Benzodiazepine compounds, their manufacturing process and medicinal effects

Abstract

This paper relates to benzodiazepine compounds, their preparation methods, and pharmaceutical effects. The benzodiazepine compounds are the compound shown in Formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof. The compounds of the present invention have high intravenous sedative and anesthetic effects, and their anesthetic effects are comparable to or superior to those of remimazolam, as evidenced by significantly lower effective doses and significantly shorter duration and recovery times. In both rat and mouse tail vein anesthesia models, the compounds of the present invention significantly improved the quality of emergence compared to remimazolam. The compounds of the present invention have rapid onset of anesthetic action, short duration of anesthesia, rapid emergence, and good tolerance, making them promising candidates for anesthesia induction, maintenance, and post-surgery anesthesia. TIFF2022539126000174.tif6599

Description

[Technical field]

[0001] The present invention belongs to the field of chemistry and medicine, specifically, to benzodiazepine compounds and their preparation method and medicinal action. [Background technology]

[0002] Midazolam is the most commonly used benzodiazepine drug, with excellent safety, and acts mainly by binding to central gamma-aminobutyric acid (GABAA) receptors. It has a relatively fast onset of action and reduces intracranial pressure and cerebral metabolism. It is generally used as a preanesthetic medication, induction and maintenance of general anesthesia, adjuvant for spinal and local anesthesia, diagnostic or therapeutic procedures such as angiography, cardiocardial defibrillation, bronchoscopy, and gastrointestinal endoscopy, and for sedation of ICU patients. However, since the metabolism of midazolam depends on the liver and kidneys, if it is infused for a long period of time, the drug generally accumulates in the body, causing adverse reactions such as excessive sedation, respiratory depression, circulatory depression, and drug resistance, and furthermore, it cannot be used for a long period of time in patients with liver or kidney dysfunction.

[0003] The parent structure of Remimazolam is midazolam. Remimazolam is an ultra-short-acting intravenous benzodiazepine sedative / analgesic that acts on GABA receptors, especially GABA-α. This drug combines the safety of midazolam with the efficacy of propofol. Remimazolam is an ultra-short-acting benzodiazepine drug that is rapidly metabolized by tissue esterases in the human body to inactive metabolites and is not metabolized by the cytochrome-dependent hepatic pathway. As an intravenous general anesthetic, it has the characteristics of rapid onset of action, short duration, rapid recovery, and good tolerance. Remimazolam is used for anesthesia induction, anesthesia maintenance, and day surgery anesthesia, and is superior to other products in cases with cardiovascular disease, respiratory disease, liver disease, and in the elderly.

[0004] However, according to related reports, remimazolam has a lower potency than other sedatives, and the dose must be increased when used clinically, increasing potential toxicity, and the structure of the free base is unstable, so by-products are quite toxic and may further affect the activity of drug-metabolizing enzymes in the body, and continued use of the drug can lead to problems such as high blood levels and drug accumulation. Therefore, there is a demand for the development of a new ultra-short-acting sedative / anesthetic with higher safety and potency. Summary of the Invention

[0005] The object of the present invention is to provide a benzodiazepine compound, a method for its preparation, and its use in medicine.

[0006] The present invention provides a compound according to formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a co-crystal thereof, or a composition thereof: TIFF0007621289000001.tif6199

[0007] Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 1 is a short chain hydrocarbon group or hydrogen, R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 2is hydrogen or a short chain hydrocarbon group, Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from a halogen, a trifluoromethyl group, a cyano group, a nitro group, a short-chain alkyl group, or an alkoxy group, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S; M is absent or is O, S, NH or C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, C 1~6 substituted by 0 to 4 substituents selected from alkoxy groups, preferably M is O; R 3 is hydrogen, a short-chain hydrocarbon group, -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, or -NHC 1-4 and the heterocycle contains 1 to 3 heteroatoms selected from N, O, or S, preferably R 3 is a short chain hydrocarbon group, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 represents a pyridine ring with nitrogen atoms at 2, 3, and 4, preferably R 4 is pyridine at the 2-position, X is independently halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; HA is an acceptable medicinal mineral and organic acid for a variety of uses. moreover, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 3-10 A cycloalkyl group or a substituted or unsubstituted 3- to 10-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~10 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 10-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, a trifluoromethyl group, a cyano group, a nitro group, C 1~8 Alkyl group, C 1~8 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3~10 a cycloalkyl group, or a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 is selected from pyridine rings with nitrogen at 2, 3, or 4; M is nothing, O, S, NH or substituted or unsubstituted C 1~5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~4 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; The HA is selected from a pharma- ceutically acceptable inorganic or organic acid; Preferably, X is independently -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 is selected from.

[0008] Further, the compound is a compound of formula II, TIFF0007621289000002.tif69105

[0009] Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 1 is a short chain hydrocarbon group or hydrogen, R2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 2 is hydrogen or a short chain hydrocarbon group, Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from a halogen, a trifluoromethyl group, a cyano group, a nitro group, a short-chain alkyl group, or an alkoxy group, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S; M is absent or is O, S, NH or C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, C 1~6 substituted by 0 to 4 substituents selected from alkoxy groups, preferably M is O; R 3 is hydrogen, a short-chain hydrocarbon group, -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, or -NHC 1-4 and the heterocycle contains 1 to 3 heteroatoms selected from N, O, or S, preferably R 3 is a short chain hydrocarbon group, a is selected from 0, 1, and 2; b is selected from 0 or 1; X is independently halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; HA is an acceptable medicinal mineral and organic acid. Preferably, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 3-10 A cycloalkyl group or a substituted or unsubstituted 3- to 10-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~10 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 10-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, a trifluoromethyl group, a cyano group, a nitro group, C 1~8 Alkyl group, C 1~8 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3~10 a cycloalkyl group, or a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 is selected from pyridine rings with nitrogen at 2, 3, or 4; M is nothing, O, S, NH or substituted or unsubstituted C 1~5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~4 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; The HA is selected from pharma- ceutically acceptable inorganic or organic acids. moreover, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~3 Alkyl groups, substituted or unsubstituted C 3-5 A cycloalkyl group or a substituted or unsubstituted 3- to 5-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1~3 Alkyl group, C 1~3alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4~6 a cycloalkyl group, or a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 is selected from pyridine rings with nitrogen at 2, 3, or 4; M is nothing, O, S, NH or substituted or unsubstituted C 1~3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~2 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1~6 Alkyl groups, substituted or unsubstituted C 1~6 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; The HA is selected from a pharma- ceutically acceptable inorganic or organic acid; Preferably, each X is independently -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 is selected from.

[0010] Further, the compound is a compound of formula III, TIFF0007621289000003.tif65101

[0011] Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 1 is a short chain hydrocarbon group or hydrogen, R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 2 is hydrogen or a short chain hydrocarbon group, Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from a halogen, a trifluoromethyl group, a cyano group, a nitro group, a short-chain alkyl group, or an alkoxy group, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S; M is absent or is O, S, NH or C 1-5alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, C 1~6 substituted by 0 to 4 substituents selected from alkoxy groups, preferably M is O; R 3 is hydrogen, a short-chain hydrocarbon group, -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, or -NHC 1-4 and the heterocycle contains 1 to 3 heteroatoms selected from N, O, or S, preferably R 3 is a short chain hydrocarbon group, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 represents a pyridine ring with nitrogen atoms at 2, 3, and 4, preferably R 4 is pyridine at the 2-position, X 1 , X 2 are halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; HA is an acceptable medicinal mineral and organic acid. Preferably, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 3-10 A cycloalkyl group or a substituted or unsubstituted 3- to 10-membered heterocyclic group, or R 1 and R 2is a substituted or unsubstituted C 3~10 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 10-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, a trifluoromethyl group, a cyano group, a nitro group, C 1~8 Alkyl group, C 1~8 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3~10 a cycloalkyl group, or a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 is selected from pyridine rings with nitrogen at 2, 3, or 4; M is nothing, O, S, NH or substituted or unsubstituted C 1~5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~4 alkoxy groups, X1 , X 2 are halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; The HA is selected from pharma- ceutically acceptable inorganic or organic acids.

[0012] Furthermore, the compound is a compound of formula III-A, TIFF0007621289000004.tif70108

[0013] Where: R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~3 Alkyl groups, substituted or unsubstituted C 3-5 A cycloalkyl group or a substituted or unsubstituted 3- to 5-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1~3 Alkyl group, C 1~3 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4~6a cycloalkyl group, or a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; M is nothing, O, S, NH or substituted or unsubstituted C 1~3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~2 alkoxy groups, X 1 , X 2 are halogen, substituted or unsubstituted C 1~6 Alkyl groups, substituted or unsubstituted C 1~6 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; The HA is selected from a pharma- ceutically acceptable inorganic or organic acid; Preferably, X 1 , X 2 are -F, -Cl, -Br, and -CH 3 , -OCH 3 , -CF 3 , -OCF 3 is selected from.

[0014] Further, the compound is a compound of formula IV, TIFF0007621289000005.tif65104

[0015] Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 1 is a short chain hydrocarbon group or hydrogen, R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group or a 3-10 membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl group, cyano group, nitro group, short chain alkyl group or alkoxy group, and the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S, preferably R 2 is hydrogen or a short chain hydrocarbon group, Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from a halogen, a trifluoromethyl group, a cyano group, a nitro group, a short-chain alkyl group, or an alkoxy group, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, or S; M is absent or is O, S, NH or C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, C 1~6 substituted by 0 to 4 substituents selected from alkoxy groups, preferably M is O; R 3 is hydrogen, a short-chain hydrocarbon group, -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, or -NHC 1-4 and the heterocycle contains 1 to 3 heteroatoms selected from N, O, or S, preferably R 3 is a short chain hydrocarbon group, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 represents a pyridine ring with nitrogen atoms at 2, 3, and 4, preferably R 4 is pyridine at the 2-position, X 1 is halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; HA is an acceptable medicinal mineral and organic acid. Preferably, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 3-10 A cycloalkyl group or a substituted or unsubstituted 3- to 10-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~10 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 10-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, a trifluoromethyl group, a cyano group, a nitro group, C 1~8 Alkyl group, C 1~8alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3~10 a cycloalkyl group, or a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; R 4 is selected from pyridine rings with nitrogen at 2, 3, or 4; M is nothing, O, S, NH or substituted or unsubstituted C 1~5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~4 alkoxy groups, X 1 is halogen, substituted or unsubstituted C 1~8 Alkyl groups, substituted or unsubstituted C 1~8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; The HA is selected from pharma- ceutically acceptable inorganic or organic acids.

[0016] Further, the compound is shown in formula IV-A: TIFF0007621289000006.tif80123

[0017] Where: R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1~3 Alkyl groups, substituted or unsubstituted C 3-5 A cycloalkyl group or a substituted or unsubstituted 3- to 5-membered heterocyclic group, or R 1 and R 2 is a substituted or unsubstituted C 3~6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4, and the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1~3 Alkyl group, C 1~3 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1~8 Alkyl group, -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4~6 a cycloalkyl group, or a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1~4 Alkyl group, C 1~4 Alkoxy group, C 2~6 Alkenyl group, C 2~6 Alkynyl group, -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1~4alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 or 1; M is nothing, O, S, NH or substituted or unsubstituted C 1~3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl group, C 1~2 alkoxy groups, X 1 is halogen, substituted or unsubstituted C 1~6 Alkyl groups, substituted or unsubstituted C 1~6 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; The HA is selected from a pharma- ceutically acceptable inorganic or organic acid; Preferably, X 1 -F, -Cl, -Br, -CH 3 , -OCH 3 , -CF 3 , -OCF 3 is selected from. The inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, hydrobromic acid, and boric acid, and the organic acid is selected from formic acid, acetic acid, oxalic acid, adipic acid, L-aspartic acid, fumaric acid, benzoic acid, (2S,3S,4S,5R)-2,3,4,5-tetrahydroxy-6-oxocaproic acid, 2-hydroxyethane-1-sulfonic acid, 2-hydroxypropane-1,2,3-tricarboxylic acid, 2-hydroxypropionic acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-hydroxysuccinic acid, stearic acid, (S)-5-oxopyrrolidine-2-carboxylic acid, 2-hydroxy-1-naphthoic acid, nicotinic acid, 1-naphthoic acid, malonic acid, tartaric acid, and maleic acid.

