WO2023169391A1 - Heterocyclic derivative, preparation method therefor, and use thereof - Google Patents

Abstract

The present invention relates to a heterocyclic derivative, a preparation method therefor, a pharmaceutical composition containing the derivative, and an application thereof in medicine. Specifically, the present invention relates to a heterocyclic derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, as well as to the use of the above as therapeutic agents, especially as RAC1 inhibitors, wherein the definitions of each substituent in general formula (I) are the same as the definitions in the description.

Description

Heterocyclic derivatives and their preparation methods and uses Technical field

The present invention relates to a heterocyclic derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a RAC1 inhibitor.

Background technique

The RAC subfamily consists of RAC1, RAC2, RAC3 and RAC1b (the splicing mutant of RAC1). RAC1 is widely distributed in various tissues, RAC2 is restricted to blood cells, and RAC3 is mainly expressed in neurons. RAC1 is an important intracellular signal transduction molecule and is closely related to the occurrence and development of malignant tumors.

The basic biological function of RAC1 is to bind and hydrolyze guanylic acid. It has two binding states, one is an activated state that binds to GTP, and the other is an inactive state that binds to GDP, and can cycle between these two states. Its activity is mainly regulated by GEFs, GAPs and Rho GDI. It is the conversion of these two active forms that makes RAC1 act as a "molecular switch" in the regulation of cell proliferation, differentiation and apoptosis, cell movement and adhesion, and transcription factors. It is an important signal transduction molecule in cells.

RAC1 protein has not been found to be mutated in most invasive tumors in humans, but it has been found to be overactive and highly expressed. Abnormally increased expression of RAC1 has been reported in gastric cancer, colon cancer, breast cancer, lung cancer, testicular cancer, pancreatic cancer, head and neck cancer, and ovarian cancer.

There are about 300,000 new cases of breast cancer in my country every year. The incidence rate in rural areas is about 40/100,000 people, and in urban areas it is about 50/100,000 people. In big cities such as Beijing, Shanghai, Guangzhou, Shenzhen, etc. it is about 70/100,000 people or more. The incidence rate ranks first among malignant tumors in women, and is still rising at a rate of 1-3% per year, indicating a large unmet clinical need.

At the same time, the RAC1 target has definite genetic confirmation. For melanomas with RAC1P29S mutations, RAC1 inhibitors have clear advantages. Currently, there are no targeted therapeutic drugs available for melanoma with RAC1P29S mutations in the world. This driver mutation is the third largest melanoma mutation after BRAF and NRAS mutations, accounting for up to 9%, making RAC1 inhibitors have a broad market. prospect.

There are no drugs on the market that selectively target RAC1. In 2021, Roche announced CDC42, RAC1 modulators (i.e., inhibitors and agonists) and their use in the treatment of diseases, including cancer (medulloblastoma, ovary, breast, head and neck, testis, prostate and other entities) hematological malignancies such as neoplasms and cellular lymphomas) and diseases in which activation of Rho GTPases plays a key role (Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes mellitus (type I), Huntington's disease, and Alzheimer's disease Heimer's disease, etc.). Currently, the project has just entered clinical phase I. As a relatively cutting-edge research direction, RAC1 inhibitors are likely to become another new direction for "undruggable" target breakthroughs after KRAS, bringing major opportunities and huge challenges to medical research and development.

Contents of the invention

In view of the above technical problems, the present invention provides a heterocyclic derivative represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

in:

Ring A is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl;

Ring B is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl or 6-14 membered fused ring, of which 6 to 14 members The fused ring is preferably a 6-10 membered fused ring;

Q is selected from N or CR ^e ;

X is selected from -O-, -S(O) _r -, -CR ^a R ^b - or -NR ^c -;

R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

R ^e is selected from hydrogen atom, C ₁ -C ₆ alkyl group or -C(O)OR ^aa ;

R ^aa is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

R ^c is selected from hydrogen atom, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups described above are optionally further substituted by one or more ^RA ;

R ^A is the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C (O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC Substituted by (O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

Alternatively, two R ^A attached to the same carbon atom together with the attached carbon atom form a -C(=O)-;

L ¹ is selected from bond, C ₁ -C ₉ alkylene, C ₂ -C ₇ alkenylene or C ₂ -C ₇ alkynylene, wherein C ₁ -C ₉ alkylene is preferably C ₁ -C ₇ alkylene group, wherein the alkylene, alkenylene or alkynylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy; and wherein One or more methylene groups in the alkylene, alkenylene or alkynylene group are optionally replaced by one or more O, S(O) _r , C(O) or NR ^d ;

R ^d is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

L ² is selected from a bond or a C ₁ -C ₆ alkylene group, wherein said alkylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy substituted; and one or more methylene groups in the alkylene group are optionally The choice is replaced by one or more O, S(O) _r , C(O) or NR ^d ;

R ¹ is the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, = O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR Substituted by ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

R ² is selected from hydrogen atom, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, 3-10 membered heterocyclyl group, C ₃ -C ₁₀ cycloalkyl group, 6-14 membered fused ring, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; wherein the aryl group, heteroaryl group, heterocyclic group, ring The alkyl group or fused ring is optionally further substituted by one or more ^RF ;

R ^F are the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C (O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(＝ Substituted by NH)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

Alternatively, two R ^F attached to the same carbon atom together with the attached carbon atom form a -C(=O)- or -C(=NOH);

^R3 is selected from a hydrogen atom or a 5-10 membered heteroaryl group, wherein the heteroaryl group is optionally further substituted by one or more ^RJ ;

R and ^J are the same or different, each independently selected from halogen, hydroxyl, cyano, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the alkyl or alkoxy is optionally further replaced by a Or substituted by multiple substituents selected from halogen, hydroxyl, cyano, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ⁴ is the same or different, each independently selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; the alkane described therein group, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further optionally further substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, oxo, C ₁ -C ₆ alkyl, C Substituted with a substituent of ₁ -C ₆ aryl, C ₁ -C ₆ alkoxy, -C(O)R ⁵ or -S(O) _r R ⁵ ;

Alternatively, two R ⁴ attached to the same carbon atom together with the attached carbon atom form a -C(=O)-;

The condition is: when the following conditions are met at the same time, at least one R ⁴ is not a hydrogen atom:

1) Q is CH, R ³ is a hydrogen atom, ring B is selected from phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

2) for Wherein R ^C , ^RD and ^RE are each independently selected from hydrogen atoms or halogens, and R ^B is selected from hydrogen atoms, halogens, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkyl groups or C ₁ - C ₆ haloalkyl;

3) L ² is selected from bond, methylene, ethylene, -C(O)-, -CH ₂ NR ^d - or -CH ₂ NR ^d C(O)-, and R ^d is selected from hydrogen atom or C ₁ -C ₆ alkyl;

4) L ¹ is selected from -(CH ₂ ) ₆ NH-;

5) R ² is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -C(O)OR ⁵ or -NR ⁶ R ⁷ ; wherein the aryl group , heteroaryl or heterocyclyl are optionally further substituted by one or more ^RF ; and ^RF is selected from halogen, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl, or two R ^F connected to the same carbon atom together with the connected carbon atom form a -C(=O)-;

R ⁵ is selected from hydrogen atom, C ₁ -C ₆ alkyl group, -NR ⁹ R ¹⁰ , C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclyl group, C ₆ -C ₁₀ aryl group or 5-10 membered group. Heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C Substituted by (O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituents;

R ⁶ and R ⁷ are each independently selected from hydrogen atom, hydroxyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl , C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more Selected from hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ -hydroxyalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -C(O)R ⁸ , - Substitution of C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituted by base;

Alternatively, R ⁶ and R ⁷ together with the atoms to which they are connected form a 4- to 8-membered heterocyclyl group, wherein the 4- to 8-membered heterocyclyl group contains one or more N, O or S(O) _r , and the The 4 to 8-membered heterocyclic group is optionally further substituted by one or more members selected from hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 Metaheteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO Substituted by ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituents;

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen atom, C ₁ -C ₆ alkyl group, amino group, C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclyl group, C ₆ -C ₁₀ aryl group Or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more hydroxyl, halogen, nitro, amino, cyanide Base, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl Substituted by a substituent of a group, a carboxyl group or a carboxylate group;

r is selected from 0, 1 or 2;

m is selected from 0, 1, 2 or 3;

n is selected from 0, 1, 2, 3 or 4.

As a preferred embodiment of the present invention, a compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or Its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

R ^B is selected from hydrogen atom, halogen, cyano group, carboxyl group, ester group, C ₁ -C ₆ alkyl group, -OR ⁵ , C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more C ₁ -C ₆ alkyl groups , Halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O) Substituted by NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

^RC , ^RD and ^RE are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, carboxyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, aryl or heteroaryl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, C ₁ -C Substituted with ₆ alkyl or C ₁ -C ₆ alkoxy substituents;

Rings B, X, Q, R ² to R ⁷ , L ¹ , L ² , r and n are as defined in general formula (I).

As a preferred embodiment of the present invention, a compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or Its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

R ^G and R ^H are the same or different, and are each independently selected from hydrogen atoms, hydroxyl, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is any is further selected from one or more C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O) Substituted by NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

Rings B, X, Q, R ² to R ⁷ , L ¹ , L ² , r and n are as defined in general formula (I).

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Q is N .

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Q is CH , CCH ₃ , CCOOH or CCOOCH ₃ .

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is - S-.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is - ^NRc- ;

R ^c is selected from hydrogen atom, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups described above are optionally further substituted by one or more ^RA ;

^RA is the same or different, each independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl group or -OR ⁵ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more C ₁ -C ₆ alkyl, =O or -OR Substituted by ⁵ substituents;

R ⁵ is selected from C ₁ -C ₆ alkyl, preferably methyl.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is selected from The following groups: -NH-,

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer Isomers or pharmaceutically acceptable salts thereof, wherein L ¹ is selected from bond, C ₁ -C ₉ alkylene, C ₂ -C ₇ alkenylene or C ₂ -C ₇ alkynylene, wherein said alkylene One or more methylene groups in the alkyl, alkenylene or alkynylene group are optionally replaced by one or more O, S(O) _r , C(O) or NR ^d ;

r is selected from 0, 1 or 2;

R ^d is selected from a hydrogen atom or a methyl group.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ¹ is selected from Autobond, -(CH ₂ ) _1-7 -, -CH ₂ C≡C(CH ₂ ) ₂ NH-, -CH ₂ C≡C(CH ₂ ) ₃ NH-, -(CH ₂ ) ₂ CH＝CH (CH ₂ ) ₂ NH-, -(CH ₂ ) ₃ O(CH ₂ ) ₃ -, -(CH ₂ ) ₃ O(CH 2 ) ₂ -, -( _{CH 2 ) 3} N(CH ₃ )(CH ₂ ) ₂ -, -(CH ₂ ) ₅ C(O)-, -O(CH ₂ ) ₅ -, -(CH ₂ ) ₅ O-, -(CH ₂ ) ₅ OCH ₂ -, -(CH ₂ ) ₆ O-, -(CH ₂ ) ₅ OCH(CH ₃ )-, -CH ₂ NHC(O)NH(CH ₂ ) ₂ NH-, -(CH ₂ ) ₂ O(CH ₂ ) ₂ O(CH ₂ ) ₂ NH-, -(CH ₂ ) ₆ N(CH ₃ )- or -(CH ₂ ) ₆ NH-.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ² is selected from from a bond or a C ₁ -C ₆ alkylene group, wherein the alkylene group is optionally further substituted by one or more halogens or hydroxyl groups; and wherein one or more methylene groups in the alkylene group optionally replaced by one or more O, S(O) _r , C(O) or NR ^d ;

r is selected from 0, 1 or 2;

R ^d is selected from a hydrogen atom or a methyl group.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ² is selected from Autobond, -C(O)-, -NH-, -O-, -CH ₂ -, -(CH ₂ ) ₂ , -CH(CH ₃ )-, -CH(OH)-, -CH ₂ NH- , -(CH ₂ ) ₂ NH-, -CH ₂ N(CH ₃ )-, -C(O)CH ₂ -, -C(O)NH-, -CH ₂ C(O)NH-, -C( O)(CH ₂ ) ₂ NH-, -CH ₂ O-, -CH ₂ N(CH ₃ )C(O)- or -CH ₂ NHC(O)-.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from From the following groups:

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is selected From hydrogen atom, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, 3-10 membered heterocyclyl group, C ₃ -C ₁₀ cycloalkyl group, 6-14 membered fused ring, -OR ⁵ , - C(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; wherein the aryl, heteroaryl, heterocyclyl, cycloalkyl or The fused ring is optionally further substituted by one or more ^RF ;

R ^F are the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, cyano, carboxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, -OR ⁵ , -NR ⁶ R ⁷ , -C(O)R ⁵ , -NHC(O)R ⁵ , -C(O)NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl group, heterocyclyl group or aryl group Optionally further selected from one or more C ₁ -C ₆ alkyl, 3-10 membered heterocyclyl, halogen, =O, -OR ⁵ , -NR ⁶ R ⁷ or -C(=NH)NR ⁶ R Substituted by ⁷ substituents;

Alternatively, two R ^F attached to the same carbon atom together with the attached carbon atom form a -C(=O)- or -C(=NOH)-;

R ⁵ is selected from hydrogen atom, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl group or 3-10 membered heterocyclic group;

R ⁶ and R ⁷ are the same or different, and are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; wherein the alkyl group or alkoxy group is optionally further substituted by one or Substituted with multiple substituents selected from halogen, hydroxyl, cyano, -NR ⁹ R ¹⁰ or C ₁ -C ₆ alkoxy;

R ⁹ and R ¹⁰ are the same or different, and are each independently selected from a hydrogen atom or a methyl group;

r is 2.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is selected From the following groups: hydrogen atoms,


Or methoxy.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is selected from from hydrogen atoms.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is selected from From 5-10 membered heteroaryl, wherein the heteroaryl is optionally further substituted by one or more ^RJ ;

R and ^J are the same or different, each independently selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more selected from halogen, Substituted with hydroxyl, cyano, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy substituents.

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is selected from From the following groups:

As a preferred embodiment of the present invention, a compound represented by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from From hydrogen atom, halogen, hydroxyl, cyano group, carboxyl group, ester group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₁₀ cycloalkyl group, 5-10 membered heteroaryl group, C ₆ -C ₁₀ aryl or -C(O)NH ₂ , wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, phenyl, oxo or cyano. ;

Alternatively, two R ⁴ 's attached to the same carbon atom together with the attached carbon atom form a -C(=O)-.

As a preferred embodiment of the present invention, a compound represented by general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^C , ^RD and ^RE are each independently Selected from hydrogen atom or phenyl group, R ^B is selected from hydrogen atom, C ₁ -C ₆ alkyl group, C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclyl group, C ₆ -C ₁₀ aryl group or 5- 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, C ₁ -C ₆ alkyl substituted by a substituent of a C ₁ -C ₆ alkoxy group.

As a preferred embodiment of the present invention, a compound represented by general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ^C and ^RE are selected from hydrogen atoms;

R ^D is selected from a hydrogen atom or a phenyl group;

R ^B is selected from a hydrogen atom, trifluoromethyl, phenyl, pyridyl, pyrazolyl, cyclohexyl or cyclopropyl.

As a preferred embodiment of the present invention, a compound represented by general formula (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^H is selected from hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group or C ₆ -C ₁₀ aryl group;

R ^G is selected from hydrogen atoms or 5-10 membered heteroaryl groups, wherein the heteroaryl group is optionally further substituted by one or more selected from C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, Substituted with C ₃ -C ₁₀ cycloalkyl or -OR ⁵ substituents;

R ⁵ is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group, which is preferably a methyl group.

As a preferred embodiment of the present invention, a compound represented by general formula (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ^H is selected from hydrogen atom, methyl, trifluoromethyl or phenyl;

R ^G is selected from the following groups: hydrogen atoms,

In the preferred embodiment of the present invention, the compound described in general formula (I) is selected from:

Or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

NOTE: If there is a difference between a drawn structure and the name given to that structure, greater weight will be given to the drawn structure.

Furthermore, the present invention provides a pharmaceutical composition containing an effective dose of the compound described in general formula (I), (II) or (III) or its stereoisomer or tautomer. body or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.

The present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (such as the aforementioned The use of the pharmaceutical composition described in the technical solution) in the preparation of RAC1 inhibitors.

The present invention also provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (such as The pharmaceutical composition described in the previous technical solution) is used in the preparation of the treatment of RAC1 Use in drugs for mutation-mediated diseases, wherein the disease mediated by RAC1 mutations is preferably selected from the group consisting of cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease disease and Alzheimer's disease, wherein the cancer is preferably selected from the group consisting of melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate carcinoma and B-cell lymphoma, more preferably melanoma.

The present invention provides a compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (such as the aforementioned The pharmaceutical composition described in the technical solution) in the preparation of drugs for the treatment of cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease Use, wherein the cancer is preferably selected from the group consisting of melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate cancer and B-cell lymphoma , more preferably melanoma.

In another aspect, the invention provides a method for preventing and/or treating diseases mediated by RAC1 mutations, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), (II) or (III) Or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (such as the pharmaceutical composition described in the aforementioned technical solution), wherein the disease mediated by RAC1 mutation is preferably Selected from cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease, wherein the cancer is preferably selected from melanoma, gastric cancer, colon cancer , breast cancer, lung cancer, testicular cell cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate cancer and B-cell lymphoma, more preferably melanoma.

The present invention provides a method for preventing and/or treating cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease, comprising administering to a patient a treatment An effective dose of the compound described in general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition (such as the aforementioned technical solution Described pharmaceutical composition), wherein said cancer is preferably selected from melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, prostate carcinoma and B-cell lymphoma, more preferably melanoma.

Detailed description of the invention

Unless stated to the contrary, some terms used in the description and claims of the present invention are defined as follows:

"Bond" means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.

"Alkyl" when used as a group or part of a group means a C ₁ -C ₂₀ linear or branched aliphatic hydrocarbon group. Preferably it is a C ₁ -C ₁₀ alkyl group, more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait. Alkyl groups may be substituted or unsubstituted.

"Alkylene" refers to a saturated C ₁ -C ₂₀ linear or branched aliphatic hydrocarbon group, which has 2 hydrogen atoms derived from the same carbon atom or two different carbon atoms of the parent alkane. The residue is preferably a C ₁ -C ₁₀ alkylene group, and more preferably a C ₁ -C ₇ alkylene group. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1, 3-propylene, 1,4-butylene, etc. Alkylene groups may be substituted or unsubstituted.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

"Alkenylene" refers to an alkylene group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a C ₂ -C ₇ alkenylene group. Examples of alkenylene groups include -CH ₂ =CH ₂ -, -CH ₂ CH=CHCH ₂ -, -CH ₂ =CH-CH=CH ₂ -, -(CH ₂ ) ₂ CH=CH(CH ₂ ) ₃ -etc. Alkenylene groups may be optionally substituted or unsubstituted.

"Alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which can be straight or branched. Preference is given to C ₂ -C ₁₀ alkynyl groups, more preferably C ₂ -C ₆ alkynyl groups, and most preferably C ₂ -C ₄ alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"Alkynylene" refers to an alkylene group as defined above containing at least one carbon-carbon triple bond, preferably a C ₂ -C ₇ alkynylene group. Examples of alkynylene groups include -C≡C-, -CH ₂ C≡CCH ₂ -, -CH ₂ C≡C(CH ₂ ) ₂ -, -CH ₂ C≡C(CH ₂ ) ₃ -, -CH ₂ C≡C(CH ₂ ) ₄ -etc. Alkynylene groups may be optionally substituted or unsubstituted.

"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. Preferred is C ₃ -C ₁₀ cycloalkyl, more preferred is C ₃ -C ₈ cycloalkyl, and most preferred is C ₃ -C ₆ cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl group, cyclooctyl group, etc., preferably cyclopropyl group and cyclohexenyl group. Cycloalkyl groups may be substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one carbon atom (called a spiro atom) with each other. The ring may contain 1 or more An aromatic system with multiple double bonds but no single ring with fully conjugated π electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into single spiro, double spiro or polyspiral cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl,

"Condensed cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members and containing two or more cyclic structures sharing a pair of carbon atoms with each other. One or more rings may contain one or more double bonds. However, aromatic systems in which none of the rings have fully conjugated π electrons are preferably 6 to 12 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed ring alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl groups. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecahydrophenanthyl.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. One or more rings may contain one or more Aromatic systems with multiple double bonds but no ring having fully conjugated π electrons are preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl,

"Heterocyclyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclyl, in which one or more ring-forming atoms are heteroatoms, such as oxygen, Nitrogen, sulfur atoms, etc., including single ring, polycyclic ring, fused ring, bridged ring and spiro ring.

Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl Phyllinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,

Monocyclic heterocyclyl groups may be substituted or unsubstituted.

"Spiroheterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and the single rings share one atom with each other. The ring may contain 1 or more double bonds, but Aromatic systems in which none of the rings have fully conjugated π electrons, in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) _p (where p is selected from 0, 1, or 2), and the remaining ring atoms for carbon. According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

Spiroheterocyclyl may be substituted or unsubstituted.

"Condensed heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other. One or more rings may contain one or more double bonds, but no ring is completely conjugated. An aromatic system of π electrons in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) _p (where p is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrro[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxin (dioxine),

"Bridged heterocyclyl" refers to a polycyclic group with 5 to 14 members, 5 to 18 members, containing two or more cyclic structures and sharing two atoms that are not directly connected to each other. One or more rings can Aromatic systems containing one or more double bonds but no ring with fully conjugated π electrons, in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _p (where p is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabi Ring[3.3.2]decyl,

Bridged heterocyclyl groups may be substituted or unsubstituted.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferred aryl groups are C ₆ -C ₁₀ aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups. Aryl groups may be substituted or unsubstituted.

"Heteroaryl" refers to an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoyl Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzo Isothiazolyl, benzoxazolyl, benzisoxazolyl, pyridone group,

Heteroaryl groups may be substituted or unsubstituted.

"Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, in which at least one ring has an aromatic system with fully conjugated π electrons, and at the same time, one or more rings can Aromatic systems containing one or more double bonds, but at least one ring that does not have fully conjugated π electrons, in which the ring atoms are selected from 0, one or more are selected from nitrogen, oxygen, or S(O) _p (where p Heteroatom selected from 0, 1 or 2), the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:

"Alkoxy" refers to the group (alkyl-O-). Among them, alkyl group is as defined in this article. C ₁ -C ₆ alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

"Hydroxyalkyl" refers to a hydroxyl-substituted alkyl group.

"Haloalkyl" refers to a halogen-substituted alkyl group.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to -NO ₂ .

"Benzyl" refers to _-CH2 -phenyl.

"DMSO" refers to dimethyl sulfoxide.

"Leaving group", also known as leaving group, is an atom or functional group that is separated from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called a substrate, and the atom or atomic group that breaks away from the substrate molecule with a pair of electrons is called a leaving group. Groups that are easy to accept electrons and have strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the leaving group is more likely to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be combined with other atoms, and the tendency to exist in the form of anion (or electrically neutral leaving group) increases. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs or -OH.

"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more substituents.

"Pharmaceutically acceptable salts" refer to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by the general formula (I), (II) or (III) may be a metal salt or an ammonium salt formed with a suitable acid.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, together with other ingredients such as physiologically acceptable carriers and excipients. form agent. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

Synthetic methods of compounds of the present invention

In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

Depending on the group, the preparation method of the compound of general formula (I) of the present invention includes:

method one:

(1):

The compound of general formula (IA) and the compound of general formula (IB) undergo a substitution reaction under the action of an alkaline reagent, and optionally further remove the protecting group to obtain the compound of general formula (I);

in:

X ¹ is a leaving group, preferably halogen;

L ¹ is -L ³ -NH-;

L ³ is selected from bond, -C ₁ -C ₈ alkylene, -C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene Optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy, and wherein one of the alkylene, alkenylene or alkynylene groups One or more methylene groups are optionally further replaced by one or more O, S(O) _r , C(O) or NR ^d ;

R ^d is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

r is selected from 0, 1 or 2;

Ring A, ring B, R ¹ to R ⁴ , X, L ² , Q, m and n are as defined in general formula (I).

(2):

The compound of general formula (IC) and the compound of general formula (IB) undergo a reductive amination reaction under the action of an alkaline reagent, and optionally further remove the protecting group to obtain the compound of general formula (I);

in:

L ¹ is -L ⁴ -CH ₂ -NH-;

L ⁴ is selected from bond, -C ₁ -C ₇ alkylene, -C ₂ -C ₅ alkenylene or C ₂ -C ₅ alkynylene, wherein said alkylene, alkenylene or alkynylene Optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy, and wherein one of the alkylene, alkenylene or alkynylene groups or multiple methylene groups are optionally further replaced by one or more O, S(O) _r , C(O) or NR ^d ; R ^d is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

r is selected from 0, 1 or 2;

Ring A, ring B, R ¹ to R ⁴ , X, L ² , Q, m and n are as defined in general formula (I).

Method Two:

The compound of general formula (ID) and the compound of general formula (IE) undergo a substitution reaction under the action of an alkaline reagent, and optionally further remove the protecting group to obtain the compound of general formula (I);

in:

X ² is a leaving group, preferably halogen;

L ¹ is -L ⁵ -OL ⁶ ;

L ⁶ is selected from bond, methylene or ethylene;

L ⁵ is selected from bond, -C ₁ -C ₈ alkylene, -C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene Optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy, and wherein one of the alkylene, alkenylene or alkynylene groups One or more methylene groups are optionally further replaced by one or more O, S(O) _r , C(O) or NR ^d ;

R ^d is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

r is selected from 0, 1 or 2;

Ring A, ring B, R ¹ to R ⁴ , X, L ² , Q, m and n are as defined in general formula (I).

Method three:

The compound of general formula (IF) and the compound of general formula (IG) undergo a substitution reaction under the action of an alkaline reagent, and optionally further perform a deprotection reaction to obtain the compound of general formula (I);

in:

X ³ is a leaving group, preferably halogen or methylsulfonyloxy;

Ring A, ring B, R ¹ to R ⁴ , X, L ¹ , L ² , Q, m and n are as defined in general formula (I).

