WO2025162114A1

WO2025162114A1 - Heterocyclic compound and use thereof

Info

Publication number: WO2025162114A1
Application number: PCT/CN2025/073925
Authority: WO
Inventors: 陈光武; 刘进; 张文胜; 张汉承; 马海军; 解振彪; 王昌华
Original assignee: Chengdu Mfs Pharma Co Ltd
Current assignee: Chengdu Mfs Pharma Co Ltd
Priority date: 2024-02-04
Filing date: 2025-01-22
Publication date: 2025-08-07
Anticipated expiration: 2026-08-04
Also published as: CN120787220A; WO2025162115A1; CN120787217A

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and provides a heterocyclic compound and a use thereof. The structure of the heterocyclic compound is as shown in formula II. The compound of the present invention has efficient sedative, hypnotic and/or anesthetic effects, can control the status epilepticus, further has an analgesic effect, and provides a new option for clinically preparing a drug having an analgesic effect, a drug having anesthetic, sedative and hypnotic effects and/or capable of controlling the status epilepticus, and a drug having anesthetic, sedative and hypnotic effects and/or capable of controlling the status epilepticus and also having the analgesic effect.

Description

A heterocyclic compound and its use

Technical Field

本发明属于药物化学技术领域，具体涉及一种杂环化合物及其用途。The present invention belongs to the technical field of medicinal chemistry, and in particular relates to a heterocyclic compound and a use thereof.

Background Art

临床上麻醉药物对患者全身麻醉的诱导、全身麻醉的维持、ICU危重病人镇静具有重要作用。丙泊酚是目前临床使用的快速、短效静脉全身麻醉药，它具有麻醉诱导起效快、苏醒迅速且功能恢复完善，术后恶心呕吐发生率低等优点。但是，包括丙泊酚、依托咪酯、磷丙泊酚二钠、环泊酚等在内的临床使用的静脉全身麻醉药物都没有镇痛作用。若化合物在具有镇静、催眠和/或麻醉作用，能够控制癫痫持续状态的同时还具有镇痛作用，能实现更完善的镇痛、明显降低阿片类镇痛药物的使用量、降低阿片类镇痛药物的不良反应、使得镇静、催眠和/或麻醉过程更加平稳。同时，还可以减少复合麻醉时其他药物的使用量、加快患者自镇静、催眠和/或麻醉状态的恢复、增加患者的安全性。因此，亟需开发出一种不仅具有镇静、催眠和/或麻醉作用，能够控制癫痫持续状态，同时还具有镇痛作用的药物。Clinically, anesthetics play an important role in the induction and maintenance of general anesthesia for patients, and in the sedation of critically ill patients in the ICU. Propofol is a fast-acting, short-acting intravenous general anesthetic currently used clinically. It has the advantages of rapid onset of anesthesia induction, rapid awakening and complete functional recovery, and a low incidence of postoperative nausea and vomiting. However, clinically used intravenous general anesthetics, including propofol, etomidate, fospropofol disodium, and propofol, do not have analgesic effects. If a compound has sedative, hypnotic, and/or anesthetic effects that can control status epilepticus while also having analgesic effects, it can achieve more complete analgesia, significantly reduce the use of opioid analgesics, reduce the adverse reactions of opioid analgesics, and make the sedation, hypnosis, and/or anesthesia process more stable. At the same time, it can also reduce the use of other drugs during combined anesthesia, accelerate the patient's recovery from sedation, hypnosis, and/or anesthesia, and increase patient safety. Therefore, there is an urgent need to develop a drug that not only has sedative, hypnotic, and/or anesthetic effects, can control status epilepticus, but also has analgesic effects.

(±)-5-[1-(2,3-二甲基苯基)乙基]-1H-咪唑作为一种咪唑类的α-2-肾上腺素受体激动剂,具有镇静镇痛作用。但是，(±)-5-[1-(2,3-二甲基苯基)乙基]-1H-咪唑的活性还有待进一步提高。因此，亟需开发出不仅具有高效的镇静、催眠和/或麻醉作用，能够控制癫痫持续状态，同时还具有镇痛作用的药物。(±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, an imidazole-type α-2-adrenergic receptor agonist, exhibits sedative and analgesic effects. However, the activity of (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole remains to be further improved. Therefore, there is an urgent need to develop drugs that not only exhibit highly effective sedative, hypnotic, and/or anesthetic effects, capable of controlling status epilepticus, but also possess analgesic properties.

Summary of the Invention

本发明的目的在于提供一种杂环化合物，及其在制备具有镇痛作用的药物，在制备具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状态的药物，以及在制备既具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状，同时还具有镇痛作用的药物中的用途。The object of the present invention is to provide a heterocyclic compound and its use in the preparation of a drug having an analgesic effect, in the preparation of a drug having an anesthetic, sedative, hypnotic effect and/or capable of controlling status epilepticus, and in the preparation of a drug having both an anesthetic, sedative, hypnotic effect and/or capable of controlling status epilepticus and an analgesic effect.

本发明提供了一种化合物、其立体异构体、其药学上可接受的盐、其溶剂合物、其前体药物、其代谢产物或其氘代衍生物，所述化合物的结构如式II所示：
The present invention provides a compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, the structure of the compound is shown in Formula II:

A环选自取代或未取代的5-6元氮杂芳基，所述5-6元氮杂芳基中，环杂原子均为N；所述取代基各自独立的选自羟基、卤素、氰基、-O、(CR₆R₇)_mR₈、
Ring A is selected from substituted or unsubstituted 5-6 membered nitrogen heteroaryl groups, wherein the ring heteroatoms of the 5-6 membered nitrogen heteroaryl groups are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, -O, (CR ₆ R ₇ ) _m R ₈ ,

未取代或被一个或两个以上R₉取代的以下基团：氨基、C_1-8烷基、C_2-8烯基、C_2-8炔基、C_1-8烷氧基、C_1-8烷硫基、3-8元饱和环烷基、3-8元饱和杂环基、芳基、杂芳基；The following groups, unsubstituted or substituted by one or more R ₉ : amino, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkylthio, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl;

m选自0、1、2、3、4、5；m is selected from 0, 1, 2, 3, 4, 5;

R₆、R₇各自独立的选自氢、C_1-8烷基；R ₆ and R ₇ are each independently selected from hydrogen and C _1-8 alkyl;

R₈选自CONR₁₀R₁₁、NR₁₀R₁₁、COOR₁₂、COR₁₂、OR₁₂、取代的芳基，所述取代基各自独立的选自卤素、羟基、硝基、氰基、C_1-8烷基、C_1-8烷氧基；R₁₀、R₁₁各自独立的选自氢、C_1-8烷基、C_1-8烷氧基、3-8元饱和环烷基、R₁₂选自C_1-8烷基、3-8元饱和环烷基、3-8元饱和杂环基、5-6元杂芳基、n选自0、1、2、3、4、5；R₁₃选自羟基、C_1-8烷氧基；R ₈ is selected from CONR ₁₀ R ₁₁ , NR ₁₀ R ₁₁ , COOR ₁₂ , COR ₁₂ , OR ₁₂ , substituted aryl, wherein the substituents are each independently selected from halogen, hydroxyl, nitro, cyano, C _1-8 alkyl, C _1-8 alkoxy; R ₁₀ and R ₁₁ are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, 3-8 membered saturated cycloalkyl, R ₁₂ is selected from C _1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R ₁₃ is selected from hydroxyl, C _1-8 alkoxy;

C环选自芳基、3-8元饱和环烷基、芳基并3-6元饱和环烷基；The C ring is selected from aryl, 3-8 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl;

e选自0、1、2、3、4、5；e is selected from 0, 1, 2, 3, 4, 5;

R_x1各自独立的选自氢、羟基、卤素、卤代或未卤代的C_1-8烷基、卤代或未卤代的C_1-8烷氧基、L₂R_2a，L₂选自无、C_1-6亚烷基，R_2a选自苯基、3-8元饱和环烷基、3-8元饱和杂环基；R _x1 is each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, L ₂ R _2a , L ₂ is selected from none, C _1-6 alkylene, R _2a is selected from phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl;

R_x2选自氢、C_1-8烷基、3-8元饱和环烷基、＝CR_xaR_xb；R_xa选自氢、C_1-8烷基，R_xb选自氢、C_1-8烷基；R _x2 is selected from hydrogen, C _1-8 alkyl, 3-8 membered saturated cycloalkyl, =CR _xa R _xb ; R _xa is selected from hydrogen, C _1-8 alkyl, R _xb is selected from hydrogen, C _1-8 alkyl;

R_x12选自氢、C_1-8烷基；R _x12 is selected from hydrogen, C _1-8 alkyl;

f选自0、1、2、3、4、5；f is selected from 0, 1, 2, 3, 4, 5;

R_x6各自独立的选自氢、卤素、卤代或未卤代的C_1-8烷基；R _x6 are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl;

R_x5选自C_1-8烷基；R _x5 is selected from C _1-8 alkyl;

R_x7选自氢、卤素、卤代或未卤代的C_1-8烷基；R _x7 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl;

R_x8选自氢、卤素、卤代或未卤代的C_1-8烷基、CONR_x9R_x10；R_x9选自氢、C_1-8烷基、C_1-8烷氧基，R_x10选自氢、C_1-8烷基、C_1-8烷氧基；R _x8 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl, CONR _x9 R _x10 ; R _x9 is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, R _x10 is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy;

所述R₉各自独立的选自卤素、羟基、氨基、巯基、C_1-8烷基、C_1-8烷氧基、C_2-8烯基、C_2-8炔基、OCOR_9a、SO₂R_9a、OR_9c、3-8元饱和环烷基、一个或两个以上R_9b取代的3-8元饱和环烷基、3-8元饱和杂环基、一个或两个以上R_9b取代的3-8元饱和杂环基、芳基、一个或两个以上R_9b取代的芳基、5-6元杂芳基、一个或两个以上R_9b取代的5-6元杂芳基；R_9a选自C_1-8烷基；R_9b各自独立的选自卤素、C_1-8烷基；R_9c选自3-8元饱和环烷基、3-8元饱和杂环基；Each of the R ₉ groups is independently selected from halogen, hydroxyl, amino, thiol, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, OCOR _9a , SO ₂ R _9a , OR _9c , a 3-8-membered saturated cycloalkyl group, a 3-8-membered saturated cycloalkyl group substituted with one or two or more R _9b , a 3-8-membered saturated heterocyclyl group, a 3-8-membered saturated heterocyclyl group substituted with one or two or more R _9b , an aryl group, an aryl group substituted with one or two or more R _9b , a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl group substituted with one or two or more R _9b ; R _9a is selected from C _1-8 alkyl; each of the R _9b groups is independently selected from halogen, C _1-8 alkyl; and R _9c is selected from a 3-8-membered saturated cycloalkyl group, or a 3-8-membered saturated heterocyclyl group.

L选自无、CR_aR_b、C(＝CR_cR_d)、NR_e、CO、CS、SO、S、O；L is selected from none, CR _a R _b , C(═CR _c R _d ), NR _e , CO, CS, SO, S, O;

R_a、R_b各自独立的选自氢、卤素、卤代或未卤代的C_1-8烷基、卤代或未卤代的C_1-8烷氧基、OH、OR_s，或者R_a、R_b连接形成3-8元饱和环烷基或3-8元饱和杂环基；R_s选自3-8元饱和环烷基、3-8元饱和杂环基、苄基；R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-8 membered saturated cycloalkyl or a 3-8 membered saturated heterocyclic group; R _s is selected from a 3-8 membered saturated cycloalkyl, a 3-8 membered saturated heterocyclic group, or benzyl;

R_c、R_d各自独立的选自氢、卤素；R _c and R _d are each independently selected from hydrogen and halogen;

R_e选自氢、C_1-8烷基；R _e is selected from hydrogen, C _1-8 alkyl;

B环为 Ring B is

X₁为N或CR₁，X₂为N或CR₂，X₃为N或CR₃，X₄为N或CR₄，X₅为N或CR₅，且X₁、X₂、X₃、X₄、X₅中至少3个不同时为N； _X1 is N or _CR1 , _X2 is N or _CR2 , _X3 is N or _CR3 , _X4 is N or _CR4 , _X5 is N or _CR5 , and at least three of _X1 , X2, _X3 , _X4 , _and _X5 are not N at the same time;

R₁、R₂、R₃、R₄、R₅、R₁₅各自独立的选自氢、羟基、卤素、卤代或未卤代的C_1-8烷基、卤代或未卤代的C_1-8烷氧基、L₁R_1a，L₁选自无、C_1-6亚烷基，R_1a选自芳基、3-8元饱和环烷基、3-8元饱和杂环基，或者R₁、R₂、R₃、R₄、R₅中两个相邻的基团连接形成未取代或被一个或两个以上R₁₄取代的苯环，所述R₁₄各自独立的选自卤素、C_1-8烷基、C_1-8烷氧基；R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₁₅ are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, L ₁ R _1a , L ₁ is selected from none, C _1-6 alkylene, R _1a is selected from aryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, or two adjacent groups among R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are linked to form a benzene ring which is unsubstituted or substituted with one or more R ₁₄ , and R ₁₄ is each independently selected from halogen, C _1-8 alkyl, and C _1-8 alkoxy;

或者A环上的取代基与R₅连接成环。Alternatively, the substituent on ring A is connected to R ₅ to form a ring.

进一步地，所述A环选自以下结构：
Furthermore, the A ring is selected from the following structures:

C环选自芳基、3-6元饱和环烷基、芳基并3-6元饱和环烷基、3-5元不饱和环烷基，优选为苯环、3-4元饱和环烷基、 C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl,

e选自0、1、2、3；e is selected from 0, 1, 2, 3;

R_x1各自独立的选自氢、羟基、卤素、卤代或未卤代的C_1-4烷基、卤代或未卤代的C_1-4烷氧基、L₂R_2a，L₂选自无、C_1-2亚烷基，R_2a选自苯基、3-4元饱和环烷基、3-4元饱和杂环基；R _x1 is each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-4 alkyl, halogenated or unhalogenated C _1-4 alkoxy, L ₂ R _2a , L ₂ is selected from none, C _1-2 alkylene, R _2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl;

R_x2选自氢、C_1-3烷基、3-4元饱和环烷基、＝CR_xaR_xb；R_xa选自氢、C_1-4烷基，R_xb选自氢、C_1-4烷基；R _x2 is selected from hydrogen, C _1-3 alkyl, 3-4 membered saturated cycloalkyl, =CR _xa R _xb ; R _xa is selected from hydrogen, C _1-4 alkyl, R _xb is selected from hydrogen, C _1-4 alkyl;

R_x12选自氢、C_1-3烷基；R _x12 is selected from hydrogen, C _1-3 alkyl;

R_x3选自氢、卤素、未取代或被一个或两个以上卤素取代的C_1-3烷基、
R _x3 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

R_x4选自氢、卤素、未取代或被一个或两个以上卤素取代的C_1-3烷基、
R _x4 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

R_x11选自氢、卤素、未取代或被一个或两个以上卤素取代的C_1-3烷基、
R _x11 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

f选自0、1、2、3；f is selected from 0, 1, 2, 3;

R_x6各自独立的选自氢、卤素、卤代或未卤代的C_1-4烷基；R _x6 are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl;

R_x5选自C_1-3烷基；R _x5 is selected from C _1-3 alkyl;

R_x7选自氢、卤素、卤代或未卤代的C_1-4烷基；R _x7 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl;

R_x8选自氢、卤素、卤代或未卤代的C_1-4烷基、CONR_x9R_x10；R_x9选自氢、C_1-4烷基、C_1-4烷氧基，R_x10选自氢、C_1-4烷基、C_1-4烷氧基；R _x8 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl, CONR _x9 R _x10 ; R _x9 is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, R _x10 is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy;

所述的杂环基至少含有一个选自N、O或S的杂原子。The heterocyclic group contains at least one heteroatom selected from N, O or S.

进一步地，所述化合物的结构如式II-1或式II-2所示：
Furthermore, the structure of the compound is shown in Formula II-1 or Formula II-2:

其中，Q选自无、CR_x2R_x12、CO、CH＝CH、 wherein Q is selected from none, CR _x2 R _x12 , CO, CH=CH,

e选自0、1、2、3；e is selected from 0, 1, 2, 3;

R_x12选自氢、C_1-3烷基；R _x12 is selected from hydrogen, C _1-3 alkyl;

f选自0、1、2、3；f is selected from 0, 1, 2, 3;

R_x5选自C_1-3烷基；R _x5 is selected from C _1-3 alkyl;

所述的杂环基至少含有一个选自N、O或S的杂原子；The heterocyclic group contains at least one heteroatom selected from N, O or S;

L、X₁、X₂、X₃、X₄、X₅如前文所述。L, X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are as described above.

进一步地，所述L选自无、CR_aR_b、C(＝CR_cR_d)、NR_e、CO、CS、SO、S、O；Further, the L is selected from none, CR _a R _b , C(═CR _c R _d ), NR _e , CO, CS, SO, S, O;

R_a、R_b各自独立的选自氢、卤素、卤代或未卤代的C_1-6烷基、卤代或未卤代的C_1-6烷氧基、OH、OR_s，或者R_a、R_b连接形成3-6元饱和环烷基或3-6元饱和杂环基；R_s选自3-6元饱和环烷基、3-6元饱和杂环基、苄基；R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-6 alkyl, halogenated or unhalogenated C _1-6 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-6 membered saturated cycloalkyl or a 3-6 membered saturated heterocyclic group; R _s is selected from a 3-6 membered saturated cycloalkyl, a 3-6 membered saturated heterocyclic group, or benzyl;

R_e选自氢、C_1-6烷基。R _e is selected from hydrogen, C _1-6 alkyl.

R_a、R_b各自独立的选自氢、卤素、卤代或未卤代的C_1-3烷基、卤代或未卤代的C_1-3烷氧基、OH、OR_s，或者R_a、R_b连接形成3-4元饱和环烷基或3-4元饱和杂环基；R_s选自3-4元饱和环烷基、3-4元饱和杂环基、苄基；R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-3 alkyl, halogenated or unhalogenated C _1-3 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-4 membered saturated cycloalkyl or a 3-4 membered saturated heterocyclic group; R _s is selected from a 3-4 membered saturated cycloalkyl, a 3-4 membered saturated heterocyclic group, or benzyl;

R_e选自氢、C_1-3烷基。R _e is selected from hydrogen, C _1-3 alkyl.

进一步地，所述B环为 Furthermore, the B ring is

R₁、R₂、R₃、R₄、R₅各自独立的选自氢、羟基、卤素、卤代或未卤代的C_1-6烷基、卤代或未卤代的C_1-6烷氧基、L₁R_1a，L₁选自无、C_1-4亚烷基，R_1a选自芳基、3-6元饱和环烷基、3-6元饱和杂环基。R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-6 alkyl, halogenated or unhalogenated C _1-6 alkoxy, L ₁ R _1a , L ₁ is selected from none, C _1-4 alkylene, and R _1a is selected from aryl, 3-6 membered saturated cycloalkyl, and 3-6 membered saturated heterocyclic group.

进一步地，所述化合物选自：

Furthermore, the compound is selected from:

进一步地，所述药学上可接受的盐为枸橼酸盐、氢氟酸盐、磷酸盐、丙酸盐、琥珀酸盐、酒石酸盐、乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐、碳酸盐、硫酸氢盐、硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环已氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、茶磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟蔡酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐、昔萘酸盐、甲烷磺酸盐或对甲苯磺酸盐。Furthermore, the pharmaceutically acceptable salt is citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, salt, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, or p-toluenesulfonate.

本发明还提供了一种药物组合物，所述药物组合物是以上述的化合物、其立体异构体、其药学上可接受的盐、其溶剂合物、其前体药物、其代谢产物或其氘代衍生物为活性成分，加上药学上可接受的辅料制备而成的制剂。The present invention also provides a pharmaceutical composition, which is a preparation prepared with the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

本发明还提供了上述的化合物、其立体异构体、其药学上可接受的盐、其溶剂合物、其前体药物、其代谢产物或其氘代衍生物在制备具有镇痛作用，和/或，具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状态的药物中的用途。The present invention also provides the use of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative in the preparation of a drug having analgesic effect, and/or anesthetic, sedative, hypnotic effect and/or capable of controlling status epilepticus.

“具有镇痛作用，和/或，具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状态的药物中的用途”包括以下三种情况：(1)具有镇痛作用；(2)具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状态；(3)既具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状，同时还具有镇痛作用。“Use in drugs having analgesic effect, and/or anesthetic, sedative, hypnotic effect and/or the ability to control status epilepticus” includes the following three situations: (1) having analgesic effect; (2) having anesthetic, sedative, hypnotic effect and/or the ability to control status epilepticus; (3) having both anesthetic, sedative, hypnotic effect and/or the ability to control status epilepticus and analgesic effect.

本发明所述“既具有麻醉、镇静、催眠作用和/或能够控制癫痫持续状，同时还具有镇痛作用”是指在本发明化合物产生镇静、催眠和/或麻醉作用时对伤害性刺激没有反应或提高对伤害性刺激的反应阈值。The term "having anesthetic, sedative, hypnotic effects and/or being able to control epileptic seizures, and at the same time having analgesic effects" as used in the present invention means that when the compound of the present invention produces sedative, hypnotic and/or anesthetic effects, it does not respond to noxious stimuli or increases the response threshold to noxious stimuli.

本发明所述“具有镇静作用的药物”是指一种有效帮助睡眠和有效改善睡眠的药物。即能避免失眠对人体的严重危害，治疗失眠病，提高睡眠质量。The "drug with sedative effect" mentioned in the present invention refers to a drug that effectively helps sleep and effectively improves sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

本发明所述“具有催眠作用的药物”是指一种能诱导睡意、促使睡眠的药物。即对中枢神经系统有抑制作用，小剂量引起镇静，过量导致全身麻醉。The term "drug with hypnotic effect" as used herein refers to a drug that can induce drowsiness and promote sleep. This means that the drug has an inhibitory effect on the central nervous system, causing sedation in small doses and general anesthesia in excessive doses.

本发明所述“具有麻醉作用的药物”是指由药物产生的一种中枢神经和(或)周围神经系统的可逆性功能抑制，这种抑制的特点主要是感觉特别是痛觉的丧失。优选地，所述麻醉为全身麻醉。The term "drug with anesthetic effect" as used herein refers to a drug that produces a reversible functional inhibition of the central nervous system and/or peripheral nervous system, wherein the main characteristic of such inhibition is the loss of sensation, especially pain. Preferably, the anesthesia is general anesthesia.

本发明所述“全身麻醉”简称全麻，是指麻醉药进入体内后对中枢神经系统产生的暂时抑制，临床表现为神志消失、全身痛觉消失、遗忘、反射抑制和骨骼肌松弛。The "general anesthesia" mentioned in the present invention is referred to as general anesthesia, which refers to the temporary inhibition of the central nervous system after the anesthetic enters the body. The clinical manifestations are loss of consciousness, loss of pain sensation throughout the body, amnesia, reflex inhibition and skeletal muscle relaxation.

