。在一些实施例中,R4是卤代(例如,氟、氯、溴或碘)。在一些实施例中,R4是氰基。在一些实施例中,R4是氧代。在一些实施例中,R4是-ORA。在一些实施例中,R4是-NRBRC。在一些实施例中,R4是-C(O)RD或-C(O)ORD。
在一些实施例中,R5a和R5b各自独立地是氢或C1-C6-烷基。在一些实施例中,R5a是氢。在一些实施例中,R5b是氢。在一些实施例中,R5a和R5b一起形成氧代基团。在一些实施例中,R5c是氢。在一些实施例中,R5c是C1-C6-烷基。在一些实施例中,R5c是C1-C6-卤代烷基(例如,-CF3或-CHF2)。在一些实施例中,R5c是-CF3。在一些实施例中,R5c是-CHF2。在一些实施例中,R5c是-C(O)RD(例如,-C(O)CH3)。在一些实施例中,R5c是-C(O)CH3)。
在一些实施例中,R5d、R5e、和R5f各自独立地是氢、C1-C6-烷基、卤代,或R5d、R5e一起形成氧代基团。在一些实施例中,R5d是氢。在一些实施例中,R5e是氢。在一些实施例中,R5f是氢。在一些实施例中,R5e和R5f一起形成氧代基团。
在一些实施例中,R7是C1-C6-烷基。在一些实施例中,R7是C2-C6-烯基。在一些实施例中,R7是C2-C6-炔基。在一些实施例中,R7是C1-C6-杂烷基。在一些实施例中,R7是C1-C6-卤代烷基。在一些实施例中,R7是未取代的C1-C6-烷基、未取代的C2-C6-烯基、未取代的C2-C6-炔基、未取代的C1-C6-杂烷基或未取代的C1-C6-卤代烷基。在一些实施例中,R7是被一个或多个R9取代的C1-C6-烷基。在一些实施例中,R7是被一个或多个R9取代的C2-C6-烯基。在一些实施例中,R7是被一个或多个R9取代的C2-C6-炔基。在一些实施例中,R7是被一个或多个R9取代的C1-C6-杂烷基。在一些实施例中,R7是被一个或多个R9取代的C1-C6-卤代烷基。在一些实施例中,R7是卤代,例如,氟、氯、溴或碘。在一些实施例中,R7是氟。在一些实施例中,R7是氰基。在一些实施例中,R7是氧代。在一些实施例中,R7是NRBC(O)RD。在一些实施例中,R7是-C(O)NRBRC。在一些实施例中,R7是-C(O)RD。在一些实施例中,R7是-SRE。
在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基。在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元杂环基。在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成5或6元芳基。在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成5或6元杂芳基。在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成5元杂环基。在一些实施例中,两个R7基团与它们所附接的原子(例如,X或Y)一起形成5元杂芳基。环烷基、杂环基、芳基或杂芳基可以被一个或多个R9取代。
在一些实施例中,R8是C1-C6-烷基。在一些实施例中,R8是C2-C6-烯基。在一些实施例中,R8是C2-C6-炔基。在一些实施例中,R8是C1-C6-杂烷基。在一些实施例中,R8是C1-C6-卤代烷基。在一些实施例中,R8是未取代的C1-C6-烷基、未取代的C2-C6-烯基、未取代的C2-C6-炔基、未取代的C1-C6-卤代烷基或未取代的C1-C6-杂烷基。在一些实施例中,R8是被一个或多个R11取代的C1-C6-烷基。在一些实施例中,R8是被一个或多个R11取代的C2-C6-烯基。在一些实施例中,R8是被一个或多个R11取代的C2-C6-炔基。在一些实施例中,R8是被一个或多个R11取代的C1-C6-卤代烷基。在一些实施例中,R8是被一个或多个R11取代的C1-C6-杂烷基。
在一些实施例中,R8是环烷基。在一些实施例中,R8是杂环基。在一些实施例中,R8是芳基。在一些实施例中,R8是杂芳基。在一些实施例中,R8是未取代的环烷基、未取代的杂环基、未取代的芳基或未取代的杂芳基。在一些实施例中,R8是被一个或多个R11取代的环烷基。在一些实施例中,R8是被一个或多个R11取代的杂环基。在一些实施例中,R8是被一个或多个R11取代的芳基。在一些实施例中,R8是被一个或多个R11取代的杂芳基。
在一些实施例中,R8是卤代(例如,氟、氯、溴或碘)。在一些实施例中,R8是氰基。在一些实施例中,R8是氧代。在一些实施例中,R8是-ORA。在一些实施例中,R8是-NRBRC。在一些实施例中,R8是-NRBC(O)RD。在一些实施例中,R8是-NO2。在一些实施例中,R8是-C(O)NRBRC。在一些实施例中,R8是-C(O)RD。在一些实施例中,R8是-C(O)ORD。在一些实施例中,R8是-SRE。在一些实施例中,R8是-S(O)xRD。
在一些实施例中,R9是C1-C6-烷基。在一些实施例中,R9是C2-C6-烯基。在一些实施例中,R9是C2-C6-炔基。在一些实施例中,R9是C1-C6-杂烷基。在一些实施例中,R9是C1-C6-卤代烷基。在一些实施例中,R9是未取代的C1-C6-烷基、未取代的C2-C6-烯基、未取代的C2-C6-炔基、未取代的C1-C6-卤代烷基或未取代的C1-C6-杂烷基。在一些实施例中,R9是被一个或多个R11取代的C1-C6-烷基。在一些实施例中,R9是被一个或多个R11取代的C2-C6-烯基。在一些实施例中,R9是被一个或多个R11取代的C2-C6-炔基。在一些实施例中,R9是被一个或多个R11取代的C1-C6-卤代烷基。在一些实施例中,R9是被一个或多个R11取代的C1-C6-杂烷基。
在一些实施例中,R9是环烷基。在一些实施例中,R9是杂环基。在一些实施例中,R9是芳基。在一些实施例中,R9是杂芳基。在一些实施例中,R9是未取代的环烷基、未取代的杂环基、未取代的芳基或未取代的杂芳基。在一些实施例中,R9是被一个或多个R11取代的环烷基。在一些实施例中,R9是被一个或多个R11取代的杂环基。在一些实施例中,R9是被一个或多个R11取代的芳基。在一些实施例中,R9是被一个或多个R11取代的杂芳基。
在一些实施例中,R9是卤代(例如,氟、氯、溴或碘)。在一些实施例中,R9是氰基。在一些实施例中,R9是氧代。在一些实施例中,R9是-ORA。在一些实施例中,R9是-NRBRC。在一些实施例中,R9是-NRBC(O)RD。在一些实施例中,R9是-NO2。在一些实施例中,R9是-C(O)NRBRC。在一些实施例中,R9是-C(O)RD。在一些实施例中,R9是-C(O)ORD。在一些实施例中,R9是-SRE。在一些实施例中,R9是-S(O)xRD。
在一些实施例中,R10是C1-C6-烷基。在一些实施例中,R10是卤代(例如,氟、氯、溴或碘)。
在一些实施例中,R11是C1-C6-烷基。在一些实施例中,R11是C1-C6-杂烷基。在一些实施例中,R11是C1-C6-卤代烷基(例如,-CF3)。在一些实施例中,R11是环烷基。在一些实施例中,R11是杂环基。在一些实施例中,R11是芳基。在一些实施例中,R11是杂芳基。在一些实施例中,R11是卤代。在一些实施例中,R11是氰基。在一些实施例中,R11是氧代。在一些实施例中,R11是-ORA。
在一些实施例中,RA是氢。在一些实施例中,RA是C1-C6烷基(例如,甲基)。在一些实施例中,RA是C1-C6卤代烷基。在一些实施例中,RA是芳基。在一些实施例中,RA是杂芳基。在一些实施例中,RA是C1-C6亚烷基-芳基(例如,苄基)。在一些实施例中,RA是C1-C6亚烷基-杂芳基。在一些实施例中,RA是C(O)RD。在一些实施例中,RA是-S(O)xRD。
在一些实施例中,RB、RC或两者各自独立地是氢、C1-C6-烷基、C1-C6-杂烷基、环烷基、杂环基或-ORA。在一些实施例中,RB和RC中的每个独立地是氢。在一些实施例中,RB和RC中的每个独立地是C1-C6烷基。在一些实施例中,RB和RC中的一个是氢,并且RB和RC中的另一个是C1-C6烷基。在一些实施例中,RB和RC与它们所附接的原子一起形成任选地被一个或多个R10(例如,1、2或3个R10)取代的3-7元杂环基环。
在一些实施例中,RD、RE或两者各自独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基(例如,苄基)或C1-C6亚烷基-杂芳基。在一些实施例中,RD和RE中的每个独立地是氢。在一些实施例中,RD和RE中的每个独立地是C1-C6烷基。在一些实施例中,RD是氢。在一些实施例中,RE是氢。在一些实施例中,RD是C1-C6烷基(例如,甲基)。在一些实施例中,RE是C1-C6烷基(例如,甲基)。在一些实施例中,RD是C1-C6杂烷基。在一些实施例中,RE是C1-C6杂烷基。在一些实施例中,RD是C1-C6卤代烷基。在一些实施例中,RE是C1-C6卤代烷基。在一些实施例中,RD是环烷基。在一些实施例中,RE是环烷基。在一些实施例中,RD是杂环基。在一些实施例中,RE是杂环基。在一些实施例中,RD是芳基。在一些实施例中,RE是芳基。在一些实施例中,RD是杂芳基。在一些实施例中,RE是杂芳基。在一些实施例中,RD是C1-C6亚烷基-芳基(例如,苄基)。在一些实施例中,RE是C1-C6亚烷基-芳基(例如,苄基)。在一些实施例中,RD是C1-C6亚烷基-杂芳基。在一些实施例中,RE是C1-C6亚烷基-杂芳基。
在一些实施例中,m是0至2的整数(例如,0、1或2)。在一些实施例中,m是0。在一些实施例中,m是1。在一些实施例中,m是2。在一些实施例中,n是0至4的整数(例如,0、1、2、3或4)。在一些实施例中,n是0。在一些实施例中,n是1。在一些实施例中,n是2。在一些实施例中,n是3。在一些实施例中,n是4。在一些实施例中,x是0至2的整数(例如,0、1或2)。在一些实施例中,x是0。在一些实施例中,x是1。在一些实施例中,x是2。
在一些实施例中,化合物是具有式(I-b)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-S(O)x-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;M和P各自独立地是C(R2)或N;X和Y各自独立地是C、C(R5a)、C(R5a)(R5b)、N或N(R5c),其中在化合价允许的情况下,X和Y之间的键可以是单键或双键,并且其中X和Y不能都是C(R5a)(R5b);每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;每个R3独立地是氢、C1-C6-烷基或C1-C6-卤代烷基;每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;R5a是氢、C1-C6-烷基或-ORF;R5b是氢或C1-C6-烷基;或R5a和R5b与它们所附接的碳原子一起形成氧代基团;每个R5c是氢、C1-C6-烷基、C1-C6-卤代烷基或C(O)RD;每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;RF是氢或C1-C6烷基;R10是C1-C6-烷基或卤代;每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;n是0、1、2、3或4;并且x是0、1或2。
在一些实施例中,本披露的特征在于具有式(I-c)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;M和P各自独立地是C(R2)或N;X和Y各自独立地是C、C(R5a)、C(R5a)(R5b)、N或N(R5c),其中在化合价允许的情况下,X和Y之间的键可以是单键或双键,并且其中X和Y不能都是C(R5a)(R5b);每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;每个R3独立地是氢、C1-C6-烷基或C1-C6-卤代烷基;每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;R5a是氢、C1-C6-烷基或-ORF;R5b是氢或C1-C6-烷基;或R5a和R5b与它们所附接的碳原子一起形成氧代基团;每个R5c是氢、C1-C6-烷基、C1-C6-卤代烷基或C(O)RD;每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;RF是氢或C1-C6-烷基;R10是C1-C6-烷基或卤代;每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;n是0、1、2、3或4;并且x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-d)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基,其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是
在一些实施例中,B选自 其中R1如本文所定义。在一些实施例中,B选自 在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f)或N,并且D、E、和F中的另一个是C(R5d)。在一些实施例中,D、E、和F中的三个各自独立地是N(R5f)或N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)。在一些实施例中,D是N(R5f)、E是C(R5d)、并且F是N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是N。在一些实施例中,D、E、和F中的一个是NH,并且D、E、和F中的其他独立地是CH或N。
在一些实施例中,D、E、和F中的一个是N(R5f)(例如,NH),并且D、E、和F中的其他独立地是O或C(R5d)(R5e)(例如,C(O))。在一些实施例中,D是N(R5f)(例如,CH),E是C(R5d)(R5e)(例如,C(O))、并且F是O。在一些实施例中,D是O、E是C(R5d)(R5e)(例如,C(O))、并且F是N(R5f)(例如,NH)。在一些实施例中,D是NH、E是C(O)、并且F是O。在一些实施例中,D是O、E是C(O)、并且F是NH。
在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S,并且E和F各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D是S、E是C(R5d)(例如,CH)、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S、E是CH、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是CH。
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f),并且D、E、和F中的另一个是C(R5d)(R5e)。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,E是N(R5f),并且D和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,F是N(R5f),并且D和E中的每个独立地是C(R5d)(R5e)。在一些实施例中,D是NH、E是C(O)、并且F是CH2。在一些实施例中,D是CH2、E是NH、并且F是C(O)。在一些实施例中,D是NH、E是CH、并且F是C(O)。
在一些实施例中,具有式(I)的化合物是具有式(I-e)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是
在一些实施例中,B选自 其中R1如本文所定义。在一些实施例中,B选自 在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f)或N,并且D、E、和F中的另一个是C(R5d)。在一些实施例中,D、E、和F中的三个各自独立地是N(R5f)或N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)。在一些实施例中,D是N(R5f)、E是C(R5d)、并且F是N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是N。在一些实施例中,D、E、和F中的一个是NH,并且D、E、和F中的其他独立地是CH或N。
在一些实施例中,D、E、和F中的一个是N(R5f)(例如,NH),并且D、E、和F中的其他独立地是O或C(R5d)(R5e)(例如,C(O))。在一些实施例中,D是N(R5f)(例如,CH),E是C(R5d)(R5e)(例如,C(O))、并且F是O。在一些实施例中,D是O、E是C(R5d)(R5e)(例如,C(O))、并且F是N(R5f)(例如,NH)。在一些实施例中,D是NH、E是C(O)、并且F是O。在一些实施例中,D是O、E是C(O)、并且F是NH。
在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S,并且E和F各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D是S、E是C(R5d)(例如,CH)、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S、E是CH、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是CH。
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f),并且D、E、和F中的另一个是C(R5d)(R5e)。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,E是N(R5f),并且D和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,F是N(R5f),并且D和E中的每个独立地是C(R5d)(R5e)。在一些实施例中,D是NH、E是C(O)、并且F是CH2。在一些实施例中,D是CH2、E是NH、并且F是C(O)。在一些实施例中,D是NH、E是CH、并且F是C(O)。
在一些实施例中,L不存在。在一些实施例中,L是氧。在一些实施例中,L是任选地被R3取代的氮。在一些实施例中,L是被R3取代的氮。在一些实施例中,R3是C1-C6烷基。在一些实施例中,L是-N(CH3)-。在一些实施例中,L是-NH-。
在一些实施例中,具有式(I)的化合物是具有式(I-f)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A1是6元环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
B1是5元环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代,
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C、C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基或C1-C6-卤代烷基;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是在一些实施例中,A是
在一些实施例中,B选自 其中R1如本文所定义。在一些实施例中,B选自 在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是在一些实施例中,B是
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f)或N,并且D、E、和F中的另一个是C(R5d)。在一些实施例中,D、E、和F中的三个各自独立地是N(R5f)或N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)。在一些实施例中,D是N(R5f)、E是C(R5d)、并且F是N。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是N。在一些实施例中,D、E、和F中的一个是NH,并且D、E、和F中的其他独立地是CH或N。
在一些实施例中,D、E、和F中的一个是N(R5f)(例如,NH),并且D、E、和F中的其他独立地是O或C(R5d)(R5e)(例如,C(O))。在一些实施例中,D是N(R5f)(例如,CH),E是C(R5d)(R5e)(例如,C(O))、并且F是O。在一些实施例中,D是O、E是C(R5d)(R5e)(例如,C(O))、并且F是N(R5f)(例如,NH)。在一些实施例中,D是NH、E是C(O)、并且F是O。在一些实施例中,D是O、E是C(O)、并且F是NH。
在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D、E、和F中的一个是S,并且D、E、和F中的其他各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S,并且E和F各自独立地是N或C(R5d)(例如,CH)。在一些实施例中,D是S、E是C(R5d)(例如,CH)、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是C(R5d)(例如,CH)。在一些实施例中,D是S、E是CH、并且F是N。在一些实施例中,D是S、并且E和F各自独立地是CH。
在一些实施例中,D、E、和F中的一个是N(R5f),并且D、E、和F中的其他各自独立地是C(R5d)(R5e)。在一些实施例中,D、E、和F中的两个各自独立地是N(R5f),并且D、E、和F中的另一个是C(R5d)(R5e)。在一些实施例中,D是N(R5f),并且E和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,E是N(R5f),并且D和F中的每个独立地是C(R5d)(R5e)。在一些实施例中,F是N(R5f),并且D和E中的每个独立地是C(R5d)(R5e)。在一些实施例中,D是NH、E是C(O)、并且F是CH2。在一些实施例中,D是CH2、E是NH、并且F是C(O)。在一些实施例中,D是NH、E是CH、并且F是C(O)。
在一些实施例中,L不存在。在一些实施例中,L是氧。在一些实施例中,L是任选地被R3取代的氮。在一些实施例中,L是被R3取代的氮。在一些实施例中,R3是C1-C6烷基。在一些实施例中,L是-N(CH3)-。在一些实施例中,L是-NH-。
在一些实施例中,具有式(I)的化合物是具有式(I-g)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A1是6元环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
B1是5元环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代,
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
D、E、和F各自独立地是C、C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基或C1-C6-卤代烷基;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,A1是任选地被一个或多个R1取代的6元杂环基。在一些实施例中,A1是6元含氮杂环基。在一些实施例中,A1是任选地取代的哌啶基。在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是在一些实施例中,A1是
在一些实施例中,L是被R3取代的氮。在一些实施例中,L是-N(CH3)-。在一些实施例中,L是-NH-。在一些实施例中,B1是任选地被一个或多个R1取代的5元杂芳基。在一些实施例中,B1是5元含氮杂芳基。在一些实施例中,B1是任选地取代的吡唑基。在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是在一些实施例中,B1是
在一些实施例中,具有式(I)的化合物是具有式(I-h)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-i)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-j)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-k)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
F是C(R5d)或N;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d是氢、卤代或C1-C6烷基;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-l)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
F是C(R5d)或N;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d是氢、卤代或C1-C6烷基;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-m)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
F是C(R5d)或N;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d是氢、卤代或C1-C6烷基;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物是具有式(I-n)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
F是C(R5d)或N;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
m是0、1或2
n是0、1、2、3或4;并且
x是0、1或2。
在一些实施例中,具有式(I)的化合物选自表1中的化合物或其药学上可接受的盐。
表1:示例性化合物
药物组合物、试剂盒和施用
本发明提供了药物组合物,其包含具有式(I)的化合物,例如,如本文描述的具有式(I)的化合物或药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体和任选地药学上可接受的赋形剂。在某些实施例中,本文描述的药物组合物包含具有式(I)的化合物或其药学上可接受的盐和任选地药学上可接受的赋形剂。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体以药物组合物中的有效量提供。在某些实施例中,有效量是治疗有效量。在某些实施例中,有效量是预防有效量。
本文描述的药物组合物可以通过在药理学领域任何已知的方法制备。通常,这样的制备方法包括以下步骤:使具有式(I)的化合物(“活性成分”)与载体和/或一种或多种其他辅助成分结合,然后(如果必要和/或需要)将产品成型和/或包装成所需单剂量或多剂量单位。
药物组合物可以呈单一单位剂量和/或呈多个单一单位剂量进行批量制备、包装、和/或出售。如本文所用的,“单位剂量”是包含预定量的活性成分的药物组合物的离散量。活性成分的量是通常等同于施用至受试者的活性成分的剂量和/或这样的剂量的合适的分数,例如,如这样的剂量的二分之一或三分之一。
本发明药物组合物中的活性成分、药学上可接受的赋形剂和/或任何另外成分的相对量将取决于所治疗受试者的特性、体型和/或状况以及进一步取决于组合物的施用途径而变化。例如,组合物可包含0.1%至100%(w/w)的活性成分。
术语“药学上可接受的赋形剂”是指不破坏与其配制的化合物的药理学活性的无毒性载体、辅助剂、稀释剂或媒介物。可用于制造本发明药物组合物的药学上可接受的赋形剂是药物配制品领域熟知的任何药学上可接受的赋形剂,包括惰性稀释剂、分散剂和/或成粒剂、表面活性剂和/或乳化剂、崩解剂、粘合剂、防腐剂、缓冲剂、润滑剂和/或油。可用于制造本发明药物组合物的药学上可接受的赋形剂包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质,例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素基物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇和羊毛脂。
本发明的组合物可以口服、肠胃外(包括皮下、肌内、静脉内和皮内)、通过吸入喷雾、局部、直肠、鼻腔、口腔、阴道或经由植入的储库而施用。在一些实施例中,提供的化合物或组合物可静脉内和/或口服施用。
如本文所用的,术语“肠胃外”包括皮下、静脉内、肌内、眼内、玻璃体内、关节内、滑膜内、胸骨内、鞘内、肝内、腹膜内、病灶内和颅内注射或输注技术。优选地,口服、皮下、腹膜内或静脉内施用组合物。本发明组合物的无菌可注射形式可以是水性悬浮液或油质悬浮液。这些悬浮液可以根据本领域已知的技术使用合适的分散剂或润湿剂和悬浮剂来配制。无菌可注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。可接受的媒介物和溶剂中可采用的是水、林格氏溶液和等渗氯化钠溶液。此外,常规地可以采用无菌不挥发性油作为溶剂或悬浮介质。
本发明的药学上可接受的组合物能以任何口服可接受的剂型(包括但不限于胶囊、片剂、水性悬浮液或溶液)口服施用。在口服使用片剂的情况下,常用的载体包括乳糖和玉米淀粉。典型地还添加润滑剂,例如硬脂酸镁。对于胶囊形式的口服施用,有用的稀释剂包括乳糖和干玉米淀粉。当需要口服使用水性悬浮液时,活性成分与乳化剂和悬浮剂组合。如果需要,也可以添加某些甜味剂、调味剂或着色剂。在一些实施例中,所提供的口服配制品被配制用于立即释放或持续/延迟释放。在一些实施例中,
组合物适用于口腔或舌下施用,包括片剂、锭剂和软锭剂。所提供的化合物也可以是微胶囊形式。
可替代地,本发明的药学上可接受的组合物能以直肠施用的栓剂形式施用。本发明的药学上可接受的组合物也可以局部施用,尤其是当治疗目标包括通过局部应用容易接近的区域或器官时,包括眼睛、皮肤或下肠道疾病。很容易为这些区域或器官中的每一个制备合适的局部配制品。
对于眼科使用,提供的药学上可接受的组合物可以配制成微粉化悬浮液或软膏如凡士林。
为了延长药物的作用,通常需要减缓药物从皮下注射或肌肉注射中的吸收。这可以通过使用水溶性差的结晶材料或无定形材料的液体悬浮液来实现。药物的吸收速度取决于其溶解速度,而溶解速度又取决于结晶大小和结晶形式。可替代地,肠胃外施用的药物形式的延迟吸收通过将药物溶解或悬浮在油媒介物中而实现。
尽管本文提供的药物组合物的描述主要针对适合施用于人的药物组合物,但本领域技术人员将理解这样的组合物通常适合施用于各种动物。对适合施用于人的药物组合物进行修饰以使该组合物适合施用于各种动物是熟知的,并且普通的兽医药理学家可以通过普通实验设计和/或进行这样的修饰。
本文提供的化合物典型地配制成剂量单位形式,例如单一单位剂型,以便于施用和剂量的均匀性。然而,应当理解,本发明组合物的总每日使用量将由主治医师在合理的医学判断范围内决定。任何特定受试者或生物体的特定治疗有效剂量水平将取决于多种因素,包括所治疗的疾病、以及障碍的严重程度;采用的特定活性成分的活性;采用的特定成分;受试者的年龄、体重、总体健康状况、性别和饮食;采用的特定活性成分的施用时间、施用途径和排泄速率;治疗的持续时间;与采用的特定活性成分组合或同时使用的药物;以及医学领域熟知的因素。
达到有效量所需的化合物的确切量将因受试者而异,这取决于例如受试者的物种、年龄和总体状况、副作用或障碍的严重程度、特定化合物的特性、施用模式等。所需剂量可以每天三次、每天两次、每天一次、每隔一天、每三天、每周、每两周、每三周或每四周递送。在某些实施例中,可以使用多次施用(例如,二、三、四、五、六、七、八、九、十、十一、十二、十三、十四或更多次施用)来递送所需剂量。
在某些实施例中,用于每天一次或多次向70kg成人施用的化合物的有效量可包含约0.0001mg至约3000mg、约0.0001mg至约2000mg、约0.0001mg至约1000mg、约0.001mg至约1000mg、约0.01mg至约1000mg、约0.1mg至约1000mg、约1mg至约1000mg、约1mg至约100mg、约10mg至约1000mg或约100mg至约1000mg的化合物/单位剂型。
在某些实施例中,具有式(I)的化合物的剂量水平可以足以每天、一天一次或多次递送从约0.001mg/kg至约100mg/kg、从约0.01mg/kg至约50mg/kg、优选从约0.1mg/kg至约40mg/kg、优选从约0.5mg/kg至约30mg/kg、从约0.01mg/kg至约10mg/kg、从约0.1mg/kg至约10mg/kg和更优选从约1mg/kg至约25mg/kg受试者体重,以获得所需治疗效果。
应当理解,如本文描述的剂量范围针对向成人施用提供的药物组合物提供了指导。向例如儿童或青少年施用的量可以由医学从业者或本领域技术人员确定,并且可以低于向成人施用的量或与向成人施用的量相同。
还应当理解,如本文描述的化合物或组合物可以与一种或多种另外的药剂组合施用。化合物或组合物可以与提高它们的生物利用度、降低和/或改变它们的代谢、抑制它们的排泄和/或改变它们在体内的分布的另外的药剂组合施用。还应当理解,所采用的疗法可以实现对相同障碍的所需效果,和/或可以实现不同效果。
化合物或组合物可以与一种或多种另外的药剂同时、在一种或多种另外的药剂之前或之后施用,可用作例如组合疗法。药剂包括治疗活性剂。药剂还包括预防活性剂。每种另外的药剂能以针对该药剂确定的剂量和/或时间表施用。另外的药剂也可以彼此一起和/或与本文描述的化合物或组合物一起以单一剂量施用或以不同剂量单独施用。在方案中采用的特定组合将考虑本发明化合物与另外药剂的相容性和/或待实现的所需治疗效果和/或预防效果。通常,预期组合中使用的另外的药剂以不超过它们单独使用时的水平使用。在一些实施例中,组合使用的水平将低于单独使用的水平。
示例性另外的药剂包括但不限于抗增殖剂、抗癌剂、抗糖尿病剂、抗炎剂、免疫抑制剂和镇痛剂。药剂包括小的有机分子,例如药物化合物(例如,美国联邦法规(CFR)中规定的美国食品和药物管理局批准的化合物)、肽、蛋白质、碳水化合物、单糖、寡糖、多糖、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白质、与蛋白质相连的小分子、糖蛋白、类固醇、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反义寡核苷酸、脂质、激素、维生素和细胞。
本发明还涵盖试剂盒(例如,药包)。本发明试剂盒可用于预防和/或治疗例如,如本文描述的增殖性疾病或非增殖性疾病。所提供的试剂盒可以包含本发明药物组合物或化合物和容器(例如,小瓶、安瓿、瓶、注射器和/或分配器包装,或其他合适的容器)。在一些实施例中,所提供的试剂盒可以任选地进一步包括第二容器,该容器包含用于稀释或悬浮本发明药物组合物或化合物的药物赋形剂。在一些实施例中,将容器和第二容器中提供的本发明药物组合物或化合物组合以形成一个单位剂型。
因此,在一方面,提供了试剂盒,其包括包含本文描述的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或其药物组合物的第一容器。在某些实施例中,本披露的试剂盒包括包含本文描述的化合物或其药学上可接受的盐或其药物组合物的第一容器。在某些实施例中,试剂盒可用于在受试者中预防和/或治疗本文描述的疾病、障碍或病症(例如,增殖性疾病或非增殖性疾病)。在某些实施例中,试剂盒进一步包括针对向受试者施用化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体或其药物组合物以预防和/或治疗增殖性疾病或非增殖性疾病的说明书。
使用方法
本文描述了可用于调节剪接的化合物。在一些实施例中,具有式(I)的化合物可用于通过增加或减少剪接位点的剪接来改变核酸(例如,前体RNA,例如前mRNA,或产生的mRNA)的量、结构或组成。在一些实施例中,增加或减少剪接导致调节产生的基因产物(例如,RNA或蛋白质)的水平或结构。在一些实施例中,具有式(I)的化合物可以调节剪接机制的组分,例如通过调节剪接机制的组分与另一实体(例如,核酸、蛋白质或其组合)的相互作用。如本文所指的剪接机制包含一种或多种剪接体组分。剪接体组分可以包含例如主要剪接体成员(U1、U2、U4、U5、U6 snRNP)或次要剪接体成员(U11、U12、U4atac、U6atac snRNP)及其辅助剪接因子中的一种或多种。
在另一方面,本披露的特征在于通过在靶标中包含剪接位点来修饰靶标(例如,前体RNA,例如前mRNA)的方法,其中该方法包括提供具有式(I)的化合物。在一些实施例中,在靶标(例如,前体RNA,例如前mRNA,或产生的mRNA)中包含剪接位点导致在靶标添加或删除一个或多个核酸(例如,新外显子,例如跳过的外显子)。在靶标添加或删除一个或多个核酸可能导致基因产物(例如,RNA,例如mRNA或蛋白质)水平的增加。
在另一方面,本披露的特征在于通过在靶标中排除剪接位点来修饰靶标(例如,前体RNA,例如前mRNA或产生的mRNA)的方法,其中该方法包括提供具有式(I)的化合物。在一些实施例中,在靶标(例如,前体RNA,例如前mRNA)中排除剪接位点导致从靶标删除或添加一个或多个核酸(例如,跳过的外显子,例如新外显子)。从靶标删除或添加一个或多个核酸可能导致基因产物(例如,RNA,例如mRNA或蛋白质)水平的减少。在其他实施例中,修饰靶标(例如,前体RNA,例如前mRNA或产生的mRNA)的方法包括例如与参比(例如,不存在具有式(I)的化合物,或在健康或患病的细胞或组织中)相比,抑制剪接位点的剪接或增强剪接位点的剪接(例如,多于约0.5%,例如1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或更多)。
本文描述的方法可用于调节例如包含特定序列(例如靶序列)的核酸的剪接。编码靶序列(例如,包含DNA或RNA(例如前mRNA)的靶序列)的示例性基因尤其包括ABCA4、ABCA9、ABCB1、ABCB5、ABCC9、ABCD1、ACADL、ACADM、ACADSB、ACSS2、ACTB、ACTG2、ADA、ADAL、ADAM10、ADAM15、ADAM22、ADAM32、ADAMTS12、ADAMTS13、ADAMTS20、ADAMTS6、ADAMTS9、ADAR、ADCY3、ADCY10、ADCY8、ADNP、ADRBK2、AFP、AGL、AGT、AHCTF1、AHR、AKAP10、AKAP3、AKNA、ALAS1、ALS2CL、ALB、ALDH3A2、ALG6、AMBRA1、ANK3、ANTXR2、ANXA10、ANXA11、ANGPTL3、AP2A2、AP4E1、APC、APOA1、APOB、APOC3、APOH、AR、ARID2、ARID3A、ARID3B、ARFGEF1、ARFGEF2、ARHGAP1、ARHGAP8、ARHGAP18、ARHGAP26、ARHGEF18、ARHGEF2、ARPC3、ARS2、ASH1L、ASH1L-IT1、ASNSD1、ASPM、ATAD5、ATF1、ATG4A、ATG16L2、ATM、ATN1、ATP11C、ATP6V1G3、ATP13A5、ATP7A、ATP7B、ATR、ATXN2、ATXN3、ATXN7、ATXN10、AXIN1、B2M、B4GALNT3、BBS4、BCL2、BCL2L1、BCL2样11(BIM)、BCL11B、BBOX1、BCS1L、BEAN1、BHLHE40、BMPR2、BMP2K、BPTF、BRAF、BRCA1、BRCA2、BRCC3、BRSK1、BRSK2、BTAF1、BTK、C2orf55、C4orf29、C6orf118、C9orf43、C9orf72、C10orf137、C11orf30、C11orf65、C11orf70、C11οrf87、C12orf51、C13orf1、C13orf15、C14orf10l、C14orf118、C15orf29、C15orf42、C15orf60、C16orf33、C16orf38、C16orf48、C18orf8、C19orf42、C1orf107、C1orf114、C1orf130、C1orf149、C1orf27、C1orf71、C1orf94、C1R、C20orf74、C21orf70、C3orf23、C4orf18、C5orf34、C8B、C8orf33、C9orf114、C9orf86、C9orf98、C3、CA11、CAB39、CACHD1、CACNA1A、CACNA1B、CACNA1C、CACNA2D1、CACNA1G、CACNA1H、CALCA、CALCOCO2、CAMK1D、CAMKK1、CAPN3、CAPN9、CAPSL、CARD11、CARKD、CASZ1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CENPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、CFTR、CFH、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、COL19A1、COL1A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6、COL5A2、COL6A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL29A1、COLQ、COMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL5、CXorf41、CXXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F3、CYP17、CYP19、CYP24A1、CYP27A1、DAB1、DAZ2、DCBLD1、DCC、DCTN3、DCUN1D4、DDA1、DDEF1、DDX1、DDX24、DDX4、DENND2D、DEPDC2、DES、DGAT2、DHFR、DHRS7、DHRS9、DHX8、DIP2A、DMD、DMTF1、DNAH3、DNAH8、DNAI1、DNAJA4、DNAJC13、DNAJC7、DNMT1、DNTTIP2、DOCK4、DOCK5、DOCK10、DOCK11、DOT1L、DPP3、DPP4、DPY19L2P2、DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1、EBF1、EBF3、ECM2、EDEM3、EFCAB3、EFCAB4B、EFNA4、EFTUD2、EGFR、EIF3A、ELA1、ELA2A、ELF2、ELF3、ELF4、EMCN、EMD、EML5、ENO3、ENPP3、EP300、EPAS1、EPB41L5、EPHA3、EPHA4、EPHB1、EPHB2、EPHB3、EPS15、ERBB4、ERCC1、ERCC8、ERGIC3、ERMN、ERMP1、ERN1、ERN2、ESR1、ESRRG、ETS2、ETV3、ETV4、ETV5、ETV6、EVC2、EWSR1、EXO1、EXOC4、F3、F11、F13A1、F5、F7、F8、FAH、FAM13A1、FAM13B1、FAM13C1、FAM134A、FAM161A、FAM176B、FAM184A、FAM19A1、FAM20A、FAM23B、FAM65C、FANCA、FANCC、FANCG、FANCM、FANK1、FAR2、FBN1、FBXO15、FBXO18、FBXO38、FCGBP、FECH、FEZ2、FGA、FGD6、FGFR2、FGFR1OP、FGFR1OP2、FGFR2、FGG、FGR、FIX、FKBP3、FLI1、FLJ35848、FLJ36070、FLNA、FN1、FNBP1L、FOLH1、FOSL1、FOSL2、FOXK1、FOXM1、FOXO1、FOXP4、FRAS1、FUT9、FXN、FZD3、FZD6、GAB1、GABPA、GALC、GALNT3、GAPDH、GART、GAS2L3、GATA3、GATAD2A、GBA、GBGT1、GCG、GCGR、GCK、GFI1、GFM1、GH1、GHR、GHV、GJA1、GLA、GLT8D1、GNA11、GNAQ、GNAS、GNB5、GOLGB1、GOLT1A、GOLT1B、GPATCH1、GPR158、GPR160、GPX4、GRAMD3、GRHL1、GRHL2、GRHPR、GRIA1、GRIA3、GRIA4、GRIN2B、GRM3、GRM4、GRN、GSDMB、GSTCD、GSTO2、GTF2I、GTPBP4、HADHA、HAND2、HBA2、HBB、HCK、HDAC3、HDAC5、HDX、HEPACAM2、HERC1、HES7、HEXA、HEXB、HHEX、HIPK3、HLA-DPB1、HLA-G、HLCS、HLTF、HMBS、HMGA1、HMGCL、HNF1A、HNF1B、HNF4A、HNF4G、HNRNPH1、HOXC10、HP1BP3、HPGD、HPRT1、HPRT2、HSF1、HSF4、HSF2BP、HSPA9、HSPG2、HTT、HXA、ICA1、IDH1、IDS、IFI44L、IKBKAP、IKZF1、IKZF3、IL1R2、IL5RA、IL7RA、IMMT、INPP5D、INSR、INTS3、INTU、IP04、IP08、IQGAP2、IRF2、IRF4、IRF8、IRX3、ISL1、ISL2、ITFG1、ITGA6、ITGAL、ITGB1、ITGB2、1TGB3、ITGB4、ITIH1、ITPR2、IWS1、JAK1、JAK2、JAG1、JMJD1C、JPH3、KALRN、KAT6A、KATNAL2、KCNN2、KCNT2、KDM2A、KIAA0256、KIAA0528、KIAA0564、KIAA0586、KIAA1033、KIAA1166、KIAA1219、KIAA1409、KIAA1622、KIAA1787、KIF3B、KIF15、KIF16B、KIF5A、KIF5B、KIF9、KIN、KIR2DL5B、KIR3DL2、KIR3DL3、KIT、KLF3、KLF5、KLF7、KLF10、KLF12、KLF16、KLHL20、KLK12、KLKB1、KMT2A、KMT2B、KPNA5、KRAS、KREMEN1、KRIT1、KRT5、KRTCAP2、KYNU、L1CAM、L3MBTL、L3MBTL2、LACE1、LAMA1、LAMA2、LAMA3、LAMB1、LARP7、LDLR、LEF1、LENG1、LGALS3、LGMN、LHCGR、LHX3、LHX6、LIMCH1、LIMK2、LIN28B、LIN54、LMBRD1、LMBRD2、LMLN、LMNA、LMO2、LMO7、LOC389634、LOC390110、LPA、LPCAT2、LPL、LRP4、LRPPRC、LRRK2、LRRC19、LRRC42、LRWD1、LUM、LVRN、LYN、LYST、MADD、MAGI1、MAGT1、MALT1、MAP2K1、MAP4K4、MAPK8IP3、MAPK9、MAPT、MARC1、MARCH5、MATN2、MBD3、MCF2L2、MCM6、MDGA2、MDM4、ASXL1、FUS、SPR54、MECOM、MEF2C、MEF2D、MEGF10、MEGF11、MEMO1、MET、MGA、MGAM、MGAT4A、MGAT5、MGC16169、MGC34774、MKKS、MIB1、MIER2、MITF、MKL2、MLANA、MLH1、MLL5、MLX、MME、MPDZ、MPI、MRAP2、MRPL11、MRPL39、MRPS28、MRPS35、MS4A13、MSH2、MSH3、MSMB、MST1R、MTDH、MTERF3、MTF1、MTF2、MTIF2、MTHFR、MUC2、MUT、MVK、MYB、MYBL2、MYC、MYCBP2、MYH2、MYRF、MYT1、MY019、MY03A、MY09B、MYOM2、MYOM3、NAG、NARG1、NARG2、NCOA1、NDC80、NDFIP2、NEB、NEDD4、NEK1、NEK5、ΝΕK11、NF1、NF2、NFATC2、NFE2L2、NFIA、NFIB、NFIX、NFKB1、NFKB2、NFKBIL2、NFRKB、NFYA、NFYB、NIPA2、NKAIN2、NKAP、NLRC3、NLRC5、NLRP3、NLRP7、NLRP8、NLRP13、NME1、NME1-NME2、NME2、NME7、NOL10、NOP561、NOS1、NOS2A、NOTCH1、NPAS4、NPM1、NR1D1、NR1H3、NR1H4、NR4A3、NR5A1、NRXN1、NSMAF、NSMCE2、NT5C、NT5C2、NT5C3、NUBP1、NUBPL、NUDT5、NUMA1、NUP88、NUP98、NUP160、NUPL1、OAT、OAZ1、OBFC2A、OBFC2B、OLIG2、OMA1、OPA1、OPN4、OPTN、OSBPL11、OSBPL8、OSGEPL1、OTC、OTX2、OVOL2、OXT、PA2G4、PADI4、PAH、PAN2、PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、PAX3、PAX8、PBGD、PBRM1、PBX2、PCBP4、PCCA、PCGF2、PCNX、PCOTH、PDCD4、PDE4D、PDE8B、PDE10A、PD1A3、PDH1、PDLIM5、PDXK、PDZRN3、PELI2、PDK4、PDS5A、PDS5B、PGK1、PGM2、PHACTR4、PHEX、PHKB、PHLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLAGL2、PLCB1、PLCB4、PLCG1、PLD1、PLEKHA5、PLEKHA7、PLEKHM1、PLKR、PLXNC1、PMFBP1、POLN、POLR3D、POMT2、POSTN、POU2AF1、POU2F2、POU2F3、PPARA、PPFIA2、PPP1R12A、PPP3CB、PPP4C、PPP4R1L、PPP4R2、PRAME、PRC1、PRDM1、PREX1、PREX2、PRIM1、PRIM2、PRKAR1A、PRKCA、PRKG1、PRMT7、PROC、PROCR、PROSC、PRODH、PROX1、PRPF40B、PRPF4B、PRRG2、PRUNE2、PSD3、PSEN1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PYGM、QRSL1、RAB11FIP2、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1、RLN3、RMND5B、RNF11、RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RPS6KA6、RREB1、RRM1、RRP1B、RSK2、RTEL1、RTF1、RUFY1、RUNX1、RUNX2、RXRA、RYR3、SAAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、SCN8A、SCNA、SCN11A、SCO1、SCYL3、SDC1、SDK1、SDK2、SEC24A、SEC24D、SEC31A、SEL1L、SENP3、SENP6、SENP7、SERPINA1、SETD3、SETD4、SETDB1、SEZ6、SFRS12、SGCE、SGOL2、SGPL1、SH2D1A、SH3BGRL2、SH3PXD2A、SH3PXD2B、SH3RF2、SH3TC2、SHOC2、SIPA1L2、SIPA1L3、SIVA1、SKAP1、SKIV2L2、SLC6A11、SLC6A13、SLC6A6、SLC7A2、SLC12A3、SLC13A1、SLC22A17、SLC25A14、SLC28A3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA1、SMARCA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、SNRK、SNRP70、SNX5、SNX6、SOD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1、SP2、SP3、SP110、SPAG9、SPATA13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、SPINK5、SPP2、SPTA1、SRF、SRM、SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAMBPLI、STARD6、STAT1、STAT3、STAT5A、STAT5B、STAT6、STK17B、STX3、STXBP1、SUCLG2、SULF2、SUPT6H、SUPT16H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、TAF2、TARDBP、TBC1D3G、TBC1D8B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBPL1、TBR1、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、TEAD3、TEAD4、TECTB、TEK、TERF1、TERF2、TET2、TFAP2A、TFAP2B、TFAP2C、TFAP4、TFDP1、TFRC、TG、TGM7、TGS1、THAP7、THAP12、THOC2、TIAL1、TIAM2、TIMM50、TLK2、TM4SF20、TM6SF1、TMEM27、TMEM77、TMEM156、TMEM194A、TMF1、TMPRSS6、TNFRSF10A、TNFRSF10B、TNFRSF8、TNK2、TNKS、TNKS2、TOM1L1、TOM1L2、TOP2B、TP53、TP53INP1、TP53BP2、TP53I3、TP63、TRAF3IP3、TRAPPC2、TRIM44、TRIM65、TRIML1、TRIML2、TRPM3、TRPM5、TRPM7、TRPS1、TSC1、TSC2、TSHB、TSPAN7、TTC17、TTF1、TTLL5、TTLL9、TTN、TTPAL、TTR、TUSC3、TXNDC10、UBE3A、UCK1、UGT1A1、UHRF1BP1、UNC45B、UNC5C、USH2A、USF2、USP1、USP6、USP18、USP38、USP39、UTP20、UTP15、UTP18、UTRN、UTX、UTY、UVRAG、UXT、VAPA、VEGFA、VPS29、VPS35、VPS39、VT11A、VT11B、VWA3B、WDFY2、WDR16、WDR17、WDR26、WDR44、WDR67、WDTC1、WRN、WRNIP1、WT1、WWC3、XBP1、XRN1、XRN2、XX-FW88277、YAP1、YARS、YBX1、YGM、YY1、ZBTB18、ZBTB20、ZC3HAV1、ZC3HC1、ZC3H7A、ZDHHC19、ZEB1、ZEB2、ZFPM1、ZFYVE1、ZFX、ZIC2、ZNF37A、ZNF91、ZNF114、ZNF155、ZNF169、ZNF205、ZNF236、ZNF317、ZNF320、ZNF326、ZNF335、ZNF365、ZNF367、ZNF407、ZNF468、ZNF506、ZNF511、ZNF511-PRAP1、ZNF519、ZNF521、ZNF592、ZNF618、ZNF763和ZWINT。
