Five-membered nitrogen heterocyclic derivative, preparation method thereof and application of five-membered nitrogen heterocyclic derivative in medicine

Abstract

The invention relates to a five-membered nitrogen heterocyclic derivative and a preparation method and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a racemate and pharmaceutically acceptable salt of the compound, an intermediate of the compound, a preparation method of the compound, and application of the compound in preparation of a medicine with a sedative or analgesic effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a compound of general formula (I) or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, intermediates, and preparation methods thereof, as well as its application in the preparation of medicaments for treating diseases related to α2 receptor agonists. Background Technology

[0002] Adrenergic receptors are G-protein-coupled receptors, divided into adrenergic α receptors and β receptors. α receptors include α1 and α2 receptors, while β receptors include β1, β2, and β3 receptors. α2 receptors are widely distributed in the central and peripheral nervous systems and other organs and tissues (blood vessels, liver, kidneys, pancreas, platelets, etc.). α2A, α2B, and α2C are three subtypes of α2 receptors. In the brain, α2A is mainly concentrated in the pons and medulla oblongata, participating in the transmission of sympathetic nerve signals from the central nervous system to the periphery. Stimulation of presynaptic α2A can regulate adrenaline release through a negative feedback mechanism; stimulation of postsynaptic α2A can cause hyperpolarization of the nerve cell membrane.

[0003] Dexmedetomidine is a highly selective α2 receptor agonist that produces sedation, analgesia, antisympathetic effects, diuresis, and anti-chilling effects. It can produce a sedative-hypnotic effect similar to natural sleep, is easy to awaken, and has no respiratory depression. Dexmedetomidine can be used before, during, and after anesthesia. Common adverse reactions include hypotension and bradycardia, and its onset and recovery are relatively slow.

[0004] To achieve better therapeutic effects and better meet market demands, we hope to develop a new generation of highly effective α2 receptor agonists that can shorten the onset time of sedation and / or the recovery time. Summary of the Invention

[0005] The purpose of this invention is to provide a novel α2 receptor agonist and to find that compounds with such a structure have good activity and exhibit the advantage of shorter wake-up time.

[0006] This invention provides a compound of general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts.

[0007]

[0008] In some implementation schemes, When selected from single bonds, Y1 is selected from N, and Y2 is selected from CH2; When selected from double bonds, Y1 is selected from CH or CD, and Y2 is selected from N;

[0009] In some embodiments, general formula (I) is selected from the compounds described in (Ia), (Ib), and (Ic), or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts.

[0010]

[0011] In some implementation schemes, A is selected from

[0012] In some implementation schemes, B is selected from C. 3-10 Cycloalkyl or 4-10-membered heterocycloalkyl, wherein the B is optionally surrounded by 1 to 6 R. b Instead, B is connected to A and C at both ends by carbon atoms, and A and C cannot be connected to the same atom of B at the same time;

[0013] In some embodiments, B is selected from 4-7-membered heteromonocycloalkyl, 4-10-membered heterocycloalkyl, 5-10-membered heterospirocycloalkyl, 5-10-membered heterobridged cycloalkyl, and C. 3-7 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, wherein the B is optionally surrounded by 1 to 5 R groups. b Instead, B is connected to A and C at both ends by carbon atoms, and A and C cannot be connected to the same atom of B at the same time;

[0014] In some implementations, B is selected from 1 to 4 Rs. b The group that is replaced is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, with carbon atoms at both ends connected to A and C respectively, and A and C cannot be connected to the same atom of B at the same time.

