Cyclic ketone compound prodrug and medical effect thereof

Abstract

The invention provides a cyclic ketone compound prodrug and a medical effect thereof, and belongs to the technical field of anesthetic drugs. The cyclic ketone compound prodrug is a compound as shown in a formula I, a stereoisomer thereof, a deuterated derivative thereof, a salt thereof and a solvate thereof. It is found for the first time that the prodrug of the cyclic ketone compound has good general anesthesia and sedative antagonism effects, has good antagonism effects on general anesthesia induced by various general anesthesia drugs, and can also play an effective antagonism effect on general anesthesia continuously infused with the general anesthesia drugs. Meanwhile, the traditional Chinese medicine composition has a good improvement effect on respiratory depression caused by opioids and inhalation anesthetics. The invention provides a new choice for antagonists of anesthetic and / or sedative drugs, especially antagonists of general anesthetic drugs, and has wide application prospects. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of anesthetic drugs, and in particular relates to a cyclic ketone compound prodrug and its medical effect. Background Art

[0002] General anesthetics, also known as general anesthetics, are a class of drugs that can inhibit the function of the central nervous system. They can reversibly cause loss of consciousness, sensation, and reflexes, and relaxation of skeletal muscles. They are mainly used for surgical anesthesia. Postoperative anesthesia recovery time has always been one of the issues of clinical concern, and it is closely related to a variety of factors. Prolonged postoperative anesthesia recovery time will increase the patient's endotracheal intubation time, prolong the patient's exposure to the risk of general anesthesia, increase the incidence of cardiovascular and pulmonary complications, and affect the prognosis of surgical patients. In addition, prolonged anesthesia recovery time will greatly reduce the utilization efficiency of the operating room, increase the vacancy rate of the operating room, and increase the cost of patients and medical staff. Moreover, with the update of the concept of day surgery, rapid anesthesia recovery and good recovery quality are the cornerstones for promoting day surgery and ensuring the safety of day surgery.

[0003] With the increasing requirements for surgical safety and controllability, antagonists of some anesthetic drugs have appeared, such as naloxone, an antagonist of opioid drugs, neostigmine, an antagonist of broad-spectrum muscle relaxants, and sugammadex, a specific antagonist of rocuronium bromide, etc. These antagonists can quickly reverse the anesthetic effects of opioid drugs or muscle relaxants, which is conducive to patient awakening and reversal of anesthetic effects in emergency situations. However, for general anesthetic drugs, there is currently a lack of means and methods to solve the problem of delayed awakening during long-term infusion and reverse the effects of general anesthetic drugs in emergency situations.

[0004] At present, the drug with clear antagonistic effect used in clinical practice is flumazenil. Flumazenil is a benzodiazepine Specific antagonists of benzodiazepines can reverse However, studies have shown that flumazenil has no significant antagonistic effect on propofol-induced anesthesia. These drugs are no longer routinely used in clinical anesthesia, and there is an urgent need to develop broader-spectrum antagonists, especially those covering common general anesthetics such as propofol and etomidate. Summary of the invention

[0005] The purpose of the present invention is to provide a cyclic ketone compound prodrug and its medical effect. The cyclic ketone compound prodrug of the present invention can be used to prepare anesthesia and / or sedation antagonist drugs.

[0006] The present invention provides a compound represented by formula I, its stereoisomers, its deuterated derivatives, its salts, and its solvates:

[0007]

[0008] in,

[0009] m1 is 1 or 2;

[0010] m2 is 0, 1 or 2; when m2 is 0, the connection between R3' and R4' and the connection between R7' and R4' If not, connect R3' or R7' When m2 is 1 or 2, the bond connecting R3' and R4' and connecting R7' and R4' is a key, connecting R3' or R7' is a key or None;

[0011] m is 0 or 1; when m is 0, the When m is 1, the connection between R4 and R0 and the connection between R4 and R3 is the key;

[0012] Connect R0', R3, R3', R8' Depending on the number of bonds connecting the carbon atoms, it is either bonded or absent;

[0013] R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form

[0014] n is an integer selected from 0 to 8;

[0015] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0016] R9 is selected from hydrogen, C1-C8 alkyl;

[0017] L is selected from

[0018] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0019] Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16are independently selected from hydrogen, C1-C8 alkyl;

[0020] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0021] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0022] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0023] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0024] a is an integer selected from 0 to 8;

[0025] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0026] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0027] b and c are independently selected from integers from 0 to 8;

[0028] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0029] p is an integer selected from 0 to 8;

[0030] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0031] R d1 , R d2 , R d3 , R d4 are independently selected from hydrogen, C1-C8 alkyl;

[0032] R0 is selected from C1-C8 alkyl;

[0033] R0' is selected from hydrogen, deuterium, tritium, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl;

[0034] R3, R3', R4', R5', R6, R6', R7', and R8' are independently selected from hydrogen and C1-C8 alkyl;

[0035] When m is 0, R4 and R5 are absent; when m is 1, R4 and R5 are independently selected from hydrogen and C1-C8 alkyl.

[0036] Further, the compound is represented by Formula IA:

[0037]

[0038] in,

[0039] R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form

[0040] n is an integer selected from 0 to 8;

[0041] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0042] R9 is selected from hydrogen, C1-C8 alkyl;

[0043] L is selected from

[0044] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0045] Each R 10 , R 11 , R 12 , R 13 , R 14 , R15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0046] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0047] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0048] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0049] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0050] a is an integer selected from 0 to 8;

[0051] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0052] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0053] b and c are independently selected from integers from 0 to 8;

[0054] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0055] p is an integer selected from 0 to 8;

[0056] Each R 21are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0057] R d1 , R d2 , R d3 , R d4 are independently selected from hydrogen, C1-C8 alkyl;

[0058] is a key or None, m is 0 or 1, and when m is 1, for nothing;

[0059] R0 is selected from C1-C8 alkyl;

[0060] R3 and R6 are independently selected from hydrogen and C1-C8 alkyl;

[0061] When m is 0, R4 and R5 are absent; when m is 1, R4 and R5 are independently selected from hydrogen and C1-C8 alkyl.

[0062] Further, the compound is represented by Formula Ia, Formula Ib, Formula Ic, Formula Id or Formula Ie:

[0063]

[0064] in,

[0065] R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form

[0066] n is an integer selected from 0 to 8;

[0067] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0068] R9 is selected from hydrogen, C1-C8 alkyl;

[0069] L is selected from

[0070] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0071] Each R 10 , R 11 , R 12 , R 13 , R14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0072] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0073] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0074] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0075] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0076] a is an integer selected from 0 to 8;

[0077] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0078] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0079] b and c are independently selected from integers from 0 to 8;

[0080] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0081] p is an integer selected from 0 to 8;

[0082] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0083] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0084] Furthermore, the compound is represented by Formula Id1 or Formula Id2:

[0085]

[0086] in,

[0087] R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form

[0088] n is an integer selected from 0 to 8;

[0089] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0090] R9 is selected from hydrogen, C1-C8 alkyl;

[0091] L is selected from

[0092] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0093] Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0094] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0095] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0096] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0097] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0098] a is an integer selected from 0 to 8;

[0099] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0100] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0101] b and c are independently selected from integers from 0 to 8;

[0102] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0103] p is an integer selected from 0 to 8;

[0104] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0105] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0106] Furthermore, the compound is represented by formula II:

[0107]

[0108] in,

[0109] X and Y are independently selected from O, S or NH;

[0110] Z1 and Z2 are independently selected from integers of 0 to 4;

[0111] R7 is a substituent at any position on the ring, and n is the number of R7;

[0112] n is an integer selected from 0 to 8;

[0113] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0114] R9 is selected from hydrogen and C1-C8 alkyl.

[0115] Furthermore, the compound is represented by formula IIa or IIb:

[0116]

[0117] in,

[0118] X and Y are independently selected from O, S or NH;

[0119] Z1 and Z2 are independently selected from integers of 0 to 4;

[0120] R7 is a substituent at any position on the ring, and n is the number of R7;

[0121] n is an integer selected from 0 to 8;

[0122] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9;

[0123] R9 is selected from hydrogen and C1-C8 alkyl.

[0124] Furthermore, the compound is represented by formula IIIa:

[0125]

[0126] in,

[0127] Y is selected from O or S;

[0128] Z2 is independently selected from 0, 1, 2, 3, 4;

[0129] R7 is a substituent at any position on the ring, and n is the number of R7;

[0130] n is selected from 0, 1, 2, 3, 4;

[0131] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano;

[0132] R9 is selected from hydrogen, C1-C8 alkyl;

[0133] Alternatively, the compound is represented by formula IIIb:

[0134]

[0135] in,

[0136] Z1 and Z2 are independently selected from 0, 1, 2, 3, and 4;

[0137] R7 is a substituent at any position on the ring, and n is the number of R7;

[0138] n is selected from 0, 1, 2, 3, 4;

[0139] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, nitro, amino, cyano. Further, the compound is represented by formula IIIa1 or formula IIIa2:

[0140]

[0141] in,

[0142] Y is selected from O or S;

[0143] Z2 is independently selected from 0, 1, 2, 3, 4;

[0144] R7 is a substituent at any position on the ring, and n is the number of R7;

[0145] n is selected from 0, 1, 2, 3, 4;

[0146] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano; R9 is selected from hydrogen, C1-C8 alkyl;

[0147] Alternatively, the compound is represented by Formula IIIb1 or Formula IIIb2:

[0148]

[0149] in,

[0150] Z1 and Z2 are independently selected from 0, 1, 2, 3, and 4;

[0151] R7 is a substituent at any position on the ring, and n is the number of R7;

[0152] n is selected from 0, 1, 2, 3, 4;

[0153] R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, nitro, amino, and cyano. Further, the compound is one of the following compounds:

