Granted Patent B2

US 12,351,565 · App. 17/045,004 · Granted Jul 8, 2025

Inventors: Tao Xue (Shanghai, CN); Jing Huang (Shanghai, CN); Wenke Wang (Shanghai, CN); Yilang Chen (Shanghai, CN)

Assignee: Shanghai Zhigen Pharmaceutical & Technology Co., Ltd.

C07D309/30A61P25/24C07C225/20C07C237/02

Abstract

Claims (60)

1. A compound represented by the following general formula (I), or a tautomer, an enantiomer, a diastereomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein,

A is CH 2 ;

N 1 is 1 and N 2 is 0, 1, 2, 3 or 4;

R 1 and R 2 are each independently hydrogen, or C 1 -C 6 alkyl, and the above-mentioned alkyl can be independently substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy;

R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or halogen; and when A is CH 2 and N 1 is 1, R 3 is not chlorine;

each R 4 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halogen, or cyano, wherein the halogen is fluorine, bromine or iodine; and R 3 and R 4 are not hydrogen at the same time; or when R 3 is fluorine, not all of the substituents at other positions of the benzene ring are hydrogen or position 5 of the benzene ring is not fluorine; and

the stereo configuration of α- or β-position carbon atom is each independently R, S or (R, S).

2. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by general formula (I-A), or (I-B):

general formula (I-A) compound

wherein, in formula (I-A), A, N 1 , N 2 , R 3 and R 4 are as defined in claim 1 ;

general formula (I-B) compound

wherein, in formula (I-B), A, N 1 , N 2 , R 3 and R 4 are as defined in claims 1 , R 1 and R 2 are each independently hydrogen or C 1 -C 6 alkyl, and the above alkyl can be independently substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy,

general formula (I-C) compound.

3. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently hydrogen, methyl, or ethyl.

4. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

R 3 is hydrogen;

R 4 is C 1 -C 6 haloalkyl.

5. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein

R 3 is halogen;

R 4 is C 1 -C 6 haloalkoxy.

6. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, fluorine, methyl, trifluoromethyl or trifluoromethoxy.

7. The compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, fluorine, methyl, methoxy, trifluoromethyl, trifluoromethoxy or cyano.

8. A pharmaceutical composition which comprises a compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.

9. A method of treating a disease related to the nervous system comprising administering the compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

10. The method of claim 9 , wherein the diseases related to the nervous system is depression.

11. A method for preparing a compound of claim 1 , or a tautomer, an enantiomer, a diastereomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein,

(1) the method comprises the steps:

wherein, A, N 1 , N 2 , R 3 and R 4 are as defined in claim 1 ;

a. compound I-1 is reacted with di-tert-butyl dicarbonate in a protic solvent or an aprotic solvent or a mixed solvent thereof to form compound I-2;

b. in an aprotic solvent, compound I-2 is reacted with trimethylchlorosilane to form compound I-3;

c. in an aprotic solvent, compound I-3 is oxidized by an oxidizing agent to form compound I-4;

d. in an aprotic solvent, a trimethylsilyl protecting group is removed from compound I-4 to form compound I-5;

e. in a polar aprotic solvent, a tert-butoxycarbonyl protecting group is removed from compound I-5 to form compound I-A;

or

(2) the method comprises the steps:

wherein, A, N 1 , N 2 , R 3 and R 4 are as defined in claims 1 , R 1 and R 2 are each independently hydrogen or C 1 -C 6 alkyl, and the above-mentioned alkyl can be independently substituted by 1 to 2 substituents selected from the group consisting of halogen, hydroxy, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 ester, and C 1 -C 4 amide;

a. in a protic or an aprotic solvent or a mixed solvent thereof and in the presence of a catalyst and a hydrogen source, the compound I-A is reacted with an aldehyde to form compound I-B.

12. The preparation method of claim 11 , wherein:

the method for preparing compound I-1 comprises the steps:

wherein, in each formula, A, N 1 , N 2 , R 3 and R 4 are as defined in claim 1 ;

a. in an aprotic solvent, compound IV-1 is reacted with a nitrating reagent under the action of a catalyst to form compound IV-2;

b. in a protic or an aprotic solvent or a mixed solvent thereof, compound IV-2 is reduced by a metal reducing agent under the action of an organic or inorganic acid to form the compound I-1;

or

the method for preparing compound I-1 comprises the steps:

wherein, in each formula, A, N 1 , N 2 , R 3 and R 4 are as defined in claim 1 ;

a. in an aprotic solvent, compound IV-1 is reacted with a halogenated reagent to form compound V-1;

b. in an aprotic solvent, compound V-1 is reacted with an azide reagent to form compound V-2;

c. in a protic or an aprotic solvent or a mixed solvent thereof, compound V-2 is reacted in the presence of a catalyst and a hydrogen source to form compound I-1.

13. The preparation method of claim 12 , wherein:

the method for preparing compound IV-1 comprises the steps:

wherein, in each formula, X can be H, Br or I; N1, N2, R3 and R4 are as defined in claim 1 ;

a. in an aprotic solvent, compound VI-1 is reacted with an epoxy compound VI-2 to form compound VI-3;

b. in an aprotic solvent, compound VI-3 is oxidized by an oxidizing agent to form the compound IV-1;

or

the method for preparing compound IV-1 comprises the steps:

wherein, in each formula, X can be Br or I; A, N1, N2, R3 and R4 are as defined in claim 1 ;

a. in an aprotic solvent, compound VI-1 is reacted with a cyclic ketone compound VII-1 under catalysis of a metal-containing catalyst and a phosphine-containing ligand to form compound IV-1.

14. A compound selected from the group consisting of:

or a tautomer, an enantiomer, a diastereomer, a racemate, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

Assignments (2)

Priority Claims (1)

Continuity (1)

References Cited (27)