Method four:

The compound of general formula (IH) and the compound of general formula (IJ) undergo a substitution reaction under the action of an alkaline reagent, and optionally further perform a deprotection reaction to obtain the compound of general formula (I);

in:

X ⁴ is a leaving group, preferably halogen;

Ring A, ring B, R ¹ to R ⁴ , X, L ¹ , L ² , Q, m and n are as defined in general formula (I).

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example

The examples provide the preparation and related structural identification data of representative compounds represented by formula (I). It must be noted that the following examples are used to illustrate the present invention but not to limit the present invention. ^{The 1} H NMR spectrum was measured with a Bruker instrument (400MHz), and the chemical shift was expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If a coupling constant is provided, its unit is Hz.

The mass spectrum is measured with an LC/MS instrument, and the ionization method can be ESI or APCI.

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai Silica Gel 200~300 mesh silica gel as the carrier.

In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are not further purified. For direct use, unless otherwise specified, commercially available manufacturers include but are not limited to Shanghai Haohong Biomedical Technology Co., Ltd., Shanghai Shaoyuan Reagents Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Sann Chemical Technology (Shanghai) Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd., etc.

MeOD-d ₄ : deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : Deuterated dimethyl sulfoxide.

Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1L.

There is no special explanation in the examples. The solution in the reaction refers to an aqueous solution.

The compound is purified using an eluent system of column chromatography and thin layer chromatography, wherein the system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system, D: methylene chloride and ethanol system, in which the volume ratio of the solvent varies according to the polarity of the compound. A small amount of acidic or alkaline reagents can also be added to condition, such as acetic acid or triethylamine, etc.

Room temperature: 20℃～30℃.

Example 1

2-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

2-Methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(3-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(3-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (300 mg, 682.94 μmol, prepared according to published patent WO2019023315), 4-(4-amino-3-methylbenzene) tert-butyl piperazine-1-carboxylate 1b (298.50 mg, 1.02 mmol, prepared according to published patent US20200354352) and potassium carbonate (188.77 mg, 1.37 mmol) were dissolved in N, N-dimethylformamide (5 mL) medium, raise the temperature to 80°C and stir for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(3-methyl-4-((6-((7-(trifluoromethyl))quinolin-4-yl )Thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 1c (246 mg), yield 59.76%. MS m/z(ESI):603.4[M+1].

Step 2

2-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

2-Methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(3-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 1c (246 mg, 408.13 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate solution to adjust the pH to 8-9, extract with ethyl acetate (50 mL 21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 2-methyl-4-(piperazin-1-yl)-N- (6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 1(100 mg), yield 48.75%.

MS m/z(ESI):503.2[M+1].

¹ H NMR (400MHz, CDCl ₃ ) δ8.72 (d, J＝4.8Hz, 1H), 8.37–8.06 (m, 2H), 7.64 (dd, J＝8.9, 1.6Hz, 1H), 7.18 (s, 1H),6.78–6.62(m,2H),6.49(d,J＝9.3Hz,1H),3.06(t,J＝7.2Hz,4H),2.94(dd,J＝13.9,6.0Hz,8H), 2.05(s,3H),1.84–1.74(m,2H),1.67–1.58(m,2H),1.57–1.49(m,2H),1.45(d,J＝6.6Hz,2H).

Example 2

3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (300 mg, 682.94 μmol, prepared according to published patent WO2019023315), 4-(4-amino-2-methylbenzene) tert-butyl piperazine-1-carboxylate 2a (298.50 mg, 1.02 mmol, prepared according to published patent WO2013051672) and potassium carbonate (188.77 mg, 1.37 mmol) were dissolved in N, N-dimethylformamide (5 mL) The solution was heated to 80°C and stirred for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(2-methyl-4-((6-((7-(trifluoromethyl))quinolin-4-yl )Thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 2b (266 mg), yield 64.62%. MS m/z(ESI):603.3[M+1].

Step 2

3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 2b (266 mg, 441.31 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9, extract with ethyl acetate (50 mL × 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), obtaining 3-methyl-4-(piperazin-1-yl)-N-( 6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 2 (70 mg), yield 31.56%.

MS m/z(ESI):503.2[M+1].

¹ H NMR (400MHz, CDCl ₃ ) δ8.78 (dd, J＝4.7, 2.2Hz, 1H), 8.40–8.18 (m, 2H), 7.71 (d, J＝8.8Hz, 1H), 7.24 (s, 1H),6.91(d,J＝8.3Hz,1H),6.52–6.39(m,2H),3.17–3.06(m,4H),2.98(d,J＝3.2Hz,4H),2.78(d,J ＝2.5Hz,4H),2.25(s,3H),1.90–1.78(m,2H),1.69–1.62(m,2H),1.61–1.55(m,2H),1.49(d,J＝6.8Hz, 2H).

Example 3

N-(6-((7-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)anilineN-(6-((7-phenylquinolin-4-yl)thio) Hexyl)-4-(piperazin-1-yl)aniline

first step

4-chloro-7-phenylquinoline

4-Chloro-7-phenylquinoline

7-Phenylquinolin-4-ol 3a (0.7g, 3.16mmol, prepared according to published patent WO2004058759) was added to phosphorus oxychloride (45.92g, 299.48mmol), and the reaction mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain 4-chloro-7-phenylquinoline 3b (0.7g) with a yield of 92.30%.

MS m/z(ESI):240.0[M+1].

Step 2

7-phenylquinoline-4-thiol

7-Phenylquinoline-4-thiol

Sodium sulfide nonahydrate (3.92g, 50.17mmol) was added to a solution of 4-chloro-7-phenylquinoline 3b (1.3g, 5.42mmol) in N,N-dimethylformamide (20mL), and the reaction mixture Stir at 80°C for 2 hours. After the reaction is complete, add water (100mL) to the reaction solution, add 1N hydrochloric acid solution dropwise to adjust the pH to 5~6, extract with ethyl acetate (100mL×3), combine the organic phases, and wash with saturated brine (100mL ), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to obtain 7-phenylquinoline-4-thiol 3c (1.2g) , yield 93.23%. MS m/z(ESI):238.0[M+1].

third step

4-((6-iodohexyl)thio)-7-phenylquinoline

4-((6-iodohexyl)thio)-7-phenylquinoline

Potassium carbonate (0.58g, 4.19mmol) was added to 7-phenylquinoline-4-thiol 3c (0.5g, 2.18mmol) and 1,6-diiodohexane 3d (2.21g, 6.54mmol, commercially available ) in acetonitrile (20 mL), the reaction mixture was stirred at room temperature for 12 hours. After the reaction is complete, add saturated sodium carbonate solution (100 mL) to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-((6-iodohexyl)thio)-7-phenylquinoline 3e (0.3g), yield 31.83 %.

MS m/z(ESI):448.0[M+1].

the fourth step

tert-butyl 4-(4-((6-((7-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-((7-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-((6-iodohexyl)thio)-7-phenylquinoline 3e (0.28g, 625.87μmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid Tert-butyl ester 3f (173.59 mg, 625.87 μmol, prepared according to published patent WO2021183994) and potassium carbonate (0.17 g, 1.25 mmol) were dissolved in N, N-dimethylformamide (5 mL) solution, and the reaction mixture was heated at 80°C Stir for 3 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(4-((6-((7-phenylquinolin-4-yl)thio)hexyl)amino)benzene (3g) piperazine-1-carboxylic acid tert-butyl ester (303 mg), yield 81.12%.

MS m/z(ESI):597.4[M+1].

the fifth step

N-(6-((7-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

3g (300mg, 502.66μmol) of 4-(4-((6-((7-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester Dissolve in a mixed solution of dichloromethane (3mL) and trifluoroacetic acid (1mL). The reaction mixture is stirred at room temperature for 2 hours. Add saturated sodium bicarbonate solution to adjust the pH to 8~9, and extract with ethyl acetate (50mL× 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: CH ₃ CN), obtaining N-(6-((7-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline 3 (24.8 mg ), yield 9.93%.

MS m/z(ESI):497.4[M+1].

¹ H NMR (400MHz, DMSO) δ8.74(d,J＝4.8Hz,1H),8.24(d,J＝1.6Hz,1H),8.15(d,J＝8.8Hz,1H),7.97(m, 1H),7.86(d,J＝7.2Hz,2H),7.54(m,2H),7.44(m,2H),6.70(d,J＝8.8Hz,2H),6.47(d,J＝8.8Hz, 2H),5.01(s,1H),3.23(m,2H),2.93(s,2H),2.82(s,8H),1.80–1.72(m,2H),1.56–1.49(m,4H),1.43 (d,J=6.8Hz,2H).

Example 4

4-(piperazin-1-yl)-N-(6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-N-(6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)aniline

first step

7-(pyridin-2-yl)quinoline-4-thiol

7-(pyridin-2-yl)quinoline-4-thiol

Sodium sulfide nonahydrate (508.93 mg, 2.12 mmol) was added to N,N-dimethylmethane of 4-chloro-7-(2-pyridyl)quinoline 4a (170 mg, 706.31 μmol, prepared according to published patent US20080234267). In amide solution (2 mL), the reaction mixture was stirred at 80 °C for 2 h. After the reaction is completed, add water (20 mL) to the reaction solution, add 1N hydrochloric acid dropwise to adjust the pH to 5-6, extract with ethyl acetate (20 mL × 3), combine the organic phases, and wash with saturated brine (20 mL). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by column chromatography (eluent: B system) to obtain 7-(pyridin-2-yl)quinoline-4-thiol 4b ( 111mg), yield 65.95%.

MS m/z(ESI):239.0[M+1].

Step 2

4-((6-iodohexyl)thio)-7-(pyridin-2-yl)quinoline

4-((6-iodohexyl)thio)-7-(pyridin-2-yl)quinoline

Potassium carbonate (70.81 mg, 2.36 μmol) was added to 7-(pyridin-2-yl)quinoline-4-thiol 4b (111 mg, 465.79 μmol) and 1,6-diiodohexane (629.69 mg, 1.86 mmol). ) in acetonitrile (4 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, add saturated sodium carbonate solution (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by column chromatography (eluent: B system) to obtain 4-((6-iodohexyl)thio)-7-(pyridin-2-yl)quinoline 4c (156 mg) , yield 74.7%.

MS m/z(ESI):449.0[M+1].

third step

tert-butyl 4-(4-((6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-((6-iodohexyl)thio)-7-(pyridin-2-yl)quinoline 4c (156 mg, 347.93 μmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert. Butyl ester 3f (144.76 mg, 521.90 μmol) and potassium carbonate (96.17 mg, 695.87 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C for 3 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to obtain 4-(4-((6-((7-(pyridin-2-yl)quinolin-4-yl)thio)) Hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 4d (50mg), Yield 24.04%.

MS m/z(ESI):598.4[M+1].

the fourth step

4-(piperazin-1-yl)-N-(6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-N-(6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)aniline

4-(4-((6-((7-(pyridin-2-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 4d( 50 mg, 83.64 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8~9, and use ethyl acetate to adjust the pH to 8-9. Extract (20mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA +H ₂ O, mobile phase B: CH ₃ CN) to obtain 4-(piperazin-1-yl)-N-(6-((7-(pyridin-2-yl)quinolin-4-yl)sulfide) Substitute)hexyl)aniline 4 (4.68 mg), yield 11.25%.

MS m/z(ESI):498.2[M+1].

¹ H NMR (400MHz, CDCl3) δ8.76 (dd, J＝11.6, 4.4Hz, 2H), 8.59 (s, 1H), 8.37–8.29 (m, 1H), 8.23 (d, J＝8.8Hz, 1H ),7.95(d,J＝8.0Hz,1H),7.83(t,J＝7.2Hz,1H),7.34–7.28(m,1H),7.18(d,J＝4.8Hz,1H),6.84(d ,J＝8.8Hz,2H),6.58(d,J＝8.8Hz,2H),3.18–3.01(m,12H),1.90–1.81(m,2H),1.70–1.54(m,4H),1.50( d,J＝6.4Hz,2H).

Example 5

5-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)quinolin-8-amine

5-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)quinolin-8-amine

first step

tert-butyl 4-(8-aminoquinolin-5-yl)piperazine-1-carboxylate

4-(8-Aminoquinolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester

4-(8-Nitroquinolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester 5a (314 mg, 876.14 μmol, prepared according to published patent CN112390751) and palladium carbon (70 mg, 657.77 μmol) were dissolved in methanol (4 mL) solution, the reaction mixture was stirred at 40°C for 3 hours under a hydrogen atmosphere. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 4-(8-aminoquinoline- 5-yl)piperazine-1-carboxylic acid tert-butyl ester 5b (256 mg), yield 88.97%.

MS m/z(ESI):329.2[M+1].

Step 2

tert-butyl 4-(8-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)quinolin-5-yl)piperazine-1-carboxylate

tert-butyl 4-(8-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)quinolin-5-yl)piperazine-1-carboxylate

4-(6-iodohexylsulfanyl)-7-(trifluoromethyl)quinoline 1a (228.28 mg, 519.68 μmol), 4-(8-aminoquinolin-5-yl)piperazine-1- Tert-butyl carboxylate 5b (256 mg, 779.52 μmol) and potassium carbonate (143.65 mg, 1.04 mmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(8-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl) )Amino)quinolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester 5c (60 mg), yield 18.05%.

MS m/z(ESI):640.2[M+1].

third step

5-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)quinolin-8-amine

5-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)quinolin-8-amine

tert-butyl 4-(8-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)quinolin-5-yl)piperazine-1-carboxylate Ester 5c (60 mg, 93.78 μmol) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.6 mL). The reaction mixture was stirred at room temperature for 2 hours, and saturated sodium bicarbonate was added to adjust the pH to 8~9. Extract with ethyl acetate (20ml :0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 5-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinoline-4- Thio)hexyl)quinolin-8-amine 5 (8.8 mg), yield 17.39%.

MS m/z(ESI):540.2[M+1].

¹ H NMR (400MHz, CDCl3) δ8.70(d,J＝4.8Hz,1H),8.64(d,J＝2.8Hz,1H),8.44(d,J＝8.0Hz,1H),8.29(s, 1H),8.17(d,J＝8.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.32(dd,J＝8.4,4.0Hz,1H),7.17(s,1H),7.03( d,J＝8.0Hz,1H),6.51(d,J＝8.0Hz,1H),3.24(t,J＝6.8Hz,2H),3.12–3.02(m,6H),3.00–2.85(m,4H ),1.85–1.70(m,4H),1.58–1.48(m,4H).

Example 6

N-(6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

first step

7-(1H-pyrazol-1-yl)quinolin-4-ol

7-(1H-pyrazol-1-yl)quinolin-4-ol

7-Bromoquinolin-4-ol 6a (0.50g, 2.23mmol, prepared according to published patent WO2021062245), 1H-pyrazole (151.92mg, 2.23mmol), copper iodide (425.01mg, 2.23mmol), carbonic acid Sodium (468.64mg, 4.46mmol) and N,N'-dimethylethylenediamine (589.14mg, 6.69mmol) were dissolved in dimethyl sulfoxide (10mL) solution, and nitrogen was replaced three times. The reaction mixture was heated at 120°C. Stir for 12 hours. After the reaction, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to obtain 7-(1H-pyrazol-1-yl)quinolin-4-ol 6b (0.21g) with a yield of 44.55%.

MS m/z(ESI):212.0[M+1].

Step 2

4-chloro-7-(1H-pyrazol-1-yl)quinoline

4-Chloro-7-(1H-pyrazol-1-yl)quinoline

7-(1H-pyrazol-1-yl)quinolin-4-ol 6b (0.2 g, 946.88 μmol) was added to phosphorus oxychloride (5 mL), and the reaction mixture was stirred at 100°C for 2 hours. After the reaction is completed, concentrate to dryness under reduced pressure to obtain 4-chloro-7-(1H-pyrazol-1-yl)quin Phenoline 6c (170 mg), yield 78.17%.

MS m/z(ESI):230.0[M+1].

third step

7-(1H-pyrazol-1-yl)quinoline-4-thiol

7-(1H-pyrazol-1-yl)quinoline-4-thiol

Sodium sulfide nonahydrate (122.27 mg, 1.57 mmol) was added to 4-chloro-7-(1H-pyrazol-1-yl)quinoline 6c (120 mg, 522.50 μmol) in N,N-dimethylformamide (5 mL ) solution, the reaction mixture was stirred at 80°C for 2 hours. After the reaction is completed, add water (50 mL) to the reaction solution, add 1N hydrochloric acid dropwise to adjust the pH to 5-6, extract with ethyl acetate (50 mL × 3), combine the organic phases, and wash with saturated brine (50 mL). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by column chromatography (eluent: B system) to obtain 7-(1H-pyrazol-1-yl)quinoline-4-sulfide. Alcohol 6d (100 mg), yield 84.21%.

MS m/z(ESI):228.0[M+1].

the fourth step

4-((6-iodohexyl)thio)-7-(1H-pyrazol-1-yl)quinoline

4-((6-iodohexyl)thio)-7-(1H-pyrazol-1-yl)quinoline

Potassium carbonate (236.80 mg, 1.72 mmol) was added to 7-(1H-pyrazol-1-yl)quinoline-4-thiol 6d (130 mg, 571.97 μmol) and 1,6-diiodohexane (193.31 mg , 571.97 μmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, add saturated sodium carbonate solution to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The residue was separated and purified by column chromatography (eluent: B system) to obtain 4-((6-iodohexyl)thio)-7-(1H-pyrazol-1-yl)quinoline 6e (150 mg) , yield 59.97%.

MS m/z(ESI):438.0[M+1].

the fifth step

4-(4-((6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(4-((6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-((6-iodohexyl)thio)-7-(1H-pyrazol-1-yl)quinoline 6e (130 mg, 297.25 μmol), 4-(4-aminophenyl)piperazine-1- Tert-butyl carboxylate 3f (82.45 mg, 297.25 μmol) and potassium carbonate (123.06 mg, 891.76 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C for 3 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to obtain 4-(4-((6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)) Thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 6f (120 mg), yield 68.80%.

MS m/z(ESI):587.6[M+1].

Step 6

N-(6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

tert-butyl 4-(4-((6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate Ester 6f (100 mg, 170.42 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 8-9. Extract with ethyl acetate (50mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining N-(6-((7-(1H-pyrazol-1-yl)quinolin-4-yl)thio)hexyl)- 4-(piperazin-1-yl)aniline 6 (21 mg), yield 25.32%.

MS m/z(ESI):487.4[M+1].

¹ H NMR (400MHz, DMSO) δ8.78(d,J＝2.4Hz,1H),8.74(d,J＝4.8Hz,1H),8.40(d,J＝2.0Hz,1H),8.16-8.24( m,2H),7.85(d,J＝1.6Hz,1H),7.41(d,J＝4.8Hz,1H),6.70(d,J＝8.8Hz,2H),6.65-6.56(m,1H), 6.46(d,J＝8.8Hz,2H),5.01(s,1H),3.23(t,J＝7.2Hz,2H),2.92(d,J＝6.8Hz,2H),2.84–2.80(m,8H ),1.82–1.69(m,2H),1.58–1.47(m,4H),1.43(d,J＝7.0Hz,2H).

Example 7

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4- yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1- tert-butyl carboxylate

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (450 mg, 1.02 mmol), 4-(4-amino-2-(trifluoromethyl)phenyl) Piperazine-1-carboxylic acid tert-butyl ester 7a (530.69 mg, 1.54 mmol, prepared according to published patent WO2018215668) and potassium carbonate (283.16 mg, 2.05 mmol) were dissolved in N, N-dimethylformamide (5 mL) solution , the reaction mixture was stirred at 80°C for 2 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 7b (312 mg), yield 46.38%.

MS m/z(ESI):658.0[M+1].

Step 2

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1 - Tert-butyl carboxylate 7b (312 mg, 475.09 μmol) was dissolved in a mixed solution of dichloromethane (9 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 8～9, extract with ethyl acetate (20mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min ; Mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 4-(piperazin-1-yl)-3-(trifluoromethyl)-N-(6-(( 7-(Trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 7 (101.4 mg), yield 38.35%.

MS m/z(ESI):557.2[M+1].

¹ H NMR (400MHz, CDCl ₃ ) δ8.79 (d, J = 4.8Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 8.8Hz, 1H), 7.71 (dd, J = 8.8, 2Hz,1H),7.25(s,1H),7.21(d,J＝8.8Hz,1H),6.80(d,J＝2.8Hz,1H),6.70(dd,J＝8.8,2.8Hz,1H), 3.16–3.09(m,4H),3.01–2.95(m,4H),2.83–2.78(m,4H),1.85(dd,J＝14.8,7.2Hz,2H),1.63–1.55(m,4H), 1.50(dd,J＝14.8,8.4Hz,2H).

Example 8

N-(6-((7-cyclohexylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-cyclohexylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

first step

7-(cyclohex-1-en-1-yl)quinolin-4-ol

7-(cyclohexyl-1-en-1-yl)quinolin-4-ol

7-bromoquinolin-4-ol 6a (1g, 4.46mmol), cyclohexen-1-ylboronic acid (2.25g, 17.85mmol), [1,1'-bis(diphenylphosphine)ferrocene ] Palladium dichloride dichloromethane complex (0.365g, 446.32μmol) and cesium carbonate (46.37g, 13.39mmol) were dissolved in a mixed solution of 1,4-dioxane (20mL) and water (4mL) , nitrogen was replaced three times, and the reaction mixture was stirred at 90°C for 20 hours. After the reaction, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to obtain 7-(cyclohexyl-1-en-1-yl)quinolin-4-ol 8a (533 mg) with a yield of 53.01%.

MS m/z(ESI):226.2[M+1].

Step 2

7-cyclohexylquinolin-4-ol

7-cyclohexylquinolin-4-ol

7-(cyclohexyl-1-en-1-yl)quinolin-4-ol 8a (0.590g, 2.62mmol), palladium on carbon (0.08g, 658.71μmol) and palladium hydroxide (0.08g, 2.62mmol) Dissolve in methanol (5 mL) solution, replace with hydrogen three times, and stir the reaction mixture at 100°C for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), the filtrate was collected and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 7-cyclohexylquinoline- 4-alcohol 8b (516 mg), yield 86.68%.

MS m/z(ESI):228.2[M+1].

third step

4-chloro-7-cyclohexylquinoline

4-Chloro-7-cyclohexylquinoline

7-Cyclohexylquinolin-4-ol 8b (0.435 g, 1.91 mmol) was added to phosphorus oxychloride (8 mL), and the reaction mixture was stirred at 100°C for 2 hours. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain 4-chloro-7-cyclohexylquinoline 8c (370 mg) with a yield of 78.67%.

MS m/z(ESI):246.2[M+1].

the fourth step

7-cyclohexylquinoline-4-thiol

7-cyclohexylquinoline-4-thiol

Sodium sulfide nonahydrate (330 mg, 4.27 mmol) was added to a solution of 4-chloro-7-cyclohexylquinoline 8c (0.35 g, 1.42 mmol) in N,N-dimethylformamide (2 mL), and the reaction mixture was Stir at 80°C for 2 hours. After the reaction is completed, add water (20 mL) to the reaction solution, add 1N hydrochloric acid dropwise to adjust the pH to 5-6, extract with ethyl acetate (20 mL × 3), combine the organic phases, and wash with saturated brine (20 mL). Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by column chromatography (eluent: B system) to obtain 7-cyclohexylquinoline-4-thiol 8d (230 mg), yield 66.36%. MS m/z(ESI):244.0[M+1].

the fifth step

7-cyclohexyl-4-((6-iodohexyl)thio)quinoline

7-Cyclohexyl-4-((6-iodohexyl)thio)quinoline

Potassium carbonate (170.37 mg, 1.23 mmol) was added to 7-cyclohexylquinoline-4-thiol 8d (0.1 g, 410.90 μmol) and 1,6-diiodohexane (418 mg, 1.23 mmol) in acetonitrile (5 mL ) solution, the reaction mixture was stirred at room temperature for 12 hours. After the reaction, add saturated sodium carbonate solution (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 7-cyclohexyl-4-((6-iodohexyl)thio)quinoline 8e (138 mg), with a yield of 74.07%. .

MS m/z(ESI):454.0[M+1].

Step 6

tert-butyl 4-(4-((6-((7-cyclohexylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-((7-cyclohexylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

7-Cyclohexyl-4-((6-iodohexyl)thio)quinoline 8e (0.08g, 176.44μmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester 3f ( 63.62 mg, 229.37 μmol) and potassium carbonate (48.7 mg, 352.87 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C for 3 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 4- (4-((6-((7-cyclohexylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 8f (85 mg), yield 79.91%.

MS m/z(ESI):603.4[M+1].

Step 7

N-(6-((7-cyclohexylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-cyclohexylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

4-(4-((6-((7-cyclohexylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 8f (120 mg, 199.05 μmol) Dissolve in a mixed solution of dichloromethane (5mL) and trifluoroacetic acid (2mL). The reaction mixture is stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8~9, and extract with ethyl acetate (50mL×3 ), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, Mobile phase B: CH ₃ CN), obtaining N-(6-((7-cyclohexylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline 8 (16 mg), Yield 15.99%.

MS m/z(ESI):503.2[M+1].

¹ H NMR (400MHz, DMSO) δ8.69 (d, J = 3.6Hz, 1H), 8.00 (d, J = 8.4Hz, 1H), 7.79 (s, 1H), 7.55 (d, J = 8.4Hz, 1H),7.38(d,J＝4.0Hz,1H),6.95-6.72(m,2H),6.70-6.50(m,2H),3.27-3.16(m,7H),3.15-3.05(m,3H) ,3.02-2.90(m,2H),2.78-2.65(m,1H),1.94–1.79(m,4H),1.78-1.65(m,3H),1.62–1.34(m,10H),1.31–1.20( m,1H).

Example 9

3-methoxy-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methoxy-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-methoxy-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-methoxy-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (200 mg, 455.29 μmol), 4-(4-amino-2-methoxyphenyl)piperazine- 1-tert-butylcarboxylate 9a (209.93 mg, 682.94 μmol, prepared according to published patent US20190106436) and potassium carbonate (125.85 mg, 910.59 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture Stir at 80°C for 2 hours. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(2-methoxy-4-((6-((7-(trifluoromethyl))quinoline-4- (Tert-butyl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate 9b (184 mg), yield 65.31%.

MS m/z(ESI):619.3[M+1].

