CN116874465B - 嘧啶类化合物及其应用 - Google Patents
嘧啶类化合物及其应用 Download PDFInfo
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- CN116874465B CN116874465B CN202310676984.4A CN202310676984A CN116874465B CN 116874465 B CN116874465 B CN 116874465B CN 202310676984 A CN202310676984 A CN 202310676984A CN 116874465 B CN116874465 B CN 116874465B
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- alkyl
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- -1 Pyrimidine compound Chemical class 0.000 title description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
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- 101000654491 Homo sapiens Serine/threonine-protein kinase SIK3 Proteins 0.000 claims abstract description 12
- 102100034377 Serine/threonine-protein kinase SIK2 Human genes 0.000 claims abstract description 12
- 102100031445 Serine/threonine-protein kinase SIK3 Human genes 0.000 claims abstract description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
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- 125000001072 heteroaryl group Chemical group 0.000 description 13
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 4
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明提供了嘧啶类化合物及其应用，具体地，本发明提出了式(I)所示化合物、其立体异构体或其药学上可接受的盐，该化合物能选择性抑制抑制SIK2和/或SIK3。
Description
技术领域
本发明属于医药领域，具体涉及嘧啶类化合物及其应用。
背景技术
Salt-inducible kinase(SIK)激酶，包括SIK1，SIK2和SIK3，属于AMP依赖的蛋白激酶(AMPK)家族，该类丝氨酸/苏氨酸激酶在细胞能量代谢调节中起着关键作用。多种细胞外信号，包括激素、驱化因子等可通过激活相应G蛋白偶联受体/cAMP信号通路，进一步激活蛋白激酶A(PKA)、蛋白激酶C(PKC)以及钙离子-钙调蛋白依赖性蛋白激酶(CaMK)等信号网络，调节糖代谢、脂代谢、能量代谢以及细胞分化等多方面功能。而SIK激酶处于蛋白激酶A(PKA)的下游，PKA直接磷酸化SIK激酶，增加其与14-3-3调节蛋白的结合，从而释放并激活SIK下游底物，主要包括两类转录因子，一类为CREB调节转录激活因子(CRTCs)，另一类为组蛋白脱乙酰酶(HDAC4/5/7/9)。被释放的CRTCs和HDACs从胞浆进入细胞核，与相应DNA调控位点结合，发挥其转录调控的作用。下游基因主要包括调控代谢的Pck1、G6PC以及参与炎症反应的Ptgs2、IL-10、TTP等等。另外，HDACs还参与炎症信号通路NF-κB蛋白的去乙酰化，从而调节NF-κB所调控的炎症因子的表达。
目前已知的SIK激酶有三个亚型，SIK1、SIK2及SIK3。小鼠基因敲除模型的研究结果发现SIK2和SIK3在促进巨噬细胞分化方面发挥更重要的作用。SIK1主要参与盐代谢，SIK1敲除小鼠对高盐引起的血压升高更为敏感。SIK2敲除小鼠表型基本正常，血浆甘油三酯类有一定升高；而SIK3敲除小鼠体重体积偏小，提示与早期骨骼发育相关。虽然通过小分子化合物对SIK激酶的抑制是否和小鼠基因敲除的表型一致目前还没有足够的研究结果，但针对自身免疫疾病开发的SIK小分子激酶抑制剂选择性靶向SIK2/SIK3，而避开对SIK1的抑制作用是一个比较安全有效的开发策略。
发明内容
在本发明的一方面，式(I)所示化合物、其立体异构体或其药学上可接受的盐；
其中，X为N或C(R1a)；
R1a为H、C1-6烷基或C1-6烷氧基；
