# US 9,517,988 B2 · Phenol derivative and preparation method and use in medicine thereof

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- Number: US 9,517,988 B2
- Document ID: US9517988B2
- Status: Granted
- Kind: B2
- Application number: 14/936,310
- Filed: 2015-11-09
- Published: 2016-03-03
- Granted: 2016-12-13
- Earliest claimed: 2013-05-09
- Assignees: Sichuan Haisco Pharmaceutical Co., Ltd.
- Applicants: Sichuan Haisco Pharmaceutical Co., Ltd.
- Inventors: Linlin Qin; Fangqiong Li; Shixu Yi; Huadong Luo; Xinfeng Luo; Songlin Wan; Lei Ren; Guoliang Liu; Yonggang Wei; Jianyu Liu; Peng Cho Tang
- Web page: https://patentgrep.com/patent/US9517988B2

## CPC

- C07C 39/17: containing other rings in addition to the six-membered aromatic rings {, e.g. cyclohexylphenol}
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 23/00: Anaesthetics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- C07C 37/00: Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C 37/001: {by modification in a side chain}
- C07C 37/62: by introduction of halogen; by substitution of halogen atoms by other halogen atoms
- C07C 39/42: containing six-membered aromatic rings and other rings
- C07C 41/18: by reactions not forming ether-oxygen bonds
- C07C 43/21: containing rings other than six-membered aromatic rings
- C07C 43/23: containing hydroxy or O-metal groups
- C07C 67/10: by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond (preparation from carboxylic acid halides C07C67/14)
- C07C 68/00: Preparation of esters of carbonic or haloformic acids
- C07C 69/07: of unsaturated alcohols
- C07C 69/157: containing six-membered aromatic rings
- C07C 69/24: esterified with monohydroxylic compounds
- C07C 69/78: Benzoic acid esters
- C07C 69/82: Terephthalic acid esters
- C07C 69/96: Esters of carbonic or haloformic acids
- C07C 227/04: Formation of amino groups in compounds containing carboxyl groups
- C07C 229/08: the nitrogen atom of the amino group being further bound to hydrogen atoms
- C07C 229/36: with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
- C07C 269/00: Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups [IMAGE cpc-sch-C07C-0964.gif], the nitrogen atom not being part of nitro or nitroso groups
- C07C 271/22: to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
- C07C 271/44: to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 213/80: in position 3
- C07D 213/803: Processes of preparation
- C07F 9/06: without P—C bonds
- C07F 9/091: {with hydroxyalkyl compounds with further substituents on alkyl}
- C07F 9/094: {with arylalkanols}
- C07F 9/12: with hydroxyaryl compounds
- C07F 9/242: {of hydroxyaryl compounds}
- C07F 9/2458: {of aliphatic amines}
- C07F 9/65744: {condensed with carbocyclic or heterocyclic rings or ring systems}
- C07C 2601/02: with a three-membered ring
- C07C 2601/04: with a four-membered ring
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention relates to a phenol derivative and the preparation method and use in medicine thereof, and particular to a phenol derivative represented by general formula (A) or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt or a cocrystal thereof, a preparation method thereof, a pharmaceutical composition comprising the same, and use of the compound or composition of the present invention in the field of the central nervous system; wherein the definitions of substituents in general formula (A) are the same as those in the Description.