Step 2

3-methoxy-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methoxy-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-methoxy-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid Tert-butyl ester 9b (160 mg, 258.59 μmol) was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 8~9. , extracted with ethyl acetate (50ml A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 3-methoxy-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl (yl)quinolin-4-yl)thio)hexyl)aniline 9 (33.3 mg), yield 24.83%.

MS m/z(ESI):519.2[M+1].

¹ H NMR (400MHz, CDCl ₃ ) δ8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.25(d,J＝8.8Hz,1H),7.74–7.66(m,1H) ,7.25(s,1H),6.81(d,J＝8.4Hz,1H),6.21–6.11(m,2H),3.82(s,3H),3.16–3.03(m,8H),2.98–2.90(m ,4H),1.88–1.83(m,2H),1.58(dd,J＝15.6,7.6Hz,4H),1.50(d,J＝6.8Hz,2H).

Example 10

3-chloro-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Chloro-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-chloro-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(2-chloro-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (200 mg, 455.29 μmol), 4-(4-amino-2-chlorophenyl)piperazine-1- Tert-butyl carboxylate 10a (212.95 mg, 682.94 μmol, prepared according to published patent WO2021074251) and potassium carbonate (125.85 mg, 910.59 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was heated at 80 Stir for 2 hours at ℃. After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System A) to obtain 4-(2-chloro-4-((6-((7-(trifluoromethyl)quinolin-4-yl)) Thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 10b (141 mg), yield 49.70%.

MS m/z(ESI):623.2[M+1].

Step 2

3-chloro-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Chloro-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

tert-butyl 4-(2-chloro-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate Ester 10b (160 mg, 256.75 μmol) was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 8-9. Extract with ethyl acetate (50mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3-chloro-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinoline) -4-yl)thio)hexyl)aniline 10 (52.2 mg), yield 38.84%.

MS m/z(ESI):523.2[M+1].

¹ H NMR (400MHz, CDCl ₃ ) δ8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.25(d,J＝8.8Hz,1H),7.71(d,J＝8.8Hz ,1H),7.26–7.23(m,1H),6.91(d,J＝8.4Hz,1H),6.65(s,1H),6.47(d,J＝8.4Hz,1H),3.13(t,J＝ 7.2Hz,2H),3.08(t,J＝7.2Hz,2H),3.05–3.01(m,4H),2.93–2.87(m,4H), 1.90–1.80(m,2H),1.60–1.54(m,4H),1.52–1.43(m,2H).

Example 11

2-(2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)acetonitrile

2-(2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)acetonitrile

first step

tert-butyl 4-(2-(chloromethyl)-4-nitrophenyl)piperazine-1-carboxylate

4-(2-(Chloromethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(hydroxymethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 11a (1.0g, 2.96mmol, commercially available), 4-toluenesulfonyl chloride (1.13g, 5.93mmol), N,N-diisopropylethylamine (1.53g, 11.86mmol) was added to dichloromethane (20mL), and the reaction was carried out at 40°C for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 4-(2-(chloromethyl)-4-nitrophenyl)piperazine-1- Tert-butyl carboxylate 11b (520 mg), yield 49.30%. MS m/z(ESI):300.0[M-55].

Step 2

tert-butyl 4-(2-(cyanomethyl)-4-nitrophenyl)piperazine-1-carboxylate

4-(2-(cyanomethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(Chloromethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 11b (520 mg, 1.46 mmol), sodium cyanide (155.03 mg, 2.92 mmol) was added to a mixed solution of ethanol (10 mL) and water (2 mL). React at 25°C for 2 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-(cyanomethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 11c (400mg), yield 79.02%.

MS m/z(ESI):291.0[M-55].

third step

tert-butyl 4-(4-amino-2-(cyanomethyl)phenyl)piperazine-1-carboxylate

4-(4-Amino-2-(cyanomethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(cyanomethyl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 11c (200 mg, 577.40 μmol), palladium on carbon (12.29 mg, 115.48 μmol, 10%) were added into methanol (4 mL), and the reaction mixture was stirred at 40°C for 2 hours under a hydrogen atmosphere. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), and concentrated under reduced pressure to obtain 4-(4-amino-2-(cyanomethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 11d (128mg), yield 70.06%.

MS m/z(ESI):317.2[M+1].

the fourth step

tert-butyl 4-(4-((6-bromohexyl)amino)-2-(cyanomethyl)phenyl)piperazine-1-carboxylate

4-(4-((6-Bromohexyl)amino)-2-(cyanomethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-(cyanomethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 11d (50 mg, 158.03 μmol), 6-bromohexanal 11e (122.05 mg, 632.12 μmol), commercial (Sold), sodium cyanoborohydride (11.92 mg, 189.64 μmol) was added to methanol (2 mL), and the reaction was carried out at 25°C for 2 hours. After the reaction, water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-bromohexane)amino)-2-(cyanomethyl)phenyl)piperazine-1- Tert-butyl carboxylate 11f (30 mg), 39.59%.

MS m/z(ESI):479.2[M+1].

the fifth step

tert-butyl 4-(2-(cyanomethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-(cyanomethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxy tert-butyl acid ester

7-(Trifluoromethyl)quinoline-4-thiol 11g (9.56mg, 41.71μmol), 4-(4-((6-bromohexane)amino)-2-(cyanomethyl)phenyl )Piperazine-1-carboxylic acid tert-butyl ester 11f (20 mg, 41.71 μmol), N,N-diisopropylethylamine (21.57 mg, 166.86 μmol) was added to N,N-dimethylformamide (1 mL) Medium, react at 25°C for 2 hours. After the reaction, water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-(cyanomethyl)-4-((6-((7-(trifluoromethyl))quinoline-4 -Tert-butyl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate 11h (15mg), yield 57.28%.

MS m/z(ESI):628.2[M+1].

Step 6

2-(2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)acetonitrile

2-(2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)acetonitrile

4-(2-(cyanomethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1- Tert-butyl carboxylate (10 mg, 15.93 μmol) was added to a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL) for 11 h, and the reaction was carried out at 25°C for 2 hours. Concentrate under reduced pressure, and the residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) , obtaining 2-(2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)acetonitrile 11 (4.4 mg), yield 52.35%.

MS m/z(ESI):528.2[M+1].

1HNMR (400MHz, MeOD-d ₄ ) δ8.75 (d, J = 5.2Hz, 1H), 8.39 (d, J = 8.8Hz, 1H), 8.26 (s, 1H), 7.87 (dd, J = 8.8, 1.6Hz,1H),7.63(d,J＝5.6Hz,1H),7.20(d,J＝8.6Hz,1H),7.01(d,J＝2.4Hz,1H),6.96(dd,J＝8.6, 2.6Hz,1H),3.84(s,2H),3.31-3.24(m,6H),3.18-3.12(m,2H),3.06-2.94(m,4H),1.86-1.75(m,2H),1.67 -1.58(m,2H),1.58-1.50(m,2H),1.48-1.39(m,2H).

Example 12

N-(6-((7-cyclopropylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-cyclopropylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

first step

7-cyclopropylquinolin-4-ol

7-cyclopropylquinolin-4-ol

In a microwave tube, 7-bromoquinolin-4-ol 6a (150 mg, 669.48 μmol) and tributyl (cyclopropyl) stannane 12a (266.02 mg, 803.38 μmol, commercially available) were dissolved in N,N- In a solution of dimethylformamide (2.5 mL), 1,1'-copper disulfide ferrocene (48.99 mg, 66.95 μmol), copper iodide (56.76 mg, 1.34 μmol) and anhydrous chloride were added. Lithium (56.76 mg, 1.34 mmol) was added to the reaction mixture, which was then replaced with nitrogen and stirred at 110°C for 16 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 7-cyclopropylquinolin-4-ol 12b (75 mg) with a yield of 60.48%.

MS m/z(ESI):186.2[M+1].

Step 2

4-chloro-7-cyclopropylquinoline

7-Cyclopropylquinoline-4-chloro

7-Cyclopropylquinolin-4-ol 12b (75 mg, 404.92 μmol) was dissolved in phosphorus oxychloride (2 mL), and the reaction mixture was stirred at 90°C for 2 hours. After the reaction is complete, phosphorus oxychloride is removed by vacuum distillation. Crude 4-chloro-7-cyclopropyl-quinoline 12c (240 mg) was obtained.

MS m/z(ESI):204.1[M+1].

third step

7-cyclopropylquinoline-4-thiol

7-cyclopropylquinoline-4-thiol

4-Chloro-7-cyclopropyl-quinoline 12c (240 mg, crude product) and sodium sulfide nonahydrate (849.08 mg, 3.54 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction mixture was Stir at 80°C for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 7-cyclopropylquinoline-4-thiol 12d (62 mg), with a two-step yield of 76.18%.

MS m/z(ESI):202.0[M+1].

the fourth step

tert-butyl 4-(4-((6-chlorohexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-chlorohexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Aminophenyl)piperazine-1-carboxylic acid tert-butyl ester 3f (1.0g, 3.61mmol) and 1-bromo-6-chlorohexane 12e (719.34 mg, 3.61 mmol) was dissolved in acetonitrile (10 mL), potassium carbonate (249.14 mg, 1.80 mmol) was added, and the reaction mixture was stirred at 70°C for 16 hours. After the reaction is complete, the reaction mixture is filtered and concentrated under reduced pressure to obtain a crude product which is purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-chlorohexyl)amino)phenyl)piperazine. -1-tert-butylcarboxylate 12f (416 mg), yield 29.14%.

MS m/z(ESI):396.2[M+1].

the fifth step

tert-butyl 4-(4-((6-((7-cyclopropylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-((7-cyclopropylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

7-Cyclopropylquinoline-4-thiol 12d (52 mg, 258.34 μmol) and 4-(4-((6-chlorohexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 12f ( 122.75 mg, 310.01 μmol) was dissolved in N,N-dimethylformamide (2 mL), potassium carbonate (71.41 mg, 516.68 μmol) and sodium iodide (1.94 mg, 12.92 μmol) were added, and the reaction mixture was stirred at 80°C. 2 hours. After the reaction was completed, the reaction mixture was filtered, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product. Purify by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-((7-cyclopropylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine -12g (66mg) of tert-butylcarboxylate, yield 45.56%.

MS m/z(ESI):561.4[M+1].

Step 6

N-(6-((7-cyclopropylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((7-cyclopropylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

12 g (56 mg, 99.86 μmol) of tert-butyl 4-(4-((6-((7-cyclopropylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate ) was dissolved in a mixed solution of dichloromethane (1 mL) and trifluoroacetic acid (0.3 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 10 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, Mobile phase B: CH ₃ CN), obtaining N-(6-((7-cyclopropylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline 12 (23.5 mg ), yield 51.08%.

MS m/z(ESI):461.2[M+1].

1H NMR (400MHz, DMSO) δ8.64(d,J＝4.8Hz,1H),7.94(d,J＝8.8Hz,1H),7.67(s,1H),7.36–7.28(m,2H),6.70 (d,J＝8.8Hz,2H),6.46(d,J＝8.8Hz,2H),4.98(s,1H),3.18(t,J＝7.2Hz,2H),2.96–2.90(m,2H) ,2.86–2.72(m,8H),2.14(dd,J＝10.8,6.0Hz,1H),1.77–1.69(m,2H),1.61–1.50(m,4H),1.45–1.36(m,2H) ,1.10–1.04(m,2H),0.83(dd,J＝6.8,4.8Hz,2H).

Example 13

N-(6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

first step

2,2-dimethyl-5-(((3-methyl-5-(trifluoromethyl)phenyl)amino)methylene)-1,3-dioxane-4,6-dione

2,2-Dimethyl-5-(((3-methyl-5-(trifluoromethyl)phenyl)amino)methylene)-1,3-dioxane-4,6-dione

3-Methyl-5-(trifluoromethyl)aniline 13a (1.68g, 9.59mmol, commercially available), 2,2-dimethyl-1,3-dioxane-4,6-dione ( 1.52 g, 10.55 mmol) and trimethyl orthoformate (7.76 mg, 73.12 μmol) were dissolved in isopropanol (15 mL) solution, and the reaction mixture was stirred at 85°C for 1 hour. After the reaction was completed, it was concentrated under reduced pressure, and the residue was washed with methyl tert-butyl ether and then filtered to obtain 2,2-dimethyl-5-(((3-methyl-5-(trifluoromethyl)phenyl) )Amino)methylene)-1,3-dioxane-4,6-dione 13b (3g), yield 94.99%.

Step 2

5-methyl-7-(trifluoromethyl)quinolin-4-ol

5-Methyl-7-(trifluoromethyl)quinolin-4-ol

2,2-Dimethyl-5-(((3-methyl-5-(trifluoromethyl)phenyl)amino)methylene)-1,3-dioxane-4,6-di Ketone 13b (1.67 g, 5.07 mmol) was added to the diphenyl ether (15 mL) solution and the reaction mixture was stirred at 220°C for 5 minutes. After the reaction was completed, the solid was washed with diethyl ether and filtered to obtain 5-methyl-7-(trifluoromethyl)quinolin-4-ol 13c (760 mg) with a yield of 65.96%.

MS m/z(ESI):228.0[M+1].

third step

4-chloro-5-methyl-7-(trifluoromethyl)quinoline

4-Chloro-5-methyl-7-(trifluoromethyl)quinoline

5-Methyl-7-(trifluoromethyl)quinolin-4-ol 13c (160 mg, 704.28 μmol) was added to phosphorus oxychloride (3 mL), and the reaction mixture was stirred at 100°C for 2 hours. After the reaction was completed, it was concentrated to dryness to obtain 4-chloro-5-methyl-7-(trifluoromethyl)quinoline 13d (150 mg) with a yield of 86.71%.

MS m/z(ESI):246.0[M+1].

the fourth step

5-methyl-7-(trifluoromethyl)quinoline-4-thiol

5-Methyl-7-(trifluoromethyl)quinoline-4-thiol

Sodium sulfide nonahydrate (150 mg, 1.83 mmol) was added to 4-chloro-5-methyl-7-(trifluoromethyl)quinoline 13d (150 mg, 610.68 μmol) in N,N-dimethylformamide ( 3 mL) solution, the reaction mixture was stirred at 80°C for 2 hours. After the reaction is completed, add water (20 mL) to the reaction solution, add 1N hydrochloric acid dropwise to adjust the pH to 5-6, extract with ethyl acetate (20 mL × 3), combine the organic phases, and use saturated sodium chloride solution (30 mL) Wash, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: B system) to obtain 5-methyl-7-(trifluoromethyl)quinoline-4-thiol 13e. (70mg), yield 47.12%.

MS m/z(ESI):244.0[M+1].

the fifth step

4-((6-iodohexyl)thio)-5-methyl-7-(trifluoromethyl)quinoline

4-((6-iodohexyl)thio)-5-methyl-7-(trifluoromethyl)quinoline

Potassium carbonate (94 mg, 678.32 μmol) was added to 5-methyl-7-(trifluoromethyl)quinoline-4-thiol 13e (55 mg, 226.11 μmol) and 1,6-diiodohexane (231 mg, 0.68 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction, add saturated sodium carbonate solution to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and use a silica gel column for the crude product Chromatography purification (eluent: B system) gave 4-((6-iodohexyl)thio)-5-methyl-7-(trifluoromethyl)quinoline 13f (53 mg), yield 51.71% .

MS m/z(ESI):454.0[M+1].

Step 6

tert-butyl 4-(4-((6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(4-((6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidine-1-carboxylate ester

4-((6-iodohexyl)thio)-5-methyl-7-(trifluoromethyl)quinoline 13f (44 mg, 97.07 μmol), 4-(4-aminophenyl)piperazine-1 - Tert-butyl carboxylate 3f (35.00 mg, 126.18 μmol) and potassium carbonate (26.8 mg, 194.13 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C for 3 hours . After the reaction, water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and washed with saturated sodium chloride solution. Wash, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-((6-((5-methyl-7-(trifluoro) Methyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidine-1-carboxylic acid tert-butyl ester 13g (30mg), yield 51.28%.

MS m/z(ESI):603.3[M+1].

Step 7

N-(6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

4-(4-((6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. 13g of butyl ester (52mg, 86.27μmol) was dissolved in a mixed solution of dichloromethane (3mL) and trifluoroacetic acid (1mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH to 8~9. Extract with ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+ H ₂ O, mobile phase B: CH ₃ CN), obtaining N-(6-((5-methyl-7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-4-( Piperazin-1-yl)aniline 13 (23 mg), yield 53.04%.

MS m/z(ESI):503.2[M+1].

1H NMR (400MHz, DMSO) δ8.72(d,J＝4.8Hz,1H),8.13(s,1H),7.65(s,1H),7.47(d,J＝4.8Hz,1H),6.70(d ,J＝8.8Hz,2H),6.47(d,J＝8.8Hz,2H),5.00(s,1H),3.16(t,J＝7.2Hz,2H),3.08(s,3H),2.98–2.88 (m,2H),2.84–2.78(m,8H),1.79–1.69(m,2H),1.60–1.50(m,4H),1.49–1.38(m,2H).

Example 14

3-benzyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Benzyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-bromo-4-nitrophenyl)piperazine-1-carboxylate

4-(2-Bromo-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve piperazine-1-carboxylic acid tert-butyl ester (1.02g, 5.45mmol) and 2-bromo-1-fluoro-4-nitrobenzene 14a (1.0g, 4.55mmol, commercially available) in N,N-bis To methylformamide (10 mL), potassium carbonate (1.88 g, 13.64 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 120°C for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-bromo-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 14b (1.55g), yielding The rate is 88.29%.

MS m/z(ESI):330.0[M-55].

Step 2

tert-butyl 4-(2-benzyl-4-nitrophenyl)piperazine-1-carboxylate

4-(2-Benzyl-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Bromo-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 14b (1.0g, 2.59mmol) and 2-benzyl-4,4,5,5-tetramethyl -1,3,2-dioxaborolane 14c (1.13g, 5.18mmol) was dissolved in 1,4-dioxane and water (10mL:1mL), and then potassium phosphate (1.10g, 5.18 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (189.44 mg, 258.91 μmol) were added to the reaction mixture, purged with nitrogen 3 to 5 times, and then the reaction mixture was Stir at 110°C overnight. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-benzyl-4-nitrophenyl)piperazine-1- Tert-butyl carboxylate 14d (835 mg), yield 81.14%.

MS m/z(ESI):398.2[M+1].

third step

tert-butyl 4-(4-amino-2-benzylphenyl)piperazine-1-carboxylate

4-(4-Amino-2-benzylphenyl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve 4-(2-benzyl-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 14d (835 mg, 2.10 mmol) and palladium carbon (80 mg, 751.74 μmol) in methanol (8 mL), The reaction mixture was exchanged with hydrogen for 3 to 5 times and stirred at 40°C for 2 hours. After the reaction was completed, the crude product was filtered and concentrated in vacuo to obtain 4-(4-amino-2-benzylphenyl)piperazine-1-carboxylic acid tert-butyl ester 14e (717 mg) with a yield of 92.87%.

MS m/z(ESI):368.2[M+1].

the fourth step

tert-butyl 4-(2-benzyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(2-benzyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (100 mg, 227.65 μmol) and 4-(4-amino-2-benzylphenyl)piperazine-1 - Tert-butyl carboxylate 14e (100.39 mg, 273.18 μmol) was dissolved in N,N-dimethylformamide (3 mL). Potassium carbonate (62.92 mg, 455.29 μmol) was added to the reaction mixture, and the reaction mixture was heated at 80 °C and stir for 2 hours. After the reaction is complete, add water (20 mL) to the reaction mixture, extract with ethyl acetate (20 mL × 3), combine the organic phases, and use Wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-benzyl-4-( (6-((7-(Trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 14f (76 mg), yield 49.18%.

MS m/z(ESI):679.4[M+1].

the fifth step

3-benzyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Benzyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-Benzyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 14f (56 mg, 82.49 μmol) was dissolved in a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.1% FA+H ₂ O, mobile phase B: CH ₃ CN), giving 3-benzyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl ) Aniline 14 (25.56mg), yield 53.54%.

MS m/z(ESI):579.4[M+1].

1H NMR (400MHz, DMSO) δ8.85(d,J＝4.8Hz,1H),8.34(s,1H),8.30(d,J＝8.8Hz,1H),7.94-7.87(m,1H),7.59 (d,J＝4.8Hz,1H),7.26–7.18(m,4H),7.12(t,J＝7.2Hz,1H),6.91(d,J＝8.4Hz,1H),6.37(dd,J＝ 8.4,2.4Hz,1H),6.33(d,J＝2.4Hz,1H),5.24(s,1H),3.90(s,2H),3.28-3.22(m,2H),2.94-2.87(m,2H ),2.83-2.75(m,4H),2.62-2.56(m,4H),1.79-1.70(m,2H),1.54-1.46(m,4H),1.44-1.35(m,2H).

Example 15

3-methyl-4-(piperazin-1-yl)-N-(2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl)aniline

3-Methyl-4-(piperazin-1-yl)-N-(2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutan Ethyl)aniline

first step

3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutane-1-carboxylic acid

3-(2-(tert-butoxy)-2-oxyethylene)cyclobutane-1-carboxylic acid

3-Oxocyclobutane-1-carboxylic acid 15a (3g, 26.29mmol, commercially available) and 2-(triphenylphosphine)acetate tert-butyl ester 15b (10.89g, 28.92mmol, commercially available) were dissolved in In toluene (50 mL), the reaction was stirred at 90°C overnight. After the reaction is completed, the temperature is lowered and concentrated, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 3-(2-(tert-butoxy)-2-oxyethylene)cyclobutane-1 -Carboxylic acid 15c (3g), yield 53.76%.

1H NMR (400MHz, CDCl3) δ5.70-5.47(m,1H),3.58-3.21(m,3H),3.21-2.81(m,2H),1.46(s,9H).

Step 2

3-(2-(tert-butoxy)-2-oxoethyl)cyclobutane-1-carboxylic acid

3-(2-(tert-butoxy)-2-oxyethyl)cyclobutane-1-carboxylic acid

Dissolve 3-(2-(tert-butoxy)-2-oxyethylene)cyclobutane-1-carboxylic acid 15c (1g, 4.71mmol) and palladium on carbon 10% (501.41mg, 4.71mmol) in methanol (10 mL), stirred at room temperature overnight under hydrogen atmosphere. After the reaction is completed, filter and concentrate the reaction solution to obtain 3-(2-(tert-butoxy)-2-oxyethyl)cyclobutane-1-carboxylic acid 15d (0.9g), with a yield of 89%

1H NMR (400MHz, CDCl3) δ3.11-2.96(m,1H),2.69-2.55(m,1H),2.47-2.28(m,4H),2.09-1.94(m,2H),1.43(s,9H ).

third step

(3-(2-(tert-butoxy)ethyl)cyclobutyl)methanol

(3-(2-(tert-butoxy)ethyl)cyclobutyl)methanol

3-(2-(tert-butoxy)-2-oxyethyl)cyclobutane-1-carboxylic acid 15d (1.01 g, 4.71 mmol) was dissolved in borane tetrahydrofuran complex (15 mL). Stir at room temperature overnight. After the reaction is completed, methanol is added to quench the reaction. After concentration, the residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain (3-(2-(tert-butoxy)ethyl)cyclobutane. base) methanol 15e (500 mg), yield 56.97%.

1H NMR(400MHz, CDCl3)δ3.53(d,J＝6.4Hz,2H),3.27(q,J＝6.8Hz,2H),2.44-2.23(m,2H),2.23-2.11(m,2H) ,1.58(q,J＝6.8Hz,2H),1.17(s,9H).

the fourth step

(3-(2-(tert-butoxy)ethyl)cyclobutyl)methyl methanesulfonate

(3-(2-(tert-Butoxy)ethyl)cyclobutyl)methanesulfonate methyl ester

Dissolve (3-(2-(tert-butoxy)ethyl)cyclobutyl)methanol 15e (300mg, 1.50mmol) and triethylamine (454.73mg, 4.49mmol) in dichloromethane (5mL), methane Sulfonyl chloride (188.75 mg, 1.65 mmol) was slowly added to the above system. React at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain (3-(2-(tert-butoxy)ethyl)cyclobutyl)methylsulfonate methyl ester 15f (400mg), with a yield of 95%, which was directly used in the next step of the reaction. .

the fifth step

4-(((3-(2-(tert-butoxy)ethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline

4-(((3-(2-(tert-butoxy)ethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline

(3-(2-(tert-butoxy)ethyl)cyclobutyl)methylsulfonate methyl ester 15f (400mg, 1.51mmol), 7-(trifluoromethyl)quinoline-4-thiol 11g (346.81 mg, 1.51 mmol) and potassium carbonate (418.20 mg, 3.03 mmol) were dissolved in N,N-dimethylformamide (8 mL) solution, and stirred at 50°C for 2 hours. After the reaction was completed, water was added to quench, and after extraction with ethyl acetate (50 mL (3-(2-(tert-butoxy)ethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline 15g (300mg), yield 49.88%. MS m/z(ESI):398.2[M+1].

Step 6

4-(((3-(2-bromoethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline

4-(((3-(2-bromoethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline

Dissolve 15g (300mg, 754.72μmol) of 4-(((3-(2-(tert-butoxy)ethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline in To dichloromethane (6 mL), boron tribromide (2 mL) was added at room temperature. Stir at room temperature for 2 hours. After the reaction is completed, it is concentrated, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(((3-(2-bromoethyl)cyclobutyl)methyl)thio)- 7-(Trifluoromethyl)quinoline 15h (200mg), yield 65.55%.

MS m/z(ESI):404.0[M+1].

Step 7

tert-butyl 4-(2-methyl-4-((2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl)amino)phenyl)piperazine-1-carboxylate

4-(2-methyl-4-((2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl)amino) Phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(((3-(2-bromoethyl)cyclobutyl)methyl)thio)-7-(trifluoromethyl)quinoline 15h (150mg, 371.02μmol), 4-(4-amino -2-Methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2a (108.11 mg, 371.02 μmol) and potassium carbonate (153.83 mg, 1.11 mmol) were dissolved in N,N-dimethylformamide (5 mL) Medium, react at 50°C for 2 hours. After the reaction was completed, water was added to quench the mixture, and then extracted with ethyl acetate (50 mL × 3). The organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-((2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl) (base)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 15i (110 mg), yield 48.23%.

MS m/z(ESI):615.3[M+1].

