TW202430519A - Spiroheterocyclical-substituted pyrimidine compound and preparation method and use thereof - Google Patents

Abstract

The present disclosure relates to a spiro-substituted pyrimidine compound and preparation method and use thereof. Specifically, the present invention provides a type of spiro-substituted pyrimidine compound represented by formula (I) or pharmaceutically acceptable salt thereof for preparing medicines, particularly for preparing medicines for preventing and/or treating diseases mediated by CCR4 factors. Each group in formula (I) is as defined in the specification.

Description

Spirocyclic substituted pyrimidine compound and preparation method and use thereof

The present disclosure belongs to the field of medicine, and specifically relates to a spiroheterocyclic substituted pyrimidine compound and a preparation method and use thereof.

This application claims the priority of Chinese Patent Application No. 2022115067066 with a filing date of 2022/11/28 and Chinese Patent Application No. 2023115671493 with a filing date of 2023/11/22. This application cites the full text of the above Chinese patent applications.

The successful operation of the host defense system is the result of several processes working together to eliminate foreign pathogens. Both the innate and acquired immune responses require coordination, and a number of secreted factors and cell-associated factors have been identified as important mediators of the coordination and regulation of these two host defense weapons. Trending factors are a family of cytokines that act as chemical attractants to direct leukocyte migration. They are secreted by a variety of cells and can be functionally divided into two categories: hemostatic trending factors and inflammatory trending factors. Hemostatic trending factors are produced constitutively in certain tissues and control cells of the immune system during immune surveillance processes, such as directing lymphocytes to lymph nodes so that they can screen for invading pathogens. Inflammatory trend factors are released by cells in response to pathological events (e.g., pro-inflammatory stimuli such as IL-1 or viruses). They function primarily as chemical attractants as part of the inflammatory response and serve to direct cells of the innate and adaptive immune systems to the site of inflammation.

C-C chemokine receptor type 4 (CCR4) is mainly expressed on Th2 cells and plays a major role in the progression of many allergic and inflammatory diseases by regulating downstream cytokines such as IL4, IL5 and IL13. Although CCR4 has attracted widespread research and development interest as a highly potential drug development target, the development of small molecule compounds that regulate CCR4 function is an ongoing challenge. So far, no small molecule drug has entered the market, so it is still necessary to actively explore new, superior, and selective CCR4 small molecule antagonists.

The CCR4-related patents that have been disclosed so far include WO2019090272A1 and WO2019147862A1.

The present disclosure provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

in:

G is CR ⁵ or N;

R ¹ is LR ⁹ ;

L is a chemical bond, NR ¹⁰ , O, S, -C(O)-, -S(O)- or -S(O) ₂ -;

R ⁹ is H, C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, NR ^9a R ^9b , C(O)NR ^9a R ^9b , S(O) ₂ R ^9c , C(O)CH ₂ CN, C(O)COOH, C(O)(3 to 8 membered heterocyclic group), C(O)OR ^9d , C(O)CH(CH ₃ )OR ^9d or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted with one or more R ^g ;

R ¹⁰ is H, C _1-6 alkyl, deuterated C _1-6 alkyl or 3 to 8 membered cycloalkyl, wherein the C _1-6 alkyl and 3 to 8 membered cycloalkyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, amino and 3 to 8 membered cycloalkyl;

Or when L is NR ¹⁰ , R ⁹ and R ¹⁰ may optionally form a 4- to 8-membered heterocyclic group together with the nitrogen atom to which they are connected, and the 4- to 8-membered heterocyclic group may be optionally substituted by one or more R ^g ;

Each R ^g is the same or different and is independently halogen, hydroxyl, oxo (=O), C _1-6 alkyl, C _1-6 alkoxy, cyano, carboxyl, -NHC(O)R ^g1 , -NHS(O) ₂ R ^g2 , -S(O) ₂ R ^g2 , -C(O)NR ^g3 R ^g4 , -S(O) ₂ NR ^g3 R ^g4 , -NR ^g3 R ^g4 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are independently selected from halogen, hydroxyl, C 1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl. The alkyl group is substituted by one or more substituents selected from C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3 to 8 membered cycloalkyl;

R ^g1 is C _1-6 alkyl or C _1-6 alkoxy;

^Rg2 is _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;

^Rg3 and ^Rg4 are the same or different and are each independently H, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;

^R2 and ^R3 are the same or different and are each independently H, halogen, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, hydroxy, cyano, amino, oxo (=O), 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ⁴ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, NR ^4a R ^4b , C(O)NR ^4a R ^4b , C(O)OR ^4c , S(O) ₂ R ^4d , NR ^4a C(O)R ^4e or NR ^4a C(O)OR ^4c , wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently and optionally selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, C substituted by one or more substituents selected from _1-6 -hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