R1b为H、C1-6烷基、C1-3烷基-5-6元杂环基或C1-3烷基-C(＝O)NH-C1-3烷基-O-C1-3烷基，所述C1-6烷基、C1-3烷基-5-6元杂环基或C1-3烷基-C(＝O)NH-C1-3烷基-O-C1-3烷基任选被1个或2个CN、卤素或C1-3烷基取代；
R1c为H或5-6元杂环基；
R2为H或C1-6烷基；
R5分别独立为H或C1-6烷基；
R3选自C1-6烷基或C1-6烷氧基；
R4选自C1-6烷基，所述C1-6烷基任选被1个、2个或3个卤素或CN取代；
RT、RU分别独立地选自H、卤素或C1-6烷基。
在本发明的一些方案中，R1a为H或-OCH3，其余变量如本发明所定义。
在本发明的一些方案中，R1b为H、-CH2CN、-C(CH3)2CN或-CH2C(＝O)NHCH2CH2OCH3，其余变量如本发明所定义。
在本发明的一些方案中，R1c为H或其余变量如本发明所定义。
在本发明的一些方案中，R4为-CH2CF3，其余变量如本发明所定义。
在本发明的一些方案中，R3为-OCH3，其余变量如本发明所定义。
在本发明的一些方案中，其具有如下结构：
在本发明的另一方面，本发明还提出了一种药物组合物。在本发明的一些方案中，所述药物组合物包含前面所述的化合物、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
在本发明的另一方面，本发明还提出了前面所述的化合物、其立体异构体或其药学上可接受的盐或前面所述的药物组合物在制备用于抑制SIK2和/或SIK3的药物中的用途。
在本发明的另一方面，本发明还提出了前面所述的化合物、其立体异构体或其药学上可接受的盐或前面所述的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途。在本发明的一些方案中，所述的疾病或病症为炎性疾病、自身免疫性疾病、增殖性疾病、纤维化疾病、移植排斥、涉及软骨转换损伤的疾病、先天性软骨畸形、涉及骨转换损伤的疾病、与TNFα、干扰素、IL-6、IL-12和/或IL-23过度分泌相关的疾病、呼吸系统疾病、内分泌系统疾病、代谢疾病、心血管疾病、皮肤病学疾病或异常血管生成相关疾病。
术语定义与说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当被理解为本申请说明书和/或权利要求书记载的范围内。
本申请通式定义中的术语“任选的”(或“任选地”、“任选”)意味着被零个、一个或多个取代基所取代的情形，例如“任选被一个或多个R取代”意味着可以不被R取代(无取代)或可以选择被一个、两个、三个或者更多个R取代。
除非另有说明，本说明书和权利要求书记载的数值范围相当于至少记载了其中每一个具体的整数数值。例如，数值范围“1-12”相当于记载了数值范围“1-12”中的每一个整数数值，即1、2、3、4、5、6、7、8、9、10、11、12。
“卤素”意指氟、氯、溴、或碘。
术语“C1-6烷基”表示具有1、2、3、4、5或6个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。其可以是一价(如CH3)、二价(-CH2-)或者多价(如次)。
术语“环烷基”意指含有3-6个碳原子的单环或多环饱和或部分不饱和非芳香族碳环。在一些实施例中，环烷基是饱和的非芳香族碳环。环烷基基团的实例包括而不限于环丙基、环丁基、环戊基、环己基。术语“C3-6环烷基”应理解为表示饱和的一价单环、二环(如稠环、桥环、螺环)烃环或三环烷烃，其具有3～6个碳原子，优选“C5-6环烷基”。术语“C3-6环烷基”应理解为表示饱和的一价单环、双环(如桥环、螺环)烃环或三环烷烃，其具有3、4、5或6个碳原子。
术语“杂环基”或“杂环烷基”意指含有碳和至少一个选自氧、氮或硫(O、N或S)的杂原子的饱和的或部分饱和的单环或多环的环，并且其中在环碳或杂原子之间没有共用的非定域的n电子(芳香性)。杂环烷基环结构可以被一个或多个取代基取代。这些取代基本身可以是任选地取代的。杂环烷基环的实例包括但不限于氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡喃基、吡咯烷基、噁唑啉基、噁唑烷基、噻唑啉基、噻唑烷基、吡喃基、噻喃基、四氢吡喃基、二噁啉基、哌啶基。杂环基可以是指饱和的或不饱和的具有3至6元的非芳族的环或环系，例如，其是3-、4-、5-或6-元的单环。除非另外说明，杂环基可以是碳基或氮基，且-CH2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。