编码靶序列(例如,包含DNA或RNA(例如前mRNA)的靶序列)的另外的示例性基因包括A1CF、A4GALT、AAR2、ABAT、ABCA11P、ZNF721、ABCA5、ABHD10、ABHD13、ABHD2、ABHD6、AC000120.3、KRIT1、AC004076.1、ZNF772、AC004076.9、ZNF772、AC004223.3、RAD51D、AC004381.6、AC006486.1、ERF、AC007390.5、AC007780.1、PRKAR1A、AC007998.2、INO80C、AC009070.1、CMC2、AC009879.2、AC009879.3、ADHFE1、AC010487.3、ZNF816-ZNF321P、ZNF816、AC010328.3、AC010522.1、ZNF587B、AC010547.4、ZNF19、AC012313.3、ZNF497、AC012651.1、CAPN3、AC013489.1、DET1、AC016747.4、C2orf74、AC020907.6、FXYD3、AC021087.5、PDCD6、AHRR、AC022137.3、ZNF761、AC025283.3、NAA60、AC027644.4、RABGEF1、AC055811.2、FLCN、AC069368.3、ANKDD1A、AC073610.3、ARF3、AC074091.1、GPN1、AC079447.1、LIPT1、AC092587.1、AC079594.2、TRIM59、AC091060.1、C18orf21、AC092143.3、MC1R、AC093227.2、ZNF607、AC093512.2、ALDOA、AC098588.1、ANAPC10、AC107871.1、CALML4、AC114490.2、ZMYM6、AC138649.1、NIPA1、AC138894.1、CLN3、AC139768.1、AC242426.2、CHD1L、ACADM、ACAP3、ACKR2、RP11-141M3.5、KRBOX1、ACMSD、ACOT9、ACP5、ACPL2、ACSBG1、ACSF2、ACSF3、ACSL1、ACSL3、ACVR1、ADAL、ADAM29、ADAMTS10、ADAMTSL5、ADARB1、ADAT2、ADCK3、ADD3、ADGRG1、ADGRG2、ADH1B、ADIPOR1、ADNP、ADPRH、AGBL5、AGPAT1、AGPAT3、AGR2、AGTR1、AHDC1、AHI1、AHNAK、AIFM1、AIFM3、AIMP2、AK4、AKAP1、AKNAD1、CLCC1、AKR1A1、AKT1、AKT1S1、AKT2、AL139011.2、PEX19、AL157935.2、ST6GALNAC6、AL358113.1、TJP2、AL441992.2、KYAT1、AL449266.1、CLCC1、AL590556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALDH1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、ANAPC10、ANAPC11、ANAPC15、ANG、RNASE4、AL163636.2、ANGEL2、ANGPTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3、ANKS3、RP11-127I20.7、ANKS6、ANKZF1、ANPEP、ANXA11、ANXA2、ANXA8L2、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893.2、RAB30、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621.1、AP1G1、AP3M1、AP3M2、APBA2、APBB1、APLP2、APOA2、APOL1、APOL3、APTX、ARAP1、STARD10、ARF4、ARFIP1、ARFIP2、ARFRP1、ARHGAP11A、ARHGAP33、ARHGAP4、ARHGEF10、ARHGEF3、ARHGEF35、OR2A1-AS1、ARHGEF35、OR2A1-AS1、ARHGEF34P、ARID1B、ARHGEF35、OR2A20P、OR2A1-AS1、ARHGEF9、ARL1、ARL13B、ARL16、ARL6、ARMC6、ARMC8、ARMCX2、ARMCX5、RP4-769N13.6、ARMCX5-GPRASP2、BHLHB9、ARMCX5-GPRASP2、GPRASP1、ARMCX5-GPRASP2、GPRASP2、ARMCX6、ARNT2、ARPP19、ARRB2、ARSA、ART3、ASB3、GPR75-ASB3、ASCC2、ASNS、ASNS、AC079781.5、ASPSCR1、ASS1、ASUN、ATE1、ATF1、ATF7IP2、ATG13、ATG4D、ATG7、ATG9A、ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1、ATP6V1D、ATP7B、ATXN1、ATXN1L、IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B3GALNT1、B3GALT5、AF064860.1、B3GALT5、AF064860.5、B3GNT5、B4GALT3、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE、BCL2L14、BCL6、BCL9L、BCS1L、BDH1、BDKRB2、AL355102.2、BEST1、BEST3、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、BLOC1S1、RP11-644F5.10、BLOC1S6、AC090527.2、BLOC1S6、RP11-96O20.4、BLVRA、BMF、BOLA1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BRDT、BRINP3、BROX、BTBD10、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C11orf54、C11orf54、AP001273.2、C11orf57、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C1orf116、C1orf159、C1orf63、C2、C2、CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2orf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33、AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、C8orf44-SGK3、C8orf44、C8orf59、C9、DAB2、C9orf153、C9orf9、CA5BP1、CA5B、CABYR、CALCA、CALCOCO1、CALCOCO2、CALM1、CALM3、CALML4、RP11-315D16.2、CALN1、CALU、CANT1、CANX、CAP1、CAPN12、CAPS2、CARD8、CARHSP1、CARNS1、CASC1、CASP3、CASP7、CBFA2T2、CBS、CBY1、CCBL1、CCBL2、RBMXL1、CCDC12、CCDC126、CCDC14、CCDC149、CCDC150、CCDC169-SOHLH2、CCDC169、CCDC171、CCDC37、CCDC41、CCDC57、CCDC63、CCDC7、CCDC74B、CCDC77、CCDC82、CCDC90B、CCDC91、CCDC92、CCNE1、CCHCR1、CCL28、CCNB1IP1、CCNC、CCND3、CCNG1、CCP110、CCR9、CCT7、CCT8、CD151、CD1D、CD200、CD22、CD226、CD276、CD36、CD59、CDC26、CDC42、CDC42SE1、CDC42SE2、CDHR3、CDK10、CDK16、CDK4、CDKAL1、CDKL3、CTD-2410N18.4、CDKN1A、CDKN2A、CDNF、CEBPZOS、CELF1、CEMIP、CENPK、CEP170B、CEP250、CEP57、CEP57L1、CEP63、CERS4、CFL1、CFL2、CFLAR、CGNL1、CHCHD7、CHD1L、CHD8、CHFR、ZNF605、CHIA、CHID1、CHL1、CHM、CHMP1A、CHMP3、RNF103-CHMP3、CHRNA2、CIDEC、CIRBP、CITED1、CKLF-CMTM1、CMTM1、CKMT1B、CLDN12、CTB-13L3.1、CLDND1、AC021660.3、CLDND1、CPOX、CLHC1、CLIP1、CLUL1、CMC4、MTCP1、CNDP2、CNFN、CNOT1、CNOT6、CNOT7、CNOT8、CNR1、CNR2、CNTFR、CNTRL、COA1、COASY、COCH、COL8A1、COLCA1、COLEC11、COMMD3-BMI1、BMI1、COPS5、COPS7B、COQ8A、CORO6、COTL1、COX14、RP4-605O3.4、COX7A2、COX7A2L、COX7B2、CPA4、CPA5、CPEB1、CPNE1、AL109827.1、RBM12、CPNE1、RP1-309K20.6、RBM12、CPNE3、CPSF3L、CPT1C、CREB3L2、CREM、CRP、CRYZ、CS、AC073896.1、CS、RP11-977G19.10、CSAD、CSDE1、CSF2RA、CSGALNACT1、CSK、CSNK2A1、CSRNP2、CT45A4、CT45A4、CT45A5、CT45A6、CTBP2、CTCFL、CTD-2116N17.1、KIAA0101、CTD-2349B8.1、SYT17、CTD-2528L19.4、ZNF607、CTD-2619J13.8、ZNF497、CTNNA1、CTNNBIP1、CTNND1、CTPS2、CTSB、CTSL、CTTN、CUL2、CUL9、CWC15、CXorf40B、CYB561A3、CYBC1、CYLD、CYP11A1、CYP2R1、CYP4B1、CYP4F22、DAG1、DAGLB、KDELR2、DARS、DBNL、DCAF11、DCAF8、PEX19、DCLRE1C、DCTD、DCTN1、DCTN4、DCUN1D2、DDR1、DDX11、DDX19B、AC012184.2、DDX19B、RP11-529K1.3、DDX25、DDX39B、ATP6V1G2-DDX39B、SNORD84、DDX42、DDX60L、DEDD、DEDD2、DEFA1、DEFA1B、DEFA1B、DEFA3、DENND1C、DENND2A、DENND4B、DET1、DGKA、DGKZ、DGLUCY、DHRS4L2、DHRS9、DHX40、DIABLO、AC048338.1、DIAPH1、DICER1、DKKL1、DLG1、DLG3、DLST、DMC1、DMKN、DMTF1、DMTN、DNAJC14、DNAJC19、DNAL1、DNASE1L1、DNMT3A、DOC2A、DOCK8、DOK1、DOPEY1、DPAGT1、DPP8、DRAM2、DRD2、DROSHA、DSN1、DTNA、DTX2、DTX3、DUOX1、DUOXA1、DUS2、DUSP10、DUSP13、DUSP18、DUSP22、DYDC1、DYDC2、DYNLL1、DYNLT1、DYRK1A、DYRK2、DYRK4、RP11-500M8.7、DZIP1L、E2F6、ECHDC1、ECSIT、ECT2、EDC3、EDEM1、EDEM2、MMP24-AS1、RP4-614O4.11、EEF1AKNMT、EEF1D、EFEMP1、EFHC1、EGFL7、EHF、EI24、EIF1AD、EIF2B5、EIF4G1、EIF2B5、POLR2H、EIF3E、EIF3K、EIF4E3、EIF4G1、ELF1、ELMO2、ELMOD1、AP000889.3、ELMOD3、ELOC、ELOF1、ELOVL1、ELOVL7、ELP1、ELP6、EML3、EMP3、ENC1、ENDOV、ENO1、ENPP5、ENTHD2、ENTPD6、EP400NL、EPB41L1、EPDR1、NME8、EPHX1、EPM2A、EPN1、EPN2、EPN3、EPS8L2、ERBB3、ERC1、ERCC1、ERG、ERI2、ERI2、DCUN1D3、ERLIN2、ERMARD、ERRFI1、ESR2、RP11-544I20.2、ESRRA、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7、EVA1A、EVC2、EVX1、EXD2、EXO5、EXOC1、EXOC2、FAAP24、FABP6、FADS1、FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM115C、FAM115C、FAM115D、FAM120B、FAM133B、FAM135A、FAM153A、FAM153B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、FAM192A、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227B、FAM234A、AC004754.1、FAM3C、FAM45A、FAM49B、FAM60A、FAM63A、FAM81A、FAM86B1、FAM86B2、FANCI、FANK1、FAR2、FAXC、FAXDC2、FBF1、FBH1、FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBXW9、FCHO1、FCHSD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、FHL2、FIBCD1、FIGNL1、FIGNL1、DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1、LUC7L2、FMC1-LUC7L2、FNDC3B、FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FOXO1、FOXP4、AC097634.4、FOXRED1、FPR1、FPR2、FRG1B、FRS2、FTO、FTSJ1、FUK、FUT10、FUT3、FUT6、FXYD3、FZD3、G2E3、GAA、GABARAPL1、GABPB1、GABRA5、GAL3ST1、GALE、GALNT11、GALNT14、GALNT6、GAPVD1、GARNL3、GAS2L3、GAS8、GATA1、GATA2、GATA4、GBA、GCNT1、GDPD2、GDPD5、GEMIN7、MARK4、GEMIN8、GGA3、GGACT、AL356966.1、GGPS1、GHRL、GID8、GIGYF2、GIMAP8、GIPC1、GJB1、GJB6、GLB1L、GLI1、GLT8D1、GMFG、GMPR2、GNAI2、GNAQ、GNB1、GNB2、GNE、GNG2、GNGT2、GNPDA1、GNPDA2、GOLGA3、CHFR、GOLGA4、GOLPH3L、GOLT1B、GPBP1L1、GPER1、GPR116、GPR141、EPDR1、GPR155、GPR161、GPR56、GPR63、GPR75-ASB3、ASB3、GPR85、GPSM2、GRAMD1B、GRB10、GRB7、GREM2、GRIA2、GSDMB、GSE1、GSN、GSTA4、GSTZ1、GTDC1、GTF2H1、GTF2H4、VARS2、GTF3C2、GUCY1A3、GUCY1B3、GUK1、GULP1、GYPC、GYS1、GZF1、HAGH、HAO2、HAPLN3、HAVCR1、HAX1、HBG2、AC104389.4、HBG2、AC104389.4、HBE1、HBG2、AC104389.4、HBE1、OR51B5、HBG2、HBE1、AC104389.28、HBS1L、HCFC1R1、HCK、HDAC2、HDAC6、HDAC7、HDLBP、HEATR4、HECTD4、HEXIM2、HHAT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV、HKR1、HLF、HMBOX1、HMGA1、HMGB3、HMGCR、HMGN4、HMOX2、HNRNPC、HNRNPD、HNRNPH1、HNRNPH3、HNRNPR、HOMER3、HOPX、HOXA3、HOXB3、HOXB3、HOXB4、HOXC4、HOXD3、HOXD3、HOXD4、HPCAL1、HPS4、HPS5、HRH1、HS3ST3A1、HSH2D、HSP90AA1、HSPD1、HTT、HUWE1、HYOU1、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS、IFI27、IFI44、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IKBKAP、IKBKB、IL11、IL18BP、IL18RAP、IL1RAP、IL1RL1、IL18R1、IL1RN、IL32、IL4I1、NUP62、AC011452.1、IL4I1、NUP62、CTC-326K19.6、IL6ST、ILVBL、IMMP1L、IMPDH1、INCA1、ING1、INIP、INPP1、INPP5J、INPP5K、INSIG2、INTS11、INTS12、INTS14、IP6K2、IP6K3、IPO11、LRRC70、IQCE、IQGAP3、IRAK4、IRF3、IRF5、IRF6、ISG20、IST1、ISYNA1、ITFG2、ITGB1BP1、ITGB7、ITIH4、RP5-966M1.6、ITPRIPL1、JADE1、JAK2、JARID2、JDP2、KANK1、KANK1、RP11-31F19.1、KANK2、KANSL1L、KAT6A、KBTBD2、KBTBD3、KCNAB2、KCNE3、KCNG1、KCNJ16、KCNJ9、KCNMB2、AC117457.1、LINC01014、KCTD20、KCTD7、RABGEF1、KDM1B、KDM4A、AL451062.3、KHNYN、KIAA0040、KIAA0125、KIAA0196、KIAA0226L、PPP1R2P4、KIAA0391、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753、KIAA0895、KIAA0895L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KIF12、KIF14、KIF27、KIF9、KIFC3、KIN、KIRREL1、KITLG、KLC1、APOPT1、AL139300.1、KLC4、KLHDC4、KLHDC8A、KLHL13、KLHL18、KLHL2、KLHL24、KLHL7、KLK11、KLK2、KLK5、KLK6、KLK7、KNOP1、KRBA2、AC135178.2、KRBA2、RP11-849F2.7、KRIT1、KRT15、KRT8、KTN1、KXD1、KYAT3、RBMXL1、KYNU、L3MBTL1、LACC1、LARGE、LARP4、LARP7、LAT2、LBHD1、LCA5、LCA5L、LCTL、LEPROTL1、LGALS8、LGALS9C、LGMN、LHFPL2、LIG4、LIMCH1、LIMK2、LIMS2、LINC00921、ZNF263、LIPF、LLGL2、LMAN2L、LMCD1、LMF1、RP11-161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6、LPHN1、LPIN2、LPIN3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、C8orf82、LRRC39、LRRC42、LRRC48、LRRC4C、LRRC8A、LRRC8B、LRRD1、LRTOMT、LRTOMT、AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L2、LUC7L3、LUZP1、LYG1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、MACC1、MAD1L1、MAD1L1、AC069288.1、MAEA、MAFF、MAFG、MAFK、MAGEA12、CSAG4、MAGEA2、MAGEA2B、MAGEA4、MAGEB1、MAGOHB、MAN2A2、MANBAL、MAOB、MAP2K3、MAP3K7CL、MAP3K8、MAP7、MAP9、MAPK6、MAPK7、MAPK8、MAPKAP1、10-Mar、7-Mar、8-Mar、MARK2、MASP1、MATK、MATR3、MATR3、SNHG4、MB、MBD5、MBNL1、MBOAT7、MCC、MCFD2、MCM9、MCOLN3、MCRS1、MDC1、MDGA2、MDH2、MDM2、ME1、MEAK7、MECR、MED4、MEF2A、MEF2B、BORCS8-MEF2B、MEF2BNB-MEF2B、MEF2B、MEF2BNB、MEF2C、MEF2D、MEGF10、MEI1、MEIS2、MELK、MET、METTL13、METTL23、MFF、MFN2、MFSD2A、MGST3、MIB2、MICAL1、MICAL3、MICOS10、NBL1、MICOS10-NBL1、MID1、MINA、MINOS1-NBL1、MINOS1、MIOS、MIPOL1、MIS12、MKLN1、MKNK1、MKNK1、MOB3C、MLF2、MLH1、MMP17、MOBP、MOCS1、MOGS、MOK、MORF4L1、MPC1、MPC2、MPG、MPI、MPP1、MPP2、MPPE1、MPST、MRAS、MRO、MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33、BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL55、MRRF、MRTFA、MRTFB、MRVI1、MS4A1、MS4A15、MS4A3、MS4A6E、MS4A7、MS4A14、MSANTD3、MSANTD4、MSH5、MSH5-SAPCD1、MSL2、MSRB3、MSS51、MTCP1、CMC4、MTERF、MTERF1、MTERF3、MTERFD2、MTERFD3、MTF2、MTG2、MTHFD2、MTHFD2L、MTIF2、MTIF3、MTMR10、MTRF1、MTRR、MTUS2、MUTYH、MVK、MX1、MX2、MYH10、MYL12A、MYB、MYD88、MYL5、MYLIP、MYNN、MYO15A、MYO1B、MYOM2、MZF1、N4BP2L2、NAA60、NAB1、NAE1、NAGK、NAP1L1、NAP1L4、NAPG、NARFL、NARG2、NAT1、NAT10、NBPF11、WI2-3658N16.1、NBPF12、NBPF15、NBPF24、NBPF6、NBPF9、NBR1、NCAPG2、NCBP2、NCEH1、NCOA1、NCOA4、NDC1、NDRG1、NDRG2、NDRG4、NDST1、NDUFAF6、NDUFB2、NDUFC1、NDUFS1、NDUFS8、NDUFV1、NEDD1、NEIL1、NEIL2、NEK10、NEK11、NEK6、NEK9、NELFA、NEU4、NFAT5、NFE2、NFE2L2、AC019080.1、NFRKB、NFYA、NFYC、NIF3L1、NIPA2、NKIRAS1、NKX2-1、NLRC3、NME1、NME1-NME2、NME2、NME1-NME2、NME2、NME4、NME6、NME9、NOD1、NOL10、NOL8、NONO、NPAS1、NPIPA8、RP11-1212A22.1、NPIPB3、NPIPB4、NPIPB9、NPL、NPM1、NPPA、NQO2、NR1H3、NR2C2、NR2F2、NR4A1、NRDC、NREP、NRF1、NRG4、NRIP1、NSD2、NSDHL、NSG1、NSMCE2、NSRP1、NT5C2、NTF4、NTMT1、NTNG2、NUBP2、NUCB2、NUDT1、NUDT2、NUDT4、NUF2、NUMBL、NUP50、NUP54、NUP85、NVL、NXF1、NXPE1、NXPE3、OARD1、OAT、OAZ2、OCIAD1、OCLN、ODF2、OGDHL、OGFOD2、AC026362.1、OGFOD2、RP11-197N18.2、OLA1、OPRL1、OPTN、OR2H1、ORAI2、ORMDL1、ORMDL2、ORMDL3、OSBPL2、OSBPL3、OSBPL5、OSBPL9、OSER1、OSGIN1、OSR2、P2RX4、P2RY2、P2RY6、P4HA2、PABPC1、PACRGL、PACSIN3、PADI1、PAIP2、PAK1、PAK3、PAK4、PAK7、PALB2、PANK2、PAQR6、PARP11、PARVG、PASK、PAX6、PBRM1、PBXIP1、PCBP3、PCBP4、AC115284.1、PCBP4、RP11-155D18.14、RP11-155D18.12、PCGF3、PCGF5、PCNP、PCSK9、PDCD10、PDCD6、AHRR、PDDC1、PDGFRB、PDIA6、PDIK1L、PDLIM7、PDP1、PDPK1、PDPN、PDZD11、PEA15、PEX2、PEX5、PEX5L、PFKM、PFN4、PGAP2、PGAP2、AC090587.2、PGAP3、PGM3、PGPEP1、PHB、PHC2、PHF20、PHF21A、PHF23、PHKB、PHLDB1、PHOSPHO1、PHOSPHO2、KLHL23、PI4KB、PIAS2、PICALM、PIF1、PIGN、PIGO、PIGT、PIK3CD、PILRB、STAG3L5P-PVRIG2P-PILRB、PIP5K1B、PIR、PISD、PIWIL4、FUT4、PKD2、PKIA、PKIG、PKM、PKN2、PLA1A、PLA2G2A、PLA2G5、PLA2G7、PLAC8、PLAGL1、PLD1、PLD3、PLEKHA1、PLEKHA2、PLEKHA6、PLEKHG5、PLIN1、PLS1、PLS3、PLSCR1、PLSCR2、PLSCR4、PLXNB1、PLXNB2、PMP22、PMS1、PNISR、PNKP、AKT1S1、PNMT、PNPLA4、PNPLA8、PNPO、PNRC1、POC1B、POFUT1、POLB、POLD1、POLH、POLI、POLL、POLR1B、POM121、POM121C、AC006014.7、POM121C、AC211429.1、POMC、POMT1、POP1、PORCN、POU5F1、PSORS1C3、PPARD、PPARG、PPHLN1、PPIL3、PPIL4、PPM1A、PPM1B、AC013717.1、PPP1CB、PPP1R11、PPP1R13L、PPP1R26、PPP1R9A、PPP2R2B、PPP3CA、PPP6R1、PPP6R3、PPT2、PPT2-EGFL8、EGFL8、PPWD1、PRDM2、PRDM8、PRELID3A、PREPL、PRICKLE1、PRKAG1、PRMT2、PRMT5、PRMT7、PROM1、PRPS1、PRPSAP2、PRR14L、PRR15L、PRR5、PRR5-ARHGAP8、PRR5L、PRR7、PRRC2B、PRRT4、PRSS50、PRSS45、PRSS44、PRUNE、PRUNE1、PSEN1、PSMA2、PSMF1、PSORS1C1、PSPH、PSRC1、PTBP3、PTHLH、PTK2、PTPDC1、PTPRM、PUF60、PUM2、PUS1、PUS10、PXN、PXYLP1、PYCR1、QRICH1、R3HCC1L、R3HDM2、RAB17、RAB23、RAB3A、RAB3D、TMEM205、RAB4B-EGLN2、EGLN2、AC008537.1、RAB5B、RAB7L1、RABL2A、RABL2B、RABL5、RACGAP1、RAD17、RAD51L3-RFFL、RAD51D、RAD52、RAE1、RAI14、RAI2、RALBP1、RAN、RANGAP1、RAP1A、RAP1B、RAP1GAP、RAPGEF4、RAPGEFL1、RASGRP2、RASSF1、RBCK1、RBM12B、RBM14、RBM4、RBM14-RBM4、RBM23、RBM4、RBM14-RBM4、RBM47、RBM7、AP002373.1、RBM7、RP11-212D19.4、RBMS2、RBMY1E、RBPJ、RBPMS、RBSN、RCBTB2、RCC1、RCC1、SNHG3、RCCD1、RECQL、RELL2、REPIN1、AC073111.3、REPIN1、ZNF775、RER1、RERE、RFWD3、RFX3、RGL2、RGMB、RGS11、RGS3、RGS5、AL592435.1、RHBDD1、RHNO1、TULP3、RHOC、AL603832.3、RHOC、RP11-426L16.10、RHOH、RIC8B、RIMKLB、RIN1、RIPK2、RIT1、RLIM、RNASE4、ANG、AL163636.6、RNASEK、RNASEK-C17orf49、RNF111、RNF123、RNF13、RNF14、RNF185、RNF216、RNF24、RNF32、RNF34、RNF38、RNF4、RNF44、RNH1、RNMT、RNPS1、RO60、ROPN1、ROPN1B、ROR2、RP1-102H19.8、C6orf163、RP1-283E3.8、CDK11A、RP11-120M18.2、PRKAR1A、RP11-133K1.2、PAK6、RP11-164J13.1、CAPN3、RP11-21J18.1、ANKRD12、RP11-322E11.6、INO80C、RP11-337C18.10、CHD1L、RP11-432B6.3、TRIM59、RP11-468E2.4、IRF9、RP11-484M3.5、UPK1B、RP11-517H2.6、CCR6、RP11-613M10.9、SLC25A51、RP11-659G9.3、RAB30、RP11-691N7.6、CTNND1、RP11-849H4.2、RP11-896J10.3、NKX2-1、RP11-96O20.4、SQRDL、RP11-986E7.7、SERPINA3、RP4-769N13.6、GPRASP1、RP4-769N13.6、GPRASP2、RP4-798P15.3、SEC16B、RP5-1021I20.4、ZNF410、RP6-109B7.3、FLJ27365、RPE、RPH3AL、RPL15、RPL17、RPL17-C18orf32、RPL17、RPL23A、RPL36、HSD11B1L、RPP38、RPS20、RPS27A、RPS3A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSRC2、RSRP1、RUBCNL、RUNX1T1、RUVBL2、RWDD1、RWDD4、S100A13、AL162258.1、S100A13、RP1-178F15.5、S100A16、S100A4、S100A3、S100A6、S100PBP、SAA1、SACM1L、SAMD4B、SAR1A、SARAF、SARNP、RP11-762I7.5、SCAMP5、SCAP、SCAPER、SCFD1、SCGB3A2、SCIN、SCML1、SCNN1D、SCO2、SCOC、SCRN1、SDC2、SDC4、SEC13、SEC14L1、SEC14L2、SEC22C、SEC23B、SEC24C、SEC61G、SEMA4A、SEMA4C、SEMA4D、SEMA6C、SENP7、SEPP1、11-Sep、2-Sep、SERGEF、AC055860.1、SERP1、SERPINA1、SERPINA5、SERPINB6、SERPING1、SERPINH1、SERTAD3、SETD5、SFMBT1、AC096887.1、SFTPA1、SFTPA2、SFXN2、SGCD、SGCE、SGK3、SGK3、C8orf44、SH2B1、SH2D6、SH3BP1、Z83844.3、SH3BP2、SH3BP5、SH3D19、SH3YL1、SHC1、SHISA5、SHMT1、SHMT2、SHOC2、SHROOM1、SIGLEC5、SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC104109.3、SLAIN1、SLC10A3、SLC12A9、SLC14A1、SLC16A6、SLC1A2、SLC1A6、SLC20A2、SLC25A18、SLC25A19、SLC25A22、SLC25A25、SLC25A29、SLC25A30、SLC25A32、SLC25A39、SLC25A44、SLC25A45、SLC25A53、SLC26A11、SLC26A4、SLC28A1、SLC29A1、SLC2A14、SLC2A5、SLC2A8、SLC35B2、SLC35B3、SLC35C2、SLC37A1、SLC38A1、SLC38A11、SLC39A13、SLC39A14、SLC41A3、SLC44A3、SLC4A7、SLC4A8、SLC5A10、SLC5A11、SLC6A1、SLC6A12、SLC6A9、SLC7A2、SLC7A6、SLC7A7、SLCO1A2、SLCO1C1、SLCO2B1、SLFN11、SLFN12、SLFNL1、SLMO1、SLTM、SLU7、SMAD2、SMAP2、SMARCA2、SMARCE1、AC073508.2、SMARCE1、KRT222、SMC6、SMG7、SMIM22、SMOX、SMPDL3A、SMTN、SMU1、SMUG1、SNAP25、SNCA、SNRK、SNRPC、SNRPD1、SNRPD2、SNRPN、SNRPN、SNURF、SNUPN、SNX11、SNX16、SNX17、SOAT1、SOHLH2、CCDC169-SOHLH2、CCDC169、SORBS1、SORBS2、SOX5、SP2、SPART、SPATA20、SPATA21、SPATS2、SPATS2L、SPDYE2、SPECC1、SPECC1L、SPECC1L-ADORA2A、SPECC1L-ADORA2A、ADORA2A、SPEG、SPG20、SPG21、SPIDR、SPIN1、SPOCD1、SPOP、SPRR2A、SPRR2B、SPRR2E、SPRR2B、SPRR2F、SPRR2D、SPRR3、SPRY1、SPRY4、SPTBN2、SRC、SRGAP1、SRP68、SRSF11、SSX1、SSX2IP、ST3GAL4、ST3GAL6、ST5、ST6GALNAC6、ST7L、STAC3、STAG1、STAG2、STAMBP、STAMBPL1、STARD3NL、STAT6、STAU1、STAU2、AC022826.2、STAU2、RP11-463D19.2、STEAP2、STEAP3、STIL、STK25、STK33、STK38L、STK40、STMN1、STON1、STON1-GTF2A1L、STRAP、STRBP、STRC、AC011330.5、STRC、CATSPER2、STRC、CATSPER2、AC011330.5、STRC、STRCP1、STT3A、STX16-NPEPL1、NPEPL1、STX5、STX6、STX8、STXBP6、STYK1、SULT1A1、SULT1A2、SUMF2、SUN1、SUN2、SUN2、DNAL4、SUOX、SUPT6H、SUV39H2、SV2B、SYBU、SYNCRIP、SYNJ2、SYT1、SYTL4、TAB2、TACC1、TADA2B、TAF1C、TAF6、AC073842.2、TAF6、RP11-506M12.1、TAF9、TAGLN、TANK、TAPSAR1、PSMB9、TAPT1、TATDN1、TAZ、TBC1D1、TBC1D12、HELLS、TBC1D15、TBC1D3H、TBC1D3G、TBC1D5、TBC1D5、SATB1、TBCA、TBCEL、TBCEL、AP000646.1、TBL1XR1、TBP、TBX5、TBXAS1、TCAF1、TCEA2、TCEAL4、TCEAL8、TCEAL9、TCEANC、TCEB1、TCF19、TCF25、TCF4、TCP1、TCP10L、AP000275.65、TCP11、TCP11L2、TCTN1、TDG、TDP1、TDRD7、TEAD2、TECR、TENC1、TENT4A、TEX264、TEX30、TEX37、TFDP1、TFDP2、TFEB、TFG、TFP1、TF、TFPI、TGIF1、THAP6、THBS3、THOC5、THRAP3、THUMPD3、TIAL1、TIMM9、TIMP1、TIRAP、TJAP1、TJP2、TK2、TLDC1、TLE3、TLE6、TLN1、TLR10、TM9SF1、TMBIM1、TMBIM4、TMBIM6、TMC6、TMCC1、TMCO4、TMEM126A、TMEM139、TMEM150B、TMEM155、TMEM161B、TMEM164、TMEM168、TMEM169、TMEM175、TMEM176B、TMEM182、TMEM199、CTB-96E2.3、TMEM216、TMEM218、TMEM230、TMEM263、TMEM45A、TMEM45B、TMEM62、TMEM63B、TMEM66、TMEM68、TMEM98、TMEM9B、TMPRSS11D、TMPRSS5、TMSB15B、TMTC4、TMUB2、TMX2-CTNND1、RP11-691N7.6、CTNND1、TNFAIP2、TNFAIP8L2、SCNM1、TNFRSF10C、TNFRSF19、TNFRSF8、TNFSF12-TNFSF13、TNFSF12、TNFSF13、TNFSF12-TNFSF13、TNFSF13、TNIP1、TNK2、TNNT1、TNRC18、TNS3、TOB2、TOM1L1、TOP1MT、TOP3B、TOX2、TP53、RP11-199F11.2、TP53I11、TP53INP2、TPCN1、TPM3P9、AC022137.3、TPT1、TRA2B、TRAF2、TRAF3、TRAPPC12、TRAPPC3、TREH、TREX1、TREX2、TRIB2、TRIM3、TRIM36、TRIM39、TRIM46、TRIM6、TRIM6-TRIM34、TRIM6-TRIM34、TRIM34、TRIM66、TRIM73、TRIT1、TRMT10B、TRMT2B、TRMT2B-AS1、TRNT1、TRO、TROVE2、TRPS1、TRPT1、TSC2、TSGA10、TSPAN14、TSPAN3、TSPAN4、TSPAN5、TSPAN6、TSPAN9、TSPO、TTC12、TTC23、TTC3、TTC39A、TTC39C、TTLL1、TTLL7、TTPAL、TUBD1、TWNK、TXNL4A、TXNL4B、TXNRD1、TYK2、U2AF1、UBA2、UBA52、UBAP2、UBE2D2、UBE2D3、UBE2E3、UBE2I、UBE2J2、UBE3A、UBL7、UBXN11、UBXN7、UGDH、UGGT1、UGP2、UMAD1、AC007161.3、UNC45A、UQCC1、URGCP-MRPS24、URGCP、USMG5、USP16、USP21、USP28、USP3、USP33、USP35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2、VAV3、VDAC1、VDAC2、VDR、VEZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS37C、VPS8、VPS9D1、VRK2、VWA1、VWA5A、WARS、WASF1、WASHC5、WBP5、WDHD1、WDPCP、WDR37、WDR53、WDR6、WDR72、WDR74、WDR81、WDR86、WDYHV1、WFDC3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE1B、XKR9、XPNPEP1、XRCC3、XRN2、XXYLT1、YIF1A、YIF1B、YIPF1、YIPF5、YPEL5、YWHAB、YWHAZ、YY1AP1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25、ZBTB33、ZBTB34、ZBTB38、ZBTB43、ZBTB49、ZBTB7B、ZBTB7C、ZBTB8OS、ZC3H11A、ZBED6、ZC3H13、ZCCHC17、ZCCHC7、ZDHHC11、ZDHHC13、ZEB2、ZFAND5、ZFAND6、ZFP1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE20、ZFYVE27、ZHX2、AC016405.1、ZHX3、ZIK1、ZIM2、PEG3、ZKSCAN1、ZKSCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZMIZ2、ZMYM6、ZMYND11、ZNF10、AC026786.1、ZNF133、ZNF146、ZNF16、ZNF177、ZNF18、ZNF200、ZNF202、ZNF211、ZNF219、ZNF226、ZNF227、ZNF23、AC010547.4、ZNF23、AC010547.9、ZNF239、ZNF248、ZNF25、ZNF253、ZNF254、ZNF254、AC092279.1、ZNF263、ZNF274、ZNF275、ZNF28、ZNF468、ZNF283、ZNF287、ZNF3、ZNF320、ZNF322、ZNF324B、ZNF331、ZNF334、ZNF34、ZNF350、ZNF385A、ZNF395、FBXO16、ZNF415、ZNF418、ZNF43、ZNF433-AS1、AC008770.4、ZNF438、ZNF444、ZNF445、ZNF467、ZNF480、ZNF493、ZNF493、CTD-2561J22.3、ZNF502、ZNF507、ZNF512、AC074091.1、ZNF512、RP11-158I13.2、ZNF512B、ZNF512B、SAMD10、ZNF521、ZNF532、ZNF544、AC020915.5、ZNF544、CTD-3138B18.4、ZNF559、ZNF177、ZNF562、ZNF567、ZNF569、ZNF570、ZNF571-AS1、ZNF540、ZNF577、ZNF580、ZNF581、ZNF580、ZNF581、CCDC106、ZNF600、ZNF611、ZNF613、ZNF615、ZNF619、ZNF620、ZNF639、ZNF652、ZNF665、ZNF667、ZNF668、ZNF671、ZNF682、ZNF687、ZNF691、ZNF696、ZNF701、ZNF706、ZNF707、ZNF714、ZNF717、ZNF718、ZNF720、ZNF721、ZNF730、ZNF763、ZNF780B、AC005614.5、ZNF782、ZNF786、ZNF79、ZNF791、ZNF81、ZNF83、ZNF837、ZNF839、ZNF84、ZNF845、ZNF846、ZNF865、ZNF91、ZNF92、ZNHIT3、ZSCAN21、ZSCAN25、ZSCAN30和ZSCAN32。
在一些实施例中,编码靶序列的基因包含HTT基因。
可由本文描述的具有式(I)的化合物调节的示例性基因还可以包括,尤其是AC005258.1、AC005943.1、AC007849.1、AC008770.2、AC010487.3、AC011477.4、AC012651.1、AC012531.3、AC034102.2、AC073896.4、AC104472.3、AL109811.3、AL133342.1、AL137782.1、AL157871.5、AF241726.2、AL355336.1、AL358113.1、AL360181.3、AL445423.2、AL691482.3、AP001267.5、RF01169和RF02271。
本文描述的化合物可进一步用于调节包含特定剪接位点序列的序列,例如RNA序列(例如前mRNA序列)。在一些实施例中,剪接位点序列包含5’剪接位点序列。在一些实施例中,剪接位点序列包含3’剪接位点序列。示例性基因序列和剪接位点序列(例如,5’剪接位点序列)包括AAAgcaaguu、AAAguaaaaa、AAAguaaaau、AAAguaaagu、AAAguaaaua、AAAguaaaug、AAAguaaauu、AAAguaacac、AAAguaacca、AAAguaacuu、AAAguaagaa、AAAguaagac、AAAguaagag、AAAguaagau、AAAguaagca、AAAguaagcc、AAAguaagcu、AAAguaagga、AAAguaaggg、AAAguaaggu、AAAguaagua、AAAguaaguc、AAAguaagug、AAAguaaguu、AAAguaaucu、AAAguaauua、AAAguacaaa、AAAguaccgg、AAAguacuag、AAAguacugg、AAAguacuuc、AAAguacuug、AAAguagcuu、AAAguaggag、AAAguaggau、AAAguagggg、AAAguaggua、AAAguaguaa、AAAguauauu、AAAguauccu、AAAguaucuc、AAAguaugga、AAAguaugua、AAAguaugug、AAAguauguu、AAAguauugg、AAAguauuuu、AAAgucagau、AAAgucugag、AAAgugaaua、AAAgugagaa、AAAgugagac、AAAgugagag、AAAgugagau、AAAgugagca、AAAgugagcu、AAAgugaggg、AAAgugagua、AAAgugaguc、AAAgugagug、AAAgugaguu、AAAgugcguc、AAAgugcuga、AAAguggguc、AAAguggguu、AAAgugguaa、AAAguguaug、AAAgugugug、AAAguguguu、AAAguuaagu、AAAguuacuu、AAAguuagug、AAAguuaugu、AAAguugagu、AAAguuugua、AACguaaaac、AACguaaagc、AACguaaagg、AACguaagca、AACguaaggg、AACguaaguc、AACguaagug、AACguaaugg、AACguaguga、AACguaugua、AACguauguu、AACgugagca、AACgugagga、AACgugauuu、AACgugggau、AACgugggua、AACguguguu、AACguuggua、AAGgcaaauu、AAGgcaagag、AAGgcaagau、AAGgcaagcc、AAGgcaagga、AAGgcaaggg、AAGgcaagug、AAGgcaaguu、AAGgcacugc、AAGgcagaaa、AAGgcaggau、AAGgcaggca、AAGgcaggga、AAGgcagggg、AAGgcaggua、AAGgcaggug、AAGgcaucuc、AAGgcaugcu、AAGgcaugga、AAGgcauguu、AAGgcauuau、AAGgcgagcu、AAGgcgaguc、AAGgcgaguu、AAGgcuagcc、AAGguaaaaa、AAGguaaaac、AAGguaaaag、AAGguaaaau、AAGguaaaca、AAGguaaacc、AAGguaaacu、AAGguaaaga、AAGguaaagc、AAGguaaagg、AAGguaaagu、AAGguaaaua、AAGguaaauc、AAGguaaaug、AAGguaaauu、AAGguaacaa、AAGguaacau、AAGguaaccc、AAGguaacua、AAGguaacuc、AAGguaacug、AAGguaacuu、AAGguaagaa、AAGguaagac、AAGguaagag、AAGguaagau、AAGguaagca、AAGguaagcc、AAGguaagcg、AAGguaagcu、AAGguaagga、AAGguaaggc、AAGguaaggg、AAGguaaggu、AAGguaagua、AAGguaaguc、AAGguaagug、AAGguaaguu、AAGguaauaa、AAGguaauac、AAGguaauag、AAGguaauau、AAGguaauca、AAGguaaucc、AAGguaaucu、AAGguaauga、AAGguaaugc、AAGguaaugg、AAGguaaugu、AAGguaauua、AAGguaauuc、AAGguaauug、AAGguaauuu、AAGguacaaa、AAGguacaag、AAGguacaau、AAGguacacc、AAGguacacu、AAGguacagg、AAGguacagu、AAGguacaua、AAGguacaug、AAGguacauu、AAGguaccaa、AAGguaccag、AAGguaccca、AAGguacccu、AAGguaccuc、AAGguaccug、AAGguaccuu、AAGguacgaa、AAGguacggg、AAGguacggu、AAGguacguc、AAGguacguu、AAGguacuaa、AAGguacuau、AAGguacucu、AAGguacuga、AAGguacugc、AAGguacugu、AAGguacuuc、AAGguacuug、AAGguacuuu、AAGguagaaa、AAGguagaac、AAGguagaca、AAGguagacc、AAGguagacu、AAGguagagu、AAGguagaua、AAGguagcaa、AAGguagcag、AAGguagcca、AAGguagccu、AAGguagcua、AAGguagcug、AAGguagcuu、AAGguaggaa、AAGguaggag、AAGguaggau、AAGguaggca、AAGguaggcc、AAGguaggcu、AAGguaggga、AAGguagggc、AAGguagggg、AAGguagggu、AAGguaggua、AAGguagguc、AAGguaggug、AAGguagguu、AAGguaguaa、AAGguaguag、AAGguagucu、AAGguagugc、AAGguagugg、AAGguaguuc、AAGguaguuu、AAGguauaaa、AAGguauaau、AAGguauaca、AAGguauacu、AAGguauaua、AAGguauauc、AAGguauaug、AAGguauauu、AAGguaucac、AAGguaucag、AAGguauccc、AAGguauccu、AAGguaucuc、AAGguaucug、AAGguaucuu、AAGguaugaa、AAGguaugac、AAGguaugag、AAGguaugau、AAGguaugca、AAGguaugcc、AAGguaugcu、AAGguaugga、AAGguauggc、AAGguauggg、AAGguaugua、AAGguauguc、AAGguaugug、AAGguauguu、AAGguauuaa、AAGguauuac、AAGguauuag、AAGguauuau、AAGguauucc、AAGguauuga、AAGguauugu、AAGguauuua、AAGguauuuc、AAGguauuug、AAGguauuuu、AAGgucaaau、AAGgucaaga、AAGgucaagu、AAGgucacag、AAGgucagaa、AAGgucagac、AAGgucagag、AAGgucagca、AAGgucagcc、AAGgucagcg、AAGgucagcu、AAGgucagga、AAGgucaggc、AAGgucaggg、AAGgucaggu、AAGgucagua、AAGgucaguc、AAGgucagug、AAGgucaguu、AAGgucauag、AAGgucaucu、AAGguccaca、AAGguccaga、AAGguccaua、AAGgucccag、AAGgucccuc、AAGguccuuc、AAGgucgagg、AAGgucuaau、AAGgucuacc、AAGgucuaua、AAGgucuccu、AAGgucucug、AAGgucucuu、AAGgucugaa、AAGgucugag、AAGgucugga、AAGgucuggg、AAGgucugua、AAGgucuguu、AAGgucuucu、AAGgucuuuu、AAGgugaaac、AAGgugaaag、AAGgugaaau、AAGgugaacu、AAGgugaagc、AAGgugaagg、AAGgugaagu、AAGgugaaua、AAGgugaaug、AAGgugaauu、AAGgugacaa、AAGgugacag、AAGgugacau、AAGgugacug、AAGgugacuu、AAGgugagaa、AAGgugagac、AAGgugagag、AAGgugagau、AAGgugagca、AAGgugagcc、AAGgugagcg、AAGgugagcu、AAGgugagga、AAGgugaggc、AAGgugaggg、AAGgugaggu、AAGgugagua、AAGgugaguc、AAGgugagug、AAGgugaguu、AAGgugauaa、AAGgugauca、AAGgugaucc、AAGgugauga、AAGgugaugc、AAGgugaugu、AAGgugauua、AAGgugauug、AAGgugauuu、AAGgugcaca、AAGgugcauc、AAGgugcccu、AAGgugccug、AAGgugcgug、AAGgugcguu、AAGgugcucc、AAGgugcuga、AAGgugcugc、AAGgugcugg、AAGgugcuua、AAGgugcuuu、AAGguggaua、AAGguggcua、AAGguggcug、AAGguggcuu、AAGgugggaa、AAGgugggag、AAGgugggau、AAGgugggca、AAGgugggcc、AAGgugggcg、AAGgugggga、AAGguggggu、AAGgugggua、AAGgugggug、AAGguggguu、AAGgugguaa、AAGgugguac、AAGgugguau、AAGguggugg、AAGgugguua、AAGgugguuc、AAGgugguuu、AAGguguaag、AAGgugucaa、AAGgugucag、AAGgugucug、AAGgugugaa、AAGgugugag、AAGgugugca、AAGgugugga、AAGguguggu、AAGgugugua、AAGguguguc、AAGgugugug、AAGguguguu、AAGguguucu、AAGguguugc、AAGguguugg、AAGguguuug、AAGguuaaaa、AAGguuaaca、AAGguuaagc、AAGguuaauu、AAGguuacau、AAGguuagaa、AAGguuagau、AAGguuagca、AAGguuagcc、AAGguuagga、AAGguuaggc、AAGguuagua、AAGguuaguc、AAGguuagug、AAGguuaguu、AAGguuauag、AAGguuauga、AAGguucaaa、AAGguucaag、AAGguuccuu、AAGguucggc、AAGguucguu、AAGguucuaa、AAGguucuga、AAGguucuua、AAGguugaau、AAGguugacu、AAGguugagg、AAGguugagu、AAGguugaua、AAGguugcac、AAGguugcug、AAGguuggaa、AAGguuggca、AAGguuggga、AAGguugggg、AAGguuggua、AAGguugguc、AAGguuggug、AAGguugguu、AAGguuguaa、AAGguugucc、AAGguugugc、AAGguuguua、AAGguuuacc、AAGguuuaua、AAGguuuauu、AAGguuuccu、AAGguuucgu、AAGguuugag、AAGguuugca、AAGguuugcc、AAGguuugcu、AAGguuugga、AAGguuuggu、AAGguuugua、AAGguuuguc、AAGguuugug、AAGguuuuaa、AAGguuuuca、AAGguuuucg、AAGguuuugc、AAGguuuugu、AAGguuuuuu、AAUgcaagua、AAUgcaaguc、AAUguaaaca、AAUguaaaua、AAUguaaauc、AAUguaaaug、AAUguaaauu、AAUguaacua、AAUguaagaa、AAUguaagag、AAUguaagau、AAUguaagcc、AAUguaagcu、AAUguaagga、AAUguaagua、AAUguaaguc、AAUguaagug、AAUguaaguu、AAUguaauca、AAUguaauga、AAUguaaugu、AAUguacauc、AAUguacaug、AAUguacgau、AAUguacgua、AAUguacguc、AAUguacgug、AAUguacucu、AAUguaggca、AAUguagguu、AAUguaucua、AAUguaugaa、AAUguaugua、AAUguaugug、AAUguauguu、AAUgucagag、AAUgucagau、AAUgucagcu、AAUgucagua、AAUgucaguc、AAUgucagug、AAUgucaguu、AAUgucggua、AAUgucuguu、AAUgugagaa、AAUgugagca、AAUgugagcc、AAUgugagga、AAUgugagua、AAUgugaguc、AAUgugagug、AAUgugaguu、AAUgugauau、AAUgugcaua、AAUgugcgua、AAUgugcguc、AAUgugggac、AAUguggguc、AAUgugggug、AAUgugguuu、AAUgugugua、AAUguuaagu、AAUguuagaa、AAUguuagau、AAUguuagua、AAUguuggug、ACAgcaagua、ACAguaaaua、ACAguaaaug、ACAguaagaa、ACAguaagca、ACAguaagua、ACAguaaguc、ACAguaagug、ACAguaaguu、ACAguacgua、ACAguaggug、ACAguauaac、ACAguaugua、ACAgucaguu、ACAgugagaa、ACAgugagcc、ACAgugagcu、ACAgugagga、ACAgugaggu、ACAgugagua、ACAgugaguc、ACAgugagug、ACAgugaguu、ACAgugggua、ACAguggguu、ACAguguaaa、ACAguuaagc、ACAguuaagu、ACAguuaugu、ACAguugagu、ACAguuguga、ACCguaagua、ACCgugagaa、ACCgugagca、ACCgugaguu、ACCgugggug、ACGguaaaac、ACGguaacua、ACGguaagua、ACGguaagug、ACGguaaguu、ACGguaauua、ACGguaauuu、ACGguacaau、ACGguacagu、ACGguaccag、ACGguacggu、ACGguacgua、ACGguaggaa、ACGguaggag、ACGguaggug、ACGguaguaa、ACGguauaau、ACGguaugac、ACGguaugcg、ACGguaugua、ACGguauguc、ACGgugaaac、ACGgugaagu、ACGgugaauc、ACGgugacag、ACGgugacca、ACGgugagaa、ACGgugagau、ACGgugagcc、ACGgugagua、ACGgugagug、ACGgugaguu、ACGgugcgug、ACGguggcac、ACGguggggc、ACGgugggug、ACGguguagu、ACGgugucac、ACGgugugua、ACGguguguu、ACGguuagug、ACGguuaguu、ACGguucaau、ACUguaaaua、ACUguaagaa、ACUguaagac、ACUguaagca、ACUguaagcu、ACUguaagua、ACUguaaguc、ACUguaaguu、ACUguacguu、ACUguacugc、ACUguaggcu、ACUguaggua、ACUguauauu、ACUguaugaa、ACUguaugcu、ACUguaugug、ACUguauucc、ACUgucagcu、ACUgucagug、ACUgugaacg、ACUgugagca、ACUgugagcg、ACUgugagcu、ACUgugagua、ACUgugaguc、ACUgugagug、ACUgugaguu、ACUgugggua、ACUgugugug、ACUguuaagu、AGAgcaagua、AGAguaaaac、AGAguaaacg、AGAguaaaga、AGAguaaagu、AGAguaaauc、AGAguaaaug、AGAguaacau、AGAguaacua、AGAguaagaa、AGAguaagac、AGAguaagag、AGAguaagau、AGAguaagca、AGAguaagcu、AGAguaagga、AGAguaaggc、AGAguaaggg、AGAguaaggu、AGAguaaguc、AGAguaagug、AGAguaaguu、AGAguaauaa、AGAguaaugu、AGAguaauuc、AGAguaauuu、AGAguacacc、AGAguaccug、AGAguacgug、AGAguacucu、AGAguacuga、AGAguacuuu、AGAguagcug、AGAguaggaa、AGAguaggga、AGAguagggu、AGAguagguc、AGAguaggug、AGAguagguu、AGAguauaua、AGAguauauu、AGAguaugaa、AGAguaugac、AGAguaugau、AGAguauguc、AGAguaugug、AGAguauguu、AGAguauuaa、AGAguauuau、AGAgucagug、AGAgugagac、AGAgugagag、AGAgugagau、AGAgugagca、AGAgugagua、AGAgugaguc、AGAgugagug、AGAgugaguu、AGAgugcguc、AGAgugggga、AGAgugggug、AGAgugugug、AGAguguuuc、AGAguuagua、AGAguugaga、AGAguugagu、AGAguugguu、AGAguuugau、AGCguaagcu、AGCguaagug、AGCgugagcc、AGCgugagug、AGCguuguuc、AGGgcagagu、AGGgcagccu、AGGgcuagua、AGGguaaaga、AGGguaaaua、AGGguaaauc、AGGguaaauu、AGGguaacca、AGGguaacug、AGGguaacuu、AGGguaagaa、AGGguaagag、AGGguaagau、AGGguaagca、AGGguaagga、AGGguaaggc、AGGguaaggg、AGGguaagua、AGGguaaguc、AGGguaagug、AGGguaaguu、AGGguaauac、AGGguaauga、AGGguaauua、AGGguaauuu、AGGguacacc、AGGguacagu、AGGguacggu、AGGguaggac、AGGguaggag、AGGguaggca、AGGguaggcc、AGGguaggga、AGGguagggu、AGGguagguc、AGGguaggug、AGGguagguu、AGGguauaua、AGGguaugac、AGGguaugag、AGGguaugau、AGGguaugca、AGGguaugcu、AGGguauggg、AGGguauggu、AGGguaugua、AGGguauguc、AGGguaugug、AGGguauuac、AGGguauucu、AGGguauuuc、AGGgucagag、AGGgucagca、AGGgucagga、AGGgucaggg、AGGgucagug、AGGgucaguu、AGGguccccu、AGGgucggga、AGGgucugca、AGGgucuguu、AGGgugaaga、AGGgugacua、AGGgugagaa、AGGgugagac、AGGgugagag、AGGgugagca、AGGgugagcc、AGGgugagcu、AGGgugagga、AGGgugaggg、AGGgugaggu、AGGgugagua、AGGgugaguc、AGGgugagug、AGGgugaguu、AGGgugggga、AGGguggggu、AGGgugggua、AGGgugggug、AGGgugugua、AGGgugugug、AGGguuaaug、AGGguuagaa、AGGguuaguu、AGGguuggug、AGGguuugug、AGGguuuguu、AGUguaaaag、AGUguaaaua、AGUguaaauu、AGUguaagaa、AGUguaagag、AGUguaagau、AGUguaagca、AGUguaagcc、AGUguaagua、AGUguaagug、AGUguaaguu、AGUguaauug、AGUguaggac、AGUguagguc、AGUguaugag、AGUguaugua、AGUguauguu、AGUguauugu、AGUguauuua、AGUgucaguc、AGUgugagag、AGUgugagca、AGUgugagcc、AGUgugagcu、AGUgugagua、AGUgugaguc、AGUgugagug、AGUgugaguu、AGUgugggua、AGUgugggug、AGUgugugua、AGUguuccua、AGUguugggg、AGUguuucag、AUAguaaaua、AUAguaagac、AUAguaagau、AUAguaagca、AUAguaagua、AUAguaagug、AUAguaaguu、AUAguaggua、AUAguauguu、AUAgucucac、AUAgugagac、AUAgugagag、AUAgugagau、AUAgugagcc、AUAgugaggc、AUAgugagua、AUAgugaguc、AUAgugagug、AUAgugcguc、AUAgugugua、AUAguucagu、AUCguaagcc、AUCguaaguu、AUCguauucc、AUCgugagua、AUGgcaagcg、AUGgcaagga、AUGgcaaguu、AUGgcaggua、AUGgcaugug、AUGgcgccau、AUGgcuugug、AUGguaaaac、AUGguaaaau、AUGguaaacc、AUGguaaaga、AUGguaaaua、AUGguaaaug、AUGguaaauu、AUGguaacag、AUGguaacau、AUGguaacua、AUGguaacuc、AUGguaacuu、AUGguaagaa、AUGguaagac、AUGguaagag、AUGguaagau、AUGguaagca、AUGguaagcc、AUGguaagcu、AUGguaagga、AUGguaaggg、AUGgu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guc、UCGguaaauu、UCGguaagag、UCGguaagcu、UCGguacauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGgucagua、UCGgucuuag、UCGgugaagu、UCGgugagaa、UCGgugagca、UCGgugaggc、UCGgugagua、UCGgugcgcu、UCGgugcuuu、UCGgugguuu、UCGguuagcu、UCUguaaaag、UCUguaagaa、UCUguaagau、UCUguaagca、UCUguaagcu、UCUguaagua、UCUguaaguc、UCUguaagug、UCUguaaguu、UCUguaauaa、UCUguaauga、UCUguaaugu、UCUguaggua、UCUguagguu、UCUguauaua、UCUguaugac、UCUguaugua、UCUguccucg、UCUgugagag、UCUgugagcu、UCUgugagga、UCUgugagua、UCUgugaguc、UCUgugagug、UCUgugaguu、UCUgugcgua、UCUgugugag、UGAguaacuu、UGAguaagau、UGAguaagca、UGAguaagcu、UGAguaaggc、UGAguaaggu、UGAguaagua、UGAguaaguc、UGAguaagug、UGAguaaguu、UGAguaaucc、UGAguaauua、UGAguacagu、UGAguacgua、UGAguacguu、UGAguacugu、UGAguagcug、UGAguaggua、UGAguauaaa、UGAguaugcu、UGAguaugga、UGAguaugua、UGAguauguc、UGAguauguu、UGAgucagag、UGAgucuacg、UGAgugaaua、UGAgugaauu、UGAgugagaa、UGAgugagau、UGAgugagca、UGAgugagcc、UGAgugagga、UGAgugagua、UGAgugagug、UGAgugaguu、UGAgugggaa、UGAguuaaga、UGAguuaaug、UGAguuacgg、UGAguuaggu、UGAguucuau、UGAguugguu、UGAguuguag、UGAguuuauc、UGCguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCguaugua、UGGgcaaguc、UGGgcaagug、UGGgcacauc、UGGgccacgu、UGGgccccgg、UGGguaaaau、UGGguaaagc、UGGguaaagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、UGGguaaauu、UGGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaagag、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGGguaaugu、UGGguaauua、UGGguaauuu、UGGguacaaa、UGGguacagu、UGGguacuac、UGGguaggga、UGGguagguc、UGGguaggug、UGGguagguu、UGGguaguua、UGGguauagu、UGGguaugaa、UGGguaugac、UGGguaugag、UGGguaugua、UGGguauguc、UGGguaugug、UGGguauguu、UGGguauuug、UGGgucuuug、UGGgugaccu、UGGgugacua、UGGgugagac、UGGgugagag、UGGgugagca、UGGgugagcc、UGGgugagga、UGGgugaggc、UGGgugaggg、UGGgugagua、UGGgugaguc、UGGgugagug、UGGgugaguu、UGGgugcgug、UGGguggagg、UGGguggcuu、UGGguggggg、UGGgugggua、UGGguggguc、UGGgugggug、UGGguggguu、UGGgugugga、UGGguguguc、UGGgugugug、UGGguguguu、UGGguguuua、UGGguuaaug、UGGguuaguc、UGGguuagug、UGGguuaguu、UGGguucaag、UGGguucgua、UGGguuggug、UGGguuuaag、UGGguuugua、UGUgcaagua、UGUguaaaua、UGUguaagaa、UGUguaagac、UGUguaagag、UGUguaaggu、UGUguaagua、UGUguaaguc、UGUguaaguu、UGUguacuuc、UGUguaggcg、UGUguaggua、UGUguaguua、UGUguaugug、UGUgucagua、UGUgucugua、UGUgucuguc、UGUgugaccc、UGUgugagau、UGUgugagca、UGUgugagcc、UGUgugagua、UGUgugaguc、UGUgugagug、UGUgugcgug、UGUgugggug、UGUguggguu、UGUgugugag、UGUguguucu、UGUguuuaga、UUAguaaaua、UUAguaagaa、UUAguaagua、UUAguaagug、UUAguaaguu、UUAguaggug、UUAgugagca、UUAgugaguu、UUAguuaagu、UUCguaaguc、UUCguaaguu、UUCguaauua、UUCgugagua、UUCgugaguu、UUGgcaagug、UUGgccgagu、UUGguaaaaa、UUGguaaaau、UUGguaaaga、UUGguaaagg、UUGguaaagu、UUGguaaauc、UUGguaaaug、UUGguaaauu、UUGguaacug、UUGguaacuu、UUGguaagaa、UUGguaagag、UUGguaagcu、UUGguaagga、UUGguaaggg、UUGguaagua、UUGguaagug、UUGguaaguu、UUGguaauac、UUGguaauca、UUGguaaugc、UUGguaaugu、UUGguaauug、UUGguaauuu、UUGguacaua、UUGguacgug、UUGguagagg、UUGguaggac、UUGguaggcg、UUGguaggcu、UUGguaggga、UUGguaggua、UUGguagguc、UUGguaggug、UUGguauaaa、UUGguauaca、UUGguauauu、UUGguaucua、UUGguaucuc、UUGguaugca、UUGguaugua、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucagaa、UUGgucagua、UUGgucucug、UUGgucugca、UUGgugaaaa、UUGgugacug、UUGgugagac、UUGgugagau、UUGgugagca、UUGgugagga、UUGgugaggg、UUGgugagua、UUGgugaguc、UUGgugagug、UUGgugaguu、UUGgugaugg、UUGgugauua、UUGgugauug、UUGgugcaca、UUGgugggaa、UUGguggggc、UUGgugggua、UUGguggguc、UUGgugggug、UUGguggguu、UUGguguggu、UUGguguguc、UUGgugugug、UUGguguguu、UUGguuaagu、UUGguuagca、UUGguuagug、UUGguuaguu、UUGguuggga、UUGguugguu、UUGguuugua、UUGguuuguc、UUUgcaagug、UUUguaaaua、UUUguaaaug、UUUguaagaa、UUUguaagac、UUUguaagag、UUUguaagca、UUUguaaggu、UUUguaagua、UUUguaaguc、UUUguaagug、UUUguaaguu、UUUguaauuu、UUUguacagg、UUUguacgug、UUUguacuag、UUUguacugu、UUUguagguu、UUUguauccu、UUUguauguu、UUUgugagca、UUUgugagug、UUUgugcguc、UUUguguguc和uGGguaccug。