本发明所述的“癫痫持续状态”是指癫痫连续发作之间意识未完全恢复又频繁再发，或发作持续30分钟以上不自行停止。长时间癫痫发作，若不及时25治疗，可因高热、循环衰竭或神经元兴奋毒性损伤导致不可逆的脑损伤，致残率和病死率很高，因而癫痫状态是内科常见的急症。"Status epilepticus," as used herein, refers to frequent recurrences of epileptic seizures with incomplete recovery of consciousness between consecutive seizures, or seizures that persist for more than 30 minutes without spontaneous cessation. Prolonged seizures, if not promptly treated, can lead to irreversible brain damage due to hyperthermia, circulatory failure, or neuronal excitotoxicity, resulting in high disability and mortality rates. Therefore, status epilepticus is a common medical emergency.

关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀C_a～b烷基表示任何含“a”至“b”个碳原子的烷基。例如，C_1～6烷基是指包含1、2、3、4、5或6个碳原子的直链或支链的烷基，C_1～6烷氧基是指包含1、2、3、4、5或6个碳原子的直链或支链的烷氧基，C_1-4亚烷基是指包含1、2、3或4个碳原子的直链或支链的亚烷基，以此类推。The minimum and maximum carbon atom content of a hydrocarbon group is indicated by a prefix. For example, the prefix Ca _-b alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. For example, _C1-6 alkyl refers to a straight or branched chain alkyl group containing 1, 2, 3, 4, 5, or 6 carbon atoms, _C1-6 alkoxy refers to a straight or branched chain alkoxy group containing 1, 2, 3, 4, 5, or 6 carbon atoms, _C1-4 alkylene refers to a straight or branched chain alkylene group containing 1, 2, 3, or 4 carbon atoms, and so on.

环状基团环原子数目的最小值和最大值通过前缀表示，例如，3-8元饱和环烷基指含3、4、5、6、7或8个环原子的饱和环烷基，3-6元饱和环烷基指含3、4、5或6个环原子的饱和环烷基，3-8元饱和杂环基指含3、4、5、6、7或8个环原子的饱和杂环基，3-6元饱和杂环基指含3、4、5或6个环原子的饱和杂环基，以此类推。The minimum and maximum number of ring atoms in a cyclic group are indicated by prefixes, for example, 3-8 membered saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, 3-6 membered saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5 or 6 ring atoms, 3-8 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, 3-6 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5 or 6 ring atoms, and so on.

本文“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换，包括该分子中同位原子或异位原子上的1个、2个或多个取代。The term "substituted" herein refers to the replacement of one, two or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two or more substitutions on isotopic or ectopic atoms in the molecule.

“芳基”指具有共轭的π电子体系的全碳单环基团，例如苯基。所述芳基不含杂原子，如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。"Aryl" refers to an all-carbon monocyclic group with a conjugated π electron system, such as phenyl. The aryl group does not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent moiety must be on a carbon atom on the ring with a conjugated π electron system.

“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括但不限于氧、硫、氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、噻唑基、恶唑基、嘧啶酮基、吡啶酮基、吲哚基、四唑基等。"Heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to herein include, but are not limited to, oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinonyl, pyridonyl, indolyl, tetrazolyl, and the like.

在一些优选的技术方案中，杂芳基为5-6元杂芳基。In some preferred technical embodiments, the heteroaryl group is a 5-6 membered heteroaryl group.

杂环化合物是由碳原子和非碳原子(杂原子)配合组成环的环状化合物，成环的原子中，除碳原子以外的非碳原子称为“环杂原子”。Heterocyclic compounds are cyclic compounds composed of carbon atoms and non-carbon atoms (heteroatoms) forming a ring. Among the atoms forming the ring, the non-carbon atoms other than carbon atoms are called "ring heteroatoms".

卤素为氟、氯、溴或碘。Halogen is fluorine, chlorine, bromine or iodine.

与现有技术相比，本发明化合物取得了以下有益效果：Compared with the prior art, the compounds of the present invention have achieved the following beneficial effects:

一方面，与(±)-5-[1-(2,3-二甲基苯基)乙基]-1H-咪唑相比，本发明咪唑类的化合物的麻醉活性明显提高；On the one hand, compared with (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, the anesthetic activity of the imidazole compounds of the present invention is significantly improved;

另一方面，本发明还提供了除咪唑类化合物以外的具有其它新型母核结构的化合物，并首次发现这些化合物具有镇静、催眠和/或麻醉作用，能够控制癫痫持续状态，为临床上制备具有镇静、催眠和/或麻醉作用及控制癫痫持续状态的药物提供了一种新的选择；On the other hand, the present invention also provides compounds with other novel core structures in addition to imidazole compounds, and for the first time discovered that these compounds have sedative, hypnotic and/or anesthetic effects and can control status epilepticus, providing a new option for the clinical preparation of drugs with sedative, hypnotic and/or anesthetic effects and for controlling status epilepticus.

此外，本发明还首次发现，本发明化合物不仅具有高效的镇静、催眠和/或麻醉作用，能够控制癫痫持续状态，同时还具有镇痛作用，临床应用时可以减少或不用如芬太尼、阿芬太尼、舒芬太尼或瑞芬太尼等阿片类镇痛药物，从而减少阿片类镇痛药物循环抑制、呼吸抑制、尿潴留、皮肤瘙痒等不良反应的发生。In addition, the present invention also discovered for the first time that the compound of the present invention not only has highly effective sedative, hypnotic and/or anesthetic effects, and can control status epilepticus, but also has analgesic effects. In clinical application, the use of opioid analgesics such as fentanyl, alfentanil, sufentanil or remifentanil can be reduced or eliminated, thereby reducing the occurrence of adverse reactions of opioid analgesics such as circulatory inhibition, respiratory depression, urinary retention, and skin itching.

显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。The following is a further detailed description of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention.

DETAILED DESCRIPTION

本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10^-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400)核磁仪，测定溶剂为氘代二甲基亚砜(d₆-DMSO)或者氘代氯仿(CDCl₃)，内标为四甲基硅烷(TMS)。The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of ^10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer in deuterated dimethyl sulfoxide (d6 _- DMSO) or deuterated chloroform ( _CDCl3 ) as the solvent, with tetramethylsilane (TMS) as the internal standard.

LCMS的测定用(Agilent LCMS1260-6110)(ESI)，柱子：Waters X-Bridge C18(50mm x 4.6mm x 3.5μm)；柱温：40℃；流速：2.0mL/min；流动相：在3分钟时间内从95％[water+0.05％TFA]和5％[CH₃CN+0.05％TFA]梯度到0％[water+0.05％TFA]和100％[CH₃CN+0.05％TFA]，在此条件下保持1分钟，再在0.05分钟内梯度到95％[water+0.05％TFA]和5％[CH₃CN+0.05％TFA]，再保持此条件0.7分钟。LCMS determination was performed using an Agilent LCMS 1260-6110 (ESI) column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH ₃ CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH ₃ CN + 0.05% TFA] over 3 minutes, maintained at these conditions for 1 minute, then gradient to 95% [water + 0.05% TFA] and 5% [CH ₃ CN + 0.05% TFA] over 0.05 minutes, and maintained at these conditions for 0.7 minutes.

1)药材与试剂1) Medicinal materials and reagents

薄层层析硅胶板使用烟台新诺化工有限公司HSGF254硅胶板，厚度为1mm。The thin layer chromatography silica gel plate used was HSGF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

薄层色谱法(TLC)使用烟台江友硅胶开发有限公司的产品，其规格为0.2±0.03mm。Thin layer chromatography (TLC) was performed using a silica gel product from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2 ± 0.03 mm.

柱层层析一般采用乳山市太阳干燥剂有限公司(山东威海)100～200目或者200～300目硅胶为载体。Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel produced by Rushan Sun Desiccant Co., Ltd. (Weihai, Shandong) as a carrier.

2)主要仪器2) Main instruments

JA2003N电子天平(上海佑科仪器仪表有限公司)；JA2003N electronic balance (Shanghai Youke Instrument Co., Ltd.);

DF-101S集热式恒温加热磁力搅拌器(郑州赛特利斯生物科技有限公司)；DF-101S heat-collecting constant temperature heating magnetic stirrer (Zhengzhou Saitelis Biotechnology Co., Ltd.);

98-2磁力搅拌器(上海司乐仪器有限公司)；98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

ZF-2三用紫外仪(上海安亭电子仪器厂)；ZF-2 three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory);

RE-2000B旋转蒸发器(郑州科泰实验设备有限公司)；RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

DLSK-5/20低温冷却液循环泵(郑州科泰实验设备有限公司)；DLSK-5/20 low-temperature coolant circulation pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

W201D恒温水浴锅(上海市申顺生物科技有限公司)；W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

SHB-III循环水式真空泵(郑州汇成科工贸有限公司)；SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

SHB-B95移动水泵(郑州汇成科工贸有限公司)；SHB-B95 mobile water pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

紫外线高压汞灯(北京天脉恒辉光源电器有限公司)。Ultraviolet high-pressure mercury lamp (Beijing Tianmai Henghui Light Source Electrical Co., Ltd.).

DGJ-10C真空冷冻干燥机(上海博登生物科技有限公司)；DGJ-10C vacuum freeze dryer (Shanghai Boden Biotechnology Co., Ltd.);

KQ5200超声波清洗器(昆山市超声仪器有限公司)；KQ5200 ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

2XZ-2型旋片式真空泵(临海市谭氏真空设备有限公司)；2XZ-2 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.);

Biotage Isolera One(Biotage Sweden AB)Biotage Isolera One (Biotage Sweden AB)

实施例1本发明化合DA-6～DA-8的制备
Example 1 Preparation of compounds DA-6 to DA-8 of the present invention

1、化合物85-7-1的制备1. Preparation of compound 85-7-1

在室温下，将化合物85-6(7.1g,16.8mmol)溶解在THF/MeOH/H₂O(55mL,v/v/v＝8/2/1)中，冰盐浴将反应体系降至0℃，将NaOH(1.3g,32.5mmol)分批加至体系，继续搅拌30分钟。经TLC监测反应完全后，将反应体系用EtOAc(3×10mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/5)监测，收集Rf＝0.3～0.4部分，得到白色固体目标化合物85-7-1(3.5g，收率77.7％)。ESI[M+H]⁺＝268.2Compound 85-6 (7.1 g, 16.8 mmol) was dissolved in THF/MeOH/ _H₂O (55 mL, v/v/v = 8/2/1) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. NaOH (1.3 g, 32.5 mmol) was added portionwise and stirring continued for 30 minutes. After completion of the reaction as monitored by TLC, the reaction system was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v _/ v) = 1/10 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/5). Fractions with Rf = 0.3 to 0.4 were collected to obtain the target compound 85-7-1 (3.5 g, 77.7% yield) as a white solid. ESI [M+H] ^⁺ = 268.2

¹H NMR(400MHz,d₆-DMSO)δ12.03(s,1H),7.49(s,1H),7.28(d,J＝7.0Hz,1H),7.20–7.09(m,2H),7.01(d,J＝1.5Hz,1H),2.28(s,3H),2.09(s,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ12.03(s,1H),7.49(s,1H),7.28(d,J＝7.0Hz,1H),7.20–7.09(m,2H),7.01(d,J＝1.5Hz,1H),2.28(s,3H),2.09(s,3H).

2、目标化合物DA-7的制备2. Preparation of target compound DA-7

在室温下，将化合物85-7-1(500mg,1.87mmol)溶解在干燥DMF(10mL)中，冰盐浴降温至0℃，将NaH(88mg,60％in mineral oil,2.2mmol)加至体系，在0℃搅拌10分钟，用注射器将BnBr(352mg,2.1mmol)缓慢加至体系，室温搅拌5小时。经TLC监测反应完全后，将反应液倒入冰水中，用EtOAc(3×5mL)萃取,合并有机相，饱和食盐水洗涤，无水Na₂SO₄干燥，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/8)并收集Rf＝0.5～0.6部分得到化合物85-7(555mg，收率83.0％)。ESI[M+H]⁺＝358.4。Compound 85-7-1 (500 mg, 1.87 mmol) was dissolved in dry DMF (10 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (88 mg, 60% in mineral oil, 2.2 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. BnBr (352 mg, 2.1 mmol) was slowly added to the mixture via syringe, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over _anhydrous _Na₂SO₄ , and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) = 1/8) and fractions with Rf = 0.5-0.6 were collected to afford compound 85-7 (555 mg, 83.0% yield). ESI [M+H] ^⁺ = 358.4.

在室温下，将85-7(555mg,1.55mmol)溶解在干燥THF(8mL)中，用氮气将反应体系置换三次，氮气保护，冰盐浴降温至-10℃，用注射器将MeLi(2.0mL,1.3mol/L in Et₂O,2.6mmol)缓慢加至体系，继续搅拌30分钟。经TLC监测反应完全后,将反应用饱和氯化铵水溶液(10mL)终止，用EtOAc(3×5mL)萃取，合并有机相，饱和食盐水洗涤，无Na₂SO₄干燥，抽滤，将滤液减压浓缩后溶解在二氯甲烷(10mL)，加入TFA(2mL)，室温搅拌3小时。经TLC监测反应完全后，减压浓缩，饱和碳酸氢钠水溶液(20mL)碱化，用二氯甲烷(3×5mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/10)，收集Rf＝0.5～0.6部分，得到无色油状目标化合物DA-7(290mg，两步收率52.6％)。At room temperature, 85-7 (555 mg, 1.55 mmol) was dissolved in dry THF (8 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. MeLi (2.0 mL, 1.3 mol/L in Et ₂ O, 2.6 mmol) was slowly added to the system via syringe and stirring continued for 30 minutes. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure and dissolved in dichloromethane (10 mL). TFA (2 mL) was added and stirred at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the reaction was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (3×5 mL), and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) = 1/10), and the fractions with Rf = 0.5-0.6 were collected to give the target compound DA-7 (290 mg, two-step yield 52.6%) as a colorless oil.

¹H NMR(400MHz,d₆-DMSO)δ7.46(d,J＝1.7Hz,1H),7.37–7.25(m,3H),7.20–7.14(m,2H),7.12–7.03(m,2H),6.97–6.93(m,1H),6.39(d,J＝2.2Hz,1H),5.47(s,1H),5.06(s,2H),4.93(s,1H),2.21(s,3H),1.96(s,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.46(d,J＝1.7Hz,1H),7.37–7.25(m,3H),7.20–7.14(m,2H),7.12–7.03(m,2H),6.97–6.9 3(m,1H),6.39(d,J=2.2Hz,1H),5.47(s,1H),5.06(s,2H),4.93(s,1H),2.21(s,3H),1.96(s,3H).

5、目标化合物DA-8的制备5. Preparation of target compound DA-8

在室温下，将化合物DA-7(58mg,0.16mmol)和10％湿钯碳(6mg)溶于MeOH(5mL)，用氢气置换体系三次，在氢气下室温搅拌2小时。经TLC监测反应完全后，抽滤，滤饼用甲醇(3×5mL)洗涤，将滤液减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/10)，并收集Rf＝0.5～0.6部分得到无色油状目标化合物DA-8(53mg，收率90.9％)。At room temperature, compound DA-7 (58 mg, 0.16 mmol) and 10% wet palladium on carbon (6 mg) were dissolved in MeOH (5 mL). The system was purged with hydrogen three times and stirred at room temperature under hydrogen for 2 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) = 1/10), and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DA-8 (53 mg, 90.9% yield) as a colorless oil.

¹H NMR(400MHz,d₆-DMSO)δ7.39–7.27(m,4H),7.25–7.19(m,2H),7.00–6.93(m,2H),6.92–6.86(m,1H),6.71(d,J＝2.1Hz,1H),5.10(s,2H),4.31(q,J＝7.1Hz,1H),2.22(s,3H),2.15(s,3H),1.39(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.39–7.27(m,4H),7.25–7.19(m,2H),7.00–6.93(m,2H),6.92–6.86(m,1H),6.71(d,J＝ 2.1Hz,1H),5.10(s,2H),4.31(q,J＝7.1Hz,1H),2.22(s,3H),2.15(s,3H),1.39(d,J＝7.1Hz,3H).

实施例2本发明化合物DA-5，DA-9的制备
Example 2 Preparation of Compounds DA-5 and DA-9 of the Present Invention

目标化合物DA-5、DA-9的制备方法使用化合物DA-5-1为原料，与溴化物或碘化物通过烷基化反应得到。The target compounds DA-5 and DA-9 are prepared by using compound DA-5-1 as a raw material and reacting it with bromide or iodide through an alkylation reaction.

化合物DA-5：11.4mg，白色固体，ESI[M+H]⁺＝282.1。Compound DA-5: 11.4 mg, white solid, ESI [M+H] ⁺ = 282.1.

化合物DA-9：36.4mg，糖浆状固体，ESI[M+H]⁺＝318.1。Compound DA-9: 36.4 mg, syrupy solid, ESI [M+H] ⁺ = 318.1.

¹H NMR(400MHz,d₆-DMSO)δ7.39(t,J＝7.6Hz,2H),7.28(dd,J＝15.3,7.3Hz,2H),7.20–7.09(m,4H),7.05–7.03(m,1H),6.29(d,J＝4.0Hz,1H),5.97(d,J＝4.0Hz,1H),2.29(s,3H),2.10(s,3H),1.99(s,3H),1.94(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.39(t,J＝7.6Hz,2H),7.28(dd,J＝15.3,7.3Hz,2H),7.20–7.09(m,4H),7.05–7.03(m,1H),6.2 9(d,J＝4.0Hz,1H),5.97(d,J＝4.0Hz,1H),2.29(s,3H),2.10(s,3H),1.99(s,3H),1.94(d,J＝7.2Hz,3H).

实施例3本发明化合物DA-1，化合物DA-2和化合物DA-3的制备
Example 3 Preparation of Compound DA-1, Compound DA-2 and Compound DA-3 of the Present Invention

1、化合物DA-1的制备1. Preparation of compound DA-1

在室温下，将氢氧化钠(2eq)的水溶液加至依托咪酯(1eq)的EtOH溶液，回流搅拌2小时。经TLC监测反应完全后，将反应液减压浓缩，用浓盐酸调节pH≈5～6，用EtOAc萃取，合并有机相用饱和食盐水洗涤，无水Na₂SO₄干燥，抽滤，减压浓缩得灰色固体化合物DA-1-1。At room temperature, an aqueous solution of sodium hydroxide (2 eq) was added to a solution of etomidate (1 eq) in EtOH and stirred under reflux for 2 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure, the pH adjusted to 5-6 with concentrated hydrochloric acid, and extracted with EtOAc. The combined organic _phases were washed with saturated brine, dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain compound DA-1-1 as a gray solid.

在冰水浴0℃下，将化合物DA-1-1(1eq),N,O-二甲基羟胺盐酸盐(2eq)，DIEA(3eq)溶解在DMF(50mL)中，分批加入HATU(1.5eq),室温搅拌过夜。经TLC监测反应完全后，将冰水加至反应体系，用EtOAc萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/5～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/1)监测，收集Rf＝0.5～0.6部分，得到无色油状化合物DA-1-2。ESI[M+H]⁺＝260.2。Compound DA-1-1 (1 eq), N,O-dimethylhydroxylamine hydrochloride (2 eq), and DIEA (3 eq) were dissolved in DMF (50 mL) in an ice-water bath at 0°C. HATU (1.5 eq) was added portionwise and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were dried over _anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/5 to 1/1) with TLC monitoring (ethyl acetate/petroleum ether (v/v) = 1/1). Fractions with Rf = 0.5-0.6 were collected to afford compound DA-1-2 as a colorless oil. ESI [M+H] ⁺ = 260.2.

在室温下，将化合物DA-1-2(610mg,2.4mmol)溶解在干燥THF(5mL)中，用氮气将反应体系置换三次，氮气保护，冰盐浴降温至0℃，用注射器将格氏试剂A(5mL,1mol/L,5mmol)缓慢加至体系，室温搅拌4小时。经TLC监测反应完全后，用冰水浴降至0℃，将饱和氯化铵水溶液(10mL)缓慢加至反应体系，用EtOAc(3×10mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/8～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/1)监测，收集Rf＝0.5～0.6部分，得到无色油状化合物DA-1(460mg，收率63.0％)ESI[M+H]⁺＝305.0At room temperature, compound DA-1-2 (610 mg, 2.4 mmol) was dissolved in dry THF (5 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. Grignard reagent A (5 mL, 1 mol/L, 5 mmol) was slowly added to the system with a syringe and stirred at room temperature for 4 hours. After the reaction was completed as monitored by TLC, the temperature was lowered to 0°C with an ice-water bath, and saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction system. The mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/8 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/1). The fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-1 (460 mg, yield 63.0%) as a colorless oil. ESI [M+H] ⁺ = 305.0

¹H NMR(400MHz,d₆-DMSO)8.50(s,1H),7.38–7.32(m,2H),7.31–7.25(m,2H),7.23–7.17(m,3H),7.14(t,J＝7.6Hz,1H),7.05(d,J＝7.3Hz,1H),6.44(q,J＝7.0Hz,1H),2.24(s,3H),1.92(s,3H),1.90(d,J＝7.3Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)8.50(s,1H),7.38–7.32(m,2H),7.31–7.25(m,2H),7.23–7.17(m,3H),7.14(t,J＝7.6Hz,1 H),7.05(d,J＝7.3Hz,1H),6.44(q,J＝7.0Hz,1H),2.24(s,3H),1.92(s,3H),1.90(d,J＝7.3Hz,3H).

将化合物DA-1溶解在乙醚中，0℃下添加HCl/EtOAc溶液，抽滤，固体用Et₂O洗涤，干燥得到化合物DA-1盐酸盐。ESI[M+H]⁺＝305.2Compound DA-1 was dissolved in diethyl ether, and HCl/EtOAc solution was added at 0°C. The mixture was filtered, and the solid was washed with Et ₂ O and dried to obtain compound DA-1 hydrochloride. ESI [M+H] ⁺ = 305.2

¹H NMR(400MHz,d₆-DMSO)δ9.36(s,1H),7.76(s,1H),7.44–7.27(m,6H),7.19(t,J＝7.6Hz,1H),7.12(d,J＝7.4Hz,1H),6.48(q,J＝7.0Hz,1H),2.27(s,3H),1.98(s,6H). ¹ H NMR (400MHz, d ₆ -DMSO)δ9.36(s,1H),7.76(s,1H),7.44–7.27(m,6H),7.19(t,J＝7.6Hz,1H ),7.12(d,J＝7.4Hz,1H),6.48(q,J＝7.0Hz,1H),2.27(s,3H),1.98(s,6H).