[0154]

[0155] Furthermore, the compound is represented by formula IV:

[0156]

[0157] in,

[0158] L is selected from

[0159] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0160] Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0161] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0162] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0163] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0164] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0165] a is an integer selected from 0 to 8;

[0166] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0167] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0168] b and c are independently selected from integers from 0 to 8;

[0169] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0170] p is an integer selected from 0 to 8;

[0171] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0172] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0173] Furthermore, the compound is represented by Formula IVa or Formula IVb:

[0174]

[0175] in,

[0176] L is selected from

[0177] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S;

[0178] Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16are independently selected from hydrogen, C1-C8 alkyl;

[0179] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0180] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0181] Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0182] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ,

[0183] a is an integer selected from 0 to 8;

[0184] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0185] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0186] b and c are independently selected from integers from 0 to 8;

[0187] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0188] p is an integer selected from 0 to 8;

[0189] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0190] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0191] Furthermore, the compound is represented by Formula V:

[0192]

[0193] in,

[0194] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0195] Each R 10 , R 11 , R 12 are independently selected from hydrogen, C1-C8 alkyl;

[0196] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ;

[0197] a is selected from 0, 1, 2, 3, 4, 5;

[0198] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0199] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0200] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0201] R 20is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0202] p is selected from 0, 1, 2, 3, 4, 5;

[0203] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0204] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0205] Furthermore, the compound is represented by formula Va or formula Vb:

[0206]

[0207] in,

[0208] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0209] Each R 10 , R 11 , R 12 are independently selected from hydrogen, C1-C8 alkyl;

[0210] R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ;

[0211] a is selected from 0, 1, 2, 3, 4, 5;

[0212] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0213] R 19Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0214] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0215] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0216] p is selected from 0, 1, 2, 3, 4, 5;

[0217] Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0218] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

[0219] Further,

[0220] R 10 , R 11 are each independently selected from hydrogen;

[0221] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0222] R 12 is selected from hydrogen, C1 alkyl, C2 alkyl, C3 alkyl;

[0223] R8 is selected from a R 18 Substituted imidazole, replaced by a R 18 Substituted phenyl, with a R 18 Indolyl, substituted by a R 18 Substituted pyridyl, with a R 18 Substituted thienyl, -C(O)NR d3 R d4 ;

[0224] a is selected from 0, 1, 2, 3, 4, 5;

[0225] Each R 18 are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0226] R 19 Selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted phenyl;

[0227] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0228] R 20 is selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl;

[0229] p is selected from 0, 1, 2, 3, 4, 5;

[0230] Each R 21 are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, nitro, amino, and cyano;

[0231] R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C4 alkyl.

[0232] Furthermore, the compound is one of the following compounds:

[0233]

[0234]

[0235]

[0236] Furthermore, the compound is represented by Formula VI:

[0237]

[0238] in,

[0239] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0240] Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl;

[0241] R8 is selected from a R18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl;

[0242] a is selected from 0, 1, 2, 3, 4, 5;

[0243] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0244] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0245] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0246] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0247] p is selected from 0, 1, 2, 3, 4, 5;

[0248] Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0249] Furthermore, the compound is represented by Formula VIa or Formula VIb:

[0250]

[0251] in,

[0252] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0253] Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl;

[0254] R8 is selected from a R 18Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl;

[0255] a is selected from 0, 1, 2, 3, 4, 5;

[0256] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0257] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl;

[0258] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0259] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0260] p is selected from 0, 1, 2, 3, 4, 5;

[0261] Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0262] Further,

[0263] n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N, or S;

[0264] Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl;

[0265] R8 is selected from a R 18 Substituted 3- to 8-membered cycloalkyl, 18 Substituted phenyl;

[0266] a is selected from 0, 1, 2, 3, 4, 5;

[0267] Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ;

[0268] R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted phenyl;

[0269] b and c are independently selected from 0, 1, 2, 3, 4, and 5;

[0270] R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl;

[0271] p is selected from 0, 1, 2, 3, 4, 5;

[0272] Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0273] Furthermore, the compound is one of the following compounds:

[0274]

[0275] Furthermore, the compound is represented by formula VII:

[0276]

[0277] in,

[0278] L is selected from

[0279] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S;

[0280] Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0281] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0282] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0283] Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0284] Furthermore, the compound is represented by Formula VIIa or Formula VIIb:

[0285]

[0286] in,

[0287] L is selected from

[0288] n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S;

[0289] Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0290] Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl;

[0291] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8;

[0292] Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0293] Further,

[0294] L is selected from

[0295] n1, n2, n3 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S;

[0296] Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl;

[0297] Ring A is selected from phenyl;

[0298] R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is selected from 0, 1, 2, 3, 4, 5;

[0299] Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

[0300] Furthermore, the compound is one of the following compounds:

[0301]

[0302]

[0303] The present invention also provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its salt, and its solvate in the preparation of anesthetic and / or sedative antagonist drugs.

[0304] Furthermore, the anesthetic and / or sedative antagonist is an antagonist of an anesthetic drug and / or an antagonist of a sedative drug.

[0305] Furthermore, the anesthetic and / or sedative antagonist drug can reverse the anesthetic and / or sedative state induced or maintained by the anesthetic and / or sedative drug.

[0306] Furthermore, the anesthetic and / or sedative antagonist drug can reduce the anesthesia and / or sedation time.

[0307] Furthermore, the anesthetic drug includes GABA A Receptor agonists.

[0308] Furthermore, the anesthetic and / or sedative antagonist is GABA A High affinity ligand for receptors, capable of acting as a competitive antagonist against GABA A Receptor agonists.

[0309] Furthermore, the anesthetic drug is a general anesthetic drug.

[0310] Furthermore, the general anesthetic is benzodiazepine Drugs, substituted phenol drugs, imidazole drugs, GABA-mimetic drugs, and phenylcyclohexylamine drugs.

[0311] Further,

[0312] The benzodiazepine The drugs in this category are diazepam, midazolam, lorazepam, and remimazolam;

[0313] The substituted phenol drugs are propofol, propofol, and fospropofol sodium;

[0314] The imidazole drug is etomidate, methoxyetomidate or a derivative thereof;

[0315] The GABA-mimicking drugs are γ-aminobutyric acid and γ-hydroxybutyric acid;

[0316] Phenylcyclohexylamine drugs include ketamine and fluamine.

[0317] The present invention also provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its salt, and its solvate in the preparation of a drug for improving respiratory function in inhalation general anesthesia with preserved spontaneous breathing.

[0318] Furthermore, the inhalation general anesthesia refers to an anesthesia method induced and maintained by isoflurane, sevoflurane, desflurane, enflurane, enflurane, and nitrous oxide.

[0319] The present invention also provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its salt, and its solvate in the preparation of a drug for improving respiratory function in respiratory depression induced by opium overdose.

[0320] Furthermore, the opioid drug is morphine, fentanyl, sufentanil, remifentanil, alfentanil, carfentanil and other fentanyl derivatives, pethidine, tramadol, dezocine, pentazocine, hydromorphone, oxycodone, buprenorphine, butorphanol, and nalbuphine.

[0321] The present invention also provides an anesthetic and / or sedative antagonist, which is a preparation prepared by using the aforementioned compound, its stereoisomer, its deuterated derivative, its salt, or its solvate as an active ingredient and adding pharmaceutically acceptable excipients.

[0322] Furthermore, the preparation is a tablet, capsule, oral liquid, granule, pill, powder, injection or powder injection.

[0323] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0324] 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 in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0325] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0326] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C8 alkyl" refers to an alkyl group containing 1 to 8 carbon atoms; "C1-C8 alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0327] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl, heptyl, octyl, etc.

[0328] "Alkenyl" refers to an unsaturated hydrocarbon chain with at least one carbon-carbon double bond. For example, C2-8 alkenyl refers to an alkenyl group having 2 to 8 carbon atoms, i.e., 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Alkenyl groups can be straight or branched. wait.

[0329] "Alkynyl" refers to an unsaturated hydrocarbon chain with at least one carbon-carbon triple bond. For example, C2-8 alkynyl refers to an alkenyl group having 2 to 8 carbon atoms, i.e., 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The alkenyl group can be straight or branched. wait.

[0330] "Halogen" is fluorine, chlorine, bromine or iodine.

[0331] "Cycloalkyl" refers to a saturated or unsaturated all-carbon monocyclic or polycyclic ring (including fused rings, spiro rings or bridged rings) without a conjugated π electron system, such as but not limited to:

[0332] "Heterocycloalkyl" refers to a cycloalkyl group in which at least one carbon atom is replaced by a heteroatom, wherein the heteroatom is O, N or S, and is a saturated or unsaturated monocyclic or polycyclic ring (including fused rings, spirocyclic rings or bridged rings) without a conjugated π electron system, such as but not limited to: Oxirane, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,

[0334] "Aryl" refers to an all-carbon monocyclic or polycyclic ring (including fused rings, spirocyclic rings or bridged rings) with a conjugated π electron system, such as but not limited to phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. The aromatic ring may be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as O, N or S, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system, such as but not limited to

[0335] "Heteroaryl" refers to an aromatic group in which at least one carbon atom in the conjugated π-electron system is replaced by a heteroatom, wherein the heteroatom is O, N or S, for example, including but not limited to:

[0336]

[0337] In the present invention, When is a bond, the compound structure shown in Formula I is When is absent, the compound structure shown in Formula I is When m is 0, R4 and R5 are absent, that is, the compound structure shown in Formula I is

[0338] L is selected from When; any carbon atom on the main chain of n1, n2, n3 can be replaced by heteroatoms such as O, N, S or not. For example, when for When The main chain can be replaced by heteroatoms wait.