术语“杂芳基”意指5个至12个环原子的单价单环芳香族基团或多环芳香族基团，其含有选自N、O或S的一个或多个环杂原子，剩余的环原子是C。如本文所定义的杂芳基还意指双环杂芳香族基团，其中杂原子选自N、O或S。芳香族基团任选地独立地被本文描述的一个或多个取代基取代。术语“杂芳基”应理解为包括这样的一价单环、二环(如稠环、桥环、螺环)或三环芳族环系：例如其具有5～12个环原子且包含1-5个独立选自N、O和S的杂原子，例如“5-10元杂芳基”。术语“5-12元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系：其具有5、6、7、8、9、10、11或12个环原子，特别是5或6或9或10个碳原子，且其包含1-5个，优选1-3各独立选自N、O和S的杂原子并且，另外在每一种情况下可为苯并稠合的。“杂芳基”还指其中杂芳族环与一个或多个芳基、脂环族或杂环基环稠合的基团，其中所述连接的根基或点在杂芳族环上。非限制性实例包括1-、2-、3-、5-、6-、7-或8-吲嗪基、1-、3-、4-、5-、6-或7-异吲哚基、2-、3-、4-、5-、6-或7-吲哚基、2-、3-、4-、5-、6-或7-吲唑基、2-、4-、5-、6-、7-或8-嘌呤基、1-、2-、3-、4-、6-、7-、8-或9-喹嗪基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、1-、4-、5-、6-、7-或8-酞嗪基(phthalazinyl)、2-、3-、4-、5-或6-萘啶基、2-、3-、5-、6-、7-或8-喹唑啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、6-或7-蝶啶基、1-、2-、3-、4-、5-、6-、7-或8-4aH咔唑基、1-、2-、3-、4-、5-、6-、7-或8-咔唑基咔唑基、1-、3-、4-、5-、6-、7-、8-或9-咔啉基、1-、2-、3-、4-、6-、7-、8-、9-或10-菲啶基等。当所述5-12元杂芳基与其它基团相连构成本发明的化合物时，可以为5-12元杂芳基环上的碳原子与其它基团相连，也可以为5-12元杂芳基环上的杂原子与其它基团相连。当所述5-12元杂芳基被取代时，其可以为单取代或者多取代。并且，对其取代位点没有限制，例如可以为杂芳基环上与碳原子相连的氢被取代，或者杂芳基环上与杂原子相连的氢被取代。
术语“螺环”是指两个环共用1个成环原子的环系。
术语“稠环”是指两个环共用2个成环原子的环系。
术语“桥环”是指两个环共用3个以上成环原子的环系。
术语“卤素”表示氟、氯、溴和碘。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(2H)，氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。在本发明的一些方案中，H为氘或氚。
“盐”意指母体化合物的离子形式或母体化合物与合适的酸或碱之间的反应以制备母体化合物的酸式盐或碱式盐的产物。本披露的化合物的盐可以通过传统化学方法从含有碱性或酸性部分的母体化合物合成。通常，通过使游离碱性或酸性母体化合物与化学计量的量或与过量的所需成盐无机或有机酸或碱在合适的溶剂或不同的溶剂组合中反应来制备盐。
“药学上可接受的盐”意指本披露的化合物的盐，其在合理的医学判断范围内，适合用于与人和低等动物的组织接触，而没有过度的毒性、刺激、过敏反应等，与合理的利益/风险比相称，通常为水溶性或油溶性或可分散的，并且使其预期用途有效。该术语包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。由于本披露的化合物在游离碱形式和盐形式两者中是有用的，实际上使用盐形式相当于使用碱形式。合适的盐的列表发现于例如，S.M.Birge等人，J.Pharm.Sci.[药物科学杂志]，1977，66，第1-19页，将其通过引用以其全文特此并入。
“药学上可接受的酸加成盐”意指那些保留游离碱的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，这些盐是与无机酸(例如盐酸、氢溴酸、氢碘酸、硫酸、氨基磺酸、硝酸、磷酸等)和有机酸(例如乙酸、三氯乙酸、三氟乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、2-乙酰氧基苯甲酸、丁酸、樟脑酸、樟脑磺酸、肉桂酸、柠檬酸、二葡萄糖酸、乙磺酸、谷氨酸、乙醇酸、甘油磷酸、半硫酸、庚酸、己酸、甲酸、富马酸、2-羟基乙磺酸(羟乙基磺酸)、乳酸、马来酸、羟基马来酸、苹果酸、丙二酸、扁桃酸、均三甲苯磺酸、甲磺酸、萘磺酸、烟酸、2-萘磺酸、草酸、双羟萘酸、果胶酸、苯基乙酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、丙酮酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、酒石酸、对甲苯磺酸、十一烷酸等)形成的。
“药学上可接受的碱加成盐”意指那些保留游离酸的生物学有效性和特性且并非是生物学或在其他方面不希望的盐，这些盐是与无机碱(例如氨或氢氧化物、碳酸盐、或碳酸氢铵)或金属阳离子(如钠、钾、锂、钙、镁、铁、锌、铜、锰、铝等)形成的。特别优选的是铵盐、钾盐、钠盐、钙盐、和镁盐。衍生自药学上可接受的有机无毒碱的盐包括以下物质的盐：伯胺、仲胺和叔胺、季胺化合物，取代的胺(包括天然存在的取代的胺)，环胺和碱性离子交换树脂，如甲胺、二甲胺、三甲胺、乙胺、二乙胺、三乙胺、异丙胺、三丙胺、三丁胺、乙醇胺、二乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、海巴明(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、四甲基铵化合物、四乙基铵化合物、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己胺、二苄胺、N,N-二苄基苯乙胺、1-二苯羟甲胺、N,N'-二苄基乙烯二胺、多胺树脂等。特别优选的有机无毒碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱、和咖啡因。
