WO2025003769A2 - Aromatic heterocyclic pyrrolidone derivative and use thereof - Google Patents

Abstract

Disclosed in the present invention is an aromatic heterocyclic pyrrolidone derivative having a new structure, which can be developed as an inhibitor targeting small molecule PI3K_γ. The PI3K_γ inhibitor has a high selectivity and a siginificant biological activity, and also has considerable potential in the prevention or treatment of diseases related to abnormal expression of the PI3K_γ signaling pathway.

Description

862-867 <ii W 0202100442!入 方 '垦瞬芙苗生物 ". Med. CiietiL 2015, 58, 517-S21和 Al：5 Med. Chem. Leit. 2021, 12, 129-135）和异 R引噪咻酮类衍生物等 < VvO2017153527Al , W 02020247496A I > W02020210379A1 L 然商现有的抑制剂往往在靶点豹抑制活性和选择性、 药代动力性质疝安全性上存在着淆多问题， 限制了其 它倡的迸一步开发。 综上所述， 如何提供一萍具有全新结构且生物学活性显著、 高选择性鸵 FT3*抑柄剂， 是本领域技术 人员尚未解决的技术难题。

基、 CM姨基、 C*3-G环烷基 4-10兀杂环基存在取代基时， 可各自独立地被卜列取代基中的 i''或多个进 行单取代或多取代： 卤索、 氤基、 羟基、 氮基、 新 ■基、 氧代基、 C）f, : tn；基' C：,w烯基、 。2一5 ’萩:基、 C〔6环烷 S , Crs B氧基、 CLG烷飒基， G一 6烷硫基、 Cm烷胺基 - 4-10 JL杂环基、 5-14 芳基或（旗口芳基； 或 说 明 书

G-6烷氧基》 卤代 G-K烷氧基或取代或未取代的 4-10兀斌环基； 进一步当 R³*、 R*中 C：*烷基、 C»K环烷

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C| 6烷硫基或 C） 6 M胺基； 或

基、 一 M夬基、 。3一6环烷基和 4-10元杂环基存在取代基时， 可各自独立地被下列取代基中的 -、个或多个进 行单取代或多取代： 卤素、 氤基、 羟基、 氨基 . 疏基、 氧代基■ C_b6烷基、 C件烯基、 C_2.6ft基、 环:烷 基、 Ci g'W氧基、 Cx烷飒墓、 烷疏基、 Ci-5烷胺基、 4-10兀杂环基、 5-14兀杂号基或 Ceis ?7基； 或

当 R³选自一 0一萨.时， 选自取代或未取代的 ng元杂环基； 迸一步当 中伞 1（）元杂环基存在取代 基时， 可各自独立地被下列取代基中的一个或多个进行单取代或多取代： 卤素、 氤基、 羟基、 氨基、 箭基、 说 明 书 氧代基、 Cw烷基、 C京烯某、 C京焕幕、 (：3一6环烷基、 Cw烷氧墓、 C»6烷砚基、 Crfi 硫基或 C抑烷胺基： 当 选自 -N-R³³R^3c H'j , R³\ 各自独立地选自取代或未取代的 C杯烷基、 囱代 G _ 6烷基" 取代或未 取代的 C：w环烷基、 C［一〈＞烷氧基、 卤代 G,*烷氧基或取代或未取代的 4-1。兀杂环基； 进 - -步当 R°"、 中 垸基、 。36还 '烷基、 4-10元杂环基存在取代基时， 可务自独立地被下列取代基中的一个或多个进行单 取代或多取代： 卤素、 氧基、 羟基、 氨基、 ：疏基， 氧代基、 G _ 6'浣基、 C-,₆ffi基、 匚2一 6：块基、 C*5环烷基 " G-6烷氧基、 G-6烷飙基、 C; f； feMl基或 烷服基；

基、 氮基、 帝基、 氧代基、 G s烷基、 卤，代 烷基、 (、：一 6烯基" 块基、 C券坏烷基、 J一技芳基 " 4-1。

说 明 书 Description Aromatic heterocyclic pyrrolidone derivatives and their uses Technical field The present invention belongs to the field of pharmaceutical chemistry. It relates to an aromatic heterocyclic pyrrolidone derivative and its preparation method and application. The compound and its pharmaceutically acceptable Ki salt, isotope derivative, solvate or isotope derivative are said to be highly selective FESKy inhibitors for preventing or treating diseases related to abnormal expression of PI3Ky signaling pathway, and have broad application prospects. Background technology

862-867 <ii W 0202100442!入方'垦瞬芙苗生物". Med. Civil 2015, 58, 517-821 and Al:5 Med. Chem. Leit. 2021, 12, 129-135) and iso-indole ketone derivatives, etc. < VvO2017153527Al, W 02020247496A I > W02020210379A1 L However, the existing inhibitors often have many problems in the inhibitory activity and selectivity of the target site, the pharmacokinetic properties and the safety, which limits the further development of other products. In summary, how to provide a FT3* inhibitor with a new structure, significant biological activity and high selectivity is a technical problem that has not yet been solved by those skilled in the art.

When a substituent exists in a C6-6 cycloalkyl, a C7-6 cycloalkyl, a C8-6 cycloalkyl 4-10 membered heterocyclic group, each of them may be independently substituted or polysubstituted by one or more of the following substituents: a halogen, an alkyl, a hydroxyl, a nitrogen, a neopentyl, an oxo, a C12-5'-13'-14'-16'-17'-13'-13'-17'-17'-18'-19'-19'-18 ... manual

G-6 alkoxy> halogenated GK alkoxy or substituted or unsubstituted 4-10 pentyl ring group; further when R ³ *, R* in C: * alkyl, C » K cycloalkane

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C| 6 alkylthio or C) 6 M amine; or

When substituents are present in the alkyl, C1-6-alkyl, C2-6-cycloalkyl and 4-10-membered heterocyclic groups, they may be independently substituted by one, two or more of the following substituents: halogen, hydrazine, hydroxyl, amino, mercapto, oxo, _C1-6- alkyl, C1-1-alkenyl, C2-6-alkyl, cycloalkyl, C1-6-oxy, _C1-6 -alkane, alkylthio, C1-5-alkylamino, 4-10-membered heterocyclic group, 5-14-membered heterocyclic group or C1-7-alkyl; or

When R ³ is selected from -0-1, -1, -2 ... In the specification, oxo, C12-alkyl, C16-alkene, C12-alkyl, C13-6-cycloalkyl, C13-alkoxy, C16-alkyl, C13-thio or C13-alkylamino: when selected from ^-NR33R3cH'j , ^R3 \ are each independently selected from substituted or unsubstituted C12-alkyl, C13-alkyl, C13-6-alkyl, C13-6-cycloalkyl, C13-alkoxy, C13-6-alkyl, C13-thio or C13-alkylamino: when selected from ^-NR33R3cH'j , R3\ are each independently selected from substituted or unsubstituted C12-alkyl, C13-alkyl, C13-6-alkyl, C13-6-cycloalkyl, C13-alkoxy, halogenated C13-alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further, when R3\, C13-alkyl, C13-alkyl, C13-6-alkyl, C13-6-cycloalkyl, C13-6-alkyl, _C13-6 -alkyl,匚2一6: alkynyl, C*5 cycloalkyl, G-6 alkoxy, G-6 alkyl, C*5M1 group or alkyl group;

4-1, 4-6-alkyl, 4-nitro, 4-piperidin, 4-nitro, 4-piperidinyl ...piperidinyl, 4-piperidinyl, 4-piperidinyl, 4-piperidinyl, 4-piper

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- — with surface 'Sa and should be stubborn to write involved in the qin and humorous Cheng Gong '3 and Xue Zhenfei stubborn tendons Sun; selected from hydrogen, halogen or Cw' courtyard group;

R, ^R5 is selected from hydrogen or C1,4-alkyl;

R" is selected from alkyl substituted by cycloalkyl;

或 -P(O)R^!sR^,b； 当瑚中 c"烷基、 CE烯基、 C»6块基、 G一 6环烷基、 膈一 "2 .芳基、 4-10 Ji：杂环基和 5-14元 杂芳基存在取代基时， 可各自独立地被下列取代基中的一个或多个进行单取代或多取代： 卤素、 氤基、 羟 基、 ’氯基、 筑基、 氧代基、 G一 6烷基、 卤代 C”烷基、 Cx烯基、 C_{2 6} ft基、 C3-5环烷基、 C6M芳基、 4- 10

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行单取代或多取代： 卤素、 氮基， 羟基、 氨基、 疏基、 氧代基' G &烷基， C抨烯基、 C_2.s ft基、 C”环烷 基、 烷氧基、 烷飒基、 G”烷硫基、 烷胺基、 4-10元杂环基、 5-14元杂芳基或 (辅技芳基： 或 和 Rjb相互连接并与 原子共同形成 3-8元的饱和或非饱和的杂环； ^R3 is selected from ^-OR3a or ^-NR3aR3c ; wherein, when R3 is selected from -0.3a, R3, is selected ^from substituted or unsubstituted 4-10 membered heterocyclic group; further, when R3 is selected from 4-10 membered heterocyclic group, when there are substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, hydrogen, thiols, oxo, C6-6 alkyl, C7-6 alkenyl, thiols, cycloalkyl, C6-6 alkoxy, C7-6 alkyl, C8-6 alkylthio or C9-6 alkylamino;

or -P(O)R ^! sR ^,b ; when C1-6 alkyl, C1-6 alkenyl, C2-6 alkynyl, C1-6 cycloalkyl, C2-6 aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, aryl, hydroxyl, chloro, oxo, C1-6 alkyl, halogenated C1-6 alkyl, _C2-6 alkenyl, C3-5 cycloalkyl, C6M aryl, 4-10 membered heterocyclic group and 5-14 membered heteroaryl.

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Rjb is mono- or poly-substituted: halogen, nitrogen, hydroxyl, amino, mercapto, oxo, C1-6 _alkyl , C2-4 alkenyl, C2-6 alkyl, C1-6 cycloalkyl, alkoxy, C1-6 alkyl, C1-6 alkylthio, alkylamino, 4-10 membered heterocyclyl, 5-14 membered heteroaryl or (co-aryl): or Rjb and Rjb are connected to each other and together with atoms form a 3-8 membered saturated or unsaturated heterocyclic ring;

R/ is selected from hydrogen, halogen or alkyl;

R\RS is selected from hydrogen or cycloalkyl; wherein is selected from cycloalkyl substituted with cycloalkyl;

更优选的， 前 :述芳杂环:并毗略浣酮美衍生物 . 为结构通式 (III)所示的化合物或其药学上可接受的盐;

式中， X选自 N或者 5咨； ^R3 is selected from ^-OR33 or ^-NR3aR3c _; wherein, when R3 is selected from -0-1, R* is selected ^from substituted or unsubstituted 0-membered heterocyclic group; further, when there is a substituent in the _0- membered heterocyclic group in R3a, it can be independently substituted or polysubstituted by one or more of the following substituents: halogen, alkyl, hydroxyl, amino, mercapto, oxo, alkyl, _C6 -alkenyl, Gm'-deoxyalkyl, Gw-cycloalkyl, alkoxy, alkylthio, G,*: alkylthio or amino; when R3 is selected from -0-1, R* is selected from substituted or unsubstituted 0-membered heterocyclic group; further, when there is a substituent in the 0-membered heterocyclic group in R3a, it can be independently substituted or polysubstituted by one or more of the following substituents: halogen, alkyl, hydroxyl, amino, mercapto, oxo, alkyl, C6-alkenyl, Gm'-deoxyalkyl, Gw-cycloalkyl, alkoxy, alkylthio, G,*: alkylthio or amino; Each is independently selected from substituted or unsubstituted C1-6 alkyl, halogenated C2-6 alkyl, substituted or unsubstituted cycloalkyl, C1-6 alkoxy, halogenated alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further, when C1-6 alkyl, C1-6 cycloalkyl or 4-10 membered heterocyclic group in R", R'° has a substituent, it can be independently substituted or polysubstituted with one or more of the following substituents: halogen, thio, hydroxy, anthracene, mercapto, oxo, C1-6 alkyl, C1-6 alkenyl, C1-6 alkyl, C1-6 cycloalkyl, C1-6 alkylthio or C1-5 alkylamino;

More preferably, the above-mentioned aromatic heterocyclic ring: and pyrrolidine derivative is a compound represented by the general structural formula (III) or a pharmaceutically acceptable salt thereof;

Wherein, X is selected from N or 5;

R' is selected from W ^{!a Rib} ;

R', ^R'b are each independently selected from hydrogen, substituted or unsubstituted C16 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C16-hydroxyl, substituted or unsubstituted C16-cycloalkyl or substituted or unsubstituted 4-membered heterocyclyl; when R'e, R'e and C16-alkyl, C16-alkenyl, C16-hydroxyl, C16-mixed cycloalkyl or 4-10 membered heterocyclyl have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxy, amino, vegetable, oxo, C16-alkyl, C16-alkenyl, C16-hydroxyl, C16-cycloalkyl, _C16 -alkoxy, C16-alkylthio, C16-alkylamino, 4-membered heterocyclyl, 5-14 membered heteroaryl or C16-aryl;

当 R3选自 -卜顷咔3。时， R：，a、 R*各自独立地选自取代或未取代的 CK烷基 . 卤代 C"烷基、 取代或未

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-NH8()2-R拈、 .C(0)NH-R3b或 „c(O)-R^3b；

筲〔基、 羟基、 氨基、 疏基、 氧代基、 C1-6烷基、 Cz-t,烯基、 C2-6)决基、 l：3-a环烷基、 (-"1-6旋:氧基、 (；-6；睫飒基、

R ² and R ^2a are independently selected from hydrogen, halogen or C t alkyl; R 2a is selected from hydrogen, halogen, C 2 alkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 2 alkyl, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2 aryl, substituted or unsubstituted C 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR ³ \ -SR ³ \ -SO2-R ^3a .-NH-R ³ \ -NHCO-R ³ \ -C(O)NH-R ^3a . -C(O)-R ³ \ -NHSO ₂ -R ^3a or -P(O)R ^ia R ^{; b} ; when R 2 is alkyl, C ₂ alkyl, C 2 cycloalkyl, C 2 aryl, 4- When there are substituents in the 10-membered heterocyclic group and the 5-14-membered heteroaryl group, they may be substituted or polysubstituted independently by one or more of the following substituents: halogen, alkyl, hydroxyl manual

When R3 is selected from -1-3-carbon, R:, a, R* are each independently selected from substituted or unsubstituted C1-4 alkyl, halogenated C1-4 alkyl, substituted or unsubstituted

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-NH802-R3b, -C(0)NH-R3b or -C(O) ^-R3b ;

alkyl, C1-6-alkyl, C2-6-alkenyl, C2-6-cycloalkyl, C1-6-cyclohexyl, C2-6-cyclohexyl,

R ² , R* are each independently selected from hydrogen, halogen or Ci _fi K group;

R\R' is selected from hydrogen or Cm alkyl; is selected from CjS alkyl substituted with Cm alkyl;

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只3七 Rm各目独立地选目氢、 C»6烷基、 卤代〔‘I E烷基、 C3-6环烷基、 C] &烷氧基、 卤代 Cg烷氧基或R ³ is selected from -OR ^3a or -N-RMR ³ ; wherein,

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Each of Rm is independently selected from hydrogen, C 6 alkyl, halogenated C 6 alkyl, C 3-6 cycloalkyl, C 6 alkoxy, halogenated C 6 alkoxy or

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本发明所述的 “化合物 ”， 包括但不限于化合物的如下情形： 游离碱、 立体异构体、 几何异构你、 互 变异构体、 同位素、 药学上可接裳的盐、 溶剂化物、 水合物、 前药 (酯)等形式。 本发明所述的 “化合物 ”， 可以是不对称的， 例如， 具有一个或多个立体异构体。 除非另有说明， 所 有立体异构体都包括， 如对映异构体和非对映异构体。 本发明中含有不对 '祢碳原子的化合物， 国以光学活 性纯的形式或外消旋形式被分离出来。 光学活性纯的形式可以通过外消旋混合物拆分、 使用手性原料或手 性试剂合成的方法获得。 本发明中 “药学上可接受的盐 ”是指本发明化合物的盐， 由本发明发现的具有特定取代基的化合物与 2 -乙酰氧基苯甲酸、 2 -羟基乙磺酸、 乙酸、 抗坏血酸， 苯磺酸、 苯甲酸、 碳酸氢根、 碳酸、 柠檬酸、 依地 酸、 乙烷二磺酸、 乙烷磺酸、 富马酸、 葡庚糖、 葡雄酸、 谷氨酸、 乙尊酸、 氢溟酸、 盐酸、 氧碘酸盐、 羟 禁、 羟乙磺酸， 乳酸、 乳糖、 十二烷基磺酸、 马来酸、 苹果酸、 扁桃酸、 甲烷磺酸、 硝酸、 草酸、 双羟荼 酸、 泛酸， 苯乙酸、 磷酸、 多聚半乳糖醛 " 丙酸、 水杨酸、 硬脂酸、 亚乙酸" 琥珀酸、 氨基磺酸， 对氨基 苯磺酸. 硫酸、 单宁 - 酒石酸和对甲苯磴酸中的一种成盐； 或含有相对酸性的功能团时 . 再以通过荏纯的 辛容液或合适的惰性 '溶剂中用足够量的碱与:这类化合物的中性形式接触的方式， 荻捋碱加成盐。 药学上可接 受的碱加成盐， 包括但不限于钠、 铮、 钙、 镁盐、 镂或有机氨。 例如： 碱金属盐、 碱土金属盐、 其他金属 盐、 无机碱盐、 有机碱盐、 无机酸盐、 低级烷磺酸盐、 芳基磺馥盐、 有机酸盐、 氨基酸盐。 本发明中 “同位素”， 是指除另有规定外， 本发明的化合物可以同位素示踪的或富集形式存在， 含有 一个或多个原子. 这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。 同 位素可以是放射性或非放射性的同位素。 通常用作同位素标记的同位素是： 氢同位素， 包括但不限于 ：H 和七： 碳同位素： 包括但不限于 "和气； 氯同位素： 包括但不限于：七1和" 1； 氟同位素： 包括但不 限于 "F； 碘同位素： 包括但不限于气和心］； 氮同位素： 包括但不限于％和 ”N； 氧同位素： 包括但 不限于 “0、 ‘O祁 ⁱ⁸0； 硫同位素： 包括但不限于* S。 这些同位素标记化合物可以用来研充药用分子在组 织中的分布情况， 尤其是 ³H ^!3c, 由于它们容易标记且方便检测， 运用更广泛。 某些重同位素， 比如重 氢 (²11) 的取代， 能增强代谢的稳定性， 延长半衰期从而达到减少剂量的目的而提供疗效优势。 同位素标 记的化合物一般从已被标记的起始物开 •始， 用已知的合成技术像存成非同位素标记的化合物- -样来完成其 合成 说 明 书

3一甲基一卜戊块基、 4 -甲基 -1 -戊决基、 3,3 -二甲基 -I -丁烷基. 3 -乙基 1丁焕基、 1 ,3 -己二焕基 , 1/1-己二焕基、 3 -甲基 3,4 -戊二块基 , 1,5 -己二烧基等。

4-! () membered heterocyclic group; heteroaryl group, heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S". More preferably, the aforementioned aromatic heterocyclic pyrrolidone derivative is a compound represented by the general structural formula or a pharmaceutically acceptable salt thereof:

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The "compounds" of the present invention include, but are not limited to, the following forms of compounds: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters), etc. The "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present invention containing asymmetric carbon atoms are separated in optically pure form or racemic form. The optically pure form can be obtained by resolving a racemic mixture, synthesizing using chiral raw materials or chiral reagents. The "pharmaceutically acceptable salt" in the present invention refers to the salt of the compound of the present invention, and the compound with specific substituents discovered by the present invention and 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, glucose, glutamic acid, acetic acid, hydrochloric acid, hydroiodide, hydroxyban, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxyparaben, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid. Sulfuric acid, Tannin-tartaric acid and p-toluene acid are used to form salts; or when the compound contains relatively acidic functional groups. Then, a sufficient amount of a base is used in a pure aqueous solution or a suitable inert solvent to contact the neutral form of such a compound to form a base addition salt. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, arsenic, calcium, magnesium salts, arsenic or organic amines. For example: alkali metal salts, alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts. In the present invention, "isotope" means that unless otherwise specified, the compound of the present invention may exist in an isotope-tagged or enriched form, containing one or more atoms. The atomic weight or mass number of these atoms is different from the atomic weight or mass number of the largest amount of atoms found in nature. Isotopes may be radioactive or non-radioactive isotopes. Isotopes commonly used for isotope labeling are: Hydrogen isotopes, including but not limited to: H and 7; Carbon isotopes: including but not limited to: 1 and 2; Chlorine isotopes: including but not limited to: 1 and 2; Fluorine isotopes: including but not limited to: 1F; Iodine isotopes: including but not limited to: 1 and 2; Nitrogen isotopes: including but not limited to: % and 1N; Oxygen isotopes: including but not limited to: 1O, ^2O , 3O; Sulfur isotopes: including but not limited to: 2S. These isotope-labeled compounds can be used to supplement the distribution of medicinal molecules in tissues, especially ^{3H !3C} , which are more widely used because they are easy to label and convenient to detect. Certain heavy isotopes, such as deuterium ( ^2-11 ), can enhance metabolic stability and prolong half-life, thereby achieving the purpose of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds generally start from labeled starting materials and use known synthesis techniques to complete their synthesis like the synthesis of non-isotope-labeled compounds. manual

3-Methyl-1-pentylynyl, 4-methyl-1-pentyl, 3,3-dimethyl-1-butanyl, 3-ethyl-1-butanyl, 1,3-hexadienyl, 1/1-hexadienyl, 3-methyl-3,4-pentanediynyl, 1,5-hexadienyl, and the like.