[0340] The present invention provides the use of a cyclic ketone compound prodrug in the preparation of an anesthetic and / or sedative antagonist. The present invention first discovered that the cyclic ketone compound prodrug has good general anesthesia and sedative antagonism. Experimental results show that the compounds of the present invention have good antagonism to general anesthesia induced by a variety of general anesthetics (including propofol, etomidate, remimazolam, ketamine, etc.), and can significantly shorten the time for mice to recover their righting reflex after general anesthesia, and significantly shorten the time for mice to recover to walk normally. Moreover, the compounds of the present invention can also play an effective antagonistic role in the general anesthesia maintained by continuous infusion of the general anesthetic propofol in rats. At the same time, it has a good improvement effect on respiratory depression caused by opioids and inhaled anesthetics.

[0341] The compounds of the present invention are used as prodrugs, which can release the parent drug in vivo. and their optical isomers, such as Compared with directly taking the parent drug, the compound of the present invention can exert the same or even better effect with a smaller dosage. The present invention provides a new choice for antagonists of anesthetic and / or sedative drugs, especially antagonists of general anesthetic drugs, and has broad application prospects.

[0342] The compound of the present invention can be used as a prodrug to release a parent drug containing a ketocarbonyl structure in vivo. Due to the existence of an interconversion equilibrium between the ketocarbonyl and the enol form, the enol form prodrug of the corresponding carbonyl parent drug is also theoretically possible.

[0343] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0344] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0345] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0346] Example 1. Preparation of Compounds

[0347] a1) Preparation of representative amino acid cyclic prodrugs 1 and 2

[0348]

[0349] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, 1-1 (954.99 mg, 7.88 mmol) and 1-2 (113.11 mg, 656.87 μmol) were added, and the mixture was heated to 120 °C, a water separator was added, and the reaction was refluxed for 24 h, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.10 g of the target compound (compound 1), with a yield of 65.57%. ESI-MS: 254.13. 1 H NMR(500MHz,Chloroform-d)δ5.01(d,J=5.1Hz,1H),3.88–3.82(m,1H),3.20–3.10(m,2H),1.86(dd,J=12.2,4.7Hz,1H),1.77(tdd q,J=6.1,4.6,2.9,1.5Hz,1H),1.72–1.58(m,3H),1.57–1.48(m,1H),1.46–1.37(m,1H),1.00–0.94(m,6H),0.93(d,J=1.5Hz,3H).

[0350] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, and 2-1 (1.18 g, 7.88 mmol) and 2-2 (113.11 mg, 656.87 μmol) were added. The mixture was heated to 120 °C, and a water separator was added. The mixture was refluxed for 24 h and monitored by TLC (DCM: MeOH = 30: 1, v / v, Rf = 0.4). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added. The mixture was then extracted with 100 mL of ethyl acetate (100 mL × 3). The organic phases were combined, washed twice with 50 mL of pure water and 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 30: 1, v / v. The target band was collected to obtain 1.20 g of the target compound (compound 2), with a yield of 64.45%. ESI-MS: 284.17. 1H NMR(500MHz,Chloroform-d)δ4.70(d,J=5.5Hz,1H),4.17(qd,J=6.3,0.8Hz,2H), 3.93(dt,J=5.3,3.2Hz,1H), 3.17(d,J=3.1Hz,2H), 1.86(dd,J=12.2,4.7Hz,1H), 1.77(ddtq,J=7.6,4.6,2.9,1.6Hz,1H),1.72–1.58(m,3H),1.57–1.48(m,1H),1. 46–1.37(m,1H),1.25(t,J=6.4Hz,3H),1.00–0.94(m,6H),0.93(d,J=1.5Hz,3H).

[0351] a2) Preparation of representative amino acid cyclic prodrugs 3 and 4

[0352]

[0353] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, 3-1 (938.96 mg, 7.88 mmol) and 3-2 (113.11 mg, 656.87 μmol) were added, and the mixture was heated to 120 °C, a water separator was added, and the reaction was refluxed for 24 h, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.95 g of the target compound (compound 3), with a yield of 57.09%. ESI-MS: 252.17. 1 H NMR(500MHz,Chloroform-d)δ3.82–3.73(m,2H),3.70–3.62(m,2H),2.12(dtd,J=12.1,4.8,2.2Hz,1H),1.93(dtd,J=12.1,4.8 ,2.2Hz,1H),1.86–1.78(m,1H),1.72–1.61(m,2H),1.64–1.57(m,1H),1.57–1.48(m,1H),1.48–1.39(m,1H),0.97–0.88(m,8H).

[0354] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, 4-1 (1.16 g, 7.88 mmol) and 4-2 (113.11 mg, 656.87 μmol) were added, and the mixture was heated to 120 °C, a water separator was added, and the reaction was refluxed for 24 h, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.87 g of the target compound (compound 4), with a yield of 47.07%. ESI-MS: 282.20. 1 H NMR(500MHz,Chloroform-d)δ4.17(q,J=6.4Hz,2H),3.81–3.73(m,2H),3.66(ddd,J= 12.5,5.1,2.4Hz,1H),3.43(d,J=7.0Hz,1H),2.11(dtd,J=12.4,5.0,2.4Hz,1H),1.9 5(dtd,J=12.5,5.2,2.5Hz,1H),1.86–1.78(m,1H),1.72–1.61(m,2H),1.64–1.57(m, 1H),1.57–1.48(m,1H),1.48–1.39(m,1H),1.25(t,J=6.4Hz,3H),0.97–0.88(m,8H).

[0355] b1) Preparation of representative amino acid imine prodrugs 15 and 16

[0356]

[0357] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 15-1 (1.30 g, 7.88 mmol) and 15-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.82 g of the target compound (compound 15), with a yield of 41.69%. ESI-MS: 298.19. 1 H NMR(500MHz,Chloroform-d)δ7.30–7.15(m,5H),4.40(t,J=8.4Hz,1H),3.12–3.00(m,2H),2.53(d d,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.01(tddd,J=7.1,4.8,3.1,1.5Hz,1H),1.85 (ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9Hz, 1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0358] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 16-1 (1.52 g, 7.88 mmol) and 16-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 30: 1, v / v, Rf = 0.4). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 30: 1, v / v, and the target band was collected to obtain 1.42 g of the target compound (compound 16), with a yield of 66.01%. ESI-MS: 328.22.1 H NMR(500MHz,Chloroform-d)δ7.30–7.15(m,5H),4.43(t,J=8.8Hz,1H),4.22(q,J=6.4Hz,2H),3.10(dt,J= 8.8,1.1Hz,2H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85(ddd, J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt ,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0359] b2) Preparation of representative amino acid imine prodrugs 11 and 12

[0360]

[0361] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 11-1 (1.22 g, 7.88 mmol) and 11-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.84 g of the target compound (compound 11), with a yield of 44.19%. ESI-MS: 288.18. 1H NMR(500MHz,Chloroform-d)δ7.63(dd,J=6.2,1.6Hz,1H),6.84(d,J=1.8Hz,1H),4.48(s,0H),3.2 9–3.14(m,2H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85 (ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9Hz, 1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0362] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 12-1 (1.44 g, 7.88 mmol) and 12-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.87 g of the target compound (compound 12), with a yield of 41.72%. ESI-MS: 318.22. 1H NMR(500MHz,Chloroform-d)δ7.63(dd,J=6.2,1.6Hz,1H),6.84(d,J=1.8Hz,1H),4.52(t,J=10.0Hz,1H),4.22(q,J=6.4Hz, 2H),3.29(dd,J=14.9,10.0Hz,1H),3.21(dd,J=14.9,10.0Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1 H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9H z,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0363] b3) Preparation of representative amino acid imine prodrugs 23 and 24

[0364]

[0365] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 23-1 (1.61 g, 7.88 mmol) and 23-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.93 g of the target compound (compound 23), with a yield of 41.83%. ESI-MS: 337.20. 1H NMR(500MHz,Chloroform-d)δ9.16(d,J=7.0Hz,1H),7.58(dd,J=7.4,1.4Hz,1H),7.35(dt,J=7.7,0.8Hz,1H),7.20–7.12(m,2H),7.09( td,J=7.4,1.1Hz,1H),4.52(t,J=8.2Hz,1H),3.33(dd,J=13.6,8.2Hz,1H),3.15(dd,J=13.6,8.2Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2 .46(dd,J=12.5,5.5Hz,1H),2.01(tddd,J=7.1,4.7,3.1,1.5Hz,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz ,1H),1.60(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0366] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 24-1 (1.83 g, 7.88 mmol) and 24-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.96 g of the target compound (compound 24), with a yield of 39.88%. ESI-MS: 367.24. 1H NMR(500MHz,Chloroform-d)δ9.16(d,J=7.0Hz,1H),7.58(dd,J=7.3,1.3Hz,1H),7.35(dt,J=7.7,0.8Hz,1H),7.20–7.12(m,2H),7.09(td,J= 7.4,1.1Hz,1H),4.56(t,J=8.6Hz,1H),4.22(q,J=6.4Hz,2H),3.35(dd,J=13.6,8.5Hz,1H),3.18(dd,J=13.6,8.5Hz,1H),2.53(dd,J=12.4,5. 6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd, J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0367] b4) Preparation of representative amino acid imine prodrugs 25 and 26

[0368]

[0369] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 25-1 (1.57 g, 7.88 mmol) and 25-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.02 g of the target compound (compound 25), with a yield of 46.51%. ESI-MS: 332.15. 1H NMR(500MHz,Chloroform-d)δ7.31–7.25(m,2H),7.18(dt,J=8.0,1.0Hz,2H),4.40(t,J=8.4Hz,1H),3.16 –3.04(m,2H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.01(tddd,J=7.1,4.7,3.1,1. 5Hz,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9, 4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0370] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 26-1 (1.79 g, 7.88 mmol) and 26-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.91 g of the target compound (compound 26), with a yield of 38.28%. ESI-MS: 362.19. 1H NMR (500MHz, Chloroform-d) δ7.31–7.25(m,2H),7.18(dt,J=8.0,1.0Hz,2H),4.43(t,J=8.8Hz,1H),4.22(q,J=6. 4Hz,2H),3.13(dt,J=8.8,1.0Hz,2H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1 H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9Hz,1H),1. 47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0371] b5) Preparation of representative amino acid imine prodrugs 31 and 32