另外的示例性基因序列和剪接位点序列(例如,5’剪接位点序列)包括AAGgcaagau、AUGguaugug、GGGgugaggc、CAGguaggug、AAGgucagua、AAGguuagag、AUGgcacuua、UAAguaaguc、UGGgugagcu、CGAgcugggc、AAAgcacccc、UAGguggggg、AGAguaacgu、UCGgugaugu、AAUgucaguu、AGGgucugag、GAGgugacug、AUGguagguu、GAGgucuguc、CAGguaugug、CAAguacugc、CACgugcgua、CCGgugagcu、CAGguacuuc、CAGgcgagag、GAAgcaagua、AGGgugagca、CAGgcaaguc、AAGgugaggc、CAGguaagua、CCAguugggu、AAGguguggg、CAGguuggag、CCGguaugaa、UGGguaaugu、CAGgugaggu、AGAguaauag、CAGguaugag、AUGguaaguu、UUGguggguc、UUUguaagca、CUCguaugcc、UAGguaagag、UAGgcaaguu、GGAguuaagu、GAGguaugcc、AAGguguggu、CAGgugggug、UUAguaagua、AAGguuggcu、UGAguaugug、CCAgccuucc、CCUguacgug、CCUguaggua、CAGguacgcu、GAGguucuuc、AAGguugccu、CGUguucacu、CGGgugggga、UAGgugggau、CGGguaagga、AAGguacuau、GGGguaagcu、ACGguagagc、CAGgugaaga、GCGguaagag、CAGguguugu、GAAguuugug、AUGgugagca、CGGguucgug、AUUguccggc、GAUgugugug、AUGgucuguu、AAGguaggau、CCGguaagau、AAGguaaaga、GGGgugaguu、AGGguuggug、GGAgugagug、AGUguaagga、UAGguaacug、AAGgugaaga、UGGguaagug、CAGguaagag、UAGgugagcg、GAGguaaaaa、GCCguaaguu、AAGguuuugu、CAGgugagga、ACAgcccaug、GCGgugagcc、CAGguaugca、AUGguaccua、CAAguaugua、AUGguggugc、UAAguggcag、UAGguauagu、CUGguauuua、AGGguaaacg、AUAguaagug、UUGguacuga、GGUguaagcc、GAGguggaua、GAUguaagaa、ACGgucaguu、UAAguaaaca、AAGguaucug、AGGguauuug、AAGgugaaug、CUGgugaauu、CAGguuuuuu、CAUguaugug、UUGguagagg、AAGguaugcc、CAGgugccac、UCGguauuga、AAGguuugug、AAUguacagg、CAUguggguu、CAUgugaguu、UUGguaaugu、AGUguaggug、GAGguaacuc、GAGguggcgc、CUGguaauug、GAGguuugcu、UGUguacgug、UAGguaaaga、CUAguaggca、UCUgugaguc、UCUguaaggc、CAGguuugug、GAGguagggc、AAGguaacca、ACUgugaguu、UAGguaauag、AAAguaagcu、AUGgugagug、UAGguuugug、AACguaggac、GUAgcaggua、GAGgucagac、AGGguaugaa、GAGguuagug、CAGgcacgug、GGGgcaagac、CAGguguguc、CAGguauuga、CAGguauguc、AAGgcaaggu、UUGgugagaa、AAGguaaaau、GGGguaagua、AAGguaucuu、GACgugaguc、UAUguaugcu、AAGguacugu、CAGgugaacu、CACguaaaug、AAGgugugau、GAAguauuug、AAGgucugug、AAGguggagg、AAGguauaug、CAGguucuua、AGGguaacca、CAGgugucac、AAAguucugu、UUGgugaguu、CAAgugaguc、UAGguagguc、GCGgugagcu、AUUgugagga、CAGgugcaca、CAGguuggaa、CUGgucacuu、GGAguaagug、GAGgugggcu、AAGguacuug、AGGguaggau、AAUguguguu、ACAguuaagu、GAGgugugug、AAGgcgggcu、AUAgcaagua、AAGguuguua、CAAgcaaggc、GUGguaauua、UCUguucagu、AGGguaggcc、AAGguaucau、UAGguaccuu、AAGguaugac、GGAguaggua、UAAguuggca、AGUgugaggc、GAGguuugug、UGGgucugcu、CAGgugaucc、CAGgucagug、AAGguaaggg、CAGgugcagu、GAGguggguc、GCUgugagug、AAGguggagu、GGGgucaguu、AGCguaagug、AGAguaugaa、GGGguagggu、AAGgccagca、CGAguaugcc、GUGgugagcg、AAUguaaauu、CAGgugcgca、GGUguaugaa、CUUgugaguu、AAGguaucuc、AGAguaagga、UAGguaagac、GAGgugagug、CAGguguguu、UUGgugagua、AGGgcgaguu、CAGguuuugc、UUUgugaguu、AGGguaagca、GAGguccucu、CCAgcaggua、GAGguucgcg、CAGgugaucu、ACUguaagua、AAGguaaauc、CAGgcaaaua、GUGguaagca、CAGguuaaau、UUGguaauaa、UAUguaggua、CAGguaguau、AAGgugugcc、UGGguaagag、CAGgcaagca、UUGguaaggg、AAGgcaggug、ACGguaaaug、GCUgugagca、AUGguacaca、GUAguguguu、ACUguaagag、CCCgcagguc、GAGgugagcc、GAGgugcugu、UAAguaugcu、GAGgccaucu、UCAgugagug、CAGgugcuac、AAUgugggug、GAGgugugaa、CUGguagguc、GUGgcgcgcg、CAGgugcaaa、UAAguggagg、CAUgugggua、GAGguagggu、AAAgugaguu、AGGguucuag、UGUgugagcu、AGGgugaauc、CAGgucaggg、AAGgucccug、CUGguagagu、UAGgucaguu、AAAguaaggg、CAAguaugug、CAGgugcuuu、AAGguaauuc、GGGgugcacg、ACUgugcuac、CAGguaccua、CAGguagcuu、UGGgugaggc、CUGguacauu、AGGguaaucu、CAGguacaag、CAGguaauuc、AGGgcacuug、UAGgugagaa、GAGguaaugc、CCAgugaguu、AAAguaugug、CUGgugaauc、UAUguaugua、CCUgcaggug、CAGguaucug、GAGgugaggu、CUGguaaaac、UGUgugugcu、CAGguuaagu、CAGguaaucc、UAGguauuug、UGGguagguc、CAGguaacag、AGCgugcgug、AAGgucagga、GGUgugagcc、CUGguaagua、GGGgugggca、AAGgugggaa、CAGgugagug、CUGguuguua、CAGguaauag、UAGgugaguu、AGAguaaguu、UAGguaaucc、CCGgugacug、GUCgugauua、CUUguaagug、UAGguaguca、CUGguaaguc、AGGgugagcg、CAGguaugga、AUUgugacca、GUUgugggua、AAGguacaag、CUAgcaagug、CUGgugagau、CAGgugggca、AUGgcucgag、CUGguacguu、UUGgugugua、GAGgugucug、GAGgugggac、GGGgugggag、GCAgcgugag、GAGguaaaga、GAGguaugua、AAGgugagac、AAGguacaau、CUGguaugag、AACguaaaau、GUGguaggga、CUGguaugug、CUUguaagca、AAGguaggga、AUUguaagcc、AUGguaagcu、CAGgugaauu、UAGgugaaua、CAAguaugga、AUGguauggc、GAGgucaugc、CAGguacccu、ACAgugagac、CAGgucugau、GAAguugggu、CUGgugcgug、CAGguacgag、ACAgugagcc、AAGguaagua、GGAguaaggc、GAGgugugua、AAGgucauuu、CAGguagucu、AUGguaucug、AAGguaaacu、GAGguaggug、CUGguaagca、AGGguaagag、AAAguaaagc、CAGguuugag、GAGgcgggua、CGAguacgau、CAGguuguug、AAAguauggg、UAGgcugguc、AAGguaagga、AAGguuuccu、UUGguaaaac、GAGguaagua、CAGguucaag、UGGguuaugu、GAGgugaguu、ACGgugaaac、GAUguaacca、AAGgugcggg、CCGguacgug、GAUgugagaa、GUGgcgguga、CAGguauuag、GAGguuggga、AAGgcuagua、AAGgugggcg、CAGgcaggga、AAUguuaguu、GAGguaaagg、CAGgugugcu、CUGguaugau、AUGguuaguc、CUGgugagaa、CAGgccggcg、CAGgugacug、AAAguaaggu、UAAguacuug、AAGguaaagc、UCGguagggg、CAGguaggaa、AGUguaagca、CCCgugagau、GUGguuguuu、CAGguuugcc、AGGguauggg、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaaaua、GAGguugggg、GAGgcgagua、CAGguagugu、GUGguaggug、CAAgugagug、AAGgugacaa、CCAgcguaau、ACGgugaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、ACGguacuua、GAGgucagca、UAAguaugua、GGGgucagac、AAUgugugag、UCCgucagua、CAGgugcuuc、CCAguuagug、CCGgugggcg、AGGgugcaug、GGGguaggau、UAGgugggcc、GAGguguucg、UUGgcaagaa、UCCguaagua、CAGguguaag、CUCgugagua、GAGguguuuu、GAGgugagca、GAGguaaagu、AAGguacguu、CAGguccagu、AUGgugaaac、GUAgugagcu、CAGgugaaaa、AGGguacagg、AAGguaacgc、AAGguauacc、CCUgugagau、GGGguacgug、GAGguauggu、UAGguauuau、GAAguaggag、UCGguaaggg、CCGguaagcg、GAAguaauua、CAGgugaguc、AAGgucaaga、AUGguaaguc、CAGgugagcu、CCAguuuuug、CAGgugggag、AAGguauuau、AAGguaaaua、AAGgugcugu、AAAguacacc、CUGguucgug、UCAguaaguc、GAAguacgug、CAGgugacaa、UGGguaagaa、UGUguagggg、GAGguaggca、UUGgugaggc、AUGgugugua、CAGguccucc、UUGguaaaug、GCUgugaguu、AUGgucugua、CAUgcaggug、CUGguacacc、CAGguccuua、CAAguaaucu、AUGgcagccu、AAGgucagaa、AACgugaggc、CAGgcacgca、ACGguccagg、UCUguacaua、GAGgugauua、ACGguaaaua、AUGguaacug、CAGgcgcguu、CAGguauaga、AAGguuuguu、CAGguaugaa、UAGguuggua、CUGgugagac、CAGguuagga、AUGgugacug、UUGguauccc、CUUguaggac、AAAguguguu、CAGguuucuu、GGGguauggc、GGGguaggac、ACUguaaguc、AUCguaagcu、UAGguucccc、GGUgugagca、CUGguuggua、GGGguuaggg、UGAguaagaa、GAGguauucc、UGGguuaguc、CAGgcucgug、UAGguagagu、UAGgugcccu、AAAgugagua、GAGguucaua、UUGguaagag、ACCgugugua、UAUguaguau、UGGguaauag、CAGgucugaa、AAAguauaaa、GUGgugaguc、AGUgugauua、UUGgugugug、CAGgugaugg、GCUgugagua、CAGguacaug、AAGguacagu、GAAguuguag、CAGgugauua、UAGgugaauu、GGUguuaaua、CAGguauuua、CAAguacucg、CAAguaagaa、AAGguaccuu、ACGgugaggg、UGAgcaggca、GGGgugaccg、GAGguaaaug、CGGguuugug、AAGgugagcg、GUGguaugga、CUGguaagga、GAGguaccag、CCGgugagug、AAGguuagaa、GAGguacuug、AGAguaaaac、UCUgugagua、AAGgcgggaa、CAGguaugcg、AGGguaaaac、AAGgugacug、AGGguauguu、AAGguaugua、CAGgucucuc、CAGgcaugua、CUGguaggua、AAGgucaugc、CAGguacaca、GAUguacguu、ACAguacgug、ACGguaccca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguaggua、CAGguaggau、CAGgucuggc、GUGguuuuaa、CAGgugggaa、UGGgugagua、CGAgugagcc、AAGguauggc、AGUguuguca、CAGgugauuu、UAGguaucuc、UAAguauguu、AAGguugagc、AGAguaaaga、GGUguaagua、GGGgugagcu、CAGguauaau、GAGguacaaa、AUGguaccaa、UAGguagggg、UGAgucagaa、AAGgcaauua、UUGguaagau、CAGguacaga、AGAguuagag、CAGgugcguc、GAGguauuac、ACGguacaga、CAGgucuucc、AAGguaaggu、GAGguaauuu、AGUguaggcu、AAAguaagcg、CCUguaagcc、AGGgugauuu、UGUguaugaa、CUGguacaca、AGGguagaga、AUAguaagca、AGAguaugua、UUGgucagca、CAGgcaaguu、AAGguauaua、AAGgucugga、CAGguacgca、AGGgugcggg、AUGguaagug、AAAgugauga、UGCgugagua、AGAguaggga、UGUguaggua、UAGguaggau、UAAgugagug、GCUguaagua、GAAguaagaa、UCGgugaggc、UAGguauuuu、AAGguacaca、AAGguaggua、UGGguagguu、ACAgcaagua、GAGguaggag、UGGgugaguu、GCGgugagau、CCUguagguu、CAGgugugua、CUGguaagcc、AAGgugauuc、CAGguagcua、GUUguaagug、AUGguaagca、AUAguaggga、GGGguucgcu、CCGgucagag、GUAguaugag、CGUguaagau、UGAguaggca、UCAguaugua、GAGguaucug、AGAguauuuu、AAGguuguag、AGUguaaguu、CGGguaaguu、UCGgugcgga、UAGguaagua、GAAguuagau、GCUgugagac、CAGgcaggua、CAGguagggg、UAAguuaaga、AUGguggguu、UAGguaaguu、CUGguaaauu、CCGguaagga、GAGgcaggca、CAUguaagug、AAGgugccua、UUGguaggga、AAGguaaaca、CGGgugugag、GGGgugugag、UCCguggguc、ACGguaaauc、UCAguaggua、CAGgucagcc、CAGgcggugg、CGAguaagcu、CCCgugagca、AAAguaauga、CUGguaagcu、CGGguaacca、CAGgucgcac、GAGguaggcc、UAGgugagcc、UAGguaggca、GCGgugcgug、AUGgugagua、GGGgugaggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、AAGguagagu、AAGgugagau、AAAguaggua、ACAgugaauc、CAGgugugcg、CAGgucggcc、AAGguaguau、ACUgucaguc、UCUgcagccu、CGAguaagug、AGAguaauua、AGUgugagug、CCGgugagcg、AAGguaaccu、AAGguugugg、AAGgcauggg、AAGgucagag、ACGguaaggu、GGGgugagca、GAGguugcuu、AAGguaucgc、CCGguaaagg、AAAguuaaug、UAGguacgag、ACCguaauua、GGGguaagga、CCGguaacgc、CAGgucagaa、AAGguacuga、GAGgugacca、GGGgugagcc、AAGguacagg、AUGguaauua、CAGgugagag、AAGgugacuc、AUAguaagua、GAGguaaacc、CAGgugggau、CAGgugagaa、AGGguaaaaa、GAGgugugac、CACguaagcu、CAGguccccc、CAGgucaggu、CGGguaaguc、ACGguauggg、GAUguaaguu、CAAguaauau、CAGguugggg、CCUgugcugg、AAGguaugau、AGGguagagg、AAGguggguu、CAGgugugaa、UUGguaugug、UUGguaucuc、GGGgugagug、CUGgugugug、AGGguagggc、GUGgugagua、CAGguaugua、AAGguacauu、UUAguaagug、AAUguauauc、CUUguaagua、GAGguuagua、CAGguaaggu、CAGguaaugu、AGGgugaggc、CAGguauuuc、CAGgucugga、GGGgugugcu、UAGgugagug、AAUguaaccu、UAAgugaguc、CAGgugcacu、ACGguaagua、GAGguauccu、UCUguaaguc、CAGguauuca、UGUguaagug、CCAgcaaggc、GAGgugaagg、AAUguggggu、UCGgugcgug、UUGguaaggc、GAGguaagug、AAAguaagau、UAGgucuuuu、GAGgucugau、CCAguuagag、UGGgugaaaa、AGAguaagau、CAGguaauug、CAGgccgguc、CCGguaagag、GAGgugagcu、CUGguaagac、CAGgugagau、CUGguuuguu、UGGguaggua、CAGguuagug、CAGguguucg、CGGguagguc、GUGguacaua、AAGguacuaa、GAUgugagua、UGUguaagac、GAGguagccg、UAGgugaucu、CAGguacgug、CUUgucaguc、GAGguaucac、GAGguaauga、AAGguaacac、CAGguaaagc、AAGgcaagua、CGCgugagcc、AGUgugcguu、GAUguaagca、AAGguaauag、GGAgcaguug、AGCguaagau、AAGgucaggc、GAGguauuca、AAUguaaagu、CAGguaacaa、UCGguaggug、AAAguaaguc、CGGgugcagu、GGUgugugca、UGAgugagaa、CACguguaag、GUGguuggua、GCAgccuuga、CGAgugugau、CAGguauaua、UAUguaugug、CCCgugguca、AUGguaagac、GAGgugugga、AGUguauccu、UGAguguguc、UGGguaaucu、AUGgcagguu、GAGguaagau、UCAgcagcgu、AAGgugggau、CGGgugcgcu、CAGgugucug、AGCgugguaa、AAUgugaaug、UCGgugagac、UAGguaaagc、CUGguaaaag、CCGgugcgga、CAGguacuca、CAGguagcaa、GAAguugagu、GAGguggagg、AGGguaugag、UAGguaugcu、UAGgugagac、CAGguaauua、CGUguaagcc、CUUguaaguu、AAGguaacuu、UCGgcaaggc、GAGguucucg、GAGgugggcg、AAGgcaugug、CUGguauguu、UAAgucauuu、CAUguaauua、AAUguaaaga、UAGgugcuca、AAGguaaugg、GAGguacuga、UGGguaagua、UGGguaaaaa、AAGgugagcu、UACgugaguu、AGGgugagcc、CGGgugagga、UGGgugagag、GGUguaagcu、CGGguggguu、CCAgcuaagu、AAGguuuguc、GAGguuagac、GAGguaccuc、UUUguaaguu、GAGguuagga、CAGguaggga、AGGguaauac、UGCgugugua、CCAguaacca、AGGgucuguc、UGGguaugua、GUGguaagcu、CAGguaaccu、AAGgugaguu、UAGguucgug、AAAguuagua、UGGgcaaguc、AAGgcacagu、GUUguaaguc、AAGguuugcc、CUUgcauggg、GCGgugagua、GGGguaagcg、GCCguaagaa、GAGgucggga、UUGguauugu、AGUgugagac、CUGgugggga、AGAguaaggu、CCGguggguc、CAGguauucu、UGGguaacgu、UUGgugagag、UAGguacccu、GGGgugcguc、AAGgcaggag、ACGguacauu、GAGguaguua、CAGguauggg、UUUguguguc、CAGguacuua、AUGguauacu、AGUgugagcc、ACAguaacga、CUGguaccca、CAGguaaccc、GGAguaagua、GAGgugggug、ACUguauguc、ACGgugagua、CUGguaaugu、AAGguaucag、CAGgugcccc、AGUgucagug、AAGguaggag、GGAguaugug、UUGguauuuu、CCUguuguga、UUUguaagaa、UAGguaacau、CAGguaagca、CAGgucacag、CAGgugugag、UAGguuugcg、CUGguaagaa、ACGguuguau、AAGguugggg、AAGgugaauu、GGGguuaguu、ACGguaaggc、CAGguuuaag、CUGguaaguu、GGGgugagag、UGGguggguu、GAGguuuguu、UGGguaaaug、CAGgcaggcc、CACgugcagg、AAGgugagcc、CAAguaagug、CAGgucaguc、GCGguauaau、UAGguaaagu、UAGguggauu、GAGgucugga、UCGgucaguu、UGGguaacug、AAGguuugau、UGUgcuggug、UGUguaccuc、UGGguacagu、AUCgucagcg、CAGgucuugg、GAAguuggua、GAAguaaaga、UUGguaagcu、UAGguaccag、AGGguaucau、CAGguaaaaa、ACGguaauuu、AUUguaaguu、GAGguacagu、CAGgugaaag、UGGguuguuu、GGGguaggug、CAGgugccca、AGCgugagau、CCAgugagug、AGGguagaug、UGGguguguc、AUCgcgugag、AGGguaagcc、AGGguagcag、UUCguuuccg、AAGguaagcg、UGGguaagcc、CAGguauggc、UGUguaagua、AAGguagaga、ACGguaauaa、CUGguacggu、GAGgucacag、UAUguaaguu、CUGguacgcc、CAAguaagau、CUAgugagua、CCGguaaccg、CUUguaaguc、GUGgugagaa、ACCguaugua、GUAguaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguuagua、CGGguaggcg、GCAgugagug、GAGgugaguc、CUGguagccu、CAUguaugua、GAAguaacuu、GAAguaagau、AAGguuagau、AAGguaauca、AAUguaugua、UGAguaagau、AGAgugagca、GUAguucuau、GAGguaauca、UAGguaugga、UAGgugggac、GAGguacaug、UGGguaaggc、CAGguacgcc、CCAguuacgc、ACUgugguga、GAGguaaguc、AUUguaggug、ACCgucagug、AAUgugaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAguagcag、GAGguaaccu、AAGgugggca、AGGgugagua、UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaaua、GAUguaagcg、GAGguaaagc、UAGgugagua、CAGguaacau、CCUguacggc、UAGguauguc、UAGguccaua、GAGgugaaaa、AAAguacuga、UUGguaagcg、CAGgcaagcg、UUUgcagguu、CAGguuuaua、CUGguaaagc、AUGgugagcu、CAGgugguug、GUAguaaguu、CAGguaauac、CAGgcaaggc、AAGguaauuu、UUUguccgug、GAGguagguu、ACCgugagug、CAAguaagcu、ACAgugagua、UUGgugagau、AAGguagucu、CAGguaaagg、GGGguaugga、UUUguaagug、GUGguaagag、AGUgugaguu、AAGgcaagcg、UAAgugagua、AGGgugagug、AGUguacgug、AGGgugcgua、GGCgugagcc、CGAguuauga、CAGguaaaga、UUGgugaaga、AGGguaaugg、AAGguccaga、AGUgugaguc、CAGguaauuu、CAGguaacgc、CUGguacacu、CUGguuagug、CAGguacuug、CACguaagua、GUGgugcggc、GAGgucaguu、AUGguaugcc、AAGgugugug、CUGguggguc、CAGgugaggc、AAGguuaguc、AAGguagcug、GAGgucagga、GUUguaggua、UGGguacaag、AUGguaggug、GAGguaagcc、AUGgcaagua、AAGguauauu、GCGgugagag、AAGgugcuuc、UAGguacauc、ACUgugguaa、GAGguaggcu、GAGguaugca、AGGguaguuc、CAGguauccu、AGGguaaguc、AGGgucaguu、CAGguuggga、CAGguggaua、GGAguagguu、GAGguaggau、GGGguuugug、UAGguaauug、AAGguaaccc、ACGguaagaa、GAGguagggg、CGAguaggug、UCCguaagug、UCGguacagg、CAAguaagcg、AAGguccgcg、AAUgugagua、CAGgugaaug、GUGguaaggc、AGAgugagug、UCUguauguc、UGGgugaguc、UCGguuagua、GAUguaugca、GAGguuggug、GAGguggggc、UGGgucaguc、GCAgugagua、CAGguugcuu、AGGguagagu、UAGgucaggu、CGCguaugua、GAGguauuaa、CAGguaaacu、AAAguaaguu、GGGgucuggc、GCUguggggu、UUGguaaguc、AAGguagaag、AAUgugaguc、AAGgucagcu、AAGguaagag、AUGgugagga、AAGguacuuc、AAGguaagaa、CCGguacagc、GCGgugcgga、CAGguacaua、CUGgugagga、CUGguaggug、AACguagguu、AUGgugugug、UUGguacuau、CAGgucggug、CAGgcauggg、AUGguaucuu、AAGguaacua、CAGgugggcg、CACgugagga、AAGgugguuc、UGGgcauucu、AUGguaagcc、AGGgucagug、AGAguacgua、AAGguaggca、AAGguauuca、CAGguagauu、GAGguauuua、GAGgucuaca、GUUguagguc、CAGguacucg、GUCguauguu、AAGguacuuu、AGAgugagau、AGUguuggua、AAUgugagug、AAGguagauu、AUGguuugua、GAGgccccag、AUGgucaguu、UCUguaagga、CAGgucgggc、CAGguaagcc、UAGgucagug、AGAguaggaa、CUGguacuuc、CUCguaagca、CAGguaacua、CAGguggcug、UGGguccgua、GAGguugugc、CAGgugcgcg、AAAguauggc、UGAguacgua、CUGguacgga、CAAgugaccu、AAGgugaugu、AAGgucugca、AAAguuugua、AAGgugagca、GAUguaagcc、CAAguaauuu、CAGgugugug、UGGgugaggg、AAGgugaccu、UAGgugugag、CAGgcagguc、UCAguaaguu、UCAgcaguga、AAGguaccac、UAAguaggug、AAGgucagcc、CAGguaacuc、AAAguaagag、AAGguagaua、AAGgcaaggg、CAGgugucgg、CAGguggcua、GAGguugcca、CAGgccgugg、UUGguauaug、GAGguugagu、GAGguagguc、GUGguaagac、UAGguccuuc、GAGgcaaguc、GAGguaacau、CAGguauauc、UCGguugguu、CAGgugaacc、CAGgucuuuu、CAGgcauggc、AAAguacuug、CAGgugauuc、UUGguagguu、UAUgugagca、CAGgugagcg、AAUguaauaa、AAAguaaggc、UAGguuuguc、UAGgugggag、GAGguaaguu、AAGguagccg、CAGguggugc、UGAgucaguu、CUGguaggcc、CAAguaagga、CGGguaaggc、AAGgcgagga、CAGguaguuc、CAGguaagga、CCUgugagug、AAGguaaaug、CCGguaauua、CAGguaaguu、AAGgugguca、CAGguaccuc、AUCguaagua、CCGguacaua、GCGgugagug、GAGgugguau、CUGgugugga、GAGguaauuc、CAAguacgua、UCUguaagug、AAUguaagug、AGGgucuguu、GAGguacugc、AGGguaaggc、AAGgcaagag、CAGguggguu、UAGguuagga、UGAguaagcu、AGAguaagag、AUGgcaggug、UAGgcaagua、AUGguaggua、GCAgcccgca、ACGguaaacu、AGGgugaguu、GUAguagucu、GUGgcugaaa、CAGguuaguc、CUGgugagca、UCAguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGguaaauu、CAUguacauc、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAAgugauuc、CAGgucgugg、GAAguaugcc、UCGgugcccu、GAGgucaguc、CAGgugagac、UUUgucugua、CAGguagaua、UGGguaucag、UAGgugggcu、AUGgugagau、CAGguaacac、CCGguauccu、UAGguaagcu、UCAguacauc、UAGguuugcc、AUGguaagaa、UUGguaagac、CCGguuaguc、GAGguaagaa、UGGguaaguu、CCGgugagaa、CCUgugaggg、ACGguaggag、ACAguauguc、CAGguauuaa、CAGguggauc、AGAgugcgua、AAGgugaccg、AGAguaggug、ACUguaugua、UAGgucaauu、AGUguguaag、CGGguaccuu、CUAgugaguu、CUAguaagug、CAGguacaac、UAGgugugug、CAUguacggc、AUGgugugag、AGGguggaag、CAGgugcgag、UAGgugcucc、AAGguggugg、AAGgucuguu、CAGgugggcc、AAGgucaguc、CAGguuuuua、AACgugaggu、CGGguaagag、UUUgucggua、UAGguuaagu、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、CAGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、AAGgugaagc、CAGgugaguu、UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUguaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGgcauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGgugagag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguaggac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、ACGguauugg、GCUgcgagua、CUGguaagug、GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、GAGguaaaac、UCUguaagau、CCAguaaguu、CAGguaaagu、GCGgugagca、UAAguaagag、CUGgcaggug、GAGguaaggg、UGAguaaguu、GAGgugagac、GCUgucuguu、AAGguaacaa、GAGguaacgg、CUGguauucu、CAAguaacug、AAGguggggu、UAGguauggc、CAGguauuuu、GUGguaaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguagacc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGgugggga、GAGgucagug、AGGguaaggu、ACAguaagua、GGUguaaggu、GAGguaauaa、CAGguauucc、CUGguauaaa、CCGgucugug、CAGguaacug、GCAguaagua、AAGguagggg、CAAguccacc、CAAguuggug、CAGgugcggu、CAGguaaaau、ACGguaagga、UGGguaauaa、UAGguaagug、CCGguagguu、AGAguaugga、CUCgugaguc、AAAgccggug、UUGguaauuu、GAGguaaaag、CCUgugugag、AAAguaagga、UGAgugagug、AAGguacaug、CCGguaaaug、CAGgugaagc、CAGguacccg、GAGguaaggc、UUUguauguu、CAGgugcucc、UCGguagguc、CGGgugaggc、AAGguaauua、ACUgugaguc、AAGgucagca、GUGgugagug、CAUguccacc、AAGgugaccc、CGGguuagua、GCGguaguaa、GCUguaggua、CCUguugagu、UAGgucuggc、GAUgugagcc、CUUgugagua、CUGguguguu、GAGgcaugug、CAGgcaagag、UUGguaagaa、GAGguguggg、GAGguauuuu、CAGguaguaa、AGGguaagac、UUUguaggca、AGGgugagau、GAGguuugua、AAGgugagug、GAGgugggag、AAGgugagaa、CUGguaagag、AUAguaaaga、GAUgugaguc、AAGgugcagg、CAGgucuguc、GAGgugauuu、CAGguuggcu、CGGguauggg、AUGguccauc、CCGguuggug、GGAguaaguc、AAUguaagga、CAGguuuguu、UAGgugugua、UAUgucuuug、ACGguacuuc、AAGgcacgcg、CUGguaaacc、CUUgugggua、UGAguaaguc、CUGgugggug、GAGguggaga、GUGguggcug、GUGguaagug、AACgugagua、GAAgcuguaa、CGGguaucuu、CAGgugucag、AAUguacgca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu、CAGguuugcu、UUGguaaguu、CAGguaguug、CCUgugaaua、GCUgugugug、CAAguaauuc、AGGguaaugu、GCUgugaguc、ACCguaaguu、CGUguaagua、GGGguaaguc、AAUguaugau、AAUgugauua、UCAguaagaa、CAGguccguc、GAAguauuga、UUGguaagga、CAGgucgguu、UAGguuagug、ACGguaaaac、AAGguagguc、UACgugagua、UUGguaagca、GCGgugaguc、GAAguaaggg、CGCgugaguu、CAGguacccc、UCUguaagac、GAGgugggca、AAUguaagac、CAGgcaaggg、CAAguaacua、AAAguuuguc、CAGguacugu、AAGgucccuc、UCGguaaguc、UGGgugagug、CUUgugagau、AGAgugagcu、UAAgugggga、UAGguaggga、CAGguuagcc、AGGguaauca、AAGguucagc、UGGgugggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauuac、CAGgugcagg、GUGgugagcu、AAGguaacau、CUGgugaugg、AUGguaaaug、CCGgugagca、AAGguaaacc、AAGguacugg、GCGgucagga、CUGgucaggg、AAAguacguu、AGAguagguu、AGGguaagcu、AUUgugagua、CCGgccacca、GAGguaacuu、GAGguaugaa、CAGgucagac、UAGgcgugug、AGGguaaguu、CAGgcaugag、CAGguaacgu、CAGgcgagca、UAGguauggu、AGAguaggau、CUGguuucaa、GAGguaaacu、CAGgcaugca、UUGguaaucu、AGGgcagaau、AUGguaaaac、GCUgcaggug、GAAgcacgug、CAUguaaaca、UGGguaagau、AGGguagcua、AGGguggggu、CCUguaaguu、UGAgugaguu、GGAguaugua、CAGgugaccu、AAAguacgga、GAGguacaga、GAUguaggua、GGGguaauug、UAGguggguu、GUGguacgua、AAGguacagc、GAGgugaaga、GGGguaagca、UGAguagguc、GGGguaaguu、AUUgugaguu、UCAguaagac、AGUgugagcu、AAGgcaaaac、CUGgugaguc、AAGgucucug、GAGgcugugc、AGAgugagac、GAGgugaugu、AGAguauggu、UGGguggguc、GCUgcugagc、CAGguagcug、UAGgucagaa、CCGguaggug、GCAguaugau、CAGguuucag、GAGguuugcc、GGGguggggg、AAGguacaua、UGGguguguu、AGAguaaggc、GCGguuagug、AAGgugacuu、AUGguaagau、AUGguaguug、CAUguaagac、CUGguaugua、UUCguaagga、GAAguaugac、CGGguaauuc、UGGguaacuu、CAGgugccua、CAUguagggc、ACCgucagga、CGUguucgau、GAGgcaggac、UAGguaauau、UCGguauacu、UAGguugugc、CCGgugaguc、CAGgugccaa、CAGgugaugc、AAGgugagga、GUGgugaggg、UGGgucagua、GAGgucaggg、UAGguacgua、GAGgcaagag、CCUguuggua、GAGguaucca、UAAguaagcu、AAGgucaguu、AAAguuaaag、GAGgugcuau、ACGguaaguu、CUGgugaggg、GAGguuaugu、CUUgugugca、UGAgcugggg、AAGguauagu、UAGguaaaac、GGGgugaggu、GAGgcaagca、GGAguaacgu、AGAguaagua、AAAguaagua、GAGgcaacca、UGUguaaguu、UAGgugaggc、ACAguaagaa、UGAguaagug、CAAgucagua、AGGguaaaug、AAGguaugca、GCUgugcgug、GAGguucgcc、AAGgcuugca、CAGgcaagug、AUAguaaguc、UUGguaggua、GCAgcaggua、AAGguauauc、AGCguaagcc、CUGguucgaa、ACGgugggug、CUGgucauug、CAGgucagga、CAAgugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugugua、CAGguaugcu、CUGguacagu、UUGguacgua、UCUguacgua、UAAguaauuc、CACguaugug、CAGgcaagua、UCGgugagug、GGUgugaguc、UCUguaagcu、AAGguucaga、AGGguacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、AUGgucaagu、AAGgugagua、GUGguuuguu、AGAgugagga、GAGguaugac、UAGgcgugag、AAGguacucc、UGAgugagga、GAGguaugau、GGGgucggua、ACGguaugca、CAGguaccac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGgugggac、GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacugc、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、UUGgcaggug、UAGguuauug、CAGguacuga、GCGguggguc、UGUguaagau、GAGgugagua、GCAgccccgg、CAGgugcuaa、AGUguaagag、CAGguacauc、CAGgugggac、AGGguaaaua、UAAguaauua、CAGguaaccg、AAGguuugca、UAGgugguuu、CAGgugaccg、UGUguaagcu、GGAgugaguc、AGGguaggag、AGGgugggug、AAGgucugag、GAUguaauau、GGGguaauua、UAGguaggua、GAGgcaagua、GAGguaagga、UAGguacuac、UCGgugggug、AAGgugugga、CAGgucugcc、UAAgugagcc、GAAguaaguu、GAAguaagcc、UAGgugcgac、GAGguauggc、GCAguaagaa、CAGgugugga、UUGguaacgu、GCUguaaaaa、UUGguuagua、AUAguaaggg、UUGguacuag、CGGgcagccg、CAGgugcugg、UAUgugaguu、CAGgucuggg、UAAguaagaa、AAGguuauua、AGAguaaagc、AGAgugugag、UAGgugcgag、CAAguaaacg、AAGguacgua、CUGgugagua、CCAguaugua、UUGgugagug、UGAguaagua、GAGguuagca、GUGguaagcc、CUGguauggc、AAAguaacac、CAGguacuaa、UCUguaaguu、GAGgugaggg、ACUgugggua、GAUguuugug、CAGgugucaa、CAGgucacca、CCGgugagua、UUGguaaaua、CAGguggggg、ACUgcaggug、UAGguauguu、GGAgcaagug、UCGgugccuc、CAAguaacuu、GAGguaacca、CAGguaauau、GGAguaagaa、GAGguaccuu、AGGguaagga、CCUgugaguc、GAGguaaugg、AUGguguguc、GGGgugagua、AGGgucaggu、UGGguaaggg、AGGguagguu、AUAgugaguu、CCCguaggcu、ACAguaugua、GACgugugua、GCGgugagga、CAGgugaccc、UAAguuuagu、ACAguugagu、CGGgugaggg、CAGguggauu、CGGguagagg、UAGgugcgug、GGGguaagaa、GAGguggggu、CACguggguu、ACGguaauug、AGAgugaguc、UUGgcuccaa、AAGgugaugc、AAGguugguc、AGCguaaguu、AUUguaugua、UCAguuaagu、CAAguacgug、CAGgugcgug、CAGguaggua、AUGguggggu、AUGgugaguu、CAGguaauca、AAGguagggu、CAGgccaagg、GUGgugagag、AAGguuggug、CAGguacucu、UAGgcaugug、UUGguaccuu、CUGgugugcc、ACAguugcca、UUGguaauau、GAGgugcaug、UUGguuugua、UUGguaagug、UGUgugugug、GUGguuugua、GCGguacaca、AGAguaugcu、UUUguaagua、UCUgugcggg、AAGgucagug、GAGguaggaa、GCGguuagca、AGGgugaggg、GAAgugagua、CAGgugacag、AAGgugauua、GAGgccagcc、GAGgucuccu、UAGguauuac、CAUguaagag、CUGguagggc、GAAguaagua、CGGguaagug、CAGguaaucu、GUGguaggua、CAGgugggua、AAGgccagug、AAAgugaauc、ACGguuacgu、AUGguaggaa、CGGgugagac、GAGguuggaa、UGGgugagcc、CCAgugagua、CUAguacgag、CAGguaugac、GCUgugaggu、CUGguaugaa、GGUguacgac、CUUgugagug、GUGgugagca、CUGguaacuu、CAGguacuau、AGGguaaggg、UUGguuaguu、GGUguaagca、UCGgugagga、UGGguaaaca、UCGguacgug、UAGguagcag、CUGguaaggc、GUGguaagga、UAAguaagca、GAGguuccaa、CUGguaugga、GGGgugggua、CAGguuuccc、CAGgucucug、GAGgugagga、CUUguggguu、AUGgugagac、CAGgugaagg、GCGguagggg、GUUguuuccc、AAAgcaucca、GUGguagguu、AAGgugugaa、CAGguacagu、AAGguaccaa、UUGguaauug、AAGgugcuca、AAGguucaac、CAGguuuaca、GCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguu、UAGguaagaa、AGGguauccu、GUGguaauau、UCUguaagua、UGGguaugga、AUGguaugga、GACgugagcc、CUGguuuggc、AUGguauauc、AAAguaaacu、AGCgugagug、CUGguauaga、CAGgugggga、AGAguauguu、UAGguacuug、GCAguaggug、AGUguauguc、AAGguuaagc、CUGguggccu、GAAgugaguc、UUGguguaag、CAGguaagaa、CGGgucucgg、GAGgugcaca、CUCguuaguu、AAGgugauca、UAUguaagaa、GAGgugcuug、CAGgugguca、ACGguaaguc、ACAguaaugu、CCUguaaggu、GAGguuaagu、UCGguaugug、UGGguauguu、AAGguauuac、CAGgugaggg、UUGguaaaca、AAGguagugu、GAGguguggc、CAGguacgga、AAGgucauca、CAAguaggca、CAGgugaaac、CAGguacugc、AAUgcaagug、CAUguaauuc、AAGguaugcu、CUGgugaguu、CAGgugguuu、UGUgugagua、AAGgucggug、AUGguaaauu、AGGguauuac、AGUguaugga、AACguaagau、GUGguaaggu、ACUguuagua、CAGguaucag、AAGguuaguu、CUGgugagcu、UUGgugagcu、UGUguacgua、GAGgucagcc、GAGguagaau、AAGguaugag、UAGguauuuc、UGUguaacac、AGUguaaggc、GAGgucugcu、AAGguuagca、CAGguaaaug、AACguaagcu、CAGgucugca、CAGguauugu、GUGguaauuc、GAGguauaug、GCCgugagcc、GAGguaagag、UGAguaugua、CAGguaaggg、GAGguaaauu、CAGgcaacuu、UGUguaaguc、CAGgugcgcu、CGGguaaacc、CCGgucaguc、UAGgugggcg、GCGgucaguu、GGGguggguc、AGCguaauag、ACGgugaguc、CUGguacuug、CAGguuggua、AGAguaugug、CUGgugggua、GAGguggcuu、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、GAAgugagug、UAGgcaaguc、UAAguaaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGguuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、AGGgugugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaaua、AAGgcaaagg、AGUguuuguu、AUGguauugg、CUGgugaggc、UUGguaaaau、ACAgugaguu、CAGgugcugu、GAGguuaaga、AGAguaagaa、GAGguccgcg、GUGgugagga、CAGgugagcc、CAGgugacau、AUGgcaagcu、UCGguaauau、CAGgcaacaa、GGGguaggga、CUGgucucgc、UAGguaacga、CGGguaaggu、UAGguaaugc、CAGgcaagaa、ACAguaggua、CAAguaugag、GCUguucgaa、AAGguuaugc、GAUgugaguu、CAGguggaga、AGAguuaguu、UGAgugugcg、GAGguacagc、CAGguaagac、CAUgugcuuu、AGGguguguu、ACAguuaagg、ACAgugaggg、GAUguauacc、UUAguaagcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AUGguaugua、AAGguaugaa、UUGgugagcc、AAGguuagga、AGGguaugua、CAGguaccga、AGAguaaacu、AAGgugcaua、AAGguaaugu、CCGgugugug、AGGguaaauu、GGGguuuggc、CAGguacacg、UUGguaacca、GAGgucaggu、UCUguuggua、CAGguuaguu、UUGguauguc、AAGgugcguc、AGGguaagaa、UUUguaagcc、AAGgucaggu、CUGguaaacu、UCGguaauuu、CUGguaggcu、GAGgucugua、GAGguacuuu、CUGguaaagg、CGGgugugug、CAGguguggu、UCGguacguc、CAGgugccag、GGGgugagaa、ACAgcuagua、AAGguauagc、CUGguaggag、GCUguacgua、AAGguaaagg、CAAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugcug、GAGguacugu、UAGguaagau、CAGgugcgaa、GAGguccagg、UUGguauaca、GGAgugagua、GAGgugagau、AAGguggggc、CAGguaaacg、UCGguaacuu、CAGguaaauu、GAGgugcgca、ACUgugagua、ACGgugugac、GUGguaaguc、CAGguaggca、CAGgucagca、GUGguaugug、AAAguaucug、CGGguaugua、AAGguaauaa、GAGgugggga、GCUguaggug、GAAgugaguu、AAAguauuua、UAUguaagua、ACGguaugag、CUGgugagug、AGAguaaaau、GCUguauggc、AUGguaaacc、GCAguaauaa、UAAguauuua、AAUgucagug、AUUgcaggag、CCGguaagaa、AAGgcaaguu、GAGguuuguc、AAGguaacug、AAAguaugag、GAUguuagua、CAGguggguc、AAGguaccga、CCAguaauua、GUGguaugcg、AUGgugcgcu、CAGgucuaug、AAGguauuua、CUAguaagau、AGAguaauuu、GAGguaacgu、AAGguagcca、CUGgucccgg、GAGguccuuc、ACGgucaccc、AAGguaauac、CAGgugcaug、AUGguaauag、UUUguaacac、UGGguaugau、CAGgcccccc、AGAguaguaa、AGUguaagaa、GAAguauguu、CAGgugugca、UUGgugaggg、UGGguugguu、CAGguacgua、GAGgugcggc、UCUguacggg、CGGgugcgug、UACguaagug、CAUguaagga、CAGgugacgg、GAUguaugcu、UCUgcaauuc、UGAguaaggc、GAGguauauu、AGAgugaguu、AAGguaagcu、UAGgugaagu、CAGguuagua、UAUguaagug、UUGguggggg、UGAgcucaaa、UCGguaugua、UAAguaugcc、AAUguaagua、CAGguuugca、ACGgugagag、CAGguguuuu、GUGgugagcc、AGGguacaua、UAGguaaccc、GUGgucagua、CUGgugagcc、CAGgugcuua、AUAgucguga、AUAgugagug、GAGgucaaaa、CGUguagcuu、CAGguguuug、CAGguuggac、CAGguaagcu、AGGgucagaa、CACguauguc、CACgugagug、GGGguacgga、AAGgcaggac、GAGgugaagc、GAGguuugaa、CAGguaagug、CAGguaacca、CAGguacucc、AAGgugcuuu、GAGguaaaua、GAGgcaggug、GAGguucgga、CAGguauuug、CAGguaaaua、CAGgugaugu、CAGgugauac、GAGgugaggc、AGGguggggg、UAAguaaguu、UGGgugaaca、UAGguacugc、CAGgcuccug、AGGguaggca、CAGgugcccg、GAGguacauc、AGGgugugug、AAGguaguaa、UGGguaugag、GGGgugugug、CUAguaggug、GAGgcaagga、AAGgcaagac、AAAgugcggu、AAGguugguu、GAGguuaaug、UUGgugaguc、UCGguuagcu、GCAguaagca、AAGgcaagca、ACAguaagcu、GAGguaacag、AAAguacgua、GAGguaauac、UUGguaggug、CUGguuaguc、GAGgugacgc、ACAguaagga、AAUguacuua、GGGguacagu、CGUguaugug、UCCguagguu、GAGguggucg、UCAgugaguc、AAAguaagca、GAGgucuggu、GAGguaauua、GUAguaagua、AAGgugggga、UCUgugagca、GAAguucgug、ACGgugaggc、UCAgugagua、UAGguaguug、GGUgucuggg、GGGguaagug、GAGguggguu、UGUgugaguu、CAUguaagua、AAGguaggug、AAUguaggag、GAGgcacguc、CAAguacauu、UUGguacaga、GAGguaguag、AAAgugaggg、UUGgucagug、AGGgugaguc、CAGgugaaca、GGUgugggcc、CGGgugagcu、GGGgugaguc、ACAgugagag、AGGgugaggu、GCUguaaguc、AUAguagguu、CAGgcaugug、AAGguaaguu、CAGguccgug、GAGgcaggua、AUGguggaag、AUGgugggcg、GAGgugagaa、AGUgugagca、UUGguaagua、CAAguaagca、GGUgugagcu、CCCgugggua、CAGguagaau、CAGgcugagc、CUGguggccc、UGAguaagag、CACguuagcu、AAGgugaguc、AAGguagcuc、UCGgugaguu、GAGgcccuuc、CAGguuaugc、CCUguaagcu、CAGgucuccu、UAGguaggcu、GGGguagggg、AAGguaguga、GAGguuguug、CAGguugguu、AAAguaagcc、ACAgugagug、UGGgugugau、CCCguaacua、AAGguguugc、AAAgcuggug、GAGguauagu、ACGguaagag、AUGguacggu、GAGgccaguu、GAGguaugcg、UCGgugggag、AAGguggaua、CCAguguggc、AGGguaagug、UCUguagguc、CAGgcaagga、CGGguaauuu、AUUgugaguc、CAGguaaacc、AAGgucaauu、AAGgugaaua、GUCguaagaa、GCGguaaguc、CUGguagagc、GAGgucgguc、CAGguaaaca、AAGgcaagga、CAGgucgucu、GGGguagggc、CUGguacuaa、GAGguagcug、CUUgucagcu、UAGguaaggc、CUGguauuac、UAAguacguc、AAGguaagcc、ACGgugaaag、CCAgccaaua、CAGguuuguc、AAGguauaau、AAGgucuuag、AGGgugagcu、AAGguuaggg、CGGguaaauu、CAGguaacgg、AGAgugugua、ACAguaaguu、GAUguaauuu、GAGguaggga、UUGgcaagug、AAAgugagga、AAGguagugc、AGAguaauuc、GGAguaaaua、GUGguaccca、CAGguauugc、GAUgugaggg、CAAguaaauc、CAGgugucuc、AAGguaacag、UUGguaaaag、CAGguaucau、ACGgugagac、CUGguaugac、CAGguucacu、GAGgugauca、AGUguaaguc、AACguaagua、AAAgugagug、GAGguacagg、CAAguaauga、GAUguaagga、UCAguucccc、GCGguaagga、UAGguacuaa、AAGgugaaag、ACUguaagug、UGGguaugug、AUGguaacag、CAGguagggu、ACAguaagug、AAGgugcucc、AAGgugugcu、AAGgugguga、ACGgugcgcc、AAGguauugc、GGGguaugug、CAGgugggcu、GAGguauguu、AACgugaaua、CAGguaaugg、UAGguaugau、CAGgcaggug、GGGguugguc、AAGguauggg、UAAgugaggc、CAAgugaucg、AAAguacggg、AGAgcuacag、GAGgugggaa、CAGguacuuu、GAGgugagag、CAGguagguc、UGGguacagc、AAGgugucag、AAGgcaagaa、GAGguaaaca、AAGguaaagu、AAGguaguca、CUGguauguc、GAGguauggg、AAGguauugu、CUGguacuga、GAGguaagcu、UGGgugggua、CAGguucgug、AAGguauggu、CAGgugagca、UGGguaaauu、UGUguaggug、UGUgugagcc、CUGguaauau、AAAguauguu、UGUguaagaa、CUAgugagaa、AGGguagguc、AAGgugggug、UCGguaagug、AGUguaaaua、GAUguaagug、AAGguuagug、UAGguaagca、CAAgugagaa、AGUguaagua、CAGgugaauc、UGGgugagac、AAGguagggc、CUGguuugug、GCGguagggc、GAGguaaucc、AUUguaauaa、CUGgugaaua、AAGguuuaaa、CCUguacugu、GCGgugagcg、AAGguaaucc、UAUgugagua、CCCgugagug、CAGgugcaga、CAGgucaguu、CAGguaggcu、AAAguaagug、UAGguugguc、CAGguugccu、AAGguaugga、GGUguggacg、AAAgugagaa、AGGgugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguacggg、GAGguucuug、AAGgugcuug、UAGguaugua、AUGgucagca、CGGguacuca、AGGgugagga、AUCgugagua、UCAguaagua、UAGguaaaua、AAGguaauug、GAAgucagug、CAGguacaaa、AAAguuaauc、AGCgugagcg、CCGgcuggug、AGUguaauuu、UGAgccacuc、GGGgucugua、AUGgcauguc、CGGguaaaga、AGGguagcau、CGGguaggag、GAGguucgug、UAAguuauuc、UAUguaagau、AAGguaguuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AAAguuagug、AAGgugccuu、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、UAUgugagug、CAGguggagg、CAGguuagac、AUAguaagac、AAGguguugu、GAGgucugug、AAGguaagau、CAUguaaguu、CUGguaauua、CAGguaggcg、AGAguaaguc、UGGgugagga、AAUguaggua、UAGguuagca、GGGguaggua、GAGguauugc、AUUguacaca、GAAguaggua、GGAguaagcu、UAGguaugug、GAGgugaaua、GAGgugggau、AAGguaaucu、GGUgugaguu、AACgugaguu、GAGguaaccg、UAGguaagga、AUUguaagaa、UGGgugagca、AAGguaaggc、CCAguaucgu、CCGgugggug、GAGguagugu、ACGgugggaa、GAGgugaccu、CACguaugua、AGGgugggga、AAUguaaguc、AAAguuaagu、CAUgugagug、AGAguauguc、GCGguaugac、CGGgugaguu、CCGguauuuu、GAGguagaac、UAGguaugaa、CAGgcgcgug、CAAguaaguc、AGUguaagau、AAGguucuac、CCAguaagua、GAGguagcag、CAGgucuguu、CAGguacaau、CCGguaaaga、UAAgugcugu、AGGgugagaa、CUCguaaggu、CAGgucagcu、CAGguaaggc、AGGgugcagg、GAGgugaaac、AGGguaagua、AAUguaugcc、AAGguaagca、ACGguacggu、AAGguaauga、UCUgcucaau、ACGguaaugu、AAGguaguug、ACGguaagug、CAGgugauga、GAGguaacac、GAGguaggua、CAGguaccuu、CAGguaauaa、UUGgugggug、CUGguaauga、UAGguaaguc、AGGgugugac、GAGgcaauaa、GUGguaaagc、CUGgugggcg、GAUguauguu、AGGgugagac、UCGgucagca、AUGgugauua、CGAgugugua、CAGguuggug、AGCgcaagua、UGGguacguu、GAGguauuug、AGUguacaua、AUGguaagua、ACAguagguu、AAGgugagag、UUGgugaagu、AAAguaugua、UGGguaagga、UAGgugccuu和CCUgugggug。