Step 8

3-methyl-4-(piperazin-1-yl)-N-(2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl)aniline

3-Methyl-4-(piperazin-1-yl)-N-(2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutan Ethyl)aniline

4-(2-methyl-4-((2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl)ethyl)amino )Phenyl)piperazine-1-carboxylic acid tert-butyl ester 15i (90 mg, 146.40 μmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, it is concentrated, and the obtained residue is purified by preparative liquid phase separation (instrument: Waters, flow rate: 20mL/min, mobile phase: acetonitrile 0.05% TFA aqueous solution, method: 23-33% acetonitrile retention time 9min) to obtain 3- Methyl-4-(piperazin-1-yl)-N-(2-(3-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclobutyl) Ethyl)aniline 15 (20 mg), yield 26.55%.

MS m/z(ESI):515.3[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.80 (d, J = 5.2Hz, 1H), 8.42 (d, J = 8.8Hz, 1H), 8.32 (s, 1H), 7.90 (dd, J = 8.9 ,1.7Hz,1H),7.63(dd,J＝10.2,5.2Hz,1H),7.26(s,1H),7.23(d,J＝1.4Hz,2H),3.41-3.36(m,4H),3.36 -3.33(m,2H),3.24-2.22(m,2H),3.18-3.11(m,4H),2.74-2.60(m,1H),2.47-2.34(m,5H),2.30-2.20(m, 1H),1.83-1.75(m,2H),1.67-1.50(m,2H).

Example 16

(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)(piperazin-1-yl)methanone

(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)(piperazin-1-yl)methanone

first step

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzoyl)piperazine-1-carboxylate

4-(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzoyl)piperazine-1-carboxylic acid tert. Butyl ester

4-(4-Amino-2-methylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester 16a (80 mg, 250.47 μmol, prepared according to published patent WO 2020126956A1), 4-((6-iodohexyl) Thio)-7-(trifluoromethyl)quinoline 1a (110.03 mg, 250.47 μmol) and potassium carbonate (34.62 mg, 250.47 μmol) were dissolved in acetonitrile (4 mL), and the reaction was stirred at 80°C for 2 hours. After the reaction is completed, the temperature is lowered and filtered, the filter cake is washed with ethyl acetate, the filtrate is spun dry, and the residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-(( 6-((7-(Trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzoyl)piperazine-1-carboxylic acid tert-butyl ester 16b (60 mg), yield 37.98%.

MS m/z(ESI):631.4[M+1].

Step 2

(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)(piperazin-1-yl)methanone

(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)(piperazin-1-yl)methanone

4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzoyl)piperazine-1-carboxylic acid Tert-butyl ester 16b (50 mg, 79.27 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.3 mL) was added to the above system, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, concentrate, and the residue is purified by preparative liquid phase separation (instrument: Waters, flow rate: 20mL/min, mobile phase: acetonitrile 0.1% FA aqueous solution, method: 30-40% acetonitrile retention time 8.5min) to obtain (2 -Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)(piperazin-1-yl)methanone 16 (10 mg ), the yield is 23.77%.

MS m/z(ESI):531.3[M+1].

1H NMR (400MHz, DMSO) δ8.85 (d, J＝4.8Hz, 1H), 8.40-8.25 (m, 2H), 7.90 (dd, J＝8.8, 1.6Hz, 1H), 7.59 (d, J＝ 4.8Hz,1H),6.90(d,J＝8.0Hz,1H),6.42-6.33(m,2H),5.79(s,1H),3.70-3.34(m,4H),3.27(t,J＝7.2 Hz,2H),3.06-2.84(m,6H),2.11(s,3H),1.85-1.66(m,2H),1.64-1.47(m,4H),1.48-1.29(m,2H).

Example 17

(E)-3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-en-1-yl)aniline

(E)-3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-ene -1-yl)aniline

first step

(E)-4-((6-bromohex-3-en-1-yl)thio)-7-(trifluoromethyl)quinoline

(E)-4-((6-bromohex-3-en-1-yl)thio)-7-(trifluoromethyl)quinoline

7-(Trifluoromethyl)quinoline-4-thiol 11g (100mg, 436.26μmol), (E)-1,6-dibromohex-3-ene 17a (211.11mg, 872.52μmol) and potassium carbonate (60.29 mg, 436.26 μmol) was dissolved in acetonitrile (4 mL) and stirred at 80°C for 2 hours. After the reaction is completed, the temperature is lowered and filtered, the filter cake is washed with ethyl acetate, the filtrate is spun dry, and the obtained residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain (E)-4-((6- Bromohex-3-en-1-yl)thio)-7-(trifluoromethyl)quinoline 17b (60 mg), yield: 35.24%.

MS m/z(ESI):392.0[M+1].

Step 2

tert-butyl(E)-4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-en-1-yl)amino)phenyl)piperazine -1-carboxylate

(E)-4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-en-1-yl)amino) Phenyl)piperazine-1-carboxylic acid tert-butyl ester

(E)-4-((6-bromohex-3-en-1-yl)thio)-7-(trifluoromethyl)quinoline 17b (60 mg, 153.74 μmol), 4-(4-amino -2-Methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2a (44.80 mg, 153.74 μmol) and potassium carbonate (42.50 mg, 307.49 μmol) were dissolved in N,N-dimethylformamide (2 mL) medium and stir at 80°C overnight. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). After the ethyl acetate phase was concentrated, the residue was purified by silica gel column chromatography (eluent: A system) to obtain (E)-4-(2-methyl-4-((6-((7-(trifluoro) Methyl)quinolin-4-yl)thio)hex-3-en-1-yl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 17c (40 mg), yield 43.31%

MS m/z(ESI):601.3[M+1].

third step

(E)-3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-en-1-yl)aniline

(E)-3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-ene -1-yl)aniline

(E)-4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hex-3-en-1-yl)amino )phenyl)piperazine-1-carboxy Acid tert-butyl ester 17c (40 mg, 66.58 μmol) was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1.5 mL) was added at room temperature and stirred at room temperature for 2 hours. After the reaction is completed, it is concentrated, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), giving (E)-3-methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio )hex-3-en-1-yl)aniline 17 (10 mg), yield: 30.0%.

MS m/z(ESI):501.2[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.78(d,J＝4.8Hz,1H),8.35(d,J＝8.8Hz,1H),8.30(s,1H),7.78(dd,J＝8.8 ,1.6Hz,1H),7.57(d,J＝5.0Hz,1H),6.91(d,J＝8.4Hz,1H),6.52(d,J＝2.4Hz,1H),6.47(dd,J＝8.4 ,2.8Hz,1H),5.76-5.58(m,2H),3.32-3.27(m,6H),3.09(t,J＝6.8Hz,2H),3.05-2.93(m,4H),2.63-2.53( m,2H),2.37-2.28(m,2H),2.20(s,3H).

Example 18

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenol

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenol

first step

tert-butyl 4-(2-hydroxy-4-nitrophenyl)piperazine-1-carboxylate

4-(2-Hydroxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve piperazine-1-carboxylic acid tert-butyl ester 18b (2.85g, 15.28mmol) and 2-fluoro-5-nitrophenol 18a (2.0g, 12.73mmol) in N,N-dimethylformamide (25mL ), potassium carbonate (5.28g, 38.19mmol) was added to the reaction mixture, and the reaction mixture was stirred at 120°C for 2 hours. After the reaction is complete, add water (100 mL) to the reaction mixture, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-hydroxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 18c (1.0 g), yield 24.29%.

MS m/z(ESI):324.2[M+1].

Step 2

tert-butyl 4-(2-(methoxymethoxy)-4-nitrophenyl)piperazine-1-carboxylate

4-(2-(Methoxymethoxy)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Hydroxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 18c (1.0g, 3.09mmol) was dissolved in tetrahydrofuran (10mL), and sodium hydride (111.34mg, 4.64mmol) ) was added to the reaction mixture at 0°C and stirred for 10 minutes. Bromo(methoxy)methane (463.75 mg, 3.71 mmol) was slowly added to the reaction mixture. The reaction mixture was then reacted at room temperature for 30 minutes. After the reaction is completed, add water to the reaction mixture to quench sodium hydride, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain crude product 4-(2-(methoxymethoxy)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 18d (1.28g).

MS m/z(ESI):368.2[M+1].

third step

tert-butyl 4-(4-amino-2-(methoxymethoxy)phenyl)piperazine-1-carboxylate

4-(4-Amino-2-(methoxymethoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(Methoxymethoxy)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 18d (1.28g, crude product) and palladium on carbon (150mg, 1.41mmol) were dissolved in (15 mL) in methanol, purge the reaction mixture with hydrogen 3 to 5 times and stir at 40°C for 3 hours. After the reaction is complete, the reaction mixture is filtered with methanol, and the organic phase is concentrated under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-amino-2-(methoxy). Methoxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 18e (982 mg), the two-step yield was 94.30%.

MS m/z(ESI):338.2[M+1].

the fourth step

tert-butyl 4-(2-(methoxymethoxy)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-(methoxymethoxy)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine- 1-tert-butylcarboxylate

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (738 mg, 1.68 mmol) and 4-(4-amino-2-(methoxymethoxy)benzene tert-butyl piperazine-1-carboxylate 18e (680 mg, 2.02 mmol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (464.40 mg, 3.36 mmol) was added to the reaction mixture. The reaction mixture was stirred at 80°C for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-(methoxymethoxy)-4-((6-((7-(trifluoro) Methyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 18f (824 mg), yield 75.60%.

MS m/z(ESI):649.2[M+1].

the fifth step

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenol

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenol

4-(2-(methoxymethoxy)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine -1-tert-butylcarboxylate 18f (100 mg, 154.14 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 6 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, Mobile phase B: CH ₃ CN) to obtain 2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino ) Phenol 18 (4.71 mg), yield 6.06%.

MS m/z(ESI):505.2[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.65 (d, J = 4.8Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.18 (s, 1H), 7.72 (d, J = 8.8 Hz,1H),7.42(d,J＝4.8Hz,1H),6.85(d,J＝8.4Hz,1H),6.34(s,1H),6.30(d,J＝8.4Hz,1H),3.29– 3.24(m,4H),3.15(t,J＝7.2Hz,2H),3.06–2.99(m,6H),1.80–1.71(m,2H),1.60–1.47(m,4H),1.44–1.36( m,2H).

Example 19

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzonitrile

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzonitrile

first step

tert-butyl 4-(4-amino-2-cyanophenyl)piperazine-1-carboxylate

4-(4-Amino-2-cyanophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-cyano-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 19a (500 mg, 1.50 mmol, prepared according to published patent US2009/99199, 2009, A1), ammonium chloride ( 402.43mg, 7.52mmol) and iron powder (420.11mg, 7.52mmol) Dissolve in ethanol (5 mL) and water (1 mL) and stir the reaction mixture at 75°C for 2 hours. After the reaction is complete, the crude product is filtered and concentrated in vacuo, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-amino-2-cyanophenyl)piperazine- 1-tert-butylcarboxylate 19b (450 mg), yield 88.84%.

MS m/z(ESI):325.2[M+23].

Step 2

tert-butyl 4-(2-cyano-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(2-cyano-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (200 mg, 455.29 μmol) and 4-(4-amino-2-cyanophenyl)piperazine-1 - Tert-butyl carboxylate 19b (206.50 mg, 682.94 μmol) was dissolved in a solution of N,N-dimethylformamide (3 mL), potassium carbonate (125.85 mg, 910.59 μmol) was added to the reaction mixture, and the reaction mixture was Stir at 80°C for 2 hours. After the reaction is complete, add water (20 mL) to the reaction mixture, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-cyano-4-((6-((7-(trifluoromethyl)quinoline- 4-yl)Thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 19c (43 mg), yield 15.39%.

MS m/z(ESI):614.4[M+1].

third step

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzonitrile

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzonitrile

4-(2-cyano-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 19c (43 mg, 70.06 μmol) was dissolved in a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.4 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, Mobile phase B: CH ₃ CN) to obtain 2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino ) Benzonitrile 19 (16.77 mg), yield 46.60%.

MS m/z(ESI):514.3[M+1].

1H NMR (400MHz, CDCl3) δ8.79(d,J＝4.8,1H),8.36(s,1H),8.24(d,J＝8.8Hz,1H),7.71(dd,J＝8.8,1.6Hz, 1H),7.25(s,1H),6.92(d,J＝8.8Hz,1H),6.79–6.70(m,2H),3.14(t,J＝7.2Hz,2H),3.11–3.05(m,6H ),3.05–2.99(m,4H),1.92–1.75(m,2H),1.69–1.55(m,4H),1.53–1.43(m,2H).

Example 20

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzamide

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzamide

first step

tert-butyl 4-(2-carbamoyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-Carbamoyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester

4-(2-cyano-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 19c (120 mg, 195.52 μmol) and acetaldehyde oxime (115.50 mg, 1.96 mmol, 0.126 mL) were dissolved in ethanol (2 mL). Palladium acetate (10.97 mg, 48.88 μmol) was added to the reaction mixture, and the reaction mixture was purged with nitrogen. Replace 3 to 5 times, raise the temperature to 80°C and stir for 4 hours. After the reaction is complete, the reaction mixture is vacuum dried, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-carbamoyl-4-((6-((7- (Trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 20a (93 mg), yield 60.23%.

MS m/z(ESI):632.4[M+1].

Step 2

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzamide

2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzamide

4-(2-carbamoyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid Tert-butyl ester 20a (93 mg, 117.77 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (0.8 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), giving 2-(piperazin-1-yl)-5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)benzamide 20 (9.77 mg), yield 12.48%.

MS m/z(ESI):532.3[M+1].

1H NMR (400MHz, CDCl3) δ10.20(s,1H),8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.25(d,J＝8.8Hz,1H),7.71(d ,J＝8.4Hz,1H),7.47(d,J＝2.8Hz,1H),7.25-7.23(m,1H),7.12(d,J＝8.8Hz,1H),6.69(dd,J＝8.8, 2.8Hz,1H),5.71(s,1H),3.19-3.10(m,4H),3.10-3.03(m,4H),2.98- 2.92(m,4H),1.92-1.80(m,4H),1.54-1.42(m,4H).

Example 21

3-(1H-imidazol-1-yl)-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-(1H-imidazol-1-yl)-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl) aniline

first step

tert-butyl 4-(2-(1H-imidazol-1-yl)-4-nitrophenyl)piperazine-1-carboxylate

4-(2-(1H-imidazol-1-yl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve imidazole (376.65mg, 5.53mmol) and sodium hydride (215.89mg, 8.30mmol) in N,N-dimethylformamide (18mL) solution. The reaction mixture is stirred at 25°C for 2 hours. 4-(2 -Fluoro-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 21a (900 mg, 2.77 mmol, prepared according to published patent WO2022055181), heat the reaction solution to 120°C and stir for 16 hours. After the reaction is completed, add water The reaction solution was quenched and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL), dried, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography ( Eluant: System A) to obtain 4-(2-(1H-imidazol-1-yl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 21b (320 mg), yield 30.98% .

MS m/z(ESI):374.2[M+1].

Step 2

tert-butyl 4-(4-amino-2-(1H-imidazol-1-yl)phenyl)piperazine-1-carboxylate

4-(4-Amino-2-(1H-imidazol-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(1H-imidazol-1-yl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 21b (320 mg, 856.98 μmol), palladium on carbon (18.24 mg, 171.40 μmol) Dissolve in methanol (6mL), replace with hydrogen three times, and react at 40°C under hydrogen atmosphere 2 Hour. After the reaction is completed, the reaction solution is filtered, and the filtrate is collected and concentrated under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-amino-2-(1H-imidazole-1). -tert-butyl)phenyl)piperazine-1-carboxylate 21c (280 mg), yield 95.14%.

MS m/z(ESI):344.2[M+1].

third step

tert-butyl 4-(2-(1H-imidazol-1-yl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-(1H-imidazol-1-yl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline)phenyl)piperazine -1-tert-butylcarboxylate

4-(4-Amino-2-(1H-imidazol-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 21c (165 mg, 480.46 μmol), 4-((6-iodohexyl)sulfide Generation)-7-(trifluoromethyl)quinoline 1a (211.05 mg, 480.46 μmol), potassium carbonate (132.80 mg, 960.92 μmol) was dissolved in N,N-dimethylformamide (4 mL), and reacted at 60°C 16 hours. After the reaction is completed, add water (5 mL) to the reaction mixture, extract with ethyl acetate (5 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (5 mL), dry over anhydrous sodium sulfate, and filter. , concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-(1H-imidazol-1-yl)-4-((6-((7 -(Trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline)phenyl)piperazine-1-carboxylic acid tert-butyl ester 21d (20 mg), yield 6.36%.

MS m/z(ESI):655.4[M+1].

the fourth step

3-(1H-imidazol-1-yl)-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-(1H-imidazol-1-yl)-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl) aniline

4-(2-(1H-imidazol-1-yl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline)phenyl)piper Tert-butylazine-1-carboxylate 21d (10 mg, 15.27 μmol) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, and saturated hydrogen carbonate was added. Adjust the pH to 8~9 with sodium, extract with ethyl acetate (20mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm , 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3-(1H-imidazol-1-yl)-4-(piperazin-1-yl)- N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 21 (3.7 mg), yield 43.68%.

MS m/z(ESI):555.2[M+1].

Example 22

3-isopropyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Isopropyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(4-nitro-2-(prop-1-en-2-yl)phenyl)piperazine-1-carboxylate

4-(4-Nitro-2-(isopropyl-1-en-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Bromo-4-nitro-phenyl)piperazine-1-carboxylic acid tert-butyl ester 22a (1.0g, 2.59mmol, prepared according to published patent WO2009/79597, 2009, A1), 2-ethyl Allyl-4,4,5,5-tetramethyl-1,3,2-pinacolborane 22b (870.13 mg, 5.18 mmol, commercially available), cesium carbonate (2.53 g, 7.77 mmol), [1 ,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (375.76mg, 517.81μmol) was dissolved in a mixed solution of water (10mL) and 1,4-dioxane (50mL), Nitrogen was replaced three times, and the reaction mixture was stirred at 90°C for 2 hours. After the reaction, add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-nitro-2-(isopropyl-1-en-2-yl)phenyl)piper Tert-butylazine-1-carboxylate 22c (853 mg), yield 94.83%.

MS m/z(ESI):348.2[M+1].

Step 2

tert-butyl 4-(4-amino-2-isopropylphenyl)piperazine-1-carboxylate

4-(4-Amino-2-cumylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Nitro-2-(isopropyl-1-en-2-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 22c (200 mg, 575.69 μmol), palladium on carbon (12.25 mg , 115.14 μmol), palladium hydroxide on carbon (16.17 mg, 115.14 μmol) was added to methanol (4 mL), replaced with hydrogen three times, and the reaction mixture was stirred at 40°C for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was collected and concentrated under reduced pressure to obtain 4-(4-amino-2-cumylphenyl)piperazine-1-carboxylic acid tert-butyl ester 22d ( 151mg), yield 82.11%.

MS m/z(ESI):320.2[M+1].

third step

tert-butyl 4-(2-isopropyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-isopropyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (173.04 mg, 393.92 μmol), 4-(4-amino-2-isopropyl-phenyl)piper Tert-butylazine-1-carboxylate 22d (151 mg, 472.70 μmol) and potassium carbonate (108.88 mg, 787.84 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, and the reaction mixture was stirred at 80°C. 2 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-isopropyl-4-((6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 22e (151 mg), yield 60.77%.

MS m/z(ESI):631.4[M+1].

the fourth step

3-isopropyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Isopropyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-isopropyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid Tert-butyl ester 22e (80 mg, 126.82 μmol) was dissolved in a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9, extract with ethyl acetate (10 mL × 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), obtaining 3-isopropyl-4-(piperazin-1-yl)-N- (6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 22 (31 mg), yield 46.06%.

MS m/z(ESI):531.2[M+1].

1H NMR (400MHz, CDCl3) δ8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.25(d,J＝8.8Hz,1H),7.71(dd,J＝9.2,8.8Hz ,1H),7.25(s,1H),7.01(d,J＝8.4Hz,1H),6.50(d,J＝2.8Hz,1H),6.43(dd,J＝8.4,8.8Hz,1H),3.53 -3.46(m,1H),3.16-3.08(m,4H),3.04-2.98(m,4H),2.83-2.76(m,4H),1.90-1.81(m,2H),1.68-1.62(m, 2H),1.62-1.56(m,2H),1.53-1.45(m,2H),1.17(d,J＝6.8Hz,6H).

Example 23

3-cyclopentyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Cyclopentyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-(cyclopent-1-en-1-yl)-4-nitrophenyl)piperazine-1-carboxylate

4-(2-(Cyclopent-1-en-1-yl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Bromo-4-nitro-phenyl)piperazine-1-carboxylic acid tert-butyl ester 23a (1.0g, 2.59mmol, prepared according to published patent WO2009/79597, 2009, A1), cyclopentyl -1-ylboronic acid 23b (579.61mg, 5.18mmol), cesium carbonate (2.53g, 7.77mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (375.76mg, 517.81 μmol) was dissolved in a mixed solution of water (10 mL) and 1,4-dioxane (50 mL), nitrogen was replaced three times, and the reaction mixture was stirred at 90°C for 2 hours. After the reaction, add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-(cyclopentyl-1-en-1-yl)-4-nitrophenyl)piper Tert-butylazine-1-carboxylate 23c (930 mg), yield 96.19%.

MS m/z(ESI):374.2[M+1].

Step 2

tert-butyl 4-(4-amino-2-cyclopentylphenyl)piperazine-1-carboxylate

4-(4-Amino-2-cyclopentylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-(Cyclopent-1-en-1-yl)-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 23c (200 mg, 535.55 μmol), palladium on carbon (11.39 mg , 107.11 μmol), palladium hydroxide on carbon (15.04 mg, 107.11 μmol) was added to methanol (4 mL), replaced with hydrogen three times, and the reaction mixture was stirred at 40°C for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), the filtrate was collected and concentrated under reduced pressure to obtain 4-(4-amino-2-cyclopentylphenyl)piperazine-1-carboxylic acid tert-butyl ester 23d (170mg), yield 91.88%.

MS m/z(ESI):346.2[M+1].

third step

tert-butyl 4-(2-cyclopentyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-Cyclopentyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (180.13 mg, 410.06 μmol), 4-(4-amino-2-cyclopentylphenyl)piperazine -1-tert-butylcarboxylate 23d (170mg, 492.07μmol), potassium carbonate (113.35mg, 820.12μmol) dissolved In a solution of N,N-dimethylformamide (4 mL), the reaction mixture was stirred at 80°C for 2 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-cyclopentyl-4-((6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 23e (149 mg), yield 55.32%.

MS m/z(ESI):657.4[M+1].

the fourth step

3-cyclopentyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Cyclopentyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-Cyclopentyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid Tert-butyl ester 23e (80 mg, 121.79 μmol) was dissolved in a mixed solution of dichloromethane (1.5 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9, extract with ethyl acetate (10 mL × 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), obtaining 3-cyclopentyl-4-(piperazin-1-yl)-N- (6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 23 (19 mg), yield 28.02%.

MS m/z(ESI):557.2[M+1].

1H NMR (400MHz, CDCl3) δ8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.25(d,J＝8.4Hz,1H),7.71(dd,J＝9.2,8.8Hz ,1H),7.25(s,1H),6.99(d,J＝8.4Hz,1H),6.52(d,J＝2.8Hz,1H),6.42(dd,J＝8.8,8.4Hz,1H),3.59 -3.48(m,1H),3.16-3.09(m,4H),3.09-3.03(m,4H),2.87-2.81(m,4H),1.90-1.79(m,4H),1.74-1.55(m, 8H),1.54-1.47(m,4H).

Example 24

N1-(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N6-(3-methyl-4-(piperazin-1 -yl)phenyl)hexane-1,6-diamine

N1-(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N6-(3-methyl- 4-(piperazin-1-yl)phenyl)hexyl-1,6-diamine

first step

tert-butyl 4-(4-((6-(((benzyloxy)carbonyl)amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((6-((benzyloxy)carbonyl)amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2a (278mg, 954.06μmol), N-(6-bromohexyl)carbamic acid benzyl ester 24a (359.74mg, 1.14 mmol, prepared according to published patent WO2005030258A2) and potassium carbonate (131.86 mg, 954.06 μmol) were dissolved in acetonitrile (6 mL), heated to 60°C and stirred overnight. After the reaction is complete, the solvent is removed under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-(((benzyloxy)carbonyl)amino)) Hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 24b (188 mg), yield 26.29%.

MS m/z(ESI):525.4[M+1].

Step 2

tert-butyl 4-(4-((6-aminohexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((6-Aminohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-((6-((benzyloxy)carbonyl)amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 24b (111 mg, 211.55 μmol) and palladium on carbon (50 mg, 469.84 μmol) were dissolved in methanol (3 mL), the reaction mixture was purged with hydrogen, and stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was filtered with MeOH and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-((6-aminohexyl)amino)- 2-Methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 24c (80 mg), yield 96.82%.

MS m/z(ESI):391.3[M+1].

third step

tert-butyl 4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-

yl)amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino )hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-Chloro-2-(1-(2-methoxyethyl)imidazol-2-yl)thieno[2,3-d]pyrimidine 24d (40 mg, 135.70 μmol, prepared according to published patent WO2021257828A1), 4 -(4-((6-Aminohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert. Butyl ester 24c (79.50 mg, 203.56 μmol) and N,N-diisopropylethylamine (35.08 mg, 271.41 μmol) were dissolved in tetrahydrofuran (3 mL), and the mixture was heated to 70°C and stirred overnight. After the reaction is complete, the solvent is removed under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-((6-((2-(1-(2-methyl) Oxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid Tert-butyl ester 24e (37 mg), yield 42.02%.

MS m/z(ESI):649.4[M+1].

the fourth step

N1-(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N6-(3-methyl-4-(piperazin-1 -yl)phenyl)hexane-1,6-diamine

N1-(2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N6-(3-methyl- 4-(piperazin-1-yl)phenyl)hexane-1,6-diamine

4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl) A mixed solution of amino)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 24e (37 mg, 57.02 μmol) dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.3 mL) , the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9, extract with ethyl acetate (10 mL × 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 10 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), obtaining N1-(2-(1-(2-methoxyethyl)-1H -imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)-N6-(3-methyl-4-(piperazin-1-yl)phenyl)hexane-1,6 - Diamine 24 (21.69 mg), yield 69.32%.