[0372]

[0373] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 31-1 (1.35 g, 7.88 mmol) and 31-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.95 g of the target compound (compound 31), with a yield of 47.35%. ESI-MS: 304.15. 1H NMR(500MHz,Chloroform-d)δ7.21(dd,J=5.3,1.8Hz,1H),6.92(dd,J=6.4,5.3Hz,1H),6.78(dd,J=6.5,1.7Hz,1H),4.4 4(t,J=7.4Hz,1H),3.35(dd,J=13.6,7.3Hz,1H),3.18(dd,J=13.4,7.3Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J =12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd ,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0374] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 32-1 (1.57 g, 7.88 mmol) and 32-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.01 g of the target compound (compound 32), with a yield of 46.11%. ESI-MS: 334.18. 1H NMR(500MHz,Chloroform-d)δ7.21(dd,J=5.3,1.8Hz,1H),6.92(dd,J=6.4,5.3Hz,1H),6.78(dd,J=6.5,1.7Hz,1H),4.44(t,J=7.8 Hz,1H),4.22(q,J=6.4Hz,2H),3.29(dd,J=13.6,7.7Hz,1H),3.17(dd,J=13.4,7.7Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J =12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6. 9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0375] b6) Preparation of representative amino acid imine prodrugs 47 and 48

[0376]

[0377] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 47-1 (1.88 g, 7.88 mmol) and 47-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.87 g of the target compound (compound 47), with a yield of 35.52%. ESI-MS: 371.17. 1H NMR(500MHz,Chloroform-d)δ8.90(d,J=6.8Hz,1H),7.62(d,J=9.2Hz,1H),7.25(dq,J=4.4,2.2Hz,2H),7.18(d,J=6.8Hz,1H),4 .52(t,J=8.2Hz,1H),3.33(dd,J=13.6,8.2Hz,1H),3.15(dd,J=13.6,8.2Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5 ,5.5Hz,1H),2.01(tddd,J=7.1,4.7,3.1,1.5Hz,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1. 60(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0378] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 48-1 (2.10 g, 7.88 mmol) and 48-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.89 g of the target compound (compound 48), with a yield of 33.79%. ESI-MS: 401.20. 1H NMR(500MHz,Chloroform-d)δ8.90(d,J=6.8Hz,1H),7.62(d,J=9.2Hz,1H),7.25(dq,J=4.4,2.2Hz,2H),7.18(d,J=6.8Hz,1H),4.56(t ,J=8.6Hz,1H),4.22(q,J=6.4Hz,2H),3.37(dd,J=13.6,8.6Hz,1H),3.19(dd,J=13.7,8.6Hz,1H),2.53(dd,J=12.4,5.6Hz,1H),2.46( dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1, 6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0379] b7) Preparation of representative amino acid imine prodrugs 56, 57 and 58

[0380]

[0381] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 56-1 (2.71 g, 7.88 mmol) and 56-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.91 g of the target compound (compound 56), with a yield of 28.95%. ESI-MS: 479.25. 1H NMR(500MHz,Chloroform-d)δ8.07(dd,J=8.6,1.6Hz,1H),7.63(td,J=7.4,1.5Hz,1H),7.56(ddd,J=8.6,7.7,2.6Hz,1H),7.51(ddt,J=7.3,2.5,1.1 Hz,1H),7.07(dt,J=8.9,1.0Hz,2H),6.86–6.80(m,2H),5.35(t,J=1.1Hz, 2H),4.43(t,J=8.8Hz,1H),4.22(q,J=6.4Hz,2H),3.16–3.10(m,2H),2.53( dd,J=12.4,5.6Hz,1H),2.46(dd,J=12.5,5.5Hz,1H),2.06–1.97(m,1H),1 .85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.6 0(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25( t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0382] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 57-1 (1.55 g, 7.88 mmol) and 57-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 ° C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.94 g of the target compound (compound 57), with a yield of 43.17%. ESI-MS: 375.15. 1H NMR(500MHz,Chloroform-d)δ8.10(dd,J=8.3,1.3Hz,1H),7.66(td,J=6.9,1.3Hz,1H),7.51(dd,J=6.6,1.7Hz,1H),7.40(ddd,J =8.2,7.2,1.7Hz,1H),4.55(t,J=6.7Hz,1H),3.69(dd,J=12.8,6.8Hz,1H),3.53(dd,J=12.8,6.6Hz,1H),2.53(dd,J=12.4,5.6Hz ,1H),2.44(dd,J=12.4,5.6Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1 .60(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.5Hz,3H).

[0383] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 58-1 (1.78 g, 7.88 mmol) and 58-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.96 g of the target compound (compound 58), with a yield of 40.65%. ESI-MS: 405.18. 1H NMR(500MHz,Chloroform-d)δ8.10(dd,J=8.2,1.3Hz,1H),7.66(td,J=6.9,1.3Hz,1H),7.51(dd,J=6.6,1.7Hz,1H),7.40(ddd,J=8. 2,7.2,1.7Hz,1H),4.66(t,J=7.1Hz,1H),4.21(q,J=6.3Hz,2H),3.58(dd,J=7.0,1.6Hz,2H),2.53(dd,J=12.4,5.7Hz,1H),2.44(dd, J=12.5,5.7Hz,1H),2.06–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6 .9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),1.25(t,J=6.4Hz,3H),0.97(d,J=1.5Hz,3H),0.95(s,3H),0.92(d,J=1.4Hz,3H).

[0384] c1) Preparation of representative ketal prodrugs 61 and 62

[0385]

[0386] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, and 61-1 (710.38 mg, 7.88 mmol) and 61-2 (113.11 mg, 656.87 μmol) were added. The mixture was heated to 120 °C, and a water separator was added. The mixture was refluxed for 24 h and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added. The mixture was then extracted with 100 mL of ethyl acetate (100 mL × 3). The organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v. The target band was collected to obtain 0.87 g of the target compound (compound 61), with a yield of 59.04%. ESI-MS:225.18. 1H NMR(500MHz,Chloroform-d)δ3.76(d,J=12.5Hz,1H),3.56(d,J=12.5Hz,1H),1.98(dd,J=12.0,4.3Hz,1H),1.84(dddq,J=7.3,4.6,2.8,1.5Hz ,1H),1.80(dd,J=12.0,4.6Hz,1H),1.72–1.59(m,2H),1.50–1.35(m,2 H),1.31(s,2H),1.26(s,2H),0.99–0.94(m,6H),0.92(d,J=1.4Hz,3H).

[0387] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, and 62-1 (710.38 mg, 7.88 mmol) and 62-2 (113.11 mg, 656.87 μmol) were added. The mixture was heated to 120 °C, and a water separator was added. The mixture was refluxed for 24 h and monitored by TLC (DCM: MeOH = 30: 1, v / v, Rf = 0.4). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added. The mixture was then extracted with 100 mL of ethyl acetate (100 mL × 3). The organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 30: 1, v / v. The target band was collected to obtain 1.12 g of the target compound (compound 62), with a yield of 76.00%. ESI-MS:225.17. 1 H NMR(500MHz,Chloroform-d)δ3.66(dd,J=12.4,3.9Hz,2H),3.53(dd,J=12.4,3.9Hz,2H),2.05–1.92(m ,2H),1.90–1.79(m,1H),1.70–1.59(m,2H),1.51–1.41(m,1H),1.41–1.31(m,1H),1.03–0.90(m,11H).

[0388] c2) Preparation of representative ketal prodrugs 71 and 72

[0389]

[0390] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, and 71-1 (710.38 mg, 7.88 mmol) and 71-2 (113.11 mg, 656.87 μmol) were added. The mixture was heated to 120 °C, and a water separator was added. The mixture was refluxed for 24 h and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added. The mixture was then extracted with 100 mL of ethyl acetate (100 mL × 3). The organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v. The target band was collected to obtain 0.68 g of the target compound (compound 71), with a yield of 46.14%. ESI-MS:225.18. 1 H NMR(500MHz,Chloroform-d)δ3.67–3.55(m,4H),1.99–1.90(m,1H),1.88–1.79(m,1H),1.72(ddt,J =5.3,3.1,1.0Hz,4H),1.71–1.59(m,2H),1.51–1.41(m,1H),1.41–1.31(m,1H),0.99–0.90(m,8H).

[0391] The parent drug (1.00 g, 6.57 mmol) was dissolved in 25 mL of toluene, and 72-1 (820.95 mg, 7.88 mmol) and 72-2 (113.11 mg, 656.87 μmol) were added. The mixture was heated to 120 °C, and a water separator was added. The mixture was refluxed for 24 h and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added. The mixture was then extracted with 100 mL of ethyl acetate (100 mL × 3). The organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v. The target band was collected to obtain 0.69 g of the target compound (compound 72), with a yield of 44.07%. ESI-MS:239.21. 1H NMR(500MHz,Chloroform-d)δ3.82(h,J=5.5Hz,1H),3.67–3.54(m,2H),1.96–1.88(m,1H),1.87–1.59(m,8H ),1.59–1.50(m,1H),1.50–1.35(m,2H),1.24(d,J=5.6Hz,3H),0.97(d,J=1.5Hz,6H),0.92(d,J=1.4Hz,3H).