## Claims

### Claim 1

A compound of general formula (A),
wherein
R is selected from F, Cl, Br, I, —OR7 or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group, or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 forms a 3- to 5-membered ring, the 3- to 5-membered ring has 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered ring is optionally further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, wherein the alkyl, alkoxy, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 5 substituents selected from hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered ring, the 3- to 5-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 5-membered may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-4 alkyl or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R9, R10, R11 and R12 are each independently selected from H, F, Cl, Br, I, hydroxyl, C1-6 alkyl or C1-6 alkoxy;
X is selected from H, F or carboxyl;
Y is selected from H, COR13, PEG, COOR13, CONR13R14, COSR13,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R13 and R14 are each independently selected from H, C1-6 alkyl, a 3- to 8-membered carbocyclic or heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocyclic group or a 3- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
R15 and R16 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, wherein the alkali metal ion is selected from Na+, K+ or Li+, the alkali earth metal ion is selected from Be2+, Mg2+ or Ca2+, the amine is selected from trometamol, triethanolamine, ethanolamine, triethylamine or N-methylglucosamine, and the amino acid is selected from arginine or lysine;
alternatively, R15 and R16 may form a 3- to 8-membered ring, the 3- to 8-membered ring may have 0 to 2 heteroatoms selected from N, O or S, and the formed 3- to 8-membered ring may optionally be further substituted with 0 to 4 R8s;
R17 is the side-chain group of an amino acid, wherein the amino acid is selected from lysine, arginine, histidine, proline, 2,3-diaminopropionic acid, 2,4-diaminopropionic acid, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, aspartate, or glutamic acid;
W1, W2 and W3 are each independently selected from NRy8, O or S;
W4 is selected from CRy9Ry10, NRy8, O, S, or is absent;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-8 carbocyclic group) or —(CH2)m1-(4- to 8-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3-to 8-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3-to 8-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry6 and Ry7 are each independently selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or C1-6 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 8-membered ring together with the atoms to which they are attached, the 5- to 8-membered ring may have 0 to 4 heteroatoms selected from N, O or S, and the 5- to 8-membered ring may optionally be further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, C1-6 alkyl or C1-6 alkoxy;
Ry8s are each independently selected from H or C1-6 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-6 alkyl;
n is selected from 1, 2 or 3;
m is selected from 1 or 2;
q is selected from 1 to 200;
m1 is selected from 0, 1, 2 or 3;
p is selected from 0, 1 or 2;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof,
provided that the compound of general formula (A) is not

### Claim 2 (depends on 1)

The compound according to claim 1, selected from compounds of general formula (I):
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein
R is selected from F, Br, —OR7 or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-5 alkyl, C1-5 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocycle, and the carbocycle may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl or C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H, C1-4 alkyl or a 3- or 4-membered carbocyclic group, wherein the alkyl or carbocyclic group may be further substituted with 0 to 3 substituents selected from F, hydroxyl or C1-3 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy;
n is selected from 1 or 2;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein
R is selected from Br or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 5 (depends on 4)

The compound according to claim 4, selected from compounds of general formula (II):
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein:
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 hydroxyl groups, and R4 and R5 are not both H;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein:
R1, R2 and R3 are each independently selected from H, hydroxyl, C1-4 alkyl or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F or hydroxyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 substituents selected from F or hydroxyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, C1-4 alkyl or a 3- to 5-membered carbocyclic group, wherein the alkyl or carbocyclic group is optionally further substituted with 0 to 3 hydroxyl groups, and R4 and R5 are not both H;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein:
R1, R2 and R3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R4 and R5 are not both H;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, selected from
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein:
R9, R10, R11 and R12 are H;
Y is selected from H, PEG,
C1-20 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1COORy1, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group;
R13 and R14 are each independently selected from H or C1-6 alkyl;
R15 and R16 are each independently selected from H or an alkali metal ion, and the alkali metal ion is selected from Na+, K+ or Li+;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein:
R is selected from Br, OR7, or
R1, R2 and R3 are each independently selected from H, F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, hydroxyl, C1-4 alkyl, C1-4 alkoxy or a 3- to 5-membered carbocyclic group, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R4 and R5 are each independently selected from H, F, Cl, Br, hydroxyl, cyano, C1-4 alkyl or C1-4 alkoxy or a 3- to 5-membered carbocyclic group, wherein the alkyl, alkoxy or carbocyclic group is optionally further substituted with 0 to 3 substituents selected from hydroxyl, C1-4 alkyl or C1-4 alkoxy, and R4 and R5 are not both H;
alternatively, R4 and R5 may form a 3- to 5-membered carbocyclic group, and the carbocyclic group may optionally be further substituted with 0 to 4 R8s;
R6 is selected from H or hydroxyl;
R7 is selected from H or C1-4 alkyl;
R8 is selected from F, Cl, Br, hydroxyl, C1-4 alkyl or C1-4 alkoxy;
X is H;
Ry1 is each independently selected from H, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, a C3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxy, —(CH2)m1—OC(═O)—C1-6 alkyl, —(CH2)m1—C(═O)O—C1-6 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-6 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or a —(CH2)m1-(4- to 6-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, an alkali earth metal ion, a protonated amine or a protonated amino acid, C1-6 alkyl, —(CRyaRyb)m1-(3-to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-6 alkyl, —(CRyaRyb)m1—OC(═O)-(3-to 6-membered ring), —(CRyaRyb)m1—C(═O)OC1-6 alkyl or —(CRyaRyb)m1—OC(═O)OC1-6 alkyl;
Ry9 and R10 are each independently selected from H, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the alkyl, carbocyclic group and heterocyclic group are each optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 8-membered carbocycle or a 3- to 8-membered heterocycle;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 12 (depends on 11)