MS m/z(ESI):549.2[M+1].

1H NMR(400MHz,DMSO)δ8.84-8.44(m,2H),7.98-7.58(m,3H),6.96-6.46(m,2H),5.17-4.85(m,2H),3.90-3.68(m ,2H),3.65-3.42(m,2H),3.28(s,3H),3.06-2.81(m,5H),2.24-2.07(m,11H),1.58(d,J＝12.0Hz,4H), 1.43-1.16(m,4H).

Example 25

N-(6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl)-3-methyl-4 -(piperazin-1-yl)aniline

N-(6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl) -3-Methyl-4-(piperazin-1-yl)aniline

first step

tert-butyl 4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((6-chlorohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2a (1.46g, 5.01mmol) and 1-bromo-6-chlorohexane 12e (1g, 5.01mmol) Dissolve in acetonitrile (10 mL), add potassium carbonate (346.35 mg, 2.51 mmol), and stir the reaction mixture at 70°C overnight. After the reaction is complete, the reaction mixture is filtered and concentrated under reduced pressure to obtain a crude product which is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-chlorohexyl)amino)-2-methyl phenyl)piperazine-1-carboxylic acid tert-butyl ester 25a (770 mg), yield 37.47%.

MS m/z(ESI):410.2[M+1].

Step 2

2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidine-4-thiol

2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidine-4-thiol

4-Chloro-2-(1-(2-methoxyethyl)imidazol-2-yl)thieno[2,3-d]pyrimidine 24d (65 mg, 220.52 μmol) and thiourea (167.86 mg, 2.21 mmol) was dissolved in N,N-dimethylformamide (3 mL), and the reaction was stirred at 100°C for 2 hours. After the reaction is completed, water is added to quench it. After extraction with ethyl acetate, the organic phase is dried and concentrated. The obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 2-(1-(2-methoxy). (ethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidine-4-thiol 25b (50mg), yield 77.55%.

MS m/z(ESI):293.0[M+1].

third step

tert-butyl 4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl )amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio Generation)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidine-4-thiol 25b (50 mg, 171.01 μmol), 4-( 4-((6-Chlohexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 25a (84.14 mg, 205.21 μmol), potassium carbonate (47.27 mg, 342.02 μmol) and iodide Sodium (1.28 mg, 8.55 μmol) was dissolved in N,N-dimethylformamide (1.5 mL). React at 80°C for 2 hours. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-((6-((2-(1-(2-methoxyethyl)) -1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 25c (80mg), yield 70.25%.

MS m/z(ESI):666.5[M+1]

the fourth step

N-(6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl)-3-methyl-4 -(piperazin-1-yl)aniline

N-(6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl) -3-Methyl-4-(piperazin-1-yl)aniline

4-(4-((6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl) Thio)hexyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 25c (80 mg, 120.14 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid ( 1 mL) and stirred at room temperature for 2 hours. After the reaction is completed, concentrate, and the obtained residue is purified by preparative liquid phase separation (instrument: C18xbridge, flow rate: 20mL/min, mobile phase: acetonitrile 0.05% TFA aqueous solution, method: 21-26% acetonitrile retention time 6.68min) to obtain N -(6-((2-(1-(2-methoxyethyl)-1H-imidazol-2-yl)thieno[2,3-d]pyrimidin-4-yl)thio)hexyl)- 3-Methyl-4-(piperazin-1-yl)aniline 25 (18 mg), yield 26.48%.

MS m/z(ESI):566.4[M+1].

1H NMR (400MHz, DMSO) δ8.80(s,2H),8.19(d,J＝6.0Hz,1H),7.95(d,J＝1.4Hz,1H),7.88(s,1H),7.62(d ,J＝6.0Hz,1H),6.98(d,J＝7.4Hz,1H),6.81(s,2H),5.03(t,J＝5.0Hz,2H),3.83(t,J＝5.0Hz,2H ),3.48(t,J＝7.0Hz,2H),3.24(s,3H),3.23-3.18(m,4H),3.15-3.01(m,2H),2.86-2.98(m,4H),2.21( s,3H),1.77-1.74(m,2H),1.63-1.53(m,2H),1.49-1.56(m,2H),1.42-1.38(m,2H).

Example 26

N-(6-((6-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((6-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

first step

6-phenylquinoline-4-thiol

6-Phenylquinoline-4-thiol

Dissolve 4-chloro-6-phenylquinoline 26a (1.41g, 5.88mmol, commercially available) and sodium sulfide (6.02g, 17.65mmol) in N,N-dimethylformamide (15mL), and the reaction mixture Stir at 80°C for 2 hours. After the reaction, add water (50 mL) to the reaction solution, adjust the pH to 5-6 with 1N hydrochloric acid solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, and wash with saturated sodium chloride solution (50 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 6-phenylquinoline-4-thiol 26b (1.0g) , yield 71.63%. MS m/z(ESI):238.0[M+1].

Step 2

4-((6-iodohexyl)thio)-6-phenylquinoline

4-((6-iodohexyl)thio)-6-phenylquinoline

Potassium carbonate (1.75 g, 12.64 mmol) was added to 6-phenylquinoline-4-thiol 26b (1.0 g, 4.21 mmol) and 1,6-diiodohexane (4.30 g, 12.64 mmol) in acetonitrile ( 15 mL) solution, the reaction mixture was stirred at room temperature for 15 hours. After the reaction, add saturated sodium carbonate solution (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-((6-iodohexyl)thio)-6-phenylquinoline 26c (654 mg). The rate is 34.69%.

MS m/z(ESI):448.0[M+1].

third step

tert-butyl 4-(4-((6-((6-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(4-((6-((6-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-((6-iodohexyl)thio)-6-phenylquinoline 26c (200 mg, 447.05 μmol), 4-(4-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester 3f (161.19 mg, 581.17 μmol) and potassium carbonate (123 mg, 894.11 μmol) were dissolved in a solution of N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. , the obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-((6-phenylquinolin-4-yl)thio)hexyl)amino )phenyl)piperazine-1-carboxylic acid tert-butyl ester 26d (46 mg), yield 17.24%.

MS m/z(ESI):597.3[M+1].

the fourth step

N-(6-((6-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

N-(6-((6-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline

4-(4-((6-((6-phenylquinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 26d (46 mg, 77.07 μmol) Dissolve in a mixed solution of dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture is stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8~9, and extract with ethyl acetate (30 mL). ×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+ _H2 O, mobile phase B: CH ₃ CN), obtaining N-(6-((6-phenylquinolin-4-yl)thio)hexyl)-4-(piperazin-1-yl)aniline 26 (20 mg ), the yield is 52.24%.

MS m/z(ESI):497.4[M+1].

1H NMR (400MHz, CDCl3) δ8.70(d,J＝4.8Hz,1H),8.30(d,J＝1.6Hz,1H),8.13(d,J＝8.8Hz,1H),7.99(s,1H ),7.73(d,J＝7.2Hz,2H),7.50(t,J＝7.6Hz,2H),7.41(s,1H),7.19(d,J＝4.8Hz,1H),6.84(d,J ＝8.8Hz,2H),6.58(d,J＝8.8Hz,2H),3.19–2.98(m,12H),1.90–1.80(m,2H),1.68–1.55(m,4H),1.54–1.43( m,2H).

Example 27

1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-amine

1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-amine

first step

tert-butyl(1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-yl)carbamate

(1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-yl)amino tert-butyl formate

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (85.19 mg, 193.94 μmol), (1-(4-amino-2-methylphenyl)piperidine -4-yl)tert-butyl carbamate 27a (77 mg, 252.12 μmol, prepared according to published patent WO2019138227A1) and potassium carbonate (53.5 mg, 387.87 μmol) were dissolved in N,N-dimethylformamide (5 mL) solution, The reaction mixture was stirred at 80°C for 2 hours. After the reaction, add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain (1-(2-methyl-4-((6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)amino)phenyl)piperidin-4-yl)carbamic acid tert-butyl ester 27b (53 mg), yield 44.31%. MS m/z(ESI):617.3[M+1].

Step 2

1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-amine

1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-amine

(1-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperidin-4-yl) Tert-butyl carbamate 27b (63 mg, 102.14 μmol) was dissolved in a mixed solution of dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, and saturated sodium bicarbonate was added to adjust the pH. to 8~9, extracted with ethyl acetate (30mL×3), combined the organic phases, concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×19mm ID; 10μm, 20mL/min ;Mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 1-(2-methyl-4-((6-((7-(trifluoromethyl)quinoline- 4-yl)thio)hexyl)amino)phenyl)piperidin-4-amine 27 (15 mg), yield 28.42%.

MS m/z(ESI):517.2[M+1].

1H NMR (400MHz, CDCl3) δ8.78(d,J＝4.8Hz,1H),8.36(s,1H),8.24(d,J＝8.8Hz,1H),7.71(dd,J＝8.8,1.6Hz ,1H),7.24(s,1H),6.88(d,J＝8.4Hz,1H),6.47(d,J＝2.4Hz,1H),6.41(d,J＝8.4Hz,1H),3.14-3.05 (m,4H),2.98(d,J＝12.4Hz,2H),2.87-2.77(m,1H),2.62(t,J＝10.8Hz,2H),2.23(s,3H),1.94-1.80( m,6H),1.66-1.45(m,8H).

Example 28

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)thio)-7-(trifluoromethyl)quinoline

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)thio)-7-(trifluoromethyl)quinoline

first step

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)oxy)phenyl)piperazine-1-carboxylate

4-(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)oxy)phenyl)piperazine-1-carboxylic acid tert. Butyl ester

4-(4-hydroxy-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 28a (175.71 mg, 600.99 μmol, prepared according to published patent WO2022076627A1), 4-((6-iodohexyl)sulfide Substitute)-7-(trifluoromethyl)quinoline 1a (220 mg, 500.82 μmol) and potassium carbonate (138.44 mg, 1.0 mmol) were dissolved in acetonitrile (7 mL), and the temperature was raised to 80°C and stirred for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-methyl-4-((6-((7-(tri Fluoromethyl)quinolin-4-yl)thio)hexyl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 28b (300 mg), yield 99.22%.

MS m/z(ESI):604.4[M+1].

Step 2

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)thio)-7-(trifluoromethyl)quinoline

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)thio)-7-(trifluoromethyl)quinoline

4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)oxy)phenyl)piperazine-1-carboxylic acid Tert-butyl ester 28b (280 mg, 463.78 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.1% FA+H ₂ O, Mobile phase B: CH ₃ CN), obtaining 4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)thio)-7- (Trifluoromethyl)quinoline 28 (52 mg), yield 22.26%.

MS m/z(ESI):504.3[M+1].

1H NMR (400MHz, CDCl3) δ8.79(d,J＝4.8Hz,1H),8.36(s,1H),8.24(d,J＝8.8Hz,1H),7.71(dd,J＝8.8,1.6Hz ,1H),7.25(s,1H),6.96(d,J＝8.8Hz,1H),6.75(d,J＝2.8Hz,1H),6.69(dd,J＝8.8,2.8Hz,1H),3.93 (t,J＝6.4Hz,2H),3.13(t,J＝7.2Hz,2H),3.06-2.97(m,4H),2.85-2.76(m,4H),2.28(s,3H),1.90- 1.83(m,2H),1.82-1.77(m,2H),1.64-1.52(m,4H).

Example 29

4-((5-((3-methyl-4-(piperazin-1-yl)benzyl)oxy)pentyl)thio)-7-(trifluoromethyl)quinolone

4-((5-((3-methyl-4-(piperazin-1-yl)benzyl)oxy)pentyl)thio)-7-(trifluoromethyl)quinoline

first step

4-((5-iodopentyl)thio)-7-(trifluoromethyl)quinoline

4-((5-iodopentyl)thio)-7-(trifluoromethyl)quinoline

Potassium carbonate (452.20mg, 3.27mmol) was added to 7-(trifluoromethyl)quinoline-4-thiol 11g (500mg, 2.18mmol) and 1,5-diiodopentane 29a (1.41g, 4.36mmol) , commercially available) in acetonitrile (10 mL), the reaction mixture was stirred at room temperature for 12 hours. After the reaction is complete, add saturated sodium carbonate solution (100 mL) to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-((5-iodopentyl)thio)-7-(trifluoromethyl)quinoline 29b (641 mg), yield 69.1%.

MS m/z(ESI):426.0[M+1].

Step 2

tert-butyl 4-(2-methyl-4-(((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)methyl)phenyl)piperazine-1-carboxylate

4-(2-methyl-4-(((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)methyl)phenyl)piperazine- 1-tert-butylcarboxylate

4-(4-(hydroxymethyl)-2-methyl-phenyl)piperazine-1-carboxylic acid tert-butyl ester 29c (100.30 mg, 327.34 μmol, prepared according to published patent EP2565182) was dissolved in N,N-di In methylformamide (2 mL), the reaction mixture was controlled at 0°C, and sodium hydride (13.09 mg, 545.56 μmol) was slowly added. After 30 minutes, 4-(5-iodopentyl)thio)-7-(trifluoromethyl)quinoline 29b (116 mg, 272.78 μmol) was added to the reaction mixture, and the reaction mixture was continued to stir at 80°C for 6 Hour. After the reaction is completed, add water to the reaction mixture, adjust the pH to 3~4 with hydrochloric acid (1N), extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated sodium chloride solution (30mL), and remove. Dry with aqueous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-(((5-((7 -(Trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)methyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 29d (76 mg), yield 11.54%. MS m/z(ESI):604.4[M+1].

third step

4-((5-((3-methyl-4-(piperazin-1-yl)benzyl)oxy)pentyl)thio)-7-(trifluoromethyl)quinoline

4-((5-((3-methyl-4-(piperazin-1-yl)benzyl)oxy)pentyl)thio)-7-(trifluoromethyl)quinoline

4-(2-methyl-4-(((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)methyl)phenyl)piperazine -1-tert-butylcarboxylate 29d (76 mg, 31.47 μmol) was dissolved in a mixed solution of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), giving 4-((5-((3-methyl-4-(piperazin-1-yl)benzyl)oxy)pentyl)thio)-7-(trifluoromethyl) Quinoline 29 (4.74 mg), yield 8.61%.

MS m/z(ESI):504.2[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.63 (d, J = 4.8Hz, 1H), 8.25 (d, J = 8.8Hz, 1H), 8.17 (s, 1H), 7.71 (d, J = 8.8 Hz,1H),7.41(d,J＝4.8Hz,1H),7.06-6.98(m,2H),6.88(d,J＝8.0Hz,1H),4.30(s,2H),3.40(t,J ＝5.6Hz,2H),3.13(t,J＝7.2Hz,2H),2.98-2.89(m,4H),2.82-2.75(m,4H),2.17(s,3H),1.78-1.70(m, 2H),1.61-1.51(m,4H).

Example 30

4-((5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)ethoxy)pentyl)thio)-7-(trifluoromethyl)quinolone

4-((5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)ethoxy)pentyl)thio)-7-(trifluoromethyl)quinoline

first step

tert-butyl 4-(4-acetyl-2-methylphenyl)piperazine-1-carboxylate

4-(4-Acetyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve 1-(4-bromo-3-methylphenyl)ethan-1-one 30a (1.0g, 4.69mmol) and piperazine-1-carboxylic acid tert-butyl ester 18b (1.05g, 5.63mmol) in toluene (10mL), palladium acetate (105.3mg, 469.33μmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (584.47mg, 9386μmol) and cesium carbonate (3.06g, 9.39mmol) were added The reaction mixture was replaced with nitrogen 3 to 5 times and stirred at 100°C for 4 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-acetyl-2-methylphenyl)piperazine-1- Tert-butyl carboxylate 30b (1.04g), yield 69.59%.

MS m/z(ESI):319.2[M+1].

Step 2

tert-butyl 4-(4-(1-hydroxyethyl)-2-methylphenyl)piperazine-1-carboxylate

4-(4-(1-Hydroxyethyl)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Acetyl-2-methyl-phenyl)piperazine-1-carboxylic acid tert-butyl ester 30b (1.0g, 3.14mmol) was dissolved in methanol (20mL), sodium borohydride (297.0mg, 7.85 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction is complete, the reaction solvent is removed under reduced pressure, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-(1-hydroxyethyl)-2-methylphenyl). ) Piperazine-1-carboxylic acid tert-butyl ester 30c (980 mg), yield 97.38%. MS m/z(ESI):321.2[M+1].

third step

tert-butyl 4-(2-methyl-4-(1-((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)ethyl)phenyl)piperazine-1-carboxylate

4-(2-methyl-4-(1-((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)ethyl)phenyl)piper Tert-butylazine-1-carboxylate

Dissolve 4-(4-(1-hydroxyethyl)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 30c (404.48mg, 1.26mmol) in N,N-dimethylformamide (8 mL), control the reaction mixture at 0°C, and slowly add sodium hydride (151.47 mg, 6.31 mmol). After 30 minutes, 4-((5-iodopentyl)thio)-7-(trifluoromethyl)quinoline 29b (671 mg, 1.58 mmol) was added to the reaction mixture, and the reaction mixture continued to stir at 80°C for 6 Hour. After the reaction was completed, it was concentrated under reduced pressure to obtain the residue The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-methyl-4-(1-((5-((7-(trifluoromethyl))quinoline-4 -Tert-butyl)thio)pentyl)oxy)ethyl)phenyl)piperazine-1-carboxylate 30d (71 mg), yield 7.28%.

MS m/z(ESI):618.4[M+1].

the fourth step

4-((5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)ethoxy)pentyl)thio)-7-(trifluoromethyl)quinolone

4-((5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)ethoxy)pentyl)thio)-7-(trifluoromethyl)quinoline

4-(2-methyl-4-(1-((5-((7-(trifluoromethyl)quinolin-4-yl)thio)pentyl)oxy)ethyl)phenyl) Piperazine-1-carboxylic acid tert-butyl ester 30d (56 mg, 90.65 μmol) was dissolved in toluene (5 mL), silica gel (100 mg) was added in batches to the reaction mixture, and stirred at 110°C for 2 hours. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, Mobile phase B: CH ₃ CN), obtaining 4-((5-(1-(3-methyl-4-(piperazin-1-yl)phenyl)ethoxy)pentyl)thio)-7 -(Trifluoromethyl)quinoline 30 (5.7 mg), yield 12.15%.

MS m/z(ESI):518.2[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.76 (d, J = 4.8Hz, 1H), 8.37 (d, J = 8.8Hz, 1H), 8.30 (s, 1H), 7.84 (d, J = 8.4 Hz,1H),7.53(d,J＝4.8Hz,1H),7.17(s,1H),7.14(d,J＝8.0Hz,1H),7.05(d,J＝8.0Hz,1H),4.36( dd,J＝12.4,6.4Hz,1H),3.34-3.30(m,6H),3.24(t,J＝7.2Hz,2H),3.14-3.06(m,4H),2.32(s,3H),1.87 -1.79(m,2H),1.67-1.58(m,4H),1.37(d,J=6.4Hz,3H).

Example 31

6-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-[1,1'-biphenyl]-3-amine

6-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-[1,1'-biphenyl]-3 -amine

first step

tert-butyl 4-(2-iodo-4-nitrophenyl)piperazine-1-carboxylate

4-(2-iodo-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester

1-Fluoro-2-iodo-4-nitrobenzene 31a (500mg, 1.87mmol), piperazine-1-carboxylic acid tert-butyl ester 18b (418.55mg, 2.25mmol) and potassium carbonate (776.45mg, 5.62mmol) Dissolve in N,N-dimethylformamide (5 mL), stir and react at 120°C overnight. After the reaction is completed, the temperature is lowered and filtered, the filter cake is washed with ethyl acetate, the filtrate is spun to dryness, and the obtained residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-iodo-4-nitrate). phenyl)piperazine-1-carboxylic acid tert-butyl ester 31b (570 mg), yield 70.26%.

MS m/z(ESI):434.2[M+1].

Step 2

tert-butyl 4-(5-nitro-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylate

4-(5-Nitro-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-iodo-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 31b (420 mg, 969.44 μmol), phenylboronic acid (141.84 mg, 1.16 mmol), [1,1'-bis (Diphenylphosphino)ferrocene]palladium dichloride (70 mg, 96.94 μmol) and potassium carbonate (133.98 mg, 969.44 μmol) were dissolved in dioxane (3 mL) and water (0.6 mL) under nitrogen atmosphere The reaction was stirred at 90°C for 2 hours. After the reaction is completed, the reaction solution is concentrated, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(5-nitro-[1,1'-biphenyl]-2-yl)piper. Tert-butylazine-1-carboxylate 31c (300 mg), yield 80.71%.

MS m/z(ESI):384.3[M+1].

third step

tert-butyl 4-(5-amino-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylate

4-(5-Amino-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylic acid tert-butyl ester

Dissolve 4-(5-nitro-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylic acid tert-butyl ester 31c (300 mg, 521.59 μmol) and palladium on carbon (30 mg, 10%) In methanol (5 mL), the reaction mixture was purged with hydrogen 3 to 5 times and reacted at 40°C for 3 hours. After the reaction is completed, filter and wash the filter cake with ethyl acetate. After the filtrate was concentrated, 4-(5-amino-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylic acid tert-butyl ester 31d (140 mg) was obtained, with a yield of 75.94%.

MS m/z(ESI):354.4[M+1].

the fourth step

tert-butyl 4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylate

4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-[1,1'-biphenyl]-2-yl)piperazine -1-tert-butylcarboxylate

4-(5-Amino-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylic acid tert-butyl ester 31d (70 mg, 198.04 μmol), 4-((6-iodohexyl)sulfide Generation)-7-(trifluoromethyl)quinoline 1a (104.40 mg, 237.65 μmol) and potassium carbonate (82.11 mg, 594.13 μmol) were dissolved in N,N-dimethylformamide (3 mL). React at 80°C for 16 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried and concentrated, and the obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(5-((6-((7-(trifluoromethyl))quinoline-4 -Tert-butyl)thio)hexyl)amino)-[1,1'-biphenyl]-2-yl)piperazine-1-carboxylate 31e (51 mg), yield 38.74%.

MS m/z(ESI):665.3[M+1].

the fifth step

6-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-[1,1'-biphenyl]-3-amine

6-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-[1,1'-biphenyl]-3 -amine

4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-[1,1'-biphenyl]-2-yl)piper Tert-butylazine-1-carboxylate 31e (50 mg, 75 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added to the above system, and the mixture was stirred at room temperature for 2 hours. After the reaction is completed, it is concentrated, and the obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), giving 6-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)-[1,1' -Biphenyl]-3-amine 31 (15 mg), yield 17.66%.

MS m/z(ESI):565.2[M+1].

1H NMR (400MHz, DMSO) δ8.86(d,J＝4.8Hz,1H),8.35(s,1H),8.31(d,J＝8.8Hz,1H),7.91(d,J＝8.6Hz,1H ),7.63-7.56(m,3H),7.44(t,J＝7.4Hz,2H),7.35(t,J＝7.2Hz,1H),7.06(d,J＝8.4Hz,1H),6.96-6.83 (m,2H),3.26(t,J＝7.2Hz,2H),3.13(t,J＝6.6Hz,2H),3.02-2.91(m,4H),2.90-2.83(m,4H),1.85- 1.69(m,2H),1.66-1.57(m,2H),1.56-1.48(m,2H),1.48-1.39(m,2H).

Example 32

3,5-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3,5-Dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2,6-dimethyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2,6-dimethyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxy tert-butyl acid ester

4-((6-iodohexyl)thio)-7-(trifluoromethyl)quinoline 1a (50 mg, 113.82 μmol), 4-(4-amino-2,6-dimethylphenyl)piper Tert-butylazine-1-carboxylate 32a (41.72 mg, 136.59 μmol, prepared according to published patent US2019/106436) and potassium carbonate (31.46 mg, 227.65 μmol) were dissolved in N,N-dimethylformamide (5 mL) , raise the temperature to 80°C and stir for 2 hours. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2,6-dimethyl-4-((6-((7-(trifluoromethyl)) Quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 32b (18 mg), yield 25.64%.

MS m/z(ESI):617.4[M+1].

Step 2

3,5-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3,5-Dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2,6-Dimethyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1- Tert-butyl carboxylate 32b (18 mg, 29.18 μmol) was dissolved in a mixed solution of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate solution to adjust the pH to 8~9, extract with ethyl acetate (50mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column C18x bridge preparative column; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.1% FA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3,5-dimethyl-4-(piperazine-1- yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 32 (5 mg), yield 33.16%.

MS m/z(ESI):517.3[M+1].

1H NMR (400MHz, DMSO) δ8.84(d,J＝4.8Hz,1H),8.43–8.15(m,2H),7.89(d,J＝8.7Hz,1H),7.59(d,J＝4.9Hz ,1H),6.15(s,2H),3.28–3.23(m,4H),3.10–2.80(m,8H),2.15(s,6H),1.79–1.71(m,2H),1.77–1.46(m ,4H),1.40–1.30(m,2H).

Example 33

4-(piperazin-1-yl)-N-(6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-N-(6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)aniline

first step

4-chloro-7-(p-tolyl)quinolone

4-Chloro-7-(p-tolyl)quinoline

7-Bromo-4-chloroquinoline 33a (500 mg, 2.06 mmol, commercially available), p-tolylboronic acid (308.35 mg, 2.27 mmol), [1,1'-bis(diphenylphosphine)ferrocene]di Palladium chloride (338 mg, 206.19 μmol) and sodium carbonate (655.60 mg, 6.19 mmol) were dissolved in a mixed solution of toluene (2 mL) and ethanol (12 mL). The reaction mixture was stirred at 120°C for 15 hours under a nitrogen atmosphere. After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 4-chloro-7-(p-tolyl)quinoline 33b (160 mg) with a yield of 30.58%.

MS m/z(ESI):254.1[M+1].

Step 2

7-(p-tolyl)quinoline-4-thiol

7-(p-Tolyl)quinoline-4-thiol

Dissolve 4-chloro-7-(p-tolyl)quinoline 33b (140 mg, 551.78 μmol) and sodium sulfide (130.85 mg, 1.66 mmol) in N,N-dimethylformamide (5 mL) solution, and the reaction mixture Stir at 80°C for 2 hours. After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the obtained residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 7-(p-tolyl)quinoline-4-thiol 33c (110 mg) with a yield of 79.32%.