R ⁵ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, NR ^5a R ^5b , C(O)NR ^5a R ^5b , C(O)OR ^5c , S(O) ₂ R ^5d , NR ^5a C(O)R ^5e or NR ^5a C(O)OR ^5c , wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently and optionally selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, C substituted by one or more substituents selected from _1-6 -hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

^R6 is H, _C1-6 alkyl, _C1-6 halogenated alkyl or 3 to 8 membered cycloalkyl;

or when G is CR ⁵ , R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl group, a 5- to 8-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered cycloalkyl group, the 5- to 8-membered heterocyclic group, the phenyl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, cyano, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group;

or when G is CR ⁵ , R ⁵ and R ⁶ together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

^R7 is H, D, halogen, _C1-6 alkyl or _C1-6 halogenated alkyl;

Each R ⁸ is the same or different and is independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 hydroxyalkyl, hydroxy, cyano or 3-8 membered cycloalkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^9a , R ^9b and R ^9d are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4c and R ^5c are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4d , R ^5d and R ^9c are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4e and R ^5e are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

n is 1 or 2;

m is 1 or 2, provided that n and m are not 2 at the same time;

k is 0, 1 or 2;

p is 0, 1, 2, 3, 4, 5 or 6;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2, 3, 4 or 5;

The heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 8-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, G is CR ⁵ or N;

R ¹ is LR ⁹ ;

L is a chemical bond, NR ¹⁰ , O, S, -C(O)-, -S(O)- or -S(O) ₂ -;

R ⁹ is H, C _1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, NR ^9a R ^9b , C(O)NR ^9a R ^9b , S(O) ₂ R ^9c , C(O)OR ^9d or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more R ^g ;

R ¹⁰ is H or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxy, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, amino and 3 to 8 membered cycloalkyl;

Or when L is NR ¹⁰ , R ⁹ and R ¹⁰ may optionally form a 4- to 8-membered heterocyclic group together with the nitrogen atom to which they are connected, and the 4- to 8-membered heterocyclic group may be optionally substituted by one or more R ^g ;

Each R ^g is the same or different and is independently halogen, hydroxyl, oxo (=O), C _1-6 alkyl, C _1-6 alkoxy, cyano, carboxyl, -NHC(O)R ^g1 , -NHS(O) ₂ R ^g2 , -S(O) ₂ R ^g2 , -C(O)NR ^g3 R ^g4 , -S(O) ₂ NR ^g3 R ^g4 , -NR ^g3 R ^g4 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are independently selected from halogen, hydroxyl, C 1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl. The alkyl group is substituted by one or more substituents selected from C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3 to 8 membered cycloalkyl;

R ^g1 is C _1-6 alkyl or C _1-6 alkoxy;

^Rg2 is _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;

^Rg3 and ^Rg4 are the same or different and are each independently H, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;

^R2 and ^R3 are the same or different and are each independently H, halogen, _C1-6 alkyl, _C1-6 halogenated alkyl, C1-6 hydroxyalkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, hydroxy, cyano, amino, oxo (=O), 3- to 8-membered cycloalkyl or 3- to 8 _- membered heterocyclic group;

R ⁴ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, NR ^4a R ^4b , C(O)NR ^4a R ^4b , C(O)OR ^4c , S(O) ₂ R ^4d , NR ^4a C(O)R ^4e or NR ^4a C(O)OR ^4c , wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently and optionally selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, C substituted by one or more substituents selected from _1-6 -hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

R ⁵ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, NR ^5a R ^5b , C(O)NR ^5a R ^5b , C(O)OR ^5c , S(O) ₂ R ^5d , NR ^5a C(O)R ^5e or NR ^5a C(O)OR ^5c , wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently and optionally selected from halogen, hydroxy, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, C substituted by one or more substituents selected from _1-6 -hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

^R6 is H, _C1-6 alkyl, _C1-6 halogenated alkyl or 3 to 8 membered cycloalkyl;

or when G is CR ⁵ , R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl group, a 5- to 8-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered cycloalkyl group, the 5- to 8-membered heterocyclic group, the phenyl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, cyano, 3- to 8-membered cycloalkyl group and 3- to 8-membered heterocyclic group;

or when G is CR ⁵ , R ⁵ and R ⁶ together with the atoms to which they are attached form a 5- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

^R7 is H, D, halogen, _C1-6 alkyl or _C1-6 halogenated alkyl;

Each R ⁸ is the same or different and is independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 hydroxyalkyl, hydroxy, cyano or 3-8 membered cycloalkyl;

R ^4a , R ^4b , R ^5a , R ^5b , R ^9a , R ^9b and R ^9d are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4c and R ^5c are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4d , R ^5d and R ^9c are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^4e and R ^5e are the same or different and are each independently H, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

n is 1 or 2;

m is 1 or 2, provided that n and m are not 2 at the same time;

k is 0, 1 or 2;

p is 0, 1, 2, 3, 4, 5 or 6;

q is 0, 1, 2, 3 or 4;

t is 0, 1, 2, 3, 4 or 5;

The heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 8-membered heterocyclic group, the 5- to 10-membered heteroaryl group or the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, some groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (this paragraph is hereinafter referred to as "in some embodiments"),

R ⁹ is C(O)CH ₂ CN, C(O)COOH, C(O)(3- to 8-membered heterocyclic group) or C(O)CH(CH ₃ )OR ^9d ;

R ¹⁰ is a deuterated C _1-6 alkyl group or a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally substituted with one or more substituents selected from halogen, hydroxyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, amino and 3- to 8-membered cycloalkyl groups.

In some embodiments, in R ⁹ , R ^9a , R ^9b , R ^9d , R ¹⁰ and R ^g , the C _1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl or tertiary butyl, for example, methyl, ethyl, n-propyl or isopropyl.

In some embodiments, in R ⁹ , the 3- to 8-membered cycloalkyl is a 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, and another example is cyclobutyl.

In some embodiments, in R ⁹ , the heteroatom in the 3- to 8-membered heterocyclic group is N, O or S, such as N; the number of the heteroatom can be 1, 2 or 3, such as 1.

In some embodiments, in R ⁹ , the 3- to 8-membered heterocyclic group is a 3- to 6-membered heterocyclic group, such as azacyclobutane ( ), pyrrolidino ( ), piperidinyl or piperidine.

In some embodiments, in R ⁹ , the 3- to 8-membered heterocyclic group is a 3- to 6-membered heterocyclic group, such as imidazolidinyl ( ). In some embodiments, in R ⁹ , the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, such as N; the number of the heteroatom may be 1, 2 or 3, such as 2.

In some embodiments, in R ⁹ , the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group or an 8- to 10-membered condensed heteroaryl group; the 5- to 6-membered heteroaryl group may be a pyrrolyl group, a pyrazolyl group or an imidazolyl group, for example or .

In some embodiments, ^R9 and ^R10 together with the nitrogen atom to which they are connected form a 4- to 8-membered heterocyclic group, wherein the heteroatom in the 4- to 8-membered heterocyclic group is N, O or S, such as N; the number of the heteroatom may be 1, 2 or 3, such as 1.

In some embodiments, ^R9 and ^R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group, such as azacyclobutane ( ) or pyrrolidinyl ( ).

In some embodiments, in R ^9a , R ^9b and R ^9d , the C _1-6 hydroxyalkyl group is independently C _1-4 hydroxyalkyl group, for example -CH ₂ CH ₂ OH.

In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof disclosed herein, G is CR ⁵ ; R ⁵ is as defined in formula (I).

In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof disclosed herein, G is N.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (II),

in:

^R4 is H, halogen, _C1-6 alkyl, hydroxyl, cyano, amino or 3-8 membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; the 3-8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano;

^R5 is H, halogen, _C1-6 alkyl, hydroxyl, cyano, amino or 3-8 membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; the 3-8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano;

^R6 is H or _C1-6 alkyl;

Alternatively, ^R4 and ^R5 may optionally form together with the carbon atom to which they are attached a 5- to 6-membered cycloalkyl group, a 5- to 6-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered cycloalkyl group, the 5- to 6-membered heterocyclic group, the phenyl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl and cyano;

R ^8A and R ^8B are the same or different and are each independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or C _1-6 hydroxyalkyl;

R ¹ , R ² , R ³ , R ⁷ , n, m, p, q and k are as defined in formula (I).

In some embodiments, the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, wherein ^R4 is H, halogen, _C1-6 alkyl, _C1-6 alkoxy, hydroxyl, cyano, amine or 3-8 membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; the 3-8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano;

^R5 is H, halogen, _C1-6 alkyl, hydroxyl, cyano, amino, C(O) _NH2 or 3 to 8 membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; the 3 to 8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano.

In some embodiments, the compound represented by formula (I) is a compound represented by formula (II-1) or formula (II-2), or

in:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ^8A , R ^8B , n, m, p, q and k are as defined in formula (II).

In some embodiments, in the compounds of formula (II), formula (II-1) or formula (II-2) disclosed herein or their pharmaceutically acceptable salts, ^R4 is H, halogen, _C1-6 alkyl, C1-6 halogenated alkyl, _C1-6 hydroxyalkyl _{, cyano or 3-8 membered cycloalkyl; R5 is H, halogen, C1-6 alkyl, C1-6 halogenated alkyl, C1-6} ^hydroxyalkyl _{, cyano or} 3-8 membered cycloalkyl.