The compound according to claim 11, wherein:
Y is selected from C1-10 alkyl, —(CH2CH2O)q—H, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-6 alkyl or a C3-6 carbocyclic group;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein:
R1, R2 and R3 are each independently selected from H, hydroxyl, methyl, ethyl or cyclopropyl, and R1, R2 and R3 are not all H;
alternatively, any pair of R1 and R2, R2 and R3, or R1 and R3 may form cyclopropyl;
R4 and R5 are each independently selected from H, hydroxyl, cyano, methyl, ethyl or cyclopropyl, and R4 and R5 are not both H;
R7 is selected from H, methyl or ethyl;
Y is selected from C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxyl, amino, cyano, carboxyl, C1-4 alkyl or a C3-6 carbocyclic group;
Ry3 is selected from H, amino, C1-6 alkyl, a C3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, —(CRyaRyb)m1—NRycRyd or —(CRyaRyb)m1—NRycC(═O)ORyd, wherein the amino group, alkyl, carbocyclic group or heterocyclic group may optionally be further substituted with 0 to 5 substituents selected from —(CH2)m1—OC(═O)—C1-4 alkyl, —(CH2)m1—C(═O)O—C1-4 alkyl, —(CH2)m1—C(═O)O(CH2)m1—(C3-6 carbocyclic group), —(CH2)m1—C(═O)—C1-4 alkyl, —(CH2)m1—(C3-6 carbocyclic group) or —(CH2)m1-(4- to 6-membered heterocyclic group), and the heterocyclic group has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CRyaRyb)m1-(3- to 6-membered ring), —(CRyaRyb)m1—OC(═O)—C1-4alkyl, —(CRyaRyb)m1—OC(═O)-(3- to 6-membered ring), —(CRyaRyb)m1—C(═O)O—C1-4alkyl or —(CRyaRyb)m1—OC(═O)O—C1-4alkyl;
Ry6 and Ry7 are each independently selected from H, C1-4 alkyl or C1-4 alkoxy;
alternatively, Ry6 and Ry7 may form a 5- to 6-membered ring together with the atoms to which they are attached, and the 5- to 6-membered ring may have 0 to 4 heteroatoms selected from N, O, or S;
Ry8s are each independently selected from H or C1-4 alkyl;
Ry9 and Ry10 are each independently selected from H, C1-6 alkyl or a 4- to 6-membered heterocyclic group, wherein the alkyl and heterocyclic group are optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-6 alkyl, C1-6 alkoxy, a 3- to 6-membered carbocycle or a 4- to 6-membered heterocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-4 alkyl;
q is selected from 1 to 10;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 14 (depends on 13)