[0018] Furthermore, said compound is one of the following compounds: JPEG0007621289000007.jpg32162JPEG0007621289000008.jpg33163JPEG0007621289000009.jpg32161JPEG0007621289000010.jpg33160JPEG0007621289000011.jpg33159JPEG0007621289000012.jpg29148JPEG0007621289000013.jpg31156JPEG0007621289000014.jpg35163JPEG0007621289000015.jpg31163JPEG0007621289000016.jpg33160JPEG0007621289000017.jpg32154JPEG0007621289000018.jpg32158JPEG0007621289000019.jpg32145TIFF0007621289000020.tif28153TIFF0007621289000021.tif32162TIFF0007621289000022.tif30157TIFF0007621289000023.tif30159TIFF0007621289000024.tif31162TIFF0007621289000025.tif31162TIFF0007621289000026.tif36162TIFF0007621289000027.tif34149TIFF0007621289000028.tif26147TIFF0007621289000029.tif28143TIFF0007621289000030.tif31130TIFF0007621289000031.tif30142TIFF0007621289000032.tif26136TIFF0007621289000033.tif28140TIFF0007621289000034.tif3996TIFF0007621289000035.tif27162TIFF0007621289000036.tif29163TIFF0007621289000037.tif33162TIFF0007621289000038.tif32162TIFF0007621289000039.tif33162TIFF0007621289000040.tif43161TIFF0007621289000041.tif27162TIFF0007621289000042.tif27162TIFF0007621289000043.tif33162TIFF0007621289000044.tif3 1162TIFF0007621289000045.tif36160TIFF0007621289000046.tif33162TIFF0007621289000047.tif30148TIFF0007621289000048.tif41102.

[0019] The present invention further provides a method for preparing the above compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a co-crystal thereof, or a composition thereof, TIFF0007621289000049.tif112151

[0020] Using polysubstituted o-aminobenzoylpyridine 1 and Boc-L-glutamic acid-5 ester 2 as starting materials, 2-(Boc-L-glutamic acid-5 ester acyl)amino polysubstituted benzoylpyridine 3 was produced under DCC and DCM conditions. The Boc protecting group was removed under the action of acid and methanol to obtain 2-(Boc-L-glutamic acid-5-ester acyl)amino polysubstituted benzoylpyridine salt 4. Under the conditions of sodium bicarbonate and acetonitrile, intramolecular condensation reaction occurred to obtain polysubstituted benzodiazepine propionate 5, which was reacted with dimorpholinophosphine chloride 6, (R)-1-amino-2-propanol 7, LDA, and THF to obtain (R)-N-(polysubstituted benzodiazepine propionate)amino-2-propanol 8, which was then reacted with Dess-Martin chloride 9. The method includes the steps of: generating an oxidative ring-closing reaction under conditions of Reagent and acetone to obtain pyridylimidazobenzodiazepine propionate 9; hydrolyzing the oxidative ring-closing reaction with sodium hydroxide to obtain the desired intermediate pyridylimidazobenzodiazepine propionate II; reacting the oxidative ring-closing reaction with Compound 10 or 11, and then forming a salt with an acid to obtain the desired compound pyridylimidazobenzodiazepine propionate salt Compound I; Here, R1 , R 2 , R 3 , R 4 , M, X, n, and HA are as defined in claim 1; Preferably, the equivalent ratio of the reaction of the compound 1 with DCC is 1:0.8-2.5, the equivalent ratio of the reaction of the compound 2 with DCC is 1:0.8-2.5, the equivalent ratio of the reaction of the compound 3 with an acid is 1:0.9-2, the equivalent ratio of the reaction of the compound 4 with sodium hydrogen carbonate is 1:15-20, the equivalent ratio of the reaction of the compound 5 with 7 is 1:1.0-2.5, the equivalent ratio of the reaction of the compound 8 with the Dess-Martin reagent is 1:2-3, the reaction temperature is between 35-60°C, the equivalent ratio of the reaction of the target intermediate (II) with 10 or 11 is 1:1.0-2.2, and the reaction temperature is 30-50°C; And / or, the equivalent ratio of the reaction with the acid in the final salt formation step is selected to be 1:1-2.

[0021] The present invention further provides the use of a compound as defined above, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a co-crystal thereof, or a composition thereof, in the manufacture of a sedative and / or anaesthetic agent, Preferably, the sedative and / or anaesthetic agent is a sedative and / or anaesthetic agent administered as intravenous sedation and / or anaesthetic.

[0022] The present invention also provides a drug that is a formulation prepared by adding the above-mentioned compound, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a cocrystal thereof, or a composition thereof as an active ingredient, and a pharma- ceutically acceptable auxiliary material or auxiliary ingredient; Preferably, the drug is a sedative and / or anaesthetic; More preferably, the sedative and / or anaesthetic agent is a sedative and / or anaesthetic agent administered as intravenous sedation and / or anaesthetic.

[0023] In the present invention, room temperature is 25±5° C., and overnight is 12±2 h.

[0024] The compounds and derivatives provided by the present invention are named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, Ohio) naming systems.

[0025] In the present invention, the term "substitution" refers to the replacement of a hydrogen atom contained in a molecule with another different atom or molecule.

[0026] In the present invention, the minimum and maximum carbon atom content in the hydrocarbon group is represented by a prefix. For example, C a ~C b The alkyl group represents an alkyl group containing any number of carbon atoms, from "a" to "b". Thus, for example, C 1~10 Alkyl group means a straight or branched chain alkyl group containing 1 to 10 carbon atoms. 1~10 An alkoxy group means an alkoxy group containing 1 to 10 carbon atoms.

[0027] In the present invention, the short chain hydrocarbon group is a linear or branched alkyl group having 1 to 10 carbon atoms.

[0028] In the present invention, C 3~10 The cycloalkyl group means a saturated cycloalkyl group having 3 to 10 carbon atoms.

[0029] In the present invention, a 3- to 10-membered heterocyclic group means a saturated heterocyclic group composed of 3 to 10 atoms, at least one of which is selected from O, S, a substituted nitrogen atom, and a silicon atom.

[0030] In the present invention, halogen is fluorine, chlorine, bromine or iodine.

[0031] The compound of the present invention has high intravenous sedative and anesthesia effects, and its anesthetic effect is equivalent to or superior to that of remimazolam, specifically, the effective dose is significantly smaller, and the duration and recovery time are significantly shortened. In addition, in the tail vein anesthesia model of rats and mice, the compound of the present invention clearly reduces the occurrence of side effects and significantly improves the quality of awakening compared to remimazolam. The compound of the present invention has a fast onset of action during anesthesia, a short duration, a rapid awakening, low toxicity, good tolerance, and can be used for anesthesia induction, anesthesia maintenance, and day surgery anesthesia, and is expected to have a future.

[0032] Naturally, based on the above content of the present invention, various other forms of modifications, substitutions or changes can be made in light of general technical knowledge and conventional means in this field, on the premise that they do not deviate from the above basic technical idea of ​​the present invention.

[0033] The above contents of the present invention will be described in more detail below by specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above contents of the present invention belongs to the scope of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] All materials and equipment used in the Detailed Description of the Invention are conventional and purchased from commercial sources.

[0035] Example 1 Preparation of Intermediate 1 of the Invention JPEG0007621289000050.jpg24135

[0036] At -40°C, 20ml (27.12mmo, 4.0eq) of n-butyllithium (2.5M) and 40ml of anhydrous ether were added to a three-neck flask, and 5.25ml (29.83mmol, 4.4eq) of 2-bromopyridine was added to the flask, stirred for 1 hour, and then 30ml of tetrahydrofuran solution containing 2.0g (6.78mmol, 1.0eq) of 2-amino-4,5-dibromobenzoic acid was added dropwise and reacted for 3 hours at 0°C. After the reaction of the material was almost completed, ice water was added, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain an oily product, which was then subjected to column chromatography to obtain 2.17g of a yellow solid (intermediate 1).

[0037] H nuclear magnetic resonance spectrum of intermediate 1 (deuterated chloroform): δ 8.78 (d, 1H), 8.43 (d, 1H),8.07 (d, 1H), 7.96 - 7.82 (m, 2H), 6.87 (d, 1H). MS: m / z: 355.90 (M+1).

[0038] Example 2 Preparation of Intermediate 2 of the Invention JPEG0007621289000051.jpg38137

[0039] 2.0g (5.62mol, 1.0eq) of 2-amino-4,5-dibromophenyl-pyridin-2-yl-ketone and 2.8g (10.72mmol, 1.9eq) of (R)-2-tert-butoxycarbonyl-amino-5-methoxy-5-oxopentanoic acid were dissolved in 30mL of dichloromethane (DCM), and 2.2g (10.68mmol, 1.9eq) of DCC (dicyclohexylcarbodiimide) was added under ice bath and reacted at room temperature overnight. The raw material was almost completely reacted when dropped onto a plate. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 3.3g of a pale yellow oil (intermediate 2).

[0040] H nuclear magnetic resonance spectrum (deuterated chloroform) of the intermediate 2: δ 11.36 (s, 1H), 8.74 (d, J = 4.8Hz, 1H), 8.57 (d, J = 9.0 Hz, 1H), 7.99 - 7.92 (m, 3H), 7.67 (dd, J= 9.0, 2.2 Hz, 1H), 7.56 - 7.51 (m, 1H), 5.42 (d, J = 6.6 Hz, 1H), 4.35(s, 1H), 3.68 (s, 3H), 2.54 - 2.24 (m, 4H), 1.44 (s, 9H).MS:m / z:600.28(M+1).

[0041] Example 3 Preparation of Intermediate 3 of the Invention JPEG0007621289000052.jpg37140

[0042] 3.3 g of (R)-4-((tert-butoxycarbonyl)amino)-5-((4,5-dibromo-2-pyridineformylphenyl)amino)-5-oxopentanoic acid methyl ester was dissolved in 20 mL of methanol, and 20 mL of HCl / MeOH solution (HCl and MeOH volume ratio 1:1) was added and reacted at room temperature overnight. The raw material was almost completely reacted when dropped onto a plate. It was used in the next step without any treatment.

[0043] Example 4 Preparation of Intermediate 4 of the Invention JPEG0007621289000053.jpg35131

[0044] 1.0g of sodium bicarbonate was added to 30mL of acetonitrile, and while stirring vigorously, 3g of the reaction solution of the compound (R)-N-chloro-1-(4,5-dibromo-2-pyridineformylphenyl)amino-5-methoxy-1,5-dioxopentan-2-ammonium was added dropwise and reacted at room temperature for 3 hours. The raw material was almost completely reacted when dropped onto a plate. After filtering the reaction solution, it was concentrated under reduced pressure and subjected to column chromatography to obtain 2g of a pale yellow oil (intermediate 4).

[0045] H nuclear magnetic resonance spectrum (deuterated chloroform) of the intermediate 4: δ 8.67 - 8.56 (m, 2H), 8.07 (d, J = 8.0Hz, 1H), 7.82 (td, J = 7.6, 1.6 Hz, 1H), 7.59 (dd, J = 8.8, 2.0 Hz, 1H), 7.52(d, J = 2.0 Hz, 1H), 7.37 (dd, J = 7.2, 5.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H),3.75 (dd, J = 7.6, 5.6 Hz, 1H), 3.67 (s, 2H), 2.72 - 2.44 (m, 4H). MS: m / z: 482.14 (M+1).