MS m/z(ESI):252.0[M+1].

third step

tert-butyl 4-(4-((6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

tert-butyl 4-(4-((6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

7-(p-Tolyl)quinoline-4-thiol 33c (50 mg, 198.93 μmol), 4-(4-((6-chlorohexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 12f (94.52mg, 238.72μmol), potassium carbonate (54.99mg, 397.86μmol) and sodium iodide (1.49 mg, 9.95 μmol) was dissolved in a solution of N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((6-((7-(p-tolyl)quinolin-4-yl)thio) )hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 33d (115 mg), yield 94.64%.

MS m/z(ESI):611.4[M+1].

the fourth step

4-(piperazin-1-yl)-N-(6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)aniline

4-(piperazin-1-yl)-N-(6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)aniline

4-(4-((6-((7-(p-tolyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 33d (115 mg, 188.26 μmol) was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours, saturated sodium bicarbonate was added to adjust the pH to 8~9, and extracted with ethyl acetate. (20ml FA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 4-(piperazin-1-yl)-N-(6-((7-(p-tolyl)quinolin-4-yl)thio )hexyl)aniline 33 (65 mg), yield 67.60%.

MS m/z(ESI):511.3[M+1].

1H NMR (400MHz, DMSO) δ8.73(d,J＝4.8Hz,1H),8.17(s,1H),8.13(d,J＝8.8Hz,1H),7.95(dd,J＝8.8,1.8Hz ,1H),7.76(d,J＝8.2Hz,2H),7.41(d,J＝4.8Hz,1H),7.35(d,J＝8.0Hz,2H),6.76(d,J＝8.8Hz,2H ),6.49(d,J＝8.8Hz,2H),3.26-3.20(m,2H),3.18-3.16(m,4H),3.07-3.05(m,4H),2.94(t,J＝6.8Hz, 2H),2.38(s,3H),1.81-1.71(m,2H),1.55-1.52(m,4H),1.44-1.42(m,2H).

Example 34

3-methyl-4-(4-methylpiperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methyl-4-(4-methylpiperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

3-Methyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 2 (146 mg, 341.57 μmol), paraformaldehyde (3.59 mg, 119.37 μmol) and sodium cyanoborohydride (12.75 mg, 202.93 μmol) were dissolved In a solution of 1,2-dichloroethane (1 mL), two drops of acetic acid were finally added, and the reaction mixture was stirred at 40°C for 12 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9, extract with ethyl acetate (30 mL × 3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN) to obtain 3-methyl-4-(4-methylpiperazin-1-yl) -N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 34 (11.4 mg), yield 6.49%.

MS m/z(ESI):517.2[M+1].

1H NMR (400MHz, CDCl3) δ8.74-8.65(m,1H),8.31(d,J＝8.8Hz,1H),8.22(s,1H),7.79(d,J＝8.8Hz,1H),7.49 (d,J＝5.2Hz,1H),7.29(s,1H),7.25-7.20(m,1H),7.17-7.10(m,1H),3.49-3.41(m,2H),3.33-3.26(m ,4H),3.18-3.14(m,2H),3.11(s,3H),3.09-3.03(m,4H),2.29(s,3H),1.78-1.67(m,2H),1.51-1.39(m ,4H),1.38-1.27(m,2H).

Example 35

N,3-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

N,3-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

first step

tert-butyl 4-(2-methyl-4-(methyl(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

4-(2-methyl-4-(methyl(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 2b (100 mg, 165.91 μmol) was dissolved in tetrahydrofuran (1 mL) solution, then sodium hydride (9.97 mg, 248.86 μmol) and methyl iodide (35.3 mg, 248.86 μmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction, add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(2-methyl-4-(methyl(6-((7-(trifluoromethyl))quin Phin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 35a (40 mg), yield 39.09%.

MS m/z(ESI):617.4[M+1].

Step 2

N,3-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

N,3-dimethyl-4-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(2-methyl-4-(methyl(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxy Tert-butyl acid ester 35a (24 mg, 38.91 μmol) was dissolved in a mixed solution of dichloromethane (2.5 mL) and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours, and saturated sodium bicarbonate was added to adjust the pH to 8～9, extract with ethyl acetate (30mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min ;Mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining N,3-dimethyl-4-(piperazin-1-yl)-N-(6-((7 -(Trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline 35 (14 mg), yield 69.64%.

MS m/z(ESI):517.2[M+1].

1H NMR (400MHz, CDCl3) δ8.78(d,J＝4.8Hz,1H),8.36(s,1H),8.24(d,J＝8.8Hz,1H),7.71(d,J＝8.8Hz,1H ),7.24(s,1H),6.95(d,J＝8.4Hz,1H),6.56(s,1H),6.53(d,J＝8.4Hz,1H),3.25(t,J＝7.2Hz,2H ),3.11(t,J＝7.2Hz,2H),3.02-2.97(m,2H),2.87(s,3H),2.83-2.79(m,2H),2.28(s,3H),1.85-1.75( m,6H),1.63-1.51(m,4H),1.46-1.35(m,2H).

Example 36

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)oxy)-7-(trifluoromethyl)quinoline

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)oxy)-7-(trifluoromethyl)quinoline

first step

4-((6-bromohexyl)oxy)-7-(trifluoromethyl)quinolone

4-((6-bromohexyl)oxy)-7-(trifluoromethyl)quinoline

Dissolve 7-(trifluoromethyl)quinolin-4-ol 13c (200mg, 938.28μmol), 1,6-dibromohexane 36a (274.69mg, 1.13mmo) and cesium carbonate (611.42mg, 1.88mmol) In a solution of N,N-dimethylformamide (4 mL), the reaction mixture was stirred at 65°C for 2 hours. After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-((6-bromohexyl)oxy)-7-(trifluoromethyl)quinoline 36b (150 mg) , yield 42.49%.

MS m/z(ESI):377.2[M+1].

Step 2

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)oxy)hexyl)oxy)phenyl)piperazine-1-carboxylate

tert-butyl 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)oxy)hexyl)oxy)phenyl)piperazine-1-carboxylate ester

4-((6-Bromohexyl)oxy)-7-(trifluoromethyl)quinoline 36b (80 mg, 212.65 μmol), 4-(4-hydroxy-2-methylphenyl)piperazine-1 - Tert-butyl carboxylate 28a (93.26 mg, 318.97 μmol) and cesium carbonate (138.57 mg, 425.29 μmol) were dissolved in a solution of N,N-dimethylformamide (4 mL), and the reaction mixture was stirred at 65°C for 2 hours. . After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(2-methyl-4-((6-((7-(trifluoromethyl)quinoline- 4-yl)oxy)hexyl)oxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 36c (100 mg), yield 80.02%.

MS m/z(ESI):588.2[M+1].

third step

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)oxy)-7-(trifluoromethyl)quinolone

4-((6-(3-methyl-4-(piperazin-1-yl)phenoxy)hexyl)oxy)-7-(trifluoromethyl)quinoline

4-(2-Methyl-4-((6-((7-(trifluoromethyl)quinolin-4-yl)oxy)hexyl)oxy)phenyl)piperazine-1-carboxylic acid tert. Butyl ester 36c (50 mg, 85.08 μmol) was dissolved in a mixed solution of dichloromethane (4 mL) and trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours, and saturated sodium bicarbonate was added to adjust the pH to 8~9. Extract with ethyl acetate (20 mL ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA + H ₂ O, mobile phase B: CH ₃ CN), obtaining 4-((6-(3-methyl-4-(piperazine-1- (yl)phenoxy)hexyl)oxy)-7-(trifluoromethyl)quinoline 36 (10 mg), yield 24.11%.

MS m/z(ESI):488.3[M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ9.05 (d, J = 6.2 Hz, 1H), 8.60 (d, J = 8.8 Hz, 1H), 8.36 (s, 1H), 7.97 (d, J = 8.8 Hz,1H),7.49(d,J＝6.4Hz,1H),7.01(d,J＝8.8Hz,1H),6.76(d,J＝2.6Hz, 1H),6.71(dd,J＝8.6,2.8Hz,1H),4.57(t,J＝6.4Hz,2H),3.96(t,J＝6.2Hz,2H),3.40-3.32(m,4H), 3.13-2.97(m,4H),2.28(s,3H),2.17-2.06(m,2H),1.95-1.78(m,2H),1.75-1.58(m,4H).

Example 37

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methyl)aniline

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl) Cyclohexyl)methyl)aniline

first step

(4-(hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate

(4-(hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate methyl ester

Dissolve cyclohexane-1,4-dimethanol 37a (500 mg, 3.47 mmol, commercially available), p-toluenesulfonyl chloride (195.63 mg, 2.77 mmol) and triethylamine (1.05 g, 10.40 mmol) in dichloromethane solution (10 mL) and stirred at room temperature for 2 hours. After the reaction, the reaction mixture was poured into water (10 ml), the aqueous phase was extracted with ethyl acetate (10 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the residue The material was separated and purified by silica gel column chromatography (eluent: System A) to obtain (4-(hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate methyl ester 37b (300 mg), with a yield of 29.00%.

MS m/z(ESI):299.1[M+1].

Step 2

(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methanol

(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methanol

7-(Trifluoromethyl)quinoline-4-thiol 11g (290mg, 1.27mmol), (4-(hydroxymethyl)cyclohexyl)methyl 4-methyl A solution of methyl benzenesulfonate 37b (251.68 mg, 843.44 μmol) and potassium carbonate (230 mg, 1.69 mmol) in N,N-dimethylformamide (5 mL) was stirred at 80°C for 2 hours. At the end of the reaction, the reaction mixture was poured into water (5 mL), the aqueous phase was extracted with ethyl acetate (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain the residue Separate and purify through silica gel column chromatography (eluent: System A) to obtain (4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methanol 37c( 104.31 mg), yield 34.80%.

MS m/z(ESI):356.0[M+1].

third step

4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexane-1-carbaldehyde

4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexane-1-carbaldehyde

(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methanol 37c (300 mg, 844.08 μmol) and Dess-Martin oxidant (430 mg, 1.01 mmol ) was dissolved in dichloromethane (2 mL) and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, saturated sodium thiosulfate (10 mL) was added, the aqueous phase was extracted with ethyl acetate (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(((7-(trifluoromethyl)quinolin-4-yl)thio) Methyl)cyclohexane-1-carbaldehyde 37d (190 mg), yield 63.69%. MS m/z(ESI):354.0[M+1].

the fourth step

tert-butyl 4-(2-(trifluoromethyl)-4-(((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methyl)amino)phenyl)piperazine-1-carboxylate

4-(2-(trifluoromethyl)-4-(((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methyl)amino )phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 7a (149 mg, 431.43 μmol), 4-((7-(trifluoromethyl) Quinolin-4-yl)thio)methyl)cyclohexane-1-carbaldehyde 37d (190.59 mg, 539.29 μmol) and sodium triacetoxyborohydride (194 mg, 916.80 μmol) were dissolved in 1,2-dichloro in ethane solution (5 mL). Stir at room temperature for 2 hours. After the reaction is completed, pour the reaction mixture into water (30 mL). The aqueous phase is extracted with ethyl acetate (20 mL × 3). The obtained organic phase is dried over anhydrous sodium sulfate. The organic phase is dried under reduced pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-(trifluoromethyl)-4-(((4-(((7-(trifluoromethyl) )quinolin-4-yl)thio)methyl)cyclohexyl)methyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 37e (120 mg), yield 32.59%.

MS m/z(ESI):683.4[M+1].

the fifth step

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methyl)aniline

4-(piperazin-1-yl)-3-(trifluoromethyl)-N-((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl) Cyclohexyl)methyl)aniline

4-(2-(trifluoromethyl)-4-(((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)cyclohexyl)methyl) A solution of amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 37e (100 mg, 146.46 μmol) and trifluoroacetic acid (16.70 mg, 146.46 μmol) was stirred at 25°C for 2 hours in dichloromethane (1 mL). The reactants were concentrated under reduced pressure, and the obtained residue was purified by preparative liquid phase separation. (Separation column prep-HPLC (Waters 3767/Qda Column: SunFire Sunfire C18; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) , obtaining 4-(piperazin-1-yl)-3-(trifluoromethyl)-N-((4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl) Cyclohexyl)methyl)aniline 37 (45 mg), yield 52.73%.

MS m/z(ESI):583.2[1/M+1].

1H NMR (400MHz, MeOD-d ₄ ) δ8.80 (d, J = 5.2Hz, 1H), 8.45 (d, J = 8.8Hz, 1H), 8.31 (s, 1H), 7.90 (d, J = 9.2 Hz,1H),7.63(t,J＝7.2Hz,1H),7.25(d,J＝8.8Hz,1H),6.84(d,J＝2.4Hz,1H),6.79(d,J＝8.8Hz, 1H),3.29-3.25(m,4H),3.20(d,J＝6.8Hz,2H),3.08-3.04(m,4H),2.96(d,J＝6.8Hz,2H),2.10(d,J ＝12.4Hz,2H),1.96(d,J＝11.6Hz,2H),1.88-1.76(m,1H),1.68-1.51(m,1H),1.28-1.16(m,2H),1.09-1.04( m,2H).

Example 38

4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl )aniline

first step

tert-butyl 2-methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate

2-Methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

1-Fluoro-4-nitro-2-(trifluoromethyl)benzene 38a (1.0g, 4.78mmol), 2-methylpiperazine-1-carboxylic acid tert-butyl ester 38b (1.44g, 7.17mmol) and potassium carbonate (1.32g, 9.56mmol) were dissolved in N,N-dimethylformamide (10mL), and the temperature was raised to 120°C and stirred for 2 hours. After the reaction is complete, add water (100 mL) to the reaction mixture, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 2-methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine- 1-tert-butylcarboxylate 38c (1.5g), yield 80.55%.

MS m/z(ESI):334.0[M-55].

Step 2

tert-butyl 4-(4-amino-2-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxylate

4-(4-Amino-2-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester

2-Methyl-4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester 38c (500mg, 1.28mmol), palladium on carbon (27.33mg, 256.83 μmol) was dissolved in a methanol (10 ml) solution, and the temperature was raised to 40°C and stirred for 4 hours under a hydrogen atmosphere. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to obtain 4-(4-amino-2-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 38d (367 mg ), yield 79.52%.

MS m/z(ESI):360.2[M+1].

third step

6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexan-1-ol

6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexan-1-ol

7-(Trifluoromethyl)quinoline-4-thiol 11g (2.0g, 8.73mmol), 6-bromohexan-1-ol 38e (2.37g, 13.09mmol) and potassium carbonate (2.41g, 17.45mmol) ) was dissolved in N,N-dimethylformamide (40 ml) solution, and the temperature was raised to 60°C and stirred for 2 hours. After the reaction is complete, add water (40 mL) to the reaction mixture, extract with ethyl acetate (40 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexan-1-ol. 38f (2.25g), yield 78.33%.

MS m/z(ESI):330.2[M+1].

the fourth step

6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexanal

6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexanal

6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexan-1-ol 38f (200 mg, 607.20 μmol), 1,1-diacetoxy-3-oxo- 1,2-Benziodooxyol-1-yl acetate (309.05 mg, 728.64 mmol) was dissolved in a dichloromethane (5 ml) solution, and stirred at 25°C for 2 hours. After the reaction was completed, the reaction mixture was filtered and concentrated under reduced pressure to obtain 38 g (147 mg) of 6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexanal, with a yield of 74.18%.

MS m/z(ESI):328.0[M+1].

the fifth step

tert-butyl 2-methyl-4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylate

2-Methyl-4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl) Piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-(trifluoromethyl)phenyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 38d (61.66 mg, 171.58 μmol), 6-((7-( Trifluoromethyl)quinolin-4-yl)thio)hexanal 38g (70mg, 214.48μmol) and sodium cyanoborohydride (20.22mg, 321.71μmol) were dissolved in methanol (2ml) solution and stirred at 25°C 2 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, water (20 mL) is added to the residue, extracted with ethyl acetate (20 mL × 3), the organic phases are combined, washed with saturated sodium chloride solution (20 mL), anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 2-methyl-4-(2-(trifluoromethyl)-4-( (6-((7-(Trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 38h (36mg), yield 25.02%.

MS m/z(ESI):671.2[M+1].

Step 6

4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)aniline

4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl )aniline

2-Methyl-4-(2-(trifluoromethyl)-4-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)phenyl ) Piperazine-1-carboxylic acid tert-butyl ester 38h (26 mg, 38.76 μmol) was dissolved in a solution of dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 mL), and stirred at 25°C for 2 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by preparative liquid phase separation (separation column SunFire C18; 19*250mm; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile Phase B: CH ₃ CN), giving 4-(3-methylpiperazin-1-yl)-3-(trifluoromethyl)-N-(6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)aniline 38 (15 mg), yield 67.81%.

MS m/z(ESI):571.4[M+1].

1H NMR (400MHz, DMSO) δ8.86(d,J＝4.8Hz,1H),8.35-8.30(m,2H),7.91(d,J＝8.8Hz,1H),7.61(d,J＝4.8Hz ,1H),7.23(d,J＝8.8Hz,1H),6.84-6.76(m,2H),3.40-3.24(m,6H),3.01(t,J＝6.8Hz,13.6Hz,2H),2.90 -2.85(m,2H),2.70-2.58(m,1H),1.80-1.74(m,2H),1.60-1.49(m,4H),1.47-1.39(m,2H),0.71(d,J＝ 6.2Hz,3H).

Example 39

3-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1-(4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidin-1 -yl)propan-1-one

3-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1-(4-(((7-(p-tolyl)quinolin-4-yl)thio) Methyl)piperidin-1-yl)propan-1-one

first step

tert-butyl 4-(4-((3-methoxy-3-oxopropyl)amino)-2-methylphenyl)piperazine-1-carboxylate

4-(4-((3-methoxy-3-oxypropyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 2a (1g, 3.43mmol), 3-bromopropionic acid methyl ester 39a (687.75mg, 4.12mol, commercially available ) and potassium carbonate (948.60 mg, 6.86 mmol) were dissolved in N,N-dimethylformamide (1 mL) solution, and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, add water (20 mL) to the reaction solution, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (20 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is purified by silica gel column chromatography (eluent: A system) to obtain 4-(4-((3-methoxy-3-oxypropyl)amino)-2-methylphenyl) Piperazine-1-carboxylic acid tert-butyl ester 39b (1.03g), yield 79.74%.

MS m/z(ESI):378.2[M+1].

Step 2

3-((4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-methylphenyl)amino)propanoic acid

3-((4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-methylphenyl)amino)propionic acid

4-(4-((3-methoxy-3-oxypropyl)amino)-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester 39b (1g, 2.65mmol) and hydroxide Lithium (222.34 mg, 5.30 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (200 mL) was added to the reaction solution dropwise. Adjust the pH to 5~6 with 1N hydrochloric acid, extract with ethyl acetate (200mL×3), combine the organic phases, wash with saturated sodium chloride solution (200mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3- ((4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-3-methylphenyl)amino)propionic acid 39c (536 mg), yield 55.67%.

MS m/z(ESI):364.2[M+1].

third step

4-chloro-7-(p-tolyl)quinoline

4-Chloro-7-(p-tolyl)quinoline

7-Bromo-4-chloroquinoline 33a (2.0g, 8.25mmol), p-tolylboronic acid 39d (1.35g, 9.90mmol), potassium phosphate (3.50g, 16.49mmol), (1,1'-bis(di) Phenylphosphino)ferrocene)palladium dichloride (603.47 mg, 824.74 μmol) was dissolved in a mixed solution of 1,4-dioxane (20 mL) and water (2 mL), and nitrogen was replaced three times. The reaction mixture was Stir at 110°C for 8 hours. After the reaction, add water (50 mL) to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-chloro-7-(p-tolyl)quinoline 39e (1g) with a yield of 47.79%. MS m/z(ESI):254.0[M+1].

the fourth step

7-(p-tolyl)quinoline-4-thiol

7-(p-Tolyl)quinoline-4-thiol

Dissolve 4-chloro-7-(p-tolyl)quinoline 39e (500 mg, 1.97 mmol) and sodium sulfide nonahydrate (1.42 g, 5.91 mmol) in N, N-dimethylformamide (10 mL) solution, The reaction mixture was stirred at 80°C for 2 hours. After the reaction is completed, add water (50 mL) to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. After concentration, the residue was purified by silica gel column chromatography (eluent: System A) to obtain 7-(p-tolyl)quinoline-4-thiol 39f (400 mg) with a yield of 80.76%.

MS m/z(ESI):252.1[M+1].

the fifth step

tert-butyl 4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylate

tert-butyl 4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylate

7-(p-Tolyl)quinoline-4-thiol 39f (200mg, 795.72μmol), 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester 39g (265.63mg, 954.86μmol) and carbonic acid Potassium (219.94 mg, 1.59 mmol) was dissolved in a solution of N,N-dimethylformamide (1 mL), and the reaction mixture was stirred at 50°C for 2 hours. After the reaction, add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is purified by silica gel column chromatography (eluent: System A) to obtain 4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1 -tert-butyl carboxylate 39h (287mg), yield 80.40%.

MS m/z(ESI):449.2[M+1].

Step 6

4-((piperidin-4-ylmethyl)thio)-7-(p-tolyl)quinolone

4-((piperidin-4-ylmethyl)thio)-7-(p-tolyl)quinoline

Dissolve 4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester 39h (280 mg, 624.14 μmol) in dichloromethane (3 mL ) and trifluoroacetic acid (1 mL), the reaction mixture was stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain 4-((piperidin-4-ylmethyl)thio)-7-(p-tolyl) ) Quinoline 39i (200 mg), yield 91.95%.

MS m/z(ESI):349.2[M+1].

Step 7

tert-butyl 4-(2-methyl-4-((3-oxo-3-(4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl )amino)phenyl)piperazine-1-carboxylate

4-(2-methyl-4-((3-oxo-3-(4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1- Base)propyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-((piperidin-4-ylmethyl)thio)-7-(p-tolyl)quinoline 39i (100 mg, 286.94 μmol), 3-((4-(4-(tert-butoxycarbonyl) )piperazin-1-yl)-3-methylphenyl)amino)propionic acid 39c (86.91 mg, 239.12 μmol), N,N-diisopropylethylamine (123.62 mg, 956.47 μmol) and O-( 7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (136.38mg, 358.68μmol) dissolved in N,N-dimethylformamide (2mL) solution, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20mL) was added to the reaction solution, extracted with ethyl acetate (20mL×3), the organic phases were combined, and saturated sodium chloride solution was used. (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(2-methyl-4-((3- Oxo-3-(4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)phenyl)piperazine-1 - Tert-butyl carboxylate 39j (134 mg), yield 80.76%.

MS m/z(ESI):694.4[M+1].

Step 8

3-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1-(4-(((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidin-1 -yl)propan-1-one

3-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1-(4-(((7-(p-tolyl)quinolin-4-yl)thio) Methyl)piperidin-1-yl)propan-1-one

4-(2-methyl-4-((3-oxo-3-(4-((7-(p-tolyl)quinolin-4-yl)thio)methyl)piperidine-1 -(Base)propyl)amino)phenyl)piperazine-1-carboxylic acid tert-butyl ester 39j (120 mg, 172.93 μmol) was dissolved in a mixed solution of dichloromethane (0.4 mL) and trifluoroacetic acid (0.1 mL), The reaction mixture was stirred at room temperature for 2 hours, concentrated under reduced pressure, and the residue was purified by preparative liquid phase separation (separation column SunFire Sunfire C18; 250×19mm ID; 10 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O , mobile phase B: ACN), obtaining 3-((3-methyl-4-(piperazin-1-yl)phenyl)amino)-1-(4-(((7-(p-tolyl)quino) Phin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one 39 (7.24 mg), yield 7.05%.

MS m/z(ESI):594.4[M+1].

¹ H NMR (400MHz, MeOD-d ₄ ) δ8.81 (d, J = 6.0 Hz, 1H), 8.47 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 1.6 Hz, 1H), 8.22 -8.17(m,1H),7.78-7.73(m,3H),7.40(d,J＝8.0Hz,2H),7.12(d,J＝8.4Hz,1H),7.00-6.92(m,2H), 4.64(d,J＝12.8Hz,1H),3.99(d,J＝14.0Hz,1H),3.54-3.25(m,2H),3.39-3.34(m,6H),3.18-3.10(m,1H) ,3.12-3.09(m,4H),2.82-2.75(m,2H),2.74-2.68(m,1H),2.44(s,3H),2.33(s,3H),2.18-2.10(m,1H) ,2.12-2.02(m,2H),1.44-1.32(m,2H).

Embodiments 40-144 were synthesized according to the synthesis method of Embodiments 1-39 of the present invention. The spectrum parameters of Examples 40-144 are as shown in the following table:

Example 145

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2,3,4,4a- tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino) -2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one

first step

tert-butyl 4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylate

tert-butyl 4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylate

11g of 7-(trifluoromethyl)quinoline-4-thiol (1.65g, 7.19mmol), 39g of 4-(bromomethyl)piperidine-1-carboxylic acid tert-butyl ester (2g, 7.19mmol) and Potassium carbonate (1.99g, 14.38mmol) was dissolved in N,N-dimethylformamide (30mL), and the temperature was raised to 120°C and stirred for 2 hours. After the reaction is complete, add water (100 mL) to the reaction mixture, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (100 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(((7-(trifluoromethyl)quinolin-4-yl) Thio)methyl)piperidine-1-carboxylic acid tert-butyl ester 145a (3.0 g), yield 97.84%.

MS m/z(ESI):427.2[M+1].

Step 2

4-((piperidin-4-ylmethyl)thio)-7-(trifluoromethyl)quinolone

4-((piperidin-4-ylmethyl)thio)-7-(trifluoromethyl)quinoline

4-(((7-(Trifluoromethyl)quinolin-4-yl)thio)methyl)piperidine-1-carboxylic acid tert-butyl ester 145a (3g, 7.03mmol) was dissolved in dichloromethane ( 20 mL), then trifluoroacetic acid (5 mL) was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 4-((piperidin-4-ylmethyl)thio)-7-(trifluoromethyl)quinoline 145b (2.1 g) with a yield of 91.47%.