另外的示例性基因序列和剪接位点序列(例如,5’剪接位点序列)包括UCCguaaguu、GUGguaaacg、CGGgugcggu、CAUguacuuc、AGAguaaagg、CGCgugagua、AGAgugggca、AGAguaagcc、AGAguaaaca、GUGguuauga、AGGguaauaa、UGAguaagac、AGAguuuguu、CGGgucugca、CAGguaaguc、AAGguagaau、CAGgucccuc、AGAguaaugg、GAGgucuaag、AGAguagagu、AUGgucagua、GAGgccuggg、AAGguguggc、AGAgugaucu、AAGguaucca、UUCguaagua、UAAgugggug、GCCgugaacg、GAGguugugg、UAUguaugca、UGUguaacaa、AGGguauuag、UGAguauauc、AGAguuugug、GAGgucgcug、GAGgucaucg、ACGguaaagc、UGAguacuug、CGAgucgccg、CUGguacguc、AGGguauugc、GAAgugaaug、CAGaugaguc、UGGguauugg、UGAguaaaga、GUGguuccug、UGAgcaagua、UAUguaagag、AAGgucuugc、AAAgcaugug、AGAguacagu、GUGguaaucc、CAGguagagg、AAGguacaac、UGGgcagcau、CCGgucauca、CCGguuugua、UGAguaaggg、GAAguaugua、GGGguagcuc、GCUguacaua、CUGgucucuu、GUGguaaaug、AUCguaagug、GAGgcaugua、AAGgucuccc、UGGgugcguu、UGUguagguu、GAAgugagca、GGUguaauuu、CUGgugaaau、AUCguaaguc、AGAguaaucc、GGAguagguc、GAGguaccaa、CUUguaggug、AAGguauaag、AGAguuggua、AUGguuugug、UGGgucagau、AGAguaggac、AGAguagugu、AGAguaggag、CAGgucucua、AAGguggaug、UGGguaucaa、GAUguaugga、AAGguguuuc、GCAguguaaa、UUAguaugua、UCUguaugca、AAUguaaaau、AGAguaaauu、GGGguacuuu、GAAguuugau、AAAguagauu、UGUguagagu、UGGguaagcg、CGGguucagg、AGGguacgac、UCGguaagaa、AGGguuggca、AAAguacagu、UAAguuaagg、AUGguaaugu、GUGguuuuac、AGAguaacaa、AAGguagccc、GCGgugaggc、AUGguucagc、AAGguacuua、AAGguccgug、UAGguaagcg、AUGguaccuu、GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、AAGgugccag、ACGgugcggc、AGGguacuga、AGAguaagcg、CUGgcaaggg、CCAgugugug、GAGguagacg、CGGgugcggg、GAUguaagcu、AUUguauuua、UGCgugagug、CUGgucuaua、GAGgugcuag、GAGgugccau、CAGguacguc、GAGguucagc、AACguaagaa、AGAguaguac、AAGguaacgg、UAGgugugac、CCGguaauag、CAGguaccag、UUUguaauug、AAUguacgaa、CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgugagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AAGgugccau、GGGgucccag、UAUguauggu、CGGguaauua、CGGguacucc、CAGgugacuu、AGUguggguu、AGAguauggc、AAGgccaaca、AAAgcaagua、UCAguagguc、GUGguggcgg、CAUguauccu、UCGgugagcc、AUAguugggu、AAUguuagcu、AUGgugaaug、CGGguaaugu、UCUguaggug、CCGgugaggc、UGAguccacu、CUAguaagag、CGGguggggc、CGAguaagca、UGUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、GGGguacagc、CAUguaaguc、AUUgugagaa、UGUguaagga、UUUguaagau、AGGgucauuu、UGGguuuguu、CGAguaagcc、GUGgugugua、AUGguauaac、UGGguacgua、AAAguagagu、UCGguaacug、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAAgucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、GAGgcauggg、AUAgcuaagu、GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACguaacuu、CAGguuacua、AGAguuaguc、UGGgcacguc、AGUguauggu、AAGguugcaa、CAGguuguua、AAGgcauccc、GAUguaaggc、AGGguacggg、GAGgucaaag、CAAgugagcg、AGAguaaucu、UCGguagcug、AAAguaguag、CAGguucguc、CGUguaugaa、AGUguaaaaa、AAGgucucac、UAGguggagc、UGAguaggug、AGAguaugcc、GAGguugcau、CAAguaagag、UCUgugugcc、GAGgugaugc、GGGgugauaa、CCCgugagcc、AGAguaacug、GCGguaagua、AGAguacauc、UCGgucuggg、UAAguaucuc、GGCguagguu、AGAguacgcc、GAUgucuucu、AGGgcaaggu、CGAguaugau、AUGguagagu、CAAguacgag、UCGguaugau、CCGguguguu、AGGgucugug、GGAguaggcu、AAGgucuaug、GCAgugcgug、UGGgugagaa、AGGguaaagu、GAGguaggac、CUAguaagca、UUAguaggcu、CUGgugggau、CUGguuagua、AAGguacgug、CGGgugagau、AAGgugcaug、AAUgugggcu、CAGguugacu、CAGguuacag、GCGguaacau、AUUgucaguc、CAAguauaca、GAUguccgcc、AAGgugcgga、AACguaagag、UGGguuggua、CAAguguaag、GUGguaacgu、CUGgugauca、AGGguggggc、UCGguaaaga、CAGguacacc、CGGguaaggg、CAAguuugcu、ACAgugcgug、UUGguauggg、GAGgcucauc、CUGguaauag、AUGguggaua、UCAgugaauu、AAUguaauua、GCAgucuaaa、AAGguauucu、GAGgucauca、UGGguccaug、AGAguuugua、AGGguagacu、AAGguaggac、UGUguguuga、UCAguacgug、AUGgucucuc、UGAguuagua、UGAguaaagu、GAGgugaccg、GAGguauauc、CAGgugccau、AGAgugguga、GUUguaagaa、AGAguaaaua、AGGgugaagg、CUGguagauu、GAGguucagg、AGGgucuuca、CUGguaaccu、ACAguacuga、AGAguggguc、AUGguaugag、AAGguuauau、AGAguauagu、AAAguaugaa、UAGguggcua、ACCguauggg、AAAguauaau、UUUguauggc、GGGgucgcgu、GUGgugguuu、CAGguuugac、GGAguaggcg、GAGguacccu、AUGgugugca、GUGguuggug、AAAguaugcu、UAAguuacau、ACAguaugag、GGAguauguu、UUUgugagaa、AAUgugcguu、CAGguagagu、AUGguguuaa、CAUgugcguc、AUAguuggau、GAGguacgua、GUUgugagaa、CAAguacauc、GAGguaguuu、ACUguacaga、CCGguuguga、UGGgucagug、GUAguaagaa、GACguacuuu、AGAgucaguc、UAGguuaguu、AGGgcagcag、AAGguccuac、AAUguaauug、CAGgugcggg、CUGguaaugg、CAAguagccc、GAAgucaguu、ACAguaauug、UUAguuagua、CCUguauuuu、AUCguaagaa、CCAgugagca、GAAguaaggc、UGAgugggua、UCAgugguag、UCUguacagg、CGAgugagug、UCCguaugug、CAUgccguuu、AAAgugacuu、AGAguaggca、GAAguaagag、CAGgcagguu、UUGguagagc、AAGguggaaa、GAGgcagguc、AUGguacgac、AGGguaggaa、AGGguaggua、UUGguaaggu、AUGguacaga、CAGguagagc、UAGguaaggu、GGGguuagag、AAGguaucaa、GAGguagccc、CAGgugccuc、GCAguaagag、ACGguagagu、UGGguaaugg、CUGgucaguu、GUGguacauu、AAAguagguu、AAGgccaaga、CGGgugggca、ACGguccggg、CGAguaugag、CUGguaugcc、GAGguggaug、CAGgccuuuc、AAAguacauc、AAAguaauca、GAGguaacug、CUGguaaaga、CGUguaagca、UGGgcaagua、GCGguggcga、GAGguggccg、AUUgcaugca、ACGgugacug、CAGgucagau、AGAguaacuc、UGAguaacag、AAGguacccg、AGGguaggcu、GGGgcaggac、CCUguaagug、AUUguaagug、ACUguacgag、GUAguagugu、AGAguaugag、UCAguguggg、UGGguauaua、UAGguagcua、GGGguaaaga、AGGguuacuu、CAUguaaaug、GGAguaguaa、CAGgucaauc、CGGguuagug、UAGguacaug、UAGguuaaga、UGGguaccuu、CGGguggaca、CAGgucuuac、AAGguggagc、AUGguaacca、UCGguaaguu、UAUguacaaa、AAUguagauu、GUAgcuagua、AAGguauugg、GAGgucuuug、GAAguucagg、UGGguaucac、AGAguacugg、CAGguuaaug、AGGguacgug、AGGgcacagg、CUGguuaguu、UUGguacgag、ACGgugauca、CCUgugagag、GAGgugaagu、AAGguacauc、UCUguaugug、UUGguggaag、UGGgcagguu、GAAguggagc、ACAguaagac、CGGguaccaa、CAAguacguc、AGAgugaggg、CGGguaagaa、AAUguaggug、AUCgugugcu、UAGgucaugg、CAGguuuuga、AAGgcaugca、GAGgugcugc、AAGguuaaua、CAGguucauc、GCGguaggug、GACgugagua、CAGgucuacu、UUGguaugag、AGCgugggca、AUGguaaggu、AUGguaccuc、UUGguauggu、UAUguaugaa、UGGguauggg、GAUguaaaua、CCGguaaguu、GAGgucugaa、GAGgugcgag、CUGgucagcc、CAGguuuugu、CGGguggugu、UAAguuagua、UUUgugugug、CAGguuaacc、UUGguacuuu、GCUguaaggc、AGGguggcug、GAUguaaaaa、AAGgucaaaa、CAGguagcgc、CAGguuuggc、GAGgugguuu、CGGguaaaua、CUGguucggu、GGAgugagcc、AAGgugcgcg、GAAguacauc、AGUgucugua、CCCgugagcu、GAGguucaca、CUAgugggua、GAGguaacua、UCGguauguc、UAAguauuug、CAGguaagcg、GAGgugguaa、CGAguaagag、CCGguaagcu、GAGgucuugu、AAGguggguc、CACguaagug、AGUguaauga、AAAgugugua、GGAgugccaa、CACgugaguu、AAGguuggau、UAUguaaaua、CUGguaggaa、UAUguaaacu、AAUguauuuu、CUGgcaagug、UGUgugguau、UAUguauguu、UUGgugacuc、GGAguaaggu、AAGguagaug、UGGguagggu、AAUguaauuc、GUGguauggc、GGAguggguu、AGGguaccac、UAGgugacag、ACAguaggca、AUGguuugaa、GCAguaacua、CCGguaggua、AGAguaggcc、AAGguugaca、CUGgugugua、GAAgucuguc、UGGgcucgga、CAGguagccu、AGAguaggua、UAAguauguc、CUGguauauc、GAGguguguu、AUGgugcaug、AAGguacgcc、UGAguaacua、GAGgugacag、GUUguccugu、UUGgugucuu、AAUgugaagg、UUGguggaua、UAGguguguu、CUGgcaaguu、GCAguaagau、GCGguggaaa、UGCguccagc、AAAguggagu、CGUgugagcc、AGAguacugu、CAGguauagc、UACguaagga、AAGgucuuua、AAGguggucu、GGGguaaauu、UCAgugagga、AGAguacguu、GAGgucguca、UAGguuugau、CAUguaaacc、AAGguggcac、CAGguagaug、AACguaaaag、UAGgucucug、AUAguaggug、UAGgcaagag、UAGgcacggc、AAGgucuuca、CCAguaugcu、CAAgugaguu、CAGgucucaa、CAGguuacau、GGAgugagca、AGAguacgca、CUGguguugg、AAGguacuca、CUAguaaggg、AGAguaaaag、AAGguaacga、CUGguccccg、UAAguauggg、GAGgucgagc、UUGguauaua、AAAgucaagg、AAGgucuagg、CGAguagguc、AGGguucguu、GAGgcaggcc、CUAguauuac、ACGguaugug、UAGgugguuc、AGAguauaac、UUGgugcguc、ACCguuaucu、CCAgugauga、GAAguaugca、GAAguauggc、CCGguaggac、AAUguaagca、AGAguaauug、AGGguugguu、GUGguaggag、AAGgcaguuu、CAAguaagcc、CUGgcaagua、CAGgcaugau、AGGguaauug、GGGguaaccu、AAAguaacua、UAGgucugcc、ACGguaugaa、AGUguauggg、UGGguuggca、UAGguaaacu、AGAgugggua、AGAguauuug、AGUguaggaa、CUUguacgua、GAUgugagau、CAGgcagcca、AAGgucacug、AAGgucugac、UAGguuccuu、CUGgugcuuu、UGAguuggug、UUGgugggau、UGAguagggu、UCGgugaggu、AAAguaaaga、AAGgcaaguc、CGGguaaagc、AAAguuaguu、UUAguaagca、GAGgucacau、UAAgugguau、UAGgugcuuu、GGAguaggca、UGAguaagga、CAGguggagc、GAUguagaag、AAUgccugcc、AUGguaaggc、UGGguaauau、CUGguaccuc、CACgugagcc、UGAguuugug、CCGguagugu、AAAgugacaa、GAAguggguu、CAGgugcagc、GAGgugggcc、UAUgugcguc、GGGguacugg、CUGguagguu、UUGgcauguu、AAUguaauac、UAGgccggug、AGAgucagua、UAAguaaauc、CAGguuccuc、UAGguacgau、AGAguuagug、GCAguaagug、AGGgugguag、GGAguaaugu、GAUguaaguc、CCAguuucgu、AAGguucggg、AUGguggagu、AAGguaccgg、GAAgugcgaa、UGGgucaguu、AAGguguaga、UGGguaggcc、CCAgugaguc、AAGgucacuu、AGCgugaggc、UCCgugguaa、AGAguacuua、GGGgucagau、AAGguggacc、AGAgugagcg、AGAgucagau、UAAguauuac、AGAguauuuc、AGAguucagc、AUGgugaagu、UAGgugaucc、GGAguaagau、UAGguaccaa、AGAguugguc、GAAgugagac、AUCguagguu、GAGguacgcu、ACGguaaggg、CAGgcauguc、UUAguaagau、UGAguagguu、AGGguacgaa、ACGguauguu、AGGguacugu、UUGguaugga、UAAguaacug、GCGgucagcc、UUUgugaguc、GUGgucagug、CUGgucugua、GAGguucuua、AUGguacuga、AAUgugcuuu、AGGguggcgu、CCGgcaggaa、CAUguggguc、UUGguuuguu、CAGguucugu、ACGguaagcg、CUGgucagua、UCAguaggcu、UGAguaggac、CAGguuuuaa、GAGguguccc、AGGguggguu、GUGgugagac、CACguaggga、GUGguauuuu、GAGauauccu、AAGgugaaca、UAAguagggc、CUGgugcggg、CUGgucaaua、AGAguaaaaa、AAGgugcagu、CGGguaagca、AAAgugagcc、AUGguaauca、GCAguacgug、AUGguacaug、AAGguuaaga、CGGguaaaug、GAGguucgca、GAGgcucugg、AUGgugggac、AACgugguag、AAGgugauag、GGGguuugca、CAUguaaggg、UCAguugagu、AAAgugcggc、AGAgugagcc、AUGgcaagaa、ACAguaaggu、AAGgucucua、GUGguaaaaa、AAAguaggug、UAGgugcacu、GUCgugguau、CAGguauagg、UGAgugagag、ACUgugagcc、AUCguuaguu、UUUguaccaa、UGGgugagau、AGAgugagaa、AGAguagggg、AGGgcaagua、CGGgucagua、UUGguaugcc、CGGguuagau、GGGgugaagu、CCCgugugaa、GCAguuugga、UGCguaagac、AGAgucugua、CACgugagca、AGGguaaaag、CAGgcugggu、GAAgucuuca、AAGgcaaaaa、GUAguaaaua、CUAgugagag、GAAguuucug、CCUguacgua、GAGgugcgcg、AAGguguaaa、CCAguauguu、CCGgucagcu、AUGguuccug、CAAguuaaau、AGAguaggcu、AUGgugggca、GGAguaagac、AGGgucacga、UAGgugauau、GAAguaaguc、CGGguaagau、CAAguagcua、UGAguaaaau、GUCguacgug、AUGguacgua、CAGgucucgg、GAGgcauguc、AGAgugggau、GUGguuagag、UGGgugguga、AAGguuaaac、CUUguuagcu、AAAguaggaa、UAGguuguau、AGGgugcgcc、AAGgugggcu、UAAguaucug、AAGguaacgu、AUGguggggc、CAAguacacg、GGCguaagug、AUAguaggac、AGAgugaggu、UUUguaaaaa、GAAguuugua、CUAguaaucu、AAGguuuuua、GAGgugcguu、UAGgcgagua、ACCgugagua、CAGgucccga、AUGguacugg、UGAguucagu、AAUguguggu、UCCguugguu、CAGgucagag、CAGgucccua、UAGguagacu、CAAguuaagg、GAGgugugcg、GAAgcugccc、CGAguacgug、CGGguaggua、UUGguauuga、AUUguaugau、UUGguaugaa、GAGgugguca、GCUguaugaa、CAGguguugc、CAGguaaaac、AUAguaaggu、CUGguuagag、AGCgugugag、AAGguuaucu、CACgugagua、AGGgucagua、GAGguauaau、CAGguuauuu、AGGguggacu、AUUguaauuc、UUUguggguu、AUGguacgug、AAGguguucc、CAGgugacgc、GAGguacuaa、ACAguucagu、GAGgucacgg、CAAguaaggc、AAGguuuggg、AAAgugggcu、GCGguucuug、GAGguggagc、UGAgucagug、CAGgucaagg、AGUguaagcu、GAGgcagaaa、AAGgucacac、GAAguagguu、GUCguaaguu、AGAguaugca、CCUgugcaaa、ACGgugaaaa、CAGguacgaa、CAUgugagga、AGCgugagua、GGUguguagg、AACgugagcu、GAGgugaacu、AGAguucagu、AACgugugua、CAGguugugg、AAGguacuag、UCAgugaaaa、AAUgucuggu、ACGguaaaau、CUGguguaag、GAGgugcgaa、AGGguuucuc、CAGguagccc、AUUguauugg、AUGguacuua、GAGgcccgac、UCGguaagac、CGGgcuguag、UAUgugugug、UAGguagaaa、GUGgucauua、UAGgugaaag、ACUguaauuc、GCAguacagg、UCGgugaguc、UAUguaggga、AUGguauguc、GUGgugugug、CUGgugaccu、AAUgugaaua、UAGgucucac、GAGguuauug、UGAguaggcu、CGGgcacgua、GCAguaaaua、CCGgugagag、UAAguugguc、CCGgugagcc、AAGguuguca、CUGguauuau、GGGguauggg、AAAgucagua、UUUguaugua、UAAguacugc、CAGguaccaa、GAAguucaga、AUGgugcggu、GUGgugaggu、UGAguaagcc、UAUguaaggg、GUGguggaaa、GAGgugauug、GGAguuugua、AAGgucacga、GUGguagagg、UAAguauauc、AAGgugucca、UAUgugguau、GAGguacaau、AAGguggggg、GGAguaggug和UAGgugacuu。
在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AGA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AAA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AAC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AAU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AAG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含ACA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AUA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AUU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AUG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AUC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CAA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CAU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CAC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CAG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GAA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GAC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GAU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GAG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GGA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GCA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GGG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GGC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GUU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GGU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GUC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GUA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GUG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UCU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UCC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UCA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UCG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UUU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UUC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UUA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UUG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UGU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UAU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含GGA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CUU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CUC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CUA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CUG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CCU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CCC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CCA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CCG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含ACU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含ACC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含ACG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AGC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AGU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含AGG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CGU。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UAC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UAA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含UAG。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CGC。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CGA。在一些实施例中,剪接位点序列(例如,5’剪接位点序列)包含CGG。在一些实施例中,剪接位点序列包含AGAguaaggg。
在实施例中,本文提供的基因序列或剪接位点序列与增殖性疾病、障碍或病症(例如,癌症、良性肿瘤或炎性疾病)有关。在实施例中,本文提供的基因序列或剪接位点序列与非增殖性疾病、障碍或病症有关。在实施例中,本文提供的基因序列或剪接位点序列与以下有关:神经疾病或障碍;自身免疫性疾病或障碍;免疫缺陷性疾病或障碍;溶酶体贮积病或障碍;心血管病症、疾病或障碍;代谢性疾病或障碍;呼吸病症、疾病或障碍;肾脏疾病或障碍;或传染性疾病(于受试者中)。在实施例中,本文提供的基因序列或剪接位点序列与神经疾病或障碍(例如,亨廷顿病)有关。在实施例中,本文提供的基因序列或剪接位点序列与免疫缺陷性疾病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与溶酶体贮积病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与心血管病症、疾病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与代谢性疾病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与呼吸病症、疾病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与肾脏疾病或障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与传染性疾病有关。
在实施例中,本文提供的基因序列或剪接位点序列与精神发育迟缓障碍有关。在实施例中,本文提供的基因序列或剪接位点序列与SETD5基因中的突变有关。在实施例中,本文提供的基因序列或剪接位点序列与免疫缺陷性障碍有关。在实施例中,本文提供的基因序列和剪接位点序列与GATA2基因中的突变有关。
在一些实施例中,本文描述的具有式(I)的化合物与剪接复合物组分(例如,核酸(例如RNA)或蛋白质)相互作用(例如结合)。在一些实施例中,剪接复合物组分选自9G8、AlhnRNP、A2 hnRNP、ASD-1、ASD-2b、ASF、BRR2、B1 hnRNP、C1 hnRNP、C2 hnRNP、CBP20、CBP80、CELF、F hnRNP、FBP11、Fox-1、Fox-2、G hnRNP、H hnRNP、hnRNP 1、hnRNP 3、hnRNP C、hnRNPG、hnRNP K、hnRNP M、hnRNP U、Hu、HUR、I hnRNP、K hnRNP、KH型剪接调节蛋白(KSRP)、LhnRNP、LUC7L、M hnRNP、mBBP、肌盲样(MBNL)、NF45、NFAR、Nova-1、Nova-2、nPTB、P54/SFRS11、多嘧啶束结合蛋白(PTB)、PRP蛋白(例如,PRP8、PRP6、PRP31、PRP4、PRP3、PRP28、PRP5、PRP2、PRP19)、PRP19复合蛋白、RBM42、R hnRNP、RNPC1、SAD1、SAM68、SC35、SF、SF1/BBP、SF2、SF3A复合物、SF3B复合物、SFRS10、Sm蛋白(例如,B、D1、D2、D3、F、E、G)、SNU17、SNU66、SNU114、SR蛋白、SRm300、SRp20、SRp30c、SRP35C、SRP36、SRP38、SRp40、SRp55、SRp75、SRSF、STAR、GSG、SUP-12、TASR-1、TASR-2、TIA、TIAR、TRA2、TRA2a/b、U hnRNP、Ul snRNP、U11snRNP、U12 snRNP、U1-70K、U1-A、U1-C、U2 snRNP、U2AF1-RS2、U2AF35、U2AF65、U4 snRNP、U5snRNP、U6 snRNP、Urp和YB1。
在一些实施例中,剪接复合物组分包含RNA(例如,snRNA)。在一些实施例中,本文描述的化合物结合剪接复合物组分(包含snRNA)。snRNA可以选自,例如U1 snRNA、U2snRNA、U4 snRNA、U5 snRNA、U6 snRNA、U11 snRNA、U12 snRNA、U4atac snRNA及其任何组合。
在一些实施例中,剪接复合物组分包含蛋白质,例如与snRNA相关的蛋白质。在一些实施例中,蛋白质包含SC35、SRp55、SRp40、SRm300、SFRS10、TASR-1、TASR-2、SF2/ASF、9G8、SRp75、SRp30c、SRp20和P54/SFRS11。在一些实施例中,剪接复合物组分包含U2 snRNA辅助因子(例如,U2AF65、U2AF35)、Urp/U2AF1-RS2、SF1/BBP、CBP80、CBP 20、SF1或PTB/hnRNP1。在一些实施例中,剪接复合物组分包含异源核糖核蛋白颗粒(hnRNP),例如hnRNP蛋白。在一些实施例中,hnRNP蛋白包含A1、A2/B1、L、M、K、U、F、H、G、R、I或C1/C2。编码hnRNP的人基因包括HNRNPA0、HNRNPA1、HNRNPA1L1、HNRNPA1L2、HNRNPA3、HNRNPA2B1、HNRNPAB、HNRNPB1、HNRNPC、HNRNPCL1、HNRNPD、HNRPDL、HNRNPF、HNRNPH1、HNRNPH2、HNRNPH3、HNRNPK、HNRNPL、HNRPLL、HNRNPM、HNRNPR、HNRNPU、HNRNPUL1、HNRNPUL2、HNRNPUL3和FMR1。
在一方面,具有式(I)的化合物和药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体及其组合物可以调节(例如,增加或减少)靶核酸序列(例如,DNA、RNA或前mRNA),例如编码本文描述的基因的核酸、或编码本文描述的蛋白质的核酸、或包含本文描述的剪接位点的核酸的剪接事件。在实施例中,剪接事件是可变剪接事件。
在实施例中,例如,如通过本领域已知的方法(例如qPCR)所确定,具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体和组合物将靶核酸(例如,RNA,例如前mRNA)上剪接位点的剪接增加约0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或更多。在实施例中,例如,如通过本领域已知的方法(例如qPCR)所确定,具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体和组合物将靶核酸(例如,RNA,例如前mRNA)上剪接位点的剪接减少约0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或更多。
在另一方面,本披露的特征在于形成复合物的方法,该复合物包含剪接体的组分(例如,主要剪接体组分或次要剪接体组分)、核酸(例如,DNA、RNA,例如前mRNA)和具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或组合物,该方法包括使该核酸(例如,DNA、RNA,例如前mRNA)与所述具有式(I)的化合物接触。在实施例中,剪接体的组分选自U1、U2、U4、U5、U6、U11、U12、U4atac、U6atac核小核糖核蛋白(snRNP)或相关辅助因子。在实施例中,在具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或组合物的存在下,剪接体的组分被募集到核酸中。
在另一方面,本披露的特征在于改变核酸(例如,DNA、RNA,例如前mRNA)的结构或构象的方法,该方法包括使该核酸与具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或组合物接触。在实施例中,改变包括在核酸(例如,DNA、RNA,例如前mRNA)中形成凸起或纽结。在实施例中,改变包括稳定在核酸(例如,DNA、RNA,例如前mRNA)中的凸起或纽结。在实施例中,改变包括减少在核酸(例如,DNA、RNA,例如前mRNA)中的凸起或纽结。在实施例中,核酸(例如,DNA、RNA,例如前mRNA)包含剪接位点。在实施例中,具有式(I)的化合物与核酸(例如,DNA、RNA,例如前mRNA)的核碱基、核糖或磷酸部分相互作用。
本披露还提供了用于治疗或预防疾病、障碍或病症的方法。在实施例中,疾病、障碍或病症涉及剪接事件(例如,由剪接事件引起),例如非意愿的剪接事件、异常的剪接事件或可变剪接事件。在实施例中,疾病、障碍或病症包含增殖性疾病(例如,癌症、良性肿瘤或炎性疾病)或非增殖性疾病。在实施例中,疾病、障碍或病症包含受试者中的神经疾病、自身免疫性障碍、免疫缺陷性障碍、心血管病症、代谢性障碍、溶酶体贮积病、呼吸病症、肾脏疾病或传染性疾病。在另一实施例中,疾病、障碍或病症包含单倍剂量不足疾病、常染色体隐性疾病(例如,具有残留功能)或旁系同源活化障碍。在另一实施例中,疾病、障碍或病症包含常染色体显性障碍(例如,具有残留功能)。这样的方法包括以下步骤:向有需要的受试者施用有效量的具有式(I)的化合物或其药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体或其药物组合物。在某些实施例中,本文描述的方法包括向受试者施用有效量的具有式(I)的化合物或其药学上可接受的盐或其药物组合物。
在某些实施例中,治疗的受试者是哺乳动物。在某些实施例中,受试者是人。在某些实施例中,受试者是驯养动物,例如狗、猫、牛、猪、马、绵羊或山羊。在某些实施例中,受试者是伴侣动物,例如狗或猫。在某些实施例中,受试者是家畜,例如牛、猪、马、绵羊或山羊。在某些实施例中,受试者是动物园动物。在另一实施例中,受试者是研究动物,例如啮齿动物、狗或非人灵长类动物。在某些实施例中,受试者是非人转基因动物,例如转基因小鼠或转基因猪。
增殖性疾病、障碍或病症也可能与生物样品或受试者中细胞凋亡的抑制相关。本文描述的或本领域已知的所有类型的生物样品都被认为在本披露的范围内。具有式(I)的化合物和药学上可接受的盐、溶剂化物、水合物、互变异构体、立体异构体及其组合物可诱导细胞凋亡,因此可用于治疗和/或预防增殖性疾病、障碍或病症。
在某些实施例中,使用具有式(I)的化合物治疗或预防的增殖性疾病是癌症。如本文所用的,术语“癌症”是指恶性肿瘤(Stedman’s Medical Dictionary[斯特德曼医学词典],第25版;Hensyl编辑.;Williams&Wilkins[威廉姆斯和威尔金斯]:费城,1990)。本文披露的或本领域已知的所有类型的癌症都被认为在本披露的范围内。示例性癌症包括但不限于:听神经瘤;腺癌;肾上腺癌;肛门癌;血管肉瘤(例如,淋巴管肉瘤、淋巴管内皮肉瘤、血管肉瘤);阑尾癌;良性单克隆丙种球蛋白;胆癌(例如胆管癌);膀胱癌;乳腺癌(例如,乳腺腺癌、乳腺乳头状癌、乳腺癌症、乳腺髓样癌);脑癌(例如,脑膜瘤、胶质母细胞瘤、胶质瘤(例如,星形细胞瘤、少突神经胶质瘤)、髓母细胞瘤);支气管癌;类癌瘤;宫颈癌(例如,宫颈腺癌);绒毛膜癌;脊索瘤;颅咽管瘤;结直肠癌(例如,结肠癌、直肠癌、结直肠腺癌);结缔组织癌;上皮癌;室管膜瘤;内皮肉瘤(例如,卡波西肉瘤、多发性特发性出血性肉瘤);子宫内膜癌(例如,子宫癌、子宫肉瘤);食道癌(例如,食道腺癌、巴雷特腺癌);尤因肉瘤;眼癌(例如,眼内黑色素瘤、视网膜母细胞瘤);普通高嗜酸性粒细胞增多症;胆囊癌;胃癌(例如,胃腺癌);胃肠道间质瘤(GIST);生殖细胞癌;头颈癌(例如,头颈部鳞状细胞癌、口腔癌(例如,口腔鳞状细胞癌)、咽喉癌(例如,喉癌、咽癌、鼻咽癌、口咽癌));造血癌(例如白血病,例如急性淋巴细胞白血病(ALL)(例如,B细胞ALL、T细胞ALL)、急性粒细胞白血病(AML)(例如,B细胞AML、T细胞AML)、慢性粒细胞白血病(CML)(例如,B细胞CML、T细胞CML)和慢性淋巴细胞白血病(CLL)(例如,B细胞CLL、T细胞CLL));淋巴瘤,例如霍奇金淋巴瘤(HL)(例如,B细胞HL、T细胞HL)和非霍奇金淋巴瘤(NHL)(例如,B细胞NHL,例如弥漫性大细胞淋巴瘤(DLCL)(例如,弥漫性大B细胞淋巴瘤)、滤泡性淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(例如,黏膜相关淋巴组织(MALT)淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤)、原发性纵隔B细胞淋巴瘤、伯基特淋巴瘤、淋巴浆细胞性淋巴瘤(即瓦尔登斯特伦巨球蛋白血症)、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B淋巴母细胞性淋巴瘤和原发性中枢神经系统(CNS)淋巴瘤;以及T细胞NHL,例如前体T淋巴母细胞性淋巴瘤/白血病、外周T细胞淋巴瘤(PTCL)(例如,皮肤T细胞淋巴瘤(CTCL)(例如蕈样肉芽肿病、塞扎里综合征)、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤和间变性大细胞淋巴瘤);如上文描述的一种或多种白血病/淋巴瘤的混合体;和多发性骨髓瘤(MM))、重链病(例如,α链病、γ链病、μ链病);血管母细胞瘤;下咽癌;炎性肌成纤维细胞瘤;免疫细胞淀粉样变性;肾癌(例如,肾母细胞瘤又称维尔姆斯瘤、肾细胞癌);肝癌(例如,肝细胞癌(HCC)、恶性肝癌);肺癌(例如,支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌);平滑肌肉瘤(LMS);肥大细胞增多症(例如,全身性肥大细胞增多症);肌肉癌;骨髓增生异常综合征(MDS);间皮瘤;骨髓增殖性障碍(MPD)(例如,真性红细胞增多症(PV)、原发性血小板增多症(ET)、原因不明性髓样化生(AMM)又称骨髓纤维化(MF)、慢性特发性骨髓纤维化、慢性粒细胞白血病(CML)、慢性中性粒细胞白血病(CNL)、嗜酸细胞增多综合征(HES));成神经细胞瘤;神经纤维瘤(例如,神经纤维瘤病(NF)1型或2型、神经鞘瘤病);神经内分泌癌(例如,胃肠胰神经内分泌肿瘤(GEP-NET)、类癌瘤);骨肉瘤(例如,骨癌);卵巢癌(例如,囊腺癌、卵巢胚胎性癌、卵巢腺癌);乳头状腺癌;胰腺癌(例如,胰腺腺癌、导管内乳头状黏液性肿瘤(IPMN)、胰岛细胞瘤);阴茎癌(例如,阴茎和阴囊的佩吉特病);松果体瘤;原始神经外胚叶肿瘤(PNT);浆细胞瘤;副肿瘤综合征;上皮内肿瘤;前列腺癌(例如,前列腺腺癌);直肠癌;横纹肌肉瘤;唾液腺癌;皮肤癌(例如,鳞状细胞癌(SCC)、角化棘皮瘤(KA)、黑色素瘤、基底细胞癌(BCC));小肠癌(例如,阑尾癌);软组织肉瘤(例如,恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性外周神经鞘瘤(MPNST)、软骨肉瘤、纤维肉瘤、黏液肉瘤);皮脂腺癌;小肠癌;汗腺癌;滑膜瘤;睾丸癌(例如,精原细胞瘤、睾丸胚胎性癌);甲状腺癌(例如,甲状腺的乳头状癌、甲状腺乳头状癌(PTC)、甲状腺髓样癌);尿道癌;阴道癌;和外阴癌(例如,外阴佩吉特病)。
在一些实施例中,增殖性疾病与良性肿瘤相关。例如,良性肿瘤可以包括腺瘤、纤维瘤、血管瘤、结节性硬化症和脂肪瘤。本文披露的或本领域已知的所有类型的良性肿瘤都被认为在本披露的范围内。
在一些实施例中,增殖性疾病与血管生成相关。本文披露的或本领域已知的所有类型的血管生成都被认为在本披露的范围内。
在一些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗非增殖性疾病。示例性非增殖性疾病包括神经疾病、自身免疫性障碍、免疫缺陷性障碍、溶酶体贮积病、心血管病症、代谢性障碍、呼吸病症、炎性疾病、肾脏疾病或传染性疾病。
在某些实施例中,非增殖性疾病是神经疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗神经疾病、障碍或病症。神经疾病、障碍或病症可包括神经退行性疾病、精神病症或肌肉骨骼疾病。神经疾病可以进一步包括重复扩张疾病,例如其特征在于基因组中核酸序列的扩张。例如,重复扩张疾病包括强直性肌营养不良、肌萎缩侧索硬化、亨廷顿病、三核苷酸重复病或多聚谷氨酰胺障碍(例如,共济失调、脆性X综合征)。在一些实施例中,神经疾病包含重复扩张疾病,例如亨廷顿病。另外的神经疾病、障碍和病症包括阿尔茨海默病、亨廷顿舞蹈症、朊病毒病(例如,克雅氏病、牛海绵状脑病、库鲁病或羊瘙痒病)、精神发育迟缓障碍(例如,由SETD5基因突变引起的障碍,例如智力残疾-面部畸形综合征、孤独症谱系障碍)、路易体病、弥漫性路易体病(DLBD)、痴呆、进行性核上性麻痹(PSP)、进行性延髓性麻痹(PBP)、假性延髓性麻痹、脊髓和延髓肌萎缩(SBMA)、原发性侧索硬化、皮克病、原发性进行性失语症、皮质基底节痴呆、帕金森病、唐氏综合征、多系统萎缩、脊髓性肌萎缩(SMA)、进行性脊髓延髓肌萎缩(例如,肯尼迪病)、脊髓灰质炎后综合征(PPS)、脊髓小脑性共济失调、泛酸激酶相关神经变性(PANK)、脊髓退行性疾病/运动神经元退行性疾病、上运动神经元障碍、下运动神经元障碍、哈勒沃登-施帕茨综合征、脑梗塞、脑外伤、慢性创伤性脑病、短暂性脑缺血发作、Lytigo-bodig(肌萎缩侧索硬化-帕金森病痴呆)、关岛-帕金森病痴呆、海马硬化、皮质基底节变性、亚历山大病、阿普勒病(Apler’s disease)、克拉伯病、神经疏螺旋体病(neuroborreliosis)、神经梅毒、桑德霍夫病(Sandhoff disease)、泰-萨克斯病、希尔德病、巴滕病、科凯恩综合征、卡恩斯-塞尔综合征、格斯特曼-施特劳斯勒-沙因克综合征和其他传染性海绵状脑病、遗传性痉挛性截瘫、利氏综合征、脱髓鞘性病变、神经元蜡样脂褐质病、癫痫、震颤、抑郁症、躁狂症、焦虑和焦虑障碍、睡眠障碍(例如,嗜睡症、致死性家族型失眠症)、急性脑损伤(例如,中风、头部受伤)、孤独症、马查多-约瑟夫病、或其组合。在一些实施例中,神经疾病包含弗里德里希共济失调或斯德奇-韦伯综合征。在一些实施例中,神经疾病包含亨廷顿病。本文披露的或本领域已知的所有类型的神经疾病都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是自身免疫性障碍或免疫缺陷性障碍。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗自身免疫性疾病、障碍或病症或免疫缺陷性疾病、障碍或病症。示例性自身免疫性和免疫缺陷性疾病、障碍和病症包括关节炎(例如,类风湿性关节炎、骨关节炎、痛风)、美洲锥虫病、慢性阻塞性肺病(COPD)、皮肌炎、1型糖尿病、子宫内膜异位症、古德帕斯丘综合征、格雷夫斯病、吉兰-巴雷综合征(GBS)、桥本氏病、化脓性汗腺炎、川崎病、强直性脊柱炎、IgA肾病、特发性血小板减少性紫癜、炎症性肠病、克罗恩病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、缺血性结肠炎、转向性结肠炎、白塞综合征、感染性结肠炎、未确定型结肠炎、间质性膀胱炎、狼疮(例如,系统性红斑狼疮、盘状狼疮、药物性狼疮、新生儿狼疮)、混合结缔组织病、硬斑病、多发性硬化、重症肌无力、嗜睡症、神经肌强直、寻常型天疱疮、恶性贫血、银屑病、银屑病关节炎、多发性肌炎、原发性胆汁性肝硬化、复发性多软骨炎、硬皮病、干燥综合征、僵人综合征、血管炎、白癜风、由GATA2突变引起的障碍(例如,GATA2缺乏;GATA2单倍剂量不足;Emberger综合征;单核细胞减少症和鸟分枝杆菌复合群/树突状细胞、单核细胞、B和NK淋巴细胞缺乏症;家族性骨髓增生异常综合征;急性髓性白血病;慢性粒单核细胞白血病)、中性粒细胞减少症、再生障碍性贫血和韦氏肉芽肿病。在一些实施例中,自身免疫性或免疫缺陷性障碍包含慢性皮肤黏膜念珠菌病。本文披露的或本领域已知的所有类型的自身免疫性障碍和免疫缺陷性障碍都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是心血管病症。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗心血管疾病、障碍或病症。心血管疾病、障碍或病症可以包括与心脏或血管系统,例如动脉、静脉或血液相关的病症。示例性心血管疾病、障碍或病症包括心绞痛,心律失常(心房或心室或两者),心力衰竭,动脉硬化,粥样斑,动脉粥样硬化,心脏肥大,心脏或血管动脉瘤,心肌细胞功能障碍,颈动脉阻塞性疾病,PTCA后的内皮损伤(经皮腔内冠状动脉成形术),高血压(包括原发性高血压、肺动脉高压和继发性高血压(肾血管性高血压、慢性肾小球肾炎)),心肌梗塞,心肌缺血,肢体、器官或组织的外周阻塞性动脉病;外周动脉闭塞性疾病(PAOD),脑、心脏或其他器官或组织缺血后的再灌注损伤、再狭窄、中风、血栓形成、短暂性脑缺血发作(TIA)、血管闭塞、血管炎和血管收缩。本文披露的或本领域已知的所有类型的心血管疾病、障碍或病症都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是代谢性障碍。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗代谢性疾病、障碍或病症。代谢性疾病、障碍或病症可以包括以异常代谢为特征的障碍或病症,例如与食物和水的消耗、消化、营养加工和废物清除有关的那些障碍。代谢性疾病、障碍或病症可以包括酸碱平衡失调、线粒体疾病、消瘦综合征、吸收不良障碍、铁代谢障碍、钙代谢障碍、DNA修复缺陷障碍、葡萄糖代谢障碍、高乳酸血症、肠道菌群紊乱。示例性代谢性病症包括肥胖症、糖尿病(I型或II型)、胰岛素抵抗、葡萄糖不耐受、乳糖不耐受、湿疹、高血压、亨特综合征、克拉伯病、镰状细胞性贫血、枫糖尿病、庞贝病和异染性脑白质营养不良。本文披露的或本领域已知的所有类型的代谢性疾病、障碍或病症都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是呼吸病症。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗呼吸疾病、障碍或病症。呼吸疾病、障碍或病症可以包括与呼吸系统的任何部分(例如,肺、肺泡、气管、支气管、鼻道或鼻)有关的障碍或病症。示例性呼吸疾病、障碍或病症包括哮喘、过敏、支气管炎、过敏性鼻炎、慢性阻塞性肺病(COPD)、肺癌、氧中毒、肺气肿、慢性支气管炎和急性呼吸窘迫综合征。本文披露的或本领域已知的所有类型的呼吸疾病、障碍或病症都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是肾脏疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗肾脏疾病、障碍或病症。肾脏疾病、障碍或病症可以包括与废物产生、储存和清除系统(包括肾脏、输尿管、膀胱、尿道、肾上腺和骨盆)的任何部分有关的疾病、障碍或病症。示例性肾脏疾病包括急性肾衰竭、淀粉样变性、奥尔波特综合征、腺病毒性肾炎、急性大叶性肾病(acute lobar nephronia)、肾小管坏死、肾小球肾炎、肾结石、尿路感染、慢性肾病、多囊肾病和局灶节段性肾小球硬化(FSGS)。在一些实施例中,肾脏疾病、障碍或病症包含HIV相关的肾病或高血压肾病。本文披露的或本领域已知的所有类型的肾脏疾病、障碍或病症都被认为在本披露的范围内。
在某些实施例中,非增殖性疾病是传染性疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗传染性疾病、障碍或病症。传染性疾病可能是由病毒或细菌等病原体引起的。示例性传染性疾病包括人免疫缺陷综合征(HIV)、获得性免疫缺陷综合征(AIDS)、脑膜炎、非洲睡眠病、放线菌病、肺炎、肉毒中毒、衣原体、美洲锥虫病、科罗拉多蜱传热、霍乱、斑疹伤寒、贾第虫病、食物中毒、埃博拉出血热、白喉、登革热、淋病、链球菌感染(例如,A组或B组)、甲型肝炎、乙型肝炎、丙型肝炎、单纯疱疹、钩虫感染、流感、爱泼斯坦-巴尔感染、川崎病、库鲁病、麻风病、利什曼病、麻疹、腮肿、诺如病毒、脑膜炎球菌病、疟疾、莱姆病、李斯特菌病、狂犬病、鼻病毒、风疹、破伤风、带状疱疹、猩红热、疥疮、寨卡热、黄热病、肺结核、弓形虫病或兔热病。在一些实施例中,传染性疾病包含巨细胞病毒。本文披露的或本领域已知的所有类型的传染性疾病、障碍或病症都被认为在本披露的范围内。
在某些实施例中,疾病、障碍或病症是单倍剂量不足疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗单倍剂量不足疾病、障碍或病症。单倍剂量不足疾病、障碍或病症可以指其中基因的等位基因具有功能丧失性病变,例如功能完全丧失性病变的单基因疾病。在实施例中,功能丧失性病变以常染色体显性遗传模式存在或源自零星事件。在实施例中,由于改变的等位基因导致的基因产物功能的降低驱动了疾病表型,尽管存在剩余的功能性等位基因(即,所述疾病对于所讨论的基因而言是单倍剂量不足的)。在实施例中,具有式(I)的化合物增加单倍剂量不足基因座的表达。在实施例中,具有式(I)的化合物增加单倍剂量不足基因座处的一个或两个等位基因。示例性单倍剂量不足疾病、障碍和病症包括罗比诺综合征、心肌病、小脑性共济失调、嗜铬细胞瘤、夏科-马里-图思病、神经病、Takenouchi-Kosaki综合征、科芬-西里斯综合征2、染色体1p35缺失综合征、脊髓小脑性共济失调47、耳聋、癫痫、肌张力障碍9、GLUT1缺乏综合征1、GLUT1缺乏综合征2、口形蛋白质缺陷型冷性充水细胞增多症(stomatin-deficient cryohydrocytosis)、基底细胞癌、基底细胞痣综合征、髓母细胞瘤、躯体畸、脑畸形、黄斑变性、锥杆营养不良、德热里纳-索塔斯病、髓鞘形成不足神经病、鲁西-莱维综合征、青光眼、自身免疫性淋巴增殖综合征、垂体激素缺乏症、癫痫性脑病、早期婴儿腘窝翼状胬肉综合征、范德沃德综合征、勒斯-迪茨综合征、Skraban-Deardorff综合征、红细胞增多症、巨脑畸形-多小脑回畸形-多趾畸形-脑积水综合征、精神发育迟缓、CINCA综合征、家族性感冒炎症综合征1、角化内皮炎一过性遗传、Muckle-Wells综合征、Feingold综合征1、急性髓性白血病、Heyn-Sproul-Jackson综合征、Tatton-Brown-Rahman综合征、沙氏-佩纳综合征、痉挛性截瘫、常染色体显性大眼球、眼组织残缺(colobomatous)伴小角膜、全前脑畸形、脑裂畸形、子宫内膜癌、家族性结直肠癌、遗传性非息肉病、智力发育障碍伴畸形面容和行为异常、卵巢过度刺激综合征、精神分裂症、Dias-Logan综合征、卵巢早衰、由于墨蝶呤还原酶缺乏的多巴反应性肌张力障碍、Beck-Fahrner综合征、染色体2p12-p11.2缺失综合征、神经元病、痉挛性截瘫、家族性成人肌阵挛性结直肠癌、甲状腺功能减退、Culler-Jones综合征、全前脑畸形、骨髓粒细胞缺乏症(myelokathexis)、WHIM综合征、莫瓦特-威尔逊综合征、精神发育迟缓、智力发育障碍、孤独症谱系障碍、癫痫、癫痫性脑病、Dravet综合征、偏头痛、精神发育迟缓障碍(例如,由SETD5基因突变引起的障碍,例如智力残疾-面部畸形综合征、孤独症谱系障碍)、由GATA2突变引起的疾病(例如,GATA2缺陷;GATA2单倍剂量不足;Emberger综合征;单核细胞减少症和鸟分枝杆菌复合群/树突状细胞、单核细胞、B和NK淋巴细胞缺乏症;家族性骨髓增生异常综合征;急性髓性白血病;慢性粒单核细胞白血病)和高热惊厥。