[0046] Example 5 Preparation of Intermediate 5 of the Invention JPEG0007621289000054.jpg41140

[0047] 1.0g (2.08mmol, 1.0eq) of (S)-3-7,8-dibromo-2-oxo-5-pyridin-2-yl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylmethyl ester propionic acid was dissolved in 10mL of tetrahydrofuran, and at -18°C, 2.5mL of 1M LDA tetrahydrofuran solution was added dropwise, and the mixture was reacted at 0°C for 30 minutes. 1.3g (5.1mmol, 2.45eq) of dimorpholinophosphine chloride was added, and the mixture was reacted for 30 minutes. Then, 40mL of a tetrahydrofuran solution containing 930mg (12.38mmol, 5.95eq) of (R)-1-aminopropan-2-ol was added dropwise, and the mixture was reacted overnight at room temperature. The mixture was added dropwise to a plate, and the raw material was almost completely reacted. A saturated ammonium chloride solution was added to the reaction liquid, which was then extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to column chromatography to obtain 520 mg of a yellow solid (Intermediate 5).

[0048] H nuclear magnetic resonance spectrum (deuterated chloroform) of the intermediate 5: δ 8.65 (d, J = 4.4 Hz, 1H), 7.91 - 7.74 (m, 2H), 7.50 (dd,J = 8.8, 2.0 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.13 (d, J = 8.8 Hz,1H), 5.81 (s, 1H), 4.03 - 3.91 (m, 1H), 3.70 (s, 3H), 3.48 - 3.18 (m, 3H), 2.83- 2.35 (m, 4H), 1.16 (d, J = 6.4 Hz, 3H). MS:m / z:538.24(M+1).

[0049] Example 6 Preparation of Intermediate 6 of the Invention JPEG0007621289000055.jpg42140

[0050] 7.0g (13mmol, 1.0eq) of 3-(S)-7,8-dibromo-2-(S)-2-hydroxypropyl)amino-5-(pyridin-2-yl)-3H-benzo[e][1,4]diazepin-3-ylpropionic acid methyl ester was dissolved in 100mL of acetone, and 13.6g (32.06mmol, 2.47eq) of Dess-Martin reagent was added and reacted at 40°C overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and further washed three times with saturated sodium bicarbonate solution and saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 5g of a yellow solid (intermediate 6) was obtained by column chromatography.

[0051] H nuclear magnetic resonance spectrum (deuterated chloroform) of the intermediate 6: δ 8.59 - 8.54 (m, 1H), 8.17 (d, J =8.0 Hz, 1H), 7.79 (td, J = 7.6, 1.6 Hz, 1H), 7.71 (dd, J = 8.8,2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.34 (ddd, J = 7.6, 4.8,0.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 0.8 Hz, 1H),4.05 (dd, J = 6.4, 4.0 Hz, 1H), 3.67 (s, 3H), 2.87 - 2.75 (m, 4H), 2.33(s, 3H). MS:m / z:519.21(M+1).

[0052] Example 7 Preparation of Intermediate 7 of the Invention JPEG0007621289000056.jpg37140

[0053] 1.0g (1.93mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4yl)propionic acid was dissolved in 20mL of methanol, 10mL of 1mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. The reaction liquid was transferred to the organic phase, and 1mol / L of HCl was added to adjust the pH to 5-6, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered to obtain the filtrate, and concentrated under reduced pressure to obtain 800mg of a yellow solid (intermediate 7).

[0054] H nuclear magnetic resonance spectrum (deuterated chloroform) of the intermediate 7: δ 8.62- 8.56 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.83 (td, J = 7.6, 1.6Hz, 1H), 7.74 (dd, J = 8.8, 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz,1H), 7.37 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.32 (d, J = 8.8 Hz,1H), 6.72 (d, J = 0.8 Hz, 1H), 4.09 (dd, J = 6.4, 4.0 Hz, 1H), 3.69 (s, 3H), 2.83 - 2.72 (m, 4H). MS:m / z:503.96(M+1).

[0055] Example 8 Preparation of Compound 8 of the Present Invention TIFF0007621289000057.tif42163

[0056] 1.5g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 427mg of methanol was added, and 1.72g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50ml of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.2g of crude product of carbonic acid chloromethyl methyl ester, which was used as it is in the next reaction.

[0057] 500 mg (1.00 mmol, 1.0 eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 400 mg (3.21 mmol, 3 eq) of the crude product of chloromethyl methyl ester of carbonic acid was added, 325 mg (2.36 mmol, 2.36 eq) of potassium carbonate was added, stirred at room temperature for 5 hours, and dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and obtained 300 mg of a pale yellow oil (compound 8) by column chromatography.

[0058] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 8: δ 8.73 (d, J = 4.8 Hz, 1H), 8.45 - 8.19 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.73 (s,1H), 7.62 (dd, J = 7.2, 5.2 Hz, 1H), 7.48 (s, 1H), 5.82 (s, 2H), 4.57 (dd, J =10.0, 4.0 Hz, 1H), 3.72 (s, 3H), 2.85 - 2.56 (m, 4H), 2.49 (d, J = 11.2 Hz,3H). MS:m / z:592.9853[M+H] + .

[0059] Example 9 Preparation of Compound 9 of the Present Invention TIFF0007621289000058.tif43162

[0060] 1.29g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 860mg of ethanol was added, and 1.9g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50ml of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.4g of a crude product of carbonic acid chloromethyl ethyl ester, which was used directly in the next reaction.

[0061] 500mg (1.00mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 327mg (2.36mmol, 2eq) of the crude product of carbonic acid chloromethyl ethyl ester was added, 324mg (2.36mmol, 2.36eq) of potassium carbonate was added, stirred at room temperature for 5 hours, and dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and obtained 600mg of a pale yellow oil (compound 9) by column chromatography.

[0062] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 9: δ 8.57 (t, J = 7.2 Hz, 1H), 8.07 -7.97 (m, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.69 (d, J =2.0 Hz, 1H), 7.58 (dd, J = 7.2, 5.2 Hz, 1H), 7.45 (s, 1H), 5.75 (s, 2H), 4.46(dd, J = 10.0, 4.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 2.95 - 2.58 (m, 4H), 2.48(s, 3H), 1.23 (t, J = 7.2 Hz, 3H).MS: m / z: 606.00 [M+H] + .

[0063] Example 10 Preparation of Compound 10 of the Present Invention TIFF0007621289000059.tif43162

[0064] 2.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 1.45g of isopropanol was added, and 2.5g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 2.1g of a crude product of carbonic acid chloromethyl isopropyl ester, which was used as it was in the next reaction.

[0065] 500mg (1.00mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 359mg (2.35mmol, 2eq) of the crude product of chloromethyl isopropyl carbonate was added, 325mg (2.36mmol, 2.36eq) of potassium carbonate was added, stirred at room temperature for 5 hours, and dropped onto the plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and obtained 600mg of a pale yellow oil (compound 10) by column chromatography.

[0066] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 10: δ 8.25 (d, J = 8.0 Hz, 1H), 8.08 - 7.98 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 7.2, 5.2 Hz, 1H), 7.46 (s, 1H), 5.74 (q, J = 6.0Hz, 2H), 4.80 (dt, J = 12.4, 6.4 Hz, 1H), 4.47 (dd, J = 10.0, 4.0 Hz, 1H), 2.93- 2.56 (m, 4H), 2.49 (s, 3H), 1.22 (dd, J = 10.4, 6.4 Hz, 6H).MS:m / z:621.02[M+H] + .

[0067] Example 11 Preparation of Compound 11 of the Present Invention TIFF0007621289000060.tif42162

[0068] 2.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 1.49g of tert-butanol was added, and 2.45g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.9g of crude product of tert-butyl carbonate (chloromethyl), which was used as it is in the next reaction.

[0069] 500 mg (1.00 mmol, 1.0 eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 390 mg (2.34 mmol, 2 eq) of carbonic acid tert-butyl ester (chloromethyl) crude product was added, 325 mg (2.36 mmol, 2.36 eq) of potassium carbonate was added, stirred at room temperature for 5 hours, and dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and obtained 530 mg of a pale yellow oil (compound 11) by column chromatography.

[0070] H nuclear magnetic resonance spectrum of the compound 11 (deuterated methanol: δ 8.77 (ddd, J = 4.8, 1.6, 0.8Hz, 1H), 7.92 (td, J = 8.0, 1.8 Hz, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 1H), 7.64(d, J = 2.0 Hz, 1H), 7.34 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.30 (d, J = 8.8 Hz,1H), 6.86 (d, J = 1.2 Hz, 1H), 5.71 (q, J = 5.6 Hz, 2H), 4.07 (t, J = 6.8 Hz,1H), 2.91 - 2.74 (m, 4H), 2.34 (d, J = 0.8 Hz, 3H), 1.48 (s,9H).MS:m / z:634.03[M+H] + .

[0071] Example 12 Preparation of Compound 12 of the Present Invention JPEG0007621289000061.jpg43165

[0072] 1.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 1.06g of 3-pentanol was added, and 1.3g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.5g of crude product of carbonic acid-3-pentyl ester chloromethyl ester, which was used as it is in the next reaction.

[0073] 500mg (1.00mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 426mg (2.37mmol, 2.37eq) of carbonic acid-3-pentyl ester chloromethyl ester crude product was added, 326mg (2.36mmol, 2.36eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and column chromatography was used to obtain 523mg of a pale yellow oil (compound 12).

[0074] H nuclear magnetic resonance spectrum of the compound 12 (deuterated methanol: δ 8.58 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H) 8.06 - 7.95 (m, 2H), 7.83 (d, J =8.8 Hz, 1H), 7.71 (s, 1H), 7.60 (dd, J = 7.2, 5.2 Hz, 1H), 7.47 (s, 1H),5.79 (dd, J = 13.2 6.0, 2H), 4.60 - 4.52 (m, 1H), 4.49 (dd, J =10.0, 4.0 Hz, 1H), 2.95 - 2.58 (m, 4H), 2.51 (s, 3H), 1.71 - 1.39 (m, 4H), 0.87(dt, J = 16.4, 7.2 Hz, 6H). MS:m / z:648.04[M+H] + .

[0075] Example 13 Preparation of Compound 13 of the Present Invention TIFF0007621289000062.tif45162

[0076] 1.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 1.0g of 3-methyl-2-butanol was added, and 1.3g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.6g of a crude product of chloromethyl (3-methylbutan-2-yl) carbonate ester, which was used as it was in the next reaction.

[0077] 500 mg (1.00 mmol, 1.0 eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 428 mg (2.37 mmol, 2.37 eq) of the crude product of chloromethyl carbonate (3-methylbutan-2-yl) ester was added, 326 mg (2.36 mmol, 2.36 eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 481 mg of a pale yellow oil (compound 13) was obtained by column chromatography.

[0078] H nuclear magnetic resonance spectrum of the compound 13 (deuterated methanol: δ 8.86 (d, J = 4.0 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.8, 2.0 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.34 (ddd, J = 7.6, 4.8, 0.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.86 (d, J =0.8 Hz, 1H), 5.77 (q, J = 5.6 Hz, 2H), 4.61 (p, J = 6.0 Hz, 1H), 4.07 (dd, J =8.4, 5.2 Hz, 1H), 2.93 - 2.72 (m, 4H), 2.33 (s, 3H), 1.66 - 1.56 (m, 4H), 0.90(td, J = 7.4, 3.3 Hz, 6H).MS:m / z:649.05[M+H] + .