In some embodiments, in the compounds of formula (II), formula (II-1) or formula (II-2) disclosed herein or their pharmaceutically acceptable salts, R ⁴ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, cyano or 3-8 membered cycloalkyl; R ⁵ is H, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 hydroxyalkyl, C(O)NH ₂ , cyano or 3-8 membered cycloalkyl.

In some embodiments, in the compounds of formula (II), formula (II-1) or formula (II-2) or their pharmaceutically acceptable salts, R ⁴ is H, -CH ₃ , -CH ₂ CH ₃ , -OCH ₃ , -CF ₃ , or .

In some embodiments, in the compounds of formula (II), formula (II-1) or formula (II-2) or their pharmaceutically acceptable salts, R ⁵ is H, F, Cl, Br, -CH ₃ , CN, , or C(O)NH ₂ .

In some embodiments, in the compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, for or .

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1) or formula (II-2) or their pharmaceutically acceptable salts disclosed herein, ^R6 is H.

In some embodiments, in the compound represented by formula (I) of the present disclosure or its pharmaceutically acceptable salt, G is CR ⁵ ; R ⁵ and R ⁶ together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group.

In some embodiments, the compound of formula (I) is a compound of formula (III), formula (IV) or formula (V), , or

in:

^R4 is H, halogen, _C1-6 alkyl, hydroxyl, cyano, amino or 3-8 membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; the 3-8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano;

R ¹¹ is H, C _1-6 alkyl or 3 to 8 membered cycloalkyl;

R ¹² and R ¹³ are the same or different and are each independently H, halogen, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

R ^8A and R ^8B are the same or different and are each independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or C _1-6 hydroxyalkyl;

R ¹ , R ² , R ³ , R ⁷ , n, m, p, q and k are as defined in formula (I).

In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-1), formula (IV-1) or formula (V-1), , or ,

in:

R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ^{8A , R 8B ,} R ¹¹ , R ¹² , R ¹³ , n, m, p, q and k are as defined in formula (III), formula (IV) or formula (V).

In some embodiments, the compound represented by formula (I) is a compound represented by formula (III-2), formula (IV-2) or formula (V-2), , or ,

in:

R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ^{8A , R 8B ,} R ¹¹ , R ¹² , R ¹³ , n, m, p, q and k are as defined in formula (III), formula (IV) or formula (V).

In some embodiments, in the compounds of formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or pharmaceutically acceptable salts thereof, ^R4 is H, halogen, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl, cyano, or 3- to 8-membered cycloalkyl.

In some embodiments, in the compounds represented by formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) disclosed herein, or their pharmaceutically acceptable salts, ^R4 is H.

In some embodiments, in the compounds represented by formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) disclosed herein, or their pharmaceutically acceptable salts, R ¹¹ is a C _1-6 alkyl group, preferably a methyl group.

In some embodiments, in the compounds of formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2) or pharmaceutically acceptable salts thereof, ^R12 is H, halogen, _C1-6 alkyl, _C1-6 halogenated alkyl or cyano, and ^R13 is H, halogen or _C1-6 alkyl.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, n is 1, m is 1, and k is 0, 1 or 2; or, n is 1, m is 2, and k is 0, 1 or 2; or, n is 2, m is 1, and k is 0, 1 or 2.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, n is 1, m is 1, and k is 0, 1 or 2.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, n is 1, m is 2, and k is 0, 1 or 2.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, n is 2, m is 1, and k is 0, 1 or 2.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, for , , , , , , , , or ; R ¹ , R ² , R ³ , p and q are as defined in formula (I).

In some embodiments, in the compounds of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2) or their pharmaceutically acceptable salts disclosed herein, R ¹ is NR ⁹ R ¹⁰ , OR ⁹ or C(O)NR ^9a R ^9b ; R ⁹ is H, C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 6 membered heteroaryl or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group are each independently optionally substituted with one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ^9a is H or C R ^9b is H, C _1-6 alkyl, C _1-6 halogenated alkyl or C _1-6 hydroxyalkyl _; R ¹⁰ is H or C _1-6 alkyl;

or ^R9 and ^R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, and the 4- to 8-membered heterocyclic group is optionally substituted by one or more ^Rg ;

Each ^Rg is the same or different and is independently halogen, hydroxyl, oxo, _C1-6 alkyl, _C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group are independently optionally substituted with one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, R ¹ is NR ⁹ R ¹⁰ , OR ⁹ or C(O)NR ^9a R ^9b ; R ⁹ is H, C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 6 membered heteroaryl, C(O)CH ₂ CN, C(O)COOH, C(O)(3 to 8 membered heterocyclic group), C(O)CH(CH ₃ )OR ^9d or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally substituted by one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ^9a is H or C _1-6 alkyl; R ^9b is H, C _1-6 alkyl, C _1-6 halogenated alkyl or C _1-6 hydroxyl alkyl; R ¹⁰ is H, C _1-6 alkyl, C _1-6 hydroxyl alkyl, deuterated C _1-6 alkyl or 3 to 8 membered cycloalkyl, wherein the 3 to 8 membered cycloalkyl is substituted by one or more halogens;

or ^R9 and ^R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, and the 4- to 8-membered heterocyclic group is optionally substituted by one or more ^Rg ;

Each ^Rg is the same or different and is independently halogen, hydroxyl, oxo, _C1-6 alkyl, _C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group are independently optionally substituted with one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl.