MS m/z(ESI):327.1[M+1].

third step

3,3-dimethoxy-1-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

3,3-Dimethoxy-1-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

3,3-Dimethoxypropionic acid 145c (283.57 mg, 2.11 mmol) and 4-((piperidin-4-ylmethyl)thio)-7-(trifluoromethyl)quinoline 145b (345 mg ,1.06mmol) was dissolved in N,N-dimethylformamide (10mL), and N,N-diisopropylethylamine (409.84mg, 3.17mmol) and O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (482.31 mg, 1.27 mmol), the reaction mixture was stirred at room temperature for 2 hours under nitrogen protection. After the reaction is complete, add water (20 mL) to the reaction mixture, extract with ethyl acetate (20 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 3,3-dimethoxy-1-(4-(((7-(trifluoromethyl))quinoline-4 -yl)thio)methyl)piperidin-1-yl)propan-1-one 145d (450 mg), yield 96.21%.

MS m/z(ESI):443.2[M+1].

the fourth step

3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propanal

3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propionaldehyde

3,3-Dimethoxy-1-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1- Ketone 145d (250 mg, 564.98 μmol) was dissolved in 1N hydrogen chloride solution (2.5 mL) and 1,4-dioxane (2.5 mL), and the reaction mixture was stirred at 60°C for 2 hours. After the reaction is complete, adjust the pH to 8-9 with saturated sodium bicarbonate solution. Add water (20 mL) to the reaction mixture, extract with ethyl acetate (20 mL × 3), combine the organic phases, and use saturated sodium chloride solution (30 mL). Wash, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piper (Din-1-yl)propionaldehyde 145e (220 mg), yield 98.23%.

MS m/z(ESI):397.2[M+1].

the fifth step

4-((benzyloxy)carbonyl)-1-(2,4-dinitrophenyl)piperazine-2-carboxylic acid

4-((benzyloxy)carbonyl)-1-(2,4-dinitrophenyl)piperazine-2-carboxylic acid

1-Fluoro-2,4-dinitrobenzene 145f (1.41g, 7.58mmol, commercially available) and 4-((benzyloxy)carbonyl)piperazine-2-carboxylic acid 145g (3.00g, 11.37mmol, Commercially available) was dissolved in N,N-dimethylformamide (40 mL), potassium carbonate (2.09 g, 15.15 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 80°C for 2 hours. After the reaction is complete, add water (80 mL) to the reaction mixture, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-((benzyloxy)carbonyl)-1-(2,4-dinitrophenyl)piperazine-2- Carboxylic acid 145h (3.2g), yield 98.14%.

MS m/z(ESI):431.2[M+1].

Step 6

benzyl 8-nitro-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylate

8-Nitro-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester

Dissolve 4-((benzyloxy)carbonyl)-1-(2,4-dinitrophenyl)piperazine-2-carboxylic acid 145h (2g, 4.65mmol) and iron powder (1.30g, 23.24mmol) In a solution of acetic acid (100 mL), the reaction mixture was stirred at 60°C for 2 hours. After the reaction is complete, add water (80 mL) to the reaction mixture, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 8-nitro-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazine [1,2-a]quinoxaline-3-carboxylic acid benzyl ester 145i (578 mg), yield 32.53%.

MS m/z(ESI):383.2[M+1].

Step 7

benzyl 8-amino-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylate

8-Amino-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester

8-Nitro-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester 145i ( 578mg, 1.51mmol), iron powder (422.12mg, 7.56mmol) and ammonium chloride (405mg, 7.56mmol) were dissolved in a mixed solution of ethanol (10mL) and water (2mL), and the reaction mixture was stirred at 80°C for 2 hours. . After the reaction is complete, add water (80 mL) to the reaction mixture, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 8-amino-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino [1,2-a]quinoxaline-3-carboxylic acid benzyl ester 145j (325 mg), yield 61.01%.

MS m/z(ESI):353.2[M+1].

Step 8

benzyl 5-oxo-8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-1,2 ,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylate

5-oxo-8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl) Propyl)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester

8-Amino-5-oxo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester 145j (20 mg ,56.76 μmol), 3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propionaldehyde 145e( 33.75 mg, 85.13 μmol) and sodium cyanoborohydride (5.35 mg, 68.11 μmol) were dissolved in methanol (0.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, add water (80 mL) to the reaction mixture, extract with ethyl acetate (80 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 5-oxo-8-((3-oxo-3-(4-((7-(trifluoromethyl) )quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1, 2-a] Quinoxaline-3-carboxylic acid benzyl ester 145k (40 mg), yield 96.17%.

MS m/z(ESI):733.4[M+1].

Step 9

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2,3,4,4a- tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino) -2,3,4,4a-Tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one

5-oxo-8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl )propyl)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoxaline-3-carboxylic acid benzyl ester 145k (180mg, 245.63μmol ) was dissolved in trifluoroacetic acid (2mL) solution. The reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8-9. Extract with ethyl acetate (50mL×3). Combine the organic phases and reduce the pressure. Concentrate, and the residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino) -2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one 145 (2.5 mg), yield 1.70%.

MS m/z(ESI):599.3[M+1].

¹ H NMR (400MHz, MeOD-d ₄ ) δ8.84 (s, 1H), 8.47 (t, J = 16.0, 7.6Hz, 1H), 8.35 (d, J = 7.2Hz, 1H), 7.93 (t, J＝16.0,6.8Hz,1H),7.68(t,J＝12.8,6.8Hz,1H),7.13-6.90(m,2H),6.87(d,J＝5.6Hz,1H),4.68-4.59(m ,1H),4.06-3.80(m,4H),3.66-3.47(m,3H),3.29-3.20(m,3H),3.18-2.95(m,2H),2.87-2.63(m,3H),2.17 -2.02(m,3H),1.43-1.24(m,3H).

Example 146

9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b] isoquinolin-6-one

9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazine And[1,2-b]isoquinolin-6-one

first step

ethyl N-benzyl-N-(3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)glycinate

N-Benzyl-N-(3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionyl)glycine ethyl ester

3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionic acid 146a (10g, 29.05mmol, commercially available) and N,N-diisopropylethylamine were mixed at 0°C. (11.26g, 87.16mmol) was dissolved in dichloromethane (100mL), then a solution of isobutyl chloroformate (4.76g, 34.86mmol) in dichloromethane (10mL) was added dropwise, stirred at 0°C for half an hour, and then 2-(Benzylamino)ethyl acetate 146b (6.74g, 34.86mmol, commercially available) was added to the reaction system, and the mixture was raised to room temperature and stirred for 2 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain N-benzyl-N-(3-(3-bromophenyl)-2-(( Tert-butoxycarbonyl)amino)propionyl)glycine ethyl ester 146c (5g), yield 33.13%.

MS m/z(ESI):541.2[M+23].

Step 2

ethyl N-(2-amino-3-(3-bromophenyl)propanoyl)-N-benzylglycinate

N-(2-amino-3-(3-bromophenyl)propionyl)-N-benzylglycine ethyl ester

Dissolve N-benzyl-N-(3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propionyl)glycine ethyl ester 146c (10g, 19.25mmol) in hydrogen dioxane chloride ring solution (200 mL) and stirred at room temperature for 1 hour. After the reaction is complete, remove the solvent under reduced pressure, adjust to alkalinity with sodium bicarbonate, and extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure to obtain N-(2-amino-3-(3-bromophenyl)propionyl)-N-benzylglycine ethyl ester 146d (7.5g). The crude product was directly put into the next reaction.

MS m/z(ESI):419.2[M+1].

third step

1-benzyl-3-(3-bromobenzyl)piperazine-2,5-dione

1-Benzyl-3-(3-bromobenzyl)piperazine-2,5-dione

Dissolve N-(2-amino-3-(3-bromophenyl)propionyl)-N-benzylglycine ethyl ester 146d (7.5g, 17.89mmol) in 1,2-dichloroethane (100mL) , the reaction mixture was raised to 60°C and stirred for 16 hours. After the reaction is complete, the solvent is removed under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 1-benzyl-3-(3-bromobenzyl)piperazine-2,5-bis. Ketone 146e (6.5g), yield 97.36%.

MS m/z(ESI):373.0[M+1].

the fourth step

1-benzyl-3-(3-bromobenzyl)piperazine

1-Benzyl-3-(3-bromobenzyl)piperazine

Dissolve 1-benzyl-3-(3-bromobenzyl)piperazine-2,5-dione 146e (6.5g, 17.41mmol) in borane tetrahydrofuran complex solution (100mL), and the reaction mixture is at room temperature. Stir for 16 hours. The reaction solution was quenched with methanol and concentrated. The resulting residue was refluxed with methanol for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System B) to obtain 1-benzyl. Base-3-(3-bromobenzyl)piperazine 146f (1.86g), yield 30.93%.

MS m/z(ESI):345.2[M+1].

the fifth step

2-benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

Dissolve 1-benzyl-3-(3-bromobenzyl)piperazine 146f (0.9g, 2.61mmol) in dichloromethane (10mL), reduce the reaction mixture to 0°C, and add sodium bicarbonate (656.94mg ,7.82mmol) was added to the reaction solution, and then triphosgene (1.93g, 6.52mmol) was dissolved in dichloromethane (5mL), added slowly, and stirred at room temperature for 2 hours. After the reaction is complete, extract with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is dissolved in phosphorus oxychloride (10 mL), and phosphorus pentoxide (3.70 g, 26.07 mmol) was slowly added to the reaction solution, and the reaction mixture was stirred at 100°C for 16 hours. After the reaction is complete, extract with dichloromethane (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 2-Benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one 146g (800mg), yield 82.67%.

MS m/z(ESI):371.0[M+1].

Step 6

2-benzyl-9-((diphenylmethylene)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

2-Benzyl-9-((diphenylmethylene)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinoline- 6-keto

146g (400mg, 1.08mmol) of 2-benzyl-9-bromo-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one ) and benzophenone imine (390.51mg, 2.15mmol) were dissolved in 1,4-dioxane:water (5mL:0.5mL), and sodium tert-butoxide (310.61mg, 3.23mmol) was added to the reaction mixture. ), tris(dibenzylideneacetone)dipalladium (98.66mg, 107.74μmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (124.68mg, 215.48μmol), react The mixture was replaced with nitrogen 3 to 5 times, and the reaction mixture was stirred at 80°C overnight. After the reaction is complete, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), and dry over anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 2-benzyl-9-((diphenylmethylene)amino)-1,2, 3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one 146h (295mg), yield 58.06%.

MS m/z(ESI):472.2[M+1].

Step 7

9-amino-2-benzyl-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

9-amino-2-benzyl-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

2-Benzyl-9-((diphenylmethylene)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinoline -6-one 146h (136 mg, 288.39 μmol) was dissolved in tetrahydrofuran solution (2.5 mL), 2N hydrochloric acid (0.5 mL) was slowly added to the reaction solution, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, adjust the pH to 8-9 with sodium bicarbonate, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce Concentrate under pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 9-amino-2-benzyl-1,2,3,4,11,11a-hexahydro-6H-pyrazine And[1,2-b]isoquinolin-6-one 146i (75 mg), yield 84.61%.

MS m/z(ESI):308.2[M+1].

Step 8

9-amino-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

9-Amino-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one

9-Amino-2-benzyl-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one 146i (50 mg, 162.66 μmol ) and 10% of the palladium-carbon hydrogenation catalyst (10 mg, 162.66 μmol) were dissolved in methanol (1 mL), replaced with hydrogen 3 to 5 times, and the reaction mixture was stirred at 40°C for 16 hours. After the reaction is complete, the crude product is filtered and concentrated in vacuum to obtain 9-amino-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinoline-6- Ketone 146j (35 mg), yield 99.04%.

MS m/z(ESI):218.2[M+1].

Step 9

tert-butyl 9-amino-6-oxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-2-carboxylate

9-Amino-6-oxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl ester

Dissolve 9-amino-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one 146j (35 mg, 161.09 μmol) in tetrahydrofuran solution (1.5 mL), di-tert-butyl dicarbonate (38.67 mg, 177.20 μmol) was slowly added to the reaction solution, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 9-amino-6-oxo-1,3,4,6,11,11a-hexahydrogen. -2H-Pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl ester 146k (30 mg), yield 58.68%.

MS m/z(ESI):318.2[M+1].

Step 10

tert-butyl 6-oxo-9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b]isoquinoline-2-carboxylate

6-oxo-9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,3,4,6,11,11a-hexahydro -2H-Pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl ester

9-Amino-6-oxo-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl ester 146k ( 30 mg, 94.52 μmol) and 38 g of 6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexanal (58 mg, 177.17 μmol) were dissolved in methanol (1 mL), and the cyanoboration was performed Sodium (7.13 mg, 113.43 μmol) was added to the reaction mixture and stirred at room temperature for 3 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 6-oxo-9-((6-((7-(trifluoromethyl))quinoline -4-yl)thio)hexyl)amino)-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl Ester 146l (45mg), yield 46.95%.

MS m/z(ESI):629.4[M+1].

Step 11

9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazino[1,2-b] isoquinolin-6-one

9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,2,3,4,11,11a-hexahydro-6H-pyrazine And[1,2-b]isoquinolin-6-one

6-oxo-9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,3,4,6,11,11a-hexa Hydrogen-2H-pyrazino[1,2-b]isoquinoline-2-carboxylic acid tert-butyl ester 146l (35mg, 55.67μmol) was dissolved in dichloromethane (1.0mL) and trifluoroacetic acid (0.2mL) The reaction mixture was stirred at room temperature for 1 hour. After the reaction is complete, the reaction solution is concentrated under reduced pressure, and the residue is separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 9-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)-1,2,3,4,11,11a -Hexahydro-6H-pyrazino[1,2-b]isoquinolin-6-one 146 (3.56 mg), yield 9.95%.

MS m/z(ESI):529.2[M+1].

¹ H NMR (400MHz, MeOD-d ₄ ) δ8.79 (d, J＝5.2Hz, 1H), 8.42 (d, J＝8.8Hz, 1H), 8.32 (s, 1H), 7.89 (d, J＝ 9.2Hz,1H),7.73(d,J＝8.8Hz,1H),7.62(d,J＝5.2Hz,1H),6.54(d,J＝9.2Hz,1H),6.36(s,1H),4.65 (d,J＝14.2Hz,1H),3.94-3.86(m,1H),3.53(d,J＝12.4Hz,2H),3.30-3.27(m,2H),3.21-3.10(m,3H), 3.10-2.98(m,3H),2.89-2.78(m,1H),1.94-1.84(m,2H),1.71-1.59(m,4H),1.56-1.48(m,2H).

Example 147

8-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)chroman-5-amine

8-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)chroman-5-amine

first step

tert-butyl 4-(4-nitro-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate

4-(4-Nitro-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(2-Hydroxy-4-nitrophenyl)piperazine-1-carboxylic acid tert-butyl ester 18c (500 mg, 1.55 mmol), 3-bromopropyl-1-yne 147a (275.93 mg, 2.32 mmol) and Cesium carbonate (1.01 g, 3.09 mmol) was dissolved in a solution of N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 65°C for 2 hours. After the reaction, add water (50 mL) to the reaction solution, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-nitro-2-(prop-2-yn-1-yloxy)phenyl)piperazine- 1-tert-butylcarboxylate 147b (500 mg), yield 89.47%.

MS m/z(ESI):362.2[M+1].

Step 2

tert-butyl 4-(4-amino-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylate

4-(4-Amino-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-nitro-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 147b (300 mg, 830.12 μmol), iron powder (231.81 mg ,4.15mmol) and ammonium chloride (223mg, 4.15mmol) were dissolved in a mixed solution of ethanol (5mL) and water (1mL), and the reaction mixture was stirred at 80°C for 2 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-amino- 2-(Prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 147c (225 mg), yield 81.79%.

MS m/z(ESI):332.2[M+1].

third step

tert-butyl 4-(5-amino-2H-chromen-8-yl)piperazine-1-carboxylate

4-(5-Amino-2H-chromen-8-yl)piperazine-1-carboxylic acid tert-butyl ester

4-(4-Amino-2-(prop-2-yn-1-yloxy)phenyl)piperazine-1-carboxylic acid tert-butyl ester 147c (20 mg, 60.35 μmol) was dissolved in N,N-di In a solution of ethylaniline (0.5 mL), the reaction mixture was stirred at 210°C for 2 hours. After the reaction, add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(5-amino-2H-chromen-8-yl)piperazine-1-carboxylic acid tert-butyl ester 147d (5 mg ), yield 25.00%. ¹ H NMR (400MHz, CDCl ₃ ) δ6.67 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 9.6 Hz, 1H), 6.24 (d, J = 8.4 Hz,1H),5.81(dt,J＝9.6,4.0Hz,1H),4.74(dd,J＝4.0,1.6Hz,2H),3.60-3.52(m,4H),2.94-2.83(m,4H) ,1.48(s,9H).

the fourth step

tert-butyl 4-(5-aminochroman-8-yl)piperazine-1-carboxylate

4-(5-Aminochroman-8-yl)piperazine-1-carboxylic acid tert-butyl ester

4-(5-Amino-2H-chromen-8-yl)piperazine-1-carboxylic acid tert-butyl ester 147d (46 mg, 138.80 μmol) and palladium carbon hydrogenation catalyst 10% (30 mg, 247.02 μmol) were dissolved in The methanol (3 mL) solution was replaced with hydrogen three times, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol (10 mL), the filtrate was collected and concentrated under reduced pressure to obtain 4-(5-aminochroman-8-yl)piperazine-1-carboxylic acid tert-butyl Ester 147e (29 mg), yield 62.66%.

MS m/z(ESI):334.2[M+1].

the fifth step

tert-butyl 4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)chroman-8-yl)piperazine-1-carboxylate

4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)chroman-8-yl)piperazine-1-carboxy tert-butyl acid ester

4-(5-Aminochroman-8-yl)piperazine-1-carboxylic acid tert-butyl ester 147e (17.85 mg, 53.53 μmol), 4-((6-bromohexyl)thio)- 7-(Trifluoromethyl)quinoline 147f (14 mg, 35.69 μmol, prepared according to published patent WO2019023315), potassium iodide (0.3 mg, 71.38 μmol) and potassium carbonate (9.4 mg, 71.38 μmol) were dissolved in N,N-dimethyl The reaction mixture was stirred at 80°C for 2 hours in a solution of methylformamide (0.5 mL). After the reaction, add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (30 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: B system) to obtain 4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)) Hexyl)amino)chroman-8-yl)piperazine-1-carboxylic acid tert-butyl ester 147g (10mg), yield 43.46%.

MS m/z(ESI):645.3[M+1].

Step 6

8-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)chroman-5-amine

8-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)chroman-5-amine

4-(5-((6-((7-(trifluoromethyl)quinolin-4-yl)thio)hexyl)amino)chroman-8-yl)piperazine-1- 147g of tert-butyl carboxylate (3mg, 4.65μmol) was dissolved in a mixed solution of dichloromethane (0.15mL) and trifluoroacetic acid (0.03mL). The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to adjust the pH. to 8~9, extract with ethyl acetate (50mL×3), combine the organic phases, and concentrate under reduced pressure. The obtained residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/ min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 8-(piperazin-1-yl)-N-(6-((7-(trifluoromethyl)) Quinolin-4-yl)thio)hexyl)chroman-5-amine 147 (2.3 mg), yield 90.76%.

MS m/z(ESI):545.4[M+1].

¹ H NMR (400MHz, MeOD-d ₄ ) δ8.74 (d, J＝4.8Hz, 1H), 8.35 (d, J＝8.8Hz, 1H), 8.28 (s, 1H), 7.81 (d, J＝ 8.8Hz,1H),7.51(d,J＝4.8Hz,1H),6.73(d,J＝8.4Hz,1H),6.17(d,J＝8.4Hz, 1H),4.71-4.47(m,2H),4.18-4.07(m,2H),3.30-3.21(m,4H),3.16-3.09(m,6H),2.45(t,J＝6.8Hz,2H) ,2.06-1.96(m,2H),1.91-1.81(m,2H),1.73-1.57(m,4H),1.56-1.45(m,2H).

Example 148

3-((2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)amino)-1-(4-(((7-(trifluoromethyl)) quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

3-((2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)amino)-1-(4-((7 -(Trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

first step

8-bromo-2,3,5,6-tetrahydro-1H-pyrazino[1,2-a]quinolin-4(4aH)-one

8-Bromo-2,3,5,6-tetrahydro1H-pyrazino[1,2-a]quinolin-4(4aH)-one

8-bromo-2,3,4a,5-tetrahydro1H-pyrazino[1,2-a]quinoline-4,6-dione 148a (380 mg, 1.29 mmol, according to the published literature Bioorganic & Medicinal Chemistry Letters ( 2016), 26(24), 5877-5882), triethylsilane (994.01mg, 5.15mmol) was added to trifluoroacetic acid (8mL), stirred at 25°C for 2 hours under nitrogen protection, after the reaction was completed, reduce Distill under pressure to obtain 8-bromo-2,3,5,6-tetrahydro1H-pyrazino[1,2-a]quinolin-4(4aH)-one 148b (280 mg), and the crude product is directly put into the next reaction .

MS m/z(ESI):281.0[M+1].

Step 2

8-bromo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolone

8-Bromo-2,3,4,4a,5,6-hexahydro1H-pyrazino[1,2-a]quinoline

8-Bromo-2,3,5,6-tetrahydro1H-pyrazino[1,2-a]quinolin-4(4aH)-one 148b (280 mg, 995.92 μmol) was added To tetrahydrofuran (4mL), add borane tetrahydrofuran solution (2M, 2mL). React at 60°C for 2 hours. After the reaction is completed, spin to dryness, add methanol (2 mL) and 35% hydrochloric acid (0.5 mL), and react at 70°C for 1 hour. Concentrate under reduced pressure to obtain 8-bromo-2,3,4,4a,5,6-hexahydro1H-pyrazino[1,2-a]quinoline 148c (180 mg). The crude product was directly put into the next reaction.

MS m/z(ESI):267.0[M+1].

third step

tert-butyl 8-bromo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylate

8-Bromo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester

8-Bromo-2,3,4,4a,5,6-hexahydro1H-pyrazino[1,2-a]quinoline 148c (180 mg, 673.74 μmol), di-tert-butyl dicarbonate (588.17 mg ,2.69mmol), 4-dimethylaminopyridine (16.46mg, 134.75μmol) and potassium carbonate (186.23mg, 1.35mmol) were added to a mixed solution of water (4mL) and acetonitrile (4mL), and reacted at 25°C for 2 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by column chromatography (eluent: System A) to obtain 8-bromo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a ] Quinoline-3-carboxylic acid tert-butyl ester 148d (104 mg), yield 42.03%.

MS m/z(ESI):367.1[M+1].

the fourth step

tert-butyl 8-((diphenylmethylene)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylate

8-((Diphenylmethylene)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester

8-Bromo-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester 148d (80 mg, 217.82 μmol), Benzophenone imine (78.95mg, 435.64μmol), tris(dibenzylideneacetone)dipalladium (39.89mg, 43.56μmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxide Mixed anthracene (50.41 mg, 87.13 μmol) and sodium tert-butoxide (62.80 mg, 653.45 μmol, 0.3 mL) were added to dioxane (1 mL) and water (0.1 mL), replaced with nitrogen, and reacted at 90°C for 4 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain 8-((diphenylmethylene)amino)-1,2,4,4a,5,6-hexahydro- 3H-Pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester 148e (41 mg), yield 40.25%.

MS m/z(ESI):468.2[M+1].

the fifth step

tert-butyl 8-amino-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylate

8-Amino-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester

8-((Diphenylmethylene)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid Butyl ester 148e (100 mg, 213.86 μmol) and palladium on carbon (45.52 mg, 42.77 μmol, 10% purity) were added to methanol (2 mL), replaced with hydrogen, and reacted at 40°C for 2 hours. After the reaction, add water (10 mL) to the reaction mixture, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (10 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. concentrate, The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 8-amino-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a] Quinoline-3-carboxylic acid tert-butyl ester 148f (22 mg), yield 33.91%.

MS m/z(ESI):304.2[M+1].

Step 6

tert-butyl 8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-1,2,4 ,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylate

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino) -1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester

3-Oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propionaldehyde 145e (33.32 mg, 84.05 μmol), 8-amino-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester 148f (17 mg, 56.03 μmol ), sodium cyanoborohydride (7.04 mg, 112.06 μmol) was added to methanol (1 mL), and the reaction was carried out at 25°C for 16 hours. After the reaction, add water (50 mL) to the reaction mixture, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (50 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: A system) to obtain 8-((3-oxo-3-(4-((7-(trifluoromethyl)quinoline-4) -yl)thio)methyl)piperidin-1-yl)propyl)amino)-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quin 148g (27mg) of tert-butyl phosphine-3-carboxylate, yield 70.47%. MS m/z(ESI):684.4[M+1].

Step 7

3-((2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)amino)-1-(4-(((7-(trifluoromethyl)) quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

3-((2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)amino)-1-(4-((7 -(Trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

8-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino )-1,2,4,4a,5,6-hexahydro-3H-pyrazino[1,2-a]quinoline-3-carboxylic acid tert-butyl ester 148g (22mg, 32.17μmol) was added to dichloro In a mixed solution of methane (2mL) and trifluoroacetic acid (0.5mL), the reaction mixture was stirred at room temperature for 2 hours. Add saturated sodium bicarbonate to adjust the pH to 8~9, extract with ethyl acetate (20mL×3), and combine The organic phase was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), obtaining 3-((2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinolin-8-yl)amino)-1-(4 -(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one 148 (8.5 mg), yield 45.26%.

MS m/z(ESI):584.4[M+1].

1HNMR (400MHz, CDCl ₃ ) δ8.81 (d, J = 5.0Hz, 1H), 8.44 (d, J = 8.8Hz, 1H), 8.32 (s, 1H), 7.89 (d, J = 8.8Hz, 1H ),7.65(d,J＝5.2Hz,1H),7.20-7.02(m,3H),4.63(d,J＝12.8Hz,1H),4.25-3.83(m,2H),3.65-3.38(m, 4H),3.26-3.16(m,2H),3.16-2.66(m,8H),2.13-2.00(m,4H),1.86-1.68(m,1H),1.38-1.23(m,4H).