[0392] d1) Preparation of representative aliphatic or aromatic imine prodrugs 95 and 120

[0393]

[0394] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 95-1 (560.63 mg, 7.88 mmol) and 95-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.76 g of the target compound (compound 95), with a yield of 56.34%. ESI-MS: 206.19. 1 H NMR(500MHz,Chloroform-d)δ3.41(p,J=5.8Hz,1H),2.51(dd,J=12.4,5.6Hz,1H),2.44(dd,J=12.4,5.6Hz,1H),2.05–1.97(m,1H),1.94–1. 64(m,8H),1.60(ddd,J=12.1,6.9,4.9Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.96(s,3H),0.92(d,J=1.5Hz,3H).

[0395] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 120-1 (844.65 mg, 7.88 mmol) and 120-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 30: 1, v / v, Rf = 0.4). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 30: 1, v / v, and the target band was collected to obtain 1.14 g of the target compound (compound 120), with a yield of 71.90%. ESI-MS: 242.19. 1 H NMR(500MHz,Chloroform-d)δ7.21(dd,J=7.8,7.1Hz,1H),6.99–6.92(m,3H),2.55(dd,J=12.5,5.3Hz,1H),2.46(dd,J=12.4,5.2Hz,1H),2.04(ddt d,J=6.7,5.1,3.5,1.7Hz,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1.72– 1.62(m,1H),1.59–1.44(m,2H),1.00–0.96(m,6H),0.93(d,J=1.5Hz,3H).

[0396] d2) Preparation of representative aliphatic or aromatic imine prodrugs 93 and 102

[0397]

[0398] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 93-1 (560.63 mg, 7.88 mmol) and 93-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.65 g of the target compound (compound 93), with a yield of 48.19%. ESI-MS: 206.19. 1 H NMR(500MHz,Chloroform-d)δ2.60(dddd,J=9.0,7.6,6.0,1.5Hz,1H),2.53(dd,J=12.4,5.6Hz,1 H),2.42(dd,J=12.4,5.6Hz,1H),2.05–1.97(m,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1H),1.69(ddt ,J=11.8,6.8,4.9Hz,1H),1.60(ddd,J=12.1,6.9,4.9Hz,1H),1.52–1.39(m,2H),1.31(dt,J=12. 4,7.6Hz,1H),1.19(dddd,J=13.9,7.9,6.0,2.0Hz,1H),1.01–0.94(m,9H),0.92(d,J=1.4Hz,3H).

[0399] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 102-1 (671.19 mg, 7.88 mmol) and 102-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.66 g of the target compound (compound 102), with a yield of 45.80%. ESI-MS: 220.21.1 H NMR(500MHz,Chloroform-d)δ3.37(p,J=5.3Hz,1H),2.51(dd,J=12.4,5.6Hz,1H),2.44(dd,J=12.4,5.6Hz,1H),2.05–1.97(m,1H),1.89–1.7 6(m,2H),1.78–1.63(m,5H),1.66–1.55(m,3H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.97(d,J=1.5Hz,3H),0.96(s,3H),0.92(d,J=1.5Hz,3H).

[0400] d3) Preparation of representative aliphatic or aromatic imine prodrugs 109 and 119

[0401]

[0402] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 109-1 (892.33 mg, 7.88 mmol) and 109-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.71 g of the target compound (compound 109), with a yield of 43.68%. ESI-MS: 248.24. 1 H NMR(500MHz,Chloroform-d)δ3.20(dtq,J=8.1,6.6,1.5Hz,1H),2.53(dd,J=12.4,5.6Hz,1H ),2.42(dd,J=12.4,5.6Hz,1H),2.06–1.97(m,1H),1.89–1.26(m,14H),1.00–0.90(m,11H).

[0403] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 119-1 (1.07 mg, 7.88 mmol) and 119-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.72 g of the target compound (compound 119), with a yield of 40.68%. ESI-MS: 270.22. 1 H NMR(500MHz,Chloroform-d)δ7.29–7.15(m,5H),3.35(t,J=6.4Hz,2H),2.68(tq,J=8.3,0.9Hz,2H),2.51–2.41(m,2H),2.14–2.05(m,1H),1.9 2–1.81(m,3H),1.69(ddt,J=11.9,7.0,4.8Hz,1H),1.60(ddd,J=12.1,7.0,5.0Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.99–0.90(m,8H).

[0404] d4) Preparation of representative aliphatic or aromatic imine prodrugs 125 and 130

[0405]

[0406] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 125-1 (1.01 g, 7.88 mmol) and 125-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.58 g of the target compound (compound 125), with a yield of 33.73%. ESI-MS: 262.13.1 H NMR(500MHz,Chloroform-d)δ7.34(s,1H),7.37–7.29(m,1H),7.26(t,J=1.8Hz,1H), 7.00(dt,J=7.3,2.0Hz,1H),2.55(dd,J=12.5,5.3Hz,1H),2.46(dd,J=12.4,5.2Hz,1 H),2.04(dtt,J=6.6,3.2,1.6Hz,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1.67(ddt, J=11.9,7.0,4.9Hz,1H),1.59–1.44(m,2H),1.00–0.96(m,6H),0.93(d,J=1.4Hz,3H).

[0407] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 130-1 (1.09 g, 7.88 mmol) and 130-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 0.60 g of the target compound (compound 130), with a yield of 33.54%. ESI-MS: 273.16. 1 H NMR(500MHz,Chloroform-d)δ8.22(ddd,J=8.2,1.9,1.2Hz,1H),7.96(t,J=2.0Hz,1H),7.62(t ,J=8.2Hz,1H),7.43(ddd,J=8.2,2.0,1.3Hz,1H),2.56(dd,J=12.4,5.2Hz,1H),2.46(dd,J=12 .4,5.2Hz,1H),2.04(dtdt,J=6.5,5.0,3.2,1.5Hz,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1. 67(ddt,J=11.9,7.0,4.9Hz,1H),1.59–1.44(m,2H),1.00–0.96(m,6H),0.93(d,J=1.4Hz,3H).

[0408] e1) Preparation of representative dimer prodrugs 135 and 143

[0409]

[0410] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 135-1 (584.30 mg, 7.88 mmol) and 135-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.04 g of the target compound (compound 135), with a yield of 46.22%. ESI-MS: 343.31. 1 H NMR(500MHz,Chloroform-d)δ3.39(td,J=6.6,2.0Hz,2H),2.51–2.40(m,2H),2.14–2.06(m,1H),1.93(q,J=6.5Hz,1H),1.85(ddd,J=12.0,7.0,4.9Hz,1 H),1.69(ddt,J=11.9,7.0,5.0Hz,1H),1.59(ddd,J=12.1,6.9,5.1Hz,1H),1 .47(ddt,J=11.9,6.8,4.9Hz,1H),0.99–0.94(m,6H),0.92(d,J=1.4Hz,3H).

[0411] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 143-1 (852.44 mg, 7.88 mmol) and 143-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 30: 1, v / v, Rf = 0.4). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 30: 1, v / v, and the target band was collected to obtain 1.86 g of the target compound (compound 143), with a yield of 75.19%. ESI-MS: 377.29. 1 H NMR(500MHz,Chloroform-d)δ7.06(s,2H),2.55(dd,J=12.5,5.3Hz,1H),2.46(dd,J=12.4,5.2Hz,1H),2.04(dtdt,J=6.6,5.0,3.2,1.5Hz ,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1.67(ddt,J=11.9,7.0,4.9Hz,1H),1.59–1.44(m,2H),1.00–0.96(m,6H),0.93(d,J=1.4Hz,3H).

[0412] e2) Preparation of representative dimer prodrugs 142 and 146

[0413]

[0414] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 142-1 (1.17 g, 7.88 mmol) and 142-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.28 g of the target compound (compound 142), with a yield of 45.25%. ESI-MS: 417.35. 1H NMR(500MHz,Chloroform-d)δ3.70(t,J=6.6Hz,2H),3.64(s,1H),3.51(td,J=6.6, 1.2Hz,2H),2.51–2.39(m,2H),2.10(dtd,J=6.8,5.1,3.6Hz,1H),1.85(ddd,J=12.2 ,7.1,4.9Hz,1H),1.69(ddt,J=11.9,7.0,4.8Hz,1H),1.60(ddd,J=12.1,6.9,5.0Hz ,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.99–0.94(m,6H),0.92(d,J=1.4Hz,3H).

[0415] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 146-1 (1.07 g, 7.88 mmol) and 146-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.14 g of the target compound (compound 146), with a yield of 42.89%. ESI-MS: 405.33. 1 H NMR(500MHz,Chloroform-d)δ7.36–7.28(m,1H),7.31–7.26(m,1H),4.69–4.65(m,2H),2.5 1(dd,J=12.3,5.3Hz,1H),2.44(dd,J=12.5,5.3Hz,1H),2.10(dtt,J=6.6,3.1,1.6Hz,1H),1 .85(ddd,J=12.2,7.1,4.9Hz,1H),1.69(ddt,J=11.9,7.0,4.8Hz,1H),1.60(ddd,J=12.1,7. 0,5.0Hz,1H),1.47(ddt,J=11.9,6.8,4.9Hz,1H),0.99–0.94(m,6H),0.92(d,J=1.4Hz,3H).

[0416] e3) Preparation of representative dimer prodrugs 150 and 159

[0417]

[0418] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 150-1 (963.01 mg, 7.88 mmol) and 150-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.15 g of the target compound (compound 150), with a yield of 44.82%. ESI-MS: 391.31. 1 H NMR(500MHz,Chloroform-d)δ7.14–7.09(m,1H),6.96(dd,J=8.6,2.2Hz,0H),2.57(ddd, J=14.5,12.5,5.2Hz,1H),2.47(ddd,J=14.1,12.4,5.2Hz,1H),2.37(s,1H),2.04(dtq,J= 6.8,3.3,1.7Hz,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1.67(ddt,J=11.8,6.8,4.9Hz, 1H), 1.52 (dddd, J=30.4, 12.1, 6.9, 4.9Hz, 2H), 1.00–0.96 (m, 6H), 0.93 (d, J=1.5Hz, 3H).