[0079] Example 14 Preparation of Compound 14 of the Present Invention TIFF0007621289000063.tif45162

[0080] 1.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 1.37g of 2,4-dimethyl-3-pentanol was added, and 1.22g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.9g of crude product of chloromethyl carbonate (2,4-dimethylpentyl ester-3-yl ester), which was used as it is in the next reaction.

[0081] 500 mg (1.00 mmol, 1.0 eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 489 mg (2.34 mmol, 2.34 eq) of chloromethyl carbonate (2,4-dimethylpentyl ester-3-yl ester) crude product was added, 326 mg (2.36 mmol, 2.36 eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto the plate. The raw material was almost completely reacted. The reaction solution was filtered, then poured into 50 mL of water and extracted with 100 mL of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, and filtered to obtain a filtrate, which was then concentrated under reduced pressure and subjected to column chromatography to obtain 550 mg of a pale yellow oil (compound 14).

[0082] H nuclear magnetic resonance spectrum of the compound 14 (deuterated methanol: δ 8.68 (dd, J = 4.8, 0.8 Hz, 1H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.78 - 7.64 (m, 2H), 7.52 (d, J = 2.4 Hz, 1H), 7.48(dd, J = 5.6, 3.2 Hz, 1H), 7.37 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.26 (d, J =8.8 Hz, 1H), 6.79 (d, J = 1.2 Hz, 1H), 5.83 (q, J = 5.6 Hz, 2H), 4.52 (t, J =6.0 Hz, 1H), 4.41 (t, J = 6.8 Hz, 2H), 3.93(d, J = 6.0 Hz, 1H), 2.85 - 2.71 (m,4H), 2.45 (d, J = 0.8 Hz, 3H), 1.21 -1.16 (m, 12H). MS:m / z:677.08[M+H] + .

[0083] Example 15 Preparation of Compound 15 of the Present Invention JPEG0007621289000064.jpg50161

[0084] 1.0g of 1-chloroethyl carbonyl chloride was added to 30mL of anhydrous dichloromethane, 448mg of methanol was added, and 1.1g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 900mg of crude product of 1-chloroethyl methyl carbonate, which was used as it is in the next reaction.

[0085] 500mg (1.00mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 325mg (2.34mmol, 2.34eq) of carbonic acid 1-chloroethyl methyl ester crude product was added, 326mg (2.36mmol, 2.36eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 400mg of a pale yellow oil (compound 15) was obtained by column chromatography.

[0086] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 15: δ 8.37 (d, J = 4.2 Hz, 1H), 7.85 (td, J = 7.6, 1.6 Hz, 1H), 7.73 - 7.68 (m, 1H), 7.63 (dd, J = 5.2, 2.4 Hz, 1H), 7.37 - 7.28 (m, 2H), 6.86 (s, 1H), 6.76 (t, J = 5.6Hz, 1H), 4.06 (dd, J = 12.4, 6.6 Hz, 1H), 3.76 (d, J = 8.8 Hz, 3H), 2.92 - 2.75(m, 4H), 2.34 (s, 3H), 1.49 (t, J = 5.2 Hz, 3H).MS:m / z:607.00[M+H] + .

[0087] Example 16 Preparation of Compound 16 of the Present Invention JPEG0007621289000065.jpg51160

[0088] 1.0g of 1-chloroethyl carbon chloride was added to 30mL of anhydrous dichloromethane, 644mg of ethanol was added, and 1.1g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 800mg of crude product of 1-chloroethyl ethyl carbonate, which was used as it is in the next reaction.

[0089] 300 mg (0.705 mmol, 1.0 eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 215 mg (1.41 mmol, 2.0 eq) of carbonic acid 1-chloroethyl ethyl ester crude product was added, 195 mg (1.41 mmol, 2.0 eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and column chromatography was used to obtain 270 mg of a pale yellow oil (compound 15).

[0090] H nuclear magnetic resonance spectrum of the compound 16 (deuterated methanol: δ 8.34 - 8.02 (m, 1H), 7.76 (td,J = 7.6, 1.6 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.54 (dd, J = 4.4, 2.4 Hz, 1H), 7.35(ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 1.2 Hz,1H), 6.76 (t, J = 5.6 Hz, 1H), 4.16 (ddd, J = 7.1, 6.1, 2.4 Hz, 2H), 4.06 (dd,J = MS:m / z:621.02[M+H] + .

[0091] Example 17 Preparation of Compound 17 of the Present Invention JPEG0007621289000066.jpg49161

[0092] 1.0g of 1-chloroethyl carbonyl chloride was added to 30mL of anhydrous dichloromethane, 839mg of isopropanol was added, and 1.1g of pyridine was added dropwise while cooling with cold water, and the mixture was stirred for 2 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once with water. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 1.2g of crude product of 1-chloroethyl isopropyl carbonate, which was used as it is in the next reaction.

[0093] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 392mg (2.0mmol, 2.0eq) of 1-chloroethyl isopropyl ester crude product was added, 326mg (2.0mmol, 2.0eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and column chromatography was used to obtain 650mg of a pale yellow oil (compound 17).

[0094] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 17: δ 8.63 (d, J = 4.4 Hz, 1H), 8.21 (dd, J = 14.4, 8.0 Hz, 2H), 7.82 (d, J = 8.8 Hz, 1H),7.72 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 7.2, 5.2 Hz, 1H), 7.47 (s, 1H), 6.73 -6.57 (m, 1H), 4.8 - 4.63 (m, 1H), 4.36 (dt, J = 8.8, 5.6 Hz, 1H), 2.87 - 2.55(m, 4H), 2.39 (s, 3H), 1.43 (t, J = 5.6 Hz, 3H), 1.25 - 1.12 (m,6H).MS:m / z:635.03 [M+H] + .

[0095] Example 18 Preparation of Compound 18 of the Present Invention TIFF0007621289000067.tif30126

[0096] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 164mg (1.4mmol, 1.4eq) of 1-hydroxycyclopropane-1-carboxylic acid methyl ester, 290mg (1.4mmol, 1.4eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 540mg of a pale yellow oil (compound 18).

[0097] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 18: δ 8.72- 8.56 (m, 1H), 7.83 (td, J = 8.0, 1.6 Hz, 1H), 7.78(dd, J = 8.8, 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.38 - 7.28 (m, 2H), 6.86 (d, J = 1.2 Hz, 1H), 4.10(dd, J = 8.0, 5.6 Hz, 1H), 3.60 (s, 3H), 2.93 - 2.77 (m, 4H), 2.34 (s, 3H),1.50 (q, J = 5.6 Hz, 2H), 1.17 (q, J = 5.6 Hz, 2H).MS:m / z:603.01[M+H] + .

[0098] Example 19: Preparation of Compound 19 of the Present Invention TIFF0007621289000068.tif29124

[0099] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, and 182.20mg (1.4mmol, 1.4eq) of 1-hydroxycyclopropane-1-carboxylic acid ethyl ester crude product, 290mg (1.4mmol, 1.4eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 583mg of a pale yellow oil (compound 19) was obtained by column chromatography.

[0100] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 19: δ 8.67 (dd, J = 4.8, 0.8 Hz, 1H), 7.83 (td, J = 8.0, 2.0 Hz, 1H), 7.76 - 7.65 (m, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz,1H), 7.30 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H), 4.15 - 4.04 (m, 3H),2.90 - 2.74 (m, 4H), 2.34 (d, J = 0.8 Hz, 3H), 1.49 (dd, J = 8.4, 5.2 Hz, 2H),1.20 - 1.12 (m, 5H).MS:m / z:617.02[M+H] + .

[0101] Example 20: Preparation of Compound 20 of the Present Invention TIFF0007621289000069.tif29124

[0102] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 126.11mg (1.4mmol, 1.4eq) of glycolic acid methyl ester, 290mg (1.4mmol, 1.4eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 512mg of a pale yellow oil (compound 20) was obtained by column chromatography.

[0103] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 20: δ 8.47 (d, J = 8.0 Hz, 1H), 8.18 - 7.92 (m, 2H), 7.81 (d, J = 8.8Hz, 1H), 7.64 (s, 1H), 7.53 (dd, J = 7.2, 5.2 Hz, 1H), 7.45 (s, 1H), 4.70 -4.58 (m, 2H), 4.55 (dd, J = 10.4, 4.4 Hz, 1H), 3.66 (s, 3H), 2.99 - 2.59 (m,4H), 2.49 (s, 3H).MS:m / z:576.99[M+H] + .

[0104] Example 21 Preparation of Compound 21 of the Present Invention TIFF0007621289000070.tif29124

[0105] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 145.75mg (1.4mmol, 1.4eq) of ethyl glycolate, 290mg (1.4mmol, 1.4eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and 534mg of a pale yellow oil (compound 21) was obtained by column chromatography.

[0106] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 21: δ 8.65 - 8.51 (m, 1H), 7.87 (td, J = 8.0, 1.6 Hz, 1H), 7.72 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J =2.4 Hz, 1H), 7.44 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H),6.86 (d, J = 1.2 Hz, 1H), 4.58 (s, 2H), 4.14 (dt, J = 9.2, 4.8 Hz, 3H), 2.98 -2.73 (m, 4H), 2.34 (d, J = 0.8 Hz, 3H), 1.23 (t, J = 7.2 Hz,3H).MS:m / z:591.01[M+H] + .

[0107] Example 22 Preparation of Compound 22 of the Present Invention TIFF0007621289000071.tif31129

[0108] 500mg (1.0mmol, 1.0eq) of 3-((4S)-8,9-dibromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 145.6mg (1.4mmol, 1.4eq) of methyl lactate, 290mg (1.4mmol, 1.4eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 521mg of a pale yellow oil (compound 22) was obtained by column chromatography.

[0109] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 22: δ 8.63 (dd, J = 4.8, 0.8 Hz, 1H), 7.86- 7.71 (m, 1H), 7.69 (dt, J =8.8, 2.0 Hz, 1H), 7.57 (dd, J = 6.0, 2.4 Hz, 1H), 7.41 (ddd, J = 7.6, 4.8, 1.2Hz, 1H), 7.35 (dd, J = 8.8, 3.2 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H), 5.11 - 5.02(m, 1H), 4.10 (td, J = 5.6, 3.2Hz, 1H), 3.66 (s, 3H), 2.92 - 2.78 (m, 4H),2.34 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H).MS:m / z:591.01[M+H] + .

[0110] Example 23: Preparation of Compound 23 of the Present Invention TIFF0007621289000072.tif31130

[0111] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-bromo-4-chlorobenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-bromo-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0112] 500mg (1.09mmol, 1.0eq) of 3-((4S)-8-bromo-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 179.87mg (1.52mmol, 1.4eq) of lactic acid ethyl ester, 313.12mg (1.52mmol, 1.4eq) of DCC and 18.32mg (0.15mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 567mg of a pale yellow oil (compound 23) was obtained by column chromatography.

[0113] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 23: δ 8.63 (d, J = 4.8 Hz, 1H), 7.91 - 7.82 (m, 1H), 7.78- 7.68 (m, 1H), 7.64 (dd, J = 5.2, 2.4 Hz, 1H), 7.36 - 7.32 (m, 1H), 7.30 (dd, J = 8.8, 3.2 Hz,1H), 6.86 (d, J = 1.2 Hz, 1H), 5.04 (dt, J = 7.2, 4.8 Hz, 1H), 4.22 - 4.04 (m,3H), 2.99 - 2.69 (m, 4H), 2.34 (s, 3H), 1.44 (t, J = 6.8 Hz, 3H), 1.21 (td, J =7.2, 2.8 Hz, 3H). MS:m / z:605.02[M+H] + .