*比嗪基、 哒嗪、 喳 &林、 呵噪、 苯并味喃、 苯并嚏吩、 苯并咪噤八 苯并 H比噬、 苯并倒定、 苯并瞰嗪等。

说 明 书

The term "alkylthio" refers to a straight or branched alkyl group connected by a sulfur atom, i.e., -S-:alkyl, such as C1-6 thio, including but not limited to methylthio, ethylthio, propylthio (including n-propylthio, isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio, tert-butylthio Instructions for Use: pentylthio (including n-pentylthio, isopentylthio, neopentylthio), hexylthio (n-hexylthio, 2-methylpentylthio, 3-methylpentylthio, 2,3-dimethylbutylthio, 2,2-dimethylbutylthio), etc. The term "spinning group" refers to a straight-chain or long-chain alkyl group connected by a base, i.e., a -SO/- alkyl group, such as a C64-alkyl group, including but not limited to methylbenzene, ZrM®, propylbenzene (including n-propyliodine and isopropylbenzene), butylthio (including n-butylbenzene, isobutylbenzene, sec-butylbenzene and tert-butylbenzene), pentylbenzene (including tert-butylbenzene, isopentylbenzene and tert-pentylbenzene), hexyl (tert-butylbenzene, 2-methylpentylbenzene, 3-methylbenzene, 2,3-dimethylbutylbenzene and 2,2-dimethylbutylbenzene), etc.

* pyrazinyl, pyridazine, benzophenone, benzophenone, benzamidan, benzophenone, benzamidan, benzophenone, benzophenone, etc.

manual

!a-1 la-2 is wherein R"', R ² , R ³ . R* and A are as defined above. The reaction process is as follows:

卤代异呵琛琳酮衍生物 lb-1经过 Miyaura硼酸酯化反应生成硼酯中间体 Ib-2,随后在锢催化下与腺类 中间体 Ib-3偶联， 得到目标产物 lb.

说 明 书

与锡

碱性条件下和甲氨基甲酰氯反应得到目标产物 Ilbo

其中 R^i?\ R\ R^?\ R⁴和 R，的定义如前所述 反应过程如下： The 2-aminohydroxyl compound la-1 and the amine fragment are condensed under the action of CD1 to obtain the hydroxyl intermediate la-2 _: the hydroxyl intermediate la-2 and the isoxadiazole intermediate la-3 are coupled with the 5-position C-bond aromatic halide under the conditions of an indium reagent and microwave reaction to obtain the target product.

The halogenated isophthalic acid derivative lb-1 was subjected to Miyaura boronation reaction to generate the boron ester intermediate Ib-2, which was then coupled with the adenine intermediate Ib-3 under the catalysis of indium to obtain the target product lb.

manual

With tin

Under alkaline conditions, it reacts with carbamoyl chloride to obtain the target product Ilbo

Wherein R ^i? \ R\ R ^? \ R ⁴ and R, are defined as above and the reaction process is as follows:

硼酯类中间体界％4与嚓哩氨基甲酸酯类中间体 lVb-2 ffiiG催化下偶联得到目标产物 IVb。

其中 V、 _R\ R\ R4和 R?的定义如前所述。 反应过程如下： 中间体 I¥e4在碱性条件下与 R^laOH发生酯交换反应捋到目标产物 Wco 前述路线 1~10中，钳试剂可以选自四三苯基麟钳、二（三苯基麟）氯化锢、三（二亚节基丙酮）二铠、［LV- 双（二叔丁基麟）二茂铁］二氯化钳、 〔1,1'-双（二苯基麟）二茂铁［二氯化专巴中的一种或几种。 前述路线 1、 路线 3、 路线 6中， 合成目标化含物这步反应的条件可以是微波， 也可以是油浴. 本发明还提供了一种药物组合物， 包含如前所述的化合物或其药学上可接受的盐作为活性成份。 进一步的， 该药物组合物， 还包括一种或多种药学上可接受的载体。 本发明中 "药物组合物”， 指 种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物 活性化合物输送至有机体 （如人） 的载体的制剂。 药物组合物的目的是有利于对有机体给药输送。 本发明中“药学上可接受的载体”， 指与活性成份共同给药、 且有利于活性成份给药的物质， 包括但 不限于药学上可接受的用于人或动物 （如家畜） 的任何助流剂. 增甜剂、 稀释剂、 防腐剂、 染料/着色剂、 矫味增强剂、 表而活性剂、 润湿剂， 分散剂、 崩解剂、 助悬剂、 稳定剂、 等渗剂， '溶剂或乳化剂。 "药学 上可接受的载体” 的非限制性实例， 包括但不限于碳酸钙、 磷酸钙、 各种糖和各类淀粉、 纤维素衍生物、 明胶、 植物油和聚乙二醇等. 本发明提供的药物组合物， 可采用本领域熟知的方法制造 , 包括但不限于混合法、 溶解法"制粒法、 制糖衣药丸法、 磨细法、 乳化法、 冷;东干燥法等。 本发明提供的药物组合物， 可阁制成固体、 半固体" 液体或气体制剂， 包括但不限于片剂. 丸剂、 胶 囊剂、 粉剂、 颗粒剂、 膏剂、 乳剂、 悬浮剂、 溶液剂、 栓剂、 注射剂、 吸入剂、 凝胶剂、 微球、 气潘胶等。 本发明提供的药物组合物. 其给药途径包括但不限于口服、 注拊、 吸入、 透疫、 黏膜、 局部、 腔道内 给药等， 给药部位包括但不眼于口腔、 舌下、 静脉、 肌肉、 肺、 胃肠道、 表皮 " 皮下 1 鼻内、 眼内、 耳内、 腹膜内、 阴道内、 直肠、 穴位等。 优选的给药途径是口服给药。 说 明 书

附图说明 图 1为本发明化合物对 AD模型小鼠来源淋巴细胞细胞因于分泌抑制率的比较， 图 2为本发明化合物对银屑病模型小鼠来源淋巴细胞 IL-17A分泌抑制率的比较。 具体实施方式

说 明 书 m-CPBA： 间氯过氧苯甲酸； HC1： ft酸； CataCxiumA： 正丁基二 (1-金刚烷基 )麟； SeF： 氟化饨； CuCN： 氤化亚铜; Xplios： 2 -二环己基 R-2',4',6'-三异丙基联苯； Pd_?(dba)₃： 三(二亚节基丙酮 )_ ®； Toh 甲苯； Cui： 碘化亚铜； E.A： 乙酸乙酯； RT： 室温； DIPEA： N-二异丙基乙胺： SOC1₂： r氯亚 R； TFA： 三氟乙

步骤 L 4 ■漠 2氟必甲基苯甲酸甲酯 (A1-2) 的合成 将 4 -溟 -2 -氯 -6 -甲基苯甲酸： A1-1 ( 1000 g, 4291 mmol )溶于 AJV-二甲基甲酰胺 ( 100 nil_J ) 中 ’ 加入 碘甲烷 (12.18 g, 8382 mmol)和碳酸钾 (17.79 g_ 12874 mmol),反应在 80P搅拌 1小时。反应加水 200 mL, 用乙酸乙酯 (3(X) mL*3) 萃取， 合并有机相， 用水洗两次 , 饱和食盐水洗一次后干燥浓缩， 得到 10.20 g (粗品) 为黄色油状物 A 1-25 jft.-fer用于下 j步。 2 - amino thiazolin compound IVa-l and chloroformate pseudo condensation, to obtain a nitroformate intermediate IVa-2: intermediate IVa-2 and intermediate IVa-3 in the presence of a reagent and microwave reaction conditions for the coupling of the 5-position CH bond and the aryl halide to obtain the target product IVa. manual

The boron ester intermediate IVb-4 was coupled with the amine carbamate intermediate IVb-2 under the catalysis of HCl to obtain the target product IVb.

Wherein V, _R \R\R4 and R? are defined as described above. The reaction process is as follows: Intermediate I¥e4 undergoes an ester exchange reaction with ^R1aOH under alkaline conditions to produce the target product Wco. In the aforementioned routes 1 to 10, the clamp reagent can be selected from one or more of tetrakistriphenylphosphine clamp, di(triphenylphosphine)indium chloride, tris(dibenzylideneacetone)dicarboxylate, [LV-bis(di-tert-butylphosphine)ferrocene]dichloride clamp, [1,1'-bis(diphenylphosphine)ferrocene[dichloride]. In the aforementioned routes 1, 3 and 6, the conditions for the step of synthesizing the target compound can be microwave or oil bath. The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a pharmaceutically acceptable salt thereof as an active ingredient. Further, the pharmaceutical composition also includes one or more pharmaceutically acceptable carriers. The "pharmaceutical composition" in the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (such as a human). The purpose of the pharmaceutical composition is to facilitate the delivery of the biologically active compound to an organism. The "pharmaceutically acceptable carrier" in the present invention refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient, including but not limited to any pharmaceutically acceptable glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier for humans or animals (such as livestock). Non-limiting examples of "pharmaceutically acceptable carriers" include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol. The pharmaceutical composition provided by the present invention can be manufactured by methods well known in the art, including but not limited to mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, cold drying, etc. The pharmaceutical composition provided by the present invention can be made into solid, semi-solid, liquid or gas preparations, including but not limited to tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres, aerosols, etc. The pharmaceutical composition provided by the present invention has administration routes including but not limited to oral administration, injection, inhalation, transmucosal administration, topical administration, intracavitary administration, etc., and administration sites include but are not limited to the oral cavity, sublingual, intravenous, muscle, lung, gastrointestinal tract, epidermis, subcutaneous, intranasal, intraocular, intraauricular, intraperitoneal, intravaginal, rectal, acupuncture points, etc. The preferred administration route is oral administration. manual

BRIEF DESCRIPTION OF THE DRAWINGS FIG1 is a comparison of the inhibition rates of the compounds of the present invention on the secretion of IL-17A from lymphocytes derived from AD model mice, and FIG2 is a comparison of the inhibition rates of the compounds of the present invention on the secretion of IL-17A from lymphocytes derived from psoriasis model mice.

Instructions: m-CPBA: m-chloroperbenzoic acid; HC1: phthalic acid; CataCxiumA: n-butyldi(1-adamantyl)phosphine; SeF: sodium fluoride; CuCN: cuprous fluoride; Xplios: 2-dicyclohexyl-2',4',6'-triisopropylbiphenyl; Pd _? (dba) ₃ : tris(dibenzyleneacetone)_®; Toh: toluene; Cui: cuprous iodide; EA: ethyl acetate; RT: room temperature; DIPEA: N-diisopropylethylamine; _SOC12 : sodium chloride; TFA: trifluoroethylamine

Step L Synthesis of 4-bromo-2-fluoro-6-methylbenzoic acid methyl ester (A1-2) 4-Na-2-chloro-6-methylbenzoic acid: A1-1 (1000 g, 4291 mmol) was dissolved in A1-4-dimethylformamide (100 ml _J ), iodomethane (12.18 g, 8382 mmol) and potassium carbonate (17.79 g_ 12874 mmol) were added, and the reaction was stirred at 80°C for 1 hour. 200 mL of water was added to the reaction, and the mixture was extracted with ethyl acetate (3 (X) mL*3), and the organic phases were combined, washed twice with water, washed once with saturated brine, and then dried and concentrated to obtain 10.20 g (crude product) of yellow oil A1-25, which was used in the next step.

ES1-MS: m/z = 247.0 [M+H].

^? H NMR (400 MHz, DMSO-a ₆ ): 57.56 (dd, J. - 9.6 Hz, J ₂ = 2.0 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H), 3.88 (s, 3H), 2.34 (s„ 3H). Step & Synthesis of 4-bromo-2-(bromomethyl)-6-fluorobenzoic acid methylbenzene (A1-3) A1-2 (10.20 g, 4128 mmol) was dissolved in carbon tetrachloride (100 inL), N-bromosuccinimide (8.08 g, 45.41nM Bd) and azobisisobutyronitrile (677.95 mg, 4.13 mmol) were added, and the reaction was stirred at 85°C for 3 hours under nitrogen protection. The reaction solution was dried by rotary evaporation, the residue was dissolved with petroleum ether, filtered, and the filtrate was dried by rotary evaporation to obtain 13.5 g (crude product) of A1-3.

ESI-MS: ro/z = 325.0, 327.0 [M+H]L Step 3: Synthesis of (S)-5-bromo-2-(1-cyclopropylethyl)-1-fluoroisoindole-1-one (vinyl) 41-3 (13.05 _& 40.04 mmol) was dissolved in acetonitrile (120 ml.). (S)-1-cyclopropylethane-1-amine hydrochloride (4.87 g, 40.04 mmol), boric acid (49509 mg, 801 mmol) and potassium carbonate (1660 g, 12011 mmol) were added, and the mixture was stirred at 85°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100 mL of ethyl acetate and washed once with water and once with saturated brine, and then dried and concentrated. The residue was separated by column chromatography, and the eluent was . ～ 20% ethyl acetate petroleum aldehyde solution, 3.17g of common intermediate A& was obtained as a yellow shield I, and the total yield of the three steps of step 1 to step 3 was 26.3%.

将共用中间体 Al C3.17 g, 10.63 mmol) 浴于乙二醇二甲醍 (30 mLJ, 氮气置换三次后加入三甲基硅 烷醇钾 (4.09 g, 31. S)0 tnmoDo 7®合液加热到 85X：S拌 1小时。 反应液倒入 IM HC1 (30n±) 中， 用乙酸 乙醍 (30 nil, *3) 莘取， 有 •机相合并后水洗一次， 饱和食盐水洗一次， 干燥浓缩， 得到 3.00 g的共用中间 说 明 书 体 A2, 为红色海状物， 收率 952% o ESJ-MS: m/z = 2980 [M+Hi 2. Preparation of Common Intermediate (5)-5-it-2-(l-cyclopropylethyl)"-hydroxyisoindole (A2)

The common intermediate Al C3.17 g, 10.63 mmol) was bathed in ethylene glycol dimethyl ether (30 mL), replaced with nitrogen three times, and potassium trimethylsilane (4.09 g, 31.5 mmol) was added. The mixture was heated to 85°C and stirred for 1 hour. The reaction solution was poured into 1M HCl (30 mL), extracted with ethyl acetate (30 mL, *3), and the organic phases were combined and washed once with water and once with saturated brine, dried and concentrated to obtain 3.00 g of the common intermediate. Description: Book type A2, red sea-like substance, yield 952% o

步骤 1： (.5)-5-漠 -2-®环丙基乙基 *7.二氯甲氧基异明嗥一 1-酮 (A3) 的合成 将共用中间体 A2 (3.00g, 1013 mmol)溶于 W-甲基毗咯烷酮 (30 ml, ) ,加入 2 -氯 -2,2-二氟乙酸钠 ( 1.85 g, 12.16 nirnol) 和磷酸钾 (430 g, 2026 irmiol), 混合液加热到

搅拌 1小时。 反应液冷至室温， 倒入 2 M HC1 (40 ml.) 中， 用乙酸乙酯 C30mI. *3)萃取， 有机相合并启用水洗两次后用无水硫酸钠干燥， 过滤 浓缩。 残留物用柱层析分离， '洗脱剂 0-10%乙酸二酷的石沌觥溶液， 得到 1.50 g的共用中间体 A3, 为淡 黄色固体， 收率 429% » ES1-MS: m/z = 296.0 3. Common intermediate (S>5

Step 1: Synthesis of (5-bromo-2-(cyclopropyl)ethyl)-7-(dichloromethoxy)isoquinoline-1-one (A3) Dissolve the common intermediate A2 (3.00 g, 1013 mmol) in N-methylpyrrolidone (30 ml, ), add sodium 2-chloro-2,2-difluoroacetate (1.85 g, 12.16 nirnol) and potassium phosphate (430 g, 2026 irmiol), and heat the mixture to 40 ℃.

Stir for 1 hour. The reaction solution was cooled to room temperature, poured into 2 M HCl (40 ml.), extracted with ethyl acetate (30 ml. *3), the organic phases were combined, washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography, with the eluent being 0-10% diacetate in sodium hydroxide solution, to obtain 1.50 g of common intermediate A3 as a light yellow solid, with a yield of 429%. »

ES1-MS: Wz -3460 [M+H]L

将共用中间体 A3 ( 1.50 g, 433 mmol) 溶于 1,4 -二氧六环 ( 15 inL) 中， 加入联硼酸频那醇酯 (1.32 g, 5.20 mmol). [撰 -双 (二苯基磷)二茂铁]二氯化窄巴 (157.22 ing₅022 mmol ) 和酯酸钾 ( 128 g, 13. (X) mmol), 反应在氮气保护下于 100 -Cg拌 1小时. 反应液减压浓缩除去溶剂， 残留物经柱层析分离， 冼脱剂 070% 乙酸乙酯的石油醍溶液， 得到 1.70g的共用中间体联 L 为米白色固体， ^^99.4%. 'H NNIR (400 WIz, DMSO-40: 8776 (s, 1H), 7.61 (■, J = 74.4 Hz, 1H) _, 748 (s, IHj, 455 (s, 2H), 3.56-3.49 (m, 1H ), 1.27 (d, J=6.8 Hz, 3H)„ 1 13-1.06 (m, 1H), 0.58-0.53 (m ₌ 1H).0.43-034 (m, 2H).025-0.20 (m, 1H) _C

The common intermediate A3 (1.50 g, 433 mmol) was dissolved in 1,4-dioxane (15 inL), and diboric acid pinacol ester (1.32 g, 5.20 mmol) was added. The reaction mixture was stirred at 100 °C for 1 hour under _nitrogen protection. The solvent was removed by concentration under reduced pressure, and the residue was separated by column chromatography, and the deionizing agent was 070% ethyl acetate petroleum nitrile solution to give 1.70g of a common intermediate link L as an off-white solid, ^^99.4%.