In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, ^R1 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, ^R1 is , , , , , , , , , , , , , , , , , , or .

In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, ^R1 is , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III- ² ), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, R2 and ^R3 are the same or different and are each independently H, halogen or _C1-6 alkyl.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III- ² ), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, R2 and ^R3 are the same or different and are each independently H.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts, for , , or ;

R ¹ is NR ⁹ R ¹⁰ , OR ⁹ or C(O)NR ^9a R ^9b ; R ⁹ is H, C _1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 5 to 6 membered heteroaryl or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group are each independently optionally substituted by one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ^9a is H or C _1-6 alkyl; R ^9b is H, C _1-6 alkyl, C _1-6 halogenated alkyl or C _1-6 hydroxyalkyl; R ¹⁰ is H or C _1-6 alkyl;

or ^R9 and ^R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, and the 4- to 8-membered heterocyclic group is optionally substituted by one or more ^Rg ;

Each ^Rg is the same or different and is independently halogen, hydroxyl, oxo, _C1-6 alkyl, _C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group, wherein the _C1-6 alkyl, _C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group are independently optionally substituted with one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl;

^R2 and ^R3 are the same or different and are each independently H, halogen or _C1-6 alkyl.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III- ^{2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) disclosed herein, or their pharmaceutically acceptable salts, R7} is _C1-6 alkyl or _C1-6 halogenated alkyl.

In some embodiments, in the compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) disclosed herein, or their pharmaceutically acceptable salts, ^R7 is a _C1-6 alkyl group, preferably a methyl group.

In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof, each R ⁸ is the same or different and is independently H, halogen or C _1-6 alkyl.

In some embodiments, in the compounds represented by formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts disclosed herein, R ^8A and R ^8B are the same or different and are each independently a halogen, preferably chlorine.

In some embodiments, in the compound of formula (I) disclosed herein or a pharmaceutically acceptable salt thereof, R ¹ is NR ⁹ R ¹⁰ or OR ⁹ ; R ⁹ is H, C _1-6 alkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, C(O)CH ₂ OR ^9d , C(O)CH ₂ CN or C(O)(3 to 8-membered heterocyclic group), wherein the C _1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently and optionally substituted by one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ¹⁰ is H or C _1-6 alkyl;

or ^R9 and ^R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, and the 4- to 8-membered heterocyclic group is optionally substituted by one or more ^Rg ;

Each ^Rg is the same or different and is independently halogen, hydroxyl, oxo, _C1-6 alkyl, or carboxyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from cyano and carboxyl;

^R2 and ^R3 are the same or different and are each independently H;

^R4 is H or _C1-6 alkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen and hydroxyl;

^R5 is halogen, _C1-6 alkyl or cyano, wherein the _C1-6 alkyl is optionally substituted by hydroxyl;

^R6 is H;

Alternatively, ^R4 and ^R5 may optionally form, together with the carbon atom to which they are attached, a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered cycloalkyl, the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with a _C1-6 alkyl group;

or when G is CR ⁵ , R ⁵ and R ⁶ together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from oxo and C _1-6 alkyl;

^R7 is _C1-6 alkyl;

R are the same or different and are each independently a halogen;

n is 1;

m is 1;

k is 1 or 2;

p is 1;

q is 1;

t is 2;

The heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4.

In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below: Table A , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In some embodiments, the exemplary specific compounds of the compound represented by formula (I) also include, but are not limited to, the structures in Table B below: Table B , , , , , , , , , , , , , , , , or .

In another aspect of the present disclosure, isotope-labeled compounds of formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1) and (V-2), or shown in Table A or Table B, are provided, wherein the isotope label is preferably deuterium (D or ² H) replacing hydrogen ( ¹ H).

In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

On the other hand, the present disclosure also provides the use of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a drug for regulating CCR4.

On the other hand, the present disclosure also provides the use of compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of drugs for inhibiting CCR4.

The present disclosure also provides the use of a compound shown in Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and/or treating a CCR4-mediated disease or condition.

The present disclosure also provides the use of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, and cancer; preferably, in the preparation of a medicament for the prevention and/or treatment of arthritis, psoriasis, systemic lupus erythematosus, and inflammatory intestinal diseases.