“溶剂化物”意指由溶质(例如具有式(I)的化合物)和溶剂(例如水、乙醇、或乙酸)形成的可变化学计量的复合物。这种物理缔合可能涉及不同程度的离子键和共价键，包括氢键。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)。一般而言，出于本披露的目的而选择的此类溶剂不会干扰溶质的生物学活性。溶剂化物涵盖溶液相和可分离的溶剂化物两者。代表性的溶剂化物包括水合物、乙醇化物、甲醇化物等。
“水合物”意指其中一种或多种溶剂分子是水的溶剂化物。
如下所讨论的本披露的化合物包括其游离碱或酸，其盐、溶剂化物和前药，并且可以在其结构中包括氧化的硫原子或季铵化的氮原子(尽管没有明确说明或显示)，特别是其药学上可接受的形式。此类形式(特别是药学上可接受的形式)旨在包括在所附权利要求中。
“异构体”意指具有相同数量和种类原子、并因此具有相同的分子量，但在空间中原子的排列或构型方面不同的化合物。该术语包括立体异构体和几何异构体。
“立体异构体”或“光学异构体”意指具有至少一个手性原子或受限旋转导致具有垂直的不对称平面(例如，某些联苯基、丙二烯和螺环化合物)并且可以使平面偏振光旋转的稳定异构体。因为不对称中心和其他化学结构存在于可以导致立体异构现象的本披露的化合物中，本披露考虑了立体异构体及其混合物。本披露的化合物及其盐包括不对称碳原子，因此可以作为单个立体异构体、外消旋体、以及对映异构体和非对映异构体的混合物存在。典型地，此类化合物将以外消旋混合物进行制备。然而，如果需要，此类化合物可以制备或分离成立体异构体，即作为单独的对映异构体或非对映异构体，或作为富集立体异构体的混合物。如下文更详细讨论的，化合物的单独的立体异构体通过从含有所需手性中心的光学活性起始材料合成来制备，或通过制备对映异构体产物的混合物随后分离或拆分(如转化成非对映异构体的混合物随后分离或重结晶、色谱技术，使用手性拆分剂、或在手性色谱柱上直接分离对映异构体)来制备。特定立体化学的起始化合物是可商购的或通过下文描述的方法制备并通过本领域熟知的技术拆分的。
“对映异构体”意指彼此为不能重叠镜像的一对立体异构体。
“非对映异构体”或“非对映体”意指彼此之间不构成镜像的光学异构体。
“外消旋混合物”或“外消旋体”意指含有等份的单个对映异构体的混合物。
“非外消旋混合物”意指含有不等份的单个对映异构体的混合物。
“几何异构体”意指由双键(例如，顺式-2-丁烯和反式-2-丁烯)或环结构(例如，顺式-1,3-二氯环丁烷和反式-1,3-二氯环丁烷)中的旋转自由度限制产生的稳定异构体。因为碳-碳双(烯属)键、C＝N双键、环结构等可以存在于本披露的化合物中，本披露考虑了由这些双键周围和这些环结构中的取代基排列产生的不同的稳定的几何异构体及其混合物中的每一种。使用顺式/反式惯例或使用E或Z系统表示取代基和异构体，其中术语“E”意指更高次序的取代基在双键的相对侧，术语“Z”意指更高次序的取代基在双键的同一侧。有关E和Z异构现象的详尽讨论提供于：J.March,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure[高等有机化学：反应、机制和结构]，第4版，John Wiley&Sons[约翰威立父子出版公司]，1992，将其通过引用以其全文特此并入。以下几个实例代表单个E异构体、单个Z异构体和E/Z异构体的混合物。E和Z异构体的确定可以通过分析方法进行，例如X射线晶体学、1H NMR和13C NMR。
本披露的一些化合物能以多于一种的互变异构形式存在。如上所提及的，本披露的化合物包括所有此类互变异构体。
本领域熟知的是化合物的生物学和药理学活性对化合物的立体化学敏感。因此，例如，对映异构体通常展示出显著不同的生物学活性，包括药代动力学特性的差异(包括代谢、蛋白结合等)和药理学特性(包括所展示的活性类型、活性程度、毒性等)。因此，本领域技术人员将理解，当相对于其他对映异构体富集时或当与其他对映异构体分开时，一种对映异构体可以更具活性或可以展示出有益作用。另外地，本领域技术人员将知道如何从本披露和现有技术的知识中分开、富集或选择性制备本披露的化合物的对映异构体。