ESI-MS: in/z = 394.0 [M+H　°

将 A4-2 (6.10 g, 20.57 mmol)溶于 MM二甲基甲酰胺 ( 10 mL. ) 中 , 加入碳酸钾 (4.27 g, 3086 mmol ) 室温搅拌 5分钟. 加入碘甲烷 (438 g, 30.86 mmo!) , 体系室温搅拌过夜。 反应液加水淬灭， 用乙酸乙酯 萃取三次 (20 mL*3) ， 合并有机相， 有机相水洗三次 (20ffiL*3) ， 饱和食盐水洗一次 (50mL) , 无水 硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物经柱层析纯化， 洗脱剂为 7%乙酸乙酯的石油酰溶液， 得到 60 g KJ A4-3, 黄色固体， 收率 93.3% o ^] 11 miR (400 N HIz, DMSO- J ₆ ): 7.74 fs, 1H), 156 (t, J = -74.4 Hz, ill), 736 (s, HI), .4.55 (s _; 2II), 357-3.50 (m„ 1H) _? 1.32 (s, ]2H), 1.28 (d, J = 68 Hz, 311), 1.12-1.08 (nr 1H) _; 0.61-0.53 (m, 1H), 0.43-033 (m, 2H), 0.25-0.18 (m, TH). Preparation of the five% common intermediate (3) 1-chloro-2" (1-cyclopropylethyl) 7-isoquinoline ketone (A4) manual

A4-2 (6.10 g, 20.57 mmol) was dissolved in MM dimethylformamide (10 mL.), potassium carbonate (4.27 g, 3086 mmol) was added and stirred at room temperature for 5 minutes. Methyl iodide (438 g, 30.86 mmol) was added and the system was stirred at room temperature overnight. The reaction solution was quenched with water, extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, washed with water three times (20 mL*3), washed with saturated brine once (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 7% ethyl acetate in petroleum ether solution, and 60 g KJ A4-3 was obtained as a yellow solid with a yield of 93.3%.

ESI-MS: 1H/Z =： 311.0 [M+H]" o

和碳酸钾 (1.06 g, 7.70 mmol) 潘于乙腊 (10 mL) 中， 升温至 60°C i%应 1小时。 混台物冷却至室温后加 水淬灭， 用乙酸乙酯萃取二次 ( 20mL*3：) , 合并有机相， 有机柜水洗一次 (20mL/> ， 饱和食盐水洗 ( 50 mL ) , 无水硫酸钠干燥， 过滤。 滤液减压浓缩。 残宙物经柱层析纯化， 洗脱剂为 LS%乙酸乙酯的石沌醴 溶液， 得到 300 mg的共用中间体 A4, 为黄色同体, 收率 32.3%。 ^; H NMR (400 MHz, DMSO-</ ₆ ) 8781 (dd, A =2.0 Hz, J ₂ = 0.8 Hz, 1H), 7.46 (dd, .71 -2.0 Hz, J ₂ = 0.8 Hz, 1H), 3.87 (s, 3H), 2.25 (t, J -0.8 Ilz, 3H) Step 3: Synthesis of 2-methyl-4-chloro-4-iodobenzoic acid methyl ester (A4-4) A4-3 (6.0 g, 1932 mmol), succinimide (6.19 g, 34.78 mmol) and dibenzoyl peroxide (317 mg, 1.93

and potassium carbonate (1.06 g, 7.70 mmol) in acetonitrile (10 mL), heated to 60°C for 1 hour. After the mixture was cooled to room temperature, it was quenched with water and extracted twice with ethyl acetate (20 mL*3), the organic phases were combined, washed once with organic water (20 mL/>, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was 16% ethyl acetate in sodium hydroxide solution, and 300 mg of common intermediate A4 was obtained as a yellow isomer with a yield of 32.3%.

ESI-MS: m/z = 362.0

和碳酸钾 (1.8 g, 13.05 mmol) 溶于乙 (10ni) 中， 升温至 6(VC反应 2小时 ■。 混合物冷却至室温后加 水淬灭， 用乙酸乙酯萃取三次 ( 20mL*3\. fir并有机相， 有机相水洗三次 ：20inL*3), 饱和食盐水洗〈20 mL), 无水硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物经柱层析纯化 . 洗脱剂为 65% 乙酸乙酯石油醮溶 液， 得到 ISOmg (粗品) 的共用中间体 A& 为油状物， 步骤 2〜步骤 4的三步反应总收率为 150%_o ^! H NMR (400 MHz, DMSO-J ₆ ): 67.98 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, iH), 4.46 (s, 2H), 3.59-3.52 (ns, HI), 1.27 (d, J - 6.8 Hz _; 3H), 1.16-106 (m, 1H), 061-0.53 (m, ITT), 043-0.34 (m, 2H) _; 025-0.16 (m, HI). Description VI. Common intermediate (5>4,6-dichloro-2-(1-cyclopropylethyl)-2-dihydro-3-pyrrolo[3*]pyrrolidine-3-one (A5) preparation

and potassium carbonate (1.8 g, 13.05 mmol) were dissolved in ethyl acetate (10 mL), heated to 60 °C and reacted for 2 hours. The mixture was cooled to room temperature and quenched with water, and extracted three times with ethyl acetate (20 mL*3\. The organic phase was washed with water three times: 20 mL * 3), washed with saturated brine (<20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography. The eluent was 65% acetic acid. ethyl ester petroleum dilution solution, to obtain 180mg (crude product) of the common intermediate A& as an oily substance, the total yield of the three-step reaction of step 2 to step 4 was 150% _.

ESI-MS: .n/z -2710

说 明 书

将共用中间体 A5 ( 100 mg, 0.37 mmoD^ 吗嘟 (48 mg, 0,53 mmol) 和三乙胺 (56 mg, 0.53 mmol) 溶 于 A/-二甲基甲酰胺 (3 mL) 中. 升温至 60°C反应 2 Z寸。 混合物冷却至室温后加水 (15 mL)淬灭. 用 乙酸乙酯莘取三次 (10 ml *3), 合并有机相， 有机相水洗三次 (i0 mL*3), 饱和食盐水 (10 mL), 无 水硫酸钠干燥， 过滤。滤液减压浓缩 , 残留物经制备薄层色谱纯化， 展开剂为的％的乙酸乙酯石油醍溶液, 得到 66 mg的共用中间体 A6, 为浅绿色油状物， 收率 55.9%.. ^! H NMR (400 MHz, DMSO-J ₆ ): 8789 (s. 1H), 462 (s, 2H) 358-351 (m, 1H) 127 (d, J = 68 Hz, 3H), 1.16- 1.07 ( iih 1H), 0.61-0.54 (in, HI), 044-035 (m, 2H), 026-019 (m, old).

manual

The common intermediate A5 (100 mg, 0.37 mmol), morpholine (48 mg, 0.53 mmol) and triethylamine (56 mg, 0.53 mmol) were dissolved in dimethylformamide (3 mL). The temperature was raised to 60°C and the reaction was continued for 2 hours. After the mixture was cooled to room temperature, water (15 mL) was added to quench. The mixture was extracted with ethyl acetate three times (10 ml * 3), the organic phases were combined, and the organic phases were washed with water three times (10 mL * 3 ), saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography using 1% ethyl acetate petroleum ether solution as the developing solvent to obtain 66 mg of the common Intermediate A6 is a light green oil with a yield of 55.9%.

ESI-MS: m/z =<<220 [M+H

步骤 L 1 ■■甲基 -3-(4 -甲基嚷隆 -2 -基)腺 (B S ) 的合成 将 2.-氨基 4甲基嚓哩盐酸盐 : BM (LOg, 6.69 mmol) 溶于二氯甲烷 ( lOniLj 中. 滴加三乙胺 (17 g, 1696 mmoi )> 室温搅拌 15分钟。 -于冰浴下加入甲，胺基甲酬氯 (745 -ng, 7.97 nimo] ) 升温至 4CTC反应 2 小时。混合物冷却至室温后加水淬灭， 用二氯甲烷莘取二次 (20血,约)，合并有机相，有机相水洗 .二次 (2() rnl^S ), 饱和食盐水洗 (20 mL), 无水硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物经柱层析纯化， 洗脱剂 为 50%乙皎乙酉旨的石油 §4'溶液， 得到 402 mg的共用中间体 B1, 为白色囹体， 吸率 35.3%o ^! H NMR (400 MHz, DMSO- ₎ : δ 706 (s „ 1H), 4.48 (s, 2H), 3.72-3.tS5 (m, 8H). 3.57-3.46 (m, 1H), 123 (d _; J -68 Hz, 3HX 1 11-102 (m, 1H) _; 058-042 (m, 1H), 040-030 (m, 2H), 023-017 (m, 1H) « VIII. Preparation of Common Intermediate 1-Methyl-3(4-methyl-2-yl)-2-yl)-2-nitropropene (B0

Step L1 Synthesis of methyl-3-(4-methylpurine-2-yl)hydrazone (BS) 2.-Amino-4-methylpurine hydrochloride: BM (10 g, 6.69 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (17 g, 1696 mmol) was added dropwise and stirred at room temperature for 15 minutes. Methylaminomethyl chloride (745 ng, 7.97 mmol) was added under ice bath and the temperature was raised to 40°C for reaction for 2 hours. The mixture was cooled to room temperature and quenched with water, extracted twice with dichloromethane (20 mL, about 10 mL), the organic phases were combined, washed with water twice (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent was a 50% ethyl acetate solution in petroleum ether, 402 mg of common intermediate B1 was obtained as a white solid with an absorbance of 35.3%.

ESI-MS: Bi/z = 172.0 [M-

步骤 L 卜(&漠 4甲基嚷陛 O基 )3甲基腿 (B2) 的合成 将 5..M-4 -甲基 BP^-2 -胺：： B24 (1.92 g, 10.0 mmol)溶于二氯甲烷 ( lOmL), 加入三乙胺 (2.02 & 20.00

II NMR (400 MHz _; DMSO-J ₆ ): d 10.36 (s, irlj, 6.53 ( _{q ;} ^J- 12 Hz _; iH), 6.41 (d, J = 4.8 Hz _; IHj, 2.67 (d, J = 4.8 IIz, 311), 2.18 (d, J- 1.21 Iz, 311). IX. Preparation of Common Intermediate Compound 1"(5-'';^-4"methylhexyl)-3-methylhydrazone (B2)

Step L Synthesis of 1-(4-bromo-4-methylthiazol-2-yl)-3-methylbenzyl (B2) Dissolve 5-(4-methyl-2-pyridine-2-amine B24 (1.92 g, 10.0 mmol) in dichloromethane (10 mL), add triethylamine (2.02 g, 20.00 mmol) and 4-(4-bromo-4-methylthiazol-2-yl)-3-methylbenzyl (B2) into a 5-(4-bromo-4-methylthiazol-2-yl)benzyl (B2) and stir until the mixture is quenched.

步骤 n (4-甲基嚷哩 -Z-基)氮基甲酸叔丁酯 (B3-2) 的合成 将如氨基 -4 -甲基圈％ B3-1 (60 g_; 52.56 mmel)浴于二氯甲烷 i lOOmL)中，加入三乙胺 (5.32 g, 52.56 mmol )和 4 -二甲氨基毗跳 (642 mg, 5.26 mmol), 室温搅拌 15分钟。冰浴卜加入二碳酸二叔「酯 ( 13.76 g,

ESI-MS: ni/z = 250.0[lvRHf\ 10. Preparation of common intermediate (4-methyl-5-(tributyltinyl)benzene-2-yl)carbamic acid tert-butyl ester (B3) manual

Step n Synthesis of tert-butyl (4-methylpurine-2-yl)carbamate (B3-2) Dissolve 4-methylamino-2-nitropropene B3-1 (60 g _; 52.56 mmol) in dichloromethane (100 mL), add triethylamine (5.32 g, 52.56 mmol) and 4-dimethylaminopyridine (642 mg, 5.26 mmol), and stir at room temperature for 15 minutes. Add di-tert-butyl dicarbonate (13.76 g, 5.26 mmol) in an ice bath.

步骤 L ◎-漠 -4 -甲基嚷哩- 2 -基｝氨基甲骏甲酯 (B4-2) 的含成 将 5 -溟 4甲基嚷哩 2胺： B4-K1.92 g, 10.00 mmol)溶于二氯甲烷 (lOroL).加入三乙胺 (2.02 & 20.00 mmol), 冰浴下滴加氯甲酸苯 Bn (1.88 g, 12.00 mmol), 室温下反应 2 h。反应结束后， 加水 (30 mL)淬灭, 用二氯甲烷萃取两次 (10 mL*2), 随后用饱和食盐水 ( 30 mL) 洗涤, 合并有机相， 浓缩后得到 2.47 g的 B3-2, 黄色固体， 收率 792%。 EST-MS: m/7 = 5050 XI. Common intermediate (5

Step L Preparation of 5-bromo-4-methylthiocyanate (B4-2): Dissolve 5-amino-4-methylthiocyanate (B4-1) (1.92 g, 10.00 mmol) in dichloromethane (100 mL). Add triethylamine (2.02 g, 20.00 mmol), add chloroformic acid benzene (1.88 g, 12.00 mmol) dropwise under ice bath, and react at room temperature for 2 h. After the reaction, add water (30 mL) to quench, extract with dichloromethane twice (10 mL*2), then wash with saturated brine (30 mL), combine the organic phases, and concentrate to obtain 2.47 g of B3-2 as a yellow solid with a yield of 792%.

将 B4-2 ( 265 mg, 0.85 mmol )溶于甲醇 ( lOmL), 随后加入甲醇钠 (92 mg, 1.71 mmol), 60°C下反应 I h. 反应结束后， 降至室温， 向反应液中加入 30 ml 乙酸乙酯, 随后用饱和食盐水 (30 mL*3) 洗三次反 应液， 合并有机相， 浓缩后残留物绿柱层析纯化， 洗脱剂为 3〜 12%乙酸乙酯的石油酸溶液， 得到 20] mg 的共用中间体 84, 为白色固体， 收率 94.7%, ESI-MS: m/z = 31.3.0, 315 Step A ◎-O-4-methyl-silanol

B4-2 (265 mg, 0.85 mmol) was dissolved in methanol (10 mL), and then sodium methoxide (92 mg, 1.71 mmol) was added. The reaction was carried out at 60°C for 1 h. After the reaction was completed, the temperature was cooled to room temperature, 30 ml of ethyl acetate was added to the reaction solution, and then the reaction solution was washed three times with saturated brine (30 mL*3). The organic phases were combined and concentrated, and the residue was purified by green column chromatography. The eluent was 3-12% ethyl acetate in petroleum acid solution to obtain 20 mg of common intermediate 84 as a white solid with a yield of 94.7%.

说 明 书

步骤 L (叔丁氧演基 )(4 -甲基嚷嗪 2 -墓)氮基甲酸叔丁酯 (C1-1) 的合成 将 BM ( 10 g, 876 mmol) 溶于四氢味隔 ( 10 mL ), 随后加入二碳酸二叔丁酯 (478 & 2190 mmol), 碳酸钠 (2.32 g, 21.90 mmol)和 4 -二甲氨基毗呢 ( 107 mg, 0.88 mmol), 60°C下反应 1 h。 反应结束后, 降 至室温， 向反应液中加入 30 mL乙酸乙酯， 随后用饱和食盐水 (3CimL*3) 洗三次反应液， 合并有机相， 浓缩后残留物经柱层析纯 剂为 (7%乙酸乙酯的石油醴溶液， 得到 297 g的 05. 为油状物粗品。 ES1-MS: m/z = 25 i.0, 253.0 [M+Hf ₀

manual

Step L Synthesis of tert-butyl (tert-butyloxy) (4-methylpurine-2-nitro)carbamate (C1-1) Dissolve BM (10 g, 876 mmol) in tetrahydrofuran (10 mL), followed by the addition of di-tert-butyl dicarbonate (478 & 2190 mmol), sodium carbonate (2.32 g, 21.90 mmol) and 4-dimethylaminopyridine (107 mg, 0.88 mmol), and the reaction was continued at 60°C for 1 h After the reaction was completed, the temperature was lowered to room temperature, 30 mL of ethyl acetate was added to the reaction solution, and then the reaction solution was washed three times with saturated saline (3CimL*3), the organic phases were combined, and the residue was purified by column chromatography after concentration. (7% ethyl acetate in petroleum liqueur solution to give 297 g of 05.5 as a crude oil.

基 )(叔丁氧貌基)氮基甲酸叔丁酯 (C1-2) 的合成 将 C1-1 (10 g, 3.18 mmol) '溶于？ 4*二甲基甲酰胺 ( 10 mL), 随后加入 N-潺代丁二酰亚胺 (623 mg, 3.50 minol), (：＞°C反应 1 h。 反应结束后， 加水淬灭 (30 inL), 随后反应液用乙酸乙酯 OO mL*3) 萃取三 次， 合并有机相， 浓缩后残留物经柱层析纯化， 洗脱剂为 〜 5%乙酸乙酯的石油酰溶液， 得到 9()。 mg的

成 ESI-MS: in/z = 315.0 Step 2: (5 • Bromo-4-methyl

Synthesis of tert-butyl)(tert-butyloxy)carbamate (C1-2) C1-1 (10 g, 3.18 mmol) was dissolved in 4-dimethylformamide (10 mL), followed by the addition of N-hydroxysuccinimide (623 mg, 3.50 minol), and the reaction was carried out at (:＞°C for 1 h. After the reaction was completed, water was added to quench (30 μL), and then the reaction solution was extracted three times with ethyl acetate (200 mL*3), the organic phases were combined, concentrated, and the residue was purified by column chromatography, the eluent was 5% ethyl acetate in petroleum ether solution, and 90 mg of

become

W C1-3 (287 g, 4.95 mmol) was dissolved in dichloromethane (20 mL), and then trifluoroacetic acid (5 mL) was added, and the reaction was allowed to react overnight at room temperature. After the reaction was completed, water (30 mL) was added to quench, and then the reaction solution was extracted with dichloromethane (30 mL*2), the organic phases were combined, concentrated, and the residue was purified by column chromatography, the eluent was (0.1% to 5% methanol in dichloromethane solution, and 1.85 g of C?-4 was obtained as a yellow isomeric product with a yield of 984%.

ESI-MS: in/z = 380.0

^] H NMR (400 MHz, DMSO-d' _s ): 88.47 (s.2H), 7.62 (t, J= 74.8 Hz, 1H), 7.51 (d, J - 1.2 Hz, 1H), 7.17 Is, 1H) , 458 (s, 2H), 3.59-3.52 (m, 1H), 2.29 (s, 3H), 128 (d, J = 6.8 Hz, 3H), 1 15-1.07 (M 1H), 0.60-0.53 (m, 1H), 0.44-0.35 (m, 2H), 0.26 -0.20 (m, 1H). Step 5: (S)-(5-(2-(1 ... Synthesis of phenyl formate (C1) Dissolve C1-4 (500 mg, 1.32 inmol) in dichloromethane (20 mL), then add triethylamine (200 mg, 1.98 mmol) and phenyl chloroformate (248 mg, 1.58 mmol) and react at room temperature for 1 hour. After the reaction was completed, water was added to quench the reaction. The reaction solution was then extracted with dichloromethane (30 mL"), and the organic phase was combined. The residue was concentrated and purified by column chromatography using 0-5% methanol in dichloromethane as the eluent. Methane solution, 350 rng of the common intermediate was obtained as a white solid, with a yield of 532%.