在某些实施例中,疾病、障碍或病症是例如具有残留功能的常染色体隐性疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗常染色体隐性疾病、障碍或病症。例如具有残留功能的常染色体隐性疾病可以指具有纯合隐性或复合杂合遗传性的单基因病。这些疾病的特征还可能是基因产物活性不足(例如,基因产物水平大于0%)。在实施例中,具有式(I)的化合物可以增加与具有残留功能的常染色体隐性疾病相关的靶标(例如,基因)的表达。具有残留功能的示例性常染色体隐性疾病包括弗里德赖希共济失调、斯塔加特病(Stargardtdisease)、厄舍综合征、无脉络膜(chlorioderma)、脆性X综合征、全色盲3、赫尔勒综合征、血友病B、α-1-抗胰蛋白酶缺乏症、戈谢病、X连锁视网膜劈裂症、威斯科特-奥尔德里奇综合征、黏多糖贮积症(圣菲利波B型)、DDC缺乏、营养不良型大疱性表皮松解症、法布里病、异染性脑白质营养不良和牙软骨发育不良。
在某些实施例中,疾病、障碍或病症是常染色体显性疾病。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗常染色体显性疾病、障碍或病症。常染色体显性疾病可以指其中突变基因是显性基因的单基因病。这些疾病的特征还可能是基因产物活性不足(例如,基因产物水平大于0%)。在实施例中,具有式(I)的化合物可以增加与常染色体显性疾病相关的靶标(例如,基因)的表达。示例性常染色体显性疾病包括亨廷顿病、软骨发育不全、抗凝血酶III缺乏症、吉尔伯特病、埃勒斯-当洛综合征、遗传性出血性毛细血管扩张症、肠息肉病、遗传性椭圆形病(elliptosis)、遗传性球形细胞增多症、大理石骨病、马方综合征、蛋白C缺乏症、特雷彻·柯林斯综合征、冯维勒布兰德病、结节性硬化症、成骨不全、多囊肾病、神经纤维瘤病和特发性甲状旁腺功能减退症。
在某些实施例中,疾病、障碍或病症是旁系同源活化障碍。在某些实施例中,具有式(I)的化合物或其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物用于预防或治疗旁系同源活化疾病、障碍或病症。旁系同源活化障碍可以包括导致基因产物功能丧失的基因座的纯合突变。在这些障碍中,可能存在编码具有重叠功能的蛋白质(例如,发育的旁系同源)的单独基因座,否则其表达不足以补偿突变的基因。在实施例中,具有式(I)的化合物将与旁系同源活化障碍相关的基因(例如,旁系同源基因)活化。
本文描述的细胞可以是异常细胞。细胞可以在体外或者体内。在某些实施例中,细胞是增殖性细胞。在某些实施例中,细胞是癌细胞。在某些实施例中,细胞是非增殖性细胞。在某些实施例中,细胞是血细胞。在某些实施例中,细胞是淋巴细胞。在某些实施例中,细胞是良性肿瘤细胞。在某些实施例中,细胞是内皮细胞。在某些实施例中,细胞是免疫细胞。在某些实施例中,细胞是神经元细胞。在某些实施例中,细胞是胶质细胞。在某些实施例中,细胞是脑细胞。在某些实施例中,细胞是成纤维细胞。在某些实施例中,细胞是原代细胞,例如,从受试者(例如,人受试者)分离的细胞。
在某些实施例中,本文描述的方法包括另外的步骤:将一种或多种另外的药剂与具有式(I)的化合物、其药学上可接受的盐或包含这样的化合物或其药学上可接受的盐的组合物组合施用。这样的另外的药剂包括但不限于抗增殖剂、抗癌剂、抗糖尿病剂、抗炎剂、免疫抑制剂和镇痛剂。另外的药剂可以协同地增强由本披露的本发明化合物或组合物在生物样品或受试者中诱导的剪接的调节。因此,本发明化合物或组合物与另外药剂的组合可用于治疗例如癌症或对使用另外药剂且没使用本发明化合物或组合物的治疗有抗性的其他疾病、障碍或病症。
实例
为了可以更充分地理解本文描述的本发明,列出以下实例。提供了本申请描述的实例以说明本文提供的化合物、药物组合物和方法,并且这些实例不应被解释为以任何方式限制其范围。
本文提供的化合物可以使用本领域技术人员熟知的对以下列出的特定合成计划的修饰,由容易获得的起始材料制备。应认识到,除非另有说明,否则在给出典型或优选的工艺条件(即反应温度、时间、反应物的摩尔比、溶剂、压力等)的情况下,也可以使用其他工艺条件。最佳反应条件可以随着使用的特定反应物或溶剂而变化,但是这样的条件可以由本领域技术人员通过常规优化程序进行决定。
此外,正如本领域技术人员将清楚的,常规保护基团对于保护某些官能团免于经受不希望的反应是必需的。选择用于特定官能团的合适的保护基团以及用于保护和去保护的合适条件是本领域熟知的。例如,众多保护基团及其引入和去除描述于Greene等人,Protecting Groups in Organic Synthesis[有机合成中的保护基团],第二版,Wiley[威利出版社],纽约,1991,及其中引用的参考文献。
可以根据本领域已知的任何合适的方法来纯化或分析反应。例如,产物形成可以通过以下监测:光谱手段,如核磁共振(NMR)光谱法(例如,1H或13C)、红外(IR)光谱法、分光光度法(例如,UV-可见光)、质谱法(MS),或色谱方法,如高效液相色谱法(HPLC)或薄层色谱法(TLC)。
质子NMR:在24℃,在5-mm o.d.管(Wildmad)中的CDCl3溶液中记录1H NMR光谱,并在400MHz在BRUKER AVANCE NEO 400上收集1H。化学位移(δ)相对于四甲基硅烷(TMS=0.00ppm)报告并以ppm表示。
LC/MS:液相色谱法-质谱法(LC/MS)在Shimadzu-2020EV上进行,使用的柱是:Shim-pack XR-ODS(C18,3μm,40℃),在ESI(+)电离模式下运行;流速=1.2mL/min。流动相=在水或CH3CN中的0.05%TFA;或在Shimadzu-2020EV上进行,使用的柱是:Poroshell HPH-C18(C18,3μm,40℃),在ESI(+)电离模式下运行;流速=1.2mL/min。流动相A:水/5mM NH4HCO3,流动相B:CH3CN。
分析型手性HPLC:分析型手性HPLC在Agilent 1260上进行,使用的柱是:CHIRALPAK IG-3、CHIRALPAK IC-3或CHIRALPAK OJ-3,流速=1.2mL/min。流动相=MTBE(DEA):EtOH=50:50。制备型HPLC纯化:使用以下HPLC条件之一进行制备型HPLC纯化:
条件1:Waters-2545,柱:X-Select CSH(C18 OBD5μm,30mm X 150mm)。流动相A:水(10mmol/L NH4HCO3),流动相B:乙腈,梯度:8min内5%B至50%B。
条件2:Shimadzu,柱:XBridge Prep C18 OBD柱,5um,19mm X 150mm;流动相A:水(10mmol/L NH4HCO3),流动相B:甲醇,梯度:在10min内,30%B直到50%。
条件3:Shimadzu,柱:Xselect CSH OBD柱,30mm X 150mm,5um,流动相A:水(10mmol/L NH4HCO3),流动相B:乙腈,梯度1:在8min内,10%相B直到60%;梯度2:在8min内,5%相B直到40%
条件4:Shimadzu,柱:XBridge Prep OBD C18柱,30X150mm,5μm;流动相A:水(10mmol/L NH4HCO3),流动相B:乙腈;梯度1:在8min内,10B至44B;梯度2:在6min内,3B至33B;梯度3:在8min内,5B至35B;梯度4:在8min内,5B至24B;梯度5:在6min内,5B至43B;梯度6:在2min内保持5B,在6min内直到55B;梯度7:在8min内,5%B至36%B;梯度8:在8min内,10%B直到65%B;梯度9:在8min内,5%B至32%B;梯度10:在8min内,5%B至50%B。
条件5:柱:Xselect CSH OBD柱30*150mm 5um,n;流动相A:水(10mmol/L NH4HCO3);流动相B:乙腈;流速:60mL/min;梯度:在10min内,10B至35B。
条件6:柱,Xselect CSH OBD柱30x150mm 5um;流动相A:水(0.1%HCl);流动相B:乙腈;梯度1:保持3%相B持续2min,然后经6min增加到23%。
条件7:柱,YMC-Actus Triart C18,30x150mm,5um;流动相A:水(10mmol/LNH4HCO3);流动相B:乙腈;梯度1:在8min内,5%B至50%B;梯度2:在8min内,5%B至45%B;梯度3:在8min内,5%B至65%B;梯度4:在8min内,15%B至50%B。
条件8:柱:Xselect CSH OBD柱30x150mm 5um;流动相A:水(0.05%HCl),流动相B:乙腈;流速:60mL/min;梯度1:在2min内,3%B至3%B;梯度2:在8min内,3%B至23%B;梯度3:在8min内,5%B至40%B;梯度4:在8min内,3%B至35%B;梯度5:在8min内,3%B至43%B。
条件9:柱:XBridge Shield RP18 OBD柱,19x150mm,5μm;流动相A:水(0.05%TFA),流动相B:乙腈;流速:20mL/min;梯度1:在8min内,5%B至22%B。
条件10:柱:SunFire Prep C18 OBD柱,19x150mm,5μm 10nm;流动相A:水(0.05%TFA),流动相B:乙腈;流速:20mL/min;梯度1:在6.9min内,10%B至55%B。
条件11:柱:XBridge Shield RP18 OBD柱,19x150mm,5μm;流动相A:水(0.05%NH3H2O),流动相B:乙腈;流速:20mL/min;梯度1:在8min内,36%B至54%B。
制备型手性HPLC:纯化通过手性HPLC在Gilson-GX 281上进行,使用的柱是:CHIRALPAK IG-3、CHIRALPAK IC-3或CHIRALPAK OJ-3。
条件1:柱,XBridge Prep OBD C18柱,30x150mm;流动相A:水(10mmol/L NH4HCO3),流动相B:乙腈;梯度1:在8min内,5%B至50%B。
通用合成方案
本披露的化合物可以使用方案A-D中任一个说明的合成计划来制备。
方案A。制备具有式(I)的化合物的示例性方法;其中A、B、L、M、P、X、Y、R7、和n如本文所定义;LG1、LG2、LG3、和LG4各自独立地是离去基团(例如,卤代);并且-B(OR12)2是硼酸酯(例如,Bpin),其中每个R12可以是C1-C6-烷基、C2-C6-杂烷基、芳基或杂芳基;或两个R12基团与它们所附接的原子一起形成杂环基或杂芳基。
方案A中提供了制备具有式(I)的化合物的示例性方法。在该方案中,在步骤1中,通过在碱(例如,在N,N-二甲基甲酰胺(DMF)中的碳酸钾(K2CO3)或氢化钠(NaH))或另一合适试剂的存在下,将A-1与A-2孵育来制备A-3。在一些情况下,通过加热反应混合物至合适的温度(例如,100℃)来制备A-3。在步骤2中,通过将A-4与A-5孵育来制备A-6。步骤2可以在1,1’-双(二苯基膦)-二茂铁)二氯化钯(II)(Pd(dppf)Cl2)和磷酸三钾(K3PO4)或类似试剂(例如碳酸钾(K2CO3))的存在下进行。还可以使用Pd(dppf)Cl2的替代性催化剂,例如,合适的钯催化剂(例如,适于铃木反应的催化剂),例如,四(三苯基膦)-钯(0)(Pd(PPh3)4)。A-4与A-5的偶联可以在二噁烷和水的混合物或类似溶剂或混合物中进行,并加热至80℃或足以提供A-6的温度(例如,100℃)。
在步骤3中,通过将A-6与适于将LG4替代为硼酸酯基团的试剂(例如(R12O)2B-B(OR12)2,例如双(频哪醇合)二硼(B2pin2))孵育来制备A-7。也可以使用其他用于安装硼酸酯基团的常用试剂(例如频哪醇硼烷)。该反应可以涉及使用三(二亚苄基丙酮)二钯(0)(Pd2(dba)3)、和乙酸钾(KOAc)或合适的替代物(例如磷酸三钾(K3PO4))。步骤3还可以使用Pd2(dba)3的替代性催化剂(例如另一钯催化剂,例如[1,1’-双(二-叔丁基膦)二茂铁]二氯钯(II)(Pd(dtbpf)Cl2)或氯(2-二环己基膦-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II)(XPhos-Pd-G2))进行。反应可以在二噁烷或类似溶剂中,在100℃或足以提供片段A-7的温度,例如80℃、90℃、110℃或120℃进行。反应可以在微波反应器中进行。
将A-3和A-7偶联以在步骤4中提供具有式(I)的化合物。偶联反应可以在Pd(dppf)Cl2和K3PO4或类似试剂例如碳酸三钾(K3PO4)的存在下进行。与步骤2相同,可以使用Pd(dppf)Cl2的替代性催化剂,例如任何合适的钯催化剂,例如四(三苯基膦)-钯(0)(Pd(PPh3)4)或氯(2-二环己基膦-2′,4′,6′-三异丙基-1,1′-联苯基)[2-(2′-氨基-1,1′-联苯基)]钯(II)(XPhos-Pd-G2)。步骤4的反应在二噁烷或二噁烷和水的混合物或其他合适的溶剂中进行,并且将混合物加热至80℃或足以提供具有式(I)的化合物或具有式(I)的化合物的前体(具有一个或多个保护基团)的温度,例如100℃。具有式(I)的化合物可以使用标准技术纯化并使用本领域已知的任何方法(例如核磁共振光谱法(NMR)或质谱法(MS))表征。
通用方案B。制备具有式(I)的化合物的示例性方法;其中A如本文所定义。
通用方案C。制备具有式(I)的化合物的示例性方法;其中B如本文所定义;LG1是离去基团硼酸或酯(例如,-B(OR12)2,例如Bpin)。
通用方案D。制备具有式(I)的化合物的示例性方法;其中A如本文所定义。
实例1:化合物101的合成
中间体B2的合成
使用微波反应器,在30mL微波管中,在120℃,将7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(B1;500mg,1.65mmol,1当量)、B2Pin2(838mg,3.30mmol,2当量)、XPhos(78mg,0.17mmol,0.1当量)、KOAc(486mg,4.95mmol,3当量)和Pd2(dba)3-CHCl3(85mg,0.08mmol,0.05当量)在二噁烷(15.0mL)中的混合物搅拌2h。
在0℃,将反应用H2O淬灭。将水层用乙酸乙酯(EA)(50mL x 3)萃取,并且将合并的有机层用盐水(50mL)洗涤、然后用Na2SO4干燥。将所得混合物过滤,并且将滤饼用EA(50mL x2)洗涤。将滤液在减压下浓缩,以提供呈固体的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B2;600mg)。LCMS(ES,m/z):395[M+H]+。
中间体B4的合成
在100℃,在氮气气氛下,将4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B2;500mg,1.27mmol,1当量)、顺式)-叔丁基-(2R,4R)-4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B3;822mg,1.90mmol,1.5当量)、Pd(PPh3)4(146mg,0.13mmol,0.1当量)和K3PO4(807mg,3.81mmol,3当量)在二噁烷(10.0mL)和H2O(5.0mL)中的混合物搅拌3h。在0℃,将反应用H2O淬灭。将水层用乙酸乙酯(EA)(50mL x 3)萃取,并且将合并的有机层用NaCl(aq)洗涤、然后用Na2SO4干燥。将残余物通过硅胶柱色谱法纯化,其中用石油醚(PE):乙酸乙酯(EA)(1:2)洗脱。将所得混合物在减压下浓缩,以提供呈固体的叔丁基(2R,4R)-2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B4;256mg)。LCMS(ES,m/z):573[M+H]+。
化合物101的合成
在0℃,在氮气气氛下,在经吹扫的50mL 3颈圆底烧瓶中,将(顺式)-叔丁基(2R,4R)-2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B4;256mg,0.45mmol,1当量)、在1,4-二噁烷(5mL)中的4M HCl、二噁烷(5mL)、和MeOH(3mL)的混合物搅拌2h。将所得混合物在减压下浓缩,然后在NH3/MeOH中搅拌3h。将所得混合物过滤,并且将滤饼用NH3/MeOH洗涤。将滤液在减压下浓缩,以提供呈固体的(顺式)-N-甲基-N-[(2R,4R)-2-甲基哌啶-4-基]-6-[4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-胺(化合物101;21mg)。LCMS(ES,m/z):389[M+H]+。1H NMR(400MHz,甲醇-d4)δ8.45(s,2H),8.33(s,2H),8.19(d,J=9.8Hz,3H),7.94(d,J=7.6Hz,2H),7.51(d,J=7.6Hz,2H),7.35(d,J=9.7Hz,2H),4.99(s,1H),4.61(s,1H),3.59(dt,J=13.0,3.4Hz,2H),3.52-3.43(m,1H),3.47(s,1H),3.37(s,1H),3.25(dd,J=13.5,8.2Hz,2H),3.10(s,6H),2.19-2.07(m,5H),2.07(d,J=3.6Hz,1H),1.92(q,J=12.4Hz,2H),1.44(d,J=6.4Hz,6H),0.12(s,2H)。
实例2:化合物103的合成
中间体B6的合成
将100-mL密封管吹扫并维持在氮气气氛下,并且将4-溴-7-氯-1H-吲唑(B5;2.7g,11.66mmol,1当量)、吡唑(3.18g,46.64mmol,4当量)、Cs2CO3(11.40g,34.99mmol,3当量)、二噁烷(60mL)、CuI(0.33g,1.75mmol,0.15当量)、(1S,2S)-N1,N2-二甲基环己烷-1,2-二胺(0.41g,2.92mmol,0.25当量)添加到管中。在100℃,将所得溶液搅拌7天,这之后通过过滤除去固体。然后将滤液用乙酸乙酯(3x100mL)萃取,并且将合并的有机层用饱和NaCl(100mL)洗涤。然后将混合物经无水硫酸钠干燥并在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:5)洗脱,以提供呈固体的7-氯-4-(吡唑-1-基)-1H-吲唑(B6;1g)。LCMS(ES,m/z):219[M+H]+。
中间体B7的合成
将20-mL小瓶吹扫并维持在氮气气氛下,并将7-氯-4-(吡唑-1-基)-1H-吲唑(B6;1g,4.57mmol,1当量)、KOAc(1.35mg,0.01mmol,3当量)、B2(pin)2(2.56mg,0.01mmol,2.20当量)、二噁烷(10mL)、Pd2(dba)3-CHCl3(0.47mg,0.01mmol,0.10当量)、和XPhos(0.87mg,0.01mmol,0.40当量)添加到小瓶中。将所得溶液在120℃搅拌2hr,并通过过滤除去固体。然后将所得溶液用乙酸乙酯(3x20mL)萃取,并且将有机层合并,以提供呈油状物的4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B7;1g)。LCMS(ES,m/z):311[M+H]+。
中间体B8的合成
将40-mL小瓶吹扫并维持在氮气气氛下,并且将4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B7;500mg,1.61mmol,1当量)、(顺式)-叔丁基-4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B3;696mg,1.61mmol,1当量)、二噁烷(20mL)、K3PO4(1026mg,4.84mmol,3当量)、和Pd(PPh3)4(93mg,0.08mmol,0.05当量)添加到小瓶中。将所得溶液在80℃搅拌7hr,然后将固体通过过滤除去。将所得溶液用乙酸乙酯(3x20mL)萃取,并且将合并的有机层在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(7:10)洗脱,以提供呈固体的(顺式)-叔丁基-2-甲基-4-[甲基([6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B8;300mg)。LCMS(ES,m/z):489[M+H]+。
化合物103的合成
将100-mL圆底烧瓶吹扫并维持在氩气气氛下,并且将(顺式)-叔丁基(2S,4S)-2-甲基-4-[甲基([6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B8;300mg,0.61mmol,1当量)和HCl/二噁烷(30mL)添加到烧瓶中。将所得溶液在室温搅拌2hr,然后在真空下浓缩。将残余物溶解于5mL甲醇中,并且通过过滤除去固体。将粗产物通过制备型HPLC纯化(条件1),以提供呈固体的N-甲基-N-[(2S,4S)-2-甲基哌啶-4-基]-6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-胺(化合物103;96.3mg)。LCMS(ES,m/z):389[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.29(s,1H),8.71(d,J=2.6Hz,1H),8.63(s,1H),8.20(d,J=9.8Hz,1H),8.00(d,J=8.0Hz,1H),7.92(d,J=1.7Hz,1H),7.62(d,J=8.0Hz,1H),7.30(d,J=9.8Hz,1H),6.66(t,J=2.2Hz,1H),4.71(s,1H),3.10-2.97(m,1H),3.02(s,3H),2.75-2.63(m,2H),2.48(d,J=7.3Hz,1H),2.08(s,1H),1.66(qd,J=11.6,11.0,4.0Hz,2H),1.60(s,1H),1.35(q,J=11.5Hz,1H),1.05(d,J=6.2Hz,3H)。
实例3:化合物104的合成
中间体B1的合成
在80℃,伴随脱氧,将K3PO4(5.50g,25.920mmol,3当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;3.12g,11.232mmol,1.3当量)、4-溴-7-氯-1H-吲唑(B5;2.0g,8.640mmol,1.0当量)和Pd(dppf)Cl2-CH2Cl2(352mg,0.432mmol,0.05当量)在二噁烷(8.0mL)和H2O(2.0mL)中的混合物搅拌2h。然后将所得混合物在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(4:1)洗脱,以得到呈固体的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(B1;1.8g)。LCMS(ES,m/z):302[M+H]+。
中间体B11的合成
在80℃,伴随脱氧,将K3PO4(807.55mg,3.80mmol,3当量)、叔丁基-(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B10;845mg,1.9mmol,1.5当量)和4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例1的B2;500mg,1.27mmol,1当量)在二噁烷(16.0mL)和H2O(4.0mL,222.03mmol)中的混合物搅拌2h。在0℃,将反应用H2O(50mL)淬灭。将沉淀的固体通过过滤收集并用乙酸乙酯(50mL x 3)洗涤。然后将所得混合物用饱和水性NaCl(50mL)洗涤,并且将有机相收集并用Na2SO4干燥。将所得混合物在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:2)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B6;480mg)。LCMS(ES,m/z):584[M+H]+。
化合物104的合成
在0℃,在氮气气氛下,在经吹扫的250mL 3颈圆底烧瓶中,将叔丁基-(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B11;480mg)、二噁烷(5mL)、在1,4-二噁烷(5mL)中的HCl和H2O(3mL)的混合物搅拌2h。然后将所得混合物在减压下浓缩。将沉淀的固体通过过滤收集并用乙腈(10mL x 2)洗涤。然后将粗沉淀物添加到具有NH3-MeOH的经吹扫的100mL 3颈圆底烧瓶中,并且将混合物搅拌2h。将所得混合物在减压下浓缩,并且将沉淀的固体通过过滤收集,以提供呈固体的(1R,3S,5S)-N-甲基-N-[6-[4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物104;129.5mg)。LCMS(ES,m/z):400[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.21(s,1H),13.08(s,1H),9.13(s,2H),8.52(s,1H),8.34(s,2H),8.20(d,J=9.8Hz,1H),7.92(d,J=7.7Hz,1H),7.48(d,J=7.6Hz,1H),7.34(d,J=9.8Hz,1H),5.21(td,J=11.8,5.9Hz,1H),4.10(s,2H),3.04(s,3H),2.54-2.48(m,3H),2.38-2.26(m,2H),2.06(s,3H),2.06(d,J=16.4Hz,1H),1.78(ddd,J=13.9,5.8,2.7Hz,2H)。
实例4:化合物105的合成
中间体B13的合成
将40-mL小瓶吹扫并维持在氮气气氛下,并且将4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B7;500mg,1.61mmol,1当量)、叔丁基(1R,3R,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B12;716mg,1.61mmol,1当量)、K3PO4(1026mg,4.84mmol,3当量)、二噁烷(20mL)、和Pd(PPh3)4(93mg,0.08mmol,0.05当量)添加到小瓶中。在80℃,将所得溶液搅拌7hr,这之后通过过滤除去固体。将所得溶液用乙酸乙酯(3x20mL)萃取,并且将所得混合物用饱和NaCl(20mL)洗涤、经无水硫酸钠干燥、然后在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(7:10)洗脱,以提供呈固体的叔丁基(1R,3R,5S)-3-[甲基([6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B13;450mg)。
化合物103的合成
在室温,将叔丁基(1R,3R,5S)-3-[甲基([6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B13;425mg,0.85mmol,1当量)和HCl/二噁烷(100mL)在100mL圆底烧瓶中搅拌2h。将所得混合物在真空下浓缩。然后将残余物溶解于甲醇(5mL)中,并且通过过滤除去固体。将粗产物通过制备型HPLC纯化,以提供呈固体的(1R,3R,5S)-N-甲基-N-[6-[4-(吡唑-1-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物105;34.90mg)。LCMS(ES,m/z):401[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.71(d,J=2.6Hz,1H),8.64(s,1H),8.21(d,J=9.8Hz,1H),8.01(d,J=8.1Hz,1H),7.92(d,J=1.7Hz,1H),7.62(d,J=7.9Hz,1H),7.32(d,J=9.7Hz,1H),6.67(t,J=2.2Hz,1H),5.14(s,1H),3.82(s,2H),3.01(s,3H),2.47(s,2H),2.04(td,J=12.6,3.0Hz,2H),1.92(s,4H),1.69(ddd,J=13.2,6.1,2.7Hz,2H)。
实例5:化合物107和108的合成
中间体B15的合成
将40-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将4-溴-7-氯-1H-吲哚(B14;1.5g,6.51mmol,1.0当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;2.17g,7.81mmol,1.2当量)、Pd(dppf)Cl2(0.24g,0.33mmol,0.05当量)、K3PO4(4.14g,19.51mmol,3.0当量)、二噁烷(10.0mL)和H2O(3.0mL)添加到烧瓶中。将所得溶液在80℃搅拌2h。然后将反应通过添加冰/盐(10mL)淬灭。将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层经无水硫酸钠干燥、然后浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/己烷(1:1)洗脱,以提供呈固体的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚(B15;1.5g)。LCMS(ES,m/z):302[M+H]+
中间体B16的合成
将20-mL密封管吹扫并维持在氮气气氛下,并且将7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚(B15;1.0g,3.31mmol,1.0当量)、双(频哪醇合)二硼(1.51g,5.97mmol,1.8当量)、乙酸钾(0.98g,9.94mmol,3.0当量)、Pd2(dba)3(0.24g,0.265mmol,0.08当量)、XPhos(0.47g,0.99mmol,0.3当量)和二噁烷(10.0mL)添加到管中。在110℃,将反应混合物用微波辐射辐照2h。然后将反应通过添加水/冰(10mL)淬灭。将所得溶液用乙酸乙酯(2x10mL)萃取,并且将合并的有机层浓缩,以提供呈油状物的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B16;1.1g)。LCMS(ES,m/z):394[M+H]+
c
将40mL小瓶吹扫并维持在氮气气氛下,并且将4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B16;1.1g,2.79mmol,1.0当量)、叔丁基4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B17;1.81g,4.19mmol,1.5当量)、Pd(dppf)Cl2(0.1g,0.14mmol,0.05当量)、K3PO4(1.78g,8.39mmol,3.0当量)、二噁烷(10.0mL)和H2O(2.5mL)添加到小瓶中。将所得溶液在80℃搅拌3h,并且将反应通过添加水/冰(10mL)淬灭。将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层经无水硫酸钠干燥,然后浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/己烷(1:1)洗脱,以提供呈固体的叔丁基2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B18;500mg)。LCMS(ES,m/z):572[M+H]+
化合物107和108的合成
将10mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B18;500mg)和在1,4-二噁烷(2.0mL)中的4M HCl添加到烧瓶中。将所得溶液在25℃搅拌1h,并且将所得混合物浓缩。将粗产物通过制备型HPLC纯化(条件2),以提供呈固体的N-甲基-N-[(2R,4S)-2-甲基哌啶-4-基]-6-[4-(1H-吡唑-4-基)-1H-吲哚-7-基]哒嗪-3-胺(化合物107;4.7mg);LCMS(ES,m/z):388[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),8.15-8.21(m,3H),7.69(d,J=7.9Hz,1H),7.47(t,J=2.8Hz,1H),7.34(d,J=7.8Hz,1H),7.26(d,J=9.8Hz,1H),6.75-6.89(m,1H),4.62-4.69(m,1H),2.99-3.09(m,1H),3.00(s,3H),2.67-2.70(m,2H),1.63-1.70(m,3H),1.27-1.40(m,1H),1.03-1.05(m,3H);和呈固体的N-甲基-N-[(2S,4S)-2-甲基哌啶-4-基]-6-[4-(1H-吡唑-4-基)-1H-吲哚-7-基]哒嗪-3-胺(化合物108;4.7mg)。LCMS(ES,m/z):388[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.06(s,1H),11.56(s,1H),8.14-8.17(m,3H),7.68(d,J=7.8Hz,1H),7.48(t,J=2.9Hz,1H),7.26-7.41(m,2H),6.83(t,J=2.7Hz,1H),4.88(s,1H),3.31-3.32(m,1H),3.01(s,3H),2.90-3.00(m,1H),2.81-2.83(m,1H),1.93(td,J=12.2,5.2Hz,1H),1.63-1.75(m,2H),1.45-1.54(m,1H),1.23-1.26(m,3H)。
实例6:化合物110和111的合成
中间体B19的合成
将40-mL小瓶吹扫并维持在氮气气氛下,并且将4-溴-7-氯-1H-吲哚(B14;2.0g,8.68mmol,1.0当量)、吡唑(1.77g,26.03mmol,3.0当量)、(1R,2S)-N1,N2-二甲基环己烷-1,2-二胺(0.25g,1.73mmol,0.2当量)、CuI(0.66g,3.47mmol,0.4当量)、Cs2CO3(8.48g,26.03mmol,3.0当量)和二噁烷(20.0mL)添加到小瓶中。将所得溶液在100℃搅拌7天,并且将反应通过添加水/冰(10mL)淬灭。将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层经无水硫酸钠干燥、然后浓缩。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷/甲醇(10:1)洗脱,以提供呈固体的7-氯-4-(吡唑-1-基)-1H-吲哚(B19;1.2g)。LCMS(ES,m/z):218[M+H]+。
中间体B20的合成
将20mL密封管吹扫并维持在氮气气氛下,并且将7-氯-4-(吡唑-1-基)-1H-吲哚(B19;1.2g,5.51mmol,1.0当量)、双(频哪醇合)二硼(2.52g,9.92mmol,1.8当量)、乙酸钾(1.62g,16.54mmol,3.0当量)、Pd2(dba)3(0.4g,0.44mmol,0.08当量)、XPhos(0.79g,1.65mmol,0.3当量)、和1,4-二噁烷(12.0mL)添加到管中。然后将反应混合物在110℃用微波辐射辐照2h,并且将反应通过添加水/冰(10mL)淬灭。然后将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层浓缩,以提供呈油状物的4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B20;1.2g)。LCMS(ES,m/z):310[M+H]+。
中间体B21的合成
将10mL圆底烧瓶吹扫并维持在氮气气氛下,并且将4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B20;500mg,1.61mmol,1.0当量)、叔丁基4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B17;908mg,2.11mmol,1.3当量)、Pd(dppf)Cl2(59mg,0.081mmol,0.05当量)、K3PO4(1029mg,4.85mmol,3.0当量)、二噁烷(4.0mL)和H2O(1mL)添加到烧瓶中。将所得溶液在80℃搅拌3h,并且将反应通过添加冰/盐(10mL)淬灭。将所得溶液用乙酸乙酯(10mL)萃取,并且将合并的有机层经无水硫酸钠干燥并浓缩。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷/甲醇(10:1)洗脱,以提供呈固体的叔丁基2-甲基-4-[甲基([6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B21;700mg)。LCMS(ES,m/z):488[M+H]+。
化合物110和111的合成
将25-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基2-甲基-4-[甲基([6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B21;700.0mg)和在1,4-二噁烷(5mL)中的4M HCl添加到烧瓶中。将所得溶液在25℃搅拌2h,然后浓缩。将粗产物通过制备型HPLC纯化(条件3),以提供呈固体的N-甲基-N-[(2R,4S)-2-甲基哌啶-4-基]-6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-胺(化合物110;28.1mg);LCMS(ES,m/z):388[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.47(d,J=2.5Hz,1H),8.18(d,J=9.8Hz,1H),7.84(d,J=1.8Hz,1H),7.78(d,J=8.2Hz,1H),7.52(t,J=2.9Hz,1H),7.45(d,J=8.1Hz,1H),7.29(d,J=9.9Hz,1H),6.95(t,J=2.7Hz,1H),6.60(t,J=2.1Hz,1H),4.91(s,1H),3.31-3.33(m,1H),3.00-3.03(m,4H),2.85-2.88(m,1H),1.96-1.99(m,1H),1.67-1.70(m,2H),1.45-1.57(m,1H),1.26(d,J=6.9Hz,3H);和呈固体的N-甲基-N-[(2R,4S)-2-甲基哌啶-4-基]-6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-胺(化合物111;66.1mg)。LCMS(ES,m/z):388[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.74(s,1H),8.47(d,J=2.5Hz,1H),8.18(d,J=9.8Hz,1H),7.84(d,J=1.8Hz,1H),7.78(d,J=8.2Hz,1H),7.52(t,J=2.9Hz,1H),7.45(d,J=8.1Hz,1H),7.29(d,J=9.9Hz,1H),6.95(t,J=2.7Hz,1H),6.60(t,J=2.1Hz,1H),4.91(s,1H),3.01-3.03(m,1H),2.95-3.00(m,3H),2.85-2.88(m,2H),1.56-1.70(m,3H),1.30-1.51(m,1H),1.06(d,J=6.9Hz,3H)。
实例7:化合物112的合成
中间体B15的合成
在80℃,伴随脱氧,在40mL样品瓶中,将4-溴-7-氯-1H-吲哚(1g,4.34mmol,1当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B14;1.33g,4.77mmol,1.1当量)、K3PO4(2.76g,13.02mmol,3当量)和Pd(dppf)Cl2-CH2Cl2(0.18g,0.22mmol,0.05当量)在二噁烷(16.0mL)和H2O(4.0mL)中的混合物搅拌3h。将所得混合物在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(3:1)洗脱,以得到呈油状物的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚(B15;1.23g)。
中间体B16的合成
在100℃,伴随脱氧,在微波反应器中,将KOAc(1.07g,10.94mmol,3当量)、B2Pin2(2.04g,8.02mmol,2.2当量)、7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚(B15;1.10g,3.65mmol,1当量)、KOAc(1.07g,10.94mmol,3当量)和Pd2(dba)3-CHCl3(0.38g,0.37mmol,0.1当量)在二噁烷(40.0mL)中的混合物搅拌1h。在0℃,将反应用H2O淬灭,并且将水层用乙酸乙酯(100mL x 3)萃取。将所得混合物用饱和水性NaCl洗涤、并使用Na2SO2干燥,并且通过过滤除去固体。将滤液在减压下浓缩,以提供呈油状物的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B16;1.4g)。LCMS(ES,m/z):394[M+H]+。
中间体B22的合成
在100℃,伴随脱氧,将4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B16;1.23g,3.13mmol,1当量)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B12;2.08g,4.69mmol,1.5当量)、K3PO4(1.99g,9.38mmol,3当量)和Pd(PPh3)4(0.36g,0.31mmol,0.1当量)在二噁烷(16mL)和H2O(4mL)中的混合物搅拌4h,并且将反应在0℃用H2O淬灭。将水层用乙酸乙酯(100mL x3)萃取,并且将所得混合物用饱和水性NaCl(100mL)洗涤、并用Na2SO4干燥。将所得混合物过滤,并且将滤饼用乙酸乙酯(50mL x 3)洗涤。将滤液在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B22;800mg)。LCMS(ES,m/z):584[M+H]+。
化合物112的合成
在0℃,在氮气气氛下,在经吹扫的50mL 3颈圆底烧瓶中,将叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲哚-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B22;800mg)、在1,4-二噁烷(8.0mL)中的HCl、二噁烷(8.0mL)和MeOH(3.0mL)的混合物搅拌2h。将混合物过滤,并且将滤液在减压下浓缩。将粗产物通过制备型HPLC纯化,以得到呈固体的(1R,3S,5S)-N-甲基-N-[6-[4-(1H-吡唑-4-基)-1H-吲哚-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物112;8mg)。LCMS(ES,m/z):400[M+H]+。1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.15(d,J=16.9Hz,3H),7.67(d,J=7.4Hz,1H),7.49(s,1H),7.34(d,J=7.7Hz,1H),7.24(d,J=9.3Hz,1H),6.83(s,1H),5.05(s,1H),3.55(s,1H),2.96(s,3H),1.85(s,2H),1.78(s,4H),1.59(s,2H)。
实例8:化合物113的合成
中间体B23的合成
将20-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲哚(B20;500mg,1.61mmol,1.0当量)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B12;1077mg,2.43mmol,1.5当量)、Pd(dppf)Cl2(59mg,0.081mmol,0.05当量)、K3PO4(1029mg,4.85mmol,3.0当量)、1,4-二噁烷(4mL)和H2O(1mL)添加到烧瓶中。将所得溶液在80℃搅拌2h,并且将反应通过添加水/冰(10mL)淬灭。将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(1R,3S,5S)-3-[甲基([6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B23;200mg)。LCMS(ES,m/z):500[M+H]+。
化合物113的合成
将10-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基(1R,3R,5S)-3-[甲基([6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B23;200mg)和在1,4-二噁烷(2mL)中的4MHCl添加到烧瓶中。将所得溶液在25℃搅拌1h,然后浓缩。将粗产物通过制备型HPLC纯化(条件4,梯度1),以提供呈固体的(1R,3R,5S)-N-甲基-N-[6-[4-(吡唑-1-基)-1H-吲哚-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物113;19mg)。LCMS(ES,m/z):400[M+H]+。1H NMR(400MHz,甲醇-d4)δ8.27(d,J=2.4Hz,1H),8.14(dd,J=9.2,5.4Hz,1H),7.83(dd,J=1.9,0.6Hz,1H),7.76(dd,J=8.1,3.5Hz,1H),7.53(dd,J=3.3,1.1Hz,1H),7.41(dd,J=8.0,1.8Hz,1H),7.27(dd,J=9.7,6.1Hz,1H),6.84(d,J=3.3Hz,1H),6.60-6.66(m,1H),5.20-5.23(m,1H),3.72(s,2H),3.01-3.03(m,3H),1.98-2.02(m,6H),1.74-1.78(m,2H)。
实例9:化合物115的合成
中间体B25的合成
将250-mL 3颈圆底烧瓶吹扫并维持在氮气气氛下,并且将4,7-二溴-1H-1,2,3-苯并三唑(B24;2g,7.222mmol,1当量)和DMF(30mL)添加到烧瓶中。将所得溶液在冰/盐浴中冷却至0℃,并且缓慢添加氢化钠(346.6mg,14.445mmol,2当量),然后将混合物加温至25℃并搅拌0.5h。然后将SEM-Cl(1.32g,7.945mmol,1.10当量)滴加到混合物中,并且将混合物再搅拌3h。然后将反应通过倾倒入水/冰(150mL)中淬灭。将所得溶液用乙酸乙酯(3x50mL)萃取,并且将合并的有机层用无水硫酸钠干燥、并通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:4)洗脱,以提供呈油状物的4,7-二溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑(B25;1.82g)。LCMS(ES,m/z):408[M+H]+。1H NMR(400MHz,氯仿-d)δ7.58(d,J=8.0Hz,1H),7.47(d,J=8.0Hz,1H),6.26(s,2H),3.69-3.61(m,2H),0.98-0.89(m,2H)。
中间体B26的合成
将100-mL 3颈圆底烧瓶吹扫并维持在氮气气氛下,并且将4,7-二溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑(B25;863.0mg,2.119mmol,1当量)和四氢呋喃(20mL)添加到烧瓶中,并且将所得溶液冷却至-78℃。然后将在己烷中的n-BuLi(142.6mg,2.225mmol,1.05当量)缓慢添加到混合物中,然后将该混合物在-78℃搅拌1h。接下来,滴加硼酸三异丙酯(797.2mg,4.239mmol,2当量),并且将混合物加温至25℃并再搅拌1h。然后将反应通过添加冰水(10mL)淬灭。将所得溶液用乙酸乙酯(3x10mL)萃取,并且将合并的有机层用无水硫酸钠干燥、然后通过C18柱快速色谱法纯化,其中用乙腈/H2O(1:1)洗脱,以提供呈固体的7-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基硼酸(B26;542mg)。LCMS(ES,m/z):374[M+H]+。
中间体B27的合成
将30mL圆底烧瓶吹扫并维持在氮气气氛下,并且将7-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基硼酸(B26;520.0mg,1.397mmol,1当量)、叔丁基(2R,4R)-4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B3;543.7mg,1.258mmol,0.90当量)、Pd(dppf)Cl2-CH2Cl2(57.1mg,0.070mmol,0.05当量)、K3PO4(889.9mg,4.192mmol,3当量)、二噁烷(10mL)和H2O(2mL)添加到烧瓶中,并且将所得溶液在80℃搅拌12h。然后将溶液用乙酸乙酯(3x20mL)萃取并经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(2R,4R)-4-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-2-甲基哌啶-1-甲酸酯(B27;397mg)。LCMS(ES,m/z):634[M+H]+。
中间体B28的合成
将25-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基(2R,4R)-4-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-2-甲基哌啶-1-甲酸酯(B27;181.0mg,0.286mmol,1当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;87.5mg,0.315mmol,1.10当量)、Pd(dppf)Cl2-CH2Cl2(23.4mg,0.029mmol,0.10当量)、K2CO3(118.6mg,0.858mmol,3当量)、二噁烷(5mL)和H2O(1mL)添加到烧瓶中。将所得溶液在80℃搅拌4h、然后用乙酸乙酯(3x10mL)萃取并经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(2R,4R)-2-甲基-4-[甲基(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B28;193mg)。LCMS(ES,m/z):704[M+H]+。
化合物115的合成
将叔丁基(2R,4R)-2-甲基-4-[甲基(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B28;180.0mg)、二氯甲烷(1mL)、和三氟乙酸(3mL)添加到10mL圆底烧瓶中,并且将所得溶液在25℃搅拌4h。将粗产物通过制备型HPLC纯化(条件4,梯度2),以提供呈固体的N-甲基-N-[(2R,4R)-2-甲基哌啶-4-基]-6-[7-(丙-1-烯-2-基)-3H-1,2,3-苯并三唑-4-基]哒嗪-3-胺(化合物115;32.7mg)。LCMS(ES,m/z):390[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.60-8.44(m,3H),8.03(d,J=7.7Hz,1H),7.70(d,J=7.6Hz,1H),7.28(d,J=9.8Hz,1H),4.74(s,1H),3.01(s,3H),2.78(ddt,J=27.0,11.9,5.3Hz,2H),1.69(td,J=11.5,4.4Hz,3H),1.42(q,J=11.7Hz,1H),1.09(d,J=6.2Hz,3H)。
实例10:化合物117的合成
中间体B29的合成
将25-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基(2R,4R)-4-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-2-甲基哌啶-1-甲酸酯(来自实例10的B27;196.0mg,0.310mmol,1.0当量)、吡唑(31.6mg,0.465mmol,1.5当量)、Pd2(dba)3(28.4mg,0.031mmol,0.1当量)、t-BuXPhos(26.3mg,0.062mmol,0.2当量)、Cs2CO3(302.8mg,0.929mmol,3.0当量)和二噁烷(5mL)添加到烧瓶中。将所得溶液在100℃搅拌4h、然后用乙酸乙酯(3x10mL)萃取、并经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(2R,4R)-2-甲基-4-[甲基([6-[7-(吡唑-1-基)-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B29;160mg)。LCMS(ES,m/z):620[M+H]+。
化合物117的合成
将叔丁基(2R,4R)-2-甲基-4-[甲基([6-[7-(吡唑-1-基)-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基])氨基]哌啶-1-甲酸酯(B29;150.0mg)、二氯甲烷(1mL)、和三氟乙酸(3mL)置于10-mL圆底烧瓶中,并且将所得溶液在25℃搅拌4h。将粗产物通过制备型HPLC纯化(条件4,梯度2),以提供呈固体的N-甲基-N-[(2R,4R)-2-甲基哌啶-4-基]-6-[7-(吡唑-1-基)-3H-1,2,3-苯并三唑-4-基]哒嗪-3-胺(化合物117;22.8mg)。LCMS(ES,m/z):390[M+H]+。1H NMR(400MHz,氯仿-d)δ9.58(s,1H),δ8.96(d,J=1.2Hz,1H),8.07(d,J=1.2Hz,1H),7.83(d,J=2.8Hz,1H),7.32-7.29(m,2H),6.62(s,1H),4.93-4.78(s,1H),3.30-3.17(m,4H),2.93(s,3H),1.97-1.67(m,4H),1.21(d,J=1.2Hz,3H)。
实例11:化合物118的合成
中间体B30的合成
将30-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将7-溴-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基硼酸(来自实例10的B26;542.0mg,1.457mmol,1当量)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B12;647.2mg,1.457mmol,1当量)、Pd(dppf)Cl2-CH2Cl2(59.5mg,0.073mmol,0.05当量)、K3PO4(927.6mg,4.370mmol,3当量)、二噁烷(10mL)和H2O(2mL)添加到烧瓶中,并且将所得溶液在80℃搅拌12h。然后将溶液用乙酸乙酯(3x10mL)萃取并经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(1R,3S,5S)-3-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B30;415mg)。LCMS(ES,m/z):646[M+H]+。
中间体B31的合成
将20-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基(1R,3S,5S)-3-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B30;20.0mg,0.031mmol,1当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;8.6mg,0.031mmol,1当量)、Pd(dppf)Cl2-CH2Cl2(2.5mg,0.003mmol,0.10当量)、K2CO3(76.0mg,0.093mmol,3当量)、二噁烷(5mL)和H2O(1mL)添加到烧瓶中,并且将所得溶液在80℃搅拌4h。然后将溶液用乙酸乙酯(3x10mL)萃取并经无水硫酸钠干燥。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:1)洗脱,以提供呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B31;126mg)。LCMS(ES,m/z):716[M+H]+。
化合物118的合成
将叔丁基(1R,3S,5S)-3-[甲基(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B31;126.0mg)、二氯甲烷(3mL)、和三氟乙酸(9mL)置于25-mL圆底烧瓶中,并且将所得溶液在25℃搅拌4h。将粗产物通过制备型HPLC纯化(条件4,梯度2),以提供呈固体的(1R,3S,5S)-N-甲基-N-[6-[7-(1H-吡唑-4-基)-3H-1,2,3-苯并三唑-4-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物118;30mg)。LCMS(ES,m/z):402[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(br,1H),8.59(s,2H),8.54(d,J=9.7Hz,1H),8.01(d,J=7.6Hz,1H),7.66(d,J=7.6Hz,1H),7.26(d,J=9.7Hz,1H),5.14(dq,J=11.9,5.9Hz,1H),2.97(s,3H),1.95(td,J=12.4,3.0Hz,2H),1.87(s,4H),1.70-1.60(m,2H)。
实例12:化合物119的合成
中间体B32的合成
将25-mL圆底烧瓶吹扫并维持在氮气气氛下,并且将叔丁基(1R,3S,5S)-3-[[6-(7-溴-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基)哒嗪-3-基](甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(来自实例12的B30;220.0mg,0.341mmol,1当量)、吡唑(34.8mg,0.512mmol,1.50当量)、CuI(6.5mg,0.034mmol,0.10当量)、Cs2CO3(333.5mg,1.024mmol,3当量)、N1,N2-二甲基环己烷-1,2-二胺(4.8mg,0.034mmol,0.10当量)和二噁烷(5mL)添加到烧瓶中,并且将所得溶液在100℃搅拌12h。然后将溶液用乙酸乙酯(3x10mL)萃取,并且将有机相浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(2:1)洗脱,以提供呈固体的叔丁基(1R,3S,5S)-3-[甲基([6-[7-(吡唑-1-基)-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B32;34mg)。LCMS(ES,m/z):632[M+H]+。
化合物119的合成
将叔丁基(1R,3S,5S)-3-[甲基([6-[7-(吡唑-1-基)-3-[[2-(三甲基甲硅烷基)乙氧基]甲基]-1,2,3-苯并三唑-4-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B32;20.0mg)、二氯甲烷(1mL)、和三氟乙酸(3mL)置于10-mL圆底烧瓶中,并且将所得溶液在25℃搅拌4h。将粗产物通过制备型HPLC纯化(条件4,梯度2),以提供呈固体的(1R,3S,5S)-N-甲基-N-[6-[7-(吡唑-1-基)-3H-1,2,3-苯并三唑-4-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物119;9.3mg)。LCMS(ES,m/z):402[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.60(d,J=2.5Hz,1H),9.05(d,J=9.7Hz,1H),8.09(d,J=7.9Hz,1H),7.85-7.75(m,2H),7.30(d,J=9.7Hz,1H),6.62(t,J=2.2Hz,1H),5.22(dt,J=12.0,6.1Hz,1H),4.06(s,2H),2.99(s,3H),2.17 -2.04(m,6H),2.02(s,1H),1.84-1.74(m,2H)。
实例13:化合物121的合成
中间体B34的合成
将4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-二氢吲哚-2-酮(B33;150.0mg,0.37mmol,1当量)、叔丁基(2R,4R)-4-[(6-碘哒嗪-3-基)(甲基)氨基]-2-甲基哌啶-1-甲酸酯(B3;158.44mg,0.37mmol,1当量)、Pd(dppf)Cl2-CH2Cl2(29.93mg,0.04mmol,0.10当量)、K3PO4(233.38mg,1.10mmol,3当量)、二噁烷(15mL)和水(3mL)添加到40mL小瓶中,并且将所得混合物在80℃在氮气气氛下搅拌2h。将反应用水淬灭,并且将所得混合物用乙酸乙酯(2x10mL)萃取。将合并的有机层用盐水(1x10mL)洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型TLC纯化,其中用二氯甲烷/甲醇(20:1)洗脱,以得到呈固体的叔丁基(2R,4R)-2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-2-氧代-1,3-二氢吲哚-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B34;14.0mg)。LCMS(ES,m/z):588[M+H]+。
化合物121的合成