2、化合物DA-2和化合物DA-3的制备2. Preparation of Compound DA-2 and Compound DA-3

在室温下，将化合物DA-1(330mg，1.1mmol)溶解在干燥THF(10mL)中，用氮气将反应体系置换三次，氮气保护，冰盐浴降温至0℃，用注射器将MeLi(4mL,1.3mol/L in Et₂O,5.2mmol)缓慢加至体系，室温搅拌4小时。经TLC监测反应完全后，将反应用饱和氯化铵水溶液(10mL)终止，用EtOAc(3×5mL)萃取，合并有机相，饱和食盐水洗涤，无水Na₂SO₄干燥，抽滤，将滤液减压浓缩后得到粗产品化合物DA-2-1。将粗产品和TFA(0.5mL)溶解在二氯甲烷(5mL)中，室温搅拌2小时。经TLC监测反应完全后，减压浓缩，用饱和碳酸氢钠水溶液(10mL)碱化，二氯甲烷(3×5mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/6)并收集Rf＝0.5～0.6部分得到淡黄色油状目标化合物DA-2(120mg，两步收率36.1％)。ESI[M+H]⁺＝303.1At room temperature, compound DA-1 (330 mg, 1.1 mmol) was dissolved in dry THF (10 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. MeLi (4 mL, 1.3 mol/L in Et ₂ O, 5.2 mmol) was slowly added to the system via syringe and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, compound DA-2-1. The crude product and TFA (0.5 mL) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (3×5 mL), and the combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) = 1/6) and the fractions with Rf = 0.5-0.6 were collected to obtain the target compound DA-2 (120 mg, two-step yield 36.1%) as a light yellow oil. ESI [M+H] ⁺ = 303.1

¹H NMR(400MHz,d₆-DMSO)δ7.97(s,1H),7.32–7.21(m,3H),7.12(d,J＝7.2Hz,1H),7.07(t,J＝7.5Hz,1H),6.94–6.87(m,3H),6.80(s,1H),5.47(d,J＝1.2Hz,1H),5.12(q,J＝7.5Hz,1H),5.09(d,J＝1.3Hz,1H),2.17(s,3H),1.85(s,3H),1.65(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.97(s,1H),7.32–7.21(m,3H),7.12(d,J＝7.2Hz,1H),7.07(t,J＝7.5Hz,1H),6.94–6.87(m,3H),6.80(s,1H) ,5.47(d,J＝1.2Hz,1H),5.12(q,J＝7.5Hz,1H),5.09(d,J＝1.3Hz,1H),2.17(s,3H),1.85(s,3H),1.65(d,J＝7.1Hz,3H).

在室温下，将化合物DA-2(80mg，0.26mmol)和10％湿钯碳(8mg)溶于MeOH(5mL)，用氢气置换体系三次，在氢气下室温搅拌2小时。经TLC监测反应完全后，抽滤，滤饼用甲醇(3×5mL)洗涤，将滤液减压浓缩得到粗产品，粗产品经制备TLC纯化(乙酸乙酯/石油醚(v/v)＝1/8)，并收集Rf＝0.5～0.6部分得到无色油状目标化合物DA-3(37mg，收率46.7％)。ESI[M+H]⁺＝305.1.Compound DA-2 (80 mg, 0.26 mmol) and 10% wet palladium on carbon (8 mg) were dissolved in MeOH (5 mL) at room temperature. The system was purged with hydrogen three times and stirred at room temperature under hydrogen for 2 hours. After completion of the reaction as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether (v/v) = 1/8). The fractions with Rf = 0.5-0.6 were collected to obtain the target compound DA-3 (37 mg, 46.7% yield) as a colorless oil. ESI [M+H] ⁺ = 305.1.

¹H NMR(400MHz,d₆-DMSO)δ7.93(s,1H),7.70(s,1H),7.36(t,J＝7.3Hz,2H),7.29(t,J＝7.3Hz,1H),7.15–7.09(m,3H),7.06–6.95(m,5H),6.89(d,J＝7.1Hz,1H),6.84(t,J＝7.6Hz,1H),6.81–6.76(m,2H),6.73–6.66(m,2H),6.57(d,J＝6.7Hz,1H),5.11(q,J＝7.1Hz,1H),4.64(q,J＝6.6Hz,1H),4.31(q,J＝6.8Hz,1H),3.93(q,J＝6.9Hz,1H),2.16(s,2H),2.13(s,3H),2.02(s,3H),1.70(d,J＝7.1Hz,3H),1.49(d,J＝7.1Hz,3H),1.46(d,J＝7.0Hz,3H),1.29(d,J＝7.0Hz,3H).(由于非对映异构体存在，核磁出现两组峰) ¹ H NMR (400MHz, d ₆ -DMSO)δ7.93(s,1H),7.70(s,1H),7.36(t,J＝7.3Hz,2H),7.29(t,J＝7.3Hz,1H),7.15–7.09(m,3H),7.06–6.95(m,5H) ,6.89(d,J＝7.1Hz,1H),6.84(t,J＝7.6Hz,1H),6.81–6.76(m,2H),6.73–6.66(m,2H),6.57(d,J＝6.7Hz,1H),5.11(q,J =7.1Hz,1H),4.64(q,J＝6.6Hz,1H),4.31(q,J＝6.8Hz,1H),3.93(q,J＝6.9Hz,1H),2.16(s,2H),2.13(s,3H),2.02(s,3H),1.70(d,J＝7.1Hz,3H),1.49(d,J＝7.1Hz,3H),1.46(d,J＝7.0Hz,3H),1.29(d,J＝7.0Hz,3H).(Due to the presence of diastereomers, two sets of peaks appear in NMR)

实施例4本发明化合物DA-10、DA-11、DA-12的制备
Example 4 Preparation of Compounds DA-10, DA-11, and DA-12 of the Invention

本发明化合物DA-10，化合物DA-11和化合物DA-12的制备方法类同于本发明化合物DA-1，化合物DA-2和化合物DA-3。The preparation methods of the compounds DA-10, DA-11 and DA-12 of the present invention are similar to those of the compounds DA-1, DA-2 and DA-3 of the present invention.

化合物211-1(5.0g)经LAH还原得到化合物211-2(4.6g，收率89.9％)，211-2和N-甲氧基-N-甲基-1H-咪唑-5-甲酰胺反应得到化合物211-5(3.3g，收率27.7％)，再同格氏试剂A反应得到无色油状本发明化合物DA-10(3.0g，收率75.6％)。1.0g化合物DA-10同甲基锂反应，三氟乙酸脱水得到无色油状本发明化合物DA-11(580mg，两步收率58.4％)，280mg化合物DA-11经钯碳还原得到白色固体本发明化合物DA-12(120mg，收率42.5％)。Compound 211-1 (5.0 g) was reduced with LAH to give compound 211-2 (4.6 g, 89.9% yield). 211-2 was reacted with N-methoxy-N-methyl-1H-imidazole-5-carboxamide to give compound 211-5 (3.3 g, 27.7% yield), which was then reacted with Grignard reagent A to give compound DA-10 (3.0 g, 75.6% yield) as a colorless oil. 1.0 g of compound DA-10 was reacted with methyl lithium and dehydrated with trifluoroacetic acid to give compound DA-11 (580 mg, 58.4% yield over two steps) as a colorless oil. 280 mg of compound DA-11 was reduced with palladium on carbon to give compound DA-12 (120 mg, 42.5% yield) as a white solid.

化合物DA-10：ESI[M+H]⁺＝269.1Compound DA-10: ESI [M+H] ⁺ = 269.1

¹H NMR(400MHz,d₆-DMSO)δ8.40(s,1H),7.34–7.28(m,1H),7.20–7.15(m,2H),7.13(s,1H),4.57–4.45(m,1H),2.29(s,3H),2.12(s,3H),1.55(d,J＝6.8Hz,3H),1.51–1.42(m,1H),0.71–0.62(m,1H),0.54–0.47(m,1H),0.47–0.38(m,1H),0.35–0.26(m,1H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.40(s,1H),7.34–7.28(m,1H),7.20–7.15(m,2H),7.13(s,1H),4.57–4.45(m,1H),2.29(s,3H),2.12(s,3H), 1.55(d,J＝6.8Hz,3H),1.51–1.42(m,1H),0.71–0.62(m,1H),0.54–0.47(m,1H),0.47–0.38(m,1H),0.35–0.26(m,1H).

化合物DA-11：ESI[M+H]⁺＝267.1Compound DA-11: ESI [M+H] ⁺ = 267.1

¹H NMR(400MHz,d₆-DMSO)δ7.93(s,1H),7.16(d,J＝7.2Hz,1H),7.09(t,J＝7.5Hz,1H),6.95(d,J＝7.5Hz,1H),6.81(s,1H),5.56(d,J＝1.4Hz,1H),5.17(d,J＝1.4Hz,1H),3.04–2.95(m,1H),2.24(s,3H),2.01(s,3H),1.30–1.22(m,1H),1.21(d,J＝6.7Hz,3H),0.56–0.47(m,1H),0.39–0.31(m,1H),-0.01–-0.08(m,1H),-0.12–-0.20(m,1H). ¹ H NMR (400 MHz, d ₆ -DMSO) δ7.93(s,1H),7.16(d,J＝7.2Hz,1H),7.09(t,J＝7.5Hz,1H),6.95(d,J＝7 .5Hz,1H),6.81(s,1H),5.56(d,J＝1.4Hz,1H),5.17(d,J＝1.4Hz,1H),3.04–2.9 5(m,1H),2.24(s,3H),2.01(s,3H),1.30–1.22(m,1H),1.21(d,J＝6.7Hz,3H),0 .56–0.47(m,1H),0.39–0.31(m,1H),-0.01–-0.08(m,1H),-0.12–-0.20(m,1H).

化合物DA-12：ESI[M+H]⁺＝269.2Compound DA-12: ESI [M+H] ⁺ = 269.2

¹H NMR(400MHz,d₆-DMSO)δ7.82(s,2H),7.03–6.92(m,4H),6.82(d,J＝6.1Hz,2H),6.66–6.54(m,2H),4.24(q,J＝6.7Hz,2H),3.06–2.94(m,1H),2.86–2.74(m,1H),2.26(s,6H),2.25(s,6H),1.43(d,J＝6.9Hz,6H),1.35(d,J＝6.7Hz,3H),1.30–1.14(m,2H),0.89(d,J＝6.7Hz,3H),0.58–0.48(m,1H),0.46–0.34(m,2H),0.26–0.14(m,2H),0.11–0.02(m,1H),-0.13–-0.24(m,1H),-0.85–-0.96(m,1H).(由于非对映异构体存在，核磁出现两组峰) ¹ H NMR (400MHz, d ₆ -DMSO)δ7.82(s,2H),7.03–6.92(m,4H),6.82(d,J＝6.1Hz,2H),6.66–6.54(m,2H),4.24(q,J＝6.7Hz ,2H),3.06–2.94(m,1H),2.86–2.74(m,1H),2.26(s,6H),2.25(s,6H),1.43(d,J＝6.9Hz,6H),1.35(d , J＝6.7Hz,3H),1.30–1.14(m,2H),0.89(d,J＝6.7Hz,3H),0.58–0.48(m,1H),0.46–0.34(m,2H),0.26–0.14(m,2H),0.11–0.02(m,1H),-0.13–-0.24(m,1H),-0.85–-0.96(m,1H).(Due to the presence of diastereomers, two groups of peaks appear in NMR)

实施例5本发明化合物DA-14、DA-15、DA-16、DA-17、DA-18、DA-20、DA-21、DA-22、DA-23、DA-24的制备
Example 5 Preparation of compounds DA-14, DA-15, DA-16, DA-17, DA-18, DA-20, DA-21, DA-22, DA-23, and DA-24 of the present invention

在室温下，将4-氟-N-甲氧基-N-甲基-1H-咪唑-5-甲酰胺(952.3mg,5.5mmol)溶解在干燥THF(10mL)中，用干冰丙酮浴将温度降至～-30℃，再将(S)-1-苯基-1-乙醇(806.3mg,6.6mmol)和PPh₃(2.16g,8.25mmol)依次加进反应体系，用注射器将DEAD(1.44g,8.27mmol)缓慢加至反应体系，室温搅拌过夜。经TLC监测反应完全后，将冰水加至反应体系，用EtOAc萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/5～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/1)监测，收集Rf＝0.5～0.6部分，得到无色油状化合物246-3(952mg，收率62.4％)。ESI[M+H]⁺＝277.9。At room temperature, 4-fluoro-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (952.3 mg, 5.5 mmol) was dissolved in dry THF (10 mL). The temperature was lowered to -30°C using a dry ice acetone bath. (S)-1-phenyl-1-ethanol (806.3 mg, 6.6 mmol) and _PPh3 (2.16 g, 8.25 mmol) were added to the reaction system in sequence. DEAD (1.44 g, 8.27 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic _phases were dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/5 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/1). Fractions with Rf = 0.5 to 0.6 were collected to give Compound 246-3 (952 mg, 62.4% yield) as a colorless oil. ESI [M+H] ⁺ = 277.9.

在室温下，将化合物246-3(952mg,3.43mmol)溶解在干燥THF(10mL)中，用氮气将反应体系置换三次，氮气保护，冰盐浴降温至0℃，用注射器将A(17.2mL,1mol/L in THF,17.2mmol)缓慢滴加至体系，室温搅拌4小时。经TLC监测反应完全后，将反应体系倾倒至冰水里，将饱和氯化铵水溶液(10mL)缓慢加至反应体系，用EtOAc(3×30mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/3)，TLC(乙酸乙酯/石油醚(v/v)＝1/2)监测，收集Rf＝0.5～0.6部分，得到无色油状化合物DA-21(805mg，收率72.8％)。ESI[M+H]⁺＝323.0。Compound 246-3 (952 mg, 3.43 mmol) was dissolved in dry THF (10 mL) at room temperature. The reaction system was purged with nitrogen three times under nitrogen protection and cooled to 0°C in an ice-salt bath. A (17.2 mL, 1 mol/L in THF, 17.2 mmol) was slowly added dropwise to the system using a syringe and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was poured into ice water. Saturated aqueous ammonium chloride (10 mL) was slowly added to the reaction system and extracted with EtOAc (3×30 mL). The combined organic _phases were dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/3) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-21 (805 mg, 72.8% yield) as a colorless oil. ESI [M+H] ^⁺ = 323.0.

1H NMR(400MHz,d₆-DMSO)δ8.29(d,J＝1.7Hz,1H),7.38(t,J＝7.4Hz,2H),7.34–7.25(m,2H),7.23(d,J＝7.3Hz,2H),7.13(t,J＝7.5Hz,1H),6.98(d,J＝7.6Hz,1H),6.34(q,J＝7.2Hz,1H),2.25(s,3H),1.94(s,3H),1.90(d,J＝7.2Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.29(d,J＝1.7Hz,1H),7.38(t,J＝7.4Hz,2H),7.34–7.25(m,2H),7.23(d,J＝7.3Hz,2H),7.13(t,J＝ 7.5Hz,1H),6.98(d,J＝7.6Hz,1H),6.34(q,J＝7.2Hz,1H),2.25(s,3H),1.94(s,3H),1.90(d,J＝7.2Hz,3H).

本发明目标化合物DA-14、DA-15、DA-16、DA-17、DA-18、DA-20、DA-22、DA-23、DA-24的制备方法类同于化合物DA-21。The preparation methods of the target compounds DA-14, DA-15, DA-16, DA-17, DA-18, DA-20, DA-22, DA-23, and DA-24 of the present invention are similar to those of compound DA-21.

化合物DA-14：629mg，ESI[M+H]⁺＝319.2Compound DA-14: 629 mg, ESI [M+H] ⁺ = 319.2

1H NMR(400MHz,d₆-DMSO)δ8.28(s,1H),7.29(d,J＝7.5Hz,1H),7.24–7.10(m,5H),7.02(d,J＝7.6Hz,1H),6.83–6.73(m,1H),6.52(q,J＝6.8Hz,1H),2.41(s,3H),2.25(s,3H),1.90(s,3H),1.84(d,J＝7.0Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.28(s,1H),7.29(d,J＝7.5Hz,1H),7.24–7.10(m,5H),7.02(d,J＝7.6Hz,1H),6.83–6. 73(m,1H),6.52(q,J＝6.8Hz,1H),2.41(s,3H),2.25(s,3H),1.90(s,3H),1.84(d,J＝7.0Hz,3H).

化合物DA-15：170mg，ESI[M+H]⁺＝323.2Compound DA-15: 170 mg, ESI [M+H] ⁺ = 323.2

1H NMR(400MHz,d₆-DMSO)δ8.40(s,1H),7.42–7.33(m,1H),7.30(d,J＝7.3Hz,1H),7.27–7.14(m,4H),7.06(d,J＝7.5Hz,1H),7.00–6.93(m,1H),6.62(q,J＝6.9Hz,1H),2.26(s,3H),1.94(s,3H),1.92(d,J＝7.2Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.40(s,1H),7.42–7.33(m,1H),7.30(d,J＝7.3Hz,1H),7.27–7.14(m,4H),7.06(d,J＝7.5H z,1H),7.00–6.93(m,1H),6.62(q,J＝6.9Hz,1H),2.26(s,3H),1.94(s,3H),1.92(d,J＝7.2Hz,3H).

化合物DA-15盐酸盐：878mg，ESI[M+H]⁺＝323.2Compound DA-15 hydrochloride: 878 mg, ESI [M+H] ⁺ = 323.2

¹H NMR(400MHz,d₆-DMSO)δ9.15(s,1H),7.69(s,1H),7.45–7.32(m,2H),7.31–7.16(m,3H),7.16–7.06(m,2H),6.63(q,J＝7.0Hz,1H),2.27(s,3H),1.99–1.92(m,6H). ¹ H NMR (400MHz, d ₆ -DMSO)δ9.15(s,1H),7.69(s,1H),7.45–7.32(m,2H),7.31–7.16(m,3H), 7.16–7.06(m,2H),6.63(q,J=7.0Hz,1H),2.27(s,3H),1.99–1.92(m,6H).

化合物DA-16：570mg，ESI[M+H]⁺＝339.1Compound DA-16: 570 mg, ESI [M+H] ⁺ = 339.1

1H NMR(400MHz,d₆-DMSO)δ8.33(s,1H),7.54–7.47(m,1H),7.40–7.27(m,3H),7.23(s,1H),7.16(t,J＝7.5Hz,1H),7.05(d,J＝7.4Hz,1H),6.90–6.82(m,1H),6.62(q,J＝6.8Hz,1H),2.26(s,3H),1.94(s,3H),1.91(d,J＝7.1Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.33(s,1H),7.54–7.47(m,1H),7.40–7.27(m,3H),7.23(s,1H),7.16(t,J＝7.5Hz,1H),7.05(d, J＝7.4Hz,1H),6.90–6.82(m,1H),6.62(q,J＝6.8Hz,1H),2.26(s,3H),1.94(s,3H),1.91(d,J＝7.1Hz,3H).

化合物DA-17：515mg，ESI[M+H]⁺＝319.2Compound DA-17: 515 mg, ESI [M+H] ⁺ = 319.2

1H NMR(400MHz,d₆-DMSO)δ8.43(s,1H),7.31(d,J＝7.5Hz,1H),7.25(t,J＝7.6Hz,1H),7.22–7.13(m,2H),7.14–7.03(m,3H),7.01(d,J＝7.8Hz,1H),6.43(q,J＝7.1Hz,1H),2.30(s,3H),2.27(s,3H),1.97(s,3H),1.91(d,J＝7.2Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.43(s,1H),7.31(d,J＝7.5Hz,1H),7.25(t,J＝7.6Hz,1H),7.22–7.13(m,2H),7.14–7.03(m,3H),7 .01(d,J＝7.8Hz,1H),6.43(q,J＝7.1Hz,1H),2.30(s,3H),2.27(s,3H),1.97(s,3H),1.91(d,J＝7.2Hz,3H).

化合物DA-18：717mg，ESI[M+H]⁺＝339.1Compound DA-18: 717 mg, ESI [M+H] ⁺ = 339.1

1H NMR(400MHz,d₆-DMSO)δ8.51(s,1H),7.45–7.34(m,2H),7.33–7.25(m,2H),7.21(s,1H),7.20–7.13(m,2H),7.08(d,J＝7.4Hz,1H),6.43(q,J＝7.1Hz,1H),2.27(s,3H),1.95(s,3H),1.94(d,J＝7.2Hz,3H).1H NMR(400MHz,d ₆ -DMSO)δ8.51(s,1H),7.45–7.34(m,2H),7.33–7.25(m,2H),7.21(s,1H),7.20–7.13(m,2H),7 .08(d,J＝7.4Hz,1H),6.43(q,J＝7.1Hz,1H),2.27(s,3H),1.95(s,3H),1.94(d,J＝7.2Hz,3H).

化合物DA-20：701mg，ESI[M+H]⁺＝283.2Compound DA-20: 701 mg, ESI [M+H] ⁺ = 283.2

1H NMR(400MHz,d₆-DMSO)δ8.38(s,1H),7.33(d,J＝7.0Hz,1H),7.24–7.10(m,3H),4.41–4.24(m,1H),2.31(s,3H),2.13(s,3H),2.06–1.93(m,2H),1.56–1.40(m,1H),0.86(t,J＝7.4Hz,3H),0.79–0.71(m,1H),0.54–0.42(m,2H),0.31–0.20(m,1H).1H NMR(400MHz,d ₆ -DMSO)δ8.38(s,1H),7.33(d,J＝7.0Hz,1H),7.24–7.10(m,3H),4.41–4.24(m,1H),2.31(s,3H),2.13(s,3H),2.06 –1.93(m,2H),1.56–1.40(m,1H),0.86(t,J＝7.4Hz,3H),0.79–0.71(m,1H),0.54–0.42(m,2H),0.31–0.20(m,1H).

实施例6本发明化合物DA-33的制备
Example 6 Preparation of Compound DA-33 of the Present Invention

DA-33的制备类同于实施例5化合物DA-21。The preparation of DA-33 was similar to that of compound DA-21 in Example 5.

DA-33-1和(S)-1-苯基-1-乙醇经Mitsunobu反应，格氏反应，经过柱层析和反向制备得到无色糖浆状化合物DA-33(370mg)。ESI[M+H]⁺＝323.0。DA-33-1 and (S)-1-phenyl-1-ethanol were subjected to Mitsunobu reaction, Grignard reaction, column chromatography and reverse phase preparative method to obtain colorless syrupy compound DA-33 (370 mg). ESI [M+H] ⁺ = 323.0.

¹H NMR(400MHz,d₆-DMSO)δ7.48–7.40(m,J＝7.5Hz,2H),7.39–7.30(m,4H),7.29–7.16(m,2H),7.00(d,J＝1.2Hz,1H),6.66(q,J＝7.2Hz,1H),2.31(s,3H),2.13(s,3H),1.95(dd,J＝7.2,2.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.48–7.40(m,J＝7.5Hz,2H),7.39–7.30(m,4H),7.29–7.16(m,2H),7.00(d,J＝1 .2Hz,1H),6.66(q,J＝7.2Hz,1H),2.31(s,3H),2.13(s,3H),1.95(dd,J＝7.2,2.1Hz,3H).

实施例7本发明化合物DA-37～DA-39,DA-44,DA-55～DA-57,DA-62～DA-64,DA-72～DA-80,DA-83,DA-86,DA-119～DA-130,DA-142～DA-147,DA-171的制备
Example 7 Preparation of compounds of the present invention DA-37～DA-39, DA-44, DA-55～DA-57, DA-62～DA-64, DA-72～DA-80, DA-83, DA-86, DA-119～DA-130, DA-142～DA-147, DA-171

化合物B-1经(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基甲苯)氯化钌还原得到B-2，部分化合物B-2直接采购。酮类化合物经硼氢化钠还原得到消旋体醇。Compound B-1 was reduced with (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride to give B-2. Some of compound B-2 was purchased directly. Ketone compounds were reduced with sodium borohydride to give racemic alcohols.