纯对映异构体或者具有所需对映异构体过量(ee)或对映异构体纯度的混合物的制备可以通过一种或多种本领域技术人员已知的用于(a)分离或拆分对映异构体、或(b)对映异构体选择性合成的许多方法，或用这些方法的组合来完成。这些拆分方法通常依赖于手性识别，包括例如使用手性固定相的色谱法、对映异构体选择性主体-客体络合、拆分或使用手性助剂合成、对映异构体选择性合成、酶促和非酶促动力学拆分、或者自发的对映异构体选择性结晶。此类方法通常披露于：Chiral Separation Techniques:APracticalApproach[手性分离技术：一种实用的方法](第2版)，G.Subramanian(编辑)，Wiley-VCH[威利-VCH公司]，2000；T.E.Beesley和R.P.W.Scott,Chiral Chromatography[手性色谱法]，John Wiley&Sons[约翰威立父子出版公司]，1999；以及Satinder Ahuja,Chiral Separations by Chromatography[通过色谱法的手性分离]，Am.Chem.Soc.[美国化学会志]，2000。此外，存在同样熟知的用于定量对映异构体过量或纯度的方法(例如GC、HPLC、CE或NMR)和用于识别绝对构型和构象的方法(例如CD ORD、X射线晶体学或NMR)。
一般而言，化学结构或化合物的所有互变异构形式和异构形式及混合物，无论是单独的几何异构体或立体异构体还是外消旋或非外消旋混合物均是预期的，除非在该化合物名称或结构中明确指出了具体的立体化学或异构形式。
可以根据已知的方法，例如通过萃取、过滤或柱层析来分离相应的稳定异构体。
如本文所使用的，术语“药物组合物”是指呈适于口服施用或肠胃外施用的形式的本披露的化合物或其药学上可接受的盐或立体异构体，以及至少一种药学上可接受的载体。
“载体”涵盖载体、赋形剂、和稀释剂，并且意指涉及从一个器官或受试者的身体部分向另一个器官或受试者的身体部分携带或运输药物药剂的材料、组合物或媒介物，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。
术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
具体实施方式
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术均涵盖在本公开旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
中间体A和B：6-溴-8-甲氧基-2-(2,2,2-三氟乙基)-3,4-二氢异喹啉-1(2H)-酮和6-(2-氯嘧啶-4-基)-8-甲氧基-2-(2,2,2-三氟乙基)-3,4-二氢异喹啉-1(2H)-酮
步骤1：
将6-溴-8-氟-3,4-二氢异喹啉-1(2H)-酮(10g,41.101mmol)溶于四氢呋喃(80mL)，缓慢加入甲醇钠(5.6M,11mL,61.650mmol)，室温搅拌2小时。反应结束后加入80毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离纯化得到中间体A-1。LCMS-ESI(m/z)[M+H]+:256.0,258.0。
步骤2：
将中间体A-1(10.0g,39.210mmol)溶于四氢呋喃(80mL)，缓慢滴加二(三甲基硅基)氨基锂(53mL,53.55mmol)，室温搅拌1小时后，缓慢加入2,2,2-三氟乙基三氟甲磺酸(11g,47.1mmol)，加热至70℃搅拌2小时。反应结束后，冷却至室温，加入80毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离纯化得到中间体A。LCMS-ESI(m/z)[M+H]+:340.2。
步骤3：
将中间体A(5.5g,16.3mmol)溶于1,4-二氧六环(30mL)和水(3mL)中，加入双联频哪醇硼酸酯(20.0g,0.309mmol)，[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(1.3g,1.6mmol)和醋酸钾(4.8g,48.9mmol)。氮气保护下，反应加热至80℃搅拌4小时。反应结束后，冷却至室温，加入60毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓酸后柱层析分离纯化得到中间体B-1。LCMS-ESI(m/z)[M+H]+:386.3。
步骤4：
将中间体B-1(100mg,0.260mmol)溶于1,4-二氧六环(1mL)和水(0.2mL)中，加入2,4-二氯嘧啶(58.01mg,0.389mmol)，[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)二氯甲烷络合物(30mg,0.037mmol)和碳酸钠(82.55mg,0.779mmol)。氮气保护下，反应加热至80℃搅拌2小时。反应结束后，冷却至室温，减压浓酸后柱层析分离纯化得到中间体B。LCMS-ESI(m/z)[M+H]+:372.0。
实施例1：8-甲氧基-6-(2-((2-甲氧基-4-(4-甲基哌嗪-1-基)苯基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-3,4-二氢异喹啉-1(2H)-酮
步骤1：