[0419] The parent drug (1.00 g, 6.57 mmol) was dissolved in 15 mL of toluene, and 159-1 (1.12 g, 7.88 mmol) and 159-2 (2.24 g, 7.88 mmol) were added. The reaction was carried out at 130 °C for 2 h under microwave, and monitored by TLC (DCM: MeOH = 20: 1, v / v, Rf = 0.2). The reaction solution was transferred to an eggplant-shaped bottle, the solvent toluene was evaporated under reduced pressure, and 100 mL of saturated sodium chloride solution was added, and then extracted with 100 mL of ethyl acetate (100 mL × 3), the organic phases were combined, washed twice with 50 mL of pure water, washed twice with 50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated, and a silica gel plate was prepared for purification. The developing solvent was DCM: MeOH = 20: 1, v / v, and the target band was collected to obtain 1.21 g of the target compound (compound 159), with a yield of 45.11%. ESI-MS: 411.25. 1 H NMR(500MHz,Chloroform-d)δ7.37–7.31(m,1H),7.22(dd,J=8.8,2.2Hz,0H),2.56(dd d,J=12.4,8.2,5.1Hz,1H),2.47(ddd,J=13.4,12.3,5.1Hz,1H),2.04(dtdt,J=6.5,5.1 ,3.3,1.5Hz,1H),1.86(ddd,J=11.9,6.9,5.1Hz,1H),1.67(ddt,J=11.8,6.9,4.9Hz,1H ),1.52(dddd,J=30.3,12.1,6.9,4.9Hz,2H),1.00–0.96(m,6H),0.93(d,J=1.5Hz,3H).

[0420] According to the similar method of the above embodiment, the following embodiment compounds in Table 1 are obtained:

[0421] Table 1. Compounds of the present invention

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0435] Test Example 1: Determination of lipid-water partition coefficient and blood-brain barrier permeability of target compound

[0436] 1) Determination of lipid-water partition coefficient

[0437] The lipid-water partition coefficient (Log P o / w ), also known as the n-octanol-water partition coefficient, refers to the logarithmic value of the ratio of the concentration of a compound in the n-octanol phase to the concentration in the water phase when the compound reaches distribution equilibrium in a mutually immiscible two-phase system (n-octanol and water) at a certain temperature. o / w The larger the value, the more lipophilic the compound is and the easier it is to dissolve in n-octanol. o / w The smaller the value, the more hydrophilic the compound is and the easier it is to dissolve in water. This coefficient is closely related to the absorption and distribution, metabolism and excretion, efficacy and selectivity of the drug. It is generally believed that the Log P of a drug o / w The ideal value should be between 1 and 3. Log P o / w <1: The compound is too hydrophilic and may have difficulty penetrating the cell membrane, resulting in poor absorption; 1≤Log P o / w ≤3: The compound has balanced hydrophilicity and lipophilicity, is easily absorbed and properly distributed in the body; Log P o / w >3: The compound is too lipophilic and may accumulate excessively in adipose tissue, leading to increased toxicity and side effects, and may be difficult to excrete through the kidneys.

[0438] This experiment uses reversed-phase high performance liquid chromatography to determine the lipid-water partition coefficient of the compound. The specific experimental scheme is as follows:

[0439] a) Select a series of standard compounds with known lipid-water partition coefficients, and their lipid-water partition coefficients are in a similar range to the test compound (roughly determined in preliminary experiments or predicted by computer).

[0440] b) Select C 18 Chromatographic columns, using methanol-water or acetonitrile-water as the mobile phase.

[0441] c) Under constant temperature and flow rate, the retention factors k of the standard compound and the test compound on the chromatographic column are determined respectively, and their logarithmic values ​​log k are calculated.

[0442] d) Using log k and log P of standard compounds o / w Establish a linear regression equation and find the regression coefficient and intercept.

[0443] e) Substitute the log k of the compound to be tested and calculate its log P according to the regression equation o / w .

[0444] The structure of the parent drug to be tested is The remaining compounds to be tested are the compounds prepared in Table 1 of Example 1. The results of the lipid-water partition coefficient test are shown in Table 2.

[0445] Table 2. Lipid-water partition coefficients of target compounds

[0446] Compound No. <![CDATA[log P o / w ]]> Compound No. <![CDATA[log P o / w ]]> parent drug 1.952 58 4.914 1 0.300 61 2.926 2 3.086 62 2.899 3 0.257 71 2.864 4 2.858 72 3.041 11 2.794 93 4.148 12 3.666 95 4.053 15 4.253 102 4.406 16 5.109 109 5.004 23 4.696 119 5.728 24 5.457 120 4.764 25 4.710 125 4.926 26 5.559 130 3.670 31 4.114 135 6.635 32 4.977 142 6.596 47 5.195 143 6.839 48 5.927 146 7.864 56 6.322 150 7.193 57 4.094 159 7.275

[0447] According to the above-mentioned LWCP results, a total of 5 compounds (compounds 4, 11, 61, 62, and 71) have relatively ideal LWCPs, with values ​​ranging from 1 to 3; a total of 4 compounds (compounds 72, 2, 12, and 130) have LWCPs ranging from 3 to 4; only compounds 1 and 3 show relatively strong hydrophilicity, with LWCPs of 0.300 and 0.257 respectively; in addition, the remaining compounds are all highly lipophilic, with LWCPs exceeding 4.000.

[0448] 2) Blood-brain barrier permeability measurement

[0449] There are several main experimental schemes for determining the blood-brain barrier permeability of compounds: (1) In vitro models: using cell culture, artificial membranes or brain capillary slices to simulate the structure and function of the blood-brain barrier, and determining the apparent permeability coefficient (P app ) or efflux rate (ER) to evaluate its blood-brain barrier permeability. (2) In vivo model: using animal experiments to measure the concentration ratio of the compound in the blood and brain tissue (B / P) or the concentration ratio of the free drug in the blood and brain tissue (K p,uu ) to evaluate its blood-brain barrier permeability. (3) In vitro and in vivo combination model: Using the blood-brain barrier permeability classifier (BPC), combined with high-throughput in vitro methods (PAMPA) and in vivo methods (brain homogenate dialysis technology), while considering the passive diffusion and active transport of the compound, predict its in situ blood-brain barrier permeability. This experiment uses the in vivo model method to measure the ratio of free drug in brain to plasma (Kp,uu The blood-brain barrier permeability of the compound is reflected by the method of the present invention. The specific test scheme is as follows:

[0450] a) The experimental animals were ICR mice, the administration method was tail vein injection, the solvent was fat emulsion, and the administration dose was 0.8×LD 50 ;

[0451] b) 30 seconds after administration, collect blood (blood from the eyeball) and brain tissue samples from the animals, prepare plasma (EP tube moistened with heparin, and add acetonitrile twice the volume of plasma) and brain homogenate (2 times the volume of brain tissue in acetonitrile, 70HZ, 30s homogenization) by appropriate methods, and then centrifuge at 20,000rpm for 10min to obtain the supernatant;

[0452] c) Determination of free drug ratio in plasma and brain homogenate by equilibrium dialysis (f u ), and the total drug concentration in plasma and brain homogenate was determined by liquid chromatography-mass spectrometry (C p and C b );

[0453] d) Calculate the free drug concentration in plasma and brain tissue based on the free drug ratio and total drug concentration (C p,u and C b,u );

[0454] e) Use nonlinear regression to fit the pharmacokinetic curves of free drugs in plasma and brain tissue, and calculate the corresponding pharmacokinetic parameters, such as half-life, clearance rate, distribution volume, etc.;

[0455] f) Calculate the exposure of free drug in plasma and brain tissue, i.e. AUC (area under the plasma concentration-time curve) or C max (maximum concentration);

[0456] g) Calculate the ratio of free drug in brain to plasma (K p,uu ) is AUC b,u / AUC p,u or C b,u / C p,u , as an indicator of blood-brain barrier permeability. Generally speaking, K p,uu A value greater than 1 indicates that the compound has a higher blood-brain barrier permeability. p,uu A value less than 0.1 indicates that the compound has a low blood-brain barrier permeability.

[0457] The structure of the parent drug to be tested is The remaining test compounds are the compounds prepared in Table 1 of Example 1. The blood-brain barrier permeability results of the compounds are shown in Table 3.

[0458] Table 3. Blood-brain barrier permeability of target compounds

[0459]

[0460]

[0461] According to the above blood-brain barrier permeability results, a total of 20 compounds (compounds 135, 1, 3, 146, 119, 150, 143, 93, 71, 4, 62, 61, 95, 159, 102, 72, 109, 120, 2, 125) have high blood-brain barrier permeability. p,uu The values ​​were all greater than 0.0; another 15 compounds (compounds 58, 11, 23, 47, 12, 15, 130, 24, 31, 25, 48, 142, 16, 32, 26) had moderate blood-brain barrier permeability, and their Log K p,uu The values ​​were all within the range of -1 to 0. In addition, two compounds (compounds 56 and 57) had poor blood-brain barrier permeability, and their LogK p,uu The values ​​are all less than -1.

[0462] Test Example 2: Antagonistic effects of various compounds on different general anesthetics

[0463] 1. Main reagents and drugs

[0464] (1) Main reagents

[0465] Propofol injection (batch number: 2010083, Xi'an Libang), etomidate injection (purity>98%), remimazolam (purity>98%), ketamine hydrochloride injection, Medium / long chain fat emulsion injection (C 6～24 )(Approval number: National Medicine Standard H20030609, manufacturer: Huarui Pharmaceutical Co., Ltd.).