手性中间体化合物B-1制备方法参照如下操作：
The preparation method of the chiral intermediate compound B-1 is as follows:

在室温下，将1-(2-氟-3-甲基苯基)乙酮(12.8g,84.2mmol),甲酸(19.38g,421.1mmol),三乙胺(25.56g,252.6mmol)依次加至异丙醇(120mL)中，氩气置换反应体系三次，将(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基甲苯)氯化钌(804mg,1.26mmol)加至反应体系，氩气保护下60℃搅拌4小时，经TLC监测反应完全后，降至室温，抽滤，用EtOAc(3×50mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/3)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.5～0.6部分，得到浅黄色油状化合物(S)-1-(2-氟-3-甲基苯基)乙-1-醇(12.561g，收率96.8％)。At room temperature, 1-(2-fluoro-3-methylphenyl)ethanone (12.8 g, 84.2 mmol), formic acid (19.38 g, 421.1 mmol), and triethylamine (25.56 g, 252.6 mmol) were added to isopropanol (120 mL) in sequence. The reaction system was replaced with argon three times. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene) ruthenium chloride (804 mg, 1.26 mmol) was added to the reaction system. The mixture was stirred at 60°C for 4 hours under argon protection. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3×50 mL). The organic phases were combined and eluted with anhydrous Na ₂ SO _{The reaction mixture} was dried, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/3) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/10). The fractions with Rf = 0.5 to 0.6 were collected to give (S)-1-(2-fluoro-3-methylphenyl)ethan-1-ol (12.561 g, yield 96.8%) as a light yellow oily compound.

本发明目标化合物DA-37～DA-39,DA-44,DA-55～DA-57,DA-62～DA-64,DA-72～DA-79,DA-86,DA-119～DA-125的制备类同于化合物DA-21。The preparation of the target compounds DA-37 to DA-39, DA-44, DA-55 to DA-57, DA-62 to DA-64, DA-72 to DA-79, DA-86, and DA-119 to DA-125 of the present invention is similar to that of compound DA-21.

化合物DA-37：2.857g，ESI[M+H]⁺＝322.9Compound DA-37: 2.857 g, ESI [M+H] ⁺ = 322.9

¹H NMR(400MHz,d₆-DMSO)δ8.45(s,1H),7.34–7.26(m,3H),7.25–7.12(m,4H),7.07(d,J＝7.4Hz,1H),6.45(q,J＝7.0Hz,1H),2.27(s,3H),1.95(s,3H),1.92(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.45(s,1H),7.34–7.26(m,3H),7.25–7.12(m,4H),7.07(d,J＝7.4Hz ,1H),6.45(q,J＝7.0Hz,1H),2.27(s,3H),1.95(s,3H),1.92(d,J＝7.2Hz,3H).

化合物DA-37盐酸盐：1.211g，ESI[M+H]⁺＝322.9Compound DA-37 hydrochloride: 1.211 g, ESI [M+H] ⁺ = 322.9

¹H NMR(400MHz,d₆-DMSO)δ9.33(s,1H),7.75(s,1H),7.43–7.30(m,3H),7.27–7.17(m,3H),7.14(d,J＝7.2Hz,1H),6.48(q,J＝7.1Hz,1H),2.28(s,3H),2.00(s,3H),1.96(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ9.33(s,1H),7.75(s,1H),7.43–7.30(m,3H),7.27–7.17(m,3H),7.14(d,J＝ 7.2Hz,1H),6.48(q,J＝7.1Hz,1H),2.28(s,3H),2.00(s,3H),1.96(d,J＝7.1Hz,3H).

化合物DA-38：3.417g，ESI[M+H]⁺＝336.9Compound DA-38: 3.417 g, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ8.36(s,1H),7.31(d,J＝7.4Hz,1H),7.24(t,J＝7.3Hz,1H),7.21(s,1H),7.17(t,J＝7.6Hz,1H),7.11–7.02(m,2H),6.77(t,J＝7.0Hz,1H),6.62(q,J＝7.1Hz,1H),2.27(s,3H),2.26(d,J＝1.7Hz,3H),1.96(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.36(s,1H),7.31(d,J＝7.4Hz,1H),7.24(t,J＝7.3Hz,1H),7.21(s,1H),7.17(t,J＝7.6Hz,1H),7.11–7.02(m,2H ),6.77(t,J＝7.0Hz,1H),6.62(q,J＝7.1Hz,1H),2.27(s,3H),2.26(d,J＝1.7Hz,3H),1.96(s,3H),1.90(d,J＝7.1Hz,3H).

化合物DA-39：596mg，ESI[M+H]⁺＝337.1Compound DA-39: 596 mg, ESI [M+H] ⁺ = 337.1

¹H NMR(400MHz,d₆-DMSO)δ8.37(s,1H),7.31(d,J＝7.5Hz,1H),7.23–7.02(m,5H),6.77(d,J＝6.9Hz,1H),6.58(q,J＝7.5Hz,1H),2.27(s,3H),2.25(s,3H),1.95(s,3H),1.90(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.37(s,1H),7.31(d,J＝7.5Hz,1H),7.23–7.02(m,5H),6.77(d,J＝6.9Hz,1H) ,6.58(q,J＝7.5Hz,1H),2.27(s,3H),2.25(s,3H),1.95(s,3H),1.90(d,J＝7.2Hz,3H).

化合物DA-44：139mg，ESI[M+H]⁺＝338.9Compound DA-44: 139 mg, ESI [M+H] ⁺ = 338.9

¹H NMR(400MHz,d₆-DMSO)δ8.34(s,1H),7.55–7.47(m,1H),7.41–7.28(m,3H),7.24(s,1H),7.16(t,J＝7.5Hz,1H),7.05(d,J＝7.3Hz,1H),6.91–6.81(m,1H),6.62(q,J＝7.0Hz,1H),2.26(s,3H),1.94(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.34(s,1H),7.55–7.47(m,1H),7.41–7.28(m,3H),7.24(s,1H),7.16(t,J＝7.5Hz,1H),7.05(d, J＝7.3Hz,1H),6.91–6.81(m,1H),6.62(q,J＝7.0Hz,1H),2.26(s,3H),1.94(s,3H),1.90(d,J＝7.1Hz,3H).

化合物DA-44盐酸盐：461mg，ESI[M+H]⁺＝338.9Compound DA-44 hydrochloride: 461 mg, ESI [M+H] ⁺ = 338.9

¹H NMR(400MHz,d₆-DMSO)δ8.94(s,1H),7.64(s,1H),7.57–7.48(m,1H),7.42–7.31(m,3H),7.19(t,J＝7.6Hz,1H),7.10(d,J＝7.4Hz,1H),7.00–6.92(m,1H),6.63(q,J＝6.9Hz,1H),2.27(s,3H),1.97(s,3H),1.93(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.94(s,1H),7.64(s,1H),7.57–7.48(m,1H),7.42–7.31(m,3H),7.19(t,J＝7.6Hz,1H),7.10(d, J＝7.4Hz,1H),7.00–6.92(m,1H),6.63(q,J＝6.9Hz,1H),2.27(s,3H),1.97(s,3H),1.93(d,J＝7.0Hz,3H).

化合物DA-55：1.26g，ESI[M+H]⁺＝353.1Compound DA-55: 1.26 g, ESI [M+H] ⁺ = 353.1

¹H NMR(400MHz,d₆-DMSO)δ8.31(s,1H),7.31(t,J＝7.0Hz,2H),7.27–7.22(m,J＝9.8,5.4Hz,2H),7.16(t,J＝7.6Hz,1H),7.05(d,J＝7.5Hz,1H),6.70(d,J＝7.7Hz,1H),6.65(q,J＝6.9Hz,1H),2.38(s,3H),2.26(s,3H),1.96(s,3H),1.89(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.31(s,1H),7.31(t,J＝7.0Hz,2H),7.27–7.22(m,J＝9.8,5.4Hz,2H),7.16(t,J＝7.6Hz,1H),7.05(d,J＝7.5 Hz,1H),6.70(d,J＝7.7Hz,1H),6.65(q,J＝6.9Hz,1H),2.38(s,3H),2.26(s,3H),1.96(s,3H),1.89(d,J＝7.0Hz,3H).

化合物DA-56：200mg，ESI[M+H]⁺＝370.9Compound DA-56: 200 mg, ESI [M+H] ⁺ = 370.9

¹H NMR(400MHz,CDCl₃)δ7.81(s,1H),7.38(s,1H),7.28(s,1H),7.20–7.11(m,2H),7.02(t,J＝8.6Hz,1H),6.91(dd,J＝8.6,5.7Hz,1H),6.83(d,J＝6.9Hz,1H),2.37(d,J＝2.2Hz,3H),2.34(s,3H),2.16(s,3H),1.97(d,J＝6.9Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ7.81(s,1H),7.38(s,1H),7.28(s,1H),7.20–7.11(m,2H),7.02(t,J＝8.6Hz,1H),6.91(dd,J＝8.6,5. 7Hz,1H),6.83(d,J＝6.9Hz,1H),2.37(d,J＝2.2Hz,3H),2.34(s,3H),2.16(s,3H),1.97(d,J＝6.9Hz,3H).

化合物DA-57：449mg，ESI[M+H]⁺＝370.9Compound DA-57: 449 mg, ESI [M+H] ⁺ = 370.9

¹H NMR(400MHz,CDCl₃)δ7.80(s,1H),7.37(s,1H),7.28(dd,J＝6.3,2.6Hz,1H),7.18–7.10(m,3H),6.84(d,J＝7.8Hz,1H),6.74(q,J＝7.0Hz,1H),2.33(s,3H),2.26(d,J＝1.6Hz,3H),2.13(s,3H),1.95(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ7.80(s,1H),7.37(s,1H),7.28(dd,J＝6.3,2.6Hz,1H),7.18–7.10(m,3H),6.84(d,J＝7.8Hz,1H ),6.74(q,J＝7.0Hz,1H),2.33(s,3H),2.26(d,J＝1.6Hz,3H),2.13(s,3H),1.95(d,J＝7.0Hz,3H).

化合物DA-62：149mg，ESI[M+H]⁺＝371.1Compound DA-62: 149 mg, ESI [M+H] ⁺ = 371.1

¹H NMR(400MHz,CDCl₃)δ7.91(s,1H),7.36(s,1H),7.28(d,J＝5.2Hz,1H),7.16(dd,J＝8.8,6.9Hz,3H),6.86(t,J＝8.1Hz,1H),6.75(q,J＝7.1Hz,1H),2.34(d,J＝2.4Hz,6H),2.14(s,3H),1.98(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ7.91(s,1H),7.36(s,1H),7.28(d,J＝5.2Hz,1H),7.16(dd,J＝8.8,6.9Hz,3H),6.86(t,J＝8 .1Hz,1H),6.75(q,J＝7.1Hz,1H),2.34(d,J＝2.4Hz,6H),2.14(s,3H),1.98(d,J＝7.1Hz,3H).

化合物DA-63：171mg，ESI[M+H]⁺＝353.1Compound DA-63: 171 mg, ESI [M+H] ⁺ = 353.1

¹H NMR(400MHz,CDCl₃)δ7.76(s,1H),7.35(s,1H),7.27–7.19(m,3H),7.14(t,J＝4.0Hz,2H),6.87(dd,J＝13.7,6.9Hz,2H),2.43(s,3H),2.33(s,3H),2.14(s,3H),1.97(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, CDCl ₃ )δ7.76(s,1H),7.35(s,1H),7.27–7.19(m,3H),7.14(t,J＝4.0Hz,2H),6.87(dd,J ＝13.7,6.9Hz,2H),2.43(s,3H),2.33(s,3H),2.14(s,3H),1.97(d,J＝7.0Hz,3H).

化合物DA-64：1.558g，ESI[M+H]⁺＝336.9Compound DA-64: 1.558 g, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ8.36(s,1H),7.31(d,J＝7.5Hz,1H),7.24(t,J＝7.2Hz,1H),7.21(d,J＝0.7Hz,1H),7.17(t,J＝7.6Hz,1H),7.12–7.03(m,2H),6.77(t,J＝7.4Hz,1H),6.62(q,J＝7.0Hz,1H),2.27(s,3H),2.26(d,J＝1.8Hz,3H),1.96(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.36(s,1H),7.31(d,J＝7.5Hz,1H),7.24(t,J＝7.2Hz,1H),7.21(d,J＝0.7Hz,1H),7.17(t,J＝7.6Hz,1H),7.12–7.03( m,2H),6.77(t,J＝7.4Hz,1H),6.62(q,J＝7.0Hz,1H),2.27(s,3H),2.26(d,J＝1.8Hz,3H),1.96(s,3H),1.90(d,J＝7.1Hz,3H).

化合物DA-76：866mg，ESI[M+H]⁺＝378.9Compound DA-76: 866 mg, ESI [M+H] ⁺ = 378.9

¹H NMR(400MHz,d₆-DMSO)δ8.28(s,1H),7.29(s,1H),7.28–7.20(m,2H),7.16(s,1H),7.07(s,1H),7.01–6.96(m,1H),6.73–6.60(m,2H),2.52(dt,J＝3.7,1.8Hz,7H),2.21(ddd,J＝10.5,6.8,4.3Hz,1H),1.90(d,J＝7.1Hz,3H),1.03(d,J＝8.1Hz,2H),0.71(s,2H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.28(s,1H),7.29(s,1H),7.28–7.20(m,2H),7.16(s,1H),7.07(s,1H),7.01–6.96(m,1H),6.73–6.60(m,2H),2. 52(dt,J＝3.7,1.8Hz,7H),2.21(ddd,J＝10.5,6.8,4.3Hz,1H),1.90(d,J＝7.1Hz,3H),1.03(d,J＝8.1Hz,2H),0.71(s,2H).

化合物DA-77：1.58g，ESI[M+H]⁺＝362.9Compound DA-77: 1.58 g, ESI [M+H] ⁺ = 362.9

¹H NMR(400MHz,d₆-DMSO)δ8.37(s,1H),7.30(s,1H),7.21(s,1H),7.17(s,1H),7.06(dd,J＝7.6,2.9Hz,2H),6.92(t,J＝6.9Hz,1H),6.71(t,J＝6.8Hz,1H),6.62(q,J＝7.1Hz,1H),2.27(s,3H),2.12–1.99(m,1H),1.95(s,3H),1.91(d,J＝7.1Hz,3H),1.04–0.94(m,2H),0.72(d,J＝2.2Hz,2H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.37(s,1H),7.30(s,1H),7.21(s,1H),7.17(s,1H),7.06(dd,J＝7.6,2.9Hz,2H),6.92(t,J＝6.9Hz,1H),6.71(t,J＝6.8Hz,1H) ,6.62(q,J＝7.1Hz,1H),2.27(s,3H),2.12–1.99(m,1H),1.95(s,3H),1.91(d,J＝7.1Hz,3H),1.04–0.94(m,2H),0.72(d,J＝2.2Hz,2H).

化合物DA-86：1.83g，ESI[M+H]⁺＝336.9Compound DA-86: 1.83 g, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ8.36(s,1H),7.30(d,J＝7.4Hz,1H),7.26–7.21(m,1H),7.20(d,J＝0.7Hz,1H),7.16(t,J＝7.6Hz,1H),7.11–7.04(m,2H),6.76(t,J＝7.0Hz,1H),6.62(q,J＝7.1Hz,1H),2.26(s,3H),2.25(d,J＝1.8Hz,3H),1.95(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.36(s,1H),7.30(d,J＝7.4Hz,1H),7.26–7.21(m,1H),7.20(d,J＝0.7Hz,1H),7.16(t,J＝7.6Hz,1H),7.11–7.04(m ,2H),6.76(t,J＝7.0Hz,1H),6.62(q,J＝7.1Hz,1H),2.26(s,3H),2.25(d,J＝1.8Hz,3H),1.95(s,3H),1.90(d,J＝7.1Hz,3H).

化合物DA-106：204mg，ESI[M+H]⁺＝310.9Compound DA-106: 204 mg, ESI [M+H] ⁺ = 310.9

¹H NMR(400MHz,d₆-DMSO)δ8.37(s,1H),7.77–7.69(m,2H),7.69–7.62(m,1H),7.58(d,J＝0.7Hz,1H),7.56–7.50(m,2H),7.51–7.43(m,1H),7.39–7.21(m,2H),6.96(dd,J＝7.2,2.3Hz,1H),6.54(q,J＝7.1Hz,1H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.37(s,1H),7.77–7.69(m,2H),7.69–7.62(m,1H),7.58(d,J＝0.7Hz,1H),7.56–7.50(m,2H),7.51 –7.43(m,1H),7.39–7.21(m,2H),6.96(dd,J＝7.2,2.3Hz,1H),6.54(q,J＝7.1Hz,1H),1.90(d,J＝7.1Hz,3H).

化合物DA-171：850mg,无色糖浆，ESI[M+H]⁺＝340.8Compound DA-171: 850 mg, colorless syrup, ESI [M+H] ⁺ = 340.8

¹H NMR(400MHz,d₆-DMSO)δ8.46(s,1H),7.46–7.33(m,1H),7.33–7.26(m,1H),7.23(s,1H),7.23–7.12(m,2H),7.06(d,J＝7.5Hz,1H),6.77–6.71(m,1H),6.61(q,J＝7.2Hz,1H),2.26(s,3H),1.94(d,J＝5.9Hz,3H),1.93(s,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.46(s,1H),7.46–7.33(m,1H),7.33–7.26(m,1H),7.23(s,1H),7.23–7.12(m,2H),7.06(d,J＝ 7.5Hz,1H),6.77–6.71(m,1H),6.61(q,J＝7.2Hz,1H),2.26(s,3H),1.94(d,J＝5.9Hz,3H),1.93(s,3H).

化合物B-2和1H-咪唑-5-羧酸乙酯经过Mitsunobu反应制备中间体化合物B-3，会收集到部分异构体化合物B-3A，B-3A经水解，酰胺化，格氏反应得到本发明化合物DA-80，DA-83。
Compound B-2 and 1H-imidazole-5-carboxylic acid ethyl ester are subjected to Mitsunobu reaction to prepare intermediate compound B-3, and some isomer compound B-3A is collected. B-3A is hydrolyzed, amidated, and Grignard-reacted to obtain compounds DA-80 and DA-83 of the present invention.

化合物DA-80：31.5mg，ESI[M+H]⁺＝322.9Compound DA-80: 31.5 mg, ESI [M+H] ⁺ = 322.9

¹H NMR(400MHz,d₆-DMSO)δ7.97(d,J＝1.0Hz,1H),7.93(d,J＝1.1Hz,1H),7.46–7.36(m,2H),7.31–7.23(m,3H),7.21–7.13(m,2H),5.90(q,J＝7.1Hz,1H),2.29(s,3H),2.12(s,3H),1.87(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.97(d,J＝1.0Hz,1H),7.93(d,J＝1.1Hz,1H),7.46–7.36(m,2H),7.31–7.23(m,3H) ,7.21–7.13(m,2H),5.90(q,J＝7.1Hz,1H),2.29(s,3H),2.12(s,3H),1.87(d,J＝7.1Hz,3H).

化合物DA-83：142mg，ESI[M+H]⁺＝336.9Compound DA-83: 142 mg, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ7.96(d,J＝1.0Hz,1H),7.92(d,J＝1.1Hz,1H),7.33–7.25(m,2H),7.23–7.10(m,4H),5.88(q,J＝7.1Hz,1H),2.29(s,3H),2.25(d,J＝2.0Hz,3H),2.12(s,3H),1.85(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.96(d,J＝1.0Hz,1H),7.92(d,J＝1.1Hz,1H),7.33–7.25(m,2H),7.23–7.10(m,4H),5 .88(q,J＝7.1Hz,1H),2.29(s,3H),2.25(d,J＝2.0Hz,3H),2.12(s,3H),1.85(d,J＝7.1Hz,3H).

实施例8本发明化合物DA-40～DA-43,DA-45,DA-103,DA-105,DA-107～DA-118,DA-148～DA-159,DA-173的制备
Example 8 Preparation of compounds of the present invention DA-40～DA-43, DA-45, DA-103, DA-105, DA-107～DA-118, DA-148～DA-159, DA-173

化合物C-1经(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基甲苯)氯化钌还原得到C-2，部分化合物C-2直接采购。参照实施例4化合物(S)-1-(2-氟-3-甲基苯基)乙-1-醇的制备方法得到。Compound C-1 was reduced with (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride to give C-2. Part of compound C-2 was purchased directly. The preparation of compound (S)-1-(2-fluoro-3-methylphenyl)ethan-1-ol was performed in accordance with the method described in Example 4.

本发明目标化合物DA-40～DA-43,DA-45,DA-103,DA-105，DA-107～DA-113,DA-155～DA-159的制备类同于化合物DA-21。The preparation of the target compounds DA-40 to DA-43, DA-45, DA-103, DA-105, DA-107 to DA-113, DA-155 to DA-159 of the present invention is similar to that of compound DA-21.

化合物DA-40：1.587g，ESI[M+H]⁺＝340.9Compound DA-40: 1.587 g, ESI [M+H] ⁺ = 340.9

¹H NMR(400MHz,d₆-DMSO)δ8.25(d,J＝1.6Hz,1H),7.43–7.33(m,1H),7.29–7.16(m,3H),7.13(t,J＝7.6Hz,1H),7.05–6.90(m,2H),6.50(q,J＝7.1Hz,1H),2.24(s,3H),1.95(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.25(d,J＝1.6Hz,1H),7.43–7.33(m,1H),7.29–7.16(m,3H),7.13(t,J＝7.6Hz,1H) ,7.05–6.90(m,2H),6.50(q,J＝7.1Hz,1H),2.24(s,3H),1.95(s,3H),1.90(d,J＝7.1Hz,3H).

化合物DA-41：1.425g，ESI[M+H]⁺＝356.9Compound DA-41: 1.425 g, ESI [M+H] ⁺ = 356.9

¹H NMR(400MHz,d₆-DMSO)δ8.20(d,J＝1.6Hz,1H),7.56–7.48(m,1H),7.42–7.31(m,2H),7.28(d,J＝7.3Hz,1H),7.14(t,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.92(dd,J＝7.2,1.9Hz,1H),6.52(q,J＝7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.20(d,J＝1.6Hz,1H),7.56–7.48(m,1H),7.42–7.31(m,2H),7.28(d,J＝7.3Hz,1H),7.14(t,J＝7.6Hz,1H),6.9 8(d,J＝7.6Hz,1H),6.92(dd,J＝7.2,1.9Hz,1H),6.52(q,J＝7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.89(d,J＝7.1Hz,3H).