The present disclosure also provides a method for inhibiting CCR4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

The present disclosure also provides a method for preventing and/or treating a CCR4-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

The present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

The present disclosure also provides a method for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the foregoing drug composition, for use as a drug.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 modulator.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned drug combination, for use as a CCR4 inhibitor.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and/or treating a CCR4-mediated disease or condition.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer.

The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory intestinal diseases.

In some embodiments, the CCR4-mediated disease is selected from an autoimmune disease, an inflammatory disease, and cancer.

In some embodiments, the CCR4-mediated disease is selected from arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.

In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.

In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.

As a drug, the disclosed compounds can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. Administration can be topical (e.g., transdermal, dermal, ocular and mucosal, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus, or can be administered, for example, by a continuous infusion pump.

In preparing the compositions of the present disclosure, the active ingredient is usually mixed with a formulation which can be in the form of tablets, pills, powders, tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid vehicle), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

The "excipient" mentioned in this disclosure refers to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants and lubricants.

On the other hand, the pharmaceutically acceptable salts of the compounds described in the present disclosure may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amine group), they can also form an internal salt.

On the other hand, the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, ( R )- and ( S )-enantiomers, diastereomers, (D )-isomers, ( L )-isomers, racemic mixtures and other mixtures, as well as enantiomer- or diastereomer-enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may exist in substituents such as alkyl groups. All of these isomers and their mixtures are included in the scope of the present disclosure.

In the chemical structure of the compound disclosed in the present invention, the bond " " indicates that the configuration is not specified, " "or" " indicates absolute configuration or relative configuration. If there are chiral isomers in the chemical structure, the key " "Can be" "or" ", or both "and" "Two configurations." "or" " can also represent relative configurations. For example, when the substituents are located on two faces of cyclobutane, When the substituents are on the same face of the cyclobutane, or express.

Key ” indicates unspecified configuration, including cis ( E ) or trans ( Z ) configuration.

In addition, the compounds and intermediates disclosed herein may also exist in different tautomeric forms, and all such forms are included in the scope of the disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via low energy bases. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam isomerization. All tautomeric forms of all compounds in the disclosure are within the scope of the disclosure. The name of a compound named in a single manner does not exclude any tautomers.

The disclosure also includes some isotopically labeled compounds of the disclosure having the same structure as described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^13N , ^15N , ^15O , ^17O , ^18O , ^31P , ^32P , ^35S , ^18F , ^123I , ^125I , and ^36Cl , respectively. All isotopic composition changes of the compounds of the disclosure, whether radioactive or not, are included in the scope of the disclosure.

Unless otherwise indicated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times greater abundance of deuterium (i.e., at least 10% deuterium incorporation) than the natural abundance of deuterium, which is 0.015%. Examples of compounds having greater than the natural abundance of deuterium may be at least 1000 times greater abundance of deuterium, at least 2000 times greater abundance of deuterium, at least 3000 times greater abundance of deuterium, at least 4000 times greater abundance of deuterium, at least 5000 times greater abundance of deuterium, at least 6000 times greater abundance of deuterium, or more. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person skilled in the art to which the present invention belongs can synthesize deuterated compounds by referring to relevant literature. Commercially available deuterated starting materials can be used to prepare deuterated compounds, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide.

The "therapeutically effective amount" of the present disclosure refers to the amount of an active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by a researcher, veterinarian, physician or other clinician, and includes one or more of the following: (1) Preventing a disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibiting a disease: for example, inhibiting a disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing the further development of the pathology and/or symptoms). (3) Relieving a disease: for example, relieving a disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and/or symptoms). For drugs or pharmacologically active agents, "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person having ordinary knowledge in the technical field to which the present invention belongs based on routine experiments.

The term "pharmaceutically acceptable" as used herein means that these compounds, materials, compositions and/or dosage forms are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.

The term "patient" as used herein refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

Definitions and Explanations

Unless otherwise stated, the terms used in the specification and invention application have the following meanings.

In this publication, " means that the corresponding group passes through the " "To connect with other fragments and groups in the compound.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms ( _C1-6 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, secondary butyl, n-pentyl, 1,1-dimethylpropyl, 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-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, etc. The alkyl group may be substituted or unsubstituted.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxy groups having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C _1-12 alkoxy), and more preferably alkoxy groups having 1 to 6 carbon atoms (C _1-6 alkoxy). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro, fused ring, and bridged rings.

The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, in which each monocyclic ring in the system shares a carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, and more preferably, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between rings, spirocycloalkyl is divided into monospirocycloalkyl, bisspirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and bisspirocycloalkyl. More preferably, it is 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include: Rui .

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, and more preferably, it is 7- to 10-membered (e.g., 7, 8, 9 or 10-membered). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan and 6 yuan/6 yuan bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include: .