将中间体B(60mg,0.161mmol)溶于1毫升N-甲基-2-吡咯烷酮后，加入2-甲氧基-4-(4-甲基哌嗪-1-基)苯胺(35.72mg,0.161mmol)和对甲苯磺酸(61.33mg,0.323mmol)。反应加热至150℃搅拌2小时。反应结束后，减压浓缩，制备液相纯化得到实施例1。1H NMR(400MHz,CD3OD)δ8.45(d,J＝5.2Hz,1H),8.14(d,J＝8.7Hz,1H),7.82(d,J＝1.5Hz,1H),7.59(d,J＝1.5Hz,1H),7.32(d,J＝5.3Hz,1H),6.71(d,J＝2.6Hz,1H),6.60(dd,J＝8.8,2.6Hz,1H),4.34(q,J＝9.2Hz,2H),3.98(s,3H),3.91(s,3H),3.71(t,J＝6.3Hz,2H),3.21(t,J＝5.1Hz,4H),3.08(t,J＝6.3Hz,2H),2.66(t,J＝5.0Hz,4H),2.38(s,3H).LCMS-ESI(m/z)[M+H]+:557.1。
实施例2：8-甲氧基-6-(2-((3-(吗啉代甲基)苯基)氨基)嘧啶-4-基)-2-(2,2,2-三氟乙基)-3,4-二氢异喹啉-1(2H)-酮
步骤1：
将中间体B(70mg,0.188mmol)溶于1毫升N-甲基-2-吡咯烷酮后，加入3-(吗啉代甲基)苯胺(35.72mg,0.161mmol)和对甲苯磺酸(73.33mg,0.376mmol)。反应加热至150℃搅拌2小时。反应结束后，减压浓缩，制备液相纯化得到实施例2。1H NMR(400MHz,CD3OD)δ8.50(d,J＝5.2Hz,1H),7.83(d,J＝1.5Hz,1H),7.74(d,J＝8.4Hz,1H),7.70(d,J＝1.8Hz,1H),7.61(s,1H),7.36(d,J＝5.3Hz,1H),7.29(t,J＝7.8Hz,1H),7.02(d,J＝7.5Hz,1H),4.34(q,J＝9.2Hz,2H),3.98(s,3H),3.70(dt,J＝9.6,5.3Hz,6H),3.54(s,2H),3.08(t,J＝6.3Hz,2H),2.48(d,J＝4.9Hz,4H).LCMS-ESI(m/z)[M+H]+:528.2。
实施例3：2-(3-((4-(8-甲氧基-1-羰基-2-(2,2,2-三氟乙基)-1,2,3,4-四氢异喹啉-6-基)嘧啶-2-基)氨基)苯基)乙酰腈
步骤1：
将中间体B(70mg,0.188mmol)溶于1毫升N-甲基-2-吡咯烷酮后，加入2-(3-氨基苯基)乙酰腈(49.38mg,0.377mmol)和对甲苯磺酸(71.56mg,0.377mmol)。反应加热至150℃搅拌2小时。反应结束后，减压浓缩，制备液相纯化得到实施例3。1H NMR(400MHz,CD3OD)δ8.54(d,J＝5.2Hz,1H),7.90(d,J＝2.0Hz,1H),7.83(d,J＝1.5Hz,1H),7.72(dd,J＝8.3,2.2Hz,1H),7.66(d,J＝1.5Hz,1H),7.41(d,J＝5.2Hz,1H),7.35(t,J＝7.9Hz,1H),7.03(d,J＝7.0Hz,1H),4.36(q,J＝9.3Hz,2H),4.01(s,3H),3.93(s,2H),3.73(t,J＝6.3Hz,2H),3.11(t,J＝6.2Hz,2H).LCMS-ESI(m/z)[M+H]+:468.2。
实施例4：2-(3-((4-(8-甲氧基-1-羰基-2-(2,2,2-三氟乙基)-1,2,3,4-四氢异喹啉-6-基)嘧啶-2-基)氨基)苯基)-N-(2-甲氧基乙基)乙酰胺
步骤1：
将2-(3-硝基苯基)乙酸(1g,5.520mmol)溶于10毫升二甲基甲酰胺，加入2-甲氧基乙烷-1-胺(0.50g,6.624mmol)，N,N,N′,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲(2.31g,6.072mmol)和二异丙基乙胺(2.737mL,16.561mmol)。氮气保护下，室温搅拌18小时，反应结束后加入100毫升水，乙酸乙酯萃取(200mL)，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后，柱层析分离纯化得到中间体4-1。LCMS-ESI(m/z)[M+H]+:239.2。
步骤2：
将中间体4-1(500mg,2.099mmol)溶于乙醇(4mL)和氯化铵溶液(2mL)，加入铁粉(140.63mg,2.518mmol)，氮气保护下70℃搅拌2小时。反应结束后，冷却至室温，加入20毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离纯化得到中间体4-2。LCMS-ESI(m/z)[M+H]+:209.2。
步骤3：