[0466] (2) Test drug

[0467] The preparation method is as follows: weigh appropriate amounts of the compounds to be tested, add appropriate amounts of medium-chain triglyceride emulsion injection with a pipette to prepare a 4 mg / mL solution of the compounds to be tested, filter with a 0.22 μm microporous filter membrane, and use immediately.

[0468] 2. Experimental methods

[0469] Male ICR mice weighing 25 g ± 1 g were randomly divided into several groups, with 8 replicates in each group. Propofol 22.11 mg / kg (1.5 times ED 50 ), etomidate 4.48mg / kg (2 times ED50 ), remimazolam 57.34mg / kg (1.5 times ED 50 ) or ketamine 80 mg / kg (1.5 times ED 50 ) for anesthesia induction, injection time 15 seconds, mice maintained righting reflex loss for 30 seconds and then injected with 30mg / kg test compound solution (medium-chain fat emulsion injection as solvent) or equal volume of medium-chain fat emulsion injection, and observed and recorded the total anesthesia time of mice. The total anesthesia time refers to the time from the disappearance of righting reflex of mice to the recovery of righting reflex of mice.

[0470] The compound to be tested is the compound prepared in Table 1 of Example 1.

[0471] 3. Experimental results

[0472] The results are shown in Table 4.

[0473] Table 4. Effects of the tested drugs on antagonizing the anesthetic effects of general anesthetics

[0474]

[0475]

[0476]

[0477]

[0478]

[0479] The experiment showed that fat emulsion did not produce an anesthetic antagonistic effect for the general anesthetic drugs propofol, etomidate, remimazolam and ketamine; however, the compounds listed in the table could play an antagonistic role in general anesthesia, and the drug effect was manifested in a significant shortening of the total anesthesia time of mice. This shows that the compounds provided by the present invention can antagonize the anesthetic effect of general anesthetic drugs and provide a faster awakening speed.

[0480] Test Example 3: Antagonistic effect of compounds on continuous infusion of general anesthetic drugs

[0481] 1. Main reagents and drugs

[0482] (1) Main reagents

[0483] Propofol injection (batch number: 2010083, Xi'an Libang), Medium / long chain fat emulsion injection (C 6～24 )(Approval number: National Medicine Standard H20030609, manufacturer: Huarui Pharmaceutical Co., Ltd.).

[0484] (2) Test drug

[0485] The preparation method is the same as that of Test Example 2.

[0486] 2. Experimental methods

[0487] Male SD rats weighing 250-300 g were randomly divided into several groups, with 6 replicates in each group. 50 ) propofol was used for continuous anesthesia induction, and anesthesia was maintained at a rate of 1 mg / (kg·min) for 30 minutes. After drug withdrawal, 30 mg / kg of the test compound solution (medium-chain fat emulsion injection as solvent) or an equal volume of medium-chain fat emulsion injection was immediately injected, and the anesthesia recovery time of the rats after drug withdrawal was observed and recorded. Among them, the anesthesia recovery time refers to the time from the cessation of propofol infusion to the recovery of the righting reflex of the rat. The test compound is the compound prepared in Table 1 of Example 1.

[0488] 3. Experimental results

[0489] The results are shown in Table 5.

[0490] Table 5. Antagonistic effect of the tested drugs on continuous infusion of propofol to maintain general anesthesia

[0491]

[0492]

[0493] It can be seen from the experimental results that the compound provided by the present invention can effectively antagonize the anesthesia-maintaining effect of continuous infusion of propofol, which is manifested in the shortening of the average awakening time of rats.

[0494] Test Example 4: Compounds improve respiratory function during inhalation general anesthesia with preserved spontaneous breathing

[0495] 1. Main reagents, equipment and drugs

[0496] (1) Main reagents

[0497] Kateli (approval number: National Medicine Standard H20040772, manufacturer: Jiangsu Hengrui Medicine Co., Ltd.).

[0498] (2) Main equipment

[0499] Unrestrained whole body plethysmography system (non-invasive respiratory measurement system) (Origin: United States, manufacturer: DATASCIENCESINTERNATIONAL)

[0500] (3) Test drug

[0501] The preparation method is the same as that of Test Example 2.

[0502] 2. Experimental methods

[0503] Male SD rats weighing 250-300 grams were randomly divided into several groups, with 6 parallel samples in each group, and the basal respiratory rate was recorded. Continuous anesthesia was induced with 2MAC sevoflurane, and anesthesia was maintained with 1.5MAC. The basal respiratory rate of the rats under anesthesia (average respiratory rate within 10 minutes) was recorded. The test drug was administered through the tail vein, and the average respiratory rate within 10 minutes after administration was observed and recorded.

[0504] 3. Experimental results

[0505] The results are shown in Table 6.

[0506] Table 6. Effects of the tested drugs on improving respiratory function during inhalation general anesthesia with preserved spontaneous breathing

[0507] Test drug dose Test drug Respiratory rate before induction Respiratory rate after anesthesia Respiratory rate after drug administration - No treatment 96.5±4.6 38.6±3.1 77.2±2.3 - Fat emulsion 110.4±4.0 44.6±4.7 88.3±7.6 30mg / kg Compound 45 105.7±3.3 42.8±1.9 84.6±5.8 30mg / kg Compound 2 91.7±6.2 55.2±7.2 73.3±8.0 30mg / kg Compound 3 115.1±2.8 52.5±3.0 99.6±5.6 30mg / kg Compound 4 100.5±2.0 45.8±7.3 95.1±8.2 30mg / kg Compound 5 101.7±8.4 57.5±7.2 82.5±5.7 30mg / kg Compound 6 101.4±7.1 50.2±2.4 103.9±8.9 30mg / kg Compound 7 99.9±8.1 46.0±6.1 90.4±5.0 30mg / kg Compound 8 100.7±3.4 40.2±6.8 81.2±3.5 30mg / kg Compound 9 96.0±1.9 40.8±2.3 79.9±4.4 30mg / kg Compound 1 115.2±9.3 40.5±6.0 80.6±6.5 30mg / kg Compound 119 98.6±2.7 50.7±7.3 89.1±7.2 30mg / kg Compound 106 112.7±8.8 49.5±9.2 90.6±2.5 30mg / kg Compound 157 90.8±7.2 50.3±8.1 86.4±3.0 30mg / kg Compound 14 91.0±6.9 48.2±3.0 103.8±1.9

[0508] The experimental results show that the compounds of the present invention can improve the respiratory function during inhalation general anesthesia while retaining spontaneous breathing.

[0509] Test Example 5: Compounds improve respiratory function in respiratory depression induced by opioid overdose

[0510] 1. Main reagents and drugs

[0511] (1) Main reagents

[0512] Fentanyl citrate injection (approval number: National Medicine Standard H220003688, manufacturer: Yichang Renfu Pharmaceutical Co., Ltd.).

[0513] (2) Main equipment

[0514] Unrestrained whole body plethysmography system (non-invasive respiratory measurement system) (Origin: United States, manufacturer: DATASCIENCESINTERNATIONAL)

[0515] (3) Test drug

[0516] The preparation method is the same as that of Test Example 2.

[0517] 2. Experimental methods

[0518] Male SD rats weighing 250-300 grams were randomly divided into several groups, with 6 parallel samples in each group, and the basal respiratory rate was recorded. 10 mg / kg fentanyl was administered through the tail vein, and the average respiratory rate within 10 minutes after the rats were given the opioid. The test drug was administered through the tail vein, and the average respiratory rate within 10 minutes after the drug was observed and recorded.

[0519] 3. Experimental results

[0520] Table 7. Effects of the tested drugs on improving respiratory function during inhalation general anesthesia with preserved spontaneous breathing

[0521]

[0522]

[0523] The experimental results show that the present invention can significantly improve the respiratory function in respiratory depression induced by opioids.

[0524] In summary, the present invention provides the use of cyclic ketone compound prodrugs in the preparation of anesthetic and / or sedative antagonists. The present invention first discovered that the cyclic ketone compound prodrug has good general anesthesia and sedative antagonism. The experimental results show that the compounds of the present invention have good antagonism to general anesthesia induced by a variety of general anesthetic drugs (including propofol, etomidate, remimazolam, ketamine, etc.), and can significantly shorten the time for mice to recover their righting reflex after general anesthesia, and significantly shorten the time for mice to recover to walk normally. Moreover, for general anesthesia maintained by continuous infusion of the general anesthetic propofol in rats, the compounds of the present invention can also play an effective antagonistic effect. At the same time, it has a good improvement effect on respiratory depression caused by opioid drugs and inhaled anesthetics. The present invention provides a new choice for antagonists of anesthetic and / or sedative drugs, especially antagonists of general anesthetic drugs, with broad application prospects.

Claims

1. The compound represented by formula I, its stereoisomer, its deuterated derivative, its salt, and its solvate: in, m1 is 1 or 2; m2 is 0, 1 or 2; when m2 is 0, the connection between R3' and R4' and the connection between R7' and R4' If not, connect R3' or R7' When m2 is 1 or 2, the bond connecting R3' and R4' and connecting R7' and R4' is a key, connecting R3' or R7' is a key or None; m is 0 or 1; when m is 0, the When m is 1, the connection between R4 and R0 and the connection between R4 and R3 is the key; Connect R0', R3, R3', R8' Depending on the number of bonds connecting the carbon atoms, it is either bonded or absent; R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen, C1-C8 alkyl; L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 are independently selected from hydrogen, C1-C8 alkyl; R0 is selected from C1-C8 alkyl; R0' is selected from hydrogen, deuterium, tritium, halogen, C 1～6 Alkyl, C 2～6 Alkenyl, C 2～6 Alkynyl; R3, R3', R4', R5', R6, R6', R7', and R8' are independently selected from hydrogen and C1-C8 alkyl; When m is 0, R4 and R5 are absent; when m is 1, R4 and R5 are independently selected from hydrogen and C1-C8 alkyl.