[0114] Example 24 Preparation of Compound 24 of the Present Invention TIFF0007621289000073.tif31129

[0115] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-bromo-4-chlorobenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-bromo-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0116] 500mg (1.09mmol, 1.0eq) of 3-((4S)-8-bromo-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 179.56mg (1.52mmol, 1.4eq) of 2-hydroxyisobutyric acid methyl ester, 313.12mg (1.52mmol, 1.4eq) of DCC and 18.32mg (0.15mmol, 0.1eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 572mg of a pale yellow oil (compound 24).

[0117] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 24: δ 8.71 (d, J = 4.0 Hz, 1H), 7.92 (td, J = 7.8, 1.7 Hz, 1H), 7.78 -7.69 (m, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.37 - 7.32 (m, 1H), 7.30 (d, J = 8.7Hz, 1H), 6.86 (d, J = 0.9 Hz, 1H), 4.05 (dd, J = 8.1, 5.4 Hz, 1H), 3.58 (s,3H), 2.92 - 2.71 (m, 4H), 2.34 (s, 3H), 1.50 (d, J = 1.1 Hz, 6H).MS: m / z: 605.02 [M+H] + .

[0118] Example 25 Preparation of Compound 25 of the Present Invention JPEG0007621289000074.jpg40161

[0119] Referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-chloro-4-(trifluoromethyl)benzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0120] 500mg (1.11mmol, 1.0eq) of 3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 164mg (1.41mmol, 1.27eq) of 1-hydroxycyclopropane-1-carboxylic acid methyl ester, 290mg (1.41mmol, 1.27eq) of DCC and 14mg (0.11mmol, 0.1eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 540mg of a pale yellow oil (compound 25).

[0121] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 25: δ 8.57 (dd, J = 4.8, 0.8 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.81(td, J = 7.8, 1.6 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz,1H), 7.36 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H), 4.15 -4.08 (m, 1H), 3.59 (s, 3H), 2.91 - 2.72 (m, 4H), 2.32 (s, 3H), 1.49 (dd, J =8.4, 5.2 Hz, 2H), 1.17 (dd, J = 8.4, 5.2 Hz, 2H). MS:m / z:533.11[M+H] + .

[0122] Example 26 Preparation of Compound 26 of the Present Invention JPEG0007621289000075.jpg39161

[0123] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-fluoro-4-methylbenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-fluoro-1,9-dimethyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0124] 500mg (1.32mmol, 1.0eq) of 3-((4S)-8-fluoro-1,9-dimethyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 180mg (1.41mmol, 1.07eq) of 1-hydroxycyclopropane-1-carboxylic acid ethyl ester, 290mg (1.41mmol, 1.07eq) of DCC and 20mg (0.16mmol, 0.12eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 563mg of a pale yellow oil (compound 26).

[0125] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 26: δ 8.52 (dd, J = 4.8, 0.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.76 (td, J = 8.0, 2.0 Hz, 1H), 7.71 - 7.67 (m, 1H), 7.62 (d, J= 2.0 Hz, 1H), 7.31 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.26 (d, J =8.8 Hz, 1H), 4.14 - 4.02 (m, 3H), 2.88 - 2.72 (m, 4H), 2.32 (d, J = 0.8Hz, 3H), 2.31(s,3H), 1.46 (dd, J = 8.4, 5.2 Hz, 2H), 1.22 - 1.13 (m,5H). MS:m / z:491.21[M+H] + .

[0126] Example 27 Preparation of Compound 27 of the Present Invention JPEG0007621289000076.jpg38161

[0127] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-fluoro-4-methoxybenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-fluoro-9-methoxy-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0128] 500mg (1.27mmol, 1.0eq) of 3-((4S)-8-fluoro-9-methoxy-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 127mg (1.41mmol, 1.11eq) of 2-hydroxyacetic acid methyl ester, 290mg (1.41mmol, 1.11eq) of DCC and 20mg (0.16mmol, 0.12eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 514mg of a pale yellow oil (compound 27).

[0129] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 27: δ 8.57 (d, J = 4.8 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 - 7.96 (m, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.67(s, 1H), 7.56 (dd, J = 7.2, 5.2 Hz, 1H), 4.71 - 4.59 (m, 2H), 4.57 (dd, J =10.4, 4.4 Hz, 1H), 3.85 (s, 3H),3.64 (s, 3H), 2.96 - 2.61 (m, 4H), 2.47 (s,3H). MS: m / z: 467.18 [M+H] + .

[0130] Example 28 Preparation of Compound 28 of the Present Invention JPEG0007621289000077.jpg38161

[0131] Referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-chloro-4-(trifluoromethoxy)benzoic acid was used as the raw material to obtain the intermediate 3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethoxy)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0132] 500mg (1.08mmol, 1.0eq) of 3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethoxy)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 147mg (1.41mmol, 1.30eq) of 2-hydroxyethyl acetate, 290mg (1.41mmol, 1.30eq) of DCC and 20mg (0.16mmol, 0.15eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 509mg of a pale yellow oil (compound 28).

[0133] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 28: δ 8.61 - 8.54 (m, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.82 (td, J = 8.0, 1.6 Hz, 1H), 7.73 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.33 (ddd, J = 7.6,4.8, 1.2 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 4.55 (s, 2H), 4.16 (dt, J= 9.2, 4.8 Hz, 3H), 2.95 - 2.76 (m, 4H), 2.35 (d, J = 0.8 Hz, 3H), 1.24(t, J = 7.2 Hz, 3H).MS:m / z:551.13[M+H] + .

[0134] Example 29: Preparation of Compound 29 of the Present Invention JPEG0007621289000078.jpg42161

[0135] By referring to the synthesis procedures of Examples 1 to 7, 6-amino-2,3,4-trichlorobenzoic acid was used as a raw material to obtain the intermediate 3-((4S)-7,8,9-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0136] 500mg (1.11mmol, 1.0eq) of 3-((4S)-7,8,9-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 147mg (1.41mmol, 1.27eq) of 2-hydroxypropionic acid methyl ester, 290mg (1.41mmol, 1.27eq) of DCC and 20mg (0.16mmol, 0.14eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 519mg of a pale yellow oil (compound 29).

[0137] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 29: δ 8.73 (dd, J = 4.8,0.8 Hz, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.73 (dt, J= 8.8, 2.0 Hz, 1H), 7.71 (dd, J = 6.0, 2.4 Hz, 1H), 5.64 (q, 1H), 4.13(td, J = 5.6, 3.2 Hz, 1H), 3.67 (s, 3H), 2.91 - 2.76 (m, 4H), 2.36 (s,3H), 1.45 (d, J = 7.2 Hz, 3H).MS: m / z: 535.07 [M+H] + .

[0138] Example 30 Preparation of Compound 30 of the Present Invention JPEG0007621289000079.jpg42161

[0139] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-3,4,5-trichlorobenzoic acid was used as a raw material to obtain the intermediate 3-((4S)-7,8,9-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0140] 500mg (1.03mmol, 1.0eq) of 3-((4S)-7,8,9-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 166mg (1.41mmol, 1.37eq) of 2-hydroxy-2-methylpropionic acid methyl ester, 290mg (1.41mmol, 1.37eq) of DCC and 20mg (0.16mmol, 0.16eq) of DMAP were added, and the mixture was reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material was almost completely reacted. After filtering the reaction solution, it was concentrated under reduced pressure and column chromatography was performed to obtain 534mg of a pale yellow oil (compound 30).

[0141] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 30: δ 8.76 (dd, J = 4.8,0.8 Hz, 1H), 7.97(t, J = 8.0 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.72 (dt, J= 8.8, 2.0 Hz, 1H), 7.68 (dd, J = 6.0, 2.4 Hz, 1H), 5.63 (q, 1H), 3.68(s, 3H), 2.93 - 2.78 (m, 4H), 2.35 (s, 3H), 1.47 (d, J = 7.2 Hz, 6H). MS:m / z:549.09[M+H] + .

[0142] Example 31 Preparation of Compound 31 of the Present Invention JPEG0007621289000080.jpg47161

[0143] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-3,4,5,6-tetrachlorobenzoic acid was used as a raw material to obtain the intermediate 3-((4S)-7,8,9,10-tetrachloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0144] 1.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 450mg of 2,4-dimethylpentan-3-ol was added, and 1.1g of pyridine was added dropwise while cooling with ice water, and the mixture was stirred for 5 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 860mg of crude product of chloromethyl (2,4-dimethylpentan-3-yl) carbonate, which was used as it is in the next reaction.

[0145] 500 mg (1.03 mmol, 1.0 eq) of intermediate 3-((4S)-7,8,9,10-tetrachloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 357 mg (1.71 mmol, 1.66 eq) of chloromethyl(2,4-dimethylpentan-3-yl)carbonate was added, 325 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. The mixture was dropped onto a plate, and the raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 400 mg of a pale yellow oil (compound 31) was obtained by column chromatography.

[0146] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 31: δ 8.76 (dd, J = 4.8,0.8 Hz, 1H), 7.97(t, J = 8.0 Hz, 1H), 7.83 - 7.74 (m, 2H), 7.72 (dt, J= 8.8, 2.0 Hz, 1H), 5.63 (q, 1H), 3.68 (s, 3H), 2.93 - 2.78 (m, 4H), 2.35 (s,3H), 1.47 (d, J = 7.2 Hz, 6H). MS:m / z:657.10[M+H]+.

[0147] Example 32 Preparation of Compound 32 of the Present Invention JPEG0007621289000081.jpg47161

[0148] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-chloro-4-(trifluoromethyl)benzoic acid and 3-bromopyridine were used as raw materials to obtain the intermediate 3-((4S)-8-chloro-1-methyl-6-(pyridin-3-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0149] 1.0g of chloroformic acid chloromethyl ester was added to 30mL of anhydrous dichloromethane, 448mg of prop-2-ol was added, and 1.1g of pyridine was added dropwise while cooling with ice water, and the mixture was stirred for 5 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 900mg of crude product of chloromethyl isopropyl carbonate, which was used as it is in the next reaction.

[0150] 500mg (1.11mmol, 1.0eq) of intermediate 3-((4S)-8-chloro-1-methyl-6-(pyridin-3-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 357mg (2.34mmol, 2.11eq) of chloromethyl isopropyl carbonate was added, 325mg of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. The mixture was dropped onto a plate, and the raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 400mg of a pale yellow oil (compound 32) was obtained by column chromatography.

[0151] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 32: δ 8.57 (d, J = 4.8 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.06 - 7.97 (m, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.67 (d, J= 2.0 Hz, 1H), 7.56 (dd, J = 7.2, 5.2 Hz, 1H), 5.76 (q, J = 6.0 Hz, 2H), 4.82(dt, J = 12.4, 6.4 Hz, 1H), 4.46 (dd, J = 10.0, 4.0 Hz, 1H), 2.95 - 2.57 (m,4H), 2.48 (s, 3H), 1.24 (dd, J = 10.4, 6.4 Hz, 6H). MS:m / z:565.15[M+H] + .

[0152] Example 33 Preparation of Compound 33 of the Present Invention JPEG0007621289000082.jpg45160

[0153] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-4-bromo-5-chlorobenzoic acid and 4-bromopyridine were used as raw materials to obtain the intermediate 3-((4S)-9-bromo-8-chloro-1-methyl-6-(pyridin-4-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0154] 1.0g of 1-chloroethyl chloroformate was added to 30mL of anhydrous dichloromethane, 448mg of 2-methylpropan-2-ol was added, 1.1g of pyridine was added dropwise under ice-water cooling, and the mixture was stirred for 5 hours. 50mL of dichloromethane was added, and the organic layer was washed twice with 2N hydrochloric acid, and then once. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain 878mg of crude tert-butyl (chloromethyl) carbonate, which was used as it was in the next reaction.

[0155] 500 mg (1.11 mmol, 1.0 eq) of intermediate 3-((4S)-9-bromo-8-chloro-1-methyl-6-(pyridin-4-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 390 mg (2.34 mmol, 2.11 eq) of tert-butyl(chloromethyl)carbonate was added, 325 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. The mixture was dropped onto a plate, and the raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 396 mg of a pale yellow oil (compound 33) was obtained by column chromatography.