化合物DA-42：22mg，ESI[M+H]⁺＝337.0Compound DA-42: 22 mg, ESI [M+H] ⁺ = 337.0

¹H NMR(400MHz,d₆-DMSO)δ8.26(d,J＝1.8Hz,1H),7.30–7.23(m,2H),7.13(dd,J＝15.1,7.5Hz,2H),7.05(s,1H),7.03–6.96(m,2H),6.31(q,J＝7.3Hz,1H),2.30(s,3H),2.25(s,3H),1.96(s,3H),1.89(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.26(d,J＝1.8Hz,1H),7.30–7.23(m,2H),7.13(dd,J＝15.1,7.5Hz,2H),7.05(s,1H),7.03 –6.96(m,2H),6.31(q,J＝7.3Hz,1H),2.30(s,3H),2.25(s,3H),1.96(s,3H),1.89(d,J＝7.2Hz,3H).

化合物DA-43：2.534g，ESI[M+H]⁺＝340.9Compound DA-43: 2.534 g, ESI [M+H] ⁺ = 340.9

¹H NMR(400MHz,d₆-DMSO)δ8.29(d,J＝1.7Hz,1H),7.35–7.26(m,3H),7.25–7.17(m,2H),7.14(t,J＝7.6Hz,1H),6.99(d,J＝7.5Hz,1H),6.34(q,J＝7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.90(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.29(d,J＝1.7Hz,1H),7.35–7.26(m,3H),7.25–7.17(m,2H),7.14(t,J＝7.6Hz,1H),6 .99(d,J＝7.5Hz,1H),6.34(q,J＝7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.90(d,J＝7.2Hz,3H).

化合物DA-45：1.471g，ESI[M+H]⁺＝356.9Compound DA-45: 1.471 g, ESI [M+H] ⁺ = 356.9

¹H NMR(400MHz,d₆-DMSO)δ8.20(d,J＝1.7Hz,1H),7.50(dd,J＝7.5,1.7Hz,1H),7.43–7.31(m,2H),7.27(d,J＝7.5Hz,1H),7.14(t,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.92(dd,J＝7.3,2.1Hz,1H),6.52(q,J＝7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.88(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.20(d,J＝1.7Hz,1H),7.50(dd,J＝7.5,1.7Hz,1H),7.43–7.31(m,2H),7.27(d,J＝7.5Hz,1H),7.14(t,J＝7.6Hz,1H) ,6.98(d,J＝7.6Hz,1H),6.92(dd,J＝7.3,2.1Hz,1H),6.52(q,J＝7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.88(d,J＝7.1Hz,3H).

化合物DA-103：4.564g，ESI[M+H]⁺＝354.9Compound DA-103: 4.564 g, ESI [M+H] ⁺ = 354.9

¹H NMR(400MHz,d₆-DMSO)δ8.22(d,J＝1.4Hz,1H),7.27(d,J＝7.5Hz,1H),7.23(t,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),7.09(t,J＝7.7Hz,1H),6.99(d,J＝7.6Hz,1H),6.81(t,J＝7.3Hz,1H),6.50(q,J＝7.1Hz,1H),2.25(s,6H),1.96(s,3H),1.88(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.22(d,J＝1.4Hz,1H),7.27(d,J＝7.5Hz,1H),7.23(t,J＝7.6Hz,1H),7.14(t,J＝7.6Hz,1H),7.09(t,J＝7.7Hz,1H ),6.99(d,J＝7.6Hz,1H),6.81(t,J＝7.3Hz,1H),6.50(q,J＝7.1Hz,1H),2.25(s,6H),1.96(s,3H),1.88(d,J＝7.1Hz,3H).

化合物DA-105：2.349g，ESI[M+H]⁺＝370.9Compound DA-105: 2.349 g, ESI [M+H] ⁺ = 370.9

¹H NMR(400MHz,d₆-DMSO)δ8.16(d,J＝1.7Hz,1H),7.35–7.22(m,3H),7.14(t,J＝7.6Hz,1H),6.98(d,J＝7.7Hz,1H),6.74(dd,J＝7.4,0.9Hz,1H),6.55(q,J＝7.0Hz,1H),2.37(s,3H),2.25(s,3H),1.97(s,3H),1.87(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.16(d,J＝1.7Hz,1H),7.35–7.22(m,3H),7.14(t,J＝7.6Hz,1H),6.98(d,J＝7.7Hz,1H),6.74(dd ,J＝7.4,0.9Hz,1H),6.55(q,J＝7.0Hz,1H),2.37(s,3H),2.25(s,3H),1.97(s,3H),1.87(d,J＝7.0Hz,3H).

化合物DA-107：1.554g，ESI[M+H]⁺＝374.8Compound DA-107: 1.554 g, ESI [M+H] ⁺ = 374.8

1H NMR(400MHz,d₆-DMSO)δ8.27(d,J＝1.6Hz,1H),7.61(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),7.13(t,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.83(dd,J＝7.8,1.2Hz,1H),6.50(q,J＝7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J＝7.0Hz,3H).1H NMR(400MHz,d ₆ -DMSO) δ8.27(d,J＝1.6Hz,1H),7.61(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),7.13(t,J＝7.6Hz,1H ),6.98(d,J＝7.6Hz,1H),6.83(dd,J＝7.8,1.2Hz,1H),6.50(q,J＝7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J＝7.0Hz,3H).

化合物DA-109：1.567g，ESI[M+H]⁺＝390.8Compound DA-109: 1.567 g, ESI [M+H] ⁺ = 390.8

¹H NMR(400MHz,d₆-DMSO)δ8.27(d,J＝1.6Hz,1H),7.61(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),7.13(t,J＝7.6Hz,1H),6.98(d,J＝7.6Hz,1H),6.83(dd,J＝7.8,1.2Hz,1H),6.50(q,J＝7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.27(d,J＝1.6Hz,1H),7.61(dd,J＝8.0,1.3Hz,1H),7.39(t,J＝8.0Hz,1H),7.27(d,J＝7.4Hz,1H),7.13(t,J＝7.6Hz,1H ),6.98(d,J＝7.6Hz,1H),6.83(dd,J＝7.8,1.2Hz,1H),6.50(q,J＝7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J＝7.0Hz,3H).

化合物DA-173：2180mg,白色固体，ESI[M+H]⁺＝358.8Compound DA-173: 2180 mg, white solid, ESI [M+H] ⁺ = 358.8

¹H NMR(400MHz,d₆-DMSO)δ8.32(d,J＝1.7Hz,1H),7.46–7.32(m,1H),7.28(d,J＝7.5Hz,1H),7.26–7.19(m,1H),7.14(t,J＝7.6Hz,1H),6.99(d,J＝7.6Hz,1H),6.85–6.76(m,1H),6.51(q,J＝7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.92(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.32(d,J＝1.7Hz,1H),7.46–7.32(m,1H),7.28(d,J＝7.5Hz,1H),7.26–7.19(m,1H),7.14(t,J＝7.6Hz,1H) ,6.99(d,J＝7.6Hz,1H),6.85–6.76(m,1H),6.51(q,J＝7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.92(d,J＝7.1Hz,3H).

化合物C-2和4-氟-1H-咪唑-5-羧酸乙酯经过Mitsunobu反应制备中间体化合物C-3，会收集到部分异构体化合物C-3A，C-3A经水解，酰胺化，格氏反应得到本发明化合物DA-154。
Compound C-2 and ethyl 4-fluoro-1H-imidazole-5-carboxylate are reacted via Mitsunobu reaction to prepare intermediate compound C-3, and some isomer compound C-3A is collected. C-3A is hydrolyzed, amidated, and Grignard-reacted to obtain compound DA-154 of the present invention.

化合物DA-154：201mg，ESI[M+H]⁺＝370.9Compound DA-154: 201 mg, ESI [M+H] ⁺ = 370.9

¹H NMR(400MHz,d₆-DMSO)δ7.81(s,1H),7.40(d,J＝7.1Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝6.7Hz,1H),7.24–7.07(m,J＝14.7,7.7Hz,3H),5.87(q,J＝7.0Hz,1H),2.38(s,3H),2.28(s,3H),2.12(s,3H),1.86(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.81(s,1H),7.40(d,J＝7.1Hz,1H),7.34(t,J＝7.6Hz,1H),7.28(d,J＝6.7Hz,1H),7.24–7.07(m, J＝14.7,7.7Hz,3H),5.87(q,J＝7.0Hz,1H),2.38(s,3H),2.28(s,3H),2.12(s,3H),1.86(d,J＝7.0Hz,3H).

实施例9本发明化合物DA-53，DA-58和DA-59的制备
Example 9 Preparation of compounds DA-53, DA-58 and DA-59 of the present invention

化合物(R)-1-(1-(2-氯苯基)乙基)-N-甲氧基-N-甲基-1H-咪唑-5-甲酰胺在NCS条件下氯代生成中间体化合物DA-53-1，DA-58-1和DA-59-1，再参考实施例43化合物DA-21的制备方法得到本发明化合物DA-53，DA-58和DA-59。Compound (R)-1-(1-(2-chlorophenyl)ethyl)-N-methoxy-N-methyl-1H-imidazole-5-carboxamide was chlorinated under NCS conditions to generate intermediate compounds DA-53-1, DA-58-1 and DA-59-1, and then referring to the preparation method of compound DA-21 in Example 43 to obtain the compounds DA-53, DA-58 and DA-59 of the present invention.

化合物DA-59：406mg，ESI[M+H]⁺＝408.8Compound DA-59: 406 mg, ESI [M+H] ⁺ = 408.8

¹H NMR(400MHz,d₆-DMSO)δ7.73–7.65(m,1H),7.51–7.44(m,1H),7.41–7.29(m,3H),7.13(t,J＝7.6Hz,1H),6.82(d,J＝7.1Hz,1H),6.21(q,J＝6.9Hz,1H),2.26(s,3H),2.09(s,3H),2.08(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.73–7.65(m,1H),7.51–7.44(m,1H),7.41–7.29(m,3H),7.13(t,J＝7.6Hz,1H),6. 82(d,J＝7.1Hz,1H),6.21(q,J＝6.9Hz,1H),2.26(s,3H),2.09(s,3H),2.08(d,J＝7.2Hz,3H).

实施例10本发明化合物DA-54，DA-60，DA-61，DA-65，DA-67，DA-69～DA-71，DA-81，DA-82和DA-84的制备
Example 10 Preparation of compounds DA-54, DA-60, DA-61, DA-65, DA-67, DA-69 to DA-71, DA-81, DA-82 and DA-84 of the present invention

化合物(R)-1-(1-(2-氯苯基)乙基)-N-甲氧基-N-甲基-1H-咪唑-5-甲酰胺在NBS条件下溴代生成中间体化合物DA-54-1，DA-60-1和DA-61-1，再参考实施例43化合物DA-21的制备方法得到本发明化合物DA-54，DA-60和DA-61。Compound (R)-1-(1-(2-chlorophenyl)ethyl)-N-methoxy-N-methyl-1H-imidazole-5-carboxamide was brominated under NBS conditions to generate intermediate compounds DA-54-1, DA-60-1 and DA-61-1, and then referring to the preparation method of compound DA-21 in Example 43 to obtain the compounds DA-54, DA-60 and DA-61 of the present invention.

化合物DA-60：42mg，ESI[M+H]⁺＝418.8Compound DA-60: 42 mg, ESI [M+H] ⁺ = 418.8

¹H NMR(400MHz,d₆-DMSO)δ8.38(s,1H),7.50–7.45(m,1H),7.42–7.27(m,3H),7.13(t,J＝7.6Hz,1H),6.97(dd,J＝7.6,1.7Hz,1H),6.86(d,J＝7.7Hz,1H),6.43(q,J＝7.1Hz,1H),2.26(s,3H),1.99(s,3H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.38(s,1H),7.50–7.45(m,1H),7.42–7.27(m,3H),7.13(t,J＝7.6Hz,1H),6.97(dd,J＝7.6,1.7 Hz,1H),6.86(d,J＝7.7Hz,1H),6.43(q,J＝7.1Hz,1H),2.26(s,3H),1.99(s,3H),1.89(d,J＝7.1Hz,3H).

在制备本发明化合物DA-65，DA-70，DA-67，DA-71时，分别收集到副产品DA-69，DA-81，DA-82，DA-84。When preparing the compounds DA-65, DA-70, DA-67 and DA-71 of the present invention, by-products DA-69, DA-81, DA-82 and DA-84 were collected respectively.

化合物DA-69：488mg，ESI[M+H]⁺＝538.9Compound DA-69: 488 mg, ESI [M+H] ⁺ = 538.9

¹H NMR(400MHz,d₆-DMSO)δ8.41(s,1H),7.75(s,1H),7.46–7.36(m,1H),7.37–7.14(m,7H),7.07–6.98(m,3H),6.87(t,J＝7.5Hz,1H),6.58(q,J＝6.7Hz,1H),6.51(q,J＝7.2Hz,1H),2.28(s,3H),2.11(d,J＝7.0Hz,3H),1.98(s,3H),1.87(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.41(s,1H),7.75(s,1H),7.46–7.36(m,1H),7.37–7.14(m,7H),7.07–6.98(m,3H),6.87(t,J＝7.5Hz,1H),6 .58(q,J＝6.7Hz,1H),6.51(q,J＝7.2Hz,1H),2.28(s,3H),2.11(d,J＝7.0Hz,3H),1.98(s,3H),1.87(d,J＝7.1Hz,3H).

化合物DA-81：32mg，ESI[M+H]⁺＝538.9Compound DA-81: 32 mg, ESI [M+H] ⁺ = 538.9

¹H NMR(400MHz,d₆-DMSO)δ8.43(s,1H),8.31(d,J＝1.1Hz,1H),7.98(d,J＝1.0Hz,1H),7.47–7.31(m,4H),7.29–7.13(m,7H),6.76(q,J＝7.0Hz,1H),5.83(q,J＝7.1Hz,1H),2.30(s,3H),2.19(s,3H),1.90(d,J＝7.1Hz,3H),1.75(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.43(s,1H),8.31(d,J＝1.1Hz,1H),7.98(d,J＝1.0Hz,1H),7.47–7.31(m,4H),7.29–7.13(m,7H),6.76( q,J＝7.0Hz,1H),5.83(q,J＝7.1Hz,1H),2.30(s,3H),2.19(s,3H),1.90(d,J＝7.1Hz,3H),1.75(d,J＝7.1Hz,3H).

化合物DA-82：627mg，ESI[M+H]⁺＝566.9Compound DA-82: 627 mg, ESI [M+H] ⁺ = 566.9

化合物DA-84：19mg，ESI[M+H]⁺＝566.9Compound DA-84: 19 mg, ESI [M+H] ⁺ = 566.9

¹H NMR(400MHz,d₆-DMSO)δ8.41(s,1H),8.31(d,J＝1.1Hz,1H),8.00–7.96(m,1H),7.40(d,J＝7.5Hz,1H),7.35(d,J＝7.6Hz,1H),7.32–7.21(m,2H),7.18(t,J＝7.6Hz,1H),7.14–6.94(m,4H),6.81–6.73(m,1H),5.81(q,J＝6.9Hz,1H),2.31(s,3H),2.24(s,6H),2.19(s,3H),1.91–1.86(m,3H),1.74(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.41(s,1H),8.31(d,J＝1.1Hz,1H),8.00–7.96(m,1H),7.40(d,J＝7.5Hz,1H),7.35(d,J＝7.6Hz,1H),7.32–7.21(m,2H),7.18(t,J＝7.6Hz, 1H),7.14–6.94(m,4H),6.81–6.73(m,1H),5.81(q,J＝6.9Hz,1H),2.31(s ,3H),2.24(s,6H),2.19(s,3H),1.91–1.86(m,3H),1.74(d,J＝7.1Hz,3H).

实施例11本发明化合物DA-68，DA-85，DA-87～DA-89的制备
Example 11 Preparation of compounds DA-68, DA-85, DA-87 to DA-89 of the present invention

在室温下，将化合物D-1(4.89g,22.4mmol)，水(0.8mL)和甲酰胺(10.1g,224mmol)依次加入到100mL的封管中，150℃反应2小时。反应完全后，反应液用稀冷NaHCO₃的水溶液调pH≈8，经乙酸乙酯萃取(3×150mL)，饱和食盐水洗(100mL)，无水Na₂SO₄干燥，抽滤，滤液浓缩得白色固体化合物D-1(1.9g，收率41％)。ESI[M+H]⁺＝209.1At room temperature, compound D-1 (4.89 g, 22.4 mmol), water (0.8 mL), and formamide (10.1 g, 224 mmol) were added sequentially to a 100 mL sealed tube and reacted at 150°C for 2 hours. After the reaction was complete, the reaction solution was adjusted to pH ≈ 8 with a dilute cold aqueous solution of NaHCO ₃ , extracted with ethyl acetate (3×150 mL), washed with saturated brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was concentrated to obtain compound D-1 (1.9 g, yield 41%) as a white solid. ESI [M+H] ⁺ = 209.1

参照本发明化合物DA-21的制备方法，D-2经水解，缩合得到化合物D-4，D-4和相应醇类化合物经Mitsunobu反应，格氏反应制得本发明目标化合物DA-68，DA-87～DA-89。Referring to the preparation method of compound DA-21 of the present invention, D-2 was hydrolyzed and condensed to obtain compound D-4. D-4 and the corresponding alcohol compound were subjected to Mitsunobu reaction and Grignard reaction to obtain the target compounds DA-68, DA-87 to DA-89 of the present invention.

在制备本发明化合物DA-68收集得到本发明化合物DA-85。The compound DA-85 of the present invention was obtained by collecting during the preparation of the compound DA-68 of the present invention.

化合物DA-68：576mg，ESI[M+H]⁺＝406.8Compound DA-68: 576 mg, ESI [M+H] ⁺ = 406.8

¹H NMR(400MHz,CD₃OD)δ8.24(s,1H),7.42–7.25(m,4H),7.13–7.07(m,1H),7.04(t,J＝7.7Hz,1H),6.90(d,J＝7.7Hz,1H),6.06(q,J＝7.0Hz,1H),2.35(s,3H),2.22(s,3H),1.96(d,J＝7.0Hz,3H) ¹ H NMR (400MHz, CD ₃ OD)δ8.24(s,1H),7.42–7.25(m,4H),7.13–7.07(m,1H),7.04(t,J=7.7Hz,1H),6.90(d ,J＝7.7Hz,1H),6.06(q,J＝7.0Hz,1H),2.35(s,3H),2.22(s,3H),1.96(d,J＝7.0Hz,3H)

化合物DA-85：1.76g，ESI[M+H]⁺＝661.7Compound DA-85: 1.76 g, ESI [M+H] ⁺ = 661.7

¹H NMR(400MHz,CD₃OD)δ8.34(d,J＝8.2Hz,1H),7.73–7.56(m,1H),7.54–7.29(m,4H),7.25–7.13(m,2H),7.03–6.64(m,2H),6.29–6.08(m,1H),3.51(s,1H),3.50(s,0.5H),3.12(s,1.5H),3.04(s,0.7H),2.80(s,1.5H),2.46(s,0.8H),2.03–1.95(m,3H),1.93–1.76(m,3H). ¹ H NMR (400MHz, CD ₃ OD)δ8.34(d,J＝8.2Hz,1H),7.73–7.56(m,1H),7.54–7.29(m,4H),7.25–7.13(m,2H),7.03–6.64(m,2H),6.29–6.08(m,1H),3. 51(s,1H),3.50(s,0.5H),3.12(s,1.5H),3.04(s,0.7H),2.80(s,1.5H),2.46(s,0.8H),2.03–1.95(m,3H),1.93–1.76(m,3H).

化合物DA-87：197mg，ESI[M+H]⁺＝390.9Compound DA-87: 197 mg, ESI [M+H] ⁺ = 390.9

¹H NMR(400MHz,d₆-DMSO)δ8.49(s,1H),7.40–7.31(m,2H),7.24–7.12(m,3H),7.07(t,J＝7.6Hz,1H),6.82(d,J＝7.6Hz,1H),5.88(q,J＝7.1Hz,1H),2.29(s,3H),2.17(s,3H),1.91(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.49(s,1H),7.40–7.31(m,2H),7.24–7.12(m,3H),7.07(t,J＝7.6Hz,1H),6.82( d,J＝7.6Hz,1H),5.88(q,J＝7.1Hz,1H),2.29(s,3H),2.17(s,3H),1.91(d,J＝7.1Hz,3H).

化合物DA-88：176mg，ESI[M+H]⁺＝404.9Compound DA-88: 176 mg, ESI [M+H] ⁺ = 404.9

¹H NMR(400MHz,d₆-DMSO)δ8.47(s,1H),7.38(d,J＝7.5Hz,1H),7.20(t,J＝7.2Hz,1H),7.08(t,J＝7.6Hz,2H),7.00–6.93(m,1H),6.85(d,J＝7.8Hz,1H),5.83(q,J＝7.0Hz,1H),2.29(s,3H),2.16(s,6H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.47(s,1H),7.38(d,J＝7.5Hz,1H),7.20(t,J＝7.2Hz,1H),7.08(t,J＝7.6Hz,2H),7.00–6.93( m,1H),6.85(d,J＝7.8Hz,1H),5.83(q,J＝7.0Hz,1H),2.29(s,3H),2.16(s,6H),1.89(d,J＝7.1Hz,3H).

化合物DA-89：299mg，ESI[M+H]⁺＝420.7Compound DA-89: 299 mg, ESI [M+H] ⁺ = 420.7

¹H NMR(400MHz,d₆-DMSO)δ8.44(s,1H),7.36(d,J＝7.5Hz,1H),7.32–7.20(m,2H),7.06(t,J＝7.6Hz,1H),6.89(d,J＝7.4Hz,1H),6.86–6.79(m,1H),5.88(q,J＝6.6Hz,1H),2.28(d,J＝1.9Hz,6H),2.08(s,3H),1.86(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.44(s,1H),7.36(d,J＝7.5Hz,1H),7.32–7.20(m,2H),7.06(t,J＝7.6Hz,1H),6.89(d,J＝7.4Hz, 1H),6.86–6.79(m,1H),5.88(q,J＝6.6Hz,1H),2.28(d,J＝1.9Hz,6H),2.08(s,3H),1.86(d,J＝7.0Hz,3H).

实施例12本发明化合物DA-90～DA-93，DA-97和DA-98的制备
Example 12 Preparation of compounds DA-90 to DA-93, DA-97 and DA-98 of the present invention

本发明目标化合物DA-90～DA-93的制备参考本发明化合物DA-21的方法制备得到。The target compounds DA-90 to DA-93 of the present invention were prepared by referring to the method for preparing the compound DA-21 of the present invention.

化合物DA-90：1.876g，ESI[M+H]⁺＝322.9Compound DA-90: 1.876 g, ESI [M+H] ⁺ = 322.9

¹H NMR(400MHz,d₆-DMSO)δ7.65(d,J＝2.0Hz,1H),7.40–7.28(m,2H),7.26–7.14(m,3H),7.11(d,J＝7.3Hz,1H),7.09–7.01(m,1H),6.81(q,J＝7.0Hz,1H),6.46(d,J＝2.0Hz,1H),2.28(s,3H),2.02(s,3H),1.89(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.65(d,J＝2.0Hz,1H),7.40–7.28(m,2H),7.26–7.14(m,3H),7.11(d,J＝7.3Hz,1H),7.09–7.01 (m,1H),6.81(q,J＝7.0Hz,1H),6.46(d,J＝2.0Hz,1H),2.28(s,3H),2.02(s,3H),1.89(d,J＝7.0Hz,3H).