步骤 ]： 4漠 -2-(漠甲基 )-6 -甲基苯甲酸甲酶 (1-1-2) 的合成 将 4 -漠 -2,6 -二甲基苯甲酸甲酯： 1-1-1 (1.21 g, 5.00nmiol) 溶于四氯化碳 ( lOniL) 中， 加入游漠代丁 二酰亚胺 ( i .07 g, 6.00mra<sl)和偶氮二异丁膀 (84 mg, 0.50 tnrael), 反应在氮气保护下于招 °C搅拌 4小时 \ 反应液旋干， 残睡物用用石浊醪 滤液旋干， 得到 1.71 g (粗品)

1-1-2 o ESI-MS: m/z = 500.0 [M+H「L

Step]: Synthesis of 4-bromo-2-(bromomethyl)-6-methylbenzoate (1-1-2): 4-bromo-2,6-dimethylbenzoic acid methyl ester: 1-1-1 (1.21 g, 5.00 nmiol) was dissolved in carbon tetrachloride (10 nmiL), and bromosuccinimide (i.07 g, 6.00 nmiol) and azobisisobutylene (84 mg, 0.50 nmiol) were added. The reaction was stirred at 4 ° C for 4 hours under nitrogen protection. The reaction solution was dried by rotary evaporation, and the residual product was dried by rotary evaporation with the filtrate to obtain 1.71 g (crude product).

1-1-2 o

ESI-MS: m/z = 320.0, 3220 Step 5 -5-hydroxy-2-(2-Q-cyclopropyl)isopropyl

0 ml,)

651 mg, 536 mmol ) 硼酸 (66 mg, 107 mmol ) 和碳酸钾 (370 g, 2680 mmol), 混合物于& 5°C搅拌 15小时。 反应混合

机相水洗三次 ( 10 mL*3), 饱和食盐水洗 ( 20 ml> ) < 尢水硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物用全 制备液相色谱仪纯化， 得到目标化合物 1-1 o W 1-1-2 (17! g _: 536 mmol)

0 ml,)

651 mg, 536 mmol) boronic acid (66 mg, 107 mmol) and potassium carbonate (370 g, 2680 mmol), the mixture was stirred at & 5 ° C for 15 hours.

The organic phase was washed with water three times (10 mL*3), washed with saturated brine (20 ml>), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by full preparative liquid chromatography to obtain the target compound 1-1.

说 明 书

合成 目标化合物 i-3的制备参考目标化合物 1-1制备方法中的步骤 3,仅将中间 # 1-1-3替换为中间体 1-3-1, 其余制备方法不变， 得到目标化合物 1-3 o ESI-MS: .rt/z = 385.0 [M+cho.

manual

Preparation of the target compound i-3 Referring to step 3 in the preparation method of the target compound 1-1, only the intermediate #1-1-3 is replaced by the intermediate 1-3-1, and the rest of the preparation method remains unchanged to obtain the target compound 1 -3 o

将共用中间体 A2 (295 mg, 1.00 mmol) 溶于乙睛 (5mL), 加入碳酸钾 ( 276 mg, 2.00 mmol)和碘甲 烷 (170 ma„ 1.2 mmol), 反应在 50X?搅拌 4小时。 反应加水 20mL, 用乙酸乙酯 (15 i；iL*3) 萃取， 合并 282 mg

ESI-MS: m/z = 456.0 [M+N] Instruction manual 4s ( ₁ V)-1-(5-(2-(1-3>F propylhexyl)-7 ■■ methoxy-1-oxoisopropylmethyl)-4-methyl-1-yl)-3-methyl-1-C 1-4 )

The common intermediate A2 (295 mg, 1.00 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (276 mg, 2.00 mmol) and iodomethane (170 mg, 1.2 mmol) were added, and the reaction was stirred at 50°C for 4 hours. 20 mL of water was added to the reaction, and the mixture was extracted with ethyl acetate (15 mL*3) and 282 mg of the product was obtained.

ES1-MS: m/z = 310.0 Step 2 Synthesis of _S (S)-1-(5-(2-(1-cyclopropylethyl-7-methoxy-1-oxoisoindole)-4-methyl)-3-methylbenzene (1-4) Preparation of target compound 1-4 Reference target compound: In step 3 of the preparation method, only the intermediate 1-1-3 is replaced by the intermediate 1-4-1, and the rest of the preparation method remains unchanged to obtain the target compound 1-4 _.

步骤 1: (S)-l-( 5-(2-(1-环丙基乙基 )-7 -二氟甲氧基 氧代异哩噪麟冬基 )4甲基嚏哩 -2 -基 )-3 -甲基腺 (1-5) 的合成 目标化合物 1-5的制备参考目标化合物 1-1制备方法中的步骤 3, 仅将中间佐 1-1-3替换为共用中间体 A3, 其亲制备方法不变， 得到目标化台物卜5, 为白色固体， 收率 182%» „

, J₆):810.74 (s, HI), 7.63 (t J=== 748IIz, 1H), 752 (s, HI), 7.19 (s, 1H), 656 (s, HI), 4.59 (s, 2H)_; 359-3.51 (tn, UT)_S 270 (d_s J=44 Hz, 3H), 235 (s, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.14-108 (m, 1H)_: 0.60-0.55 (m₅1H), 044-0.35 (m 2H), 0.27-022 (m, 1H),

说 明 书

将 1-6-1 (840 mg, 277 nimoD溶于二氧六环 (iOn±) 中， 滴加 3 N的盐酸水溶液， 室温搅拌 1小时。 混合物加水淬灭， 用饱和碳酸氢钠调节什「为 6〜7, 用乙酸乙酩萃取二次 Q0mI?3) , 合并有机相， 有机 相水洗一次 ( 20mL) , 饱和食盐水洗 (50niL) , 无水硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物经柱层 析纯化， 洗脱剂为〕 5%乙醪乙酯的石油醍溶液， 得到 836 mg (粗品) 的 1-6-2, 为黄色固体 ° ES1-MS: m/z = 40 i.0 [M+H]. Example 5. Preparation of (S>1-(5-(2-(1-propylethyl)-7-diazomethoxy-1-oxoisoindol-1-yl-1-methylthiazole-2-yl)-3-methylhydrazone (1-5)

Step 1: Synthesis of (S)-1-(5-(2-(1-cyclopropylethyl)-7-difluoromethoxyoxoisoindolyl)-4-methyl-2-yl)-3-methylhydrazine (1-5) Preparation of target compound 1-5 Referring to step 3 in the preparation method of target compound 1-1, only intermediate 1-1-3 was replaced by common intermediate A3, and the preparation method remained unchanged to obtain target compound 1-5 as a white solid with a yield of 182%.

, J ₆ ): 810.74 (s, HI), 7.63 (t J=== 748IIz, 1H), 752 (s, HI), 7.19 (s, 1H), 656 (s, HI), 4.59 (s, 2H) _; 359-3.51 (tn, UT) _S 270 (d _s J=44 Hz, 3H), 235 (s, 3H), 1.28 (d, J=6.8 Hz, 3H), 1.14-108 (m, 1H) _: 0.60-0.55 (m ₅ 1H), 044-0.35 (m 2H), 0.27-022 (m, 1H),

manual

1-6-1 (840 mg, 277 nimol) was dissolved in dioxane (10 mL), 3 N aqueous hydrochloric acid solution was added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water, the pH was adjusted to 6-7 with saturated sodium bicarbonate, and extracted twice with ethyl acetate (20 mL/min), the organic phases were combined, the organic phases were washed once with water (20 mL), washed with saturated brine (50 niL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, the eluent being 15% ethyl acetate in petroleum ether solution, to obtain 836 mg (crude) of 1-6-2 as a yellow solid.

\ ESI-MS: m/z = 278.0

\

残留物经柱层析纯化， 洗脱剂为 20%乙酸己酯的石油酰溶液， 得到 540 mg的 R-3, 为黄色固体， 三步反 应总收率 61.1%, ^; 11 NN4R (400 WIz, DMSO-</ ₆ ): 87.83 (d. J- 2.0 Hz, iH), 746 (d, J- 2.0 ITz.. 1H), 4.60 (s, 2II), 358-3.51 ( m„ IH), 2.63 (s, 3H), 128 (d, J - 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-053 (in. 1H\ 0.43-036 (m, 2¥l),

The residue was purified by column chromatography using a 20% hexyl acetate solution in petroleum ether as the eluent to obtain 540 mg of R-3 as a yellow solid. The total yield of the three-step reaction was 61.1%.

将 L6-3 (250nig_? 0.85 rnmo]) 、 共用中间体明 Q19 mg. L28 mmol) 、 醋酸耙 ( 19 rng.0.17 imnol) 、 正丁基二 ( 1 •金刚烷基)麟 (61 mg, 0.17 mmol )和氟化锥 (259 mg, \ .70 mmol ) 溶于 N,N ■二甲基甲酬胺 ( 2 raL ) 中，氮气鼓吹 30秒， 90%微波反应 [小时。混合液冷却至室温后加水淬灭，用乙酸乙酯萃取二次 (SmL*3), 合并有机相， 有机相水洗三次 (20n]L^3) , 饱和食盐水洗一次 (50mL) ， 无水硫酸钠干燥， 过滤。 滤液 减压浓缩 "残留物经制备薄层色谱绳化， 洗脱剂为 70%乙酸乙酯的石油醍溶液， 得到 5.0 mg的目标化合物 1-6, 为黄色固体， 假率 L4%o ES1-MS: nVz = 294.0 [M+H]L

L6-3 (250 mg _, 0.85 mmol), common intermediate amine (19 mg, 1.28 mmol), pyridine acetate (19 mg, 0.17 mmol), n-butyldi(1-adamantyl)phosphine (61 mg, 0.17 mmol) and fluorinated amine (259 mg, 0.70 mmol) were dissolved in N,N-dimethylformamide (2 mL), nitrogen was blown for 30 seconds, and microwave reaction was performed at 90% for 1 hour. After the mixture was cooled to room temperature, it was quenched with water, extracted twice with ethyl acetate (8 mL*3), the organic phases were combined, washed three times with water (20 mL^3), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography using a 70% ethyl acetate solution in petroleum ether as the eluent to obtain 5.0 mg of the target compound 1-6 as a yellow solid with a yield of 1.4%.

说 明 书

化钮 (19 mg.0.03 inmol) 和碳酸艳 (342 mg_, 1.05 imnol) 溶于二氧六环 /水 ( 10 niL/1 mL) 的混合溶剂中, 氮气置换三次， 90°C反应 2小时。 混合液冷却至室温后加水淬灭， 用乙酸乙酯萃取三次 (20inI^3) , 合 并有机相 "有机相水洗一次 ＜20mL) ， 饱和食盐水洗一次 (50mL) , 无水硫酸钠干燥， 过滤。 滤液减压 浓缩。残留物经制备薄层色谱纯化， •冼脱剂为 4%甲醇的二氯甲烷溶液， 得到 5.(( ing的目标化合物 47, 为 白色固体， 步骤 2与步骤 3两步反应总收率为 24% ₁： ESI-MS: -n/z = 429.0

manual

Palladium (19 mg, 0.03 inmol) and cesium carbonate (342 mg _, 1.05 imnol) were dissolved in a mixed solvent of dioxane/water (10 niL/1 mL), replaced with nitrogen three times, and reacted at 90°C for 2 hours. The mixed solution was cooled to room temperature and quenched with water, extracted with ethyl acetate three times (20 inI^3), the organic phases were combined (the organic phase was washed once with water <20 mL), washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography, the eluent was 4% methanol in dichloromethane solution, and the target compound 47 of 5.((ing) was obtained as a white solid. The total yield of the two-step reaction of step 2 and step 3 was 24% ₁ :

说 明 书

步骤 L 1宓丙基 3(4 -甲基瘗哇 -2 -基漏ESLMS: nv'z = 396.0 [M+H H NMR (400 MHz, DMSO-r/ ₆ ): 510.77 (s, 1H), 7.95 (s, 211), 655 (s, III), 464 (s, 2H), 3.62-3.55 (m, 1H), 270 (d, J = 44 Hz. 3H), 2.36 (s. 3H), 1.31 (d _; J = 6.8 Hz, 3H), 1.16-112 (m, 1H). 0.60-0.56 (m _; 1H), 0.45-0.39 (m, 2H), 028-023 (m, 1H)

manual

Step L 1: propyl 3 (4-methylpyrrolidone-2-yl)

依次加

# B1-1 ( 570 mg, 5.00 mmol ) was dissolved in tetrahydrofuran

Add

® (1-9) Synthesis The preparation of target compound A9 was carried out by referring to step 3 in the preparation method of target compound L4. Only the common intermediate 81 was replaced by intermediate

1-9-1, intermediate 1-1-3 was replaced by common intermediate A3 to obtain the target compound 1-9 =

ES1-MS: nVz = 463.0 [M+H] ⁺ o

ESI-MS: m/z -212 0 [M+H] Step 2s Synthesis of (S)-A"(5"(2"(1-propyl-difluoromethoxy-D-oxoisoxoyl)-4-methylthiophene)pyrrolidinecarboxamide Preparation of the target compound 140 Refer to step 3 in the preparation method of the target compound 1, except that the intermediate 8 is replaced by the intermediate

1-10-1, intermediate 1-1-3 is replaced by common intermediate A3 to obtain the target compound 1-10.

说 明 书

将共用中间体 AS (200 mg_? U.74 mmol)溶于 AW-二甲基甲酰胺。 mL ),加入 4 -甲基哌暧 ( 170 mg, 1 .48 mmol) 和三乙胺 ( 224 mg, 2.21 mmoD, 升温至 6U°C下反应 2 h。 反应结束后， 加水淬灭， 用乙酸乙酯萃 说 明 书

ES1-MS: m/z = 477.0 [M+H] -(difluoromethoxy-2-((2-((((trifluoromethoxy)-1,2-dioxoisoindole)-4 ...trifluoromethoxy)-1,2-dioxoisoindole)-4-(((trifluoromethoxy)-1,2-dioxoisoind

manual

The common intermediate AS (200 mg _, 1.74 mmol) was dissolved in 4-dimethylformamide (mL), 4-methylpiperidinium (170 mg, 1.48 mmol) and triethylamine (224 mg, 2.21 mmol) were added, and the temperature was raised to 6U°C for 2 h. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. manual

# H-1-1 (184 mg, 0.55 mmol) was dissolved in 1,4-dioxane (5 mL), and tert-butyl (4-methyl-5-(tris(2-methyltin)-2-yl)amine (415 mg, 0.82 mmol) and tetrakistriphenylphosphine lithium (63 mg, 0.11 mmol) were added to the mixture. The mixture was replaced with N-N- and microwaved at 120°C for 1 h. After the reaction was completed, the mixture was cooled to room temperature, and a 40% aqueous potassium fluoride solution (3 mL) was added to the reaction solution and stirred for 30 min. The mixture was extracted with ethyl acetate (30 mL*3), and the organic phases were combined. After concentration, the residue was purified by column chromatography, and the eluent was 1%~5% methanol in dichloromethane to obtain 6 mg of H-1-2 as a black oily substance with a yield of 21.3%. %o

将 n-i-2 (60 mg, 0.117 mmol)溶于盐酸-乙酸乙酯溶液中 ( 5 mL, 4M ) 中， 室温下搅拌 4 h。 反应结束 后， 浓缩去除盐酸和乙酸乙酯， 得到 S2 mg粗品的 H-1-3, 直接用于下一步。 ES1-MS: m/z = 513.0 [M+ Step 3: (S)-6-(2-Methyl-[3, 4-triazine-3-yl]-hydroxybenzoate (II-

Dissolve ni-2 (60 mg, 0.117 mmol) in hydrochloric acid-ethyl acetate solution (5 mL, 4M) and stir at room temperature for 4 h. After the reaction, concentrate to remove hydrochloric acid and ethyl acetate to obtain S2 mg crude product H-1-3, which is directly used in the next step.

ES1-MS: m/z = 413.0[M+]. Step 3 Synthesis of 3-(2-cyclopropylethyl)-4-(4-methyloxazine-L-yl)-3-oxo-2,3-dihydro-pyrrolo-4-pyrrolo&yl)-4-methylthiophene-2-yl)-3-methylhydrazone (114) The crude product of 3-II-1-3 obtained in the previous step was dissolved in dichloromethane (2 mL), and methylaminoformyl chloride (22 mg. 0.23 mmol) and triethylamine (SS rog/DJS mmol; . The reaction was carried out at room temperature. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by full preparative liquid chromatography to obtain 4 mg of the target product 11-1 i formate as a white solid. The total yield of the two-step reaction of step 3 and step 4 was 6.5%. o

ESL-MS: rn/z = 470 0[M+H] ⁺ .,

6.54 (d, J = 5.0 Hz, 1H), 4.50 (s, ^! H NMR (400 MHz„ DMSO-d ₆ ): 5 10.64 (s, ! H), 8.19 (s„ 1H), 7.16

6.54 (d, J = 5.0 Hz, 1H), 4.50 (s,

说 明 书

说 明 书

毗暧 基卜 4-甲基嚏哩 ~2・基 *3 -甲基腺 ( II-4 ) 的制备 说 明 书

20 mg的目标产物 II-4, 为白色固体， 步骤 3利 4两步 •反应总收率为 7.3%。 3.70 (s, 4H), 3.56-3.49 (m, 1H), 2.70 (d, J - 4.8 Hz, 3H), 2.52 (s, 3H), 2.49 (s, 4H), 2.24 (s, 3H), 1.24 (d, J - 6.8 Hz, 3H), 1.09-1.04 (m, 1H), 0.57-0.54 (m, 1H), 0.41-0.32 (m, 2H), 0.23-0.82 (ir, 1H). Example 13: (X(&(2-(1-propylethyl)-3-oxo-4-(2-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)-4-oxopyrrolidin-1-yl)-2,3-diazopyrrolidin-1-yl)- Preparation of 2-(2-methyl)-3-methylpyrrolidone (II-2)

manual

manual

Preparation of 4-methyl-2-amino-3-methylpyridinium (II-4) manual

20 mg of the target product II-4 was a white solid. The total yield of steps 3 and 4 was 7.3%.

ESLMS: nvz = 485.0[M-iH]\

说 明 书

说 明 书

不变, 得到 203 mg St; II-6-1 , zj黄色油状物, 收率 78.2%。 ^! H NMR (400 MHz, DMSO-zfc): 8 10.61 (s, 1H), 7. 16 (s, 1H), 6.48 (s, HI), 4.50 (s _; 2H), 4.48 -4.41 (m, 2H ), 3,73-3.66 (m, 2H), 3.56-3.52 (m, 1H), 2.70 (d, J = 4.4 Hz, 3H), 2.58^2.54 (m, 2H), 2.52 (s, 3H), 1.24 (d, J = 6.8 Hz, 3M), 1 14 (dd, J; = 6.0 Hz, J ₂ - 1.6 Hz _; 6H), 1.09-1 06 (m, 1H), 0.58-0.53 (m. 1H) ₅ 0 42-0.32 (m _s 2H), 0.25-0.20 (m, 1H). Example 16, pyridin-6-yl)-a-methyl

manual

manual

The reaction mixture was unchanged, and 203 mg St; II-6-1 was obtained as a yellow oil with a yield of 78.2%.

ESI-MS: n/z = 352 0[M+Hf . Step 2: Synthesis of tert-butyl ((1-cyclopropylethyl)-4-(4-(4-methyl)-3-oxo-2,6-dihydropyrrolo[3,4-e] Hit®-6-yl)-4 •methylbenzene-2-yl)carbamate (11-6-2) Referring to the synthesis of intermediate IM-2 in step 2 of Example 12, only intermediate IM-1 was replaced with II-6-L and the rest of the preparation method remained unchanged to obtain 220 mg of 11-6-2 as a black oil with a yield of 73.1%.