将中间体4-2(67mg,0.322mmol)溶于5毫升N-甲基-2-吡咯烷酮后，加入中间体B(59.80mg,0.161mmol)和对甲苯磺酸(55.40mg,0.322mmol)。反应加热至150℃搅拌2小时。反应结束后，冷却至室温，加入10毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后，制备液相纯化得到实施例4。1H NMR(400MHz,DMSO-d6)δ9.71(s,1H),8.60(d,J＝5.1Hz,1H),8.10(t,J＝5.6Hz,1H),7.76(s,1H),7.75(s,1H),7.70(s,1H),7.67(d,J＝8.0Hz,1H),7.51(d,J＝5.2Hz,1H),7.23(t,J＝7.8Hz,1H),6.88(d,J＝7.9Hz,1H),4.35(q,J＝9.6Hz,2H),3.92(s,3H),3.64(t,J＝6.0Hz,2H),3.41(s,2H),3.35–3.33(m,2H),3.23(s,3H),3.22–3.17(m,2H),3.02(t,J＝6.1Hz,2H).LCMS-ESI(m/z)[M+H]+:544.2。
实施例5：2-(6-((4-(8-甲氧基-1-羰基-2-(2,2,2-三氟乙基)-1,2,3,4-四氢异喹啉-6-基)嘧啶-2-基)氨基)吡啶-2-基)乙酰腈
步骤1：
将2-(6-溴吡啶-2-基)乙酰腈(200mg,1.015mmol)溶于5毫升甲苯，加入2-叔丁基氨基甲酸酯(118.92mg,1.015mmol)，醋酸钯(22.79mg,0.102mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(117.47mg,0.203mmol)和碳酸钾(420.85mg,3.045mmol)，氮气保护下，反应加热至80℃搅拌3小时。反应结束后，冷却至室温，加入50毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离纯化得到中间体5-1。LCMS-ESI(m/z)[M+H-tBu]+:178.0。
步骤2：
将中间体5-1(130mg,0.557mmol)溶于3.5毫升甲酸，40℃搅拌2小时。反应结束后，减压浓缩，柱层析分离纯化得到中间体5-2。LCMS-ESI(m/z)[M+H]+:134.2。
步骤3：
将中间体5-2溶于5毫升1,4-二氧六环，依次加入中间体B(62.82mg,0.169mmol)，三(二亚苄基丙酮)二钯(30.95mg,0.034mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(39.11mg,0.068mmol)和碳酸钾(140.12mg,1.014mmol)。氮气保护下，反应加热至80℃搅拌3小时。反应结束后，加入5毫升水，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后，制备液相分离纯化得到实施例5。1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.69(d,J＝5.2Hz,1H),8.32(d,J＝8.4Hz,1H),7.89–7.81(m,2H),7.70(s,1H),7.65(d,J＝5.3Hz,1H),7.06(d,J＝7.4Hz,1H),4.35(q,J＝9.6Hz,2H),4.12(s,2H),3.93(s,3H),3.64(t,J＝6.1Hz,2H),3.02(t,J＝6.1Hz,2H).19F NMR(377MHz,DMSO-d6)δ-72.0(s,3F).LCMS-ESI(m/z)[M+H]+:469.3。
实施例6：2-(3-((4-(8-甲氧基-1-羰基-2-(2,2,2-三氟乙基)-1,2,3,4-四氢异喹啉-6-基)嘧啶-2-基)氨基)苯基)-2-甲基丙腈
步骤1：
将2-(3-氨基苯基)-2-甲基丙腈(60mg,0.374mmol)溶于3毫升异丙醇，加入中间体B(27.31mg,0.749mmol)和盐酸-1,4-二氧六环溶液(0.1mL)。反应加热至150℃搅拌2小时。反应结束后，冷却至室温，减压浓缩后，制备液相分离纯化得到实施例6。1H NMR(400MHz,CD3OD)δ8.53(d,J＝5.2Hz,1H),8.02(t,J＝2.1Hz,1H),7.78(d,J＝1.6Hz,1H),7.74(ddd,J＝8.2,2.2,1.0Hz,1H),7.65(d,J＝1.6Hz,1H),7.40–7.34(m,2H),7.16(ddd,J＝7.8,2.0,1.0Hz,1H),4.34(q,J＝9.3Hz,2H),3.98(s,3H),3.71(t,J＝6.2Hz,2H),3.08(t,J＝6.2Hz,2H),1.76(s,6H).19F NMR(377MHz,CD3OD)δ-72.0(s,3F).LCMS-ESI(m/z)[M+H]+:496.2。
实施例A：SIK激酶ADP-Glo活性测试
化合物准备：将化合物溶于DMSO，配制成10mM的澄清溶液。
测试流程：
(1)用Echo 655将化合物的稀释溶液转移到多孔板(6007290,Perkin Elmer)，DMSO的最终浓度为1％；
(2)盖上多孔板，1000g下离心1分钟；
(3)配制1x的激酶缓冲液：50mM HEPES缓冲液，10mM氯化镁，0.01％聚环氧乙烯月桂酰醚，1mM乙二醇双氨乙基醚四乙酸，2mM二硫苏糖醇；
(4)用1x的激酶缓冲液配制2x的激酶溶液(SIK1:4nM；SIK2:1nM；SIK3:40nM)；
(5)加入5μL的2x激酶溶液到多孔板，1000g离心一分钟，然后室温孵育15分钟；