[0015] In some implementations, B is selected from 1 to 4 Rs. b One of the following groups is replaced: In some implementations, S1 and S2 are each independently selected from 0, 1, and 2, and S1 and S2 are not both 0 at the same time; S3 and S4 are each independently selected from 0, 1, and 2, and S3 and S4 are not both 0 at the same time; Z is selected from O, S, and NH; in some implementations, B is selected from any of 1 to 4 R. b One of the following groups is replaced: In some implementation schemes, S1 is selected from 1 and 2;

[0016] In some implementations, B is selected from 1 to 4 Rs. b One of the following groups is replaced:

[0017] In some implementations, C is selected from

[0018] In some implementation schemes, X1 and X2 are each independently selected from O, S, and NH;

[0019] In some implementations, Z1 is selected from CR z1 R z2 O, S, NR z1 In some implementation schemes, Z1 is selected from CH2, O, S, and NH;

[0020] In some implementations, C is selected from In some implementation schemes, t is selected from 1 and 2;

[0021] In some implementations, C is selected from

[0022] In some implementation schemes, R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0023] In some implementation schemes, R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0024] In some implementation schemes, R b Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups are optionally surrounded by 1 to 4 R groups. k Replaced;

[0025] In some implementation schemes, R b Each is independently selected from deuterium, F, Cl, Br, methyl, methoxy, CF3, CH2F, CHF2, CD3, and OCD3;

[0026] In some implementation schemes, R c Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 6 R groups. kReplaced;

[0027] In some implementation schemes, R c Selected from C 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 5 R groups. k Replaced;

[0028] In some implementation schemes, R c Selected from 1 to 4 Rs k The following groups are substituted: methyl, ethyl, propyl, isopropyl;

[0029] In some implementation schemes, R c Each is independently selected from methyl, ethyl, propyl, isopropyl, CF3, CH2F, CHF2, and CD3;

[0030] In some implementation schemes, R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0031] In some implementation schemes, R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0032] In some implementation schemes, R 1 R 2 R x1 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, or cyclopropyl groups are optionally prefixed with 1 to 4 R groups. k Replaced;

[0033] In some implementation schemes, R 1 R 2 Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, SH, NO2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl groups are optionally substituted by 1 to 4 substituents of deuterium, F, Cl, and Br;

[0034] In some implementation schemes, R 1 R 2 Each is independently selected from F, Cl, Br, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, CF3, CH2F, CHF2, CD3;

[0035] In some implementation schemes, R x1 R z1 R z2 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3, CH2F, CHF2, and CD3;

[0036] In some implementation schemes, R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C)1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0037] In some implementation schemes, R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0038] In some implementation schemes, R 3 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, is optionally prefixed with 1 to 4 R groups. k Replaced; in some implementations, R 3 Each is independently selected from deuterium, F, Cl, Br, methyl, CF3, CH2F, CHF2, CD3, OCF3, OCH2F, OCHF2, ethyl, propyl, isopropyl, methoxy, ethoxy, and methylthio.

[0039] In some implementation schemes, R 3 Each is independently selected from F, Cl, Br, I, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, CF3, CH2F, CHF2, CD3, OCF3, OCD3;

[0040] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0041] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0042] In some implementation schemes, R k Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, and oxacyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, and oxacyclobutyl groups are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, and ethoxy;

[0043] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio;

[0044] In some implementation schemes, R k Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, methoxy, and ethoxy.

[0045] In some implementation schemes, m is selected from 0, 1, and 2;

[0046] In some implementations, n is selected from 0, 1, 2, 3, or 4;

[0047] In some implementation schemes, n is selected from 0, 1, and 2;

[0048] In some implementations, p is selected from 0, 1, and 2; q is selected from 1 and 2;

[0049] In some implementations, s is selected from 2, 3, or 4;

[0050] Optionally, general formula (I) is not selected from

[0051] Optionally, when C is selected from When, B is selected from C. 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups containing only one heteroatom, and whose general formula (I) is not selected from

[0052] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof...