43 mg的目标产物 11-6, 为白色固体， 步骤 3和步骤 4两步反应总收率为 21.7%o ES1-MS: m/z = 530.0[M+r-Ij\

43 mg of the target product 11-6 was a white solid. The total yield of step 3 and step 4 was 21.7%.

ESi-MS: m/z = 487 0[M+H] ⁺ „

说 明 书

参考实施例 12中步骤 1 中间体？? -0的合成， 仅将甲基哌嗪替换成 4,5,6, 7 -四氢毗嚏并 [i_;5-A]lt嗪双 盐酸盐， 其余制备方法不变， 得到 270 mg的复 -74, 为黄色固体， 收率 51.5% ,,

参考实施例 12中步骤 3中间体 n」-3的合成， 仅将 IIM-2替换成 n-7-2, 其汆制备方祛不变， 得到的 粗品 H-7-3宜接用于下 -步。 ^? H NMR (400 MHz, DMSO-a ^? ₆ ): § 10 63 (s. 1H), 7.16 (s, 1H), 6.50 (d, J = 4.8 Hz, 1H), 4 50 (s, 2H), 4.20 (d, J = 13 2 Hz. 2H\ 3.55-3.50 (m, 1H), 3.26-3 23 (m. 2H), 2.70 (d. J = 4.8 Hz, 3H). 2.52 (s, 3H) _; 1 85-1.77 (m, 4H) _, 1.40 ( d, J = 22.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 3H), l. l li .06 (m, ]H), 0.57-0.53 <m, 1H), 0.41-0.33 (m, 2H), 0.25-0.21 (m, IH).

manual

Referring to the synthesis of intermediate ??-0 in step 1 of Example 12, only methylpiperazine was replaced by 4,5,6,7-tetrahydropyrido[i _; 5-A]ltazine dihydrochloride The rest of the preparation method remained unchanged, and 270 mg of compound-74 was obtained as a yellow solid with a yield of 51.5%.

Referring to the synthesis of intermediate H-3 in step 3 of Example 12, only IIM-2 is replaced by H-7-2, and the preparation method remains unchanged. The obtained crude product H-7-3 is preferably used directly in the following step. -step.

ES1-MS: m/z = 436.0 [M+II] Step 4 Synthesis of _S (^-1-(5-(2-(1-5F-propylethyl)-4-(6,7-dihydropyrimidine [L5-a] oxo-2#-dihydro-1H<pyrimidine 4-yl]-4-methylpyrimidine-2-yl)-3-methylhydrazone (II-7) Refer to the synthesis of the target compound 113 in step 4 of Example 12, except that 11-1-3# is replaced with II-7-3, and the rest of the preparation method remains unchanged to obtain 200 mg of the target product 11-7 as a white solid. The total yield of the two-step reaction of step 3 and step 4 is 18.8%.

ESi-MS: m/z = 493 0[M+H] ⁺ „

将氢化钠 (66 mg, 278 mmol) 加入到 2,2 -二氟乙烷 醇 ( 136 mg, 1.66 mmol) 中， 室温搅拌 15分钟, 随后滴入共用中间体 AS (300 mg, 1 11 mmoi) 的二氧六环潘液 (10 ml.), 体系升温至 60^c，C 应 2小时。 混合物冷却至室温后加水淬灭，用乙酸乙酯萃取三次 (20mL*3),合并有机相，臼机相水洗三次 (SmL*3), 饱和食盐水洗一次 (50 nsL),无水硫酸钠干燥，过滤。滤液减压浓缩，残留物经柱层析纯化，洗脱剂为 30% 乙酸乙酯的石油酰溶液， ^? H NMR (400 MHz, DMSO-^g): 5 10.65 (s, 1H), 7.43 (d, J = 2.0 Hz. 1H), 7.27 (s. 1H), 6.48 (d. ,/ = 4.8 Hz, 1H) _; 6.17 (d. J = 2.0 Hz. 1H), 4.89 (s_ 2H), 4.55 (s. 2H), 4.32-4.29 (m, 2H)„ 4 20-4.17 (m, 2H) _S 3 59-3.55 (m, !H) ₌ 2.71 (d, J = 4.4 Hz, 3H), 2.54 (s, 3H), 1.26 (d, 6.8 Hz, 3H), 1.10-1.08 (m, 1H), 0.58-0.55 (m, 1Hh 0.42-0.35 (m, 2H). 0.25-0.21 (m, 1H). Example 19. (S)-l-(5-(2 -(1-cyclopropylethyl)-4-(2,2-difluoroethoxy)-3-oxo-2,3-dihydro-1-pyrrolo[3,4-e]pyrrolo[1,4-e]- Preparation of 6-nitro-2-methyl-1-nitro-3-methyl-1-nitro-2-methyl-2-nitro-3-methyl-2-nitro ...nitro-3-methyl-2-nitro-1-nitro-2-nitro-3-methyl-2-nitro-1-nitro-2-nitro-3-methyl-2-nitro-2-ni manual

Sodium hydride (66 mg, 278 mmol) was added to 2,2-difluoroethane alcohol (136 mg, 1.66 mmol), stirred at room temperature for 15 minutes, and then common intermediate AS (300 mg, 1.11 mmol) was added dropwise. The system was heated to 60 ^°C for 2 hours. The mixture was cooled to room temperature and quenched with water. It was extracted with ethyl acetate three times (20 mL*3). The organic phases were combined and mortared. The organic phase was washed three times with water (SmL*3), washed once with saturated brine (50 nsL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with 30% ethyl acetate as the eluent. Petroleum acyl solution,

ESI-MS: in/z = 317.0

将 II-8-2 (208 mg, 0.42 mmol) 溶于二氯甲烷 (10 mL) 中， 滴加三氟乙酸 (2mL；＞, 室温搅拌过夜。 混合液加水淬灭， 用饱和碳酸氢钠调节 pH为 6〜 7, 二氯甲烷萃取三次 (3 mL*3), 合并有机相， 有机相 水洗一次 (20rnL), 饱利食盐水洗 --次 (50 mL), 无水硫酸钠干燥. 过滤。 滤液减压浓缩得到 II-8-3的粗 品 , 直接用于下一步 O NMR (400 MHz, DMSO-d;): 87.47 (s, 1H), 6.55 (tt, ,/j = 54.4 Hz, J ₂ = 3.6 Hz, IH)„ 473 (td„ J-. = 14.8 Hz,, = 36 Hz, 2H), 4.57 (s, 2H), 352-3.45 (m, ill), 1,25 (d, J - 6.8 Hz, 3H), 1,134.04 (dm 1H), 0.6C-0.52 (m,

II-8-2 (208 mg, 0.42 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL; >) was added dropwise, and stirred at room temperature overnight. The mixture was quenched with water and adjusted with saturated sodium bicarbonate. The pH value was 6 to 7. Extract with dichloromethane three times (3 mL*3). Combine the organic phases, wash with water once (20 mL), wash with saturated brine once (50 mL), dry with anhydrous sodium sulfate and filter. The filtrate was concentrated under reduced pressure to obtain the crude product II-8-3, which was used directly in the next step.

4两步 ■反应总收率为 238% 0 ESI-MS: in/z - 395.0 Step (S)-1-(5-(2-(2-(2-ethoxy)-3-oxo-2-dihydro-HZ-pyrrolo-6-yl)-4-methylpiperidin-2-yl)-3-methylpyrrolidone. Add triethylamine (58 mg, 0.57 mmol) to the crude product (10 mL) prepared in the previous step and stir for 5 minutes. Add methylhydrogen methyl 2-imnol dropwise under ice bath and react at room temperature for 3 hours. The mixture was quenched with water, extracted with dichloromethane three times (2.0 mL*3), combined with organic matter once (20 mL), washed with saturated salt on ice once (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by residual spectrum, and the developing solvent was 1-5% methanol in dichloromethane solution, and 45 mg of the target product: n-8 was obtained as a yellow solid.

4 The total yield of the two-step reaction was 238%

ESI-MS: m/z = 4520

^; H NMR (400 MHz, DMSO-a _fi ): 810.74 (s, 114), 7.44 (s, 1H), 6,59 (it, = 544 Hz, = 3.6 Hz, 1H), 6.52 (s, manual

1H), 4.75 (td, J = 148 Hz, J ₂ - 36 Hz, 2H), 4.58 (2H) _, 3.54-3.47 (m _; 1H) _; 2/70 (d, J - 44 Hz, 3H) _: 2.55 (s, 3H): 1-25 (d, J- 6.8 Hz, 3H), 1.134.05 (m, 1H).0.58-053 (nx HI), 043-0.34 (m, 2H), 024^0.20 (m _; 1H). Example 2: 1. (5. (2. (1. Cyclopropylethyl)-3-oxo-4-((tetrahydrofuran-3-yl)oxy) g dihydro-1H-pyridin-4-ol

45 mg的目标产物 II-9, 为黄色固体， 步骤 3和步骤 4两步反应总收率为 22.4% » Preparation of 6'-methyl)-4-methylthiazine-2-yl)-3-methylthiazine (II-9)

45 mg of target product II-9, yellow solid, total yield of step 3 and step 4 is 22.4% »

ESI-MS: nvz - 458.0 [M+H]L

^; H NMR (400 MHz, DMSO-d ₆ ): 810.69 (s, 1H), 7.38 (s, 1H), 650 (s, 1H) _; 559-5.55 (m, 1H), 454 (s, 2H) _; 405-401 (m, IH), 3.91-3.75 (m _s 3H), 352-3.45 (in, 1H), 2.70 (d, J= 4.8 Hz, 311), 2.54 (s, 3H), 2.37-2.28 (rn, 1H), 208-203 (■«, 1H), 125 (<i, 6.8 Hz, 3H).. 1.12-104 (nr 1H) _; 058-0 S3 (m. 1H).0.43-0.32 (tn, 2H), 0.24-0.20

嚏哩 -2 -基 )-3 -甲基，腿 (11-10) 的制备 说 明 书

说 明 书

得到 200 mg的 II-11-2, 为黄色固体， 收率 76.5 %.

得到｝ 80 mg的 II-12-2 , 收率 745%。 说 明 书

到 19 mg的目标化合物 11-12, 为黄色固体， 步骤 3和步骤 4两步反应总畋率为 11.7%。 (m, iH) Example 21 >(>V)-i-(5-(4 -cyclopropyloxy-

Preparation of 2-(2-hydroxy-3-methyl)-1-nitropropene (11-10) manual

manual

200 mg of II-11-2 was obtained as a yellow solid with a yield of 76.5%.

80 mg of II-12-2 was obtained, with a yield of 745%. manual

19 mg of the target compound 11-12 was obtained as a yellow solid. The total reaction yield of step 3 and step 4 was 11.7%.

ESI-MS: m/z = 430.0 [M+H]L

3.2 IIz, 611), 1.25 (d, J == 6.8 Hz, 3H), l l-105(m, 111),058-0.52 (ni, 1H), 04 i -0.33 (m, 2H)„ 0.23-019 (m_; HI). 实施例 24, （；5）- 1-（5-（2-（ 1-环丙基 基）-4 ■（二甲基氮基）-3 -氧代 -2, 3 -二氢 -1/1 -毗咯并 [3,4-c]t^-6-^）-4 - 甲基嚏哇 -2 -基卜3 -甲基朦 （11-13） 的制备

步骤 L ⑸ 4 -氯 -2-(1.环丙基乙基 >4-(二甲基氨基 .)-1, 2 -二氯 -3压毗咯荆 3, "｝毗略 3 -酮 (II-13-1) 的 合成 将共用中间体 A5 (200 mg, 0.74 mmol )溶于 N 二甲基甲酰胺 ( 10 mL )中 ,加入三乙胺 ( 187 mg, 1.84 mmol) 和二甲胺盐酸盐 (72 mg, 089 mmol)升温至 "C反应 i小时 "混合物冷却至室温后加水淬灭， 用 乙酸乙酯萃取三次 <20mL*3) , 合并有机相， 有机相水洗三次 ( 20mL*3^ , 饱和食盐水洗一次〈50mL) , 无水硫酸钠干燥， 过滤。 滤液减压浓缩。 残留物经柱层析纯化， 洗脱剂为 18%乙酸乙酯的石油酰溶液， 得 到 165 mg的 EI43-L 为黄色固体， 收 $ 801%., ^! H NMR (400 MHz, DMSO-<7 ₆ ): 610.66 (s, 1H), 7.33 (s, 1H), 648 (s„ 1H), 543-5.37 (m, 1H), 452 (s„ 2H) , 3.52-3.44 (m, HI), 2,70 (d, J - 4,8 Hz, 311), 2.54 (s, 311), 1.37 (dd, 6.4 Hz,

3.2 IIz, 611), 1.25 (d, J == 6.8 Hz, 3H), l l-105(m, 111),058-0.52 (ni, 1H), 04 i -0.33 (m, 2H)… 0.23- 019 (m _; HI). Example 24, (; 5) -1- (5- (2- (1-cyclopropyl) -4 ■ (dimethylamino) -3 - oxo-2, Preparation of 3-dihydro-1/1-pyrrolo[3,4-c]t^-6-(4-methyl)-4-oxazolidin-2-yl-3-methylpyridine (11-13)

Step L (5) 4-chloro-2-(1-cyclopropylethyl)-4-(dimethylamino)-1,2-dichloro-3-pyrrole-3-one ( II-13-1) Synthesis of the common intermediate A5 (200 mg, 0.74 mmol) was dissolved in N-dimethylformamide (10 mL), and triethylamine (187 mg, 1.84 mmol) and dimethylamine salt were added. The mixture was cooled to room temperature and then quenched with water. The mixture was extracted with ethyl acetate three times (20 mL*3), the organic phases were combined, and the organic phases were washed with water three times (20 mL*3). ^, washed once with saturated brine (<50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 18% ethyl acetate in petroleum ether as the eluent. 165 mg of EI43-L was obtained as a yellow solid, yield $ 801%.,

ESI-MS: nvz = 280.0 [M+H

^; H NMR (600 MHz, DMSO-J ₆ ): 66.91 (s, 1H), 444 ( _s ; 2H) 353-348 (m, 1H 316 (s, 6H), 1.2.2 (d. J = 6.8 Hz, 3H), i 08-1.03 (m, 1H), 0.56-0.52 (m, 1H), 0.40-0.31 (m, 2H), 0.23-0.19 (m, 1H) Step 2: (,S)-1-(S-(2-(1-SF-propylethyl)-2-dimethyl-MS)-3-M-hydroxy-2-hydroxy-2-nitro-pyrrolidone[3-(2-(1-SF-propylethyl)-2-dimethyl-MS)-3-M-hydroxy-2-nitro-pyrrolidone[3-(2-(1-SF-propylethyl)-2-dimethyl-MS)-3-M-hydroxy-2-hydroxy-2-nitro-pyrrolidone[3-(2-(1-SF-propylethyl)-2-dimethyl-MS)-3-M-hydroxy-2-hydroxy-2-nitro-pyrrolidone(11-13) Refer to Step 4 in Example 6 184 mg of target compound 11-13,

ESI-MS: ni/z = 415.0 [M+H

说 明 书 宿 NMR (400 MIIz, DMSO-64)： 610.60 (s, 1H), 7.14 (s, 1H), 6.47 (s, 1H), 4.51 (s, 2H), 4.27 -4.17 (m, 2H)_; 3.97-3.92 (m, 2H), 3.57-350 (m, 1H)„ 2.70 (d, J = 4.8 Hz, 3H), 2.53 (s, 3H), 247 - 243 (ro, 2H)„ 125 (d, J = 6.8 Hz, 3H), 1 12-103 im, 1H), 058-053 (m, 1H), 042-033 (m, 2H), 02S-021 (m, 1H)

的合成

的合成

^! II NMR (400 MHz, DMSO-</ ₆ ): 810.54 (s, 1H), 7.07 (s, 1H) _; 645 (s, 1H), 448 (s, 2H), 3.57-350 (m, 1H) , 3.18(s, 611),2.70 (d,J-4.8Ilz, 311),2.53 (s, 311), 1.24 (i,/-6.8Hz _; 31 n 1.10-104 (m, HI), 0.58-0.52 (m, 111), 0.41-0.32 (m, 2H), 0.25-0.21 (m, 1H) Example 25, (S)-1-(5-(2-(1-cyclopropylethyl)-4-methoxy-3-oxo-2#-dihydro-LH-pyrrolo[ ... Preparation of 4-hydroxy-4-methylthiophene-2-yl-3-methylthiophene (II-U)

H NMR (400 MIIz, DMSO-64): 610.60 (s, 1H), 7.14 (s, 1H), 6.47 (s, 1H), 4.51 (s, 2H), 4.27 -4.17 (m, 2H) _; 3.97 -3.92 (m, 2H), 3.57-350 (m, 1H)… 2.70 (d, J = 4.8 Hz, 3H), 2.53 (s, 3H), 247 - 243 (ro, 2H)… 125 (d, J = 6.8 Hz, 3H), 1 12-103 im, 1H), 058-053 (m, 1H), 042-033 (m, 2H), 02S-021 (m, 1H)

Synthesis

Synthesis

^; H NMR (400 NHIz, DMSO-<f _fi ): 610.63 (s, iH), 716 (s, 1H), 652 (d, J = 5.2 Hz, LH), 477 (d, J = 7.2 Hz, 1H ), 4.51 (s, 2H), 4.09-4.06 (m, 1H), 392 (d, J = 10.8 Hz, 1H), 3.72-3.49 (m, 5H), 2.69 (d, J = 4.8 Hz, 3H), 2.52 manual

(s, 3H). 1.25 (d, J - 6 4 Hz, 3H) _, 1.19 (d _; J = 6,4 Hz, 3H), L 09-1 05 (m, 1H), 0 584).52 ( m _: 1H) _, 0.404).32 (m _: 211), 0.3^0 19 (m _; 1H).

ESLMS: nVz = 441.0 [M+HJ^o

步骤 1： ㈤ .6 -氯 -2-0 -环丙基乙基）4（二 Z/氨基） -1卫-二氢 -3压毗咯并 [3,4-<?]%®-3-gs （II-19-1） 的合 成 参考实施例 24中步骤 1中目标化合物 II-13-1的台成， 仅将二甲胺盐酸盐替换成二乙胺盐酸盐， 其余

说 明 书

步骤 & (g氯 2(1 -环丙基乙基 )*8 ■氧杂或 -氯杂螺［4.S］癸烷 -2 -基 )" -二氢 -3弘毗咯并 p,4-c］lft® -3 -酮 ( H-2J-1) 的合成 参考实施例 24中步骤 1中目标化合物 II-13-1的合成，仅将二甲胺盐酸盐替换成 &氧杂 -2 -氮杂螺［45］ 癸烷， 其余制备方法不变， 捋到 260 mg的 II-21-1, 收率 93.7% . 'H NMR (400 MI1Z, DMSO-«y: 8 10.58 (s, HI), 6.98 (s, 1H), 6.49 (d, J - 5.2 Hz, 1H), 4.46 (s, 2H), 3.75-3.68 ( m, 4H), 3.56-3 48 fm, 1H), 2 69 (d, J = 4 4 Hz, 3H), 2.52 (s. 3H), 1.90- 1.84 (in, 4H), 1.23 (d, J = 6 8 Hz, 3H), 1 09-1.02 (m, 1H), 0 58-0.52 (m ₇ 1H), 0.41-0.31 (m, 2H), 0.24-0.19 (m, 1H). Implementation of 30, (S) <i-(5-(2-(5-cyclopropylethyl)-(diethylchloro)-3-hydroxy-20-diol Preparation of Hydrogen-pyrrolo-4-(4-(4-nitro-pyrrolo-4-yl)-4-(SHS-2-yl)-3-methyladenine (N-hydroxy)

Step 1: (V) 6-chloro-2-(6-cyclopropylethyl)-4-(di(Z/amino)-1-(2-hydroxy-2-nitro-pyrrolo[3,4-[(2-(4-(2-nitro-1-yl)ethyl)- ...1-(2-hydroxy-2-nitro-1-yl)ethyl)-3-(2-nitro-1-yl)pyrrolo[3,4-[ Synthesis of -gs (II-19-1) Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced by diethylamine hydrochloride, and the rest

manual

Step & (g-chloro-2(1-cyclopropylethyl)*8 ■oxa-or-chloro-spiro［4.S］decane-2-yl)"-dihydro-3-pyrrolo-p,4 Synthesis of -c］lft® -3-one (H-2J-1) Referring to the synthesis of the target compound II-13-1 in step 1 of Example 24, only dimethylamine hydrochloride was replaced by & oxa- 2-Azaspiro［45］decane, the rest of the preparation method remains unchanged, and 260 mg of II-21-1 is obtained, with a yield of 93.7%.