The term "bridged cycloalkyl" refers to a 5-20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6-14-membered, and more preferably, it is 7-10-membered (e.g., 7, 8, 9, or 10-membered). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include , , etc.; preferred and The cycloalkyl group may be substituted or unsubstituted.

The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, wherein one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally substituted with oxo (i.e., forming sulfone or sulfone), but does not include the ring part of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms, of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperonyl, morpholinyl, thiomorpholinyl, homopiperidinyl, and the like. The polycyclic heterocyclic group includes spirocyclic, fused-ring and bridged-ring heterocyclic groups.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, in which each monocyclic ring in the system shares an atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be arbitrarily oxidized (i.e., forming sulfone or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6 to 14 yuan, and more preferably, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between rings, the spiro heterocyclic group is divided into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include: Rui .

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). 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 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan and 6-yuan/6-yuan bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include: .

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 yuan, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be substituted with oxygen (i.e., forming sulfone or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably, it is 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include: .

The heterocyclic ring includes a heterocyclic group (including a monocyclic ring, a spiro heterocyclic ring, a fused heterocyclic ring and a bridged heterocyclic ring) as described herein fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include: and The heterocyclic group may be substituted or unsubstituted.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include: and The aryl group may be substituted or unsubstituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrimidyl, pyrazolyl, pyrimidyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: and The heteroaryl group may be substituted or unsubstituted.

The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclic", "aryl" and "heteroaryl" and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents selected from halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include the residue derived from the parent ring atom by removing one hydrogen atom, or the residue derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.

The term "heterocyclooxy" refers to heterocyclo-O-, wherein heterocyclo is as defined herein.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

The term "halogen" refers to F, Cl, Br or I.

The term "hydroxy" refers to -OH.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" or "oxo" refers to "=0".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined herein.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not occur. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art to which the present invention belongs can determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond.

Based on the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the best embodiments of the present invention.

The reagents and raw materials used in the present invention are commercially available.

The positive and advanced effect of the present invention is that: the present invention provides a small molecule compound having a spirocyclic substituted pyrimidine structure, which can be used as a CCR4 inhibitor, such as the compounds shown in formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), or shown in Table A or Table B. Such compounds or drug compositions can be used to effectively treat or prevent CCR4-mediated diseases.

The following will further explain the technical solution of the present invention in combination with specific embodiments. It should be understood that the following embodiments are only for illustrative purposes to illustrate and explain the present invention, and should not be interpreted as limiting the scope of protection of the present invention. All technologies realized based on the above content of the present invention are covered within the scope of protection intended by the present invention. The experimental methods without specific conditions in the following embodiments are selected according to conventional methods and conditions, or according to the product instructions.

The experimental methods without specifying specific conditions in the following examples were carried out according to conventional methods and conditions, or selected according to the product instructions.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

Mass spectra (MS) were measured by Waters 2767 HPLC/ Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/ Waters liquid chromatography-mass spectrometry.

Chiral HPLC analysis was performed using Shimadzu LC-20AD.

Thin layer chromatography silica plate uses GF254 silica plate of Chenghua (Shanghai) Co., Ltd. The specification of silica plate used in thin layer chromatography (TLC) is 0.2~0.25mm, and the specification used for thin layer chromatography separation and purification products is 0.4~0.5mm.

Column chromatography generally uses 100~200 mesh silica gel as the carrier.

High performance liquid chromatography (HPLC) was performed using Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatographs.

Chiral separation column analysis was performed using Gilson GX-281 preparative HPLC.

Unless otherwise specified in the examples, the reactions were all carried out under a nitrogen atmosphere. Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 liter.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

Unless otherwise specified, the reaction temperature is room temperature, ranging from 20°C to 30°C.

Those with ordinary knowledge in the art to which the present invention belongs should understand that the resolved chiral compounds can be distinguished by the order of retention time in the chiral chromatographic column. Therefore, the chiral compounds resolved by retention time are distinguished by corresponding number suffixes such as P1 and P2. That is, the suffix P1 corresponds to the chiral structure resolved first, and the suffix P2 corresponds to the chiral structure resolved later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it corresponds one-to-one with the compounds with the number suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with the number suffixes P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.