[0053] B is selected from C. 3-10 Cycloalkyl or 4-10-membered heterocycloalkyl, wherein the B is optionally surrounded by 1 to 6 R. b The atoms that are replaced by B, and A and C cannot be simultaneously attached to the same atom of B;

[0054] C is selected from

[0055] One of X1 and X2 is selected from O, S, and NH, and the other is selected from CR. x1 ;

[0056] Z1 is selected from CR z1 R z2 O, S, NR z1 ;

[0057] When selected from single bonds, Y1 is selected from N, and Y2 is selected from CH2; When selected from double bonds, Y1 is selected from CH or CD, and Y2 is selected from N;

[0058] R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0059] R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0060] R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0061] R c Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 6 R groups. k Replaced;

[0062] R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0063] m is selected from 0, 1, and 2;

[0064] p is selected from 0, 1, 2; q is selected from 1, 2;

[0065] n is selected from 0, 1, 2, 3 or 4;

[0066] s is selected from 2, 3, or 4;

[0067] The condition is that general formula (I) is not selected from

[0068] The condition is that when C is selected When, B is selected from C. 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups containing only one heteroatom, and whose general formula (I) is not selected from

[0069] As a second embodiment of the present invention, the compound represented by the following general formula (I), or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, are used.

[0070] A is selected from

[0071] B is selected from 4-7 member heteromonocycloalkyl, 4-10 member heterocyclic cycloalkyl, 5-10 member heterospirocycloalkyl, 5-10 member heterobridged cycloalkyl, C 3-7 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, wherein the B is optionally surrounded by 1 to 5 R groups. b Instead, B is connected to A and C at both ends by carbon atoms, and A and C cannot be connected to the same atom of B at the same time;

[0072] R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0073] R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0074] R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced;

[0075] R c Selected from C 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 5 R groups. k Replaced;

[0076] R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0077] The remaining definitions are the same as those in the first embodiment of the present invention.

[0078] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, are used.

[0079] n is selected from 0, 1, and 2;

[0080] B is selected from 1 to 4 R's. b The group that is replaced is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, with carbon atoms at both ends connected to A and C respectively, and A and C cannot be connected to the same atom of B at the same time.

[0081] Alternatively, B can be selected from any of 1 to 4 R's. b One of the following groups is replaced: S1 and S2 are each independently selected from 0, 1, and 2, and S1 and S2 are not both 0 at the same time; S3 and S4 are each independently selected from 0, 1, and 2, and S3 and S4 are not both 0 at the same time; Z is selected from O, S, and NH.

[0082] R 1 R 2 R x1 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, or cyclopropyl groups are optionally prefixed with 1 to 4 R groups. k Replaced;

[0083] R 3 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, is optionally prefixed with 1 to 4 R groups. k Replaced;

[0084] R bEach of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups are optionally surrounded by 1 to 4 R groups. k Replaced;

[0085] R c Selected from 1 to 4 Rs k The following groups are substituted: methyl, ethyl, propyl, isopropyl;

[0086] R k Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio;

[0087] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0088] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof...

[0089] B is selected from 1 to 4 R's. b One of the following groups is replaced:

[0090] R b Each is independently selected from deuterium, F, Cl, Br, methyl, methoxy, CF3, CH2F, CHF2, CD3, and OCD3;

[0091] C is selected from t is selected from 1 and 2; X1 and X2 are each independently selected from O, S, and NH;

[0092] R c Each is independently selected from methyl, ethyl, propyl, isopropyl, CF3, CH2F, CHF2, and CD3;

[0093] R x1 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3, CH2F, CHF2, and CD3;

[0094] R 3Each is independently selected from F, Cl, Br, I, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, CF3, CH2F, CHF2, CD3, OCF3, OCD3;

[0095] R 1 R 2 Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, SH, NO2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl groups are optionally substituted by 1 to 4 substituents of deuterium, F, Cl, or Br; preferably, R 1 R 2 Each is independently selected from F, Cl, Br, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, CF3, CH2F, CHF2, CD3;

[0096] The remaining definitions are the same as those in the first, second, or third embodiments of the present invention.

[0097] As a fifth embodiment of the present invention, the compounds represented by the aforementioned general formulas Ia), (Ib), and (Ic), or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, are used.

[0098]

[0099] S1 is independently selected from 1 and 2;

[0100] The remaining definitions are the same as those in the first, second, third, or fourth embodiments of this invention.