将叔丁基(2R,4R)-2-甲基-4-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-2-氧代-1,3-二氢吲哚-7-基]哒嗪-3-基)氨基]哌啶-1-甲酸酯(B34;14.0mg,0.02mmol,1当量)、三氟乙酸(0.4mL)和二氯甲烷(2.0mL)添加到4mL小瓶中,并且将所得混合物在室温搅拌1h。将所得混合物在减压下浓缩,并且将粗产物通过制备型HPLC纯化(条件1),以得到呈固体的7-(6-[甲基[(2R,4R)-2-甲基哌啶-4-基]氨基]哒嗪-3-基)-4-(1H-吡唑-4-基)-1,3-二氢吲哚-2-酮(化合物121;5.8mg)。LC-MS(ES,m/z):404[M+H]+。1H NMR(400MHz,甲醇-d4):δ8.50(d,J=10.1Hz,1H),8.16(d,J=8.6Hz,3H),7.84(d,J=8.5Hz,1H),7.52(d,J=8.4Hz,1H),4.71-4.59(m,1H),3.64(dt,J=13.1,3.4Hz,1H),3.56-3.46(m,1H),3.34(s,2H),3.27(s,4H),2.24-2.11(m,3H),2.01(q,J=12.2Hz,1H),1.45(d,J=6.4Hz,3H)。
实例14:化合物123的合成
中间体B33的合成
将7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-二氢吲哚-2-酮(B35;150.0mg,0.47mmol,1当量)、双(频哪醇合)二硼(239.74mg,0.94mmol,2当量)、Pd2(dba)3(43.23mg,0.05mmol,0.10当量)、XPhos(45.01mg,0.10mmol,0.20当量)、KOAc(138.98mg,1.42mmol,3当量)和二噁烷(15mL)添加到40mL小瓶中,并且将所得混合物在100℃在氮气气氛下搅拌1h。将粗产物(B33)不经进一步纯化直接用于下一步骤。LCMS(ES,m/z):410[M+H]+
中间体B36的合成
将4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-二氢吲哚-2-酮(B33;150.0mg,0.366mmol,1当量)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B12;162.84mg,0.37mmol,1当量)、Pd(dppf)Cl2-CH2Cl2(29.93mg,0.04mmol,0.10当量)、K3PO4(233.38mg,1.10mmol,3当量)、二噁烷(15mL)和水(3mL)添加到40mL小瓶中,并且将所得混合物在80℃在氮气气氛下搅拌2h。将反应用水淬灭,并且将所得混合物用乙酸乙酯(2x10mL)萃取。将合并的有机层用盐水(1x10mL)洗涤、经无水Na2SO4干燥、过滤、并在减压下浓缩。将残余物通过制备型TLC纯化,其中用二氯甲烷/甲醇(20:1)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-2-氧代-1,3-二氢吲哚-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B36;20.0mg)。LCMS(ES,m/z):600[M+H]+。
化合物123的合成
将叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-2-氧代-1,3-二氢吲哚-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B36;20.0mg,0.03mmol,1当量)、三氟乙酸(0.4mL)和二氯甲烷(2.0mL)添加到4mL小瓶中,并且将所得混合物在室温搅拌1h、然后在减压下浓缩。将粗产物通过制备型HPLC纯化(条件1),以得到呈固体的7-[6-[(1R,3S,5S)-8-氮杂双环[3.2.1]辛烷-3-基(甲基)氨基]哒嗪-3-基]-4-(1H-吡唑-4-基)-1,3-二氢吲哚-2-酮(化合物123;1.70mg)。LC-MS(ES,m/z):416[M+H]+。1H NMR(400MHz,甲醇-d4)δ8.49(d,J=10.1Hz,1H),8.18(d,J=9.0Hz,2H),7.83(d,J=8.5Hz,1H),7.54(d,J=8.5Hz,1H),4.77(d,J=5.6Hz,1H),4.27(s,2H),3.34(s,2H),3.26(s,3H),2.43-2.22(m,6H),2.10(d,J=13.4Hz,2H)。
实例23:化合物131的合成
中间体B50的合成
向6-溴-3-氯-2-氟苯甲醛(B49;50g,21.1mmol,1当量)在二甲基甲酰胺中的溶液中缓慢添加(甲基磺酰基)钠(1.48g,21.1mmol,1当量),并且将混合物在室温搅拌4h。然后将混合物用乙酸乙酯(150mL)和水(100mL)稀释,并且将水层用乙酸乙酯(2x100mL)萃取。将合并的有机层用饱和盐水(200mL)洗涤、经无水硫酸钠干燥、并浓缩。将残余物通过硅胶柱色谱法纯化(120g硅胶),其中用在石油醚中的18%乙酸乙酯洗脱,以得到呈固体的6-溴-3-氯-2-(甲基磺酰基)苯甲醛(B50;3g)。1H NMR(400MHz,DMSO-d6,ppm)δ10.26(s,1H),7.77(d,J=8.7Hz,1H),7.68(d,J=8.4Hz,1H),2.41(s,3H)。
中间体B52的合成
在0℃,在氮气气氛下,将6-溴-3-氯-2-(甲基磺酰基)苯甲醛(B50;3g,11.3mmol,1当量)添加到Ohira-Bestmann试剂(B51;3.26g,16.9mmol,1.5当量)和K2CO3(4.68g,33.9mmol,3当量)在甲醇(30mL)中的混合物中,并且将所得混合物加温至室温并搅拌2h。然后将混合物用二乙醚(30mL)和水(30mL)稀释,并且将水层用二乙醚(2x30mL)萃取。将合并的有机层用饱和盐水(50mL)洗涤、经无水硫酸钠干燥并浓缩,以得到残余物。将残余物通过硅胶柱色谱法纯化(80g硅胶柱),其中用在石油醚中的15%乙酸乙酯洗脱,以得到呈固体的1-溴-4-氯-2-乙炔基-3-(甲基磺酰基)苯(B52;2.2g)。1H NMR(400MHz,DMSO-d6,ppm)δ7.72(d,J=8.7Hz,1H),7.52(d,J=8.7Hz,1H),5.03(s,1H),2.50(s,3H)。
中间体B53的合成
向1-溴-4-氯-2-乙炔基-3-(甲基磺酰基)苯(B52;2.2g,8.4mmol,1当量)在甲苯(40mL)中的溶液中添加硅胶(14g,233mmol,27.7当量),并且将反应混合物在90℃在氮气气氛下搅拌16h。然后将所得混合物过滤,并且将滤饼用二氯甲烷洗涤。然后将滤液在减压下浓缩,以得到呈固体的4-溴-7-氯-1-苯并噻吩(B53;1.8g)。1H NMR(400MHz,DMSO-d6,ppm)δ8.07(d,J=5.5Hz,1H),7.69(d,J=8.1Hz,1H),7.54(d,J=5.6Hz,1H),7.46(d,J=8.1Hz,1H)。
中间体B54的合成
向4-溴-7-氯-1,3-苯并噻唑(B53;1g,4mmol,1当量)和1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;1.34g,5mmol,1.2当量)在二噁烷(8mL)和水(2mL)中的溶液中添加三磷酸钾(2.56g,12mmol,3当量)和Pd(dppf)Cl2(147.2mg,0.2mmol,0.05当量),并且将所得混合物在100℃在氮气气氛下搅拌过夜。然后将混合物在减压下浓缩并用乙酸乙酯(25mL)和水(30mL)稀释。将水层用乙酸乙酯(2x25mL)萃取,并且将合并的有机层用饱和盐水(40mL)洗涤、经无水硫酸钠干燥、并浓缩,以得到残余物。将残余物通过硅胶柱色谱法纯化(40g硅胶),其中用在石油醚中的35%乙酸乙酯洗脱,以得到呈油状物的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(B54;1g)。LCMS(ES,m/z):319.00[M+H]+。1H NMR(400MHz,DMSO-d6,ppm)δ8.41(d,J=0.8Hz,1H),7.98(d,J=0.8Hz,1H),7.96(d,J=5.5Hz,1H),7.77(d,J=5.6Hz,1H),7.57-7.50(m,2H),5.49(dd,J=10.1,2.1Hz,1H),4.01-3.94(m,1H),3.71-3.61(m,1H),2.21(dddd,J=13.5,10.0,8.0,3.3Hz,1H),2.03-1.93(m,2H),1.71(qdt,J=9.2,6.7,3.5Hz,1H),1.57(tq,J=6.0,3.8Hz,2H)。
中间体B55的合成
向4-(7-氯-1-苯并噻吩-4-基)-1-(噁烷-2-基)吡唑(B54;800mg,2.5mmol,1当量)和双(频哪醇合)二硼(765mg,3mmol,1.2当量)在二噁烷(8mL)中的溶液中添加乙酸钾(739mg,7.5mmol,3当量)和XPhos Pd G2(98.6mg,0.13mmol,0.05当量),并且将所得混合物在100℃在氮气气氛下搅拌过夜。然后将混合物在减压下浓缩并用乙酸乙酯(10mL)和水(15mL)稀释,并且将水层用乙酸乙酯(2x10mL)萃取。然后将合并的有机层用饱和盐水(20mL)洗涤、经无水硫酸钠干燥、并浓缩,以提供呈油状物的1-(噁烷-2-基)-4-[7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-苯并噻吩-4-基]吡唑(B55;1.5g)。LCMS(ES,m/z):411.10[M+H]+。
中间体B57的合成
向6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(来自实例23的B56;300mg,0.8mmol,1当量)和1-(噁烷-2-基)-4-[7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-苯并噻吩-4-基]吡唑(B55;493mg,1.2mmol,1.5当量)在二噁烷(4mL)和水(1mL)中的溶液中添加磷酸三钾(510mg,2.4mmol,3当量)和XPhos Pd G2(31.5mg,0.04mmol,0.05当量),并且将所得混合物在100℃在氮气气氛下搅拌过夜。然后将混合物在减压下浓缩并用乙酸乙酯(15mL)和水(12mL)稀释,并且将水层用乙酸乙酯(2x15mL)萃取。将合并的有机层用饱和盐水(30mL)洗涤、经无水硫酸钠干燥、并浓缩,以提供残余物。然后将残余物通过硅胶柱色谱法纯化(40g硅胶),其中用在二氯甲烷中的46%甲醇洗脱,以得到呈固体的N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B57;90mg)。LCMS(ES,m/z):531.25[M+H]+。
化合物131的合成
向N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B57;90mg,1当量)在二噁烷(2mL)中的溶液中添加HCl在1,4-二噁烷(2mL)中的溶液,并且将所得混合物在室温搅拌2h。然后将混合物在真空下浓缩、并通过制备型HPLC纯化(条件3),以得到呈固体的N-甲基-6-[4-(1H-吡唑-4-基)-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(化合物131;17.8mg)。LCMS(ES,m/z):447.15[M+H]+。1H NMR(400MHz,甲醇-d4,ppm)δ8.07(d,J=9.8Hz,1H),8.05(s,2H),7.84(d,J=7.8Hz,1H),7.78-7.69(m,2H),7.59(d,J=7.7Hz,1H),7.25(d,J=9.8Hz,1H),5.19(s,1H),3.05(s,3H),1.75(dd,J=12.7,3.6Hz,2H),1.65(t,J=12.5Hz,2H),1.45(s,6H),1.28(s,6H)。
实例24:化合物137的合成
中间体B56的合成
将3,6-二碘哒嗪(3.9g,11.8mmol,1当量)、N,2,2,6,6-五甲基哌啶-4-胺(2g,11.8mmol,1当量)和K2CO3(1.6g,11.8mmol,1当量)在二甲基甲酰胺(20mL)中的混合物在100℃在氮气气氛下搅拌过夜。在0℃,将反应用H2O淬灭,并且将水层用乙酸乙酯(50mL x 2)萃取。将残余物通过硅胶柱色谱法纯化,其中用石油醚:乙酸乙酯(0.5)洗脱,以得到呈固体的6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B56;2g)。LCMS(ES,m/z):375[M+H]+。
中间体B59的合成
将K3PO4(242.3mg,1.14mmol,3当量)、4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例1的B2;150mg,0.38mmol,1当量)、6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B56;170.9mg,0.46mmol,1.2当量)和XPhos钯(II)联苯基-2-氯化胺(29.9mg,0.04mmol,0.1当量)在二噁烷(4mL)和H2O(1mL)中的混合物在80℃在氮气气氛下搅拌4h。在0℃,将反应用H2O淬灭,并且将水层用乙酸乙酯(20mL x 2)萃取。将所得混合物用饱和氯化钠溶液(10mL)洗涤,并且将有机萃取物经硫酸钠干燥、过滤,并且将滤饼用乙酸乙酯洗涤。将滤液在减压下浓缩,以提供残余物。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷/甲醇(15%)洗脱,以得到呈油状物的N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B59;100mg)。LCMS(ES,m/z):515[M+H]+。
化合物137的合成
在0℃,在氮气气氛下,将N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B59;100mg)、在1,4-二噁烷(2.5mL)中的HCl和MeOH(2.0mL)的混合物搅拌1h。将所得粗产物通过制备型HPLC纯化(条件5),以得到呈固体的N-甲基-6-[4-(1H-吡唑-4-基)-1H-吲唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(8.5mg)。LCMS(ES,m/z):431[M+H]+。1H NMR(400MHz,DMSO-d6,ppm)δ13.19(s,1H),13.08(s,1H),8.52(s,1H),8.31(s,2H),8.17(d,J=9.8Hz,1H),7.90(d,J=7.7Hz,1H),7.48(d,J=7.6Hz,1H),7.26(d,J=9.8Hz,1H),5.08(s,1H),3.00(s,3H),1.61-1.43(m,4H),1.30(s,6H),1.12(s,6H)。
实例25:化合物138的合成
中间体B62的合成
在0℃,向2,2,6,6-四甲基哌啶-4-醇(B61;641mg,4mmol)在二甲基甲酰胺(10mL)中的溶液中分批添加氢化钠(150mg,3.75mmol,60%)。然后将所得混合物加温至20℃并搅拌30min。然后将3-氯-6-碘哒嗪(B60;1g,4.1mmol)在0℃滴加到混合物中,并且在20℃将所得混合物再搅拌21h。将反应通过添加水/冰(40mL)淬灭、并用乙酸乙酯(40mL)萃取。将合并的有机层用饱和氯化钠溶液(3x50mL)洗涤、经无水Na2SO4干燥、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷:甲醇(5:1)洗脱,以得到呈固体的3-碘-6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪(B62;679mg)。LCMS(ES,m/z):362[M+H]+。
中间体B63的合成
在20℃,在氮气气氛下,将三磷酸钾(2M,0.57mL,1.14mmol)的水溶液滴加到3-碘-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪(B62;165mg,0.46mmol)、4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例1的B2;150mg,0.381mmol)、和XPhos Pd G2(30mg,0.04mmol)在1,4-二噁烷(4mL)中的溶液中。将所得混合物在80℃搅拌3h、然后在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷:甲醇(10:1)洗脱,以得到呈固体的4-(1-(四氢-2H-吡喃-2-基)-1H-吡唑-4-基)-7-(6-((2,2,6,6-四甲基哌啶-4-基)氧基)哒嗪-3-基)-1H-吲唑(B63;120mg)。LCMS(ES,m/z):502[M+H]+。
化合物138的合成
将4-[1-(噁烷-2-基)吡唑-4-基]-7-[6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基]-1H-吲唑(B63;120mg,0.24mmol)和在1,4-二噁烷(4mL)中的HCl的混合物在20℃搅拌30min、然后在减压下浓缩。将粗产物通过制备型HPLC纯化(条件4,梯度1),以得到呈固体的4-(1H-吡唑-4-基)-7-[6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基]-1H-吲唑(化合物138;11.3mg)。LCMS(ES,m/z):418[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),13.17(s,1H),8.56(s,1H),8.50(s,1H),8.41(d,J=9.5Hz,1H),8.22(s,1H),8.00(d,J=7.7Hz,1H),7.52(d,J=7.6Hz,1H),7.32(d,J=9.3Hz,1H),5.79(s,1H),2.18-2.06(m,2H),2.00(s,1H),1.41(s,1H),1.33(d,J=11.6Hz,2H),1.27(s,8H),1.22(d,J=17.9Hz,1H),1.13(s,6H)。
实例26:化合物142的合成
中间体B65的合成
在0℃,将氢化钠(0.24g,6mmol)分批添加到叔丁基-3-羟基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B64;0.93g,4.1mmol)在二甲基甲酰胺(10mL)中的溶液中,并且将所得混合物加温至20℃并搅拌30min。然后在0-5℃,将3-氯-6-碘哒嗪(B60;1g,4.1mmol)滴加到混合物中,并且将所得混合物在20℃再搅拌18h。将反应通过添加水/冰(50mL)淬灭、并用乙酸乙酯(50mL)萃取。将合并的有机层用饱和氯化钠溶液(3x50mL)洗涤并经无水Na2SO4干燥。将所得混合物在减压下浓缩,以得到呈固体的叔丁基(1R,3R,5S)-3-((6-碘哒嗪-3-基)氧基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B65;1.58g)。LCMS(ES,m/z):432[M+H]+。
中间体B66的合成
在20℃,在氮气气氛下,将K3PO4(2M,609μL,1.22mmol)的水溶液滴加到叔丁基-3-[(6-碘哒嗪-3-基)氧基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B65;193mg,0.45mmol)、4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例1的B2;160mg,0.41mmol)和XPhos Pd G2(32mg,0.041mmol)在1,4-二噁烷(5mL)中的溶液中。然后将所得混合物加热至80℃并搅拌3h。将所得混合物在减压下浓缩、并通过硅胶柱色谱法纯化,其中用乙酸乙酯洗脱,以得到呈固体的B66(95mg)。LCMS(ES,m/z):572[M+H]+。
化合物142的合成
在20℃,将叔丁基(1R,3S,5S)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氧基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(95mg,0.17mmol)、在1,4-二噁烷(4mL)中的HCl和甲醇(2mL)的混合物搅拌30min。将所得混合物在减压下浓缩、并通过制备型HPLC纯化(条件4,梯度3),以得到呈固体的7-[6-[(1R,3S,5S)-8-氮杂双环[3.2.1]辛烷-3-基氧基]哒嗪-3-基]-4-(1H-吡唑-4-基)-1H-吲唑(化合物142;17.8mg)。LCMS(ES,m/z):388[M+H]+。
1H NMR(400MHz,DMSO-d6)δ13.21(d,J=16.9Hz,2H),8.55(s,1H),8.40(d,J=9.4Hz,1H),8.37(s,2H),8.00(d,J=7.7Hz,1H),7.51(d,J=7.6Hz,1H),7.30(d,J=9.4Hz,1H),5.62(tt,J=11.0,6.0Hz,1H),3.54(t,J=3.3Hz,2H),2.22(ddd,J=12.4,6.1,2.8Hz,2H),1.74(hept,J=7.2,6.4Hz,4H),1.63(td,J=11.6,3.0Hz,2H)。
实例27:化合物143的合成
中间体B68的合成
将4-溴-7-氯-1H-吲唑(B5;1g,4.25mmol,1当量)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑(B67;1.1g,5.1mmol,1.2当量)、K3PO4(2.76g,13mmol,3当量)、Pd(dppf)Cl2-CH2Cl2(177mg,0.22mmol,0.05当量)在二噁烷(16mL)和H2O(4mL)中的混合物在80℃搅拌4h。然后将反应通过添加水/冰(50mL)淬灭。将所得溶液用乙酸乙酯(3x50mL)萃取,并且将合并的有机层用饱和水性NaCl(100mL)洗涤、然后经无水硫酸钠干燥并过滤。将滤液在真空下浓缩、用甲醇(20mL)洗涤并过滤,以提供呈固体的7-氯-4-(1-甲基-1H-吡唑-4-基)-1H-吲唑(B68;730mg)。LCMS(ES,m/z):233[M+H]+。
中间体B69的合成
在30-mL微波管中,在110℃,将7-氯-4-(1-甲基-1H-吡唑-4-基)-1H-吲唑(B68;300mg,1.3mmol,1当量)、B2(Pin)2(591mg,2.3mmol,1.8当量)、KOAc(380mg,3.9mmol,3当量)、XPhos(184.6mg,0.39mmol,0.3当量)、Pd2(dba)3.CHCl3(107mg,0.1mmol,0.08当量)和二噁烷(9mL)的混合物搅拌1h。然后通过过滤除去固体,以获得粗制B69,将其不经进一步纯化直接添加到下一步骤。LCMS(ES,m/z):325[M+H]+。
中间体B71的合成
将4-(1-甲基-1H-吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B69;300mg,0.92mmol,1当量)、叔丁基(1R,3r,5S)-3-((6-碘哒嗪-3-基)(甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;493mg,1.11mmol,1.2当量)、K3PO4(589mg,2.8mmol,3当量)、XPhos钯(II)联苯基-2-氯化胺(36.4mg,0.05mmol,0.05当量)、二噁烷(16mL)和H2O(4mL)的混合物在80℃搅拌16h。然后将反应通过添加水/冰(2mL)淬灭,并且将所得溶液用乙酸乙酯(3x10mL)萃取。将合并的有机层用饱和水性NaCl(50mL)洗涤。将固体在烘箱中在减压下干燥。将固体滤出。将所得混合物在真空下浓缩、并通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(7:3)洗脱,以提供呈固体的叔丁基(1R,3r,5S)-3-(甲基(6-(4-(1-甲基-1H-吡唑-4-基)-1H-吲唑-7-基)哒嗪-3-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B71;210mg)。LCMS(ES,m/z):515[M+H]+。
化合物143的合成
在吹扫并维持在氮气惰性气氛下的50-mL圆底烧瓶中,在室温,将叔丁基(1R,3r,5S)-3-(甲基(6-(4-(1-甲基-1H-吡唑-4-基)-1H-吲唑-7-基)-哒嗪-3-基)-氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B71;210mg,0.41mmol,1当量)、二噁烷(2mL)、和在二噁烷(2mL)中的4M HCl的混合物搅拌3h。然后将反应混合物用水/冰浴冷却并通过添加甲醇淬灭。将所得混合物在真空下浓缩并通过制备型HPLC纯化(条件4,梯度5),以提供呈固体的6-[6-[8-氮杂双环[3.2.1]-辛烷-3-基(甲基)氨基]-哒嗪-3-基]-3-(1H-吡唑-4-基)-1H-吡啶-2-酮(化合物143;5.6mg)。LCMS(ES,m/z):415[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.48(dd,J=3.2,1.1Hz,2H),8.18-8.08(m,2H),7.89(d,J=7.8Hz,1H),7.43(d,J=7.6Hz,1H),7.24(d,J=9.8Hz,1H),5.04(dd,J=11.6,6.1Hz,1H),3.96(s,3H),3.51(s,2H),2.97(s,3H),2.16(s,1H),1.88-1.74(m,3H),1.76(s,4H),1.56(dq,J=12.2,4.0,3.4Hz,2H)。
实例28:化合物146的合成
中间体B73的合成
在100℃,将3,6-二碘哒嗪(B57;1g,2.95mmol)、叔丁基-3-氨基-1,5-二甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B72;751mg,2.95mmol)和K2CO3(1.22g,8.86mmol)在二甲基甲酰胺(15mL)中的混合物搅拌3天。然后将混合物冷却至20℃并倾倒入盐水(100mL)中。将所得混合物用乙酸乙酯(3x100mL)萃取,并且将合并的有机层用盐水(2x100mL)洗涤、经无水Na2SO4干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈油状物的叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)氨基]-1,5-二甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B73;300mg)。LCMS(ES,m/z):459[M+H]+。
中间体B74的合成
在0℃,将氢化钠(46mg,1.16mmol,60%)分批添加到叔丁基-3-[(6-碘哒嗪-3-基)氨基]-1,5-二甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B73;360mg,0.77mmol)在二甲基甲酰胺(5mL)中的溶液中,并且将所得混合物在0℃搅拌30min。然后将甲基碘(73mg,1.155mmol)滴加到反应中,并且将混合物加温至25℃并再搅拌30min。将反应混合物倾倒入水(20mL)中并用乙酸乙酯(3x20mL)萃取。将合并的有机层用盐水(2x20mL)洗涤、经无水Na2SO4干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(10:1)洗脱,以得到呈油状物的叔丁基-3-[(6-碘哒嗪-3-基)(甲基)氨基]-1,5-二甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B74;150mg)。LCMS(ES,m/z):473[M+H]+。
中间体B75的合成
将叔丁基-3-[(6-碘哒嗪-3-基)(甲基)氨基]-1,5-二甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B74;165mg,0.34mmol)、4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例1的B2;135mg,0.34mmol)、Pd(PPh3)4(27mg,0.023mmol)和K2CO3(218mg,1.58mmol)在二噁烷(5mL)中的溶液在80℃在氮气气氛下搅拌4h。然后将混合物冷却至20℃并在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的叔丁基-1,5-二甲基-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B75;160mg)。LCMS(ES,m/z):613[M+H]+。
化合物146的合成
将叔丁基-1,5-二甲基-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B75;160mg,0.26mmol)和在1,4-二噁烷(5mL)中的HCl的混合物在25℃搅拌30min,并且将所得混合物在减压下浓缩。将粗产物通过制备型HPLC纯化(条件4,梯度6),以得到呈固体的N,1,5-三甲基-N-[6-[4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物146;15.2mg)。LCMS(ES,m/z):429[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.51(s,1H),8.33(s,1H),8.16(d,J=9.8Hz,2H),7.89(d,J=7.7Hz,1H),7.47(d,J=7.6Hz,1H),7.26(d,J=9.8Hz,1H),5.08(s,1H),2.98(s,3H),1.87(d,J=7.6Hz,2H),1.57(t,J=11.2Hz,6H),1.21(s,6H)。
实例29:化合物150的合成
在20-mL小瓶中,将4-(吡唑-1-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(来自实例2的B7;250mg,0.81mmol,1当量)、6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(来自实例24的B56;362mg,0.97mmol,1.2当量)、K3PO4(513mg,2.42mmol,3当量)、XPhos钯(II)联苯基-2-氯化胺(63.4mg,0.081mmol,0.1当量)、二噁烷(8mL)和水(2mL)的混合物吹扫并维持在氮气惰性气氛下,然后加热至80℃持续4h。将所得混合物在真空下浓缩并通过硅胶柱色谱法纯化,其中用二氯甲烷/甲醇(10:1)洗脱。将所得产物通过制备型HPLC进一步纯化(条件3),以提供呈固体的N-甲基-6-[4-(吡唑-1-基)-1H-吲唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(化合物150;2.9mg)。LCMS(ES,m/z):431[M+H]+。1H NMR:(400MHz,DMSO-d6,ppm)δ13.26(s,1H),8.70(d,J=2.5Hz,1H),8.63(d,J=1.7Hz,1H),8.20(d,J=9.8Hz,1H),7.99(d,J=8.0Hz,1H),7.92(d,J=1.7Hz,1H),7.62(d,J=8.0Hz,1H),7.29(d,J=9.8Hz,1H),6.69-6.64(m,1H),5.11(s,1H),3.02(s,4H),1.59(s,5H),1.33(s,6H),1.15(s,6H)。
实例30:化合物132的合成
中间体B78的合成
将苯甲酰异硫氰酸酯(B77;17.4g,107mmol)滴加到2-溴-5-氯苯胺(B76;20g,97)在丙酮(200mL)中的溶液中,并且将反应混合物加热至回流持续3h、然后倾倒入冰水中、并再搅拌30min。将沉淀物通过过滤收集并用更多水洗涤。然后将粗材料溶解于甲醇(200mL)中并用氢氧化钠(1N,50mL)处理,并加热至80℃持续2h。然后将混合物冷却、并倾倒入冰水中,并且使用1N HCl中和混合物的pH。将沉淀物通过过滤收集并干燥,以得到2-溴-5-氯苯基硫脲(B78;22.1)。LCMS(ES,m/z):264.85[M+H]+。
中间体B79的合成
经1h的时间段,将溴化铵(1.83g,18.8mmol)添加到2-溴-5-氯苯基硫脲(B78;5g,18.8mmol)在浓H2SO4(15mL)中的溶液中,并且将反应混合物加热至100℃持续2h。然后将反应混合物冷却至室温,然后倾倒入冰水(150mL)中。使用水性氢氧化铵溶液中和混合物的pH值,并且将沉淀物通过过滤收集、用水洗涤并真空干燥,以得到呈固体的4-溴-7-氯-1,3-苯并噻唑-2-胺(B79;4g)。LCMS(ES,m/z):262.85[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.13(s,2H),7.45(d,J=8.4Hz,1H),7.02(d,J=8.5Hz,1H)。
中间体B80的合成
经20min,将4-溴-7-氯-1,3-苯并噻唑-2-胺(3.9g,14.8mmol)在四氢呋喃(12mL)中的溶液滴加到亚硝酸异戊酯(2.6g,22.2mmol)和二甲亚砜(115.63mg,1.48mmol)在THF(28mL)中的溶液中。将混合物在30℃搅拌3h、然后用乙酸乙酯(50mL)和水(60mL)稀释,并且将水层用乙酸乙酯(2x50mL)萃取。将合并的有机层用饱和盐水(100mL)洗涤、经无水硫酸钠干燥并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用在石油醚中的20%乙酸乙酯洗脱,以得到呈固体的4-溴-7-氯-1,3-苯并噻唑(B80;2.2g)。1H NMR(400MHz,DMSO-d6)δ9.58(s,1H),7.84(d,J=8.3Hz,1H),7.56(d,J=8.3Hz,1H)。
中间体B81的合成
将磷酸三钾(5.38g,25mmol)和Pd(dppf)Cl2(309mg,0.42mmol)添加到4-溴-7-氯-1,3-苯并噻唑(B80;2.1g,8mmol)和1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(2.59g,9mmol)在二噁烷(16mL)和H2O(4mL)中的溶液中,并且将混合物在100℃在氮气气氛下搅拌过夜。然后将混合物在减压下浓缩、用乙酸乙酯(25mL)和水(30mL)稀释,并且将水层用乙酸乙酯(2x25mL)萃取。将合并的有机层用饱和盐水(40mL)洗涤、经无水硫酸钠干燥并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用在石油醚中的35%乙酸乙酯洗脱,以得到呈固体的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(B81;2.1g)。LCMS(ES,m/z):320.05[M+H]+。
中间体B82的合成
将乙酸钾(460mg,4.69mmol)和Pd(dtbpf)Cl2(51mg,0.078mmol)添加到7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(B81;500mg,1.56mmol)和双(频哪醇合)二硼(437mg,1.72mmol)在二噁烷(5mL)中的溶液中,并且将混合物在100℃在氮气气氛下搅拌过夜。将所得混合物在减压下浓缩并用乙酸乙酯(10mL)和水(15mL)稀释,并且将水层用乙酸乙酯(2x10mL)萃取。将合并的有机层用饱和盐水(20mL)洗涤、经无水硫酸钠干燥并浓缩,以给出呈油状物的粗制4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(B82;1g)。LCMS(ES,m/z):412.10[M+H]+。
中间体B83的合成
将磷酸三钾(510mg,2.4mmol)和XPhos Pd G2(31mg,0.04mmol)添加到6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B56;300mg,0.8mmol)和4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(B82;989mg,2.4mmol)在二噁烷(2mL)和H2O(8mL)中的溶液中,并且将混合物在100℃在氮气气氛下搅拌过夜。将所得混合物在减压下浓缩、用乙酸乙酯(15mL)和水(12mL)稀释,并且将水层用乙酸乙酯(2x15mL)萃取。将有机层合并、并用饱和盐水(30mL)洗涤、经无水硫酸钠干燥并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用在石油醚中的40%乙酸乙酯洗脱,以得到呈固体的N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B83;170mg)。LCMS(ES,m/z):532.25[M+H]+。
化合物132的合成
将HCl在1,4-二噁烷(2mL)中的溶液添加到在二噁烷(2mL)中的N-甲基-6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B83;170mg,0.32mmol)中,并且将混合物在室温搅拌2h。然后将混合物在真空下浓缩,并且将粗产物通过制备型HPLC纯化(条件1),以得到呈固体的N-甲基-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(化合物132;29mg)。LCMS(ES,m/z):448.20[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),9.51(s,1H),8.63(s,1H),8.47(s,1H),8.27(d,J=9.8Hz,1H),8.11(d,J=8.1Hz,1H),7.99(d,J=7.9Hz,1H),7.27(d,J=9.7Hz,1H),5.01(s,1H),3.01(s,3H),1.55(dd,J=12.0,3.6Hz,2H),1.46(t,J=12.0Hz,2H),1.29(s,6H),1.11(s,6H)。
实例31:化合物163的合成
中间体B85的合成
在室温,在氮气气氛下,将碳酸钾(3g,21.8mmol)和Pd(dppf)Cl2.CH2Cl2(0.3g,0.36mmol)分批添加到4,7-二溴-1H-1,3-苯并二唑(B84;2g,7.25mmol)和4-硼烷基-1-(噁烷-2-基)吡唑(B9;1.19g,7.25mmol)在二噁烷(20mL)和H2O(10mL)中的混合物中,并且将所得混合物在80℃搅拌过夜。然后将混合物用乙酸乙酯(2x50mL)萃取,并且将合并的有机层用盐水(2x100mL)洗涤、经无水Na2SO4干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(13:7)洗脱,以得到呈固体的4-溴-7-[1-(噁烷-2-基)吡唑-4-基]-3H-1,3-苯并二唑(B85;700mg)。LCMS(ES,m/z):347[M+H]+。
中间体B86的合成
在室温,在氮气气氛下,将乙酸钾(254mg,2.59mmol)、XPhos(41.2mg,0.086mmol)和Pd2(dba)3(39.6mg,0.043mmol)分批添加到4-溴-7-[1-(噁烷-2-基)吡唑-4-基]-3H-1,3-苯并二唑(B85;300mg,0.86mmol)和双(频哪醇合)二硼(329mg,1.3mmol)在二噁烷(3mL)中的混合物中,然后将所得混合物加热至80℃持续3h。将所得混合物过滤并在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(3:2)洗脱,以得到呈固体的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-1,3-苯并二唑(B86;160mg)。LCMS(ES,m/z):395[M+H]+。
中间体B87的合成
在室温,在氮气气氛下,将磷酸三钾(234mg,1.1mmol)和Pd(dppf)Cl2(21.3mg,0.018mmol)分批添加到4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-1,3-苯并二唑(B86;145mg,0.37mmol)和叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;245mg,0.55mmol)在二噁烷(2mL)和H2O(1mL)中的混合物中。将所得混合物在80℃搅拌过夜、然后过滤。将滤液在减压下浓缩、并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(13:7)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3H-1,3-苯并二唑-4-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B87;120mg)。LCMS(ES,m/z):585[M+H]+。
化合物163的合成
在室温,在氮气气氛下,将HCl在1,4-二噁烷(3mL)中的溶液滴加到(1R,3S,5S)-N-甲基-N-(6-[7-[1-(噁烷-2-基)吡唑-4-基]-3H-1,3-苯并二唑-4-基]哒嗪-3-基)-8-氮杂双环[3.2.1]辛烷-3-胺(B87;120mg,0.25mmol)在甲醇(3mL)中的溶液中,并且将所得混合物搅拌1h。然后将混合物过滤,并且将滤液在减压下浓缩。将残余物通过制备型HPLC纯化(条件4,梯度2),以得到呈固体的(1R,3S,5S)-N-甲基-N-[6-[7-(1H-吡唑-4-基)-3H-1,3-苯并二唑-4-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物163;44.2mg)。LCMS(ES,m/z):401[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),12.51(s,1H),8.69(s,1H),8.40(s,1H),8.22(s,1H),8.13(d,J=9.8Hz,1H),7.75(d,J=8.0Hz,1H),7.61(d,J=7.9Hz,1H),7.24(d,J=9.8Hz,1H),5.04(s,1H),3.52(s,2H),2.96(s,3H),1.82(t,J=11.7Hz,2H),1.76(s,4H),1.56(d,J=11.6Hz,2H),1.24(s,1H)。
实例32:化合物164的合成
中间体B89的合成
在100℃,在氮气气氛下,将4-溴-7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B88;1g,2.71mmol)、NaN3(352mg,5.42mmol)、抗坏血酸钠(108mg,0.54mmol)、碘化亚铜(52mg,0.27mmol)和反式-N,N-二甲基环己烷-1,2-二胺(58mg,0.41mmol)在H2O(6mL)和乙醇(14mL)中的混合物搅拌1h。然后将混合物冷却至20℃、并倾倒入水(100mL)中。将所得混合物用乙酸乙酯(3x100mL)萃取、经无水Na2SO4干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(10:1)洗脱,以得到呈油状物的4-叠氮基-7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B89;550mg)。LCMS(ES,m/z):324[M+H]+。
中间体B90的合成
在100℃,在氮气气氛下,将4-叠氮基-7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B89;500mg,1.51mmol)、三甲基甲硅烷基乙炔(223mg,2.27mmol)、CuSO4(24mg,0.15mmol)和抗坏血酸钠(60mg,0.3mmol)在叔丁醇(8mL)和H2O(2mL)中的溶液搅拌16h。然后将混合物冷却至20℃并倾倒入水(30mL)中。将所得混合物用乙酸乙酯(3x30mL)萃取、经无水Na2SO4干燥、过滤、并在减压下浓缩。将粗产物(B90)不经进一步纯化直接用于下一步骤。LCMS(ES,m/z):350[M+H]+。
中间体B91的合成
将7-氯-4-(1,2,3-三唑-1-基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B90;粗制)和三氟乙酸(1mL)在二氯甲烷(3mL)中的混合物在25℃搅拌30min。然后将所得混合物在减压下浓缩、并通过C18硅胶柱反相快速色谱法纯化,其中用水(10mmol/LNH4HCO3)和乙腈(30%保持2min、然后经20min增加至55%)洗脱,以得到呈固体的7-氯-4-(1,2,3-三唑-1-基)-1H-吲唑(B91;110mg)。LCMS(ES,m/z):220[M+H]+。
中间体B92的合成
在110℃,在氮气气氛下,将7-氯-4-(1,2,3-三唑-1-基)-1H-吲唑(B91;100mg,0.45mmol)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(B2Pin2;227mg,0.89mmol)、Pd2(dba)3.CHCl3(23mg,0.022mmol)、XPhos(21mg,0.045mmol)和乙酸钾(132mg,1.34mmol)在二噁烷(3mL)中的溶液用微波辐照2h。将所得混合物在真空下浓缩、并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-4-(1,2,3-三唑-1-基)-1H-吲唑(B92;110mg)。LCMS(ES,m/z):312[M+H]+。
中间体B93的合成
在100℃,在氮气气氛下,将7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-4-(1,2,3-三唑-1-基)-1H-吲唑(B92;110mg,0.35mmol)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;185mg,0.42mmol)、Pd(PPh3)4(40mg,0.035mmol)和K2CO3(2M;0.52mL,1.04mmol)在二噁烷(3mL)中的溶液搅拌16h。然后将混合物冷却至25℃并在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基([6-[4-(1,2,3-三唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B93;45mg)。LCMS(ES,m/z):502[M+H]+。
化合物164的合成
将叔丁基(1R,3R,5S)-3-[甲基([6-[4-(1,2,3-三唑-1-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B93;45mg,0.088mmol)和在1,4-二噁烷(2mL)中的HCl的混合物在25℃搅拌30min。将所得混合物在减压下浓缩、并通过制备型HPLC纯化(条件4,梯度3),以得到呈固体的(1R,3R,5S)-N-甲基-N-[6-[4-(1,2,3-三唑-1-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物164;7mg)。LCMS(ES,m/z):402[M+H]+。1H NMR(400MHz,DMSO-d6,ppm)δ13.48(s,1H),9.06(d,J=1.2Hz,1H),8.53(s,1H),8.23(d,J=9.8Hz,1H),8.12-8.05(m,2H),7.74(d,J=7.9Hz,1H),7.29(d,J=9.8Hz,1H),5.12(s,1H),3.58(s,2H),3.00(s,3H),1.93-1.82(m,2H),1.80(s,4H),1.60(dd,J=13.0,5.4Hz,2H)。
实例33:化合物144的合成
中间体B95的合成
在0℃,将甲基碘(143mg,1mmol)滴加到7-氯-4-(3H-1,2,3-三唑-4-基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B94;300mg,0.84mmol)和碳酸钾(232mg,1.68mmol)在二甲基甲酰胺(3mL)中的混合物中,并且将所得混合物在25℃搅拌8h、然后倾倒入水(30mL)中并用乙酸乙酯(2x30mL)萃取。将合并的有机层用盐水(3x30mL)洗涤、经无水硫酸钠干燥、过滤、并在减压下浓缩,以得到呈固体的7-氯-4-(2-甲基-1,2,3-三唑-4-基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B95;300mg)。LCMS(ES,m/z):364[M+H]+。
中间体B96的合成
将7-氯-4-(2-甲基-1,2,3-三唑-4-基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B95;300mg,0.82mmol)在HCl的1,4-二噁烷混合物(5mL)中的溶液在25℃搅拌30min。将所得混合物在真空下浓缩、并通过C18柱反向快速色谱法纯化,其中用在水性碳酸铵中的乙腈(10mmol/L)(20%乙腈持续5min、然后经20min增加至50%)洗脱,以得到呈固体的7-氯-4-(2-甲基-1,2,3-三唑-4-基)-1H-吲唑(B96;80mg)。LCMS(ES,m/z):234[M+H]+。
中间体B97的合成
在110℃,在氮气气氛下,将7-氯-4-(2-甲基-1,2,3-三唑-4-基)-1H-吲唑(B96;80mg,0.34mmol)、双(频哪醇合)二硼(128mg,0.5mmol)、Pd2(dba)3(15mg,0.02mmol)、XPhos(16mg,0.03mmol)和乙酸钾(66mg,0.672mmol)在1,4-二噁烷(5mL)中的溶液搅拌2h。然后将所得混合物在减压下浓缩并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的4-(2-甲基-1,2,3-三唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B97;80mg)。LCMS(ES,m/z):326[M+H]+。
中间体B98的合成
在80℃,在氮气气氛下,将4-(2-甲基-1,2,3-三唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B97;80mg,0.24mmol)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;129mg,0.29mmol)、Pd(PPh3)4(28mg,0.02mmol)和K3PO4(153mg,0.72mmol)在1,4-二噁烷(7mL)和H2O(1mL)中的溶液搅拌16h。然后将所得混合物用水(50mL)稀释、用乙酸乙酯(2x50mL)萃取、经无水硫酸钠干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:3)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基([6-[4-(2-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B98;60mg)。LCMS(ES,m/z):516[M+H]+。
化合物144的合成
将叔丁基(1R,3S,5S)-3-[甲基([6-[4-(2-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B98;60mg,0.114mmol)在HCl的1,4-二噁烷混合物(3mL)中的溶液在25℃搅拌30min。将所得混合物在减压下浓缩并通过制备型HPLC纯化(条件3),以得到呈固体的(1R,3S,5S)-N-甲基-N-[6-[4-(2-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物144;26.3mg)。LCMS(ES,m/z):416[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.66(s,1H),8.51(s,1H),8.19(d,J=9.8Hz,1H),7.98(d,J=7.7Hz,1H),7.75(d,J=7.6Hz,1H),7.26(d,J=9.8Hz,1H),5.08(s,1H),4.31(s,3H),3.53(s,2H),2.98(s,3H),1.89-1.79(m,2H),1.77(d,J=2.5Hz,4H),1.57(ddd,J=12.6,5.8,2.6Hz,2H)。
实例34:化合物165的合成
中间体B99的合成
将在20℃的4-溴-7-氯-1H-吲唑(B5;5g,21.6mmol)、三甲基甲硅烷基乙炔(2.55g,0.026mmol)、Pd(PPh3)4(2.5g,2.16mmol)、碘化亚铜(411mg,2.16mmol)和三乙胺(2.19g,21.6mmol)在四氢呋喃(50mL)中的混合物在80℃在氮气气氛下搅拌17h。然后将所得混合物在减压下浓缩、用乙酸乙酯(50mL)稀释、用饱和氯化钠(3x30mL)洗涤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的7-氯-4-[2-(三甲基甲硅烷基)乙炔基]-1H-吲唑(B99;4g)。LCMS(ES,m/z):249[M+H]+。
中间体B100的合成
在室温,将7-氯-4-[2-(三甲基甲硅烷基)乙炔基]-1H-吲唑(B99;3.5g,0.014mmol)和四丁基氟化铵(3.68g,0.014mmol)在四氢呋喃(14mL)中的溶液搅拌2h。然后将所得混合物在减压下浓缩、用乙酸乙酯(50mL)稀释、用饱和氯化钠(3x10 mL)洗涤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的7-氯-4-乙炔基-1H-吲唑(B100;1.09g)。LCMS(ES,m/z):177[M+H]+。
中间体B101的合成
在0℃,将氢化钠(0.22g,9.3mmol)添加到7-氯-4-乙炔基-1H-吲唑(B100;1.09g,6.17mmol)在二甲基甲酰胺(10mL)中的溶液中,随后在0℃,经5min滴加[2-(氯甲氧基)乙基]三甲基硅烷(2.06g,12.3mmol)。将所得混合物在20℃再搅拌2h、然后用冰水(10mL)淬灭。将所得混合物用乙酸乙酯(30mL)稀释、用饱和氯化钠(3x10mL)洗涤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈油状物的7-氯-4-乙炔基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B101;1.2g)。LCMS(ES,m/z):307[M+H]+。
中间体B102的合成
在室温,在氩气气氛下,将7-氯-4-乙炔基-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吲唑(B101;1g,3.4mmol)、(叠氮甲基)三甲基硅烷(2.21g,0.017mmol)、碘化亚铜(0.07g,0.34mmol)和二异丙基乙胺(0.44g,3.42mmol)在二氯甲烷(10mL)中的混合物搅拌17h。然后将所得混合物用乙酸乙酯(30mL)稀释、用饱和氯化钠(3x10mL)洗涤,并且将有机层在真空下浓缩。然后将残余物添加到二氯甲烷(10mL)和三氟乙酸(585mg,5.1mmol)中并在20℃搅拌1h、然后在真空下浓缩。接下来,将残余物添加到四丁基氟化铵(1.34g,5.13mmol)在四氢呋喃(10mL)中的溶液中并在20℃搅拌1h、然后在真空下浓缩。将残余物用乙酸乙酯(30mL)稀释并用饱和氯化钠(3x10mL)洗涤。将合并的有机层在真空下浓缩,并且将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的7-氯-4-(1-甲基-1,2,3-三唑-4-基)-1H-吲唑(B102;300mg)。LCMS(ES,m/z):234[M+H]+。
中间体B103的合成
在110℃,将7-氯-4-(1-甲基-1,2,3-三唑-4-基)-1H-吲唑(B102;270mg,1.16mmol)、B2pin2(587mg,2.31mmol)、Pd2(dba)3(52.9mg,0.06mmol)、X-Phos(55mg,0.12mmol)和K3PO4(736mg,3.47mmol)在二噁烷(15mL)中的混合物用微波辐照2h。然后将所得混合物在真空下浓缩并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的4-(1-甲基-1,2,3-三唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B103;90mg)。LCMS(ES,m/z):325[M+H]+。
中间体B104的合成
在80℃,在氩气气氛下,将4-(1-甲基-1,2,3-三唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(B103;90mg,0.28mmol)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;123mg,0.28mmol)、Pd(PPh3)4(32mg,0.03mmol)和K3PO4(176mg,0.83mmol)在二噁烷(8mL)和H2O(1.6mL)中的混合物搅拌17h。将所得混合物在减压下浓缩、用乙酸乙酯(20mL)稀释、并用饱和氯化钠(3x5mL)洗涤。将所得混合物在减压下浓缩、并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基([6-[4-(1-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B104;45mg)。LCMS(ES,m/z):516[M+H]+。
化合物165的合成
将叔丁基(1R,3S,5S)-3-[甲基([6-[4-(1-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基])氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(45mg,0.09mmol)、在1,4-二噁烷中的HCl(2mL,35mmol)、和甲醇(2mL)的混合物在20℃搅拌1h。将所得混合物在减压下浓缩、并通过制备型HPLC纯化(条件4,梯度3),以得到(1R,3S,5S)-N-甲基-N-[6-[4-(1-甲基-1,2,3-三唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物165;14.3mg)。LCMS(ES,m/z):416[M+H]+。1H NMR(400MHz,DMSO-d6,ppm)δ13.19(s,1H),8.85(s,1H),8.68(s,1H),8.18(d,J=9.8Hz,1H),7.98(d,J=7.7Hz,1H),7.74(d,J=7.6Hz,1H),7.27(d,J=9.8Hz,1H),5.09(s,1H),4.18(s,3H),3.58(s,2H),2.98(s,3H),1.88(td,J=12.1,3.0Hz,2H),1.80(s,4H),1.60(dd,J=13.3,6.0Hz,2H)。
实例35:化合物166的合成
中间体B105的合成
将1-溴-4-氯-2-乙炔基-3-(甲基磺酰基)苯(来自实例23的B52;640mg,2.45mmol)和氯化金(57mg,0.25mmol)在二噁烷/水(4:1;8mL)中的混合物在25℃在氮气气氛下搅拌6h,。然后将反应通过添加水(20mL)淬灭,并且将所得溶液用乙酸乙酯(3x20mL)萃取、经无水硫酸钠干燥、过滤、并在真空下浓缩,以得到呈固体的4-溴-7-氯-2-甲基-1-苯并噻吩(B105;780mg)。
中间体B106的合成
将4-溴-7-氯-2-甲基-1-苯并噻吩(B105;750mg,2.87mmol)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;957mg,3.44mmol)、K3PO4(1.22g,5.73mmol)、和Pd(dppf)Cl2-CH2Cl2(117mg,0.14mmol)在二噁烷/水(4:1;15mL)中的混合物在100℃搅拌4h。然后将反应用水(20mL)淬灭并用乙酸乙酯(3x20 mL)萃取。将合并的有机层经无水硫酸钠干燥、过滤、并在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用乙酸乙酯/石油醚(1:5)洗脱,以得到呈油状物的4-(7-氯-2-甲基-1-苯并噻吩-4-基)-1-(噁烷-2-基)吡唑(B106;690mg)。LCMS(ES,m/z):333[M+H]+。
中间体B107的合成
在90℃,将4-(7-氯-2-甲基-1-苯并噻吩-4-基)-1-(噁烷-2-基)吡唑(B106;220mg,0.66mmol)、双(频哪醇合)二硼(336mg,1.32mmol)、乙酸钾(195mg,1.98mmol)、X-Phos(63mg,0.13mmol)、和Pd2(dba)3CHCl3(68.4mg,0.066mmol)在二噁烷(5mL)中的混合物搅拌1.5h。然后将固体过滤,并且将滤液直接用于下一步骤。LCMS(ES,m/z):425[M+H]+。
中间体B108的合成
在100℃,在氮气气氛下,将4-[2-甲基-7-(4,4,5-三甲基-1,3,2-二氧杂环戊硼烷-2-基)-1-苯并噻吩-4-基]-1-(噁烷-2-基)吡唑(B107;194mg,0.47mmol)、6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B56;265mg,0.71mmol)、K3PO4(301mg,1.4mmol)、和XPhos Pd G2(18.6mg,0.024mmol)在二噁烷/水(4:1;80mL)中的混合物搅拌4h。然后将反应通过添加水(15mL)淬灭,并且将所得溶液用乙酸乙酯(3x15mL)萃取。将合并的有机层经无水硫酸钠干燥、过滤、并在真空下浓缩。将残余物通过硅胶柱色谱法纯化,其中用二氯甲烷/甲醇(10:1)洗脱,以得到呈固体的N-甲基-6-[2-甲基-4-[1-(噁烷-2-基)吡唑-4-基]-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B108;220mg)。LCMS(ES,m/z):545[M+H]+。
化合物166的合成
将N-甲基-6-[2-甲基-4-[1-(噁烷-2-基)吡唑-4-基]-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(B108;210mg,0.39mmol)、在1,4-二噁烷中的HCl(1mL,17.5mmol)和甲醇(4mL)的混合物在25℃搅拌2h、然后在真空下浓缩。然后将残余物溶解于甲醇(3mL)中并过滤。将粗产物通过制备型HPLC纯化(条件4,梯度1),以得到呈固体的甲基-6-[2-甲基-4-(1H-吡唑-4-基)-1-苯并噻吩-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(化合物166;26.7mg)。LCMS(ES,m/z):461[M+H]+。1H NMR(400MHz,甲醇-d4,ppm)δ8.04(d,J=9.7Hz,1H),7.75(d,J=7.6Hz,1H),7.72(s,2H),7.35(d,J=7.6Hz,1H),7.32-7.24(m,2H),5.22(s,1H),3.07(s,3H),2.07(d,J=1.1Hz,3H),1.77(dd,J=12.6,3.6Hz,2H),1.65(t,J=12.5Hz,2H),1.45(s,6H),1.29(s,6H),0.12(s,1H)。