Example 149

3-((4-((2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl )piperidin-1-yl)propan-1-one

3-((4-((2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((7-(trifluoromethyl)) Quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

first step

tert-butyl(2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamate

(2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester

(2-Aminoethyl)(methyl)carbamate tert-butyl ester 149a (200 mg, 1.15 mmol, commercially available) was dissolved in dichloromethane (2.5 mL), and di-tert-butyl dicarbonate (2.5 mL) was added to the reaction mixture. 200.41 mg, 918.27 μmol), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is complete, the solvent is removed under reduced pressure, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain (2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamic acid. Tert-butyl ester 149b (300 mg), yield 95.26%.

1H NMR (400MHz, CDCl ₃ ) δ3.23 (dd, J = 26.4, 4.8Hz, 4H), 2.81 (s, 3H), 1.38 (d, J = 12.8Hz, 18H).

Step 2

tert-butyl(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-nitro-2-(trifluoromethyl)phenyl)carbamate

(tert-butyl 2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-nitro-2-(trifluoromethyl)phenyl)carbamate

Dissolve (2-((tert-butoxycarbonyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester 149b (150 mg, 546.74 μmol) in tetrahydrofuran (1.5 mL), and then add sodium hydride (65.61 mg, 1.64 mmol), the reaction mixture was stirred at room temperature, and after 0.5 hours, a solution of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene 38a (91.46 mg, 437.39 μmol) in tetrahydrofuran (0.5 mL) was added , the reaction mixture was stirred at room temperature for 2 hours. After the reaction is complete, add water (30 mL) to the reaction mixture, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash with saturated sodium chloride solution (40 mL), dry over anhydrous sodium sulfate, filter, and reduce pressure. Concentrate, and the residue is separated and purified by silica gel column chromatography (eluent: System A) to obtain (2- ((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-nitro-2-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester 149c (150 mg), yield 59.20%.

MS m/z(ESI):464.1[M+1].

third step

tert-butyl(4-amino-2-(trifluoromethyl)phenyl)(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)carbamate

(4-Amino-2-(trifluoromethyl)phenyl)(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)carbamic acid tert-butyl ester

(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)(4-nitro-2-(trifluoromethyl)phenyl)carbamic acid tert-butyl ester 149c (150 mg, 323.66 μmol) and palladium on carbon (30 mg, 323.66 μmol, 10% purity) were dissolved in methanol (3 mL), replaced with hydrogen 3 to 5 times, and the reaction mixture was stirred at 40°C for 2 hours. After the reaction is complete, the crude product is filtered and concentrated in vacuo to obtain (4-amino-2-(trifluoromethyl)phenyl)(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino Tert-butyl formate 149d (140 mg), yield 99.79%.

MS m/z(ESI):434.4[M+1].

the fourth step

tert-butyl(2-((tert-butoxycarbonyl)(4-((3-oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl) propyl)amino)-2-(trifluoromethyl)phenyl)amino)ethyl)(methyl)carbamate

(2-((tert-butoxycarbonyl)(4-((3-oxo-3-(4-((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)methyl) -1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)amino)ethyl)(methyl)carbamic acid tert-butyl ester

(4-Amino-2-(trifluoromethyl)phenyl)(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)carbamic acid tert-butyl ester 149d (50 mg, 115.35 μmol) and 3-Oxo-3-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propionaldehyde 145e (91.46 mg, 230.70 μmol ) was dissolved in methanol (1 mL), sodium cyanoborohydride (10.87 mg, 173.02 μmol) and acetic acid (6.93 mg, 115.35 μmol) were added to the reaction mixture, and stirred at 50°C for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain (2-((tert-butoxycarbonyl)(4-((3-oxo-3-() 4-((7-(trifluoromethyl)quinolin-4-yl)thio)methyl)piperidin-1-yl)propyl)amino)-2-(trifluoromethyl)phenyl)amino )Ethyl)(methyl)carbamic acid tert-butyl ester 149e (57 mg), yield 60.71%.

MS m/z(ESI):814.4[M+1].

the fifth step

3-((4-((2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((7-(trifluoromethyl)quinolin-4-yl)thio)methyl )piperidin-1-yl)propan-1-one

3-((4-((2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((7-(trifluoromethyl)) Quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one

(2-((tert-butoxycarbonyl)(4-((3-oxo-3-(4-((7-(trifluoromethyl))quinolin-4-yl)thio)methyl) Tert-butyl (trifluoromethyl)phenyl)amino)ethyl)(methyl)carbamate 149e (47 mg, 57.75 μmol) was dissolved in dichloromethane ( 1 mL) and trifluoroacetic acid (0.2 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction is complete, reduce Concentrate under pressure, and the residue is purified by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 10μm, 20mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), Obtain 3-((4-((2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)amino)-1-(4-(((7-(trifluoromethyl) )quinolin-4-yl)thio)methyl)piperidin-1-yl)propan-1-one 149 (17.57 mg), yield 41.81%.

MS m/z(ESI):614.2[M+1].

¹ H NMR (400MHz, MeOD-d ₄ ) δ8.83 (d, J = 5.4Hz, 1H), 8.46 (d, J = 8.8Hz, 1H), 8.34 (s, 1H), 7.93 (dd, J = 8.8,1.6Hz,1H),7.70(d,J＝5.4Hz,1H),7.55-7.49(m,2H),7.05(d,J＝8.8Hz,1H),4.61(d,J＝13.2Hz, 1H),3.92(d,J＝13.6Hz,1H),3.65-3.58(m,2H),3.60-3.55(m,2H),3.35-3.26(m,3H),3.6-2.20(m,3H) ,3.17-3.09(m,1H),2.82(d,J＝4.8Hz,1H),2.74(s,3H),2.14-2.01(m,3H),1.42-1.26(m,2H).

biological evaluation

Test example 1, TIAM1:RAC1 binding experiment

The following method is used to determine the ability of compounds of the invention to block the TIAM1:RAC1 protein interaction under in vitro conditions. This method is carried out using homogeneous time-resolved fluorescence (HTRF) technology.

The experimental process is briefly described as follows: First, use reaction buffer (20mM Tris pH 7.5, 50mM NaCl, 1mM MgCl ₂ , 1mM DTT, 10μM GDP) to prepare His tagged RAC1 protein (purchased from cytoskeleton, Cat. No. RC01-A), take 4μL and add 384 In the well plate, the final concentration of RAC1 protein was 0.5 μM. Dissolve the test compound in DMSO to prepare a 10mM stock solution, and then dilute it with reaction buffer. Add 2μL to a 384-well plate. The final concentration of the test compound is 100μM or 10μM. Centrifuge, shake, and incubate at 30°C for 15 minutes. . After that, use the reaction buffer to prepare MBP tagged TIAM1 protein (purchased from cytoskeleton, product number CS-GE04), add 4 μL into a 384-well plate, the final concentration of TIAM1 protein is 0.5 μM, centrifuge, shake, and incubate at 30°C for 60 minutes.

Finally, add 10 μL of MAb Anti MBP-d2 (purchased from cisbio, catalog number 61MBPDAA) and MAb Anti 6HIS-Eu cryptate (purchased from cisbio, catalog number 61HISKLA) premixed with PPI Europium detection buffer (purchased from cisbio, catalog number 61DB9RDF). , incubate at 30°C for 120 minutes, use a microplate reader in TF-FRET mode to measure the fluorescence intensity of each well emitting wavelengths of 620nm and 665nm under the excitation wavelength of 304nm, and calculate the fluorescence intensity ratio of 665/620 in each well. By comparing the fluorescence intensity ratio with the control group (0.1% DMSO), the percentage inhibition rate of the test compound at the specified concentration was calculated, see Table 1.

Table 1 Ability of compounds of the present invention to block TIAM1:RAC1 protein interaction


NA means not tested.

Conclusion: It can be seen from Table 1 that the compounds of the present invention have a strong blocking effect on the interaction between TIAM1 and RAC1 proteins.

Test Example 2. Determination of cell proliferation activity of compounds of the present invention on NCI-H2030 cell line

The following method was used to determine the effect of the compounds of the present invention on the proliferation of NCI-H2030 cells. NCI-H2030 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. and cultured in RPMI 1640 medium containing 10% fetal calf serum, 100 U penicillin and 100 μg/mL streptomycin. cell viability through Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for the determination.

The experimental method follows the steps in the kit instructions, and is briefly described as follows: The test compound is first dissolved in DMSO to prepare a 10mM storage solution, and then diluted with culture medium to prepare a test sample. The final concentration range of the compound is 20000nM-3.05nM. . Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1,000 cells per well and cultured overnight in a 37°C, 5% _CO2 incubator. Then, the test compound was added and cultured for 72 hours. After the incubation, add 50 μL of CellTiter-Glo detection solution to each well, shake for 5 minutes and let stand for 10 minutes. Then use the Luminescence mode on a microplate reader to read the luminescence value of each well of the sample. The percentage inhibition rate of the compound at each concentration point was calculated by comparing with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed using the logarithm of compound concentration-inhibition rate in GraphPad Prism 5 software to obtain the compound's inhibition of cell proliferation. For IC ₅₀ values, see Table 2.

Table 2 IC ₅₀ data of compounds of the present invention inhibiting NCI-H2030 cell proliferation

Conclusion: It can be seen from Table 2 that the compounds of the present invention have a strong inhibitory effect on NCI-H2030 cell proliferation.

Test Example 3. Determination of cell proliferation activity of compounds of the present invention on SW1573 cell line

The following method was used to determine the effect of the compounds of the present invention on SW1573 cell proliferation. SW1573 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd. and cultured in DMEM medium containing 10% fetal calf serum, 100 U penicillin and 100 μg/mL streptomycin. cell viability through Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) was used for the determination.

The experimental method follows the steps in the kit instructions, and is briefly described as follows: The test compound is first dissolved in DMSO to prepare a 10mM storage solution, and then diluted with culture medium to prepare a test sample. The final concentration range of the compound is 20000nM-3.05nM. . Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate at a density of 1,000 cells per well and cultured overnight in a 37°C, 5% _CO2 incubator. Then, the test compound was added and cultured for 72 hours. After the incubation, add 50 μL of CellTiter-Glo detection solution to each well, shake for 5 minutes and let stand for 10 minutes. Then use the Luminescence mode on a microplate reader to read the luminescence value of each well of the sample. The percentage inhibition rate of the compound at each concentration point was calculated by comparing with the value of the control group (0.3% DMSO), and then a nonlinear regression analysis was performed using the logarithm of compound concentration-inhibition rate in GraphPad Prism 5 software to obtain the compound's inhibition of cell proliferation. For IC ₅₀ values, see Table 3.

Table 3 IC ₅₀ data of the compounds of the present invention inhibiting SW1573 cell proliferation

Conclusion: It can be seen from Table 3 that the compounds of the present invention have a strong inhibitory effect on SW1573 cell proliferation.

Unless otherwise specified, the terms used in the present invention have the meanings commonly understood by those skilled in the art.

The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of the present invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention does not limit the scope of the present invention. It is limited to the above-described embodiments and is limited only by the claims.

Claims (28)

1. A compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
   

   in:

   Ring A is selected from C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl;

   Ring B is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl or 6-14 membered fused ring, of which 6 to 14 members The fused ring is preferably a 6-10 membered fused ring;

   Q is selected from N or CR ^e ;

   X is selected from -O-, -S(O) _r -, -CR ^a R ^b - or -NR ^c -;

   R ^a and R ^b are the same or different, and are each independently selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

   R ^e is selected from hydrogen atom, C ₁ -C ₆ alkyl group or -C(O)OR ^aa ;

   R ^aa is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

   R ^c is selected from hydrogen atom, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups described above are optionally further substituted by one or more ^RA ;

   R ^A is the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C (O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC Substituted by (O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

   Alternatively, two R ^A attached to the same carbon atom together with the attached carbon atom form a -C(=O)-;

   L ¹ is selected from bond, C ₁ -C ₉ alkylene, C ₂ -C ₇ alkenylene or C ₂ -C ₇ alkynylene, wherein C ₁ -C ₉ alkylene is preferably C ₁ -C ₇ alkylene group, wherein the alkylene, alkenylene or alkynylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy; and wherein One or more methylene groups in the alkylene, alkenylene or alkynylene group are optionally replaced by one or more O, S(O) _r , C(O) or NR ^d ;

   R ^d is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

   L ² is selected from a bond or a C ₁ -C ₆ alkylene group, wherein said alkylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or C ₁ -C ₆ alkoxy Substituted; and one or more methylene groups in the alkylene group are optionally replaced by one or more O, S(O) _r , C(O) or NR ^d ;

   R ¹ is the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, = O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR Substituted by ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

   R ² is selected from hydrogen atom, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, 3-10 membered heterocyclyl group, C ₃ -C ₁₀ cycloalkyl group, 6-14 membered fused ring, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; wherein the aryl group, heteroaryl group, heterocyclic group, ring The alkyl group or fused ring is optionally further substituted by one or more ^RF ;

   R ^F are the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, nitro, cyano, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₁₀ cycloalkyl base, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl group, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O )R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O ) _r R ⁵ ; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from one or more C ₁ -C ₆ alkyl, Halogen, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C (O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(＝ Substituted by NH)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

   Alternatively, two R ^F attached to the same carbon atom together with the attached carbon atom form a -C(=O)- or -C(=NOH)-;

   ^R3 is selected from a hydrogen atom or a 5-10 membered heteroaryl group, wherein the heteroaryl group is optionally further substituted by one or more ^RJ ;

   R and ^J are the same or different, each independently selected from halogen, hydroxyl, cyano, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the alkyl or alkoxy is optionally further replaced by a Or substituted by multiple substituents selected from halogen, hydroxyl, cyano, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

   R ⁴ is the same or different, each independently selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; the alkane described therein group, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further optionally further substituted by one or more selected from the group consisting of halogen, hydroxyl, cyano, oxo, C ₁ -C ₆ alkyl, C Substituted by a substituent of ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, -C(O)R ⁵ or -S(O) _r R ⁵ ;

   Alternatively, two R ⁴ attached to the same carbon atom together with the attached carbon atom form a -C(=O)-;

   The condition is: when the following conditions are met at the same time, at least one R ⁴ is not a hydrogen atom:

   1) Q is CH, R ³ is a hydrogen atom, ring B is selected from phenyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl;

   2) for Wherein R ^C , ^RD and ^RE are each independently selected from hydrogen atoms or halogens, and R ^B is selected from hydrogen atoms, halogens, hydroxyl groups, C ₁ -C ₆ alkoxy groups, C ₁ -C ₆ alkyl groups or C ₁ - C ₆ haloalkyl;

   3) L ² is selected from bond, methylene, ethylene, -C(O)-, -CH ₂ NR ^d - or -CH ₂ NR ^d C(O)-, and R ^d is selected from hydrogen atom or C ₁ -C ₆ alkyl;

   4) L ¹ is selected from -(CH ₂ ) ₆ NH-;

   5) R ² is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, -C(O)OR ⁵ or -NR ⁶ R ⁷ ; wherein the aryl group , heteroaryl or heterocyclyl are optionally further substituted by one or more ^RF ; and ^RF is selected from halogen, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl or C ₁ -C ₆ Haloalkyl, or two R ^F connected to the same carbon atom together with the connected carbon atom form a -C(=O)-;

   R ⁵ is selected from hydrogen atom, C ₁ -C ₆ alkyl group, -NR ⁹ R ¹⁰ , C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclyl group, C ₆ -C ₁₀ aryl group or 5-10 membered group. Heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C Substituted by (O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituents;

   R ⁶ and R ⁷ are each independently selected from hydrogen atom, hydroxyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl , C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more Selected from hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ -hydroxyalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -C(O)R ⁸ , - Substitution of C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituted by base;

   Alternatively, R ⁶ and R ⁷ together with the atoms to which they are connected form a 4- to 8-membered heterocyclyl group, wherein the 4- to 8-membered heterocyclyl group contains one or more N, O or S(O) _r , and the The 4 to 8-membered heterocyclic group is optionally further substituted by one or more members selected from hydroxyl, halogen, nitro, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 Metaheteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO Substituted by ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ substituents;

   R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen atom, C ₁ -C ₆ alkyl group, amino group, C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclyl group, C ₆ -C ₁₀ aryl group Or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more hydroxyl, halogen, nitro, amino, cyanide Base, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl Substituted by a substituent of a group, a carboxyl group or a carboxylate group;

   r is selected from 0, 1 or 2;

   m is selected from 0, 1, 2 or 3;

   n is selected from 0, 1, 2, 3 or 4.
2. The compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1, which is the compound represented by the general formula (II) or its stereoisomer Isomers, tautomers or pharmaceutically acceptable salts thereof:
   

   in:

   R ^B is selected from hydrogen atom, halogen, cyano group, carboxyl group, ester group, C ₁ -C ₆ alkyl group, -OR ⁵ , C ₃ -C ₁₀ cycloalkyl group, 3-10 membered heterocyclic group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from one or more C ₁ -C ₆ alkyl groups , Halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O) Substituted by NR ⁶ R ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

   ^RC , ^RD and ^RE are the same or different, and are each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, carboxyl group, C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, aryl or heteroaryl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, C ₁ -C Substituted with ₆ alkyl or C ₁ -C ₆ alkoxy substituents;

   Rings B, X, Q, ^R2 to ^R7 , ^L1 , ^L2 , r and n are as defined in claim 1.
3. The compound represented by the general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to claim 1, which is the compound represented by the general formula (III) or its stereoisomer Isomers, tautomers or pharmaceutically acceptable salts thereof:
   

   in:

   R ^G and R ^H are the same or different, and are each independently selected from hydrogen atoms, hydroxyl, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is any is further selected from one or more C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, nitro, cyano, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, =O, -OR ⁵ , -C(O)R ⁵ , -C(O)OR ⁵ , -NHC(O)R ⁵ , -NHC(O)OR ⁵ , -NR ⁶ R ⁷ , -C(O)NR ⁶ R Substituted by ⁷ , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ substituents;

   Rings B, X, Q, ^R2 to ^R7 , ^L1 , ^L2 , r and n are as defined in claim 1.
4. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Q is N.
5. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Q is CH, CCH ₃ , CCOOH or CCOOCH ₃ .
6. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is -S-.
7. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is ^-NRc- ;

   R ^c is selected from hydrogen atom, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups described above are optionally further substituted by one or more ^RA ;

   ^RA is the same or different, each independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl group or -OR ⁵ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more C ₁ -C ₆ alkyl, =O or -OR Substituted by ⁵ substituents;

   R ⁵ is selected from C ₁ -C ₆ alkyl, preferably methyl.
8. The compound according to claim 7 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X is selected from the following groups: -NH-,
   
9. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ¹ is selected from the group consisting of bonds, C ₁ -C ₉ alkylene, C ₂ -C ₇ alkenylene or C ₂ -C ₇ alkynylene, wherein one or more methylene groups in the alkylene, alkenylene or alkynylene group are optionally replaced by one or more O , S(O) _r , C(O) or NR ^d replaced;

   r is selected from 0, 1 or 2;

   R ^d is selected from a hydrogen atom or a methyl group.
10. The compound according to claim 9 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ¹ is selected from the group consisting of bonds, -(CH ₂ ) _1-7 -, -CH ₂ C≡ C(CH ₂ ) ₂ NH-, -CH ₂ C≡C(CH ₂ ) ₃ NH-, -(CH ₂ ) ₂ CH＝CH(CH ₂ ) ₂ NH-, -(CH ₂ ) ₃ O(CH ₂ ) ₃ -, -(CH ₂ ) ₃ O(CH ₂ ) ₂ -, -(CH ₂ ) ₃ N(CH ₃ )(CH ₂ ) ₂ -, -(CH ₂ ) ₅ C(O)-, -O (CH ₂ ) ₅ -, -(CH ₂ ) ₅ O-, -(CH ₂ ) ₅ OCH ₂ -, -(CH ₂ ) ₆ O-, -(CH ₂ ) ₅ OCH(CH ₃ )-, -CH ₂ NHC(O)NH(CH ₂ ) ₂ NH-, -(CH ₂ ) ₂ O(CH ₂ ) ₂ O(CH ₂ ) ₂ NH-, -(CH ₂ ) ₆ N(CH ₃ )-or-( CH ₂ ) ₆ NH-.
11. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ² is selected from a bond or a C ₁ -C ₆ alkylene group, wherein the alkylene group is optionally further substituted by one or more halogens or hydroxyl groups; and wherein one or more methylene groups in the alkylene group are optionally substituted by one or more O, S(O ) _r , C(O) or NR ^d ;

    r is selected from 0, 1 or 2;

    R ^d is selected from a hydrogen atom or a methyl group.
12. The compound according to claim 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ² is selected from the group consisting of bond, -C(O)-, -NH-, -O-, -CH ₂ -, -(CH ₂ ) ₂ -, -CH(CH ₃ )-, -CH(OH)-, -CH ₂ NH-, -(CH ₂ ) ₂ NH-, -CH ₂ N(CH ₃ )-, -C(O)CH ₂ -, -C(O)NH-, -CH ₂ C(O)NH-, -C(O)(CH ₂ ) ₂ NH-, -CH ₂ O-, - CH ₂ N(CH ₃ )C(O)- or -CH ₂ NHC(O)-.
13. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring B is selected from the following groups:
    
14. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, C ₆ -C ₁₀ aryl group, 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C ₃ -C ₁₀ cycloalkyl, 6-14 membered fused ring, -OR ⁵ , -C(O)R ⁵ , -C(O) OR ⁵ , -NR ⁶ R ⁷ or -NR ⁶ C(O)R ⁷ ; wherein the aryl, heteroaryl, heterocyclyl, cycloalkyl or fused ring is optionally further replaced by one or more R ^F substitution;

    R ^F are the same or different, each independently selected from C ₁ -C ₆ alkyl, halogen, cyano, carboxyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl, -OR ⁵ , -NR ⁶ R ⁷ , -C(O)R ⁵ , -NHC(O)R ⁵ , -C(O)NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl group, heterocyclyl group or aryl group Optionally further selected from one or more C ₁ -C ₆ alkyl, 3-10 membered heterocyclyl, halogen, =O, -OR ⁵ , -NR ⁶ R ⁷ or -C(=NH)NR ⁶ R Substituted by ⁷ substituents;

    Alternatively, two R ^F attached to the same carbon atom together with the attached carbon atom form a -C(=O)- or -C(=NOH)-;

    R ⁵ is selected from hydrogen atom, -NR ⁹ R ¹⁰ , C ₁ -C ₆ alkyl group or 3-10 membered heterocyclic group;

    R ⁶ and R ⁷ are the same or different, and are each independently selected from a hydrogen atom, a C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group; wherein the alkyl group or alkoxy group is optionally further substituted by one or Substituted with multiple substituents selected from halogen, hydroxyl, cyano, -NR ⁹ R ¹⁰ or C ₁ -C ₆ alkoxy;

    R ⁹ and R ¹⁰ are the same or different, and are each independently selected from a hydrogen atom or a methyl group;

    r is 2.
15. The compound according to claim 14 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R2 is selected from the following groups: hydrogen atom,
    
    Or methoxy.
16. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R3 is selected from a hydrogen atom.
17. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R3 is selected from 5-10 membered heteroaryl, wherein said The heteroaryl group is optionally further substituted by one or more ^RJ ;

    R and ^J are the same or different, each independently selected from C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more selected from halogen, Substituted with hydroxyl, cyano, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy substituents.
18. The compound according to claim 17, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is selected from the following groups:
    
19. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^R4 is selected from hydrogen atom, halogen, hydroxyl, cyano group, carboxyl group , ester group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₁₀ cycloalkyl, 5-10 membered heteroaryl, C ₆ -C ₁₀ aryl or –C(O )NH ₂ , wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, phenyl, oxo or cyano;

    Alternatively, two R ⁴ 's attached to the same carbon atom together with the attached carbon atom form a -C(=O)-.
20. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ^RC , ^RD and ^RE are each independently selected from a hydrogen atom or a phenyl group, ^RB Selected from hydrogen atoms, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; wherein Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from halogen, hydroxyl, cyano, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy substituted by substituents.
21. The compound according to claim 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: R ^C and ^RE are selected from hydrogen atoms;

    R ^D is selected from a hydrogen atom or a phenyl group;

    R ^B is selected from a hydrogen atom, trifluoromethyl, phenyl, pyridyl, pyrazolyl, cyclohexyl or cyclopropyl.
22. The compound according to claim 3 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

    R ^H is selected from hydrogen atom, C ₁ -C ₆ alkyl group, C ₁ -C ₆ haloalkyl group or C ₆ -C ₁₀ aryl group;

    R ^G is selected from hydrogen atoms or 5-10 membered heteroaryl groups, wherein the heteroaryl group is optionally further substituted by one or more selected from C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ haloalkyl, Substituted with C ₃ -C ₁₀ cycloalkyl or -OR ⁵ substituents;

    R ⁵ is selected from a hydrogen atom or a C ₁ -C ₆ alkyl group, which is preferably a methyl group.
23. The compound according to claim 22 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

    R ^H is selected from hydrogen atom, methyl, trifluoromethyl or phenyl;

    R ^G is selected from the following groups: hydrogen atoms,
    
    
24. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:
    
    
    
    
    
    
    
    
    
    
25. A pharmaceutical composition containing an effective dose of the compound according to any one of claims 1 to 24 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.
26. The compound according to any one of claims 1 to 24 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25 in the preparation of RAC1 inhibitor uses in.
27. The compound according to any one of claims 1 to 24 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25 when prepared for treatment Use in medicines for diseases mediated by RAC1 mutations, wherein the diseases mediated by RAC1 mutations are preferably selected from the group consisting of cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, and diabetes (type I) , Huntington's disease and Alzheimer's disease, wherein the cancer is preferably selected from melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cell cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma , prostate cancer and B-cell lymphoma, more preferably melanoma.
28. The compound according to any one of claims 1 to 24 or its stereoisomer, tautomer or its possible Pharmaceutically acceptable salts, or pharmaceutical compositions according to claim 25 for use in the treatment of cancer, Menkes disease, rheumatoid arthritis, atherosclerosis, diabetes (type I), Huntington's disease and Alzheimer's disease Use in medicine for Heimer's disease, wherein the cancer is preferably selected from the group consisting of melanoma, gastric cancer, colon cancer, breast cancer, lung cancer, testicular cancer, pancreatic cancer, head and neck tumors, ovarian cancer, medulloblastoma, Prostate cancer and B-cell lymphoma, more preferably melanoma.