[0156] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 33: δ 8.58 (ddd, J = 4.8,1.6, 0.8 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.81 (td, J = 8.0,1.8 Hz, 1H), 7.70 (dd, J = 8.8, 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz,1H), 7.32 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.28 (d, J = 8.8 Hz,1H), 5.73 (q, J = 5.6 Hz, 2H), 4.05 (t, J = 6.8 Hz, 1H), 2.93 -2.76 (m, 4H), 2.35 (d, J = 0.8 Hz, 3H), 1.45 (s, 9H). MS:m / z:589.09[M+H] + .

[0157] Example 34 Preparation of Compound 34 of the Present Invention TIFF0007621289000083.tif37143

[0158] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-bromobenzoic acid was used as a raw material to obtain the intermediate 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0159] Referring to the synthesis procedure of Example 8, 1.5g of chloroformic acid chloromethyl ester is added to 30mL of anhydrous dichloromethane, 427mg of methanol is added, and 1.72g of pyridine is added dropwise while cooling with cold water, and stirred for 2 hours. 50ml of dichloromethane is added, and the organic layer is washed twice with 2N hydrochloric acid, and then washed once with water. The organic layer is separated, dried with anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness to obtain 1.2g of crude carbonic acid chloromethyl methyl ester, which is used directly in the next reaction.

[0160] 500 mg (1.18 mmol, 1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 292.8 mg (2.35 mmol, 2.0 eq) of the crude product of carbonic acid chloromethyl methyl ester was added, 325 mg (2.36 mmol, 2.0 eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 547 mg of a pale yellow oil (compound 34) was obtained by column chromatography.

[0161] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 34: δ 8.56 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.05 - 7.99 (m, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.69(s, 1H), 7.58 (dd, J = 7.2, 5.2 Hz, 1H), 7.46 (s, 1H), 5.76 (s, 2H), 4.46 (dd,J = 10.0, 4.0 Hz, 1H), 3.74 (s, 3H), 2.93 - 2.59 (m, 4H), 2.51 (d, J = 11.2 Hz,3H). MS: m / z: 513.08 [M+H] + .

[0162] Example 35 Preparation of Compound 35 of the Present Invention TIFF0007621289000084.tif36137

[0163] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-bromobenzoic acid was used as a raw material to obtain the intermediate 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0164] Referring to the synthesis procedure of Example 9, 1.29g of chloroformic acid chloromethyl ester is added to 30mL of anhydrous dichloromethane, 860mg of ethanol is added, and 1.9g of pyridine is added dropwise while cooling with cold water, and stirred for 2 hours. 50ml of dichloromethane is added, and the organic layer is washed twice with 2N hydrochloric acid, and then washed once with water. The organic layer is separated, dried with anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness to obtain 1.4g of carbonic acid chloromethyl ethyl ester crude product, which is used directly in the next reaction.

[0165] 500 mg (1.18 mmol, 1.0 eq) of 3-((4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10 mL of DMF, 326.95 mg (2.36 mmol, 2 eq) of the crude product of carbonic acid chloromethyl ethyl ester was added, 324 mg (2.36 mmol, 2.36 eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50 mL of water, extracted with 100 mL of dichloromethane, the organic layer was separated, dried with anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 597 mg of a pale yellow oil (compound 35) was obtained by column chromatography.

[0166] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 35: δ 8.57 (t, J = 7.2 Hz, 1H), 8.18 - 8.13 (m, 1H), 8.07 -7.97 (m, 2H), 7.80 (d, J = 8.8Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 7.2, 5.2 Hz, 1H), 7.45 (s,1H), 5.75 (s, 2H), 4.46 (dd, J = 10.0, 4.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H),2.95 - 2.58 (m, 4H), 2.48 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). MS:m / z:527.09[M+H] + .

[0167] Example 36 Preparation of Compound 36 of the Present Invention TIFF0007621289000085.tif43162

[0168] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-4-chlorobenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0169] Referring to the synthesis procedure of Example 9, 1.29g of chloroformic acid chloromethyl ester is added to 30mL of anhydrous dichloromethane, 860mg of ethanol is added, and 1.9g of pyridine is added dropwise while cooling with cold water, and stirred for 2 hours. 50ml of dichloromethane is added, and the organic layer is washed twice with 2N hydrochloric acid, and then washed once with water. The organic layer is separated, dried with anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness to obtain 1.4g of carbonic acid chloromethyl ethyl ester crude product, which is used directly in the next reaction.

[0170] 500mg (1.32mmol, 1.0eq) of 3-((4S)-9-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DMF, 326.95mg (2.36mmol, 2eq) of the crude product of carbonic acid chloromethyl ethyl ester was added, 324mg (2.36mmol, 2.36eq) of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours, then dropped onto a plate. The raw material reacted almost completely. After filtering the reaction solution, it was poured into 50mL of water, extracted with 100mL of dichloromethane, the organic layer was separated, dried over anhydrous sodium sulfate, filtered to obtain the filtrate, concentrated under reduced pressure, and 567mg of a pale yellow oil (compound 36) was obtained by column chromatography.

[0171] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 36: δ 8.67 (t, J = 7.2 Hz, 1H), 8.28 - 8.19 (m, 1H), 8.07 -7.97 (m, 2H), 7.80 (d, J = 8.8Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 7.2, 5.2 Hz, 1H), 7.45 (s,1H), 5.75 (s, 2H), 4.46 (dd, J = 10.0, 4.0 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H),2.95 - 2.58 (m, 4H), 2.48 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). MS:m / z:483.14[M+H] + .

[0172] Example 37 Preparation of Compound 37 of the Present Invention TIFF0007621289000086.tif32132

[0173] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-3-chlorobenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-10-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0174] 500mg (1.32mmol, 1.0eq) of 3-((4S)-10-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 191.58mg (1.84mmol, 1.4eq) of glycolic acid ethyl ester, 379mg (1.84mmol, 1.4eq) of DCC and 14mg (0.13mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 534mg of a pale yellow oil (compound 37) was obtained by column chromatography.

[0175] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 37: δ 8.59- 8.53 (m, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.80 (td, J = 8.0, 1.6 Hz, 1H), 7.71(dd, J = 8.8, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.34 (ddd, J = 7.6, 4.8,1.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 1.2 Hz, 1H), 4.58 (s, 2H),4.14 (dt, J = 9.2, 4.8 Hz, 3H), 2.98 - 2.73 (m, 4H), 2.34 (d, J = 0.8 Hz, 3H),1.23 (t, J = 7.2 Hz, 3H). MS:m / z:467.15[M+H] + .

[0176] Example 38 Preparation of Compound 38 of the Present Invention TIFF0007621289000087.tif35144

[0177] By referring to the synthesis procedures of Examples 1 to 7, 2-amino-5-chlorobenzoic acid was used as the raw material to obtain the intermediate 3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid.

[0178] 500mg (1.32mmol, 1.0eq) of 3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionic acid was dissolved in 10mL of DCM, 191.58mg (1.84mmol, 1.4eq) of glycolic acid ethyl ester, 379mg (1.84mmol, 1.4eq) of DCC and 14mg (0.13mmol, 0.1eq) of DMAP were added and reacted at room temperature overnight. The mixture was dropped onto a plate, and the raw material reacted almost completely. The reaction solution was filtered, concentrated under reduced pressure, and 542mg of a pale yellow oil (compound 38) was obtained by column chromatography.

[0179] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 38: δ 8.63- 8.54 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.79 (td, J = 8.0, 1.6 Hz, 1H), 7.68(dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.27 (ddd, J = 7.6, 4.8,1.2 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 4.68 (s, 2H),4.24 (dt, J = 9.2, 4.8 Hz, 3H), 2.98 - 2.73 (m, 4H), 2.34 (d, J = 0.8 Hz, 3H),1.23 (t, J = 7.2 Hz, 3H). MS:m / z:467.15[M+H] + .

[0180] Example 39: Preparation of Compound 39 of the Present Invention JPEG0007621289000088.jpg42161

[0181] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-4-chloro-4-(trifluoromethyl)benzoic acid was used as a raw material to obtain 1-((3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0182] 200 mg (0.36 mmol, 1.0 eq) of 1-((3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 5 mL of ethyl acetate, and 5 mL of ethanol solution of 100 mg (0.53 mmol, 1.47 eq) of p-toluenesulfonic acid monohydrate was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The resulting product was crystallized using ethyl acetate to obtain 201 mg of the corresponding p-toluenesulfonic acid salt (compound 39), which is a white powdery solid.

[0183] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 39: δ 8.60 - 8.52 (m, 1H), 8.19(d, J = 8.0 Hz, 1H), 7.80 (td, J = 8.0, 1.6 Hz, 1H), 7.78-7.47(m, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz,1H), 7.38 - 7.28 (m, 1H), 4.10 (dd, J = 8.0, 5.6 Hz, 1H), 3.60 (s, 3H),2.93 - 2.77 (m, 4H), 2.46(dd, 3H), 2.35(s, 3H), 1.50 (q, J = 5.6 Hz,2H), 1.17 (q, J = 5.6 Hz, 2H).MS:m / z:719.16(M+1).

[0184] Example 40 Preparation of Compound 40 of the Present Invention JPEG0007621289000089.jpg42160

[0185] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-5-chloro-4-(trifluoromethyl)benzoic acid was used as a raw material to obtain 1-((3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0186] 200mg (0.36mmol, 1.0eq) of 1-((3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 10mL of ethyl acetate, and an equivalent concentration of 0.1mol / L hydrochloric acid-methanol solution was added dropwise under ice bath, stirred for 1 hour, and concentrated under reduced pressure until dry. Drying under vacuum gave 173mg of a pale yellow solid (compound 40).

[0187] H nuclear magnetic resonance spectrum (deuterated chloroform) of the compound 40: δ 8.62- 8.53 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.83 (td, J = 8.0, 1.6 Hz, 1H), 7.66(dd, J = 8.8, 2.4 Hz, 1H), 7.64 (d, J =2.4 Hz, 1H), 7.36 - 7.24 (m, 1H), 6.82 (d, J = 1.2 Hz, 1H), 4.13 (dd, J= 8.0, 5.6 Hz, 1H), 3.65 (s, 3H), 2.91 - 2.76 (m, 4H), 2.34 (s, 3H), 1.49 (q, J= 5.6 Hz, 2H), 1.16 (q, J = 5.6 Hz, 2H). MS:m / z:583.11(M+1).

[0188] Example 41 Preparation of Compound 41 of the Present Invention JPEG0007621289000090.jpg41161

[0189] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-3-chloro-4-(trifluoromethyl)benzoic acid was used as a raw material to obtain 1-((3-((4S)-10-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0190] 200mg (0.36mmol, 1.0eq) of 1-((3-((4S)-10-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 10mL of ethyl acetate, and an equivalent concentration of 0.1mol / L sulfuric acid-methanol solution was added dropwise under ice bath, and the mixture was concentrated under reduced pressure until dry. The mixture was dried under vacuum to obtain 195mg of a pale yellow solid (compound 41).

[0191] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 41: δ 8.63 (d, J = 4.8 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.05 - 7.94 (m,1H), 7.78 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.51 (dd, J = 7.2,5.2 Hz, 1H), 7.41 (s, 1H), 5.72 (s, 2H), 4.43 (dd, J = 10.0, 4.0 Hz,1H), 3.71 (s, 3H), 3.36(s,3H)2.87- 2.59 (m, 4H), 2.51 (d, J = 11.2 Hz, 3H). MS: m / z: 645.11(M+1).