[0101] This invention relates to a compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table E-1 below:

[0102] Table E-1

[0103]

[0104]

[0105]

[0106]

[0107]

[0108] This invention relates to a pharmaceutical composition comprising the above-described compound or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0109] This invention relates to the use of the above-mentioned compounds or their stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments for treating diseases related to α2 receptor agonists.

[0110] This invention relates to the use of the above-mentioned compounds or their stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions in the preparation of medicaments with sedative or analgesic effects.

[0111] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and pharmaceutical excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength").

[0112] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, or pharmaceutical compositions. In some embodiments, the mammals described in the present invention include humans.

[0113] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg. g, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 25 0-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 7 5-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200 mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0114] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,

[0115] 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg,

[0116] The compounds of the present invention, or their stereoisomers, tautomers, racemates, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, in doses of 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, or 300 mg.

[0117] A method for sedation or analgesia in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, preferably 1-1500 mg.

[0118] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses, and in some embodiments, the daily dose including but not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, etc. 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, and 800mg / day.

[0119] This invention relates to a kit that may include a single-dose or multi-dose composition comprising a compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts thereof, wherein the amount of the compound of the present invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is the same as the amount in the aforementioned pharmaceutical composition.

[0120] The compounds of the present invention also include their isotopic compounds, solvates, prodrugs, metabolites, and cocrystals.

[0121] In this invention, the amount of the compound of the invention or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts is converted in each case as a free base.

[0122] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0123] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0124] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125I, phosphorus isotopes include 31 P, 32 P.

[0125] “CN” refers to cyano.

[0126] "Halogen" refers to F, Cl, Br or I.

[0127] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0128] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0129] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0130] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0131] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0132] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2... -Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0133] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0134] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0135] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0136] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spirocyclic ring. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0137] A "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally, may contain 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2). Non-limiting embodiments include:

[0138]

[0139] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0140] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). n Or O, where n is 0, 1, or 2). The number of ring atoms in a cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0141] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0142] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0143]

[0144] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0145] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0146] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0147] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0148] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0149] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0150] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0151] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0152] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0153] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0154] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) m S(=O) n R a -(CH2) m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0155] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0156] The XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered elements. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0157] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 ….C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0158] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0159] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0160] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0161] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0162] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0163] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0164] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0165] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0166] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0167] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0168] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0169] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0170] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0171] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0172] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0173] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0174] Thin-layer chromatography silica gel plates used were from Yantai Huanghai HSGF. 254 Or Qingdao GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, while those used for TLC separation and purification of products have a diameter of 0.4mm-0.5mm.

[0175] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier; the starting materials of this invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0176] Synthesis method:

[0177]

[0178] Each GP is independently selected from an amino protecting group, preferably Trt (triphenylmethyl). PMB (p-methoxybenzyl);

[0179] X is selected from leaving groups, preferably halogens, OMs, OTs or Otf;

[0180] The definitions of the remaining functional groups are consistent with those of the aforementioned general formula compound (I);

[0181] Compounds of general formula (A-1) and general formula (A-2) are coupled to give compounds of general formula (A-3);

[0182] Compounds of general formula (A-3) can be converted into compounds of general formula (A-4) via cyclization reactions;

[0183] Compounds of general formula (A-4) are given by deamination of protecting groups to give compounds of general formula A.

[0184] Example 1: Synthesis of Compound 1-A and Compound 1-B

[0185]

[0186] Step 1: Preparation of 1b

[0187] Palladium dichloride bis(triphenylphosphine) (210 mg, 0.30 mmol) was added to a solution of 1a (2.00 g, 9.94 mmol), 2,3-dimethylbromobenzene (2.76 g, 14.91 mmol), and triethylamine (2.01 g, 19.88 mmol) in N,N-dimethylformamide (20 mL). The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 1b (2.40 g, yield: 79%).