The compound according to claim 13, wherein:
Y is selected from C1-4 alkyl, —(CRyaRyb)m1—(W1)p—C(═O)(W4Ry3) or —(CRyaRyb)m1—(W1)p—P(═O)(W2Ry4)(W3Ry5) or
wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, C1-4 alkyl or a C5-6 carbocyclic group;
Ry3 is selected from amino, C1-4 alkyl, —(CRyaRyb)m1NRycRyd, —(CRyaRyb)m1NRycC(═O)ORyd, a C3-6 carbocyclic group or a 3- to 6-membered heterocyclic group, wherein the amino group, alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 4 substituents selected from —OC(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl or —C(═O)OCH2—(C5-6 carbocyclic group), and the heterocyclic group has at least 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CRyaRyb)m1-(5- to 6-membered ring), —(CRyaRyb)m1—OC(═O)C1-4 alkyl, —(CRyaRyb)m1—C(═O)OC1-4 alkyl or —(CRyaRyb)m1—OC(═O)OC1-4 alkyl;
Ry6 and Ry7 are each independently H or C1-4 alkyl;
alternatively, Ry6 and Ry7 may form a 5- to 6-membered ring together with the atoms to which they are attached, and the 5- to 6-membered ring may have 0 to 4 heteroatoms selected from N, O, or S;
Ry8 is selected from H or C1-4 alkyl;
Ry9 is selected from H or C1-4 alkyl;
Ry10 is selected from H or C1-4 alkyl, wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, hydroxyl, amino, mercapto, carboxyl, guanidino, carbamoyl, C1-4 alkyl, or a 5- to 6-membered carbocycle;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 15 (depends on 14)

The compound according to claim 14, wherein:
W1, W2, W3 are each independently selected from NH or O;
W4 are each independently selected from CHRy10 or O, or is absent;
Ry3 is selected from amino, C1-4 alkyl, —(CH2)m1NRycRyd, —(CH2)m1NRycC(═O)ORyd, a C5-6 carbocyclic group or a 5- to 6-membered heterocyclic group, wherein the amino group, alkyl, carbocyclic group or heterocyclic group is optionally further substituted with 0 to 4 substituents selected from —OC(═O)—C1-4 alkyl, —C(═O)O—C1-4 alkyl or —C(═O)OCH2—(C5-6 carbocyclic group), and the heterocyclic group at least has 1 to 2 heteroatoms selected from N, O or S;
Ry4 and Ry5 are each independently selected from H, an alkali metal ion, C1-4 alkyl, —(CH2)m1-(5- to 6-membered ring), —(CH2)m1—OC(═O)C1-4 alkyl, —(CH2)m1—C(═O)OC1-4 alkyl or —(CH2)m1—OC(═O)OC1-4 alkyl;
Ry10 is selected from H or C1-4 alkyl, wherein the alkyl is optionally further substituted with 0 to 4 substituents selected from H, C1-4 alkyl, or a 5- to 6-membered carbocycle;
Rya, Ryb, Ryc and Ryd are each independently selected from H or C1-4 alkyl;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein:
the
is selected from the structures below:
Y is selected from methyl, hydroxyethyl, —CH2OC(═O)(Ry3), —C(═O)(Ry3), —CH2OC(═O)(W4Ry3), —C(═O)(W4Ry3), —CH(CH3)OC(═O)(W4Ry3), —CH2OP(═O)(W2Ry4)(W3Ry5), —P(═O)(W2Ry4)(W3Ry5) or
W2 and W3 are each independently selected from NH or O;
W4 is selected from CHRy10 or O;
Ry3 is selected from amino, aminomethylene, isopropyl, t-butyl, (t-butoxycarbonyl)amino, (t-butoxycarbonyl)aminomethylene, pyrrolylalkyl, phenyl or pyridinyl, wherein the amino group, pyrrolylalkyl, phenyl and pyridinyl are optionally further substituted with 0 to 4 substituents selected from t-butoxycarbonyl, acetoxy, or benzyloxycarbonyl;
Ry4 and Ry5 are each independently selected from H, Na+, K+, ethyl, benzyl, —CH2OC(═O)C(CH3)3, —CH(CH3)OC(═O)CH(CH3)2, —CH2OC(═O)CH2CH3, —CH2C(═O)OCH2CH3 or —CH2OC(═O)OCH(CH3)2;
Ry6 and Ry7 form phenyl together with the atoms to which they are attached;
Ry10 is selected from H, methyl, isopropyl, sec-butyl, 2-methylpropyl or benzyl;
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 17 (depends on 16)

The compound according to claim 16, wherein:
the
is selected from the structures below:
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 18 (depends on 1)

The compound according to claim 1, selected from the structures below:
or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof.