[0192] Example 42 Preparation of Compound 42 of the Present Invention JPEG0007621289000091.jpg43161

[0193] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-5-chloro-4-(trifluoromethoxy)benzoic acid was used as a raw material to obtain 1-((3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethyl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0194] 200mg (0.36mmol, 1.0eq) of 1-((3-((4S)-8-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethoxy)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1 carboxylic acid ester was dissolved in 5mL of ethyl acetate, and an equal amount of glacial acetic acid was added dropwise under ice bath, concentrated under reduced pressure, and dried in vacuum to obtain 193mg of a pale yellow solid (compound 42).

[0195] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 442: δ 8.65 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.04 - 7.97 (m,1H), 7.84 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 8.0 Hz,1H), 7.57 (dd, J = 7.2, 5.2 Hz, 1H), 5.78 (s, 2H), 4.47 (dd, J =10.0, 4.0 Hz, 1H), 3.75 (s, 3H), 2.92 - 2.62 (m, 4H), 2.53 (d, J = 11.2Hz, 3H), 2.35 (s, 3H). MS:m / z:623.15(M+1).

[0196] Example 43 Preparation of Compound 43 of the Present Invention JPEG0007621289000092.jpg41161

[0197] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-6-chloro-4-(trifluoromethoxy)benzoic acid was used as a raw material to obtain 1-((3-((4S)-10-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethoxy)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0198] 200 mg (0.36 mmol, 1.0 eq) of 1-((3-((4S)-7-chloro-1-methyl-6-(pyridin-2-yl)-9-(trifluoromethoxy)-4H-benzo[f]imidazo[1,2-a][1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 5 mL of ethyl acetate, and carbon dioxide gas was introduced for 10 minutes (flow rate: 2 mL / min), concentrated under reduced pressure, and dried in vacuum to obtain 197 mg of a pale yellow solid (compound 43).

[0199] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 43: δ 8.67(d, J = 4.8 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.13(s, 1H), 8.03- 7.96 (m, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J =8.0 Hz, 1H), 5.75 (s, 2H), 4.46 (dd, J = 10.0, 4.0 Hz, 1H), 3.73 (s,3H), 2.91 - 2.63 (m, 4H), 2.54 (d, J = 11.2 Hz, 3H), 2.37 (s, 3H) . MS: m / z: 625.13 (M+1).

[0200] Example 44 Preparation of Compound 44 of the Present Invention JPEG0007621289000093.jpg41161

[0201] With reference to the synthesis procedures of Examples 1 to 7 and 25, 1-((3-((4S)-10-bromo-8-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was obtained using 2-amino-5-bromo-3-chlorobenzoic acid as a raw material.

[0202] 200 mg (0.36 mmol, 1.0 eq) of 1-((3-((4S)-10-bromo-8-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 5 mL of ethyl acetate, 1.0 eq of methanesulfonic acid was added, and the mixture was concentrated under reduced pressure to obtain 201 mg of a pale yellow solid (compound 44).

[0203] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 44: δ 8.67 (d, J = 4.8 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.01 - 7.92 (m,1H), 7.82 (d, J = 8.8 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J = 8.0 Hz,1H), 7.55 (dd, J = 7.2, 5.2 Hz, 1H), 5.75 (s, 2H), 4.46 (dd, J =10.0, 4.0 Hz, 1H), 3.72 (s, 3H), 3.32(s, 1H), 2.94 - 2.65 (m, 4H), 2.54 (d, J= 11.2 Hz, 3H), 2.36 (s, 3H). MS:m / z:653.05(M+1).

[0204] Example 45 Preparation of Compound 45 of the Present Invention JPEG0007621289000094.jpg41161

[0205] With reference to the synthesis procedures of Examples 1 to 7 and 25, 1-((3-((4S)-9-bromo-8-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was obtained using 2-amino-4-bromo-5-chlorobenzoic acid as a raw material.

[0206] 200 mg (0.36 mmol, 1.0 eq) of 1-((3-((4S)-9-bromo-8-chloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 5 mL of ethyl acetate, and an equivalent amount of 0.1 mol / L hydrobromic acid-methanol solution was added dropwise under ice bath, and concentrated under reduced pressure to obtain 193 mg of a pale yellow solid (compound 45).

[0207] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 45: δ 8.64- 8.56 (m, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.85 (td, J = 8.0, 1.6 Hz, 1H), 7.67(dd, J = 8.8,2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.38 - 7.25 (m, 1H), 6.81 (d, J= 1.2 Hz, 1H), 4.15 (dd, J = 8.0, 5.6 Hz, 1H), 3.64 (s, 3H), 2.89 - 2.74(m, 4H), 2.33 (s, 3H), 1.48 (q, J = 5.6 Hz, 2H), 1.15 (q, J = 5.6Hz, 2H). MS:m / z:638.99(M+1).

[0208] Example 46 Preparation of Compound 46 of the Present Invention JPEG0007621289000095.jpg47161

[0209] With reference to the synthesis procedures of Examples 1 to 7 and 25, 2-amino-3,4,5-trichlorobenzoic acid was used as a raw material to obtain intermediate 1-((3-((4S)-8,9,10-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester.

[0210] 200 mg (0.36 mmol, 1.0 eq) of 1-((3-((4S)-8,9,10-trichloro-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1]1,4]diazepin-4-yl)propionyl)oxy)cyclopropane-1-carboxylic acid ester was dissolved in 5 mL of ethyl acetate, 1.0 eq of D-tartaric acid was added, and the mixture was concentrated under reduced pressure to obtain 213 mg of a pale yellow solid (compound 46).

[0211] H nuclear magnetic resonance spectrum (deuterated methanol) of the compound 46: δ 8.63- 8.57 (m, 1H), 8.14 (d, J= 8.0 Hz, 1H), 7.87 (td, J = 8.0, 1.6 Hz, 1H), 7.65(dd, J = 8.8,2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.36 - 7.24 (m, 1H), 4.81(s, 6H),4.13 (dd, J = 8.0, 5.6 Hz, 1H), 3.65 (s, 3H), 2.87 - 2.72 (m, 4H), 2.31(s, 3H), 1.47 (q, J = 5.6 Hz, 2H), 1.12 (q, J = 5.6 Hz, 2H). MS:m / z:697.09(M+1).

[0212] According to the methods of the above examples, compounds 47 to 81 of Examples 47 to 81 were produced. The specific structures, names, raw materials and property data of compounds 47 to 81 are as shown in Table 1.

[0213] [Table 1] TIFF0007621289000097.tif224170TIFF0007621289000098.tif224170TIFF0007621289000099.tif228170TIFF000 7621289000100.tif225170TIFF0007621289000101.tif219170TIFF0007621289000102.tif225170TIFF00076212890 00103.tif225170TIFF0007621289000104.tif219170TIFF0007621289000105.tif225170TIFF0007621289000106.t if199170TIFF0007621289000107.tif225170TIFF0007621289000108.tif219170TIFF0007621289000109.tif183170

[0214] Compounds 8 to 84 of the present invention were evaluated for pharmacological activity, efficacy and safety.

[0215] In clinical use, it is necessary to strictly control the effect of anesthetic drugs so that the process of surgery, diagnosis, etc. can proceed smoothly, and the anesthesia can be terminated as soon as possible after the procedure is completed, and the patient can be quickly awakened. If the duration of anesthesia is too long, it may cause adverse effects on the cardiovascular system and respiratory system, such as drowsiness and dizziness. Therefore, an ideal anesthetic drug has the advantages of fast onset of action, fast recovery, and high safety.

[0216] Test Example 1 Experiment on induction of loss of righting reflex in mice by the compound of the present invention The compounds were injected into the tail vein of KM mice (male, 18-22 g) to obtain the ED 50 Measure the 2ED from the tail vein 50 After a single bolus dose, the duration of loss of righting reflex and recovery time of the mice were recorded. The compound remimazolam was used as a control, and the experimental results are shown in Table 2.

[0217] [Table 2] TIFF0007621289000111.tif233170TIFF0007621289000112.tif185170In Table 2, duration of anesthesia is the time from loss of righting reflex to recovery of righting reflex, and recovery time is the time from recovery of righting reflex to being able to move freely. Regarding quality of awakening, "+" indicates <1min, "++" indicates 1-3min, "+++" indicates 3-5min, "++++" indicates 5-10min, and "++++++" indicates >10min.

[0218] As can be seen from Table 2, the anesthetic effect of the compounds of the present invention is equivalent to or better than that of remimazolam, and the quality of awakening is better than that of remimazolam. Compounds 15, 16, 24, 27, 28, 31, 34, 42, 49, 53, 54, 55, 57, and 59 have effective doses significantly lower than that of remimazolam, and duration and recovery time are significantly shorter than that of remimazolam, and they have fast onset of anesthesia, rapid recovery, higher safety, and better anesthesia performance.

[0219] Test Example 2 Experiment on induction of loss of righting reflex in rats by the compound of the present invention The ED2000-1000 mg / kg compound was administered to the tail vein of male SD rats (220-300 g). 50 Measure the 2ED from the tail vein 50 After a single bolus dose, the duration of loss of righting reflex and recovery time of the rats were recorded. The compound remimazolam was used as a control, and the experimental results are shown in Table 3.

[0220] [Table 3] TIFF0007621289000114.tif251168TIFF0007621289000115.tif200168In Table 3, duration of anesthesia is the time from loss of righting reflex to recovery of righting reflex, and recovery time is the time from recovery of righting reflex to being able to move freely. Regarding quality of awakening, "+" indicates <1min, "++" indicates 1-3min, "+++" indicates 3-5min, "++++" indicates 5-10min, and "++++++" indicates >10min.

[0221] As can be seen from table 3, the anesthetic effect of the compounds of the present invention is equivalent to or better than that of remimazolam, and the quality of awakening is better than that of remimazolam. Compounds 15, 16, 24, 27, 28, 31, 34, 42, 46, 49, 53, 54, 55, 57, 59, and 71 have effective doses significantly lower than that of remimazolam, and duration and recovery time are significantly shorter than that of remimazolam, and they have fast onset of anesthesia, rapid recovery, higher safety, and better anesthesia performance.

[0222] As can be seen from the above test results, the compound of the present invention, as an ultra-short-acting anesthetic, has a good anesthetic cycle and is expected to play a very important role in the pharmaceutical industry.

[0223] As described above, the compound of the present invention has high intravenous sedative and anesthetizing effects, and its anesthetic effect is equivalent to or superior to that of remimazolam, specifically, the effective dose is significantly smaller, and the duration and recovery time are significantly shorter. In both rat and mouse tail vein anesthesia models, the compound of the present invention significantly improved the quality of awakening compared to remimazolam. The compound of the present invention has a fast onset of action during anesthesia, a short duration, a rapid awakening, and good tolerance, and can be used for anesthesia induction, anesthesia maintenance, and day surgery anesthesia, and is expected to have a future.

Claims

1. A compound of formula I, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; M is absent or is O, S, NH and C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, and C 1～6 substituted by 0 to 4 substituents selected from alkoxy groups; R 3 is hydrogen, short chain hydrocarbon groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and -NHC 1-4 substituted with 0-4 substituents selected from alkyl groups, and the heterocycle contains 1-3 heteroatoms selected from N, O, and S; a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 represents pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups, X is independently halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; A compound, or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer thereof, or a solvate thereof, characterized in that n is selected from 1, 2, 3, and 4.

2. A compound according to claim 1, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1～8 Alkyl groups, substituted or unsubstituted C 3-10 cycloalkyl groups and substituted or unsubstituted 3- to 10-membered heterocyclic groups, or R 1 and R 2 is a substituted or unsubstituted C 3～10 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 10-membered cycloalkyl group, and the number of the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4. The substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1～8 Alkyl groups and C 1～8 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3～10 A cycloalkyl group and a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 is selected from pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups; M is nothing, O, S, NH and substituted or unsubstituted C 1～5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～4 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; A compound, or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer thereof, or a solvate thereof, characterized in that n is selected from 1, 2, 3, and 4.