[0188] LCMS m / z = 306.1 [M+1] +

[0189] Step 2: Preparation of 1c-a and 1c-b

[0190] At 0°C, N-methyl-N-nitrosourea (1.30 g, 12.58 mmol) was added to a 20% potassium hydroxide aqueous solution (4 mL) and an ether solution (4 mL), and the reaction was carried out at 0°C for 1 hour. At 0°C, the organic phase of the above mixed solution was added to a ether solution (4 mL) containing 800 mg (2.62 mmol) of solution 1b, and palladium acetate (5.90 mg, 0.03 mmol) was added. The reaction was carried out at 0°C for 0.5 h. The mixture was filtered, and the filter cake was washed with dichloromethane (5 mL x 3). The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by SFC (instrument and preparative column: SFCPrep150 AP, preparative column model: Daicel IG (19mm×250mm)). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45μm filter membrane to prepare the sample solution. Mobile phase system: A for CO2; B for methanol. Gradient elution method: 71% mobile phase B was used for isogradient elution for 0-5 min, and 55% mobile phase B was used for isogradient elution for 5-35 min (flow rate: 40mL / min; elution time: 40 min). After lyophilization, 1c-a (40mg, t=11.55min, yield: 4.78%) and 1c-b (30mg, t=17.95min, yield: 3.59%) were obtained. One of 1c-a and 1c-b is designated as 1c-1, and the other as 1c-2.

[0191] Step 3: Preparation of compound 1-A

[0192] 1 mL of an aqueous solution of sodium hydroxide (83 mg, 2.08 mmol) was added to 1 mL of ethanol solution containing 40 mg, 0.13 mmol of sodium hydroxide. The mixture was microwaved at 140 °C for 4 hours. The pH was adjusted to approximately 7 with 1 N hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC system, column model XBridge@PrepC18, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: acetonitrile / water (containing 0.05% NH3·H2O). Gradient elution method: Acetonitrile was eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min), and after lyophilization, compound 1-A (3 mg, yield: 11%) was obtained. Compound 1-A and compound 1-B were also used, one of which is compound 1-1 and the other is compound 1-2.

[0193] LCMS m / z = 213.1 [M+H] +

[0194] Step 4: Preparation of compound 1-B

[0195] Compound 1-B was synthesized using 1c-b as a substrate, following the preparation method of compound 1-A (compound 1-A and compound 1-B, one of which is compound 1-1 and the other is compound 1-2).

[0196] LCMS m / z = 213.1 [M+H] +1 H NMR(400MHz,CD3OD)δ7.55(s,1H),7.02-6.92(m,3H),6.87(s,1H),2.29(s, 3H),2.26(s,3H),2.25-2.18(m,1H),1.97-1.88(m,1H),1.36-1.25(m,2H).

[0197] Example 2: Synthesis of Compound 2-1 and Compound 2-2

[0198]

[0199] Step 1: Preparation of 2a

[0200] Palladium dichloride bis(triphenylphosphine) (470 mg, 0.67 mmol) was added to a solution of 1a (4.5 g, 22.36 mmol), 2,6-dimethylbromobenzene (6.21 g, 33.54 mmol), and triethylamine (4.53 g, 44.72 mmol) in N,N-dimethylformamide (45 mL). The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After cooling to room temperature, water (20 mL) and ethyl acetate (20 mL x 3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, column model XBridge@Prep C18, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in DMF and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was used to elute from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min). After lyophilization, compound 2a was obtained (3.5 g, yield: 51%).

[0201] LCMS m / z = 305.9[M+1]+

[0202] Step 2: Preparation of 2b

[0203] A 1M toluene solution of diethylzinc (4.92 mL, 4.92 mmol) was added to 10 mL of dichloromethane, and diiodomethane (2200 mg, 8.2 mmol) was added dropwise at 0 °C. The reaction was carried out at 0 °C for 0.5 h, and then 5 mL of a dichloromethane solution of 2a (500 mg, 1.64 mmol) was added, and the reaction was carried out at room temperature for 16 h. Water (10 mL) was added, and the pH was adjusted to approximately 7 with a 1N hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2b (600 mg, crude product).