### Claim 19 (depends on 1)

The compound according to claim 1, or a stereoisomer, a solvate, a metabolite, a prodrug, a pharmaceutically acceptable salt, or a cocrystal thereof,
wherein the salt includes an ammonium salt, a potassium salt, a sodium salt, a calcium salt, a magnesium salt, a tetramethylammonium salt, a tetraethylammonium salt, a tetrapropylammonium salt, a tetrabutylammonium salt, a tetra(isopentyl)ammonium salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, trimethylamine salt, N-methylglucosamine salt, hydrochloride sulfate, phosphate, acetate, trifluoroacetate, fumarate, hemifumarate, maleate, malate, citrate, succinate, benzenesulfonate, or p-toluenesulfonate.

### Claim 20 (depends on 1)

A method for preparing a compound according to claim 1, comprising:
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b) to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), and further removing R′ from the product of the Grignard reaction to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), and removing hydroxyl from the product of the Grignard reaction by a reducing agent, to afford a compound of general formula (I);
or
conducting a Grignard reaction between a compound of general formula (I-a) and a compound of general formula (I-b), removing R′ from the product of the Grignard reaction, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I);
wherein R′ is selected from H, methyl, ethyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, or t-butyl(dimethyl)silyl; R, R4, R5 and n have the same definitions as those for the compound of general formula (I); X is selected from F, Cl, Br or I;
or,
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, and then removing R″ to afford a compound of general formula (I); or
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, then removing R″, and further removing hydroxyl therefrom by a reducing agent, to afford a compound of general formula (I); or
allowing a compound of general formula (I-c) to either undergo a Grignard reaction, or react with a compound of general formula (I-d) under the action of an organolithium reagent, further alkylating the product thereof, and then removing R″ therefrom to afford a compound of general formula (I);
wherein R″ is selected from, methyl, ethyl, benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, or t-butyl(dimethyl)silyl; R, R4, R5 and n have the same definitions as those for the compound of general formula (I).

### Claim 21 (depends on 10)

A method for preparing a compound according to claim 10, comprising:
wherein
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-B); or
allowing a compound of general formula (I) and a compound of general formula (I-A) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-B), and allowing the intermediate to further react with a nucleophilic reagent under the action of an alkali to afford a compound of general formula (I-B);
or,
allowing a compound of general formula (I) and a compound of general formula (I-C) to undergo nucleophilic substitution to afford a compound of general formula (I-D); and then
allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to directly afford a compound of general formula (I-F); or
allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and subjecting the intermediate to hydrolysis and then to an exchange reaction with a metal salt to afford a compound of general formula (I-F); or
allowing the compound of general formula (I-D) and a compound of general formula (I-E) to undergo nucleophilic substitution under the action of an alkali to afford an intermediate for a compound of general formula (I-F), and allowing the intermediate to further react with an electrophilic reagent under the action of an alkali to afford a compound of general formula (I-F);
wherein, R18 or R19 is each independently selected from F, Cl, Br, I, C1-10 alkyl or C1-10 alkoxy,
R20, R21 and R22 are each independently selected from H, F, Cl, Br, I or C1-10 alkyl;
V is selected from F, Cl, Br, I;
n, R, R4, R5 and R6 have the same definitions as those in general formula (I).

### Claim 22 (depends on 1)

A pharmaceutical composition, comprising:
a compound according to claim 1, or a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal, or a prodrug thereof; and
one or more pharmaceutically acceptable vehicles and/or excipients.

### Claim 23 (depends on 1)

A method for inducing and maintaining anesthesia in an animal or a human, facilitating sedation and hypnosis of an animal or a human, or treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion, and epilepsy comprising:
administering a compound according to claim 1, or a stereoisomer, a solvate, a metabolite, a pharmaceutically acceptable salt, a cocrystal, or a prodrug thereof.