3. 2. The compound of claim 1, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, wherein the compound is a compound of formula II: Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; M is absent or is O, S, NH and C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, and C 1～6 substituted by 0 to 4 substituents selected from alkoxy groups; R 3 is hydrogen, short chain hydrocarbon groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and -NHC 1-4 substituted with 0-4 substituents selected from alkyl groups, and the heterocycle contains 1-3 heteroatoms selected from N, O, and S; a is selected from 0, 1, and 2; b is selected from 0 and 1; X is independently halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; n is selected from 1, 2, 3, and 4; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3～10 A cycloalkyl group and a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; M is nothing, O, S, NH and substituted or unsubstituted C 1～5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～4 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; A compound, or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer thereof, or a solvate thereof, characterized in that n is selected from 1, 2, 3, and 4.

4. A compound according to claim 3, or a pharma- ceutically acceptable salt of an inorganic or organic acid thereof, or a stereoisomer thereof, or a solvate thereof, R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1～3 Alkyl groups, substituted or unsubstituted C 3-5 cycloalkyl groups and substituted or unsubstituted 3- to 5-membered heterocyclic groups, or R 1 and R 2 is a substituted or unsubstituted C 3～6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4. The substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1～3 Alkyl groups, and C 1～3 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4～6 A cycloalkyl group and a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; M is nothing, O, S, NH and substituted or unsubstituted C 1～3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～2 alkoxy groups, X is independently halogen, substituted or unsubstituted C 1～6 Alkyl groups and substituted or unsubstituted C 1～6 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; A compound, or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer thereof, or a solvate thereof, characterized in that n is selected from 1, 2, 3, and 4.

5. 2. The compound of claim 1, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, wherein the compound is a compound of formula III: Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; M is absent or is O, S, NH and C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, and C 1～6 substituted by 0 to 4 substituents selected from alkoxy groups; R 3 is hydrogen, short chain hydrocarbon groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and -NHC 1-4 substituted with 0-4 substituents selected from alkyl groups, and the heterocycle contains 1-3 heteroatoms selected from N, O, and S; a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 represents pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups, X 1 , X 2 are halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3～10 A cycloalkyl group and a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 is selected from pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups; M is nothing, O, S, NH and substituted or unsubstituted C 1～5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～4 alkoxy groups, X 1 , X 2 are halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 or an alkoxy group, wherein the substituent of said alkyl or alkoxy group is selected from the group consisting of halogen, a phenyl group ...

6. 6. The compound of claim 5, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, wherein the compound is a compound of formula III-A: Where: R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1～3 Alkyl groups, substituted or unsubstituted C 3-5 cycloalkyl groups and substituted or unsubstituted 3- to 5-membered heterocyclic groups, or R 1 and R 2 is a substituted or unsubstituted C 3～6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4. The substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1～3 Alkyl groups, and C 1～3 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4～6 A cycloalkyl group and a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; M is nothing, O, S, NH and substituted or unsubstituted C 1～3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～2 alkoxy groups, X 1 , X 2 are halogen, substituted or unsubstituted C 1～6 Alkyl groups and substituted or unsubstituted C 1～6 or an alkoxy group, wherein the substituent of said alkyl or alkoxy group is selected from the group consisting of halogen, a phenyl group ...

7. 2. The compound of claim 1, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, wherein the compound is a compound of formula IV: Where: R 1 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; R 2 is hydrogen, short chain hydrocarbon group, C 3-10 a cycloalkyl group and a 3- to 10-membered heterocyclic group, the short chain hydrocarbon group, the cycloalkyl group or the heterocyclic group being substituted with 0-4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1-3 heteroatoms selected from N, O, and S; Or R 1 and R 2 is C 3-10 a cycloalkyl group or a 3- to 10-membered heterocyclic group, the cycloalkyl group or the heterocyclic group being substituted with 0 to 4 substituents selected from halogen, trifluoromethyl, cyano, nitro, short-chain alkyl, and alkoxy groups, and the heterocyclic ring containing 1 to 3 heteroatoms selected from N, O, and S; M is absent or is O, S, NH and C 1-5 alkylene groups, the alkylene groups being selected from halogen, trifluoromethyl groups, and C 1～6 substituted by 0 to 4 substituents selected from alkoxy groups; R 3 is hydrogen, short chain hydrocarbon groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is C 3-10 The hydrocarbon group, the cycloalkyl group, or the heterocyclic group may be a halogen atom, a trifluoromethyl group, an amino group, a C 1-4 Alkyl group, C 1-4 Alkoxy group, C 2-6 Alkenyl group, C 2-6 Alkynyl groups and -NHC 1-4 substituted with 0-4 substituents selected from alkyl groups, and the heterocycle contains 1-3 heteroatoms selected from N, O, and S; a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 represents pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups, X 1 is halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 an alkoxy group, the substituents of said alkyl or alkoxy group being halogen; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 3～10 A cycloalkyl group and a substituted or unsubstituted 3- to 10-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; R 4 is selected from pyridin-2-yl, pyridin-3-yl and pyridin-4-yl groups; M is nothing, O, S, NH and substituted or unsubstituted C 1～5 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～4 alkoxy groups, X 1 is halogen, substituted or unsubstituted C 1～8 Alkyl groups and substituted or unsubstituted C 1～8 or an alkoxy group, wherein the substituent of said alkyl or alkoxy group is selected from the group consisting of halogen, a phenyl group ...

8. 8. The compound of claim 7, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, wherein the compound is a compound of formula IV-A, Where: R 1 or R 2 each independently represents hydrogen, substituted or unsubstituted C 1～3 Alkyl groups, substituted or unsubstituted C 3-5 cycloalkyl groups and substituted or unsubstituted 3- to 5-membered heterocyclic groups, or R 1 and R 2 is a substituted or unsubstituted C 3～6 The substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is a 3- to 6-membered cycloalkyl group, and the number of the substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group is 1, 2, 3, or 4. The substituents of the substituted alkyl group, the substituted cycloalkyl group, or the substituted heterocyclic group are halogen, trifluoromethyl group, cyano group, nitro group, C 1～3 Alkyl groups and C 1～3 alkoxy groups, the heteroatoms of said heterocyclic groups being selected from N, O, and S, the number of said heteroatoms being 1, 2 or 3; R 3 is hydrogen, C 1～8 Alkyl groups, and -(CH 2 ) a -(O) b -R 5 where R 5 is a substituted or unsubstituted C 4～6 A cycloalkyl group and a substituted or unsubstituted 4- to 6-membered heterocyclic group, the number of substituents of the substituted cycloalkyl group or the substituted heterocyclic group being 1, 2, 3 or 4, and the substituents of the substituted cycloalkyl group or the substituted heterocyclic group being selected from halogen, trifluoromethyl group, amino group, C 1～4 Alkyl group, C 1～4 Alkoxy group, C 2～6 Alkenyl group, C 2～6 Alkynyl groups, and -NHR 6 the heteroatoms of the heterocyclic group are selected from N, O, and S, the number of the heteroatoms is 1, 2, or 3, and R 6 is C 1～4 alkyl groups, a is selected from 0, 1, and 2; b is selected from 0 and 1; M is nothing, O, S, NH and substituted or unsubstituted C 1～3 The number of substituents of the substituted alkylene group is 1, 2, 3 or 4, and the substituents of the substituted alkylene group are selected from halogen, trifluoromethyl and C 1～2 alkoxy groups, X 1 is halogen, substituted or unsubstituted C 1～6 Alkyl groups and substituted or unsubstituted C 1～6 a phenyl group, ...

9. 9. A compound according to any one of claims 1 to 8, or a pharma- ceutically acceptable salt of an inorganic or organic acid thereof, or a stereoisomer thereof, or a solvate thereof, wherein the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, carbonic acid, hydrobromic acid, and boric acid, and the organic acid is selected from formic acid, acetic acid, oxalic acid, adipic acid, L-aspartic acid, fumaric acid, benzoic acid, (2S,3S,4S,5R)-2,3,4,5-tetrahydroxy-6-oxocaproic acid, 2-hydroxyethane-1-sulfonic acid, 2-hydroxyethane-1-sulfonic acid, 2-hydroxybutanol-1-one ... or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer or solvate thereof, characterized in that the compound is selected from the group consisting of hydroxypropane-1,2,3-tricarboxylic acid, 2-hydroxypropionic acid, sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-hydroxysuccinic acid, stearic acid, (S)-5-oxopyrrolidine-2-carboxylic acid, 2-hydroxy-1-naphthoic acid, nicotinic acid, 1-naphthoic acid, malonic acid, tartaric acid and maleic acid.

10. 9. The compound according to claim 1 , or a stereoisomer thereof, or a solvate thereof, characterized in that the compound is one of the following compounds:

11. A method for preparing a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable inorganic or organic acid salt thereof, or a stereoisomer thereof, or a solvate thereof, comprising the steps of: Using polysubstituted o-aminobenzoylpyridine 1 and Boc-L-glutamic acid-5 ester 2 as starting materials, 2-(Boc-L-glutamic acid-5 ester acyl)amino polysubstituted benzoylpyridine 3 was produced under DCC and DCM conditions, and the Boc protecting group was removed under the action of acid and methanol to obtain 2-(Boc-L-glutamic acid-5-ester acyl)amino polysubstituted benzoylpyridine salt 4, which was then subjected to intramolecular condensation reaction under the conditions of sodium bicarbonate and acetonitrile to obtain polysubstituted benzodiazepine propionate 5, which was then reacted with diamine to obtain diamine. The method includes the steps of reacting fluorophosphine chloride 6, (R)-1-amino-2-propanol 7, LDA, and THF to obtain (R)-N-(multi-substituted benzodiazepine propionate)amino-2-propanol 8, which is then subjected to oxidative ring-closure under Dess-Martin reagent and acetone conditions to obtain pyridyl imidazobenzodiazepine propionate 9, which is hydrolyzed with sodium hydroxide to obtain the desired intermediate pyridyl imidazobenzodiazepine propionate II, which is then reacted with compound 10 or 11 to obtain the desired compound; Here, R 1 , R 2 , R 3 , R 4 , M, X, and n are as defined in claim 1; the equivalent ratio of the reaction of compound 1 with DCC is 1:0.8-2.5, the equivalent ratio of the reaction of compound 2 with DCC is 1:0.8-2.5, the equivalent ratio of the reaction of compound 3 with acid is 1:0.9-2, the equivalent ratio of the reaction of compound 4 with sodium bicarbonate is 1:15-20, the equivalent ratio of the reaction of compound 5 with 7 is 1:1.0-2.5, the equivalent ratio of the reaction of compound 8 with Dess-Martin reagent is 1:2-3, and the reaction temperature is between 35-60°C; the equivalent ratio of the reaction of the target intermediate II with 10 or 11 is 1:1.0-2.2, and the reaction temperature is 30-50°C.

12. Use of a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt of an inorganic or organic acid, or a stereoisomer thereof, or a solvate thereof, in the manufacture of a sedative and / or anesthetic agent, comprising The use, wherein the sedative and / or anesthetic agent is a sedative and / or anesthetic agent administered as intravenous sedation and / or anesthesia.

13. A drug, comprising a compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt of an inorganic acid or salt of an organic acid, or a stereoisomer or a solvate thereof as an active ingredient, and prepared by adding a pharma- ceutically acceptable auxiliary material or auxiliary ingredient; the drug is a sedative and / or anaesthetic; The drug, characterized in that the sedative and / or anesthetic agent is a sedative and / or anesthetic agent administered as intravenous sedation and / or anesthesia.

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