[0204] LCMS m / z = 320.1 [M+H] +

[0205] Step 3: Preparation of Compound 2

[0206] A 6 mL aqueous solution of sodium hydroxide (1.13 g, 28.20 mmol) was added to a 6 mL ethanol solution of compound 2b (600 mg, 1.88 mmol), and the mixture was microwaved at 140 °C for 4 h. The pH was adjusted to approximately 7 with 1 N hydrochloric acid. The crude product was concentrated under reduced pressure and purified by SFC (instrument and preparative column: SFC Prep 150AP, preparative column model: Daicel IG (19 mm × 250 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter membrane to prepare the sample solution. Mobile phase system: A for CO2; B for methanol. Gradient elution method: 71% mobile phase B was used for isogradient elution for 0-5 min, and 55% mobile phase B was used for isogradient elution for 5-35 min (flow rate: 40 mL / min; elution time: 40 min). After lyophilization, compound 2 was obtained.

[0207] LCMS m / z = 213.1 [M+H] +1 H NMR (400MHz, CD3OD) δ7.56(d,1H),7.03-6.88(m,4H),2.38(s,6H),2.14-2.04(m,1H),2.01-1.90(m,1H),1.48-1.37(m,1H),1.15-1.05(m,1H).

[0208] Step 4: Preparation of Compound 2-A and Compound 2-B

[0209] Compound 2 was purified using an SFC on an AD column (instrument and preparative column: CAS 05Prep-SFC, Chiral IK column model. Preparation method: Compound 2 was dissolved in a mixed solvent of acetonitrile and methanol, and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in methanol). Gradient elution method: 50% mobile phase B was used for isogradient elution (flow rate: 120 mL / min; elution time: 5 min). After lyophilization, compounds 2-A and 2-B were obtained (one of compounds 2-A is compound 2-1, and the other is compound 2-2).

[0210] Analytical methods (instruments and preparative column: High performance liquid chromatography – normal phase chromatography, column model: SHIMADZULC-30ADsf); Mobile phase system: A for CO2; B for 0.05% M NH3 in methanol; Column temperature: 35℃; Flow rate: 3.0 mL / min. Retention time T = 0.988 min was for compound 2-A, and retention time T = 1.093 min was for compound 2-B.

[0211] Compound 2-A:

[0212] LCMS m / z = 213.2[M+H] +1 H NMR(400MHz,DMSO-d6)δ12.01-11.51(m,1H),7.53-7.44(m,1H),7.11-6.84( m,4H),2.34(s,6H),2.06-1.80(m,2H),1.43-1.32(m,1H),1.15-0.92(m,1H).

[0213] Compound 2-B:

[0214] LCMS m / z = 213.2[M+H] +1 H NMR(400MHz,DMSO-d6)δ12.13-11.50(m,1H),7.49(s,1H),7.15-6.78(m,4 H),2.34(s,6H),2.03-1.80(m,2H),1.43-1.32(m,1H),1.15-0.92(m,1H).

[0215] Following the synthetic methods of compound 1 or compound 2, and using similar starting materials, the following compounds were synthesized:

[0216] Biological test cases

[0217] Example 1: The effect of the compound on adrenergic α 2A Receptor binding activity assay

[0218] In human recombinant CHO-K1 cells, through interaction with radioligands ([ 3 Competitive binding of [H]Rauwolscine] was tested, and the compounds were evaluated for their effects on adrenergic α-reactive protein (ARP). 2A Receptor binding ability. Through the interaction of compounds with [ 3 H]Rauwolscine competitive binding was detected, free radioactive ligands were assessed, and binding inhibition rates were calculated using MathIQ. TM (ID Business Solutions Ltd., UK) Computing IC 50 The Cheng and Prusoff equations are used to calculate the Ki value.

[0219] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an effect on adrenergic α-reactivity. 2A Receptors have binding activity.