实例36:化合物167的合成
中间体B110的合成
在0℃,将氢化钠(253mg,6.32mmol,60%)分批添加到4-溴-7-氯-1H-吡唑并[3,4-c]吡啶(B109;1g,4.22mmol)在二甲基甲酰胺(10mL)中的溶液中,并且将混合物在25℃搅拌30min。然后经5min,在0℃滴加[2-(氯甲氧基)乙基]三甲基硅烷(843mg,5mmol),并且将所得混合物在25℃再搅拌1h。然后将混合物倾倒入水(100mL)中并用乙酸乙酯(2x100mL)萃取。将合并的有机层用盐水(2x100mL)洗涤、经无水硫酸钠干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(10:1)洗脱,以得到呈油状物的4-溴-7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶(B110;1.2g)。LCMS(ES,m/z):363/365[M+H]+。
中间体B111的合成
在80℃,在氮气气氛下,将4-溴-7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶(B110;1.2g,3.24mmol)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(B9;902mg,3.24mmol)、Pd(dppf)Cl2.CH2Cl2(264mg,0.32mmol)和K3PO4(2.06g,9.7mmol)在1,4-二噁烷(18mL)和H2O(6mL)的混合物搅拌16h。然后将所得混合物倾倒入水(150mL)中、用乙酸乙酯(3x150mL)萃取、经无水硫酸钠干燥、过滤、并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的4-(7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-4-基)-1-(噁烷-2-基)吡唑(B111;630mg)。LCMS(ES,m/z):434[M+H]+。
中间体B112的合成
在100℃,在氮气气氛下,将4-(7-氯-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-4-基)-1-(噁烷-2-基)吡唑(B111;630mg,1.42mmol)、六丁基二锡(1.65g,2.84mmol)和Pd(PPh3)4(164mg,0.142mmol)在1,4-二噁烷(10mL)中的溶液搅拌过夜。将所得混合物在真空下浓缩、并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(1:1)洗脱,以得到呈油状物的1-(噁烷-2-基)-4-[7-(三丁基甲锡烷基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-4-基]吡唑(B112;100mg)。
中间体B113的合成
在100℃,在氮气气氛下,将1-(噁烷-2-基)-4-[7-(三丁基甲锡烷基)-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-4-基]吡唑(B112;100mg,0.15mmol)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B70;65mg,0.15mmol)和Pd(PPh3)4(17mg,0.015mmol)在1,4-二噁烷(3mL)中的溶液搅拌16h。将所得混合物在真空下浓缩、并通过硅胶柱色谱法纯化,其中用石油醚/乙酸乙酯(5:1)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B113;40mg)。LCMS(ES,m/z):716[M+H]+。
化合物167的合成
将叔丁基(1R,3S,5S)-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1-[[2-(三甲基甲硅烷基)乙氧基]甲基]吡唑并[3,4-c]吡啶-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(B113;40mg,0.022mmol)在1,4-二噁烷(1mL)中的HCl中的溶液在25℃搅拌30min。然后将所得混合物在减压下浓缩、并通过制备型HPLC纯化(条件6,梯度1),以得到呈固体的(1R,3S,5S)-N-甲基-N-[6-[4-(1H-吡唑-4-基)-1H-吡唑并[3,4-c]吡啶-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(化合物167;4.9mg)。LCMS(ES,m/z):402[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.66(s,1H),8.60(d,J=9.7Hz,1H),8.50(s,2H),7.71(d,J=9.9Hz,1H),5.07(s,1H),4.14(s,2H),3.12(s,3H),2.26(t,J=12.5Hz,2H),2.08(s,4H),1.88(d,J=12.7Hz,2H)。
实例37:化合物147的合成
中间体B115的合成
在0℃,在氮气下,向4-溴-2,5-二氟苯酚(B114,9.00g,42.203mmol)在DMF(90mL)中的搅拌溶液中分批添加NaH(2.53g,63.305mmol,60%)。将所得混合物在0℃搅拌30min,然后在0℃滴加溴甲氧基-甲烷(6.33g,50.644mmol)。将所得混合物在室温再搅拌1h,然后将所得混合物倾倒入水/冰(500mL)中。将混合物用EA(2x500mL)萃取,并且将合并的有机层用盐水(3x500mL)洗涤、经无水Na2SO4干燥,然后将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(10:1)洗脱,以得到呈无色油状物的1-溴-2,5-二氟-4-(甲氧基甲氧基)苯(B115,10g,91.77%)。LCMS(ES,m/z):253/255[M+H]+
中间体B116的合成
在-78℃,在氮气下,向1-溴-2,5-二氟-4-(甲氧基甲氧基)苯(B115,10.00g,38.729mmol)在THF(100mL)中的搅拌溶液中滴加LDA(25.00mL,50.347mmol)。将所得混合物在-78℃搅拌30min,然后在-78℃经15min滴加DMF(3.11g,42.548mmol)。将所得混合物在-78℃再搅拌2h、然后倾倒入饱和碳酸氢钠水溶液(500mL)中并用EA(3x500mL)萃取。将合并的有机层用盐水(2x1L)洗涤、经无水Na2SO4干燥,并且将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用PE/EtOAc(10:1)洗脱,以得到固体2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛(7g,63.02%)。LCMS(ES,m/z):281/283[M+H]+
中间体B118的合成
在室温,向O-甲基羟基胺盐酸盐(2.21g,26.462mmol)和NaOAc(2.37g,28.891mmol)在THF(69mL))和H2O(23mL)中的搅拌溶液中滴加2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛(6.90g,24.060mmol)。将所得混合物在80℃搅拌2h。将混合物冷却至25℃,并且将水层用EA(2x200mL)萃取。将所得混合物在减压下浓缩,以得到呈固体的(E)-[[2-溴-3,6-二氟-5-(甲氧基甲氧基)苯基]亚甲基](甲氧基)胺(7g,91.95%)。LCMS(ES,m/z):310/312[M+H]+
中间体B120的合成
在80℃,在氮气气氛下,将4-溴-5-氟-7-(甲氧基甲氧基)-1H-吲唑(2.00g,7.125mmol)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(2.18g,7.837mmol)、Pd(DtBPF)Cl2(464mg,0.713mmol)和K2CO3(2M)(10.5mL,21.345mmol)在1,4-二噁烷(20mL)和H2O(5mL)中的溶液搅拌4h。将混合物冷却至室温。将所得混合物倾倒入水(100mL)中、然后用EA(2x100mL)萃取、经无水Na2SO4干燥、过滤、然后在减压下浓缩。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(5:1)洗脱,以得到呈固体的5-氟-7-(甲氧基甲氧基)-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(2g,79.42%)。LCMS(ES,m/z):347[M+H]+
中间体B121的合成
在室温,将5-氟-7-(甲氧基甲氧基)-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(1.80g,5.093mmol)在1,4-二噁烷(20mL)中的HCl(气体)中的溶液搅拌30min。将所得混合物在减压下浓缩,并且将残余物通过反向快速色谱法纯化(条件4,梯度3),以得到呈固体的5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-醇(600mg,52.91%)。LCMS(ES,m/z):219[M+H]+
中间体B122的合成
在0℃,向5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-醇(350mg,1.572mmol)和Cs2CO3(512mg,1.572mmol)在THF(3mL)中的搅拌混合物中滴加在THF(2mL)中的1,1,1-三氟-N-(吡啶-2-基)-N-三氟甲磺酰基甲磺酰胺(563mg,1.572mmol)。将所得混合物在0℃搅拌4h、然后倾倒入水(50mL)中、用EA(2x50mL)萃取、并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:1)洗脱,以得到呈固体的5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(130mg,23.14%)。LCMS(ES,m/z):351[M+H]+
中间体B123的合成
在100℃,在氮气气氛下,将5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(130mg,0.364mmol)、双(频哪醇合)二硼(138mg,0.546mmol)、Pd(dppf)Cl2(30mg,0.036mmol)、Dppf(20mg,0.036mmol)和AcOK(107mg,1.092mmol)在1,4-二噁烷(5.00mL)中的溶液搅拌16h。将混合物冷却至室温、然后倾倒入水(50mL)中、用EA(2x50mL)萃取、并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,以得到呈固体的5-氟-4-(1H-吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(70mg,57.47%)。LCMS(ES,m/z):329[M+H]+
中间体B124的合成
在80℃,在氮气气氛下,将5-氟-4-(1H-吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(70mg,0.209mmol)、叔丁基(1R,3S,5S)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(111mg,0.251mmol)、Pd(PPh3)4(24mg,0.021mmol)和K2CO3(87mg,0.627mmol)在1,4-二噁烷(3.00mL)和H2O(0.30mL)中的溶液搅拌16h。将混合物冷却至室温、在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:2)洗脱,以得到呈固体的叔丁基(1R,3S,5S)-3-([6-[5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基](甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(20mg,18.45%)。LCMS(ES,m/z):519[M+H]+
化合物147的合成
在室温,将叔丁基(1R,3S,5S)-3-([6-[5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基](甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(20mg,0.039mmol)在1,4-二噁烷(1.00mL)中的HCl(气体)中的溶液搅拌30min。将所得混合物在减压下浓缩,并且将粗产物通过制备型HPLC纯化(条件3,梯度2),以得到呈固体的(1R,3S,5S)-N-[6-[5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]-N-甲基-8-氮杂双环[3.2.1]辛烷-3-胺(3.1mg,18.82%)。LCMS(ES,m/z):419[M+H]+1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),13.19(s,1H),8.49(s,1H),8.28(s,2H),8.22(d,J=9.8Hz,1H),7.94(d,J=12.6Hz,1H),7.27(d,J=9.8Hz,1H),5.15-5.07(m,1H),3.65(s,2H),2.99(s,3H),1.92(td,J=12.3,3.0Hz,2H),1.83(s,4H),1.67-1.57(m,2H)。
实例38:化合物187、196、197、和209的合成
中间体B126的合成
将苯甲酰异硫氰酸酯(52.17g,319.659mmol,1.10当量)滴加到2-溴-5-氯苯胺(60.00g,290.598mmol,1.00当量)在丙酮(600.00mL)中的搅拌溶液中。将反应混合物加热至回流持续3h。这之后,将反应混合物倾倒入冰水中、并再搅拌30min,以形成沉淀物。将沉淀物通过过滤收集并用水洗涤。将固体溶解于甲醇(600mL)中并用1N·NaOH(150mL)处理。将反应混合物加热至80℃持续2h。冷却后,将反应混合物倾倒入水-冰混合物中,并且添加足够的水性1N HCl以产生中性(pH约7)溶液。将形成的沉淀物通过过滤收集并干燥,以得到2-溴-5-氯苯基硫脲(70g,90%)。LCMS(ES,m/z):265[M+H]+。
中间体B127的合成
经1h过程,向2-溴-5-氯苯基硫脲(70.00g,263.606mmol,1.00当量)在浓H2SO4(200mL)中的搅拌溶液中添加NH4Br(23.79g,263.606mmol,1.00当量)。将反应混合物在100℃加热2h、然后冷却至室温并倾倒入冰水(1500mL)中,以得到沉淀物。用水性氢氧化铵溶液将混合物中和至pH约7。将固体通过过滤收集、用水洗涤、并真空干燥,以得到呈固体的4-溴-7-氯-1,3-苯并噻唑-2-胺(65g,92%)。LCMS(ES,m/z):263[M+H]+。
中间体B128的合成
在25℃,经20min,将4-溴-7-氯-1,3-苯并噻唑-2-胺(55.00g,208mmol,1.00当量)在THF(300mL,4937mmol,23.66当量)中的溶液滴加至t-BuNO2(32.28g,313mmol,1.50当量)和DMSO(1.630g)在THF(100mL)中的混合物中。将反应混合物在25℃搅拌3h、然后在乙酸乙酯(300mL)和水(360mL)之间分配。将水层用乙酸乙酯(2x300mL)萃取。将有机层合并、并用饱和盐水(300mL)洗涤、经无水硫酸钠干燥、并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EtOAc(5:1)洗脱,以得到呈固体的4-溴-7-氯-1,3-苯并噻唑(40.4g,78%)。LCMS(ES,m/z):248[M+H]+。
中间体B129的合成
在100℃,在氮气气氛下,将4-溴-7-氯-1,3-苯并噻唑(43.00g,173mmol,1.00当量)、1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(52.94g,190mmol,1.10当量)、Pd(dppf)Cl2 CH2Cl2(7.10g,8.704mmol,0.05当量)、K3PO4(110.18g,519mmol,3.00当量)在H2O(100mL)和二噁烷(400mL)中的混合物搅拌3h。将所得混合物在减压下浓缩、然后在乙酸乙酯(200mL)和水(200mL)之间分配。将水层用乙酸乙酯(3x300mL)萃取。将有机层合并、用饱和盐水(300mL)洗涤、经无水硫酸钠干燥、并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EtOAc(3:1)洗脱,以得到呈固体的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(36g,65%)。LCMS(ES,m/z):320[M+H]+。
中间体B130的合成
向7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(15.00g,46.9mmol,1.00当量)和B2pin2(23.82g,0.094mmol,2.00当量)在二噁烷(200mL)中的溶液中添加KOAc(13.81g,140mmol,3.00当量)和Pd(dttbp)Cl2(3.820g,4.690mmol,0.10当量)。在100℃,在氮气气氛下,将反应混合物搅拌过夜。将所得混合物过滤,将滤饼用乙酸乙酯(3x15mL)洗涤,并且将滤液用乙酸乙酯(3x100mL)萃取。将有机层合并、并用饱和盐水(150mL)洗涤、经无水硫酸钠干燥、并浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EtOAc(3:1)洗脱,以得到呈油状物的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(16g粗产物,55%纯度,产率41.47%)。LCMS(ES,m/z):412[M+H]+。
中间体B131的合成
在80℃,在氮气气氛下,向4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(16.00g,21.411mmol,1.00当量,55%)、3-氯-6-碘哒嗪(5.138g,21.411mmol,1.00当量)、Pd(dppf)Cl2.CH2Cl2(1747.56mg,2.141mmol,0.10当量)、和K2CO3(8877.6mg,64.233mmol,3.00当量)在二噁烷(100.00mL)和H2O(20.00mL)混合物中的混合物中搅拌过夜。将所得混合物过滤,将滤饼用乙酸乙酯(3x20mL)洗涤。将滤液用乙酸乙酯(100mL)和水(100mL)稀释,并且将水层用乙酸乙酯(3x100mL)萃取。将合并的有机层用盐水(1x200mL)洗涤、经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用CH2Cl2/MeOH(10:1)洗脱,以得到呈固体的7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(5.4g,59.31%)。LCMS(ES,m/z):397[M+H]+。
中间体B132的合成
向7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(100mg,0.251mmol,1.00当量)和叔丁基2,6-二氮杂螺[3.5]壬烷-6-甲酸酯(85.32mg,0.377mmol,1.5当量)在DMSO(10mL)中的搅拌溶液中滴加DIEA(97.45mg,0.753mmol,3当量)。将反应混合物在120℃搅拌20h、然后冷却至25℃。在室温,将反应混合物用水淬灭、并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基2-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸酯(130mg,66.88%)。LCMS(ES,m/z):588[M+H]+。
化合物187的合成
在25℃,将叔丁基2-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-2,6-二氮杂螺[3.5]壬烷-6-甲酸酯和TFA(1mL,13.463mmol,60.87当量)在DCM(5mL)中的混合物搅拌3h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件4,梯度7),以得到呈固体的7-(6-{2,6-二氮杂螺[3.5]壬烷-2-基}哒嗪-3-基)-4-(1H-吡唑-4-基)-1,3-苯并噻唑(58.6mg,62.14%)。
化合物196、197、和209根据此实例38中概述和由方案B概括的相同程序制备。下表2提供了这些程序中使用的中间体和最终的化合物表征数据。
表2:根据实例38计划和通用方案B制备的化合物的中间体和表征数据
实例39:化合物211的合成
中间体B133的合成
在氮气气氛下,向5-氯-2-甲基哒嗪-3-酮(100mg,0.69mmol,1.00当量)、B2pin2(351.33mg,1.384mmol,2当量)、KOAc(135.78mg,1.38mmol,2.00当量)、和X-Phos(32.98mg,0.069mmol,0.10当量)在二噁烷(1.00mL)中的混合物中添加Pd2(dba)3CHCl3(35.80mg,0.035mmol,0.05当量)。将反应混合物在90℃搅拌5h。LCMS(ES,m/z):155[M+H]+。
化合物211的合成
在90℃,在氮气气氛下,将6-(7-氯-1,3-苯并噻唑-4-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(100mg,0.240mmol,1.00当量)、1-甲基-6-氧代哒嗪-4-基硼酸(74.01mg,0.480mmol,2当量)、Pd(dtpdf)Cl2(19.58mg,0.024mmol,0.1当量)、和K2CO3(99.67mg,0.720mmol,3当量)在二噁烷(0.8mL)和水(0.2mL)中的混合物搅拌3h。将所得混合物在真空下浓缩,以给出残余物。将残余物通过硅胶柱色谱法(用CH2Cl2/MeOH(10:1))、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的2-甲基-5-[6-(哌啶-4-基)吡啶并[3,2-d]嘧啶-2-基]吲唑-4-醇(0.8mg,1.6%)。LCMS(ES,m/z):490[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.52(d,J=9.7Hz,1H),8.34(d,J=1.5Hz,2H),7.93(d,1H),7.28(s,1H),7.20(d,J=9.8Hz,1H),5.16(s,1H),3.76(s,3H),2.98(s,3H),1.55(d,J=11.1Hz,2H),1.46(t,J=12.1Hz,2H),1.28(s,6H),1.11(s,6H)。
实例40:化合物212的合成
中间体B134的合成
在氮气气氛下,向6-氯-3-甲基嘧啶-4-酮(100mg,0.692mmol,1.00当量)、B2pin2(351.33mg,1.384mmol,2当量)、KOAc(135.78mg,1.384mmol,2.00当量)、和X-Phos(32.98mg,0.069mmol,0.10当量)在二噁烷(1.00mL,11.81mmol,17.06当量)中的溶液中添加Pd2(dba)3CHCl3(35.80mg,0.035mmol,0.05当量)。将反应混合物在90℃搅拌5h。LCMS(ES,m/z):155[M+H]+。
化合物212的合成
在90℃,在氮气气氛下,将6-(7-氯-1,3-苯并噻唑-4-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(100mg,0.240mmol,1.00当量)、(1-甲基-6-氧代-1,6-二氢哒嗪-4-基)硼酸(74.01mg,0.48mmol,2当量)、Pd(dtpdf)Cl2(19.58mg,0.02mmol,0.1当量)和K2CO3(99.67mg,0.72mmol,3当量)在二噁烷(0.8mL)和H2O(0.2mL,11.10mmol,46.18当量)中的混合物搅拌3h。将所得混合物在真空下浓缩,以给出残余物。将残余物通过硅胶柱色谱法(用CH2Cl2/MeOH(10:1))、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的2-甲基-5-[6-(哌啶-4-基)吡啶并[3,2-d]嘧啶-2-基]吲唑-4-醇(0.8mg,1.6%)。LCMS(ES,m/z):463[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.78(s,1H),8.52(d,J=9.7Hz,1H),8.34(d,J=1.5Hz,2H),7.28(s,1H),7.20(d,J=9.8Hz,1H),5.16(s,1H),3.51(s,3H),2.98(s,3H),1.55(d,J=11.1Hz,2H),1.46(t,J=12.1Hz,2H),1.28(s,6H),1.11(s,6H)。
实例41:化合物213的合成
中间体B135的合成
在0℃,向叔丁基(外型)-3-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(150mg,0.255mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,5mg)。将反应混合物搅拌15min。添加CH3I(43.47mg,0.306mmol,1.2当量),并将反应混合物加温至室温并再搅拌1h。将反应混合物用水淬灭并用DCM(3x25mL)萃取。将合并的有机层在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(100mg,65.11%)。LCMS(ES,m/z):602[M+H]+。
化合物213的合成
将叔丁基(外型)-3-[甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(120mg,0.199mmol,1.00当量)、在二噁烷中的HCl(2M)、和甲醇(2mL,49.398mmol,247.72当量)的混合物在室温搅拌1h。将反应混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的(外型)-N-甲基-N-{6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基}-8-氮杂双环[3.2.1]辛烷-3-胺(10.3mg,12.01%)。LCMS(ES,m/z):418[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.51(s,1H),8.54(s,2H),8.24(d,J=9.9Hz,1H),8.10(d,J=8.1Hz,1H),7.98(d,J=7.9Hz,1H),7.26(d,J=9.8Hz,1H),5.00(s,1H),3.51(d,J=3.9Hz,2H),2.98(s,3H),1.87-1.77(m,2H),1.77(s,4H),1.61-1.52(m,2H)。
实例42:化合物214的合成
中间体B136的合成
将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(400mg,1.005mmol,1.00当量)、叔丁基4-氨基哌啶-1-甲酸酯(302.02mg,1.507mmol,1.5当量)、DIEA(389.80mg,3.015mmol,3当量)、和DMSO(20mL,281.571mmol,280.08当量)的混合物在120℃搅拌2h。将反应混合物冷却至室温、然后用水淬灭并用乙酸乙酯(3x20mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(500mg,88.54%)。LCMS(ES,m/z):562[M+H]+。
化合物214的合成
将叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(120mg)、在1,4-二噁烷(0.5mL)中的HCl(气体)、和甲醇(0.5mL)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-胺(22mg,27.28%)。LCMS(ES,m/z):378[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.01(s,1H),9.51(s,1H),8.54(s,2H),8.16(d,J=9.5Hz,1H),8.05(d,J=8.1Hz,1H),7.98(d,J=7.9Hz,1H),7.06(d,J=7.6Hz,1H),6.98(d,J=9.5Hz,1H),4.07(s,2H),3.03(d,J=12.4Hz,2H),2.66(t,J=11.4Hz,2H),1.99(d,J=12.2Hz,2H),1.46-1.37(m,1H),1.36(dd,J=11.5,3.7Hz,1H)。
实例43:化合物222的合成
中间体B137的合成
在0℃,向叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(120mg,0.214mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,1mg)。将反应混合物搅拌15min。添加CH3I(45.48mg,0.321mmol,1.5当量),并将混合物加温至室温并再搅拌1h。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x5mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基4-[甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg,81.30%)。LCMS(ES,m/z):576[M+H]+。
化合物222的合成
在室温,将叔丁基4-[甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg,0.174mmol,1.00当量)、MeOH(2mL,49.398mmol,284.40当量)、和在1,4-二噁烷(2mL)中的HCl(气体)合并。将所得混合物在室温搅拌1h、然后在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的N-甲基-N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-胺(10mg,14.71%)。LCMS(ES,m/z):392[M+H]+1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.52(s,1H),8.67-8.42(s,2H),8.27(d,J=9.8Hz,1H),8.12(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.30(d,J=9.8Hz,1H),4.69(s,1H),3.09(d,J=12.3Hz,2H),3.02(s,3H),2.72(d,J=11.8Hz,2H),1.72(t,J=10.9Hz,2H),1.64(d,J=11.6Hz,2H)。
实例44:化合物223的合成
中间体B137的合成
在0℃,向叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(120mg,0.214mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,10mg)。将反应混合物搅拌15min。添加CD3I(46.45mg,0.321mmol,1.5当量),并将反应混合物加温至室温并搅拌1h。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x20mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基4-[(D3)甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg,80.88%)。LCMS(ES,m/z):579[M+H]+。
化合物223的合成
将叔丁基4-[(2H3)甲基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg)、MeOH(2mL)、和在1,4-二噁烷(2mL)中的HCl(气体)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的N-(D3)甲基-N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-胺(10.5mg)。LCMS(ES,m/z):395[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),9.51(s,1H),8.7-8.4(s,2H),8.26(d,J=9.8Hz,1H),8.11(d,J=8.1Hz,1H),7.98(d,J=8.0Hz,1H),7.29(d,J=9.8Hz,1H),4.67(s,1H),3.08(d,J=12.1Hz,2H),2.75-2.64(m,2H),1.78-1.60(m,4H)。
实例45:化合物224的合成
中间体B138的合成
在0℃,向叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(120mg,0.214mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,10mg)。将混合物搅拌15min。添加C2H5I(46.45mg,0.321mmol,1.5当量)。将反应混合物加温至室温并再搅拌1h,然后在室温用水淬灭,并用乙酸乙酯(3x20mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基4-[乙基(6-{4-(1-(四氢-2H-吡喃-2-基)苯并[d]噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg,80.88%)。LCMS(ES,m/z):590[M+H]+。
化合物224的合成
将叔丁基4-[乙基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(100mg,0.170mmol,1.00当量)、甲醇(2mL,49.398mmol,291.33当量)、和在1,4-二噁烷中的HCl(气体)(2mL,35.035mmol,206.62当量)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的N-乙基-N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-胺(12mg,17.45%)。LCMS(ES,m/z):406[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),9.51(s,1H),8.54(s,2H),8.23(d,J=10.0Hz,1H),8.10(d,J=7.9Hz,1H),7.98(d,J=8.0Hz,1H),7.23(d,J=10.0Hz,1H),4.69-4.62(m,1H),3.56(q,J=7.5,6.9Hz,2H),3.05(d,J=12.0Hz,2H),2.64(t,J=6.6Hz,2H),1.68(s,4H),1.19(t,J=6.9Hz,3H)。
实例46:化合物186的合成
中间体B139的合成
在120℃,将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(800mg,2.011mmol,1.00当量)、2,2,6,6-四甲基哌啶-4-胺(471.32mg,3.017mmol,1.5当量)、DIEA(779.59mg,6.033mmol,3当量)、和n-BuOH(40.00mL,437.674mmol,217.64当量)的混合物搅拌过夜。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10 mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(80mg,7.69%)。LCMS(ES,m/z):518[M+H]+。
化合物186的合成
将6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(70.00mg)、在1,4-二噁烷(2.00mL)中的HCl(气体)、和甲醇(2.00mL)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(10mg)。LCMS(ES,m/z):433[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.08(s,1H),9.50(s,1H),8.53(s,2H),8.15(d,J=9.6Hz,1H),8.05(d,J=8.1Hz,1H),7.97(d,J=7.9Hz,1H),6.96(d,J=9.5Hz,1H),6.91(d,J=7.8Hz,1H),4.46(dt,J=7.9,6.0Hz,1H),1.93(dd,J=12.3,3.7Hz,2H),1.65(s,1H),1.26(s,6H),1.08(s,6H),1.07(t,J=12.1Hz,2H)。
实例47:化合物231的合成
中间体B140的合成
在120℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(600mg,1.542mmol,1.00当量)、2,2,6,6-四甲基哌啶-4-胺(240.91mg,1.542mmol,1当量)、和DIEA(597.71mg,4.626mmol,3当量)在DMSO(5.88mL)中的混合物搅拌16h。将反应混合物冷却至室温、然后在乙酸乙酯和水之间分配、并用乙酸乙酯(1x30mL)萃取。将合并的有机层用DMSO(3x30mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(416mg,52.13%)。LCMS(ES,m/z):518[M+H]+。
中间体B141的合成
将6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(60mg,0.114mmol,1.00当量)在DMF(1mL,12.922mmol,113.77当量)中的溶液用NaH(4.09mg,0.171mmol,1.5当量)处理。将反应混合物在0℃搅拌30min。在0至室温,滴加CD3I(24.70mg,0.171mmol,1.5当量)。将所得混合物倾倒入水(30mL)中、然后用乙酸乙酯(1x30mL)萃取。将合并的有机层用DMF(3x30mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的N-(2H3)甲基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(22mg,36.22%)。LCMS(ES,m/z):535[M+H]+。
化合物231的合成
将N-(2H3)甲基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(80mg,0.150mmol,1.00当量)、甲醇(1mL)、和在1,4-二噁烷(4M,1mL)中的HCl(气体)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件7,梯度2),以得到呈固体的N-(2H3)甲基-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(8.2mg,11.91%)。LCMS(ES,m/z):451[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.51(s,1H),8.68(s,1H),8.40(s,1H),8.27(d,J=9.8Hz,1H),8.10(d,J=8.0Hz,1H),7.99(d,J=8.0Hz,1H),7.26(d,J=9.7Hz,1H),5.00(s,1H),1.56(dd,J=12.4,3.6Hz,1H),1.46(t,J=12.1Hz,2H),1.27(d,J=11.1Hz,7H),1.11(s,6H),0.07(s,1H)。
实例48:化合物225的合成
中间体B142的合成
在120℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(600mg,1.542mmol,1.00当量)、2,2,6,6-四甲基哌啶-4-胺(240.91mg,1.542mmol,1当量)、和DIEA(597.71mg,4.626mmol,3当量)在DMSO(6.00mL)中的溶液搅拌16h。将反应混合物冷却至室温。将所得混合物用乙酸乙酯(1x30mL)萃取。将合并的有机层用盐水(3x30mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(416mg,52.13%)。LCMS(ES,m/z):518[M+H]+。
中间体B143的合成
将6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(60mg,0.116mmol,1.00当量)在DMF(0.60mL)中的溶液用NaH(4.17mg,0.174mmol,1.5当量)处理。在0℃,在氮气气氛下,将反应混合物搅拌30min。在0℃,滴加碘乙烷(27.11mg,0.174mmol,1.50当量),并且将所得混合物在室温搅拌1h。将所得混合物倾倒入水(5mL)中并用乙酸乙酯(2x5mL)萃取。将合并的有机层用盐水(3x5mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的N-乙基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(27mg,42.69%)。LCMS(ES,m/z):546[M+H]+。
化合物225的合成
将N-(2,2-二甲基哌啶-4-基)-N-乙基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-胺(27mg,0.052mmol,1.00当量)、甲醇(1mL)、和在1,4-二噁烷(1mL)中的HCl(气体)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度1,梯度2),以得到呈固体的N-乙基-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(3.1mg,12.88%)。LCMS(ES,m/z):462[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.50(s,1H),8.68(s,1H),8.40(s,1H),8.25(d,J=9.9Hz,1H),8.09(d,J=8.1Hz,1H),7.98(d,J=8.0Hz,1H),7.20(d,J=9.9Hz,1H),5.02(s,1H),3.56(d,J=7.2Hz,2H),1.61(d,J=11.0Hz,2H),1.45(t,J=12.2Hz,2H),1.29(s,6H),1.19(t,J=6.9Hz,3H),1.11(s,6H)。
实例49:化合物202的合成
中间体B144的合成
在150℃,将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(1.80g,4.524mmol,1.00当量)和KF(1.58g,0.027mmol,6当量)在DMSO(6.00mL,84.471mmol,18.67当量)中的混合物搅拌8h。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(1.3g,75.34%)。LCMS(ES,m/z):382[M+H]+。
中间体B145的合成
在120℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(800.00mg,2.097mmol,1.00当量)、叔丁基(外型)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(712.02mg,3.146mmol,1.50当量)、和DIEA(813.21mg,6.292mmol,3当量)在DMSO(5.00mL,63.989mmol,33.56当量)中的混合物搅拌过夜。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(1.3g,105.46%)。LCMS(ES,m/z):588[M+H]+。
化合物202的合成
将叔丁基(外型)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(100.00mg)、在1,4-二噁烷(3.00mL)中的HCl(气体)、和甲醇(3.00mL)的混合物在室温搅拌30min。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的(外型)-N-[6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(17.0mg)。LCMS(ES,m/z):404[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.49(s,1H),8.52(s,2H),8.12(d,J=9.6Hz,1H),8.03(d,J=8.1Hz,1H),7.97(d,J=8.0Hz,1H),6.95(d,J=9.5Hz,1H),4.35(dt,J=11.4,6.0Hz,1H),1.96(dt,J=12.7,3.8Hz,2H),1.76(s,4H),1.51-1.40(m,2H)。
实例50:化合物210的合成
中间体B146的合成
在0℃,向叔丁基(外型)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(150.00mg,0.255mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,3mg)。将混合物搅拌15min。添加CD3I(55.49mg,0.383mmol,1.5当量),并将混合物加温至室温并搅拌2h。将反应混合物通过水淬灭并用DCM(3x25mL)萃取。将反应混合物在室温用水淬灭,并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[(D3)甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(100mg,64.79%)。LCMS(ES,m/z):605[M+H]+。
化合物210的合成
将叔丁基(外型)-3-[(D3)甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(10mg)、在1,4-二噁烷(0.5mL)中的HCl(气体)、和甲醇(0.5mL)的混合物在室温搅拌1h。将反应混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的(外型)-N-(D3)甲基-N-[6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(19.6mg)。LCMS(ES,m/z):420[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.51(s,1H),8.54(s,2H),8.24(d,J=9.8Hz,1H),8.10(d,J=8.1Hz,1H),7.98(d,J=8.0Hz,1H),7.25(d,J=9.8Hz,1H),5.00(s,1H),3.51(s,2H),1.83(dd,J=12.2,3.0Hz,2H),1.77(s,4H),1.61-1.52(m,2H)。
实例51:化合物203的合成
中间体B147的合成
在0℃,向叔丁基(外型)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(150.00mg,0.255mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,3mg)。将反应混合物搅拌15min。添加C2H5I(65.08mg,0.383mmol,1.5当量),并将反应混合物加温至室温、然后搅拌2h。将反应混合物通过水淬灭并用DCM(3x25mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[乙基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(100mg,63.63%)。LCMS(ES,m/z):616[M+H]+。
化合物203的合成
将叔丁基(外型)-3-[乙基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(100.00mg)、在1,4-二噁烷(3.00mL)中的HCl(气体)、和甲醇(3.00mL)的混合物在室温搅拌1h。将反应混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的(外型)-N-乙基-N-[6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺6mg)。LCMS(ES,m/z):432[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.09(s,1H),9.51(s,1H),8.54(s,2H),8.21(d,J=9.9Hz,1H),8.08(d,J=8.1Hz,1H),7.98(d,J=7.9Hz,1H),7.20(d,J=9.8Hz,1H),4.96(s,1H),3.53(d,J=7.3Hz,1H),3.50(s,3H),1.76(s,6H),1.66-1.57(m,2H),1.16(t,J=6.9Hz,3H)。
实例52:化合物204的合成
中间体B148的合成
在120℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(60.00mg,0.157mmol,1.00当量)、叔丁基(外型)-3-氨基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(53.40mg,0.236mmol,1.5当量)、DIEA(60.99mg,0.472mmol,3.00当量)、和DMSO(3.00mL,38.396mmol,268.50当量)的混合物搅拌2h。将反应混合物在室温用水淬灭,然后用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(60mg,64.90%)。LCMS(ES,m/z):588[M+H]+。
中间体B149的合成
在0℃,向叔丁基(外型)-1,5-二甲基-3-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(50.00mg,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,3mg)。将反应混合物搅拌15min。添加CH3I(5.00mg,1.50当量),并将反应混合物加温至室温并再搅拌1h。将反应混合物用水淬灭并用DCM(3x25mL)萃取,以得到呈固体的叔丁基(外型)-1,5-二甲基-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(41mg)。LCMS(ES,m/z):630[M+H]+。
化合物204的合成
将叔丁基(外型)-1,5-二甲基-3-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(36.00mg)、在1,4-二噁烷(2.00mL)中的HCl(气体)、和甲醇(2.00mL)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的(外型)-N,1,5-三甲基-N-[6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基]-8-氮杂双环[3.2.1]辛烷-3-胺(7.8mg)。LCMS(ES,m/z):446[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.51(s,1H),8.65(s,1H),8.44(s,1H),8.25(d,J=9.9Hz,1H),8.10(d,J=8.1Hz,1H),7.98(d,J=8.0Hz,1H),7.26(d,J=9.8Hz,1H),5.03(s,1H),2.97(s,3H),1.85(d,J=7.4Hz,2H),1.54(t,J=10.0Hz,6H),1.19(s,6H)。
实例53:化合物194的合成
中间体B150的合成
在120℃,将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(100mg,0.246mmol,1.00当量)、叔丁基(外型)-六氢-1H-吡咯并[3,4-c]吡咯-2-甲酸酯(78.43mg,0.369mmol,1.5当量)和DIEA(95.50mg,0.738mmol,3当量)在DMSO(1mL)中的混合物搅拌20h。将混合物冷却至25℃。将所得混合物倾倒入水(10mL)中、然后用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-5-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-六氢吡咯并[3,4-c]吡咯-2-甲酸酯(51mg,36.09%)。LCMS(ES,m/z):574[M+H]+。
化合物194的合成
在室温,将叔丁基(外型)-5-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-六氢吡咯并[3,4-c]吡咯-2-甲酸酯(51mg,0.087mmol,1.00当量)和TFA(1mL)在DCM(2mL)中的溶液搅拌30min。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度3),以得到呈固体的7-{6-[(外型)-六氢-1H-吡咯并[3,4-c]吡咯-2-基]哒嗪-3-基}-4-(1H-吡唑-4-基)-1,3-苯并噻唑盐酸盐(13.4mg,33.62%)。LCMS(ES,m/z):390[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),9.61(s,1H),9.50(s,1H),8.71(d,J=9.9Hz,1H),8.60(s,2H),8.31(d,J=8.1Hz,1H),8.07(d,J=8.0Hz,1H),7.73(d,J=9.6Hz,1H),3.87(dt,J=11.7,5.7Hz,4H),3.46(dt,J=12.3,6.1Hz,2H),3.28(m,4H)。
实例54:化合物198的合成
中间体B151的合成
在120℃,将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(80mg,0.197mmol,1.00当量)、(外型)-2-甲基-六氢-1H-吡咯并[3,4-c]吡咯(37.30mg,0.295mmol,1.50当量)、和DIEA(76.40mg,0.591mmol,3.00当量)在正丁醇(0.80mL)中的溶液搅拌20h。将所得混合物在真空下浓缩、然后倾倒入水(10mL)中并用乙酸乙酯(3x10mL)萃取、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的7-{6-[(外型)-5-甲基-六氢吡咯并[3,4-c]吡咯-2-基]哒嗪-3-基}-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(50mg,51.00%)。LCMS(ES,m/z):488[M+H]+。
化合物198的合成
在室温,将7-{6-[(外型)-5-甲基-六氢吡咯并[3,4-c]吡咯-2-基]哒嗪-3-基}-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(50mg,0.100mmol,1.00当量)和TFA(1mL)在DCM(2mL)中的溶液搅拌30min。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度3),以得到呈固体的7-{6-[(外型)-5-甲基-六氢吡咯并[3,4-c]吡咯-2-基]哒嗪-3-基}-4-(1H-吡唑-4-基)-1,3-苯并噻唑盐酸盐(13.4mg,30.07%)。LCMS(ES,m/z):404[M+H]+。1H NMR(400MHz,甲醇-d4)δ9.45(d,J=1.7Hz,1H),8.83(d,J=2.6Hz,2H),8.76(t,J=10.9Hz,1H),8.27(t,J=7.7Hz,1H),8.11(dd,J=8.1,4.8Hz,1H),7.92(dd,J=14.7,9.9Hz,1H),4.16-4.04(m,5H),3.85(d,J=12.1Hz,1H),3.68(s,1H),3.62-3.48(m,2H),3.08(d,J=8.3Hz,1H),3.01(s,3H)。
实例55:化合物205的合成
中间体B152的合成
在120℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(200.00mg,0.524mmol,1.00当量)、叔丁基(外型)-6-氨基-3-氮杂双环[3.1.0]己烷-3-甲酸酯(155.94mg,0.787mmol,1.5当量)、DIEA(203.30mg,1.573mmol,3.00当量)、和DMSO(10.00mL,140.786mmol,268.50当量)的混合物搅拌过夜。将反应混合物在室温用水淬灭、并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-6-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-3-氮杂双环[3.1.0]己烷-3-甲酸酯(260mg,88.60%)。LCMS(ES,m/z):560[M+H]+。
中间体B153的合成
在0℃,向叔丁基(外型)-6-[(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-3-氮杂双环[3.1.0]己烷-3-甲酸酯(10.00mg,0.018mmol,1.00当量)在DMF中的溶液中添加氢化钠(在油中60%,3mg)。将反应混合物搅拌15min。添加CH3I(3.80mg,0.027mmol,1.5当量),并将反应混合物加温至室温并搅拌2h。将反应混合物用水淬灭并用DCM(3x25mL)萃取。将所得混合物在减压下浓缩,以得到呈固体的叔丁基(外型)-6-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-3-氮杂双环[3.1.0]己烷-3-甲酸酯(200mg,83.03%)。LCMS(ES,m/z):574[M+H]+。
化合物205的合成
将叔丁基(外型)-6-[甲基(6-[4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基]哒嗪-3-基)氨基]-3-氮杂双环[3.1.0]己烷-3-甲酸酯(180.00mg)、TFA(1.00mL)、和DCM(5.00mL)的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件7,梯度1)纯化,以得到呈固体的(外型)-N-甲基-N-[6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基]-3-氮杂双环[3.1.0]己烷-6-胺(10mg)。LCMS(ES,m/z):390[M+H]+。1H NMR(400MHz,DMSO-d6)δ12.86(brs,1H),9.56(s,1H),8.49(s,2H),8.24(d,J=9.6Hz,1H),8.05(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.35(d,J=9.6Hz,1H),3.3(s,3H),3.14(d,J=10.8Hz,2H),2.85(d,J=10.8Hz,2H),2.565(s,1H),1.78(s,2H)。
实例56:化合物235的合成
化合物235的合成
在室温,向(外型)-N-甲基-N-{6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基}-3-氮杂双环[3.1.0]己烷-6-胺(80mg,0.205mmol,1.00当量)、CH2O(0.5mL)、和甲醇(2mL,49.398mmol,240.49当量)的混合物中分批添加NaBH3CN(10mg)。将所得混合物在室温搅拌2h、然后在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法(硅胶柱;流动相,在水中的乙腈;梯度:在10min内,10%至50%;UV检测器,254nm)、随后通过制备型HPLC(条件8,梯度1,梯度4)纯化,以得到呈固体的(外型)-N,3-二甲基-N-{6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-基}-3-氮杂双环[3.1.0]己烷-6-胺盐酸盐(2mg,2.21%)。LCMS(ES,m/z):440[M+H]+。1HNMR(400MHz,DMSO-d6)δ10.68(s,1H),9.55(s,1H),8.58(s,2H),8.44(d,J=9.8Hz,1H),8.20(d,J=8.0Hz,1H),8.03(d,J=7.9Hz,1H),7.50(d,J=9.8Hz,1H),3.89(dd,J=11.5,5.1Hz,2H),3.41(t,J=9.2Hz,2H),3.3(m,1H),3.27(s,3H),2.82(d,J=4.5Hz,3H),2.29(s,2H)。
实例57:化合物200的合成
中间体B154的合成
在100℃,将7-(6-氯哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(80mg,0.197mmol,1.00当量)、叔丁基(外型)-3-磺酰基-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(71.93mg,0.295mmol,1.5当量)、和Cs2CO3(76.40mg,0.591mmol,3当量)在乙腈(0.8mL)中的混合物搅拌2h。将反应混合物冷却至25℃、然后倾倒入水(10mL)中并用乙酸乙酯(3x10mL)萃取。将合并的有机层用盐水(2x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的叔丁基(外型)-3-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)磺酰基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(60mg,49.34%)。LCMS(ES,m/z):605[M+H]+。