2. The compound according to claim 1, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by Formula IA: in, R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen, C1-C8 alkyl; L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 are independently selected from hydrogen, C1-C8 alkyl; is a key or None, m is 0 or 1, and when m is 1, for nothing; R0 is selected from C1-C8 alkyl; R3 and R6 are independently selected from hydrogen and C1-C8 alkyl; When m is 0, R4 and R5 are absent; when m is 1, R4 and R5 are independently selected from hydrogen and C1-C8 alkyl.

3. The compound according to claim 2, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by Formula Ia, Formula Ib, Formula Ic, Formula Id or Formula Ie: in, R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen, C1-C8 alkyl; L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

4. The compound according to claim 3, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula Id1 or formula Id2: in, R1 and R2 are connected to form a 3-10-membered cycloalkyl substituted by n R7s, a 3-10-membered heterocycloalkyl substituted by n R7s, a 6-10-membered aryl substituted by n R7s, or a 5-10-membered heteroaryl substituted by n R7s; or R1 and R2 are connected to form n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen, C1-C8 alkyl; L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

5. The compound according to claim 2, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is shown in formula II: in, X and Y are independently selected from O, S or NH; Z1 and Z2 are independently selected from integers of 0 to 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen and C1-C8 alkyl.

6. The compound according to claim 5, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula IIa or IIb: in, X and Y are independently selected from O, S or NH; Z1 and Z2 are independently selected from integers of 0 to 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is an integer selected from 0 to 8; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR9, -C(O)R9; R9 is selected from hydrogen and C1-C8 alkyl.

7. The compound according to claim 5, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula IIIa: in, Y is selected from O or S; Z2 is independently selected from 0, 1, 2, 3, 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is selected from 0, 1, 2, 3, 4; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano; R9 is selected from hydrogen, C1-C8 alkyl; Alternatively, the compound is represented by formula IIIb: in, Z1 and Z2 are independently selected from 0, 1, 2, 3, and 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is selected from 0, 1, 2, 3, 4; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano.

8. The compound according to claim 7, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula IIIa1 or formula IIIa2: in, Y is selected from O or S; Z2 is independently selected from 0, 1, 2, 3, 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is selected from 0, 1, 2, 3, 4; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano; R9 is selected from hydrogen, C1-C8 alkyl; Alternatively, the compound is represented by Formula IIIb1 or Formula IIIb2: in, Z1 and Z2 are independently selected from 0, 1, 2, 3, and 4; R7 is a substituent at any position on the ring, and n is the number of R7; n is selected from 0, 1, 2, 3, 4; R7 is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano.

9. The compound according to any one of claims 5 to 8, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is one of the following compounds:

10. The compound according to claim 2, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is shown in formula IV: in, L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

11. The compound according to claim 10, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula IVa or IVb: in, L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by a heteroatom or not; the heteroatom is O, N or S; Each R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 , a is an integer selected from 0 to 8; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from integers from 0 to 8; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is an integer selected from 0 to 8; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

12. The compound according to claim 10, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula V: in, n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; Each R 10 , R 11 , R 12 are independently selected from hydrogen, C1-C8 alkyl; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

13. The compound according to claim 12, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula Va or formula Vb: in, n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; Each R 10 , R 11 , R 12 are independently selected from hydrogen, C1-C8 alkyl; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl, -C(O)NR d3 R d4 ; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C8 alkyl.

14. The compound according to claim 12 or 13, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: R 10 , R 11 are each independently selected from hydrogen; n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; R 12 is selected from hydrogen, C1 alkyl, C2 alkyl, C3 alkyl; R8 is selected from a R 18 Substituted imidazole, replaced by a R 18 Substituted phenyl, with a R 18 Indolyl, substituted by a R 18 Substituted pyridyl, with a R 18 Substituted thienyl, -C(O)NR d3 R d4 ; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted phenyl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 are independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxy, nitro, amino, and cyano; R d1 , R d2 , R d3 , R d4 Each is independently selected from hydrogen and C1-C4 alkyl.

15. The compound according to claim 12 or 13, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is one of the following compounds:

16. The compound according to claim 10, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula VI: in, n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

17. The compound according to claim 16, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by Formula VIa or Formula VIb: in, n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl; R8 is selected from a R 18 Substituted 3- to 10-membered cycloalkyl, 18 substituted 3- to 10-membered heterocycloalkyl, 18 substituted 6- to 10-membered aryl, with a R 18 Substituted 5- to 10-membered heteroaryl; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted 6- to 10-membered aryl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

18. The compound according to claim 16 or 17, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: n1 is selected from 0, 1, 2, 3, 4, and 5; and any carbon atom on the main chain in n1 is replaced by 1 or 2 or more heteroatoms or not replaced by heteroatoms; the heteroatom is O, N, or S; Each R 10 , R 11 are independently selected from hydrogen, C1-C8 alkyl; R8 is selected from a R 18 Substituted 3- to 8-membered cycloalkyl, 18 Substituted phenyl; a is selected from 0, 1, 2, 3, 4, 5; Each R 18 are independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino, cyano, -C(O)OR 19 、-C(O)R 19 、-O(CH2) b R 19 ; R 19 Selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, (CH2) c C(O)R 20 , by p R 21 Substituted phenyl; b and c are independently selected from 0, 1, 2, 3, 4, and 5; R 20 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl; p is selected from 0, 1, 2, 3, 4, 5; Each R 21 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

19. The compound according to claim 16 or 17, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is one of the following compounds:

20. The compound according to claim 10, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by formula VII: in, L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S; Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

21. The compound according to claim 20, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is represented by Formula VIIa or Formula VIIb: in, L is selected from n1, n2, n3 are independently selected from integers of 0 to 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S; Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is an integer selected from 0 to 8; Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

22. The compound according to claim 20 or 21, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: L is selected from n1, n2, n3 are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; and any carbon atom on the main chain of n1, n2, n3 is replaced by 1 or 2 or more heteroatoms or not by heteroatoms; the heteroatom is O, N or S; Each R 10 , R 11 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, C1-C8 alkyl; Ring A is selected from phenyl; R 17 is a substituent on ring A, n4 is R 17 The number of; n4 is selected from 0, 1, 2, 3, 4, 5; Each R 17 Each is independently selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxy, nitro, amino and cyano.

23. The compound according to claim 20 or 21, its stereoisomer, its deuterated derivative, its salt, or its solvate, characterized in that: The compound is one of the following compounds:

24. Use of the compound according to any one of claims 1 to 23, its stereoisomer, its deuterated derivative, its salt or its solvate in the preparation of anesthetic and / or sedative antagonist drugs.

25. The use according to claim 24, characterized in that: The anesthetic and / or sedative antagonist is an antagonist of an anesthetic drug and / or an antagonist of a sedative drug.

26. The use according to claim 24, characterized in that: The anesthetic and / or sedative antagonist can reverse the anesthetic and / or sedative state induced or maintained by the anesthetic and / or sedative drug.

27. The use according to claim 24, characterized in that: The anesthesia and / or sedation antagonist drug can reduce the anesthesia and / or sedation time.

28. The use according to claim 25 or 26, characterized in that: The anesthetic drugs include GABA A Receptor agonists.

29. The use according to claim 24, characterized in that: The anesthetic and / or sedative antagonist is GABA A High affinity ligand for receptors, capable of acting as a competitive antagonist against GABA A Receptor agonists.

30. The use according to claim 25 or 26, characterized in that: The anesthetic drug is a general anesthetic drug.

31. The use according to claim 30, characterized in that: The general anesthetic drug is benzodiazepine Drugs, substituted phenol drugs, imidazole drugs, GABA-mimetic drugs, and phenylcyclohexylamine drugs.

32. The use according to claim 31, characterized in that: The benzodiazepine The drugs in this category are diazepam, midazolam, lorazepam, and remimazolam; The substituted phenol drugs are propofol, propofol, and fospropofol sodium; The imidazole drug is etomidate, methoxyetomidate or a derivative thereof; The GABA-mimicking drugs are γ-aminobutyric acid and γ-hydroxybutyric acid; Phenylcyclohexylamine drugs include ketamine and fluamine.

33. Use of the compound according to any one of claims 1 to 23, its stereoisomer, its deuterated derivative, its salt or its solvate in the preparation of a medicament for improving respiratory function in inhalation general anesthesia with preserved spontaneous breathing.

34. The use according to claim 33, characterized in that: The inhalation general anesthesia refers to anesthesia induced and maintained by isoflurane, sevoflurane, desflurane, enflurane, enflurane, and nitrous oxide.

35. Use of the compound according to any one of claims 1 to 23, its stereoisomer, its deuterated derivative, its salt or its solvate in the preparation of a medicament for improving respiratory function in respiratory depression induced by opium overdose.

36. The use according to claim 35, characterized in that: The opioid drugs are morphine, fentanyl, sufentanil, remifentanil, alfentanil, carfentanil and other fentanyl derivatives, pethidine, tramadol, dezocine, pentazocine, hydromorphone, oxycodone, buprenorphine, butorphanol, and nalbuphine.

37. An anesthetic and / or sedative antagonist, characterized in that: The invention relates to a preparation prepared by using the compound described in any one of claims 1 to 23, its stereoisomer, its deuterated derivative, its salt or its solvate as an active ingredient and adding pharmaceutically acceptable auxiliary materials.

38. The anesthetic and / or sedative antagonist according to claim 37, characterized in that: The preparation is a tablet, capsule, oral liquid, granule, pill, powder, injection or powder injection.

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