20 mg的目标代合物 11-22, /g S色固体， 收率 7 0%₍₁ ESI-MS: nvz = 376.0［M+HR Step 2: N-(5-(2-(1-cyclopropylethyl)-3-oxo-4-(8-(4 ... manual

20 mg of target compound 11-22, /g S-colored solid, yield 7 0% ₍₁

ES1-MS: nVz = 512.0[M+H]\

说 明 书

398-3.94 (m, 2H), 3.54-3.50 (m, 1H), 3.44-3.33 (m, 2H), 2.70 (d, J= 4.4 Hz, 3H), 2.52 (s, 3H), 1.60-1.53 (ni, 4H), 124 (d, J - 68 Hz, 3H)_; 1.16 (s, 3H), 1.09- 1.04 (m, 1H), 057-0.54 (m, II T), 0.41-032 (m, 2H), 0.23-0.20 (m, 1H) 实施例 35, GM-C］毗嚏 -6 -基}

步骤 1： (SM-氯 -2-(1 -环丙基乙基＞4-(2 -氧杂 6氮杂螺［3.3］庚烷瑚-基 )-1.2 -二氢 -3H-毗咯［3如］毗慷 3 酮 (n-24-n 的合成 参考实施例 24中岁骤 1中目标化合物 II-13-1的合成，仅粉二甲胺盐酸盐替换成如氧杂 -6 -氮杂 ®L3.3］ 庚烷， 其余制备方法不变， 得 ■到 400 mg的 n~24-l, 为黄色、淹状物， 收 $ 64.9%,

, , , , , , , , , , , 440-4.34 (m, 4H), 3.52-3.48 (m, 1H), 2.70 (d, J = 4/1 Hz„ 3H)„ 253 (s„ 3H), 124 (d, J =6.8 Hz, 3H), 1.07-1.05 (m, ;H), 0.57-0.52 (m, IH), 0.40-032 (m, 2H), 0.23-0. i 9 (m, 1H) 实施例! 36, (S)-l-(5-(2-(l-环丙基

-2 -基 )3甲基腿 (11-25) 的制备 说 明 书

基 )-3 -甲基腺 (11-25) 的台成 目标化合物 n-25的制备参考实施例 1中目标化合物 1-1制备方法的步骤 3. 仅将中间体 1-1-3替换为 共用中间体 A6其余制备方 '法不变， 得到目标化合物 11-25, 为白色固体， 收率 ! 3 2%„ JI NMR (400 MHz, DMSO- J ₆ ): 6 10 57 (s, 1H), 7.16 (s, 1H) _S 6 48 (s _; 1H), 4.57 (t, J = 6 4 Hz, 2H), 4.50 (s, 2H), 4.48-4.47 (m, 2H), 3.71 (s, 4H), 3.54-3.50 fm, iH), 3.47-3.42 (m, 1H), 2.69 (d, J - 4 4 Hz, 3H) _S 2.52 (s, 3H), 2 41 (d _; J = 5.2 Hz, 4IT), 1.2.4 (d, J = 6 8 Hz, 3H), 1.09- 1.04 (:n _; LIT), 0.57-0.52 (m, 1H), 0.40-0.32 (m, 2H), 0.23-0.19 (m, III). Example 34, GV)-l-(5-(2 -(1-cyclopropylethyl)-4-(4-hydroxy-1-methyl)-1-oxo-2-(3-hydroxy-2-(1-cyclopropylethyl)-1-oxo-2-(1 ...cyclopropylethyl)-1-oxo-2-(1-cyclopropylethyl)-1-oxo-2-(1-cyclopropylethyl)-1-oxo-2-(1-cyclopropylethyl)-1-oxo-2-(1-cyclopropylethyl)-1-oxo-2-(1-cyclopropylethyl)-1-oxo-2-(1-cyclopropyl Preparation of (3,4-c]pyridin-6-yl)4-methylpurin-2-yl)3-methylpyridin-2-yl (H-23)

manual

398-3.94 (m, 2H), 3.54-3.50 (m, 1H), 3.44-3.33 (m, 2H), 2.70 (d, J= 4.4 Hz, 3H), 2.52 (s, 3H), 1.60-1.53 ( ni, 4H), 124 (d, J - 68 Hz, 3H) _; 1.16 (s, 3H), 1.09- 1.04 (m, 1H), 057-0.54 (m, II T), 0.41-032 (m, 2H ), 0.23-0.20 (m, 1H) Example 35, GM-C]pyridin-6-yl}

Step 1: (SM-chloro-2-(1-cyclopropylethyl＞4-(2-oxa6-azaspiro［3.3］heptanefluorenyl)-1.2-dihydro-3H-pyrrole［ Synthesis of 3-nitropropane-3-one (n-24-n) Referring to Example 24, the synthesis of target compound II-13-1 in step 1 was carried out except that dimethylamine hydrochloride was replaced with 6-nitropropane-3-one (n-24-n) The remaining preparation methods were the same as above, and 400 mg of n-24-1 was obtained as a yellow, flooded substance with a yield of 64.9%.

, , , , , , , , , , , , 440-4.34 (m, 4H), 3.52-3.48 (m, 1H), 2.70 (d, J = 4/1 Hz„ 3H)„ 253 (s„ 3H), 124 (d, J =6.8 Hz, 3H), 1.07-1.05 (m, ;H), 0.57-0.52 (m, 1H), 0.40-032 (m, 2H), 0.23-0. i 9 (m, 1H ) Example 36, (S)-1-(5-(2-(1-cyclopropyl

Preparation of 2-methyl-3-methyl-1-nitropropene (11-25) manual

Preparation of target compound n-25 by reference to step 3 of the method for preparing target compound 1-1 in Example 1. Only the intermediate 1-1-3 is replaced by The rest of the preparation method of the common intermediate A6 remained unchanged to obtain the target compound 11-25 as a white solid with a yield of 3.2%.

ESI-MS: m/z = 457 0 [M+H　.

目标化合物 11-26 Kl制备参考实施例 1中目标化合物口制备方法的步骤 3, 仅将中间体 1-1-3替换为 共用中间体 A6, 共用中间体 B1替换为中间体： PM, 其余制备方法木变， 得到目标化台物 II-26o ^; H NMR (400 MHz, OMSO-t/s): 8.45 (s, 1H)„ 7 19 (s. 1H)_ 6 79 (d. J = 5 2 Hz, 1H), 4.52 (s_ 2H), 3.75 (t. J = 4.4 Hz, 4H), 3.68 ft, J = 4 0 Hz, 4H), 3 56-3.49 (m, 1H), 2.69 (d, J - 4.8 Hz. 3H), 2.53 (s, 3H), 1.25 (d. J = 6.8 Hz, 3H) _: 1 11 -J .04 (m, HI), 0.60-0.53 (m, 1H), 0.43-0.31 (m, 2H), 0.24-0. S9 (m, 1H) =

Preparation of target compound 11-26 K1 Referring to step 3 of the preparation method of target compound I in Example 1, only intermediate 1-1-3 is replaced by common intermediate A6, common intermediate B1 is replaced by intermediate PM, and the rest is prepared The method was changed to obtain the target compound II-26o

说 明 书

步骤 1： !-(4-Ep基暖嗦 -2 -基卜 M2 -吗嘟 4墓廨 ( 11-29- O 的合成 参考实施例 9中步骤 1 中间体耳-9-i的合成， 仅将中间体环丙胺替换成 2 -吗再林乙醇胺, CB替换为甲 氮基甲酰氯 , 溶剂由四氢映喃替换为二氯中％ 其余制备方法不变， 制备得到中间体 11-29- ! = ES1-MS: m/z =483.0 [M+H | ⁺ .

manual

Step 1: Synthesis of 11-29-0: Referring to the synthesis of intermediate 11-9-i in step 1 of Example 9, only the intermediate cyclopropylamine was replaced with 2-morpholinethanolamine, CB was replaced with methylaminocarbonyl chloride, and the solvent was replaced with dichloromethane by tetrahydrofuran. The rest of the preparation method remained unchanged to prepare intermediate 11-29-11-29-0:

说 明 书

ESL-MS: m/z -271.0 [M+H

manual

步骤 L (S)-(5-(2-(l-5f丙基乙基 )-7-(二氟甲氧基 )-1-氧代异哪柴瞬冬基 )-4 -甲基 I® St-2 -基)氮基甲酸 -2,2- 二氟乙酯 (IV4) 的合成 将氢化钠 ( 14 mg, 0.60 mmol)加入到 2,2 -二氧乙烷 -I -醇 ( 1 mL ) 中， 室温搅拌 15分钟。 隔后将共用 中间 #- C1 ( 100 mg, 0.20 mmol )溶于二氧六环 ( 5 mL ) 中， 滴入上述混合液中， 体系升温至 50°。反应 1 小时。 反应结束后冷去 k至室温， 加水淬灭， 随后反应液用己酸乙酯 ( 30 ml, *3 ) ：¥取， 合并有机相， 浓缩 后残留物经柱层析纯化， 洗脱剂为 0-3%甲醇的二氯甲烷溶液， 得到 193 mg的目标化合物狞-L 为白色 固体， 收率 20.4% o EST-MS: m/z = 497 0 [M+H　hl NMR (600 MIlz, DMSO-CM): 8 10.77 (s _: ill), 7.20 (s, HI), 4.52 (s, 211), 3.75 ( LJ = 4.8 Ilz, 411), 3.68 (t, J = 4.8 Hz, 4H), 3 55-3.50 (m 1H) _; 3 39 (s, 4H), 2.56 (s, 3H), 1.85 (s, 4H) _; 1 24 (d, J - 4.4 Hz, 311), 1 10-1.05 (m, 1H), 0.58-0.54 (m„ 1H), 0.42-0.37 (m, 2H), 0.36-0.32 (m, 1H). Example 42. (A> (5-(2-(1S-propylethyl*7-(difluoromethoxy)-1-hydroxyisoquinoline) Preparation of (1-(4-methyl)-2-(4-yl)carbamic acid-1-(2-ethyl) ester (1-(4-yl)carbamate)

Step L (S)-(5-(2-(1-5F propylethyl)-7-(difluoromethoxy)-1-oxoisoquinoline)-4-methyl Synthesis of 2,2-difluoroethyl St-2-yl)carbamate (IV4) Sodium hydride (14 mg, 0.60 mmol) was added to 2,2-dioxyethane-1-ol (1 mL ) and stirred at room temperature for 15 minutes. After a while, the common intermediate #-C1 (100 mg, 0.20 mmol) was dissolved in dioxane (5 mL) and added dropwise to the above mixture. The system was heated to 50°. Reaction 1 Hour. After the reaction was completed, the mixture was cooled to room temperature and quenched with water. The reaction solution was then extracted with ethyl hexanoate (30 ml, *3). The organic phases were combined and concentrated. The residue was purified by column chromatography. The eluent was 0-3% methanol in dichloromethane solution, 193 mg of the target compound carbuncle-L was obtained as a white solid, with a yield of 20.4%.

ES1-MS: nVz = 488.0 [M+H]L

说 明 书

, , , , , , , , , , J- 08 Hz, 1H)_S 460 (s, 2H), 3.97 (d, J -6.4 Hz, 2H), 3.59-352 (in, 1H), 2.37 (s_; 3H), 2.00489 (m, 1H), 1.28 (d, J -6.8 Hz, 3H), 1.15-1.07 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H)_S 0.60-0.54 (m, IH), 0.44-035 (m, 2H), 0.27-0.22 (m, 1H) 实施例 47、2 -甲氧基乙基 GS）-（5-（2-（l-环丙基乙基）-7-（二氟甲氧基）-如氧代异呼噪晰 -S-基）-4 -甲基嚏哩 -2- 基）氯基甲酸酯 （IV-6） 的制备

步骤 1 : 2-甲氧基乙基 •■环丙基乙基卜 7=(二氟甲氧基卜 1 ■■氧代异呵瞭嘛 基｝ T -甲基嚏哩 -2 -基) 氨基甲酸酯 (1V-6) 的合 目标化合物 IV-6的 实施例 42的步骤 1, 仅将 2,2.二氟乙烷 -1 ••醇替换为乙二醇甲略 得 到 25 mg的目标化合物 I 固体， 收:率 28.1%。 ⁵ H NMR (400 MHz, DMSO-tZ ₆ ): 8 12 23 (s, 1H). 7.64 (t, J = 74.8 Hz, 1H), 7.57 (d, J - 1,2 Hz, 1H>, 7.24 ( s, 1H), 6.48 (it, J:, = 54.0 Hz, J ₂ = 3.2 Hz, 1H), 4.60 (s, 2H), 4.54 (Ed, % = 15.2 Hz, J ₂ = 3.2 Hz, 2H), 3.59-3.52 (m, 1H), 2.38 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-0.54 (m, 1H). 0.44-0.35 (m, 2H), 0.26-022 (m, 1H) Embodiment 43s Tetrahydroxanthan-3-yl (5-(2-((＞S)-1-cyclopropylethyl)-7-(difluoromethoxy)-1-oxoisopropyl)- Preparation of 1,2-dimethylthiazol-2-ylcarbamate (1V-2)

manual

, , , , , , , , , , J - 08 Hz, 1H) _S 460 (s, 2H), 3.97 (d, J -6.4 Hz, 2H), 3.59-352 (in, 1H), 2.37 (s _; 3H), 2.00489 (m, 1H), 1.28 (d, J -6.8 Hz, 3H), 1.15-1.07 (m, 1H), 0.93 (d, J = 6.4 Hz, 6H) _S 0.60-0.54 (m, IH ), 0.44-035 (m, 2H), 0.27-0.22 (m, 1H) Example 47, 2 -methoxyethyl GS)-(5-(2-(l-cyclopropylethyl)-7-(difluoromethoxy)-isoquinoline-S-yl)-4- Preparation of methyl chloroformate (IV-6)

Step 1: 2-methoxyethyl-cyclopropylethyl-7-(difluoromethoxy-1-oxoisocyanato-1-yl)-2-methyl-1-amino Formate (1V-6) Compound IV-6 Example 42 Step 1, only 2,2.difluoroethane-1 • • alcohol was replaced with ethylene glycol to give 25 mg of the target Compound I was solid, with a yield of 28.1%.

ESI-MS: m/z = 482.0

11.94 (s_s IH), 763 (t, J = 74.8 Hz. 1H), 7.56 (d, J = 12 Hz_; HI), 7.22 (d. J = 12 Hz. 1H), 460 (s, 2H), 431-429 (m, 2H), 359-357 (m, 2H), 356-352 (m, 1H), 328 (s, 3H), 23? (s, 3H), 1.28 (d, ./=6.8Hz, 3H). i.15- 107 (m, 1H), 060-054 (m, HD, 044-.035 (m, 2H), 027 - 022 (m, iH)

说 明 书 哩 -2 -基）氨基甲酸酯 （IV-7） 的制备

^! II NMR (400 MHz, D

11.94 (s _s IH), 763 (t, J = 74.8 Hz. 1H), 7.56 (d, J = 12 Hz _; HI), 7.22 (d. J = 12 Hz. 1H), 460 (s, 2H), 431-429 (m, 2H), 359-357 (m, 2H), 356-352 (m, 1H), 328 (s, 3H), 23? (s, 3H), 1.28 (d, ./=6.8Hz, 3H). i.15- 107 (m, 1H), 060-054 (m, HD, 044-.035 (m, 2H), 027 - 022 (m, iH)

Instructions for the preparation of 2-(4-(2-amino-1-yl)carbamate (IV-7)

步骤 L ⑶ -（5-（2-。 -环丙基乙基）-7-（二策甲氧基）4 -氧代异吧噪嗽 -5 -基 甲基嘟坐 -2 -基）氨基甲酸甲 说 明 书

rv-io-1 步骤 h (5)20 -环丙基乙基 )3 -修 -羟基丙烷 -2 ■■基 )-机如5 ■四甲基 -L3,2 -二氧硼杂环戊烷 2基)异哪噪 聊 4 ■■酮 (IV-iO-D 的合成 化合物 IV-W-1的制备可参考实施例 7中步 ■骤 2中化合物 1-7-2的制备方法， 仅将中间体 L7-1替换为 化合物抑- & 其余制备方法不变， 得到 610 mg的 IV-W-1. 白色固体， 收率 93.0%. ESI-MS: m/z = 551.0 [M+H　 Sink NMR (400 MHz. DMSO-J ₆ ): 311.85 (s, 1H), 7.63 (t _; J = 74.8 Hz, 1H), 7.55 (d, J - 12 Hz, 1H) _: 7.22 (d, .1= i 2Jfz. 1H) _, 459 (s.2H\ 422 (t..7 = 64 Hz, 2H)„ 359-352 (m, 5H) _; 238-233 (m.9H), 1 S3 (Q, J = 68 Hz, 2H), 1.28 (d, J- 6.8 Hz, 3H), 1.16-1.07 (m, 1H), 0.60-0.54 (m, 1H), 044-0.35 (m, 2H), 027-0.22 (m, 1H). Example 50, (,SX5-(2-a-propylethyl) ~7-(di Fluoromethoxy 7-oxoisoquinoline-5-yl-3-methyl-1-chloroformate (IV-1).

Step L (3) -(5-(2-cyclopropylethyl)-7-(dimethoxy)-4-oxoisopropyl-5-ylmethylpiperidin-2-yl)amino Methyl formate manual

rv-io-1 Step h (5) 20-cyclopropylethyl)3-hydroxypropane-2-yl)-organic acid 5-tetramethyl-L3,2-dioxaborolane The preparation of compound IV-W-1 can refer to the preparation method of compound 1-7-2 in step 2 of Example 7, except that The intermediate L7-1 was replaced by compound IV-W-1 and the rest of the preparation method remained unchanged to obtain 610 mg of IV-W-1. White solid, yield 93.0%.

ES1-MS (nm): 386.0 [M+H] ⁺ _t , Step 2, Synthesis of (S)-(5-(2-(1-propylethyl)-7-(2-methylpropane-2-yl)-1-oxoisopropyl-5-yl)-4-methyl-2-yl)carbamate (WW) The preparation of the target compound IV-10 can refer to the preparation method of the target compound L7 in step 3 of Example 7, only the intermediate 1-7-2 is replaced by compound IV-10-1, and the rest of the preparation method remains unchanged to obtain 2 mg of the target compound IV-10 as a white solid, with a yield of 1.2%.