[0220] Example 2: The effect of the compound on adrenergic α 2A receptor agonistic activity test

[0221] High expression of human adrenergic α 2AAlpha 2A-Gqi5-HEK cells of the receptor were cultured in DMEM medium (containing 10% fetal bovine serum, 1 μg / mL puromycin, and 400 μg / mL G418) at 37°C with 5% CO2. Alpha 2A cells were digested and collected, resuspended in DMEM medium, counted, and seeded into 384-well plates. The plates were incubated at 37°C with 5% CO2 for 16–20 hours. Assay Buffer was prepared according to the FLIPR Calcium 6 Assay Kit instructions. 20× Component A was thawed to room temperature and diluted with Assay Buffer to 1× loading buffer, then stored at room temperature. The culture medium was removed from the cell plate, and 40 μL of 1× loading buffer was quickly added to each well. After centrifugation at 1000 rpm for 1 minute at room temperature, the cell plate was incubated at 37°C in the dark for 120 minutes. 5× working solution of the test compound was prepared, and 20 μL / well was transferred to each well of a 384-well compound source plate. The cell plate, compound source plate, and pipette tip were then placed in their respective positions on the high-throughput real-time fluorescence detection system. Using FLIPR Tetra, 10 μL of the released compound was added to each well, and data were collected at wavelengths of 515 nm–575 nm. EC was fitted using Graphpad Prism software. 50 value.

[0222] Table 1. Effects of tested compounds on adrenergic α-reactivity. 2A Results of receptor agonistic activity

[0223] Compound numbering <![CDATA[IC 50 (nM)]]> Compound 1-B A Compound 2 A Compound 2-B A

[0224] Note: A < 5nM, 5nM ≤ B < 50nM, 50nM ≤ C

[0225] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an effect on adrenergic α-reactivity. 2A The receptor has an agonistic effect.

[0226] Example 3: Evaluation Test of Compound Sedative Efficacy

[0227] ICR mice, half male and half female, 6-8 weeks old, 18-20g. After arriving at the enclosure, the animals should have an acclimatization period of at least 3 days. The day before the experiment, they should be fasted, and their drinking water should be replaced with a 20% glucose solution.

[0228] On the day of the experiment, the animals were weighed and randomly divided into groups of at least four, half male and half female. The medication was administered via tail vein injection at a volume of 10 mL / kg. After administration, at a designated time point, the animals were moved to an open area for sedation behavior assessment. After the assessment, the animals were transferred back to their cages.

[0229] The total score was calculated for each animal's behavioral assessment, and the mean and standard deviation (Mean ± SD) were determined. Statistical analysis was performed using GraphpadPrism software. P < 0.05 was considered statistically significant.

[0230] Conclusion: The compounds of the present invention, such as those in the examples, significantly reduced the sedation behavior scores in mice.