化合物DA-91：1.614g，ESI[M+H]⁺＝336.9Compound DA-91: 1.614 g, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ7.65(d,J＝1.8Hz,1H),7.35(d,J＝7.4Hz,1H),7.26–7.16(m,2H),7.11(d,J＝7.5Hz,1H),7.05(t,J＝7.6Hz,1H),6.89–6.73(m,2H),6.46(d,J＝1.9Hz,1H),2.29(s,3H),2.24(s,3H),2.03(s,3H),1.88(d,J＝6.9Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.65(d,J＝1.8Hz,1H),7.35(d,J＝7.4Hz,1H),7.26–7.16(m,2H),7.11(d,J＝7.5Hz,1H),7.05(t,J＝7.6H z,1H),6.89–6.73(m,2H),6.46(d,J＝1.9Hz,1H),2.29(s,3H),2.24(s,3H),2.03(s,3H),1.88(d,J＝6.9Hz,3H).

化合物E-2和1H-吡唑-5-羧酸乙酯经过Mitsunobu反应制备中间体化合物E-3和E-3A，E-3A经水解，酰胺化，格氏反应得到本发明化合物DA-97，DA-98。
Compound E-2 and 1H-pyrazole-5-carboxylic acid ethyl ester were subjected to Mitsunobu reaction to prepare intermediate compounds E-3 and E-3A. E-3A was hydrolyzed, amidated, and Grignard-reacted to obtain compounds DA-97 and DA-98 of the present invention.

化合物DA-97：2.469g，ESI[M+H]⁺＝322.9Compound DA-97: 2.469 g, ESI [M+H] ⁺ = 322.9

¹H NMR(400MHz,d₆-DMSO)δ8.06(d,J＝2.4Hz,1H),7.45–7.34(m,1H),7.31(d,J＝7.3Hz,1H),7.27–7.12(m,5H),6.84(d,J＝2.4Hz,1H),5.96(q,J＝7.1Hz,1H),2.28(s,3H),2.09(d,J＝4.0Hz,3H),1.82(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.06(d,J＝2.4Hz,1H),7.45–7.34(m,1H),7.31(d,J＝7.3Hz,1H),7.27–7.12(m,5H),6.84( d,J＝2.4Hz,1H),5.96(q,J＝7.1Hz,1H),2.28(s,3H),2.09(d,J＝4.0Hz,3H),1.82(d,J＝7.1Hz,3H).

化合物DA-98：1.674g，ESI[M+H]⁺＝336.9Compound DA-98: 1.674 g, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ8.05(d,J＝2.4Hz,1H),7.31(d,J＝7.3Hz,1H),7.31(d,J＝7.3Hz,1H),7.28–7.20(m,2H),7.17(t,J＝7.5Hz,1H),7.09(t,J＝7.6Hz,1H),7.04–6.96(m,1H),6.84(d,J＝2.4Hz,1H),5.94(q,J＝7.0Hz,1H),2.29(s,3H),2.24(d,J＝1.9Hz,3H),2.09(s,3H),1.81(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.05(d,J＝2.4Hz,1H),7.31(d,J＝7.3Hz,1H),7.31(d,J＝7.3Hz,1H),7.28–7.20(m,2H),7.17(t,J＝7.5Hz,1H),7.09(t,J＝7.6Hz,1H ),7.04–6.96(m,1H),6.84(d,J＝2.4Hz,1H),5.94(q,J＝7.0Hz,1H),2.29(s,3H),2.24(d,J＝1.9Hz,3H),2.09(s,3H),1.81(d,J＝7.1Hz,3H).

实施例13本发明化合物DA-95，DA-99～DA-102和DA-104的制备
Example 13 Preparation of compounds DA-95, DA-99 to DA-102 and DA-104 of the present invention

在室温下，将化合物DA-15(1.5g,4.65mmol)溶解在无水THF(10mL)中，用冰水浴将反应体系降至0℃，用注射器将甲基溴化镁(4.7mL,3mol/L in THF,14.1mmoL)缓慢加至反应体系，0℃搅拌1小时。经TLC监测反应完全后，将反应体系用冰水浴降至0℃，将饱和氯化铵水溶液(20mL)缓慢加至反应体系，用乙酸乙酯(3×20mL)萃取，合并有机相用无水硫酸钠干燥，无水硫酸钠干燥，抽滤，减压浓缩得到粗产品，将部分粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/3)监测，收集Rf＝0.5～0.6部分，得到白色固体化合物DA-99(70mg，收率64％)。ESI[M+H]⁺＝338.9。Compound DA-15 (1.5 g, 4.65 mmol) was dissolved in anhydrous THF (10 mL) at room temperature. The reaction system was cooled to 0°C using an ice-water bath. Methylmagnesium bromide (4.7 mL, 3 mol/L in THF, 14.1 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction system was cooled to 0°C using an ice-water bath. Saturated aqueous ammonium chloride (20 mL) was slowly added to the reaction system and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/3). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-99 (70 mg, 64% yield) as a white solid. ESI[M+H] ⁺ =338.9.

¹H NMR(400MHz,d₆-DMSO)δ7.99(s,1H),7.66(d,J＝8.2Hz,1H),7.19–7.02(m,3H),6.98–6.85(m,2H),6.82–6.64(m,2H),6.48(t,J＝7.2Hz,1H),5.89(s,1H),5.66(q,J＝7.3Hz,1H),1.81(s,3H),1.71(s,3H),1.64(s,3H),1.58(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.99(s,1H),7.66(d,J＝8.2Hz,1H),7.19–7.02(m,3H),6.98–6.85(m,2H),6.82–6.64(m,2H),6.48(t,J ＝7.2Hz,1H),5.89(s,1H),5.66(q,J＝7.3Hz,1H),1.81(s,3H),1.71(s,3H),1.64(s,3H),1.58(d,J＝7.2Hz,3H).

在室温下，将粗品化合物DA-99溶解在二氯甲烷(5V)中，用冰水浴将反应体系降至0℃，将三氟乙酸(10V)加至反应体系，室温搅拌过夜。经TLC监测反应完全后，将反应体系减压浓缩，用饱和碳酸氢钠缓慢加至反应体系，用乙酸乙酯(3×20mL)萃取，合并有机相用无水硫酸钠干燥，抽滤，减压浓缩得到粗产品，将部分粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/3)监测，收集得到无色油状化合物DA-100(130mg)。ESI[M+H]⁺＝320.9。Crude compound DA-99 was dissolved in dichloromethane (5V) at room temperature. The reaction system was cooled to 0°C using an ice-water bath. Trifluoroacetic acid (10V) was added to the reaction system and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, the reaction system was concentrated under reduced pressure. Saturated sodium bicarbonate was slowly added to the reaction system and extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/3) to obtain compound DA-100 (130 mg) as a colorless oil. ESI [M+H] ⁺ = 320.9.

¹H NMR(400MHz,d₆-DMSO)δ7.96(d,J＝0.7Hz,1H),7.37–7.26(m,1H),7.19–7.06(m,J＝16.9,11.9,7.0Hz,3H),7.03(t,J＝7.5Hz,1H),6.89(d,J＝0.9Hz,1H),6.86–6.74(m,2H),5.50(d,J＝1.5Hz,1H),5.31(q,J＝7.1Hz,1H),5.09(d,J＝1.5Hz,1H),2.16(s,3H),1.87(s,3H),1.64(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.96(d,J＝0.7Hz,1H),7.37–7.26(m,1H),7.19–7.06(m,J＝16.9,11.9,7.0Hz,3H),7.03(t,J＝7.5Hz,1H),6.89(d,J＝0.9Hz,1H), 6.86–6.74(m,2H),5.50(d,J＝1.5Hz,1H),5.31(q,J＝7.1Hz,1H),5.09(d,J＝1.5Hz,1H),2.16(s,3H),1.87(s,3H),1.64(d,J＝7.1Hz,3H).

在室温下，将化合物DA-100(590mg,1.84mmol)溶解在二氯甲烷(3mL)中，用冰水浴将反应体系降至0℃，将间氯过氧苯甲酸(747.7mg,3.68mmol)加至反应体系，室温搅拌过夜。经TLC监测反应完全后，将饱和碳酸氢钠缓慢加至反应体系，用二氯甲烷(3×20mL)萃取，合并有机相用无水硫酸钠干燥，抽滤，减压浓缩得到粗产品，将部分粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/1)，TLC(乙酸乙酯/石油醚(v/v)＝1/3)监测，收集得到灰色固体化合物DA-95和无色油状化合物DA-104(13mg)At room temperature, compound DA-100 (590 mg, 1.84 mmol) was dissolved in dichloromethane (3 mL). The reaction system was cooled to 0°C using an ice-water bath. Meta-chloroperbenzoic acid (747.7 mg, 3.68 mmol) was added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated sodium bicarbonate was slowly added to the reaction system. The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/1) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/3) to obtain compound DA-95 as a gray solid and compound DA-104 (13 mg) as a colorless oil.

化合物DA-95：63mg，ESI[M+H]⁺＝336.9Compound DA-95: 63 mg, ESI [M+H] ⁺ = 336.9

¹H NMR(400MHz,d₆-DMSO)δ8.57(d,J＝1.6Hz,1H),7.38–7.29(m,1H),7.25–7.16(m,2H),7.14–6.99(m,4H),6.91(d,J＝7.4Hz,1H),5.67(s,1H),5.32(s,1H),5.18(q,J＝6.8Hz,1H),2.16(s,3H),1.94(s,3H),1.54(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.57(d,J＝1.6Hz,1H),7.38–7.29(m,1H),7.25–7.16(m,2H),7.14–6.99(m,4H),6.91(d,J＝7.4H z,1H),5.67(s,1H),5.32(s,1H),5.18(q,J＝6.8Hz,1H),2.16(s,3H),1.94(s,3H),1.54(d,J＝7.1Hz,3H).

化合物DA-104：13mg，ESI[M+H]⁺＝352.9Compound DA-104: 13 mg, ESI [M+H] ⁺ = 352.9

在冰水浴0℃下，将NaH(24mg,60％in mineral oil,0.60mmol)缓慢加至DA-99(170mg,0.50mmol)的DMF(2mL)溶液中，加完后在0℃继续搅拌30分钟。用注射器将碘甲烷(85.2mg,0.60mmol)缓慢加至体系，室温搅拌过夜。经TLC监测反应完全后，将冰水缓慢加至反应体系，用乙酸乙酯(3×5mL)萃取，合并有机相用饱和食盐水洗，无水硫酸钠干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/1)，得到化合物DA-102(8mg)In an ice-water bath at 0°C, NaH (24 mg, 60% in mineral oil, 0.60 mmol) was slowly added to a DMF (2 mL) solution of DA-99 (170 mg, 0.50 mmol). After the addition, stirring was continued at 0°C for 30 minutes. Iodomethane (85.2 mg, 0.60 mmol) was slowly added to the system using a syringe and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was slowly added to the reaction system and extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/1) to obtain compound DA-102 (8 mg).

在室温下，将DA-99(170mg,0.53mmol)和10％湿钯碳(17mg)溶于MeOH(10mL)中，用氢气置换体系三次，在氢气下搅2小时。经TLC监测反应完全后，抽滤，滤饼用甲醇洗涤(3×5mL)，将滤液减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/5)，TLC(乙酸乙酯/石油醚(v/v)＝1/1)监测，得到灰色固体化合物DA-101(140mg，收率81.8％)。ESI[M+H]⁺＝322.9At room temperature, DA-99 (170 mg, 0.53 mmol) and 10% wet palladium on carbon (17 mg) were dissolved in MeOH (10 mL), the system was replaced with hydrogen three times, and the mixture was stirred under hydrogen for 2 hours. After the reaction was complete as monitored by TLC, the mixture was filtered, the filter cake was washed with methanol (3×5 mL), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/5) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/1) to obtain a gray solid compound DA-101 (140 mg, yield 81.8%). ESI [M+H] ⁺ = 322.9

DA-101是非对映异构体，核磁有两组峰。DA-101 is a diastereomer and has two sets of peaks in NMR.

¹H NMR(400MHz,d₆-DMSO)δ7.90(s,1H),7.13–7.06(m,1H),6.91–6.84(m,2H),6.82(s,1H),6.69(d,J＝7.3Hz,1H),6.65–6.59(m,2H),6.54–6.48(m,1H),5.44(q,J＝6.9Hz,1H),4.36(q,J＝6.8Hz,1H),2.11(s,3H),2.05(s,3H),1.72(d,J＝7.1Hz,3H),1.45(d,J＝6.9Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.90(s,1H),7.13–7.06(m,1H),6.91–6.84(m,2H),6.82(s,1H),6.69(d,J＝7.3Hz,1H),6.65–6.59(m,2H),6.54–6.48 (m,1H),5.44(q,J＝6.9Hz,1H),4.36(q,J＝6.8Hz,1H),2.11(s,3H),2.05(s,3H),1.72(d,J＝7.1Hz,3H),1.45(d,J＝6.9Hz,3H).

¹H NMR(400MHz,d₆-DMSO)δ7.96(s,1H),7.43–7.34(m,1H),7.28–7.18(m,2H),7.06–6.96(m,3H),6.95–6.90(m,1H),6.57–6.54(m,1H),4.91(q,J＝6.6Hz,1H),4.00–3.92(m,1H),2.30(s,3H),2.15(s,3H),1.47(d,J＝6.6Hz,3H),1.35(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.96(s,1H),7.43–7.34(m,1H),7.28–7.18(m,2H),7.06–6.96(m,3H),6.95–6.90(m,1H),6.57–6.54(m,1H ),4.91(q,J＝6.6Hz,1H),4.00–3.92(m,1H),2.30(s,3H),2.15(s,3H),1.47(d,J＝6.6Hz,3H),1.35(d,J＝7.0Hz,3H).

实施例14本发明化合物DA-164，DA-165，DA-166，DA-167和DA-34的制备
Example 14 Preparation of compounds DA-164, DA-165, DA-166, DA-167 and DA-34 of the present invention

在室温下，将2-氯-3-甲基苯甲酸(1.26g,7.39mmol)溶于氯化亚砜(6.3mL)，120℃下搅拌2小时。经检测反应完成后，将反应液减压浓缩得到粗产品DA-164-1，粗产品未经纯化直接用于下一步反应。Dissolve 2-chloro-3-methylbenzoic acid (1.26 g, 7.39 mmol) in thionyl chloride (6.3 mL) at room temperature and stir at 120°C for 2 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain the crude product DA-164-1, which is used directly in the next reaction without purification.

室温下，将2-甲基吡咯(500.0mg,6.16mmol)的乙醚(5mL)溶液滴加到乙基溴化镁(3.17mL,2mol/L in THF,6.34mmol)的乙醚(5mL)溶液中，40℃下搅拌30分钟。将反应体系冷却至室温，滴加DA-164-1的乙醚溶液(10mL)，室温搅拌过夜。经TLC监测反应完全后，将反应体系降至0℃，然后倒入饱和氯化铵水溶液(20mL)中，用EtOAc(3×20mL)萃取，合并有机相用饱和食盐水洗涤，无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/50～1/3)，TLC(乙酸乙酯/石油醚(v/v)＝1/3)监测，收集Rf＝0.3～0.5部分，得到白色固体化合物DA-164-2(793.9mg，两步收率46.0％)。ESI[M+H]⁺＝234.1。At room temperature, add a solution of 2-methylpyrrole (500.0 mg, 6.16 mmol) in diethyl ether (5 mL) dropwise to a solution of ethylmagnesium bromide (3.17 mL, 2 mol/L in THF, 6.34 mmol) in diethyl ether (5 mL) and stir at 40°C for 30 minutes. Cool the reaction system to room temperature, add a solution of DA-164-1 in diethyl ether (10 mL) dropwise, and stir at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C and poured into saturated aqueous ammonium chloride (20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/50 to 1/3) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/3). Fractions with Rf = 0.3 to 0.5 were collected to give compound DA-164-2 (793.9 mg, 46.0% yield for two steps) as a white solid. ESI [M+H] ⁺ = 234.1.

将化合物DA-164-2(200.0mg,0.86mmol)溶于DCE(5mL)中，加入环丙基硼酸(147.5mg,1.72mmol)，碳酸钠(181.9mg,1.72mmol)，醋酸铜(171.5mg,0.86mmol)和2,2'-联吡啶(134.1mg,0.86mmol)，90℃下搅拌4小时。经TLC监测反应完全后，将反应液减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/100～1/10)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.3～0.4部分，得到白色固体化合物DA-164(86.3mg，收率36.8％)。ESI[M+H]⁺＝274.1。Compound DA-164-2 (200.0 mg, 0.86 mmol) was dissolved in DCE (5 mL), and cyclopropylboronic acid (147.5 mg, 1.72 mmol), sodium carbonate (181.9 mg, 1.72 mmol), copper acetate (171.5 mg, 0.86 mmol), and 2,2'-bipyridine (134.1 mg, 0.86 mmol) were added. The mixture was stirred at 90°C for 4 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/100 to 1/10) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound DA-164 (86.3 mg, 36.8% yield) as a white solid. ESI [M+H] ⁺ = 274.1.

¹H NMR(400MHz,d₆-DMSO)δ7.50–7.43(m,1H),7.31(t,J＝7.5Hz,1H),7.24(dd,J＝7.5,1.3Hz,1H),6.19(d,J＝4.0Hz,1H),5.96–5.88(m,1H),3.36–3.30(m,1H),2.39(s,3H),2.37(s,3H),1.18–1.09(m,2H),0.95–0.81(m,2H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.50–7.43(m,1H),7.31(t,J＝7.5Hz,1H),7.24(dd,J＝7.5,1.3Hz,1H),6.19(d,J＝4.0Hz,1H), 5.96–5.88(m,1H),3.36–3.30(m,1H),2.39(s,3H),2.37(s,3H),1.18–1.09(m,2H),0.95–0.81(m,2H).

目标化合物DA-165，DA-166，DA-167和DA-34的制备方法类同于目标化合物DA-164，分别使用不同取代的苯甲酸为原料制备得到。The preparation methods of the target compounds DA-165, DA-166, DA-167 and DA-34 are similar to that of the target compound DA-164, and are prepared using different substituted benzoic acids as raw materials.

化合物DA-165：78.1mg，白色固体，ESI[M+H]⁺＝258.1。Compound DA-165: 78.1 mg, white solid, ESI [M+H] ⁺ = 258.1.

¹H NMR(400MHz,d₆-DMSO)δ7.43(t,J＝7.0Hz,1H),7.34–7.25(m,1H),7.17(t,J＝7.5Hz,1H),6.33(d,J＝4.0Hz,1H),5.93(d,J＝4.0Hz,1H),3.36–3.31(m,1H),2.37(s,3H),2.29(d,J＝1.8Hz,3H),1.19–1.05(m,2H),0.87–0.75(m,2H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.43(t,J＝7.0Hz,1H),7.34–7.25(m,1H),7.17(t,J＝7.5Hz,1H),6.33(d,J＝4.0Hz,1H),5.93(d,J ＝4.0Hz,1H),3.36–3.31(m,1H),2.37(s,3H),2.29(d,J＝1.8Hz,3H),1.19–1.05(m,2H),0.87–0.75(m,2H).

化合物DA-166：64.6mg，白色固体，ESI[M+H]⁺＝278.1。Compound DA-166: 64.6 mg, white solid, ESI [M+H] ⁺ = 278.1.

¹H NMR(400MHz,d₆-DMSO)δ7.60–7.43(m,2H),7.31(d,J＝7.3Hz,1H),6.28(d,J＝4.0Hz,1H),5.95(d,J＝4.0Hz,1H),3.38–3.33(m,1H),2.39(s,3H),1.23–1.08(m,2H),0.95–0.81(m,2H). ¹ H NMR (400MHz, d ₆ -DMSO) δ7.60–7.43(m,2H),7.31(d,J＝7.3Hz,1H),6.28(d,J＝4.0Hz,1H),5.95(d,J ＝4.0Hz,1H),3.38–3.33(m,1H),2.39(s,3H),1.23–1.08(m,2H),0.95–0.81(m,2H).

化合物DA-167：67.5mg，白色固体，ESI[M+H]⁺＝278.1。Compound DA-167: 67.5 mg, white solid, ESI [M+H] ⁺ = 278.1.

¹H NMR(400MHz,d₆-DMSO)δ7.79–7.69(m,1H),7.53–7.44(m,1H),7.32(t,J＝7.8Hz,1H),6.41(d,J＝4.0Hz,1H),5.97(d,J＝4.0Hz,1H),3.36–3.31(m,1H),2.38(s,3H),1.15–1.10(m,2H),0.87–0.74(m,2H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.79–7.69(m,1H),7.53–7.44(m,1H),7.32(t,J＝7.8Hz,1H),6.41(d,J＝4.0Hz,1H), 5.97(d,J＝4.0Hz,1H),3.36–3.31(m,1H),2.38(s,3H),1.15–1.10(m,2H),0.87–0.74(m,2H).

化合物DA-34：229.2mg，白色固体，ESI[M+H]⁺＝254.1。Compound DA-34: 229.2 mg, white solid, ESI [M+H] ⁺ = 254.1.

¹H NMR(400MHz,d₆-DMSO)δ7.26(d,J＝6.9Hz,1H),7.17–7.07(m,2H),6.16(d,J＝3.9Hz,1H),5.92–5.86(m,1H),3.36–3.32(m,1H),2.37(s,3H),2.29(s,3H),2.13(s,3H),1.19–1.06(m,2H),0.87–0.76(m,2H). ¹ H NMR (400MHz, d ₆ -DMSO)δ7.26(d,J＝6.9Hz,1H),7.17–7.07(m,2H),6.16(d,J＝3.9Hz,1H),5.92–5.86(m,1H),3. 36–3.32(m,1H),2.37(s,3H),2.29(s,3H),2.13(s,3H),1.19–1.06(m,2H),0.87–0.76(m,2H).

实施例15本发明化合物DA-110，DA-130，和DA-157的制备
Example 15 Preparation of compounds DA-110, DA-130, and DA-157 of the present invention

本发明目标化合物DA-110，DA-130，和DA-157的制备类同于化合物DA-21。The preparation of the target compounds DA-110, DA-130, and DA-157 of the present invention is similar to that of compound DA-21.

化合物DA-110：155mg，白色固体，ESI[M+H]⁺＝351.1。Compound DA-110: 155 mg, white solid, ESI [M+H] ⁺ = 351.1.