(6)用1x的激酶缓冲液配制2x的底物(SIK:10.2mg/ml AMARA；SIK2和SIK3:0.1mg/ml AMARA)和ATP溶液(SIK1和SIK3:120μM；SIK2:100μM)；
(7)加入5μL的2x底物和ATP溶液；
(8)1000g离心1分钟；
(9)盖上多孔板，室温孵育60分钟；
(10)加入5μL的ADP-Glo试剂，1000g离心1分钟，室温孵育60分钟；
(11)加入10μL的激酶检测试剂，1000g离心1分钟，室温孵育60分钟；
(12)1000g离心1分钟；
(13)在Envision 2104上读取冷荧光值；
数据处理：抑制剂(％)通过下面的公式计算得到：
SignalAve_PC：阳性参照HG-9-91-01(1μM)的平均值；
SignalAve_VC：阴性参照二甲基亚砜的平均值；
计算IC50和绘制化合物的效应-剂量曲线：IC50通过Graphpad非线性拟合抑制率和化合物浓度对数值计算得到。
表1
| Ex. | SIK1 IC50(nM) | SIK2 IC50(nM) | SIK3 IC50(nM) |
| 1 | 60 | 19 | NT |
| 2 | 182 | 87 | 90 |
| 3 | NT | 13 | 32 |
| 4 | 251 | 40 | 25 |
| 5 | NT | NT | 30 |
| 6 | 93 | 41 | 2 |
NT:未测试
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。
Claims (7)
1.式(I)所示化合物、其立体异构体或其药学上可接受的盐；
其中，X为N或C(R1a)；
R1a为H或-OCH3；
R1b为H、C1-6烷基、C1-3烷基-5-6元杂环基或C1-3烷基-C(＝O)NH-C1-3烷基-O-C1-3烷基，所述C1-6烷基被1个或2个CN取代；
R1c为H或5-6元杂环基；
R2为H；
R5分别独立为H；
R3选自C1-3烷基或C1-3烷氧基；
R4选自CH2CF3；
RT、RU分别独立地选自H、卤素。
2.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，R1b为H、
-CH2CN、-C(CH3)2CN或-CH2C(＝O)NHCH2CH2OCH3。
3.根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，R1c为H或
4.具有如下结构的化合物、其立体异构体或其药学上可接受的盐：
5.一种药物组合物，其中，所述药物组合物包含权利要求1-4中任一项所述的化合物、其立体异构体或其药学上可接受的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
6.权利要求1-4中任一项所述的化合物、其立体异构体或其药学上可接受的盐或权利要求5所述的药物组合物在制备用于抑制SIK2和/或SIK3的药物中的用途。
7.权利要求1-4中任一项所述的化合物、其立体异构体或其药学上可接受的盐或权利要求5所述的药物组合物在制备用于治疗和/或预防疾病或病症的药物中的用途，其中，所述的疾病或病症为炎性疾病、自身免疫性疾病、纤维化疾病、移植排斥、涉及软骨转换损伤的疾病、先天性软骨畸形、涉及骨转换损伤的疾病、与TNFα、干扰素、IL-6、IL-12和/或IL-23过度分泌相关的疾病、呼吸系统疾病、内分泌系统疾病、代谢疾病、皮肤病学疾病或异常血管生成相关疾病。
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| CN113264920A (zh) * | 2021-05-10 | 2021-08-17 | 中国药科大学 | 一种嘧啶苯并六元环母核的cdk6抑制剂及其制备方法和应用 |
| CN114516856A (zh) * | 2020-11-20 | 2022-05-20 | 中国科学院合肥物质科学研究院 | 二氢异喹啉酮和异吲哚啉酮衍生物及其用途 |
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| CN114516856A (zh) * | 2020-11-20 | 2022-05-20 | 中国科学院合肥物质科学研究院 | 二氢异喹啉酮和异吲哚啉酮衍生物及其用途 |
| CN113264920A (zh) * | 2021-05-10 | 2021-08-17 | 中国药科大学 | 一种嘧啶苯并六元环母核的cdk6抑制剂及其制备方法和应用 |
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| Chen, Weijiao等. Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer.Journal of Medicinal Chemistry (.2022,第66卷(第22期), 15102-15122. * |
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