Claims

1. A compound or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from compounds represented by general formula (I), wherein, B is selected from C. 3-10 Cycloalkyl or 4-10-membered heterocycloalkyl, wherein the B is optionally surrounded by 1 to 6 R. b Instead, B is connected to A and C at both ends by carbon atoms, and A and C cannot be connected to the same atom of B at the same time; C is selected from One of X1 and X2 is selected from O, S, and NH, and the other is selected from CR. x1 ; Z1 is selected from CR z1 R z2 O, S, NR z1 ; When selected from single bonds, Y1 is selected from N, and Y2 is selected from CH2; When selected from double bonds, Y1 is selected from CH or CD, and Y2 is selected from N; R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-6 Alkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced; R c Selected from C 1-6 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 6 R groups. k Replaced; R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; m is selected from 0, 1, and 2; p is selected from 0, 1, 2; q is selected from 1, 2; n is selected from 0, 1, 2, 3 or 4; s is selected from 2, 3, or 4; The condition is that general formula (I) is not selected from The condition is that when C is selected When, B is selected from C. 3-10 Cycloalkyl or 4-10 membered heterocyclic alkyl groups containing only one heteroatom, and whose general formula (I) is not selected from 2. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, A is selected from B is selected from 4-7 member heteromonocycloalkyl, 4-10 member heterocyclic cycloalkyl, 5-10 member heterospirocycloalkyl, 5-10 member heterobridged cycloalkyl, C 3-7 Monocycloalkyl, C 4-10 cycloalkyl, C 5-10 Spirocycloalkyl, C 5-10 Bridged cycloalkyl groups, wherein the B is optionally surrounded by 1 to 5 R groups. b Instead, B is connected to A and C at both ends by carbon atoms, and A and C cannot be connected to the same atom of B at the same time; R 1 R 2 R x1 R z1 R z2 Each element is independently selected from H, deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R 3 Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, ynyl or cycloalkyl group is optionally surrounded by 1 to 4 R groups. k Replaced; R b Each element is independently selected from deuterium, halogens, OH, NH2, CN, NO2, and C. 1-4 Alkyl, C 1-4 Alkoxy, wherein the alkyl or alkoxy group is optionally surrounded by 1 to 4 R groups. k Replaced; R c Selected from C 1-4 Alkyl groups, wherein the alkyl group is optionally surrounded by 1 to 5 R groups. k Replaced; R k Each element is independently selected from deuterium, halogens, OH, CN, NH2, NO2, COOH, CONH2, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, wherein the alkyl, alkylene, alkenyl, or alkynyl group is optionally selected from 1 to 4 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, n is selected from 0, 1, and 2; B is selected from 1 to 4 R's. b The group that is replaced is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, with carbon atoms at both ends connected to A and C respectively, and A and C cannot be connected to the same atom of B at the same time. R 1 R 2 R x1 R z1 R z2 Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, or cyclopropyl groups are optionally prefixed with 1 to 4 R groups. k Replaced; R 3 Each of the following groups is independently selected from deuterium, F, Cl, Br, I, CN, OH, SH, NO2, COOH, CONH2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, is optionally prefixed with 1 to 4 R groups. k Replaced; R b Each of the following is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, and ethoxy groups are optionally surrounded by 1 to 4 R groups. k Replaced; R c Selected from 1 to 4 Rs k The following groups are substituted: methyl, ethyl, propyl, isopropyl; R k Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NO2, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, and methylthio.

4. The compound according to claim 3, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, B is selected from 1 to 4 R's. b One of the following groups is replaced: Preferably, B is selected from R b Each is independently selected from deuterium, F, Cl, Br, methyl, methoxy, CF3, CH2F, CHF2, CD3, and OCD3; C is selected from t is selected from 1 and 2; X1 and X2 are each independently selected from O, S, and NH; R c Each is independently selected from methyl, ethyl, propyl, isopropyl, CF3, CH2F, CHF2, and CD3; R x1 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3, CH2F, CHF2, and CD3; R 3 Each is independently selected from F, Cl, Br, I, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, CF3, CH2F, CHF2, CD3, OCF3, OCD3; R 1 R 2 Each of the following groups is independently selected from deuterium, F, Cl, Br, CN, OH, SH, NO2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, and cyclopropyl groups are optionally substituted by 1 to 4 substituents of deuterium, F, Cl, or Br; preferably, R 1 R 2 Each is independently selected from F, Cl, Br, CN, OH, SH, NO2, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, CF3, CH2F, CHF2, CD3.

5. A compound of general formula (I) according to claim 2, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein, General formula (I) is selected from (Ia), (Ib), and (Ic). S1 is selected independently from 1 and 2.

6. The compound according to claim 1, or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound is selected from one of the structures in Table E-1: Table E-1 7. A pharmaceutical composition comprising the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, preferably, the pharmaceutical composition containing 1-1500 mg of the compound of any one of claims 1-6 or its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts.

8. The use of the compound or its stereoisomer, tautomer, racemate, pharmaceutically acceptable salt, or composition of claim 7 in the preparation of a medicament for treating diseases associated with α2 receptor agonists, according to any one of claims 1-6.

9. The use of the compound or its stereoisomer, tautomer, racemate, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 7 in the preparation of a medicament for sedation or analgesia.

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