¹H NMR(400MHz,d₆--DMSO)δ8.11(d,J＝1.7Hz,1H),7.27(d,J＝7.4Hz,1H),7.14(d,J＝7.6Hz,1H),7.10(d,J＝5.3Hz,2H),6.95(d,J＝7.6Hz,1H),6.66–6.59(m,1H),6.51(d,J＝7.0Hz,1H),2.27(d,J＝5.1Hz,6H),2.24(s,3H),1.94(s,3H),1.80(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ --DMSO)δ8.11(d,J＝1.7Hz,1H),7.27(d,J＝7.4Hz,1H),7.14(d,J＝7.6Hz,1H),7.10(d,J＝5.3Hz,2H),6.95(d,J＝7.6Hz, 1H),6.66–6.59(m,1H),6.51(d,J＝7.0Hz,1H),2.27(d,J＝5.1Hz,6H),2.24(s,3H),1.94(s,3H),1.80(d,J＝7.0Hz,3H).

化合物DA-130：67mg，白色固体，ESI[M+H]⁺＝353.1。Compound DA-130: 67 mg, white solid, ESI [M+H] ⁺ = 353.1.

¹H NMR(400MHz,d₆-DMSO)δ8.18(s,1H),7.51(d,J＝6.9Hz,1H),7.34(t,J＝7.6Hz,1H),7.25(s,1H),7.20(t,J＝6.0Hz,1H),7.11(t,J＝4.7Hz,2H),6.75(d,J＝7.0Hz,1H),6.58(d,J＝6.9Hz,1H),2.37(s,3H),2.27(d,J＝7.0Hz,6H),1.83(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.18(s,1H),7.51(d,J＝6.9Hz,1H),7.34(t,J＝7.6Hz,1H),7.25(s,1H),7.20(t,J＝6.0Hz,1H),7.11(t,J＝4 .7Hz,2H),6.75(d,J＝7.0Hz,1H),6.58(d,J＝6.9Hz,1H),2.37(s,3H),2.27(d,J＝7.0Hz,6H),1.83(d,J＝7.0Hz,3H).

化合物DA-157：453mg，无色油状，ESI[M+H]⁺＝359.1。Compound DA-157: 453 mg, colorless oil, ESI [M+H] ⁺ = 359.1.

¹H NMR(400MHz,d₆-DMSO)δ8.25(d,J＝1.7Hz,1H),7.30(dd,J＝14.7,5.1Hz,2H),7.18–7.07(m,3H),7.00(d,J＝7.6Hz,1H),6.47(d,J＝7.1Hz,1H),2.26(s,3H),1.97(s,3H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.25(d,J＝1.7Hz,1H),7.30(dd,J＝14.7,5.1Hz,2H),7.18–7.07(m,3H),7.00(d ,J＝7.6Hz,1H),6.47(d,J＝7.1Hz,1H),2.26(s,3H),1.97(s,3H),1.90(d,J＝7.1Hz,3H).

实施例16本发明化合物DA-115的制备
Example 16 Preparation of Compound DA-115 of the Present Invention

在室温下，将1-(2,3-甲基苯基)乙酮(20.0g,135mmol),甲酸(31.07g,675mmol),三乙胺(40.98g,405mmol)依次加至异丙醇(200mL)中，氩气置换反应体系三次，将(S,S)-N-(对甲苯磺酰)-1,2-二苯乙烷二胺(对异丙基甲苯)氯化钌(1.29g,2.03mmol)加至反应体系，氩气保护下60℃搅拌4小时，经TLC监测反应完全后，降至室温，抽滤，用EtOAc(3×50mL)萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/3)，TLC(乙酸乙酯/石油醚(v/v)＝1/10)监测，收集Rf＝0.5～0.6部分，得到浅黄色油状化合物DA-115.2(19.26g，收率95.1％)。At room temperature, 1-(2,3-methylphenyl)ethanone (20.0 g, 135 mmol), formic acid (31.07 g, 675 mmol), and triethylamine (40.98 g, 405 mmol) were added to isopropanol (200 mL) in sequence. The reaction system was replaced with argon three times. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene) ruthenium chloride (1.29 g, 2.03 mmol) was added to the reaction system. The mixture was stirred at 60°C for 4 hours under argon protection. After the reaction was complete as monitored by TLC, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3×50 mL). The organic phases were combined and eluted with anhydrous Na ₂ SO _{The reaction mixture} was dried, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/3) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/10). The fractions with Rf = 0.5 to 0.6 were collected to give the compound DA-115.2 (19.26 g, 95.1% yield) as a light yellow oil.

在室温下，将5-氟-1H-咪唑-4-甲醛(1.44g,12.58mmol)溶解在干燥THF(30mL)中，用干冰丙酮浴将温度降至～-30℃，再将DA-115.2(2.44g,16.35mmol)和PBu₃(5.08g,25.16mmol)依次加进反应体系，用注射器将DEAD(4.38g,25.16mmol)缓慢加至反应体系，室温搅拌过夜。经TLC监测反应完全后，将冰水加至反应体系，用EtOAc萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品，粗产品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/2)，TLC(乙酸乙酯/石油醚(v/v)＝1/2)监测，收集Rf＝0.5～0.6部分，得到无色油状化合物DA-115.3(1.54g，两部反应总收率49.7％)。ESI[M+H]⁺＝247.1。At room temperature, 5-fluoro-1H-imidazole-4-carbaldehyde (1.44 g, 12.58 mmol) was dissolved in dry THF (30 mL). The temperature was lowered to -30°C using a dry ice acetone bath. DA-115.2 (2.44 g, 16.35 mmol) and PBu ₃ (5.08 g, 25.16 mmol) were then added to the reaction system in sequence. DEAD (4.38 g, 25.16 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic _phases were dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/2) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-115.3 (1.54 g, total yield of two reactions, 49.7%) as a colorless oil. ESI [M+H] ^⁺ = 247.1.

在干冰丙酮浴-78℃下，将3-氯-2-氟溴苯(628mg,3mmol)溶解在干燥THF(10mL)中，氮气保护下，将正丁基锂(0.96mL,2.5mol/L in THF 2.4mmol)加进反应体系，搅拌0.5小时。用注射器将化合物DA-115.5(368mg,1.5mmol)的THF(5mL)溶液缓慢加至反应体系，搅拌1小时。经TLC监测反应完全后，将冰水加至反应体系，用EtOAc萃取，合并有机相用无水Na₂SO₄干燥，抽滤，减压浓缩得到粗产品化合物DA-115.6，粗产品溶解在干燥DCM(30mL)中，再将二氧化锰(2.61g,30mmol)加进反应体系，回流搅拌过夜。经TLC监测反应完全后，抽滤，减压浓缩得到粗产品，经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)＝1/10～1/2)，TLC(乙酸乙酯/石油醚(v/v)＝1/2)监测，收集Rf＝0.5～0.6部分，得到白色固体化合物DA-115(154mg，两部反应总收率27.4％)。ESI[M+H]⁺＝375.1。In a dry ice-acetone bath at -78°C, 3-chloro-2-fluorobromobenzene (628 mg, 3 mmol) was dissolved in dry THF (10 mL). Under nitrogen, n-butyllithium (0.96 mL, 2.5 mol/L in THF (2.4 mmol) was added to the reaction system and stirred for 0.5 hour. A solution of compound DA-115.5 (368 mg, 1.5 mmol) in THF (5 mL) was slowly added to the reaction system via syringe and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water was added to the reaction system and extracted with EtOAc. The combined organic phases were dried over _anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to afford the crude product, compound DA-115.6. This crude product was dissolved in dry DCM (30 mL), and manganese dioxide (2.61 g, 30 mmol) was added to the reaction system. The mixture was stirred at reflux overnight. After the reaction was complete as monitored by TLC, the mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) = 1/10 to 1/2) and monitored by TLC (ethyl acetate/petroleum ether (v/v) = 1/2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-115 (154 mg, total yield of two reactions 27.4%) as a white solid. ESI [M+H] ⁺ = 375.1.

¹H NMR(400MHz,d₆-DMSO)δ8.18(d,J＝1.7Hz,1H),7.86–7.74(m,1H),7.43(t,J＝6.3Hz,1H),7.34(s,1H),7.15–7.04(m,2H),6.70–6.61(m,1H),6.44(q,J＝6.9Hz,1H),2.28(d,J＝3.4Hz,6H),1.79(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.18(d,J＝1.7Hz,1H),7.86–7.74(m,1H),7.43(t,J＝6.3Hz,1H),7.34(s,1H),7.15–7.0 4(m,2H),6.70–6.61(m,1H),6.44(q,J＝6.9Hz,1H),2.28(d,J＝3.4Hz,6H),1.79(d,J＝7.0Hz,3H).

实施例17本发明化合物DA-117,DA-127～DA-129,DA-174,DA-175,DA-178～DA-180,DA-182～DA-184,和DA-187～DA-231的制备
Example 17 Preparation of compounds DA-117, DA-127～DA-129, DA-174, DA-175, DA-178～DA-180, DA-182～DA-184, and DA-187～DA-231 of the present invention

本发明目标化合物DA-117,DA-127～DA-129,DA-174,DA-175,DA-178～DA-180,DA-182～DA-184,和DA-187～DA-231，的制备类同于化合物DA-115。The preparation of the target compounds DA-117, DA-127 to DA-129, DA-174, DA-175, DA-178 to DA-180, DA-182 to DA-184, and DA-187 to DA-231 of the present invention is similar to that of compound DA-115.

化合物DA-117：159mg，白色固体，ESI[M+H]⁺＝355.1。Compound DA-117: 159 mg, white solid, ESI [M+H] ⁺ = 355.1.

¹H NMR(400MHz,d₆-DMSO)δ8.11(d,J＝1.8Hz,1H),7.48(t,J＝6.7Hz,1H),7.23(t,J＝6.1Hz,1H),7.19(d,J＝7.4Hz,1H),7.13–7.06(m,2H),6.77–6.62(m,1H),6.46(q,J＝6.9Hz,1H),2.27(s,6H),2.25(d,J＝1.7Hz,3H),1.79(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.11(d,J＝1.8Hz,1H),7.48(t,J＝6.7Hz,1H),7.23(t,J＝6.1Hz,1H),7.19(d,J＝7.4Hz,1H),7.13–7.0 6(m,2H),6.77–6.62(m,1H),6.46(q,J＝6.9Hz,1H),2.27(s,6H),2.25(d,J＝1.7Hz,3H),1.79(d,J＝7.0Hz,3H).

化合物DA-127：221mg，白色固体，ESI[M+H]⁺＝357.1。Compound DA-127: 221 mg, white solid, ESI [M+H] ⁺ = 357.1.

¹H NMR(400MHz,d₆-DMSO)δ8.29(s,1H),7.80(td,J＝8.0,1.7Hz,1H),7.55(s,1H),7.44(ddd,J＝7.8,6.2,1.7Hz,1H),7.34(t,J＝7.9Hz,1H),7.14–7.04(m,2H),6.70–6.63(m,1H),6.52(d,J＝7.0Hz,1H),2.27(d,J＝3.4Hz,6H),1.81(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.29(s,1H),7.80(td,J＝8.0,1.7Hz,1H),7.55(s,1H),7.44(ddd,J＝7.8,6.2,1.7Hz,1H),7.34(t,J＝7.9H z,1H),7.14–7.04(m,2H),6.70–6.63(m,1H),6.52(d,J＝7.0Hz,1H),2.27(d,J＝3.4Hz,6H),1.81(d,J＝7.0Hz,3H).

化合物DA-128：111mg，无色糖浆，ESI[M+H]⁺＝357.1。Compound DA-128: 111 mg, colorless syrup, ESI [M+H] ⁺ = 357.1.

¹H NMR(400MHz,d₆-DMSO)δ8.24(s,1H),7.58(dd,J＝13.0,4.8Hz,1H),7.50(td,J＝8.0,5.1Hz,1H),7.39(s,1H),7.25(d,J＝7.5Hz,1H),7.15–7.06(m,2H),6.72(d,J＝6.8Hz,1H),6.55(q,J＝7.1Hz,1H),2.27(d,J＝4.6Hz,6H),1.81(t,J＝6.4Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.24(s,1H),7.58(dd,J＝13.0,4.8Hz,1H),7.50(td,J＝8.0,5.1Hz,1H),7.39(s,1H),7.25(d,J＝7.5Hz,1 H),7.15–7.06(m,2H),6.72(d,J＝6.8Hz,1H),6.55(q,J＝7.1Hz,1H),2.27(d,J＝4.6Hz,6H),1.81(t,J＝6.4Hz,3H).

化合物DA-129：310mg，无色糖浆，ESI[M+H]⁺＝337.1。Compound DA-129: 310 mg, colorless syrup, ESI [M+H] ⁺ = 337.1.

¹H NMR(400MHz,d₆-DMSO)δ8.23(s,1H),7.48(s,1H),7.44(s,1H),7.25(d,J＝6.1Hz,1H),7.19(t,J＝7.5Hz,1H),7.09(d,J＝7.1Hz,2H),6.74–6.66(m,1H),6.54(d,J＝7.0Hz,1H),2.27(s,6H),2.26(s,3H),1.81(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.23(s,1H),7.48(s,1H),7.44(s,1H),7.25(d,J＝6.1Hz,1H),7.19(t,J＝7.5Hz,1H),7.09(d,J ＝7.1Hz,2H),6.74–6.66(m,1H),6.54(d,J＝7.0Hz,1H),2.27(s,6H),2.26(s,3H),1.81(d,J＝7.0Hz,3H).

化合物DA-174：340mg，无色糖浆，ESI[M+H]⁺＝341.1。Compound DA-174: 340 mg, colorless syrup, ESI [M+H] ⁺ = 341.1.

¹H NMR(400MHz,d₆-DMSO)δ8.29(s,1H),7.70–7.61(m,1H),7.58(s,1H),7.30(s,2H),7.09(d,J＝7.1Hz,2H),6.67(d,J＝6.9Hz,1H),6.52(q,J＝7.0Hz,1H),2.27(d,J＝2.8Hz,6H),1.81(d,J＝7.0Hz,3H). ^1H NMR(400MHz,d ₆ -DMSO)δ8.29(s,1H),7.70–7.61(m,1H),7.58(s,1H),7.30(s,2H),7.09(d,J＝7.1Hz,2H), 6.67(d,J＝6.9Hz,1H), 6.52(q,J＝7.0Hz,1H), 2.27(d,J＝2.8Hz,6H), 1.81(d,J＝7.0Hz,3H).

化合物DA-175：134mg，白色固体，ESI[M+H]⁺＝359.1。Compound DA-175: 134 mg, white solid, ESI [M+H] ⁺ = 359.1.

¹H NMR(400MHz,d₆-DMSO)δ8.19(d,J＝1.6Hz,1H),7.65(dd,J＝17.6,9.2Hz,1H),7.37–7.23(m,2H),7.14–7.05(m,2H),6.65(dd,J＝6.0,3.0Hz,1H),6.44(q,J＝6.9Hz,1H),2.28(d,J＝4.4Hz,6H),1.79(d,J＝7.0Hz,3H). ^1H NMR(400MHz,d ₆ -DMSO)δ8.19(d,J＝1.6Hz,1H),7.65(dd,J＝17.6,9.2Hz,1H),7.37–7.23(m,2H),7.14–7.05(m,2H) ,6.65(dd,J＝6.0,3.0Hz,1H),6.44(q,J＝6.9Hz,1H),2.28(d,J＝4.4Hz,6H),1.79(d,J＝7.0Hz,3H).

化合物DA-178：96mg，白色固体，ESI[M+H]⁺＝367.1。Compound DA-178: 96 mg, white solid, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.40(d,J＝1.7Hz,1H),7.66(dd,J＝10.3,2.3Hz,1H),7.45–7.36(m,1H),7.36–7.27(m,2H),7.26–7.18(m,1H),6.85(t,J＝7.1Hz,1H),6.44(d,J＝7.1Hz,1H),1.91(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.40(d,J＝1.7Hz,1H),7.66(dd,J＝10.3,2.3Hz,1H),7.45–7.36(m,1H),7.36–7.27(m ,2H),7.26–7.18(m,1H),6.85(t,J＝7.1Hz,1H),6.44(d,J＝7.1Hz,1H),1.91(d,J＝7.1Hz,3H).

化合物DA-179：142mg，白色固体，ESI[M+H]⁺＝363.1。Compound DA-179: 142 mg, white solid, ESI [M+H] ⁺ = 363.1.

¹H NMR(400MHz,d₆-DMSO)δ8.31(d,J＝1.7Hz,1H),7.66(dd,J＝10.4,2.3Hz,1H),7.39–7.27(m,2H),7.24(d,J＝7.1Hz,1H),7.10(t,J＝7.6Hz,1H),6.85(d,J＝7.1Hz,1H),6.43(d,J＝7.1Hz,1H),2.25(d,J＝1.7Hz,3H),1.88(d,J＝7.1Hz,3H). ^1H NMR(400MHz,d ₆ -DMSO) δ8.31(d,J＝1.7Hz,1H),7.66(dd,J＝10.4,2.3Hz,1H),7.39–7.27(m,2H),7.24(d,J＝7.1Hz,1H),7.10 (t,J＝7.6Hz,1H),6.85(d,J＝7.1Hz,1H),6.43(d,J＝7.1Hz,1H),2.25(d,J＝1.7Hz,3H),1.88(d,J＝7.1Hz,3H).

化合物DA-180：310g，白色固体，ESI[M+H]⁺＝379.1。Compound DA-180: 310 g, white solid, ESI [M+H] ⁺ = 379.1.

¹H NMR(400MHz,d₆-DMSO)δ8.26(d,J＝1.7Hz,1H),7.66(d,J＝8.4Hz,1H),7.40–7.22(m,4H),6.76(d,J＝7.3Hz,1H),6.48(d,J＝7.0Hz,1H),2.38(s,3H),1.87(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.26(d,J＝1.7Hz,1H),7.66(d,J＝8.4Hz,1H),7.40–7.22(m,4H),6.7 6(d,J＝7.3Hz,1H), 6.48(d,J＝7.0Hz,1H), 2.38(s,3H), 1.87(d,J＝7.0Hz,3H).

化合物DA-182：321mg，白色固体，ESI[M+H]⁺＝349.1。Compound DA-182: 321 mg, white solid, ESI [M+H] ⁺ = 349.1.

¹H NMR(400MHz,d₆-DMSO)δ8.55(d,J＝6.4Hz,1H),7.66(ddd,J＝10.1,7.8,3.9Hz,1H),7.62(s,1H),7.39(td,J＝9.7,1.5Hz,1H),7.35–7.28(m,2H),7.27–7.18(m,1H),6.79(t,J＝7.2Hz,1H),6.53(q,J＝7.1Hz,1H),1.93(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.55(d,J＝6.4Hz,1H),7.66(ddd,J＝10.1,7.8,3.9Hz,1H),7.62(s,1H),7.39(td,J＝9.7,1.5Hz,1H) ,7.35–7.28(m,2H),7.27–7.18(m,1H),6.79(t,J＝7.2Hz,1H),6.53(q,J＝7.1Hz,1H),1.93(d,J＝7.1Hz,3H).

化合物DA-183：226mg，无色油状，ESI[M+H]⁺＝345.1。Compound DA-183: 226 mg, colorless oil, ESI [M+H] ⁺ = 345.1.

¹H NMR(400MHz,d₆-DMSO)δ8.44(s,1H),7.66(d,J＝5.8Hz,1H),7.59(s,1H),7.39–7.28(m,2H),7.24(s,1H),7.09(t,J＝7.6Hz,1H),6.80(s,1H),6.53(d,J＝7.1Hz,1H),2.25(d,J＝1.7Hz,3H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.44(s,1H),7.66(d,J＝5.8Hz,1H),7.59(s,1H),7.39–7.28(m,2H),7.24(s,1H),7.09(t ,J＝7.6Hz,1H),6.80(s,1H),6.53(d,J＝7.1Hz,1H),2.25(d,J＝1.7Hz,3H),1.89(d,J＝7.1Hz,3H).

化合物DA-184：101mg，白色固体，ESI[M+H]⁺＝361.1。Compound DA-184: 101 mg, white solid, ESI [M+H] ⁺ = 361.1.

¹H NMR(400MHz,d₆-DMSO)δ8.38(s,1H),7.70–7.61(m,1H),7.60(s,1H),7.37–7.27(m,3H),7.25(t,J＝7.6Hz,1H),6.72(d,J＝7.0Hz,1H),6.57(q,J＝7.0Hz,1H),2.38(s,3H),1.89(t,J＝6.3Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.38(s,1H),7.70–7.61(m,1H),7.60(s,1H),7.37–7.27(m,3H),7.25(t,J＝7.6H z,1H),6.72(d,J＝7.0Hz,1H),6.57(q,J＝7.0Hz,1H),2.38(s,3H),1.89(t,J＝6.3Hz,3H).

化合物DA-187：253mg，白色固体，ESI[M+H]⁺＝365.1。Compound DA-187: 253 mg, white solid, ESI [M+H] ⁺ = 365.1.

¹H NMR(400MHz,d₆-DMSO)δ8.28(d,J＝1.5Hz,1H),7.72–7.60(m,1H),7.54–7.48(m,1H),7.36(ddd,J＝12.1,5.7,3.5Hz,4H),6.99–6.90(m,1H),6.45(d,J＝7.0Hz,1H),1.88(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.28(d,J＝1.5Hz,1H),7.72–7.60(m,1H),7.54–7.48(m,1H),7.36(ddd,J＝12 .1,5.7,3.5Hz,4H),6.99–6.90(m,1H),6.45(d,J＝7.0Hz,1H),1.88(d,J＝7.0Hz,3H).

化合物DA-188：256mg，白色固体，ESI[M+H]⁺＝383.0。Compound DA-188: 256 mg, white solid, ESI [M+H] ⁺ = 383.0.

¹H NMR(400MHz,d₆-DMSO)δ8.35(d,J＝1.5Hz,1H),7.66(dd,J＝10.4,2.0Hz,1H),7.45–7.36(m,2H),7.36–7.26(m,2H),6.77(d,J＝6.4Hz,1H),6.43(d,J＝7.0Hz,1H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.35(d,J＝1.5Hz,1H),7.66(dd,J＝10.4,2.0Hz,1H),7.45–7.36(m,2H),7.3 6–7.26(m,2H),6.77(d,J＝6.4Hz,1H),6.43(d,J＝7.0Hz,1H),1.89(d,J＝7.1Hz,3H).

化合物DA-189：178mg，白色固体，ESI[M+H]⁺＝399.0。Compound DA-189: 178 mg, white solid, ESI [M+H] ⁺ = 399.0.

¹H NMR(400MHz,d₆-DMSO)δ8.36(s,1H),7.70–7.64(m,1H),7.62(d,J＝6.8Hz,1H),7.39(s,1H),7.37–7.26(m,2H),6.86(d,J＝6.9Hz,1H),6.44(q,J＝7.0Hz,1H),1.88(d,J＝7.0Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.36(s,1H),7.70–7.64(m,1H),7.62(d,J＝6.8Hz,1H),7.39(s,1H),7.37 –7.26(m,2H),6.86(d,J＝6.9Hz,1H),6.44(q,J＝7.0Hz,1H),1.88(d,J＝7.0Hz,3H).

化合物DA-190：223mg，无色油状，ESI[M+H]⁺＝349.1。Compound DA-190: 223 mg, colorless oil, ESI [M+H] ⁺ = 349.1.