ESl-MS(nVz): 430.0 [M+H

步骤 h ㈤一 S履一 2-(1 ~环丙基乙基 )-7 -吗瞩异哪斜林-璀国 (1V-H-1) 的合成 说 明 书 将共用中间体 4 (400 mg, 1.48 mmol)溶于 -二卒基乙酸胺 ClOniL), 随后加入吗嘟 (578m_g> 2,96 mmol) 和三乙胺 (597 mg_; 5.95 mmol), 130°C下微波反应 1 h。 反应结柬后， 降至室温， 向反应液中加入 30 mL乙酸乙酯. 随后用饱和食盐水 (30 niL*3 ) 洗反应液， 合并有机相， 浓缩后残留物经柱层析纯化， 洗脱剂为 KK25%乙酸乙酯的石油醵溶液， 得到 180 mg的 IV-M-L 为黄色固体， 收率 735%。 'H NMR (400 ?vnIz _; DMSO-cfe): 6 1 1 .89 (s, ill), 7 57 (d, J = 1.2 Hz„ III), 7 43 (d, J = 1.6 Hz, 1H) 7.17 (s, 1H), 4.66 (s, 2H), 3 75 (s, 3H) _t 3.67-3.60 (m, 1H), 2.37 (s, 3H), 1 56 (i J - 2.0 Hz, 6H) _S 1.32 (d _t J - 6 8 Hz, 3H) _; 1 18-1 1 i (m , IH), 0.62-0.56 (m, 1H), 0.46-0.37 (m, 2H) _; 0 29-0.24 (m, 1H). Example 52. (.S)-(5-(2-(l-5F propylethyl)-7-morpholine-X-oxoisopropyl-& Preparation of methyl 2-methyl-2-hydroxy-2-carboxylate (IV-2)

Step h (V) Synthesis of 2-(1-cyclopropylethyl)-7-morpholinoisopalmitoyl-1-hydroxy- ... Instructions: Dissolve the common intermediate 4 (400 mg, 1.48 mmol) in diethyl amine (10 mL), then add morpholine (578 _mg> 2.96 mmol) and triethylamine (597 mg _; 5.95 mmol), 130 The reaction was carried out under microwave at 40 °C for 1 h. After the reaction was completed, the temperature was cooled to room temperature and 30 mL of ethyl acetate was added to the reaction solution. The reaction solution was then washed with saturated saline (30 niL*3), the organic phases were combined, and the residue was concentrated. The product was purified by column chromatography with 25% ethyl acetate in petroleum ether solution as the eluent to obtain 180 mg of IV-ML as a yellow solid with a yield of 735%.

ESI-MS: m/z = 365.0[M+Hr ^h =

步骤 h Q-甲基嚏唾 -2 -基)氨基 将 I-H-1 (200 mg, 0.85 mmol) 应 lh。 反应结束后， 降至室温， 向

液， 合并有机相， 浓缩后残留物经柱层析纯化， 洗脱剂为 10-12%乙酸乙酯的石油醵溶液， 得到 130 mg的 1V-12-1， 为白色固体， 收率 88.4% o 'HNMR (400 IvflIz, DMSO<4) 8 H 88 (s, III), 7.16 (d, J= 1.2 Hz, HI), 6.84 (d, J - i 2 Hz, HI).448 (s, 2H) , 3.77-3.75 (m, TH), 3.58-3.51 (m, IH), 3.27-320 (m, 4H), 2.37 (s, 3H), 1.25 (d, J= 6.8 Hz, 3H), 1.12-1.04 (m, nT), 060-053 (m _; ilT), 042-031 ( m, 2H) _; 024-019 (n\ IH) Embodiment 53, (S)-(5-(2-(1-SF-propylethyl)-4-nitropropene)-3-oxo-2,3-dihydro-1-pyrrolo-4-pyrrole Preparation of methyl (4-methyl)-2-(2-yl)-4-methylpyroxene-2-yl)carbamate (IV-12)

Step h: IH-1 (200 mg, 0.85 mmol) was reacted with 2-(2-methyl-1,2-dihydro-1-yl)amino for 1 h. After the reaction was completed, the temperature was cooled to room temperature and

The organic phases were combined and concentrated, and the residue was purified by column chromatography with a 10-12% ethyl acetate solution in petroleum ether as the eluent to obtain 130 mg of 1V-12-1 as a white solid with a yield of 88.4%. o

对照化合物 2 GP1-549)： 参考 WO2015051244A 1 中的实施例 1中化合物 4的制备方浅制容捋到。 说 明 书

实施例 55、 本发明化合物的 PIJKy抑制活性 本发明以 IPI-549为对照， 采用 ADP Gio assay测试化合物在体外结合和抑制 P13K_y活性的能力。 化台物溶液配制 "先用 DMSO 将化合物溶解， 再用无菌去离子超纯水将待测化合物依次 3倍梯度稀 释得到 8个浓度的化合物溶液。 实验方法： 在激翳缓冲液中配置 2xPI3Ky酶溶液， 在底物缕冲液中配置含 2xPIP2:3PS及 ATP的底物 溶液。 向 384孔板中加入盘 L各梯度浓度的化合物溶液， 离心 . 再加入 5 pL的 2xPI3Ky fifi溶液以及无醇 激酶缓冲液， 离心， 每孔中加入 5 [.il. 2xPIP2:3PS和 ATP的底物溶液， 混匀离心后室温孵育 90分钟， 向每 孔加入 10 gL ADP-Glo reagent以停止反应， '混匀离心， 室温孵育 60分钟后再向每孔加入 20 |.iL ADP-Glo Kinase Detection Reagent, 离心， 平 后在酶标仪上读数并测定每个化合物的抑制率。 将最终结果 输入（Sraphpad Prism作图， 得到曲 结果见下表： 表 L 芳 烷酮类化合物的 PI3Ky抑制活性

说 明 书

采用 ADP Gio assay测试化合物在体外结合祁抑；Wj PI3K«, PI3Kp, PI3K8活性的能力。 在激酶缓冲液中配置 2xP13Ka/p/8酶溶液， 在底物缓冲液中配置含 2xPIP2:3PS及 ATP的底物溶液。 向 384孔板中加入 1叫,各梯度浓度的化合物溶液， 离心， 再加入 5皿曰勺 2xPI3K.p酶溶液以及无酶激醇缓 冲液， 即 L), 每孑 I •中加入 5 uL 2xPIP2:3PS和 ATF的底物溶液' 混匀圈心后室温孵育 9。分钟' 问每孔加入 10 pL /vDP-Glo reagent以停止反应， 混匀离心， 室温孵育 60分钟后再向每孔加入 20 uL ADP-Glo Kinase Detectiot) Reagent, 离心. 平衡 6。分钟后隹酶标仪上读数并测定每个化合物的抑制率。 表 2. 本发明化合物的 PI3Ka . PI3Kps PI3K8抑制活性

由表 2的数据可知， 本发明提供的化合物， 对 H3Ky亚型的选择性显著强于 PI3Ka. P13K|3, PI3K5, 表明了本发明提供的化合物相对于 IPI-549， 脱靶效应减少。

EST-MS: rn/z = 1730[M+1lf Step 2: Synthesis of (S)-(5-(2-(1-nitroethyl)-3-oxo-2,3-dihydro-1//-pyrrolo-1//-yl)-4-(4-methyl)carbamate (IV-12) IV-4-2-(1-nitroethyl)-3-oxo-2,3-dihydro-1//-pyrrolo-1//-yl ... The temperature was cooled to room temperature, and then the reaction solution was extracted with ethyl acetate (30 mL*3). The organic phases were combined, concentrated, and the residue was purified by preparative liquid chromatography to obtain 40 mg of the target compound IV-12 as a white solid with a yield of 28.2%. manual

Reference compound 2 GP1-549): Refer to the preparation method of compound 4 in Example 1 in WO2015051244A1. manual

Example 55. PI13Ky inhibitory activity of the compounds of the present invention The present invention used IPI-549 as a control and adopted ADP Gio assay to test the ability of the compounds to bind to and inhibit _PI13Ky activity in vitro. Preparation of compound solution: First, dissolve the compound with DMSO, and then dilute the compound to be tested 3-fold in sequence with sterile deionized ultrapure water to obtain 8 concentrations of compound solution. Experimental method: Prepare 2xPI3Ky enzyme solution in the stimulation buffer, and prepare the substrate solution containing 2xPIP2:3PS and ATP in the substrate buffer. Add 5 μL of compound solution of each gradient concentration to the 384-well plate, centrifuge. Then add 5 μL of 2xPI3Ky fifi solution and alcohol-free kinase buffer, centrifuge, add 5 μL of 2xPIP2:3PS and ATP substrate solution to each well, mix and centrifuge, incubate at room temperature for 90 minutes, add 10 μL ADP-Glo reagent to each well to stop the reaction, mix and centrifuge, incubate at room temperature for 60 minutes, then add 20 μL ADP-Glo Kinase Detection Reagent to each well, centrifuge, After the level was balanced, the reading was performed on an ELISA reader and the inhibition rate of each compound was determined. The final results were input into (Sraphpad Prism for plotting, and the results are shown in the following table: Table L PI3Ky Inhibitory Activity of Aromatic Alkanone Compounds

manual

ADP Gio assay was used to test the ability of the compounds to bind to and inhibit the activity of PI3Kα, PI3Kβ, and PI3K8 in vitro. 2xPI3Kα/β/8 enzyme solution was prepared in kinase buffer, and substrate solution containing 2xPIP2:3PS and ATP was prepared in substrate buffer. 1 μL of compound solution of each gradient concentration was added to a 384-well plate, centrifuged, and then 5 μL of 2xPI3Kα enzyme solution and enzyme-free kinase buffer (i.e., 1 μL) was added. 5 μL of substrate solution of 2xPIP2:3PS and ATF was added to each well. After mixing well, the well was incubated at room temperature for 9 minutes. 10 μL/vDP-Glo reagent was added to each well to stop the reaction, mixed well, centrifuged, incubated at room temperature for 60 minutes, and then 20 μL ADP-Glo Kinase Detectiot) Reagent was added to each well, centrifuged, and balanced for 6 minutes. After 10 minutes, the plate reader was used to read the results and the inhibition rate of each compound was determined. Table 2. PI3Ka, PI3Kps and PI3K8 inhibitory activities of the compounds of the present invention

From the data in Table 2, it can be seen that the compounds provided by the present invention have significantly stronger selectivity for H3Ky subtype than PI3Ka, P13K|3, and PI3K5, indicating that the compounds provided by the present invention have reduced off-target effects compared with IPI-549.

(1) A 96-well plate was coated with 100 μL of CD3 antibody at a concentration of 3 μg/ml in advance and incubated at 4°C overnight. Afterwards, the plate was washed twice with sterile PBS to remove free CD3 antibody in the plate for later use.

(2) Control and AD mice were killed by cervical dislocation and immersed in 75% ethanol solution for 5 min, and then the ear drainage lymph was removed in a clean bench. According to the instructions, use an appropriate amount of RPMI-1640 blank culture medium to grind into a single cell suspension in a 200-mesh sieve. After sieving the 70-mesh secretory cell sieve, centrifuge at 4°C and 1200 rpm to obtain lymphocytes.

Oueway-ANOWs法进行统计， 以 P<0.05 具有统计学差异。

实施例 58.本发明化合物对嗦喳莫特乳膏诱导银屑病小鼠来源淋巴细胞分泌细胞因子 II.-17A拥制活

(3) Grind and separate single lymphocytes using a 70 μM cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count.

The Oueway-ANOWs method was used for statistical analysis, and P < 0.05 was considered statistically significant.

Example 58. The inhibitory activity of the compounds of the present invention on the secretion of cytokine II.-17A by lymphocytes derived from psoriasis mice induced by thiamethoxam cream

释 1()倍。 将方案要求测定、 观察的结果和数据记录至适当的表格中， 并在 Excel 表格中统一分析， 计量 资料以平均值土标准误差来表示， 所有数据统计均采用 Pnsm统计学软件进行 . 采用 Oneway-ANO'、於法进 行统计 . 以 P <0 05 为具有统计学差异。 实验结果见图 2, 由图 2 成知， 本发明化合物对味嗟莫特乳膏诱导银屑病小鼠来源淋巴细胞 IL-37A的分泌水平具有强 效的抑制作用， 可用于预防或治疗银屑病， 实施例游、 本发明化合物的药代动力学试验 检测方法:雄性 SD大鼠，体重约 200g,随机分为 2组,每组 3只大鼠，其中 -组单次静脉注射 0.5 my/kg 说 明 书

实验结果可知， 相比于 IPL549， 本发明部分化合物口服给药后的血浆暴露量， 口服生物利用度显著提 局。

用。 用 pCLAMP 10 (Molecular Devices, Union City, CA) 采集和分析资料， 实验员对分析结果进行审查" 本 发明化合物对人类 bERG离子通道的抑制作用结果尧下表； 表 4. 本发明化合物对 hERG离子通道的阻断率

实验结果可知， 本发明部分化合物口服给药后的安全性好 (3) Grind and separate single lymphocytes using a 70 μl cell sieve. Centrifuge at 300 g for 5 min. Resuspend in complete medium and count.

10 times. The results and data of the measurement and observation required by the scheme were recorded in appropriate tables and analyzed uniformly in Excel tables. The quantitative data were expressed as mean ± standard error. All data statistics were performed using Pnsm statistical software. Oneway-ANO' was used for statistics. P <0.05 was considered statistically significant. The experimental results are shown in Figure 2. As shown in Figure 2, the compounds of the present invention have a strong inhibitory effect on the secretion level of IL-37A in lymphocytes derived from psoriasis mice induced by vinblastine cream, and can be used to prevent or treat psoriasis. Example 3 Pharmacokinetic test of the compounds of the present invention: Male SD rats, weighing about 200g, were randomly divided into 2 groups, each with 3 rats, of which one group was intravenously injected with 0.5 my/kg manual

The experimental results show that, compared with IPL549, the plasma exposure and oral bioavailability of some compounds of the present invention after oral administration are significantly improved.

pCLAMP 10 (Molecular Devices, Union City, CA) was used to collect and analyze data, and the laboratory technicians reviewed the analysis results. The results of the inhibitory effect of the compounds of the present invention on human bERG ion channels are shown in the following table: Table 4. Blocking rate of the compounds of the present invention on hERG ion channels

The experimental results show that some compounds of the present invention have good safety after oral administration.

Claims

The claim book ~ two supplements beside chrysanthemum * hernia thin collar rattan cloth car - mine Yu Jiabiao I cloud W two factory truth stubborn and I Ji or color Jin E humorous hill blessing;

In the formula, Ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and Ring A contains at least one substituent R ² ; B is selected from NR ^{, a} R ^{! b} or OR ^{, a} _; R ⁱ² > R ^lb are each independently selected from hydrogen, substituted or unsubstituted C 16 alkyl, substituted or unsubstituted C 26 alkenyl, substituted or unsubstituted C 26 cycloalkyl, or substituted or unsubstituted 4-10 membered heterocyclyl; when the C 26 alkyl, C _{26 alkenyl, C 26} cycloalkyl, and 4-10 membered heterocyclyl mentioned in R 1 and R 1 have substituents, they can be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxy, hydroxyl, hydroxyl, oxo, C 16 alkyl, C 26 alkenyl, C 26 cycloalkyl ...

R\R\R\ are each independently selected from hydrogen, halogen, oxy, hydroxy, amino, alkyl, C-6 alkyl, halogenated C-6 alkyl, C-6 alkenyl, C-6 alkyl,

Halogenated C1-6 alkoxy, C1-6 alkylthio or C1-6 alkylamino; X and Y are each independently selected from N or CR%

alkyl, substituted or unsubstituted C _3.6 cycloalkyl, substituted or unsubstituted C 1-1 aryl, substituted or unsubstituted C 4-10 membered heterocyclyl, substituted or unsubstituted 5-14 membered heteroaryl, -OR ³ \ -SR ³ \ -SO ₂ -R ³ \ -NR ³ⁿ R ³ . -NH-R ³ \ -NHCO-R ^3a , -C(O)NH-R ³ \ -C(O)-R ³ \ -NHSO ₂ -R ^3a or -C(O)2-R 3: When the alkyl, alkenyl, C12-aryl (e.g., cycloalkyl, C13-aryl, C14-membered heterocyclyl and 5-14-membered heteroaryl) mentioned above have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxo, hydroxyl, amino, 9-hydroxy, oxo, C16-alkyl, halogenated C16-alkyl, C13-alkenyl, C14-heptyl, C16-cycloalkyl, C12-aryl, 4-3-membered heterocyclyl, 5-14-membered heteroaryl, -OR 3 \ -SR 3 \ -SO 2 -R 3 \ -NH-R 3 \ -NHCO-R 3a or -C(O)2-R 3: When the alkyl, alkenyl, C12-aryl (e.g., cycloalkyl, C13-aryl, C14-membered heterocyclyl and 5-14-membered heteroaryl) have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxo, hydroxyl, amino, 9-hydroxy, oxo, C16-alkyl, halogenated C16-alkyl, C13-alkenyl, C13-heptyl, C13-cycloalkyl, C12-aryl, 4-3-membered heterocyclyl, 5-14-membered heteroaryl, -OR ³ \ -SR ³ \ -SO ₂ -R ³ \ -NH-R ³ \ -NHCO-R ³ \ -NHSO,-R ³ \

When a cycloalkyl or 4-10 membered heterocyclic group has a substituent, it may be independently substituted or polysubstituted by one or more of the following substituents: halogen, halogen, hydroxyl, amino, mercapto, oxo, C16-alkyl, C16-alkenyl, C12-alkyl, C14-cycloalkyl, C16-alkoxy, C16-alkylthio, C16-alkylamino; R\ ^R5 are each independently selected from hydrogen, halogen, oxy, hydroxy, amino, substituted or unsubstituted.

The C2.6 _- hydroxyl and C6-cycloalkyl groups may be independently mono- or poly-substituted by one or more of the following substituents: halogen, hydrazine, hydroxyl, amino, thiophene, oxo, C2-6-alkyl, C2-6-alkenyl, alkynyl, C2-6-cycloalkyl, C2-6-hydroxyoxy, C2-6-alkylthio, C2-6-alkylthio or C2-6-amino; or may be connected to each other with R' and form a 3-8-membered saturated or unsaturated aliphatic ring or heterocyclic ring together with the C atoms on the ring: Claims R6 is selected from substituted or unsubstituted C2-alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted C2-M2-alkyl or substituted or unsubstituted

One or more of the following are mono- or poly-substituted: halogen, alkyl, C _2.6 B, C 4.6 C 6.6 B, C 5.8 C 6.9 C 7.2 C 8.4 C 9.8 C 10.6 C 11.3 C 12.4 C 13.2 C 14.6 C 15.8 C 16.9 C 17.9 C 18.9 C 19.9 C 20.9 C 21.9 C 22.9 C 23.9 C 24.9 C 25.9 C 26.9 C 27.9 C 28.9 C 29.9 C 30.9 C 31.9 C 32.9 C 33.9 C 34.9 C 35.9 C 36.9 C 37.9 C 38.9 C 39.9 C 30.9 C 31 2. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: it is a compound represented by the general structural formula ! --) or a pharmaceutically acceptable salt thereof:

Ring A is selected from a 5- to 16-membered aromatic ring or heteroaromatic ring, and contains at least one substituent R ² ; R is selected from I\R ^la R ^ib or OR ¹³ ; R ^ia , R 'b are each independently selected from hydrogen, substituted or unsubstituted C 6 alkyl, substituted or unsubstituted C 2.6 alkenyl, substituted or unsubstituted G 6 _alkynyl , substituted or unsubstituted C 6 cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when the C 6 alkyl, C 2.6 alkenyl, C _2.6 alkyl, G 6 cycloalkyl and G 6 cycloalkyl 4-10 membered heterocyclic group in R ^ia . R ^ib have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: carnitine, thiocyanate, hydroxyl, hydrogen, thiocyanate, oxo, G 6 alkyl, C 6 alkenyl, heptyl, heptyl, cycloalkyl, G 6 alkoxy, C 6 alkoxy, thiocyanate ...