化合物200的合成
将叔丁基(外型)-3-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)磺酰基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(50mg,0.081mmol,1.00当量)和在1,4-二噁烷(0.5mL)中的HCl(气体)的混合物在室温搅拌30min。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度5),以得到呈固体的7-{6-[(外型)-8-氮杂双环[3.2.1]辛烷-3-基磺酰基]哒嗪-3-基}-4-(1H-吡唑-4-基)-1,3-苯并噻唑(14.2mg,40.76%)。LCMS(ES,m/z):421[M+H]+。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),9.20(s,1H),9.06(s,1H),8.61(s,2H),8.48(d,J=9.3Hz,1H),8.31(d,J=8.1Hz,1H),8.07(d,J=8.0Hz,1H),7.83(d,J=9.2Hz,1H),4.66(t,J=7.0Hz,1H),4.06(q,J=3.6Hz,2H),2.75(ddd,J=16.1,7.3,3.4Hz,2H),2.26(t,J=7.1Hz,2H),2.17-2.05(m,4H)。
实例58:化合物242的合成
中间体B155的合成
在120℃,将3,6-二碘哒嗪(1.00g,3.013mmol,1.00当量)、叔丁基4-(甲基氨基)哌啶-1-甲酸酯(0.77g,3.616mmol,1.2当量)、和K2CO3(1.25g,9.039mmol,3当量)在DMF(10mL)中的混合物搅拌16h。将反应混合物冷却至室温、并倾倒入水中。将水层用乙酸乙酯(3x100mL)萃取。将合并的有机层经无水Na2SO4干燥、过滤,并且将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(0-100%)洗脱,以得到呈固体的叔丁基4-[(6-碘哒嗪-3-基)(甲基)氨基]哌啶-1-甲酸酯(500mg,39.67%)。LCMS(ES,m/z):419[M+H]+。
中间体B156的合成
向4-溴-7-氯-1H-吲唑(3.10g,13.392mmol,1当量)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(3.34g,16.070mmol,1.2当量)在二噁烷(32mL)和H2O(8mL)中的溶液中添加Pd(DtBPF)Cl2(0.48g,0.738mmol,0.0551当量)和K3PO4(8.53g,40.176mmol,3当量)。在80℃,在氮气气氛下,将反应混合物搅拌4h,然后冷却至室温。将所得混合物用乙酸乙酯(3x20mL)萃取。将合并的有机层用水(1x60mL)和盐水(1x60mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用DCM/MeOH(20/1)洗脱,以得到呈固体的7-氯-4-(1-甲基吡唑-4-基)-1H-吲唑(2.1g,67.40%)。LCMS(ES,m/z):233[M+H]+。
中间体B157的合成
向7-氯-4-(1-甲基吡唑-4-基)-1H-吲唑(50mg,0.215mmol,1当量)和双(频哪醇合)二硼(65mg,0.258mmol,1.2当量)在二噁烷(1mL)中的混合物中添加Xphos(10mg,0.022mmol,0.1当量)和KOAc(63mg,0.645mmol,3当量)。在80℃,在氮气气氛下,将反应混合物搅拌16h,然后冷却至室温。在室温,向反应混合物中添加叔丁基4-[(6-碘哒嗪-3-基)(甲基)氨基]哌啶-1-甲酸酯(64mg,0.154mmol,1当量)、Pd(dtbpf)Cl2(10mg,0.015mmol,0.1当量)、K3PO4(98mg,0.462mmol,3当量)和水(40μL)。将所得混合物在80℃再搅拌1h、然后冷却至室温并用乙酸乙酯(3x20mL)萃取。将合并的有机层用水(1x60mL)和盐水(1x60mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用DCM/MeOH(20/1)洗脱,以得到呈固体的叔丁基4-[甲基({6-[4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基})氨基]哌啶-1-甲酸酯(60mg,79.62%)。LCMS(ES,m/z):489[M+H]+。
化合物242的合成
在室温,将叔丁基4-[甲基({6-[4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基})氨基]哌啶-1-甲酸酯(60mg)和HCl(g)在MeOH(1mL)中的混合物搅拌3h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件9,梯度1),以得到呈固体的N-甲基-6-[4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]-N-(哌啶-4-基)哒嗪-3-胺;三氟乙酸(23mg,37.27%)。LCMS(ES,m/z):389[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.04(s,1H),8.61(s,1H),8.50(d,J=9.3Hz,2H),8.29(d,J=9.8Hz,2H),8.13(s,1H),7.97(d,J=7.7Hz,1H),7.49-7.42(m,2H),4.85(s,1H),3.96(s,3H),3.46(d,J=12.4Hz,2H),3.11(q,J=11.9Hz,2H),3.04(s,3H),2.07-1.97(m,2H),1.95-1.85(m,2H)。
实例59:化合物243的合成
化合物243的合成
向7-氯-4-(1-甲基吡唑-4-基)-1H-吲唑(50mg,0.215mmol,1当量)和双(频哪醇合)二硼(65mg,0.258mmol,1.2当量)在二噁烷(1mL)中的混合物中添加Xphos(10mg,0.022mmol,0.1当量)和KOAc(63mg,0.645mmol,3当量)。在80℃,在氮气气氛下,将反应混合物搅拌16h,然后冷却至室温。向反应混合物中添加6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(58mg,0.154mmol,1当量)、Pd(dtbpf)Cl2(10mg,0.015mmol,0.1当量)、K3PO4(98mg,0.462mmol,3当量)和H2O(40μL)。将所得混合物在80℃再搅拌1h、然后冷却至室温。将所得混合物用乙酸乙酯(3x20mL)萃取。将合并的有机层用水(1x60mL)和盐水(1x60mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件10,梯度1),以得到N-甲基-6-[4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺;三氟乙酸(10.2mg,11.84%)(呈固体)。LCMS(ES,m/z):445[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(Br,1H),8.75(d,J=12.2Hz,1H),8.50(d,J=11.4Hz,2H),8.27(d,J=9.8Hz,1H),8.12(s,1H),7.95(d,J=7.7Hz,1H),7.85(d,J=12.1Hz,1H),7.45(dd,J=8.5,4.3Hz,2H),5.24(s,1H),3.96(s,3H),3.04(s,3H),1.97-1.84(m,4H),1.57(s,6H),1.45(s,6H)。
实例60:化合物232的合成
化合物232的合成
向7-氯-4-(1-甲基吡唑-4-基)-1H-吲唑(50mg,0.215mmol,1当量)和双(频哪醇合)二硼(65mg,0.258mmol,1.2当量)在二噁烷(1mL)中的混合物中添加Xphos(10mg,0.022mmol,0.1当量)和KOAc(63mg,0.645mmol,3当量)。在80℃,在氮气气氛下,将反应混合物搅拌16h,然后冷却至室温。在室温,向反应混合物中添加3-碘-6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪(55mg,0.154mmol,1当量)、Pd(dtbpf)Cl2(10mg,0.015mmol,0.1当量)、K3PO4(98mg,0.462mmol,3当量)和H2O(40μL)。将所得混合物在80℃再搅拌1h、然后冷却至室温并用乙酸乙酯(3x20mL)萃取。将合并的有机层用水(1x60mL)和盐水(1x60mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件11,梯度1),以得到呈固体的4-(1-甲基吡唑-4-基)-7-{6-[(2,2,6,6-四甲基哌啶-4-基)氧基]哒嗪-3-基}-1H-吲唑(12.9mg,19.38%)。LCMS(ES,m/z):432[M+H]+。1HNMR(400MHz,DMSO-d6)δ13.17(s,1H),8.52(d,J=8.1Hz,2H),8.40(d,J=9.4Hz,1H),8.14(s,1H),8.00(d,J=7.7Hz,1H),7.48(d,J=7.7Hz,1H),7.32(d,J=9.3Hz,1H),5.79(tt,J=11.3,4.2Hz,1H),3.96(s,3H),2.13(dd,J=12.0,4.1Hz,2H),1.36-1.18(m,9H),1.13(s,6H)。
实例61:化合物174-179、233、和234的合成
中间体B158的合成
向4-溴-7-氯-1,3-苯并噻唑(5g,20.11mmol,1.0当量)和双(频哪醇合)二硼(6.13g,24.14mmol,1.2当量)在1,4-二噁烷(50mL,567.5mmol,28.2当量)中的混合物中添加KOAc(5.92g,60.35mmol,3当量)和Pd(dppf)Cl2.CH2Cl2(0.82g,1.006mmol,0.05当量)。将反应混合物在100℃在氮气气氛下搅拌3h、然后过滤,将滤饼用甲醇(3x30 ml)洗涤。将滤液浓缩,以得到呈油状物的7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(5g,84.1%)。LCMS(ES,m/z):296[M+H]+。
中间体B159的合成
向7-氯-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3-苯并噻唑(4.5g,15.24mmol,1.0当量)和6-碘-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(6.84g,18.26mmol,1.2当量)在1,4-二噁烷(40mL,454.0mmol,29.82当量)和H2O(10mL,555.08mmol,36.46当量)中的溶液中添加K2CO3(6.31g,45.67mmol,3当量)和Pd(dppf)Cl2.CH2Cl2(0.62g,0.761mmol,0.05当量)。将反应混合物在80℃在氮气气氛下搅拌3h、然后在减压下浓缩,以给出残余物。将残余物通过制备型TLC/硅胶柱色谱法纯化,其中用(DCM/MeOH=9/1)洗脱,以得到呈固体的6-(7-氯-1,3-苯并噻唑-4-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(2.1g,33.1%)。LCMS(ES,m/z):416[M+H]+。
化合物175的合成
向6-(7-氯-1,3-苯并噻唑-4-基)-N-甲基-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(70mg,0.168mmol,1.00当量)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(38.51mg,0.185mmol,1.1当量)在1,4-二噁烷(2mL)和H2O(0.5mL)中的溶液中添加K2CO3(69.77mg,0.504mmol,3当量)和Pd(dtbpf)Cl2(11.1mg,0.017mmol,0.1当量)。将反应混合物在100℃在氮气气氛下搅拌2h、然后在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件4,梯度8),以得到呈固体的N-甲基-6-[7-(1-甲基吡唑-4-基)-1,3-苯并噻唑-4-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(7.2mg,9.27%)。
化合物174、176-179、233和234根据此实例61中概述和由方案C概括的相同程序制备。下表3提供了这些程序中使用的中间体和最终的化合物表征数据。
表3:根据实例61计划和通用方案C制备的化合物的中间体和表征数据
实例62:化合物283的合成
中间体B160的合成
将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(730.00mg,1.9mmol,1.00当量)、叔丁基4-氨基哌啶-1-甲酸酯(421.64mg,2.1mmol,1.10当量)、和DIEA(742.06mg,5.7mmol,3.00当量)在DMSO(22.0mL)中的混合物在100℃搅拌2h。将反应混合物冷却至室温、然后用水(20.0mL)稀释。沉淀物形成,并且将固体通过过滤收集并用水(2x20.0mL)洗涤,以得到呈固体的叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(750.00mg,69.7%)。LCMS(ES,m/z):562[M+H]+。
中间体B161的合成
在70℃,在氧气气氛下,将叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(700.00mg,1.2mmol,1.00当量)、环丙基硼酸(214.10mg,2.4mmol,2.00当量)、联吡啶基(194.64mg,1.2mmol,1.00当量)、Cu(OAc)2(226.35mg,1.2mmol,1.00当量)、和Na2CO3(264.16mg,2.4mmol,2.00当量)在DCE(35.0mL)中的混合物搅拌过夜。将反应混合物冷却至室温、用水(50.0mL)稀释、并用EA(2x50.0mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:2)洗脱,以得到呈固体的叔丁基4-[环丙基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(150.00mg,20.0%)。LCMS(ES,m/z):602[M+H]+。
化合物283的合成
将叔丁基4-[环丙基(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(135mg,0.2mmol,1.00当量)和HCl(气体)在1,4-二噁烷(1.35mL)和甲醇(4.05mL)中的溶液在室温搅拌1h。将所得混合物在真空下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件7,梯度3),以得到呈固体的N-环丙基-N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]哒嗪-3-胺(41.70mg,43.7%)。LCMS(ES,m/z):418[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.10(s,1H),9.52(s,1H),8.55(s,2H),8.31(d,J=9.6Hz,1H),8.12(d,J=8.1Hz,1H),8.00(d,J=8.0Hz,1H),7.50(d,J=9.7Hz,1H),4.57(tt,J=12.1,3.9Hz,1H),3.05(d,J=11.9Hz,2H),2.68-2.56(m,3H),1.98(qd,J=12.1,4.0Hz,2H),1.82(d,J=11.8Hz,2H),1.01(dd,J=7.1,5.0Hz,2H),0.68(p,J=4.6Hz,2H)。
实例63:化合物284的合成
中间体B162的合成
将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(300.00mg,0.7mmol,1.00当量)、2,2,6,6-四甲基哌啶-4-胺(135.20mg,0.8mmol,1.10当量)和DIEA(304.95mg,2.3mmol,3.00当量)在DMSO(9.0mL)中的混合物在100℃搅拌2h。将反应混合物冷却至室温、然后用水(20.0mL)稀释。沉淀物形成,并且将固体通过过滤收集并用水(2x20.0mL)洗涤。将所得混合物在真空下浓缩,以得到呈固体的6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(395.00mg,97.0%)。LCMS(ES,m/z):518[M+H]+。
中间体B163的合成
在70℃,在氧气气氛下,将6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(520.00mg,1.0mmol,1.00当量)、环丙基硼酸(172.56mg,2.0mmol,2.00当量)、联吡啶基(156.88mg,1.0mmol,1.00当量)、Cu(OAc)2(182.44mg,1.0mmol,1.00当量)和Na2CO3(212.92mg,2.0mmol,2.00当量)在DCE(26.0mL)中的混合物搅拌过夜。将反应混合物冷却至室温、用水(50.0mL)稀释、并用乙酸乙酯(2x50.0mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:2)洗脱,以得到呈固体的N-环丙基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(158.00mg,28.2%)。LCMS(ES,m/z):558[M+H]+。
化合物284的合成
将N-环丙基-6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(150.00mg,0.2mmol,1.00当量)和在1,4-二噁烷(1.5mL)中的HCl(气体)和甲醇(1.5mL)的混合物在室温搅拌1h。将所得混合物在真空下浓缩,以给出残余物。将残余物通过手性制备型HPLC纯化(条件1,梯度1),以得到呈固体的N-环丙基-6-[4-(1H-吡唑-4-基)-1,3-苯并噻唑-7-基]-N-(2,2,6,6-四甲基哌啶-4-基)哒嗪-3-胺(14.50mg,11.3%)。LCMS(ES,m/z):474[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.50(s,1H),8.69(s,1H),8.41(s,1H),8.30(d,J=9.8Hz,1H),8.12(d,J=8.1Hz,1H),8.00(d,J=8.0Hz,1H),7.52(d,J=9.7Hz,1H),5.09(s,1H),3.3(m,1H),1.76(m,4H),1.28(s,6H),1.12(s,6H),1.01(d,J=6.1Hz,2H),0.65(s,2H)。
实例64:化合物215、226-228、265、266、276、277、和285-289的合成中间体B164的合成
在100℃,将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑(130mg,0.334mmol,1.00当量)、叔丁基1,6-二氮杂螺[3.4]辛烷-1-甲酸酯(78.00mg,0.367mmol,1.1当量)、和DIEA(129.50mg,1.002mmol,3当量)在DMSO(1.3mL)中的混合物搅拌过夜。将反应混合物冷却至室温、然后用水(20mL)稀释。沉淀物形成,并且将固体通过过滤收集并用水(2x20mL)洗涤。将所得混合物在真空下浓缩,以得到呈固体的叔丁基6-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-1,6-二氮杂螺[3.4]辛烷-1-甲酸酯(120mg,61.37%)。LCMS(ESI,m/z):574[M+H]+。
化合物265的合成
将叔丁基6-(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1,3-苯并噻唑-7-基}哒嗪-3-基)-1,6-二氮杂螺[3.4]辛烷-1-甲酸酯(30mg,0.051mmol,1.00当量)和在1,4-二噁烷(0.25mL)中的HCl(气体)在甲醇(0.90mL)中的混合物在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件4,梯度9),以得到呈固体的7-(6-{1,6-二氮杂螺[3.4]辛烷-6-基}哒嗪-3-基)-4-(1H-吡唑-4-基)-1,3-苯并噻唑(6.8mg,33.41%)。LCMS(ESI,m/z):390[M+H]+。
化合物287的合成
在室温,向7-(6-{1,6-二氮杂螺[3.4]辛烷-6-基}哒嗪-3-基)-4-(1H-吡唑-4-基)-1,3-苯并噻唑(60mg,0.151mmol,1.00当量)和甲醛(34.00mg,0.453mmol,3.00当量)在甲醇(1.2mL)中的搅拌混合物中分批添加NaBH3CN(28.46mg,0.453mmol,3当量)。将所得混合物在室温搅拌2h、然后在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件7,梯度4),以得到呈固体的7-(6-{1-甲基-1,6-二氮杂螺[3.4]辛烷-6-基}哒嗪-3-基)-4-(1H-吡唑-4-基)-1,3-苯并噻唑(12.2mg,18.85%)。LCMS(ESI,m/z):404[M+H]+。
化合物215、226-228、266、276、277、285、286、288、和289根据此实例XX中概述和由方案D概括的相同程序制备。下表4提供了这些程序中使用的中间体和最终的化合物表征数据。
表4:根据实例64计划和通用方案D制备的化合物的中间体和表征数据
实例65:化合物216的合成
中间体B165的合成
在室温,将5-氟-7-(甲氧基甲氧基)-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(800.00mg,2263.528mmol,1.00当量)在1,4-二噁烷(8mL)中的HCl(气体)中的溶液搅拌30min。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(柱,C18硅胶;流动相A,水(10mmol/LNH4HCO3);流动相B,乙腈;梯度,在20min内,5%B至35%B;UV检测器220nm),以得到呈固体的5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-醇(350mg,69.45%)。LCMS(ES,m/z):219[M+H]+
中间体B166的合成
在0℃,向5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-醇(350.00mg,1.572mmol,1.00当量)和Cs2CO3(512mg,1.572mmol,1.00当量)在THF(12.00mL)中的搅拌混合物中滴加在THF(2mL)中的1,1,1-三氟-N-(吡啶-2-基)-N-三氟甲磺酰基甲磺酰胺(563mg,1.572mmol,1.00当量)。将所得混合物在0℃搅拌4h、然后倾倒入水(50mL)中并用乙酸乙酯(2x50mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:1)洗脱,以得到呈固体的5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(300mg,53.40%)。LCMS(ES,m/z):351[M+H]+。
中间体B167的合成
在80℃,在氮气气氛下,将5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(300.00mg,0.839mmol,1.00当量)、双(频哪醇合)二硼(319.74mg,1.259mmol,1.50当量)、Pd(dppf)Cl2(68.38mg,0.084mmol,0.10当量)、dppf(46.37mg,0.084mmol,0.10当量)、和KOAc(247.14mg,2.518mmol,3.00当量)在1,4-二噁烷(15.00mL)中的混合物搅拌16h。将反应混合物冷却至室温、然后倾倒入水(50mL)中并用乙酸乙酯(2x50mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以得到呈固体的5-氟-4-(1H-吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(200mg,71.16%)。LCMS(ES,m/z):329[M+H]+
中间体B168的合成
在60℃,在氮气气氛下,将5-氟-4-(1H-吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(100.00mg,0.299mmol,1.00当量)、叔丁基(外型)-3-[(6-碘哒嗪-3-基)氧基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(128.80mg,0.299mmol,1.00当量)、[1,3-双[2,6-双(丙-2-基)苯基]-2,3-二氢-1H-咪唑-2-基]二氯(3-氯吡啶-1-鎓-1-基)钯(20.35mg,0.030mmol,0.10当量)、和K2CO3(82.55mg,0.598mmol,2.00当量)在1,4-二噁烷(5.00mL)和H2O(1.00mL)中的混合物搅拌16h。将所得混合物倾倒入水(50mL)中并用乙酸乙酯(2x50mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:1)洗脱,以得到呈固体的叔丁基(外型)-3-([6-[5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]氧基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(50mg,33.12%)。LCMS(ES,m/z):506[M+H]+。
化合物216的合成
将叔丁基(外型)-3-([6-[5-氟-4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基]氧基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(50.00mg,0.097mmol,1.00当量)在1,4-二噁烷(2.50mL)中的HCl(气体)中的溶液在室温搅拌1h、然后在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件7,梯度1),以得到呈固体的7-[6-[(外型)-8-氮杂双环[3.2.1]辛烷-3-基氧基]哒嗪-3-基]-5-氟-4-(1H-吡唑-4-基)-1H-吲唑(7.3mg,18.41%)。LCMS(ES,m/z):406[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.33(s,2H),8.54(s,1H),8.46(d,J=9.4Hz,1H),8.32(s,2H),8.06(d,J=12.4Hz,1H),7.33(d,J=9.4Hz,1H),5.63(tt,J=11.0,5.8Hz,1H),3.54(d,J=4.4Hz,2H),2.26-2.17(m,2H),1.73(dd,J=9.7,6.6Hz,4H),1.64(td,J=11.8,2.9Hz,2H)。
实例66:化合物290的合成
中间体B169的合成
在0℃,向4-溴-2,5-二氟苯酚(90.00g,430.643mmol,1.00当量)在DMF(500.00mL)中的搅拌溶液中滴加NaH(20.67g,861.285mmol,2.00当量)持续30min。在25℃,经1h,向反应混合物中分批添加溴甲氧基甲烷(80.72g,645.964mmol,1.50当量)。将所得混合物用水稀释并用乙酸乙酯(3x1000mL)萃取。将合并的有机层用水(3x500mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:4)洗脱,以得到呈油状物的1-溴-2,5-二氟-4-(甲氧基甲氧基)苯(98g,80.94%)。
中间体B170的合成
向1-溴-2,5-二氟-4-(甲氧基甲氧基)苯(86g,339.863mmol,1.00当量)在THF(500mL)中的搅拌溶液中分批添加LDA(40.05g,373.849mmol,1.1当量),并且将反应混合物在-78℃在N2气氛下搅拌30min。在-78℃,经1h过程,向反应混合物中分批添加DMF(27.33g,373.849mmol,1.1当量)。在0℃,将反应混合物用H2O(500mL)淬灭。将所得混合物用乙酸乙酯(3x400mL)萃取。将合并的有机层用H2O(3x300mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1/10)洗脱,以得到呈固体的2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛(80g,83.75%)。
中间体B171的合成
将2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛(80g,284.644mmol,1.00当量)在THF(300mL)和H2O(100mL)中的溶液用NaOAc(30.36g,370.037mmol,1.3当量)处理,并且将反应混合物在25℃在氮气气氛下搅拌30min。向反应混合物中滴加O-甲基羟基胺(16.07g,341.573mmol,1.2当量),并且将反应混合物在80℃搅拌2h。将混合物冷却至25℃。将所得混合物用乙酸乙酯(3x300mL)萃取。将合并的有机层用H2O(3x300mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:3)洗脱,以得到呈固体的(E)-2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛O-甲基肟(90g,101.96%)。LCMS(ES,m/z):295[M+H]+。
中间体B172的合成
在90℃,将(E)-2-溴-3,6-二氟-5-(甲氧基甲氧基)苯甲醛O-甲基肟(88g,283.784mmol,1.00当量)和NH2NH2.H2O(142.06g,2837.840mmol,10当量)在THF(800mL)中的混合物搅拌3天。将反应混合物冷却至25℃。将所得混合物用乙酸乙酯(3x800mL)萃取。将合并的有机层用H2O(3x500mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:3)洗脱,以得到呈固体的4-溴-5-氟-7-(甲氧基甲氧基)-1H-吲唑(36g,46.12%)。LCMS(ES,m/z):275[M+H]+。
中间体B173的合成
向4-溴-5-氟-7-(甲氧基甲氧基)-1H-吲唑(4g,14.541mmol,1.00当量)和1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(4.54g,21.812mmol,1.5当量)在二噁烷(10mL)和H2O(2mL)的中搅拌混合物中添加Pd(dtbpf)Cl2(0.95g,1.454mmol,0.1当量)和K2CO3(6.03g,43.623mmol,3当量)。将反应混合物在80℃在N2气氛下搅拌4h,然后冷却至25℃。将所得混合物用乙酸乙酯(3x15mL)萃取。将合并的有机层用H2O(3x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:3)洗脱,以得到呈固体的5-氟-7-(甲氧基甲氧基)-4-(1-甲基吡唑-4-基)-1H-吲唑(3.1g,77.17%)。LCMS(ES,m/z):277[M+H]+。
中间体B174的合成
将5-氟-7-(甲氧基甲氧基)-4-(1-甲基吡唑-4-基)-1H-吲唑(3.1g,11.221mmol,1.00当量)和TFA(10mL,134.630mmol,12.00当量)在DCM(30mL)中的混合物在25℃搅拌6h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的乙腈(10mmol/L NH4HCO3);梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-醇(1.6g,61.40%)。LCMS(ES,m/z):233[M+H]+。
中间体B175的合成
将5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-醇(2.8g,12.058mmol,1.00当量)在THF(6mL)中的溶液用Cs2CO3(7.86g,24.116mmol,2当量)处理。在0℃,在氮气气氛下,将反应混合物搅拌30min。向反应混合物中滴加1,1,1-三氟-N-苯基-N-三氟甲磺酰基甲磺酰胺(4.74g,13.264mmol,1.1当量),并且将反应混合物在25℃再搅拌4h。将所得混合物用乙酸乙酯(3x20mL)萃取。将合并的有机层用H2O(3x20mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过反向快速色谱法纯化(硅胶柱;流动相,在水中的MeCN(10mmol/LNH4HCO3);梯度:在10min内,10%至50%;UV检测器,254nm),以得到呈固体的5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(1.1g,25.04%)。LCMS(ES,m/z):365[M+H]+。
中间体B176的合成
向5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基三氟甲磺酸酯(1g,2.745mmol,1.00当量)和双(频哪醇合)二硼(1.05g,4.117mmol,1.5当量)在二噁烷(10mL,118.041mmol,43.00当量)中的搅拌混合物中添加Pd(dppf)Cl2(0.20g,0.275mmol,0.1当量)、dppf(0.30g,0.549mmol,0.2当量)、和AcOK(0.54g,5.490mmol,2当量)。将反应混合物在100℃在N2气氛下搅拌4h,然后冷却至25℃并用乙酸乙酯(3x20mL)萃取。将合并的有机层用H2O(3x15mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(4:1)洗脱,以得到呈固体的5-氟-4-(1-甲基吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(700mg,74.52%)。LCMS(ES,m/z):343[M+H]+。
中间体B177的合成
向5-氟-4-(1-甲基吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(100mg,0.292mmol,1.00当量)和叔丁基(外型)-3-[(3-碘-1,2,4-三嗪-6-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(156.17mg,0.350mmol,1.2当量)在二噁烷(5mL)和H2O(1mL)中的搅拌混合物中添加Pd(dtbpf)Cl2(19.05mg,0.029mmol,0.1当量)和K3PO4(124.07mg,0.584mmol,2当量)。将反应混合物在90℃在N2气氛下搅拌4h,然后冷却至25℃。将所得混合物用乙酸乙酯(3x20mL)萃取。将合并的有机层用H2O(3x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:1)洗脱,以得到呈固体的叔丁基(外型)-3-({3-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]-1,2,4-三嗪-6-基}(甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(66mg,42.32%)。LCMS(ES,m/z):534[M+H]+。
化合物290的合成
在室温,将叔丁基(外型)-3-({3-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]-1,2,4-三嗪-6-基}(甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(60mg,0.112mmol,1.00当量)和HCl(2mL,65.824mmol,585.41当量)在二噁烷(6mL)中的混合物搅拌。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度3),以得到呈固体的(外型)-N-{3-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]-1,2,4-三嗪-6-基}-N-甲基-8-氮杂双环[3.2.1]辛烷-3-胺盐酸盐(22.5mg,42.58%)。LCMS(ES,m/z):434[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.23(s,1H),9.43(d,J=10.3Hz,1H),9.24(s,1H),9.01(s,1H),8.53(s,1H),8.45(d,J=1.5Hz,1H),8.10(d,J=2.1Hz,1H),8.03(d,J=12.4Hz,1H),5.26(m,1H),4.14(s,2H),3.99(s,3H),3.19(s,3H),2.41-2.29(m,2H),2.10(dd,J=9.2,4.5Hz,2H),1.97(t,J=6.9Hz,2H),1.81(d,J=12.7Hz,2H)。19F NMR(376MHz,DMSO-d6)δ-124.87。
实例67:化合物291的合成
中间体B178的合成
向5-氟-4-(1-甲基吡唑-4-基)-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(100mg,0.292mmol,1.00当量)和叔丁基(外型)-3-[(6-碘哒嗪-3-基)(甲基)氨基]-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(155.82mg,0.350mmol,1.2当量)在二噁烷(5mL)和H2O(1mL)中的搅拌混合物中添加Pd(dtbpf)Cl2(19.05mg,0.029mmol,0.1当量)和K3PO4(124.07mg,0.584mmol,2当量)。将反应混合物在90℃在N2气氛下搅拌4h,然后冷却至25℃。将所得混合物用乙酸乙酯(3x20mL)萃取。将合并的有机层用H2O(3x10mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用EA/PE(1:1)洗脱,以得到呈固体的叔丁基(外型)-3-({6-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基}(甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(70mg,44.97%)。LCMS(ES,m/z):533[M+H]+。
化合物291的合成
在25℃,将叔丁基(外型)-3-({6-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基}(甲基)氨基)-8-氮杂双环[3.2.1]辛烷-8-甲酸酯(75mg,0.141mmol,1.00当量)和HCl(2mL,65.824mmol,467.46当量)在二噁烷(4.00mL)中的溶液搅拌3h。将所得混合物浓缩。将粗产物通过制备型HPLC纯化(条件4,梯度10),以得到呈固体的(外型)-N-{6-[5-氟-4-(1-甲基吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-基}-N-甲基-8-氮杂双环[3.2.1]辛烷-3-胺(23.1mg,37.93%)。LCMS(ES,m/z):433[M+H]+。1H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.49(s,1H),8.43(s,1H),8.21(d,J=9.8Hz,1H),8.08(d,J=2.1Hz,1H),7.94(d,J=12.6Hz,1H),7.26(d,J=9.7Hz,1H),5.08(s,1H),3.98(s,3H),3.55(s,2H),2.98(s,3H),1.89-1.80(m,2H),1.78(s,4H),1.58(s,2H)。19FNMR(376MHz,DMSO-d6):δ-125.05。
实例68:化合物的合成
中间体B179的合成
在80℃,在氮气气氛下,将4-溴-7-氯-1H-吲唑(2g,8.467mmol,1.00当量)和1-(噁烷-2-基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡唑(2.40g,8.467mmol,1.00当量)、Pd(dtbpf)Cl2(0.84g,1.270mmol,0.15当量)、和K3PO4(5.50g,25.401mmol,3.00当量)在1,4-二噁烷二噁烷(80mL)和H2O(20mL)中的混合物搅拌16h,。将所得混合物用乙酸乙酯(2x200mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:01)洗脱,以得到呈固体的7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(7.3mg,0.06%)。LCMS(ES,m/z):303[M+H]+。
中间体B180的合成
在80℃,在氮气气氛下,将7-氯-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(7.3g,24.112mmol,1.00当量)、4,4,5,5-四甲基-2-(四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(12.25g,48.224mmol,2当量)、Pd2(dba)3(1.10g,1.206mmol,0.05当量)、KOAc(7.10g,72.336mmol,3当量)、和XPhos(11.49g,24.112mmol,1当量)在二噁烷(73mL)中的混合物搅拌5h。将反应混合物冷却至室温、用水稀释、并用乙酸乙酯(2x200mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:1)洗脱,以得到呈油状物的4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑。LCMS(ES,m/z):395[M+H]+。
中间体B181的合成
在70℃,在氮气气氛下,将3-溴-6-氟哒嗪(1.5g,8.476mmol,1.00当量)和4-[1-(噁烷-2-基)吡唑-4-基]-7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吲唑(3.34g,8.476mmol,1.00当量)、K2CO3(2.34g,16.952mmol,2当量)、和Pd(dppf)Cl2(0.62g,0.848mmol,0.1当量)在二噁烷(15mL)和H2O(3mL)中的混合物搅拌16h。将反应混合物冷却至室温并用乙酸乙酯(1x50mL)萃取。将合并的有机层经无水Na2SO4干燥并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物从PE/EA(5:01 18mL)重结晶,以得到呈固体的7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(3g,97.14%)。LCMS(ES,m/z):365[M+H]+。
中间体B182的合成
将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1H-吲唑(2.5g,6.861mmol,1.00当量)在DMF(25mL,323.044mmol,47.08当量)中的溶液用NaH(0.33g,13.722mmol,2当量)处理。在0℃,在氮气气氛下,将反应混合物搅拌30min。在室温,向反应混合物中滴加SEM-Cl(1.37g,8.233mmol,1.2当量)。将所得混合物倾倒入水(100mL)中并用乙酸乙酯(2x100mL)萃取。将合并的有机层用盐水(3x100mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物从PE/EA(5:1,30mL)重结晶,以得到呈固体的7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}吲唑(3g,88.40%)。LCMS(ES,m/z):495[M+H]+。
中间体B183的合成
将7-(6-氟哒嗪-3-基)-4-[1-(噁烷-2-基)吡唑-4-基]-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}吲唑(500mg,1.011mmol,1.00当量)、叔丁基4-氨基哌啶-1-甲酸酯(263.18mg,1.314mmol,1.3当量)、和在DMSO中的DIEA(5mL,70.393mmol,69.64当量)的混合物在100℃搅拌16h。将反应混合物冷却至室温、用水稀释、并用乙酸乙酯(2x20mL)萃取。将合并的有机层用盐水(3x20mL)洗涤、经无水Na2SO4干燥、并过滤。过滤后,将滤液在减压下浓缩,以给出残余物。将残余物通过硅胶柱色谱法纯化,其中用PE/EA(1:1)洗脱,以得到呈固体的叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}吲唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(262mg,38.40%)。LCMS(ES,m/z):675[M+H]+。
化合物263的合成
将叔丁基4-[(6-{4-[1-(噁烷-2-基)吡唑-4-基]-1-{[2-(三甲基甲硅烷基)乙氧基]甲基}吲唑-7-基}哒嗪-3-基)氨基]哌啶-1-甲酸酯(80mg,0.119mmol,1.00当量)、甲醇(1.14mL,28.339mmol,238.14当量)、和在1,4-二噁烷中的HCl(气体)(1.14mL,37.762mmol,317.33当量)中的溶液在室温搅拌1h。将所得混合物在减压下浓缩,以给出残余物。将残余物通过制备型HPLC纯化(条件8,梯度1,梯度2),以得到呈固体的N-(哌啶-4-基)-6-[4-(1H-吡唑-4-基)-1H-吲唑-7-基]哒嗪-3-胺氯化氢(4.3mg,9.92%)。LCMS(ES,m/z):361[M+H]+。
化合物215、226-228、266、276、277、285、286、288、和289根据此实例XX中概述和由方案E概括的相同程序制备。下表6提供了这些程序中使用的中间体和最终的化合物表征数据。
表6:根据实例68计划和通用方案E制备的化合物的中间体和表征数据
实例69:用于监测剪接变体表达水平的示例性剪接测定
为了进行10uL RT-qPCR反应,将细胞裂解物转移到含有根据下表的预混液的384孔qPCR板中。将板密封,轻轻涡旋,并在运行前向下旋转。在一些以20uL进行反应的情况下,相应地调整体积。下表总结了RT-qPCR反应的组分:
在以下快速循环条件下,使用QuantStudio(ThermoFisher公司)进行RT-qPCR反应。至少一式两份地分析所有样品和标准品。在一些情况下,在进行qPCR之前,所有板都完成了5-10分钟的总体室温(RT)步骤。下表总结了PCR循环:
通过首先确定ΔCt对比管家基因进行数据分析。然后将该ΔCt针对DMSO对照(ΔΔCt)进行归一化,并使用2^(-ΔΔCt)方程转换为RQ(相对量化)。然后,通过任意设置HTT-CJ的3.5ΔCt的测定窗口和HTT-AJ的9ΔCt的测定窗口,将RQ转换为响应百分比。这些测定窗口对应于在最具活性的化合物的高浓度下观察到的最大调节。然后将响应百分比拟合到4参数逻辑方程以评估化合物处理的浓度依赖性。AJ mRNA的增加被报告为AC50(对AJ增加具有50%响应的化合物浓度),而CJ mRNA水平的降低报告为IC50(对CJ降低具有50%响应的化合物浓度)。
这些结果的总结如表7所示,其中“A”代表AC50小于500nM;“B”代表AC50为500nM至5μM;并且“C”代表AC50大于5μM。
表7:示例性化合物对RNA剪接的调节
下表8中提供了另外的结果,其中“A”代表AC50/IC50小于100nM;“B”代表AC50/IC50为100nM至1μM;并且“C”代表AC50/IC50为1μM至10μM;并且“D”代表AC50/IC50大于10μM。
表8:示例性化合物对RNA剪接的调节
使用上面提供的计划对更大的基因小组进行了另外的研究。侧翼上游和下游外显子之间的连接用于设计规范连接qPCR测定。正向引物、反向引物或CY5标记的5′核酸酶探针(带有3'猝灭剂,如ZEN/Iowa Black FQ)中的至少一个被设计为与外显子连接重叠,以捕获CJ mRNA转录物。BLAST用于确认探针组的特异性,并且在其设计期间考虑了参数,如解链温度、GC含量、扩增子大小和引物二聚体形成。本小组中分析的三个示例性基因(HTT、SMN2和靶标C)的CJ mRNA水平降低的数据报告为IC50(对CJ降低具有50%响应的化合物浓度)。
来自小组的结果的总结如表9所示,其中“A”代表IC50小于100nM;“B”代表IC50为100nM至1μM;并且“C”代表IC50为1μM至10μM;并且“D”代表IC50大于10μM。
表9:示例性化合物对RNA剪接的调节
等效原则和范围
本申请引用了不同发布的专利、出版的专利申请、杂志文章和其他出版物,将其全部通过引用并入本文。如果在任一个并入的参考文献和本说明书之间有冲突,以本说明书为准。此外,在现有技术之内的本发明的任何特定实施例可以从任何一个或多个权利要求中明确排除。因为,这样的实施例被认为是本领域普通技术人员已知的,因此它们可以被排除,即使该排除在本文没有被明确陈述。本发明的任何特定实施例可以因为任何原因从任一权利要求中排除,不管是否与存在的现有技术相关。
本领域技术人员仅使用常规实验就将认识到或能够确定本文描述的特定实施例的许多等效形式。本文描述的实施例的范围不旨在限于以上说明书、附图或实例,而是如所附权利要求中所述。本领域普通技术人员应理解,在不脱离如以下权利要求中所限定的本发明的精神或范围下,可以对本说明书进行各种改变和修饰。
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Claims (53)
1.一种具有式(I-d)的化合物:
或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体,其中:
A和B各自独立地是环烷基、杂环基、芳基或杂芳基,其各自任选地被一个或多个R1取代;
L不存在,是C1-C6-亚烷基、C1-C6-杂亚烷基、-O-、-C(O)-、-N(R3)-、-N(R3)C(O)-或-C(O)N(R3)-,其中每个亚烷基和杂亚烷基任选地被一个或多个R4取代;
M和P各自独立地是C(R2)或N;
D、E、和F各自独立地是C(R5d)、C(R5d)(R5e)、N、N(R5f)、S或O,其中在化合价允许的情况下,包含D、E和F的环中的原子之间的键可以是单键或双键;
每个R1独立地是氢、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、C1-C6亚烷基-芳基、C1-C6亚烯基-芳基、C1-C6亚烷基-杂芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中每个烷基、亚烷基、烯基、亚烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;或
两个R1基团与它们所附接的原子一起形成3-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R8取代;
每个R2独立地是氢、卤代、氰基、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基或-ORA;
每个R3独立地是氢、C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基或杂环基;其中每个烷基、杂烷基、卤代烷基、环烷基和杂环基任选地被一个或多个R12取代;
每个R4是C1-C6-烷基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、卤代、氰基、氧代、-ORA、-NRBRC、-C(O)RD或-C(O)ORD;
R5d和R5e各自独立地是氢、卤代或C1-C6烷基;或
R5d和R5e一起形成氧代基团;
R5f是氢、卤代或C1-C6烷基;
每个R7独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、卤代、氧代、氰基、NRBC(O)RD、-C(O)NRBRC、-C(O)RD或-SRE,其中烷基、烯基、炔基、杂烷基和卤代烷基任选地被一个或多个R9取代;或
两个R7基团与它们所附接的原子(例如,X或Y)一起形成4-7元环烷基、杂环基、芳基或杂芳基,其中每个环烷基、杂环基、芳基和杂芳基任选地被一个或多个R9取代;
R8和R9各自独立地是C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-杂烷基、C1-C6-卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代、-ORA、-NRBRC、-NRBC(O)RD、-NO2、-C(O)NRBRC、-C(O)RD、-C(O)ORD、-SRE或-S(O)xRD,其中烷基、烯基、炔基、杂烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基中的每个任选地被一个或多个R11取代;
每个RA独立地是氢、C1-C6烷基、C1-C6卤代烷基、芳基、杂芳基、C1-C6亚烷基-芳基、C1-C6亚烷基-杂芳基、-C(O)RD或-S(O)xRD;
RB和RC中的每个独立地是氢、C1-C6烷基、C1-C6-杂烷基、环烷基、杂环基、-ORA;或
RB和RC与它们所附接的原子一起形成任选地被一个或多个R10取代的3-7元杂环基环;
每个RD和RE独立地是氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、C1-C6亚烷基-芳基或C1-C6亚烷基-杂芳基;
每个R10独立地是C1-C6-烷基或卤代;
每个R11独立地是C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;
每个R12独立地是氘、C1-C6烷基、C1-C6杂烷基、C1-C6卤代烷基、环烷基、杂环基、芳基、杂芳基、卤代、氰基、氧代或-ORA;n是0、1、2、3或4;并且
x是0、1或2。
2.如权利要求1所述的化合物,其中A是单环或双环杂环基。
3.如前述权利要求中任一项所述的化合物,其中A是含氮杂环基。
10.如前述权利要求中任一项所述的化合物,其中L是-O-或-N(R3)-。
11.如前述权利要求中任一项所述的化合物,其中L是-N(R3)-,并且R3是氢、C1-C6-烷基或环烷基,其中每个烷基和杂烷基各自任选地被一个或多个R12取代。
12.如前述权利要求中任一项所述的化合物,其中L是-N(CH3)-或-N(H)-。
13.如前述权利要求中任一项所述的化合物,其中L是-N(CH3)-。
16.如前述权利要求中任一项所述的化合物,其中M和P中的每个独立地是C(R2)(例如,CH)。
17.如前述权利要求中任一项所述的化合物,其中M和P中的一个独立地是C(R2)(例如,CH),并且M和P中的另一个独立地是N。
18.如前述权利要求中任一项所述的化合物,其中M是CH并且P是N。
19.如前述权利要求中任一项所述的化合物,其中D、E、和F中的一个独立地是N或N(R5f)。
20.如前述权利要求中任一项所述的化合物,其中D、E、和F中的两个独立地是N或N(R5f)。
21.如前述权利要求中任一项所述的化合物,其中D是N、N(R5f)、或S。
22.如前述权利要求中任一项所述的化合物,其中D是N或N(R5f)(例如,NH)。
23.如前述权利要求中任一项所述的化合物,其中D和E中的每个独立地是N或N(R5f)。
24.如前述权利要求中任一项所述的化合物,其中F是C(R5d)或C(R5d)(R5e)。
34.如权利要求1所述的化合物,其中
A是单环、双环或三环杂环基;
B是单环杂环基或杂芳基;
L不存在,是-N(R3)-或-O-;
M是CH;
P是CH或N;
D是N(R5f)、C(R5d)、或S;
E和F各自独立地是N、NH、C(R5d)、C(R5d)(R5e);
R7是卤代;并且
m是0或1。
35.如前述权利要求中任一项所述的化合物,其中该化合物选自表1所示化合物中的任一个或其药学上可接受的盐、溶剂化物、水合物、互变异构体或立体异构体。
36.一种药物组合物,该药物组合物包含如前述权利要求中任一项所述的化合物和药学上可接受的赋形剂。
37.如权利要求1-35中任一项所述的化合物或如权利要求36所述的药物组合物,其中该化合物改变靶核酸(例如,RNA,例如前mRNA)。
38.如权利要求1-35中任一项所述的化合物或如权利要求36所述的药物组合物,其中该化合物结合靶核酸(例如,RNA,例如前mRNA)。
39.如权利要求1-35中任一项所述的化合物或如权利要求36所述的药物组合物,其中该化合物稳定靶核酸(例如,RNA,例如前mRNA)。
40.如权利要求1-35中任一项所述的化合物或如权利要求36所述的药物组合物,其中例如,如通过qPCR所确定,该化合物将靶核酸(例如,RNA,例如前mRNA)上剪接位点的剪接增加约0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或更多。
41.如权利要求1-35中任一项所述的化合物或如权利要求36所述的药物组合物,其中例如,如通过qPCR%所确定,该化合物将靶核酸(例如,RNA,例如前mRNA)上剪接位点的剪接减少约0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或更多。
42.一种形成复合物的方法,该复合物包含剪接体的组分(例如,主要剪接体组分或次要剪接体组分)、核酸(例如,DNA、RNA,例如前mRNA)和如权利要求1-35中任一项所述的具有式(I)的化合物,该方法包括:使该核酸(例如,DNA、RNA,例如前mRNA)与具有式(I)的化合物接触。
43.如权利要求42所述的方法,其中在该具有式(I)的化合物的存在下,该剪接体的组分被募集到该核酸中。
44.一种改变核酸(例如,DNA、RNA,例如前mRNA)的构象的方法,该方法包括使该核酸与如权利要求1-35中任一项所述的具有式(I)的化合物或如权利要求36所述的药物组合物接触。
45.如权利要求44所述的方法,其中该改变包括在该核酸中形成凸起。
46.如权利要求44所述的方法,其中该改变包括稳定该核酸中的凸起。
47.如权利要求44所述的方法,其中该改变包括减少该核酸中的凸起。
48.如权利要求44-47中任一项所述的方法,其中该核酸包含剪接位点。
49.一种用于在治疗受试者的疾病或障碍中使用的组合物,该组合物包括向该受试者施用如权利要求1-35中任一项所述的具有式(I)的化合物或如权利要求36所述的药物组合物。
50.用于如权利要求49所述使用的组合物,其中该疾病或障碍包含增殖性疾病(例如,癌症、良性肿瘤或血管生成)。
51.用于如权利要求49所述使用的组合物,其中该疾病或障碍包含神经疾病或障碍、自身免疫性疾病或障碍、免疫缺陷性疾病或障碍、溶酶体贮积病或障碍、心血管疾病或障碍、代谢性疾病或障碍、呼吸疾病或障碍、肾脏疾病或障碍或传染性疾病。
52.用于如权利要求49所述使用的组合物,其中该疾病或障碍包含神经疾病或障碍。
53.用于如权利要求49所述使用的组合物,其中该疾病或障碍包含亨廷顿病。
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Patent Citations (2)
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WO2018232039A1 (en) * | 2017-06-14 | 2018-12-20 | Ptc Therapeutics, Inc. | Methods for modifying rna splicing |
WO2019028440A1 (en) * | 2017-08-04 | 2019-02-07 | Skyhawk Therapeutics, Inc. | METHODS AND COMPOSITIONS FOR MODULATING SPLICING |
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WO2021174176A1 (en) | 2021-09-02 |
JP2023515617A (ja) | 2023-04-13 |
CN115551843A (zh) | 2022-12-30 |
AU2021228288A1 (en) | 2022-09-22 |
IL295953A (en) | 2022-10-01 |
US20230365526A1 (en) | 2023-11-16 |
WO2021174176A9 (en) | 2022-09-15 |
WO2021174170A1 (en) | 2021-09-02 |
IL295954A (en) | 2022-10-01 |
US20230140983A1 (en) | 2023-05-11 |
JP2023515618A (ja) | 2023-04-13 |
BR112022017107A2 (pt) | 2022-11-16 |
CA3169643A1 (en) | 2021-09-02 |
AU2024201568A1 (en) | 2024-03-28 |
CA3169667A1 (en) | 2021-09-02 |
KR20220157407A (ko) | 2022-11-29 |
AU2021228286A1 (en) | 2022-10-06 |
MX2022010634A (es) | 2023-01-19 |
WO2021174170A9 (en) | 2022-09-15 |
EP4110774A1 (en) | 2023-01-04 |
KR20220158236A (ko) | 2022-11-30 |
BR112022017089A2 (pt) | 2022-11-16 |
EP4110771A1 (en) | 2023-01-04 |
MX2022010637A (es) | 2023-01-19 |
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