¹H NMR(400MHz,d₆-DMSO)δ8.34(d,J＝1.5Hz,1H),7.70–7.60(m,1H),7.31(s,3H),7.22(d,J＝7.9Hz,2H),7.05(t,J＝7.6Hz,1H),6.44(q,J＝7.0Hz,1H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.34(d,J＝1.5Hz,1H),7.70–7.60(m,1H),7.31(s,3H),7.22(d,J＝7. 9Hz, 2H), 7.05 (t, J = 7.6Hz, 1H), 6.44 (q, J = 7.0Hz, 1H), 1.90 (d, J = 7.1Hz, 3H).

化合物DA-191：235mg，无色油状，ESI[M+H]⁺＝349.1。Compound DA-191: 235 mg, colorless oil, ESI [M+H] ⁺ = 349.1.

¹H NMR(400MHz,d₆-DMSO)δ8.37(d,J＝1.8Hz,1H),7.66(ddd,J＝10.5,7.8,2.2Hz,1H),7.39–7.29(m,4H),7.21(t,J＝8.9Hz,2H),6.27(q,J＝7.2Hz,1H),1.90(d,J＝7.2Hz,3H). ^1H NMR(400MHz,d ₆ -DMSO)δ8.37(d,J＝1.8Hz,1H),7.66(ddd,J＝10.5,7.8,2.2Hz,1H),7.39–7.2 9(m,4H),7.21(t,J＝8.9Hz,2H),6.27(q,J＝7.2Hz,1H),1.90(d,J＝7.2Hz,3H).

化合物DA-192：291mg，无色油状，ESI[M+H]⁺＝367.1。Compound DA-192: 291 mg, colorless oil, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.33(d,J＝1.4Hz,1H),7.67(d,J＝8.0Hz,1H),7.42–7.26(m,3H),7.23–7.06(m,2H),6.39(d,J＝7.1Hz,1H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.33(d,J＝1.4Hz,1H),7.67(d,J＝8.0Hz,1H),7.42–7.26(m,3H),7.23–7.06(m,2H),6.39(d,J＝7.1Hz,1H),1.89(d,J＝7.1Hz,3H).

化合物DA-212：188mg，白色固体，ESI[M+H]⁺＝363.1。Compound DA-212: 188 mg, white solid, ESI [M+H] ⁺ = 363.1.

¹H NMR(400MHz,d₆-DMSO)δ8.28(d,J＝1.7Hz,1H),7.49(t,J＝6.9Hz,1H),7.29(ddd,J＝12.2,9.6,4.3Hz,2H),7.19(t,J＝7.5Hz,1H),7.16–7.07(m,2H),6.40(t,J＝7.1Hz,1H),2.26(d,J＝1.8Hz,3H),1.88(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.28(d,J＝1.7Hz,1H),7.49(t,J＝6.9Hz,1H),7.29(ddd,J＝12.2,9.6,4.3Hz,2H),7.19(t,J ＝7.5Hz,1H),7.16–7.07(m,2H),6.40(t,J＝7.1Hz,1H),2.26(d,J＝1.8Hz,3H),1.88(d,J＝7.1Hz,3H).

化合物DA-217：262mg，白色固体，ESI[M+H]⁺＝367.1。Compound DA-217: 262 mg, white solid, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.34(d,J＝1.8Hz,1H),7.72–7.62(m,1H),7.39–7.28(m,3H),7.23(ddd,J＝12.2,8.2,3.6Hz,1H),6.95(ddd,J＝9.0,5.8,3.1Hz,1H),6.39(q,J＝7.1Hz,1H),1.90(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.34(d,J＝1.8Hz,1H),7.72–7.62(m,1H),7.39–7.28(m,3H),7.23(ddd,J＝12.2,8.2 ,3.6Hz,1H),6.95(ddd,J＝9.0,5.8,3.1Hz,1H),6.39(q,J＝7.1Hz,1H),1.90(d,J＝7.1Hz,3H).

化合物DA-218：138mg，白色固体，ESI[M+H]⁺＝367.1。Compound DA-218: 138 mg, white solid, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.39(d,J＝1.8Hz,1H),7.67(ddd,J＝10.0,5.6,3.0Hz,1H),7.35(dd,J＝6.1,3.0Hz,2H),7.20(tt,J＝9.3,2.3Hz,1H),7.01(dd,J＝8.5,2.0Hz,2H),6.24(d,J＝7.1Hz,1H),1.90(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.39(d,J＝1.8Hz,1H),7.67(ddd,J＝10.0,5.6,3.0Hz,1H),7.35(dd,J＝6.1,3.0Hz,2H),7.2 0(tt,J＝9.3,2.3Hz,1H),7.01(dd,J＝8.5,2.0Hz,2H),6.24(d,J＝7.1Hz,1H),1.90(d,J＝7.2Hz,3H).

化合物DA-219：410mg，无色糖浆，ESI[M+H]⁺＝367.1。Compound DA-219: 410 mg, colorless syrup, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.42(s,1H),7.65(dd,J＝10.5,1.7Hz,1H),7.40(dd,J＝11.7,5.2Hz,1H),7.33(d,J＝4.5Hz,1H),7.26(d,J＝5.9Hz,1H),7.09(t,J＝8.7Hz,2H),6.35(d,J＝7.2Hz,1H),1.97(d,J＝7.2Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.42(s,1H),7.65(dd,J＝10.5,1.7Hz,1H),7.40(dd,J＝11.7,5.2Hz,1H),7.33(d,J＝4.5H z,1H),7.26(d,J＝5.9Hz,1H),7.09(t,J＝8.7Hz,2H),6.35(d,J＝7.2Hz,1H),1.97(d,J＝7.2Hz,3H).

化合物DA-221：306mg，无色糖浆，ESI[M+H]⁺＝367.1。Compound DA-221: 306 mg, colorless syrup, ESI [M+H] ⁺ = 367.1.

¹H NMR(400MHz,d₆-DMSO)δ8.37(d,J＝1.8Hz,1H),7.68–7.58(m,1H),7.31(dd,J＝15.3,5.9Hz,1H),7.24(t,J＝8.2Hz,2H),7.11(dd,J＝7.6,1.6Hz,2H),6.40(q,J＝7.0Hz,1H),1.89(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO)δ8.37(d,J＝1.8Hz,1H),7.68–7.58(m,1H),7.31(dd,J＝15.3,5.9Hz,1H),7.24(t, J＝8.2Hz,2H),7.11(dd,J＝7.6,1.6Hz,2H),6.40(q,J＝7.0Hz,1H),1.89(d,J＝7.1Hz,3H).

化合物DA-228：160mg，无色糖浆，ESI[M+H]⁺＝359.1。Compound DA-228: 160 mg, colorless syrup, ESI [M+H] ⁺ = 359.1.

¹H NMR(400MHz,d₆-DMSO)δ8.26(d,J＝1.7Hz,1H),7.48(t,J＝6.8Hz,1H),7.24(d,J＝6.7Hz,2H),7.20(d,J＝7.5Hz,1H),7.09(s,1H),6.81(s,1H),6.44(s,1H),2.25(s,6H),1.87(d,J＝7.1Hz,3H). ¹ H NMR (400MHz, d ₆ -DMSO) δ8.26(d,J＝1.7Hz,1H),7.48(t,J＝6.8Hz,1H),7.24(d,J＝6.7Hz,2H),7.20(d,J＝ 7.5Hz,1H),7.09(s,1H),6.81(s,1H),6.44(s,1H),2.25(s,6H),1.87(d,J＝7.1Hz,3H).

以下通过试验例证明本发明的有益效果。The beneficial effects of the present invention are demonstrated by the following test examples.

试验例1本发明化合物的药理数据测定Test Example 1 Pharmacological Data Determination of the Compounds of the Invention

1.试验方法1. Test methods

1.1测试本发明化合物在大鼠尾静脉注射后的麻醉效果(最小麻醉有效剂量的测定)：1.1 Testing the anesthetic effect of the compound of the present invention after tail vein injection in rats (determination of the minimum anesthetic effective dose):

实验动物选用7-9周龄SD雄性大鼠，尾静脉给药(给药速度0.02mL/s，给药容积0.6mL/只)。每次试验化合物的初始剂量从1mg/kg开始，实际给药量按照每只大鼠试验前称量的体重计算。根据实验大鼠是否出现翻正反射消失确定后续剂量的递增或递减，将出现翻正反射消失的最低剂量确定为最小麻醉有效剂量。Experimental animals were 7-9 week old male Sprague-Dawley rats, and administration was performed via the tail vein (dosage rate 0.02 mL/s, dosing volume 0.6 mL/rat). The initial dose of each test compound started at 1 mg/kg, and the actual dose was calculated based on the pre-test body weight of each rat. Subsequent dose increases or decreases were determined based on whether the rats exhibited loss of righting reflex. The lowest dose that resulted in loss of righting reflex was determined as the minimum anesthetic effective dose.

在测试本发明化合物对大鼠尾静脉注射后是否有麻醉效果的同时，还测定化合物是否具有镇痛作用。一旦确定化合物有麻醉作用(翻正反射消失≥30s)，立即观察给药后大鼠对伤害性刺激(鳄鱼夹夹持大鼠尾部中外1/3处持续30s)有无反应，若30s内大鼠无反应，则判定为有镇痛作用，反之则无镇痛作用；如果化合物无麻醉作用(翻正反射消失＜30s)，在给药1min后，对鼠给予伤害性刺激(鳄鱼夹夹持大鼠尾部中外1/3处持续30s)。若30s内大鼠无反应，则判定为有镇痛作用；反之则判定为无镇痛作用。本发明中将开始出现有镇痛作用的剂量确定为最小镇痛有效剂量。本发明中最小麻醉有效剂量和最小镇痛有效剂量进一步归类为：A≤10mg/kg；10mg/kg＜B≤20mg/kg；20mg/kg<C≤30mg/kg；30mg/kg<D≤40mg/kg；E＞40mg/kg。While testing whether the compound of the present invention has an anesthetic effect after tail vein injection in rats, the compound is also tested for analgesic effects. Once it is determined that the compound has an anesthetic effect (loss of righting reflex ≥ 30 seconds), the rat is immediately observed for any reaction to a noxious stimulus (approximately clamping the middle and outer third of the rat's tail for 30 seconds) after administration. If the rat does not react within 30 seconds, it is determined to have an analgesic effect; otherwise, it is determined to have no analgesic effect. If the compound has no anesthetic effect (loss of righting reflex < 30 seconds), the rat is given a noxious stimulus (approximately clamping the middle and outer third of the rat's tail for 30 seconds) 1 minute after administration. If the rat does not react within 30 seconds, it is determined to have an analgesic effect; otherwise, it is determined to have no analgesic effect. In the present invention, the dose at which an analgesic effect begins to appear is determined to be the minimum analgesic effective dose. The minimum anesthetic effective dose and the minimum analgesic effective dose in the present invention are further classified as: A≤10 mg/kg; 10 mg/kg＜B≤20 mg/kg; 20 mg/kg<C≤30 mg/kg; 30 mg/kg<D≤40 mg/kg; E＞40 mg/kg.

1.2本发明化合物主要药理效应测定1.2 Determination of the main pharmacological effects of the compounds of the present invention

1.2.1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED₅₀ 1.2.1 _ED50 of the general anesthetic effect of the compounds of the present invention using the loss of righting reflex in rats as the evaluation index

选择7-9周龄雄性SD大鼠进行试验。采用序贯法(Up-and-down method)测定本发明化合物以翻正反射消失作为判定指标的全身麻醉作用的半数有效剂量(median effective dose,ED₅₀)。试验时经大鼠尾静脉给药，每只大鼠给药体积为0.6mL、给药速度为0.02mL/s。以翻正反射消失(LORR)≥30s作为产生麻醉效应的判定标准。Male Sprague-Dawley rats aged 7-9 weeks were used for the study. The median effective dose ( _ED50 ) of the compounds of this invention for general anesthetic efficacy was determined using the up-and-down method, using loss of righting reflex as the criterion. Administration was via the tail vein of the rats, with a volume of 0.6 mL per rat and a dosing rate of 0.02 mL/s. Anesthetic effect was determined by loss of righting reflex (LORR) ≥ 30 seconds.

1.2.2以大鼠致翻正反射消失2ED₅₀剂量比较本发明化合物的药理效应1.2.2 Comparison of the pharmacological effects of the compounds of the present invention using a dose of _2ED50 that causes loss of righting reflex in rats

测得发明化合物ED₅₀后，采用致大鼠翻正反射消失的2ED₅₀剂量进行试验。试验时经大鼠尾静脉给药，每只大鼠给药体积为0.6mL、给药速度0.02mL/s。以翻正反射消失(LORR)的时间记为开始产生麻醉效应的时间。给药后记录并观察大鼠翻正反射消失、翻正反射恢复时间以及不良反应症状和起止时间等。After determining the _ED50 of the inventive compound, a dose of _2ED50 , which causes loss of righting reflex in rats, was used for testing. The compound was administered via the tail vein of the rats, with a volume of 0.6 mL per rat and a dosing rate of 0.02 mL/s. The onset of the anesthetic effect was recorded as the time of loss of righting reflex (LORR). Following administration, the loss of righting reflex, the time to recovery of righting reflex, and the onset and end time of adverse reactions were recorded and observed.

2ED₅₀的等效剂量的药理特点：Pharmacological characteristics of the equivalent dose of _2ED50 :

在上述试验中，除了记录出现翻正反射消失的剂量，还可以记录自给药开始至麻醉作用的起效时间和恢复时间、翻正反射的持续时间和产生镇静作用的持续时间等。在本发明化合物致翻正反射消失的剂量，还可以观察到化合物对实验动物呼吸的影响。In the above test, in addition to recording the dose at which the righting reflex is lost, the time from the start of administration to the onset and recovery of the anesthetic effect, the duration of the righting reflex, and the duration of the sedative effect can also be recorded. At the dose of the compound of the present invention that causes the righting reflex to be lost, the effect of the compound on the respiration of the experimental animal can also be observed.

2.实验结果2. Experimental Results

表1.本发明化合物单次静脉注射具有麻醉作用的药理数据

Table 1. Pharmacological data of the anesthetic effect of the compounds of the present invention after a single intravenous injection

表2.本发明化合物单次静脉注射的最小镇痛有效剂量
Table 2. Minimum analgesic effective dose of the compounds of the present invention for a single intravenous injection

表3.本发明部分化合物以大鼠翻正反射消失的ED₅₀和2ED₅₀剂量的药理特征
Table 3. Pharmacological characteristics of some compounds of the present invention _{at ED50} and _2ED50 doses of loss of righting reflex in rats

实验结果表明，本发明化合物具有高效的麻醉、镇静、催眠作用，能够控制癫痫持续状态，同时还具有镇痛作用。Experimental results show that the compound of the present invention has highly effective anesthetic, sedative and hypnotic effects, can control status epilepticus, and also has analgesic effects.

实验结果表明，本发明化合物具有高效的麻醉、镇静、催眠作用，能够控制癫痫持续状态。Experimental results show that the compound of the present invention has highly effective anesthetic, sedative and hypnotic effects and can control status epilepticus.

Claims

A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that the structure of the compound is as shown in Formula II:

Ring A is selected from substituted or unsubstituted 5-6 membered nitrogen heteroaryl groups, wherein the ring heteroatoms of the 5-6 membered nitrogen heteroaryl groups are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, -O, (CR ₆ R ₇ ) _m R ₈

The following groups, unsubstituted or substituted by one or more R ₉ : amino, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _1-8 alkoxy, C _1-8 alkylthio, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl;

m is selected from 0, 1, 2, 3, 4, 5;

R ₆ and R ₇ are each independently selected from hydrogen and C _1-8 alkyl;

R ₈ is selected from CONR ₁₀ R ₁₁ , NR ₁₀ R ₁₁ , COOR ₁₂ , COR ₁₂ , OR ₁₂ , substituted aryl, wherein the substituents are each independently selected from halogen, hydroxyl, nitro, cyano, C _1-8 alkyl, C _1-8 alkoxy; R ₁₀ and R ₁₁ are each independently selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, 3-8 membered saturated cycloalkyl, R ₁₂ is selected from C _1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R ₁₃ is selected from hydroxyl, C _1-8 alkoxy;

The C ring is selected from aryl, 3-8 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl;

e is selected from 0, 1, 2, 3, 4, 5;

R _x1 is each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, L ₂ R _2a , L ₂ is selected from none, C _1-6 alkylene, R _2a is selected from phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl;

R _x2 is selected from hydrogen, C _1-8 alkyl, 3-8 membered saturated cycloalkyl, =CR _xa R _xb ; R _xa is selected from hydrogen, C _1-8 alkyl, R _xb is selected from hydrogen, C _1-8 alkyl;

R _x12 is selected from hydrogen, C _1-8 alkyl;

f is selected from 0, 1, 2, 3, 4, 5;

R _x6 are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl;

R _x5 is selected from C _1-8 alkyl;

R _x7 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl;

R _x8 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl, CONR _x9 R _x10 ; R _x9 is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy, R _x10 is selected from hydrogen, C _1-8 alkyl, C _1-8 alkoxy;

Each of the R ₉ groups is independently selected from halogen, hydroxyl, amino, thiol, C _1-8 alkyl, C _1-8 alkoxy, C _2-8 alkenyl, C _2-8 alkynyl, OCOR _9a , SO ₂ R _9a , OR _9c , a 3-8-membered saturated cycloalkyl group, a 3-8-membered saturated cycloalkyl group substituted with one or two or more R _9b , a 3-8-membered saturated heterocyclyl group, a 3-8-membered saturated heterocyclyl group substituted with one or two or more R _9b , an aryl group, an aryl group substituted with one or two or more R _9b , a 5-6-membered heteroaryl group, a 5-6-membered heteroaryl group substituted with one or two or more R _9b ; R _9a is selected from C _1-8 alkyl; each of the R _9b groups is independently selected from halogen, C _1-8 alkyl; and R _9c is selected from a 3-8-membered saturated cycloalkyl group, or a 3-8-membered saturated heterocyclyl group.

L is selected from none, CR _a R _b , C(═CR _c R _d ), NR _e , CO, CS, SO, S, O;

R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-8 membered saturated cycloalkyl or a 3-8 membered saturated heterocyclic group; R _s is selected from a 3-8 membered saturated cycloalkyl, a 3-8 membered saturated heterocyclic group, or benzyl;

R _c and R _d are each independently selected from hydrogen and halogen;

R _e is selected from hydrogen, C _1-8 alkyl;

Ring B is

_X1 is N or _CR1 , _X2 is N or _CR2 , _X3 is N or _CR3 , _X4 is N or _CR4 , _X5 is N or _CR5 , and at least three of _X1 , X2, _X3 , _X4 , _and _X5 are not N at the same time;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , and R ₁₅ are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-8 alkyl, halogenated or unhalogenated C _1-8 alkoxy, L ₁ R _1a , L ₁ is selected from none, C _1-6 alkylene, R _1a is selected from aryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, or two adjacent groups among R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are linked to form a benzene ring which is unsubstituted or substituted with one or more R ₁₄ , and R ₁₄ is each independently selected from halogen, C _1-8 alkyl, and C _1-8 alkoxy;

Alternatively, the substituent on ring A is connected to R ₅ to form a ring.

The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that the A ring is selected from the following structures:

C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl,

e is selected from 0, 1, 2, 3;

R _x1 is each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-4 alkyl, halogenated or unhalogenated C _1-4 alkoxy, L ₂ R _2a , L ₂ is selected from none, C _1-2 alkylene, R _2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl;

R _x2 is selected from hydrogen, C _1-3 alkyl, 3-4 membered saturated cycloalkyl, =CR _xa R _xb ; R _xa is selected from hydrogen, C _1-4 alkyl, R _xb is selected from hydrogen, C _1-4 alkyl;

R _x12 is selected from hydrogen, C _1-3 alkyl;

R _x3 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

R _x4 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

R _x11 is selected from hydrogen, halogen, C _1-3 alkyl which is unsubstituted or substituted by one or more halogens,

f is selected from 0, 1, 2, 3;

R _x6 are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl;

R _x5 is selected from C _1-3 alkyl;

R _x7 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl;

R _x8 is selected from hydrogen, halogen, halogenated or unhalogenated C _1-4 alkyl, CONR _x9 R _x10 ; R _x9 is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy, R _x10 is selected from hydrogen, C _1-4 alkyl, C _1-4 alkoxy;

The heterocyclic group contains at least one heteroatom selected from N, O or S.

The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that the structure of the compound is as shown in Formula II-1 or Formula II-2:

wherein Q is selected from none, CR _x2 R _x12 , CO, CH=CH,

e is selected from 0, 1, 2, 3;

R _x12 is selected from hydrogen, C _1-3 alkyl;

f is selected from 0, 1, 2, 3;

R _x5 is selected from C _1-3 alkyl;

The heterocyclic group contains at least one heteroatom selected from N, O or S;

L, X ₁ , X ₂ , X ₃ , X ₄ , and X ₅ are as described in claim 1.

The compound according to any one of claims 1 to 3, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that L is selected from none, CR _a R _b , C(═CR _c R _d ), NR _e , CO, CS, SO, S, O;

R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-6 alkyl, halogenated or unhalogenated C _1-6 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-6 membered saturated cycloalkyl or a 3-6 membered saturated heterocyclic group; R _s is selected from a 3-6 membered saturated cycloalkyl, a 3-6 membered saturated heterocyclic group, or benzyl;

R _c and R _d are each independently selected from hydrogen and halogen;

R _e is selected from hydrogen, C _1-6 alkyl.

The compound according to claim 4, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that L is selected from none, CR _a R _b , C(═CR _c R _d ), NR _e , CO, CS, SO, S, O;

R _a and R _b are each independently selected from hydrogen, halogen, halogenated or unhalogenated C _1-3 alkyl, halogenated or unhalogenated C _1-3 alkoxy, OH, or OR _s ; or R _a and R _b are linked to form a 3-4 membered saturated cycloalkyl or a 3-4 membered saturated heterocyclic group; R _s is selected from a 3-4 membered saturated cycloalkyl, a 3-4 membered saturated heterocyclic group, or benzyl;

R _c and R _d are each independently selected from hydrogen and halogen;

R _e is selected from hydrogen, C _1-3 alkyl.

The compound according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that the B ring is

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C _1-6 alkyl, halogenated or unhalogenated C _1-6 alkoxy, L ₁ R _1a , L ₁ is selected from none, C _1-4 alkylene, and R _1a is selected from aryl, 3-6 membered saturated cycloalkyl, and 3-6 membered saturated heterocyclic group.

The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that the compound is selected from:

According to any one of claims 1 to 7, the compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that the pharmaceutically acceptable salt is citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, formate, fumarate salt, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogenphosphate, dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, or p-toluenesulfonate.

A pharmaceutical composition, characterized in that the pharmaceutical composition is a preparation prepared by using the compound according to any one of claims 1 to 7, its stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites or deuterated derivatives thereof as an active ingredient, and adding pharmaceutically acceptable excipients.

Use of the compound according to any one of claims 1 to 7, its stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites or deuterated derivatives thereof in the preparation of a drug having analgesic and/or anesthetic, sedative, hypnotic effects and/or capable of controlling status epilepticus.