For example, R' and R'b are connected to each other and together with the N atom form a 3-8 membered saturated or unsaturated heterocyclic ring; R', R'b are each independently selected from hydrogen, halogen, oxy, hydroxy, amino, alkyl, C_6 alkyl, halogenated C_6 alkyl (benzene, C_3-6 alkyl. _1'3-6 cycloalkyl, C_6 alkoxy, halogenated C_6 alkoxy, C_6 alkylthio or C_6 alkylamino; and R' and Y are each independently selected from N or CR ^2a -

or -P(O)R ^{iBR :b} ; when R, the C 2 6 alkyl, C _{2 6} alkyl, C _{2 6} alkyl,

When there are substituents in the heteroaryl group, they can be independently substituted by one or more of the following substituents: halogen, nitrogen,

C4-6 alkyl, C6-6 alkyl, C3-6 cycloalkyl, _C4-6 alkyl, C6 ...

alkyliodo, G〈alkylthio or G〈alkylamino; or Claims R? and R? are connected to each other and together with the C atoms on the ring form a 3-8 membered saturated or unsaturated aliphatic ring or heterocyclic ring: R6 is selected from substituted or unsubstituted C1_4 alkyl, substituted or unsubstituted C1_6 alkenyl, substituted or unsubstituted C1_7 alkenyl or substituted or unsubstituted C1_8 alkenyl.

It is mono- or poly-substituted by one or more of the following substituents: halogen, oxo, C1-6 alkyl, C2-6 alkenyl, C1-6 alkyl or C2-6 cycloalkyl: the heterocyclic ring, heteroaryl. The heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S.O. 3. The aromatic heterocyclic pyrrolidone derivative according to claim 1, characterized in that: it is a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

Wherein. Ring A is selected from a 5-16-membered aromatic ring or heteroaromatic ring, and Ring A contains at least one substituent R ² ; R' is selected from NR^R'b or OR ¹³ :

When there are substituents on alkenyl, C1-6-alkynyl, C2-6-cycloalkyl and 4-10-membered heterocyclic groups, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, alkyl, hydroxyl, nitrogen,

C",'alkynyl'C:"*cycloalkyl, Cm alkoxy, halogenated Cm hydroxyl, Cm alkylthio or G-alkylamino; X and Y are each independently selected from N or CR ^2a ; R\R ⁵ are each independently selected from hydrogen, halogen, hydroxyl, nitrogen, substituted or unsubstituted alkyl, substituted or unsubstituted

(When the C3-6-alkynyl and _C4-6 -cycloalkyl groups have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, hydroxyl, amino, hydroxyl, oxo, C6-alkyl, C7-6-alkenyl, C8-alkynyl, C12-cycloalkyl, C12-alkoxy, C13-alkynyl, C12-alkoxy, C13-alkynyl, C13-cycloalkyl, C13-alkoxy, C13-alkoxy, C13-alkynyl ...cycloalkyl, C13-alkoxy, C13-alkoxy, C13-alkoxy, C13-alkynyl, C13-alkynyl, C13-cycloalkyl, C13-alkoxy, C13-alkoxy, C13-alkoxy, C13

is monosubstituted or polysubstituted by one or more of the following substituents: halogen, nitrogen group, C1-6 alkyl, _C2-6 B group, C1-6 hydroxyl group or C1-6 cycloalkyl group; ^R3 is selected from -OR& or ^-NR3aR3C ; wherein, when R3 is selected from -O-, R3 is selected ^from substituted or unsubstituted 4-membered heterocyclic group; wherein the 4-10-membered heterocyclic group is present Claims

wherein R3 is selected from C1-6, C2-7, C3-16, C4-17, C5-18, C6-19, C7-20, C8-30, C9-40, C10-50, C11-60, C12-70, C13-31, C14-32, C15-33, C16-34, C17-35, C18-36, C19-40, C24-37, C19-41, C14-38, C14-39, C15-42, C16-43 ^, C17-44, C18-45, C19-46, C19-47, C19-48, C19-49, C24-40, C19-41, ^C19-47 , C19-48, C19-49, C19-49, C

When there are substituents in the C6-alkyl, C7-cycloalkyl and C4-10-membered ring groups, they can be independently substituted or polysubstituted by one or more of the following substituents: hematoxylin, oxyl, hydroxyl, oxyl, mercapto, oxo, C6-hydroxyl, C1-alkenyl, C2-6-hydroxyl, C16-cycloalkyl, C2-alkoxy, C3-alkylthio, C1-alkylthio or C16-alkylamino; the heterocyclic ring, heteroaryl and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and C. 4. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 3, characterized in that: in the general structural formula (I), ring A is selected from 1, 2, 3, 4 or 5. 5. The aromatic heterocyclic polyols according to claim 4, characterized in that: it is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof:

When substituents are present in alkenyl, _C2-6 alkynyl, C3-6 cycloalkyl and 4-10 membered heterocyclic groups, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, fluoro, hydroxy, nitrogen, carbonyl, oxo, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C1 ...

alkyl, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C4-10 membered heterocyclic group, substituted or unsubstituted 5-14 membered heteroaryl, -eR%, ^-SR3 \ _-SO2 -R; ^, \ -NH- ^R3 \ -NHCO- ^R3,1 , -C(O)NH- ^R3 \ -C(O) ^-R3,1 . -NHSO2 _- ^R3a or -P((J)R"RE; when the C6-alkyl, C6-alkynyl, C6-3-cycloalkyl, C6-i2- ^J /j-alkyl, 4-i0 membered heterocyclic group and S-14 membered heteroaryl in R° have substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, amino, Oxygen, hydroxyl, Cm-1 alkyl, C7.6-1-4-2-4-6-1-1 cycloalkyl, Cg.;:;?7 alkyl, 4-10 membered heterocyclic group, 5-14 membered heteroaryl, -OR ^3b , -S

NHCO-R ^3b , -NHSO ₂ -R ^3b > -C((:))NH-R ^3b or -C:(O)-R ^3h ; R" and R" are each independently selected from hydrogen, C1-6 alkyl, halogenated C1-5 alkyl, C2-6 cycloalkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; Claim 1__ The mineral paste is hydrogen or is selected from a C16 alkyl group substituted by a C12 cycloalkyl group; the heterocycle, heteroaryl group, and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O. 6. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula I or a pharmaceutically acceptable salt thereof:

In the formula, R' is selected from W ^la R ^ib ; R ^ia , R ^{, b} are each independently selected from hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 6-6 alkyl, substituted or unsubstituted C 2-6 cycloalkyl or substituted or unsubstituted 4-membered heterocyclic group; when the C 1-6 alkyl, C 2-6 alkenyl, C _2-5 alkyl, C 3-4 cycloalkyl and 4-membered heterocyclic group in R 'a , R * have substituents, they can be replaced by one or more of the following substituents:

R2 is selected from hydrogen, halogen or Ci% alkyl; R*, R? are selected from hydrogen or C1-6 alkyl;

Electrolyte C1-alkyl; ^R3 is selected ^{from -OR3'1} or -NR&R% wherein, when R3 is selected from -OR&, R& is selected from a substituted or unsubstituted 4-10 membered heterocyclic group; further, when the 4-10 membered heterocyclic group in R& has a substituent, each of them can be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, nitrogen group,

when R3 is selected from ^-NR3aR *, R3, R* are independently selected from substituted or unsubstituted C1-5 alkyl, halogenated C1-6 alkyl, substituted or unsubstituted C1-6 cycloalkyl, C1-6 alkoxy, halogenated alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further, when the C1-6 alkyl, C1-6 cycloalkyl, 4-10 membered heterocyclic group in ^R3a , R3c has a substituent, it can be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxy, amino, mercapto, oxo, C1-6 alkyl, C1-6 alkenyl, alkynyl, C1-6 cycloalkyl;

The heterocycle, heteroaryl, and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O. 7. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof: Claims

R', R'-4'-alkyl, R'-5'-alkyl, R'-6'-alkyl, R'-7'-alkyl, R'-8'-alkyl, R'-9'-alkyl, R'-10'-alkyl, R'-11'-alkyl, R'-12'-alkyl, R'-13'-alkyl, R'-14'-alkyl, R'-15'-alkyl, R'-16'-alkyl, R'-17'-alkyl, R'-18'-alkyl, R'-19'-alkyl, R'-20'-alkyl, R'-21'-alkyl, R'-22'-alkyl, R'-23'-alkyl, R'-24'-alkyl, R'-25'-alkyl, R'-26'-alkyl, R'-30'-alkyl, R'-31'-alkyl, R'-32'-alkyl, R'-33'-alkyl, R'-34'-alkyl, R'-35' ^R2 is selected from hydrogen, halogen or Cm alkyl; R3 is selected from hydrogen, halogen, alkyl, substituted or unsubstituted _C2-6 alkyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C4-10 membered aryl, substituted or unsubstituted C4-10 membered heterocyclyl, substituted or

or -cro)-R ^3b :

The heterocyclic ring, heteroaryl group, and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, R, and O. 8. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula II or a pharmaceutically acceptable salt thereof:

The claims include: the at least one alkyl group is substituted with one or more of the following: alkyl, alkyl, alkyl, alkyl, alkylene ...

R is selected from hydrogen, halogen or C-6 alkyl; R", ^R5 is selected from hydrogen or C1<alkyl; / is selected from C"-alkyl substituted by C"-cycloalkyl; R3 is selected from -OR ³³ or -NR* 1 henry; wherein, when R1 is selected from -0-R*, R* is selected from substituted or unsubstituted 4-10 membered heterocyclic group; further, when the 4-10 membered heterocyclic group in R* has a substituent, each of them can be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxyl, amino,

unsubstituted C1-6 cycloalkyl, C2-alkoxy, halogenated C1-6 alkoxy or substituted or unsubstituted 4-10 membered heterocyclic group; further, when the C1-6 alkyl, C2-cycloalkyl or 4-10 membered heterocyclic group in ^R5 \ ^R3C has a substituent, it can be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, thio, oxo, C1-6 alkyl, C2-alkenyl, C2-alkyl, C3-cycloalkyl, C4-alkoxy, C5-alkyl, C6-alkylthio or C6-alkylamino; the heterocyclic ring, heteroaryl or heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, S and O. 9. The aromatic heterocyclic pyrrolidone derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula III or a pharmaceutically acceptable salt thereof:

In the formula, X is selected from N or CR ^2a : R' is selected from NR ^{, a} R ^lb _: ^R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R40, R41, R49, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R40, R49, R40, R41, R42, R43, R44, R45 ^, R46, R47, R48, R49, R49, R40, R41 _, R44, R46, R47, R48, R49, R49, R40, R41, R49, R40, R41, R42, R43, R44, R46, R47, R48, R49, R49, R40, R49, R40, R41, R4

Huan group, substituted or unsubstituted Gw cycloalkyl, substituted or unsubstituted drinking technology aryl, substituted or unsubstituted 0 <J 4-10 yuan heterocyclic group. Substituted or Claims

When a membered heteroaromatic group has a substituent, it may be independently substituted or polysubstituted by one or more of the following substituents: halogen, nitrogen group, hydroxyl group, amino group, mercapto group, oxo group, C-alkyl group, halogenated C-alkyl group, C-alkenyl group, C-family group, C-cycloalkyl group, C-aryl group, 4-1. membered heterocyclic group, 5-14 membered heteroaryl group, -OR ³¹ \ -SR ³ \ -SO,-R ³ \ -NH-R ³ \ -NHCO-R ³ \ -NHS0 ₂ -R ^3b . -C(O)NH-R ^3b or -C(O)-R ^3b : R ³ \ R ^3b are each independently selected from hydrogen, C1-C1 alkyl, halogenated C1-C1 alkyl, C1-C1 cycloalkyl, C1-C1 alkoxy or halogenated C1-C1 alkoxy;

R' is selected from a J* alkyl group substituted by a G* cycloalkyl group; the heterocyclic ring, heteroaryl group, and polycyclic ring group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S, and O. 10. The aromatic heterocyclic pyrrolidine derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula HI or a pharmaceutically acceptable salt thereof:

When there are substituents, the alkenyl, C2/heptyl, C6-cycloalkyl and 4-10 membered heterocyclic groups may be independently substituted or polysubstituted by one or more of the following substituents: halogen, C6-hydroxyl, amino, C6-base, oxo, C6-alkyl, C6-alkenyl, C6-cycloalkyl ...

R\PL is selected from hydrogen or GMalkyl: is selected from Cmalkyl substituted by C&cycloalkyl; ^R3 is selected from ^-OR3a or -NI* ^R3C _; wherein, when R3 is selected from -OR3a, R* is selected from a substituted or unsubstituted 4- to 10-membered heterocyclic group; further, when the 4- to 10-membered heterocyclic group described in the preceding paragraph has a substituent, each of them may be independently substituted or polysubstituted by one or more of the following substituents: halogen, oxy, hydroxy, amino, S1-1, oxo, C1-6-alkyl, C2-6-alkenyl, C3-6-cycloalkyl, C1-6-alkoxy, C1-6-alkylthio or C1-6-alkylamino; when R3 is selected from ^-NR3a , R ^* is independently selected from a substituted or unsubstituted alkyl, halogenated C*alkyl, substituted or

When the C1-6 alkyl, C1-6 cycloalkyl, and 4-3 membered heterocyclic group have substituents, they may be independently substituted by one or more of the following substituents: Claims: wherein the compound comprises a 1,2-dimethyl-1,2-dihydro ... 11. The aromatic cyclophilic pyrrolidone derivative according to claim 4, characterized in that: it is a compound having the general structural formula shown by or a pharmaceutically acceptable salt thereof:

a C-6-alkylthio group, a C-6-alkylamino group, a 4-10-membered heterocyclic group, a S-14-membered heteroaryl group or a C-6-alkylthio group; R ² , R ³ :] are each independently selected from hydrogen, halogen or C 1-6 alkyl; R 2 is selected from hydrogen, halogen, cyclopentyl, substituted or unsubstituted C 2.6 alkyl, substituted or unsubstituted C _2.6 alkyl, substituted or unsubstituted C 1-6

or -P(O)R ^ia R, ^b ; when R" is alkyl, C 2 -C 6 alkenyl, C _{2 -C 6} alkyl, C 6 -C 6 cycloalkyl, C 2 -C 6 aryl, 30-membered heterocyclic group and 5-14-membered heteroaryl, when there are substituents, they may be independently substituted or polysubstituted by one or more of the following substituents: halogen, alkyl,

R6 is selected from C1-4 alkyl substituted by C1-4 cycloalkyl; the heterocyclic ring, aryl group and heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S and O. 12. The aromatic heterocyclic pyrrolidinone derivative according to claim 4, characterized in that: it is a compound represented by the general structural formula W or a pharmaceutically acceptable salt thereof: 73 Claims

In the formula, X is selected from N or CR ^2a : wherein CR 2a is selected from OR 2a ; Si is selected from hydrogen, substituted or unsubstituted C 6 alkyl

substituted _C3-6 cycloalkyl or substituted or unsubstituted 4-10 membered heterocyclic group; when _{the C4-6} alkyl, alkenyl, 2-6 alkynyl, 3-6 cycloalkyl and 4-3 membered heterocyclic group in R'a has a substituent, each of them may be independently substituted or polysubstituted by one or more of the following substituents:

alkyl, _C16 -alkylthio, C12-alkylamino, 4-14-membered heterocyclic group, 5-14-membered heteroaryl or C12-aryl; R\R are each independently selected from hydrogen, halogen or G-<, alkyl;

F is selected from G/C alkyl substituted by C3-6 cycloalkyl; ^R3 is selected from -OR* or -N-RE R3.: Wherein, when R3 is selected from -OR* or -N-RE R3.: wherein, when R3 is selected from -OR* or -N-RE R3., ^R3 is selected from substituted or unsubstituted 4- to 10-membered heterocyclic group: further, when the 4- to 10-membered heterocyclic group in R3 has a substituent, each of them can be independently substituted or polysubstituted by one or more of the following substituents: halogen, nitrogen, hydroxyl, amino,

The heterocycle, heteroaryl, or heterocyclic group contains at least one heteroatom, and the heteroatom is selected from one or more of N, R, and C. 13. The aromatic heterocyclic pyrrolidone derivative according to claim II or 12, characterized in that: it is a compound represented by the general structural formula N-1 or a pharmaceutically acceptable salt thereof:

In the formula, R is selected from substituted or unsubstituted C4 alkyl or ^-OR3a : When the C4 alkyl in R3 has a substituent, it can be independently substituted or polysubstituted by one or more of the following substituents: halogen, hydroxyl, amino, oxo, C4 alkyl, halogenated Claims 8 2 Cambodia "6 2 Ru Tomb "" 2 'quality 1;'—'3 匚琢 EM1TEZ;; next tomb "yuan and no case Lin set Ding MTT yuan 'table next to the straw: two Jia?' Ding 3:1? room -SO ₂ -R ^3b , -NH-R ³ \ -NHCO-R ^3b , -NHSO ₂ -R ^3b , -C(O)NH-R ^3b jS-C(O)-R ^3b ; R ³ and R 4 are each independently selected from hydrogen, C 6 alkyl, halogenated C 6 alkyl, C 2 -cycloalkyl, C 6 alkoxy, halogenated C 6 alkoxy or 4-10 2E* cyclic group; the heteroaryl group and the heterocyclic group contain at least one heteroatom, and the heteroatom is selected from one or more of N, S". 14. ® The aromatic heterocyclic pyrrolidone derivative according to claim 7 or 8,

A compound or a pharmaceutically acceptable salt thereof:

When the 4-10 membered heterocyclic group has substituents, they may be independently substituted by one or more of the following substituents: halogen, nitrogen group, hydroxyl group, nitrogen group,

or a 4-1 membered heterocyclic group;

15. The aromatic heterocyclic pyrrolidone derivative according to any one of claims 1 to 14, characterized in that it is selected from the following characteristic compounds or their isomers or pharmaceutically acceptable salts:

Claims

76 Claims

Claims 15. A pharmaceutical composition comprising at least one active ingredient as described in any one of claims 1 to 14 and at least one pharmaceutically acceptable carrier or excipient. 16. A method for preparing a compound as described in any one of claims 1 to 14 or a pharmaceutical composition as described in claim 15 for preventing or treating a disease associated with a PBK? signaling pathway. 1. The use according to claim 16, characterized in that the diseases include but are not limited to: 1) chronic inflammatory diseases, such as gout, nephritis, atherosclerosis, non-alcoholic fatty hepatitis, hepatitis, diabetes, enteritis, etc.; 2) acute inflammatory diseases, such as traumatic brain injury, wounds, toothache, acute nephritis, viral infection, sepsis, burns, septic shock; 3) cardiovascular diseases, such as myocardial ischemia, heart failure, etc.; 4) nervous system diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, meningitis, headache, neuropathic pain, etc.; 5) autoimmune diseases, such as atopic dermatitis, rheumatoid arthritis, systemic analgesia; 6) respiratory diseases, such as COPD, asthma, pneumonia, tuberculosis, etc.; 7) metabolic syndrome, such as obesity, diabetes, 8) Digestive system, such as viral hepatitis, liver cirrhosis, liver fibrosis, enteritis, etc.; 9) Tumors and tumor metastasis, tumor complications, etc. 18. The use according to claim 0, characterized in that the disease is selected from atopic dermatitis.