The Chinese names corresponding to the abbreviations of some reagents in the examples are as follows: Reagent abbreviation Chinese name of reagent DIEA/DIPEA N,N-Diisopropylethylamine EtOAc Ethyl acetate DCM Dichloromethane MeOH Methanol CH ₃ CN Acetonitrile DMSO N, N-Dimethylsulfoxide Cs ₂ CO ₃ Csium carbonate NaBH ₃ CN Sodium cyanoborohydride NH ₄ HCO ₃ Ammonium bicarbonate DMF N,N-Dimethylformamide HATU 2-(7-Azabenzotriazole)-tetramethyluronium hexafluorophosphate m-CPBA m-Perchlorobenzoic acid AcOH Acetic acid NaBH(OAc) ₃ Sodium tri(acetyl)borohydride LiOH·H ₂ O Lithium Hydroxide Monohydrate

Example 1 (Compound 1)

first step

At 0 ^o C, sodium cyanoborohydride (0.99 g, 26.64 mmol) was added in batches to a well-stirred mixture of compound 1-1 (5.00 g, 22.20 mmol) and methylamine hydrochloride (1.22 g, 22.20 mmol) in 1,2-dichloroethane (50 mL). After the addition, the cooling bath was removed, the reaction solution was naturally raised to room temperature and the stirring reaction was continued for 3 hours. The reaction was completed. The reaction solution was slowly poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column separation (petroleum ether:ethyl acetate = 1:0 - 0:1) to obtain compound 1-2 (2.70 g). MS m/z (ESI): 241.1 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 1-2 (2.70 g, 11.23 mmol), iodoethanol (1.93 g, 11.22 mmol) and potassium carbonate (4.65 g, 33.70 mmol) in acetonitrile (30 mL) was heated to 80 ^° C and stirred for 3 hours. The reaction was completed. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 1-3 (3.00 g). MS m/z(ESI):285.1 (M+H) ⁺ .

Step 3

Under nitrogen protection and 0 ^° C, slowly add hydrogen chloride/1,4-dioxane solution (15 mL, 4 M) to a solution of compound 1-3 (3.00 g, 10.10 mmol) in 1,4-dioxane (15 mL). After the addition, remove the cold bath, naturally raise the reaction solution to room temperature and continue to stir for 1 hour. A large amount of solid precipitates, filter, wash the filter cake with 1,4-dioxane (5 mL x 1), and vacuum dry to obtain compound 1-4 (1.98 g). MS m/z(ESI): 185.1 (M+H) ⁺ .

Step 4

Under nitrogen protection, N,N-diisopropylethylamine (650 mg, 5.01 mmol) and compound 1-6 (222 mg, 1.66 mmol) were added to a solution of compound 1-5 (300 mg, 1.66 mmol) in acetonitrile (3 mL) in sequence. The resulting reaction solution was stirred at room temperature for 3 hours. The reaction was completed. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 – 0:1) to obtain compound 1-7 (470 mg). MS m/z(ESI): 334.1 (M+H) ⁺ .

Step 5

Under nitrogen protection, a solution of compound 1-7 (50 mg, 0.15 mmol), compound 1-4 (166 mg, 0.18 mmol) and anhydrous cesium carbonate (146.3 mg, 0.45 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred overnight. After the reaction was completed, the mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 – 10:1) and reverse phase preparative column purification to obtain compound 1 (17.6 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 – 7.35 (m, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 5.43 (d, J = 3.4 Hz, 0H), 5.14 (s, 1H), 3.97 – 3.59 (m, 6H), 3.22 (s, 1H), 2.88 (s, 2H), 2.58 (s, 3H), 2.20 (d, J = 2.9 Hz, 4H), 2.02 (s, 3H), 1.86 (t, J = 6.2 Hz, 2H), 1.51 (d, J = 7.0 Hz, 3H), 1.25 (s, 4H ). MS m/z(ESI): 482.1 (M+H) ⁺ .

Example 2 (Compound 2)

first step

Under nitrogen protection, a solution of compound 2-1 (200 mg, 1.41 mmol), compound 1-6 (268 mg, 1.41 mmol) and N,N-diisopropylethylamine (546 mg, 4.23 mmol) in acetonitrile (2 mL) was stirred at room temperature for 3 hours. The reaction was completed. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 2-2 (54 mg). MS m/z (ESI): 330.0 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 2-2 (54 mg, 0.16 mmol), compound 1-4 (36 mg, 0.16 mmol) and cesium carbonate (159 mg, 0.49 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred for 12 hours. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 2 (11 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 8.9 Hz, 1H), 7.64 (dd, J = 7.6, 1.4 Hz, 1H), 7.48 (dd, J = 7.9, 1.4 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.67 ( d, J = 8.9 Hz, 1H), 4.88 (s, 1H), 3.87 (d, J = 10.6 Hz, 1H), 3.38 (s, 3H), 3.22 (s, 1H), 2.26 (d, J = 12.9 Hz, 2H), 2.17 – 2.09 (m, 2H), 1.4 4 (dd, J = 10.2, 3.0 Hz, 2H), 1.31 (dd, J = 10.6, 3.1 Hz, 3H). MS m/z(ESI): 478.2(M+H) ⁺ .

Example 3 (Compound 3)

first step

Under nitrogen protection, a solution of compound 3-1 (200 mg, 1.06 mmol), compound 1-6 (222 mg, 1.06 mmol) and N,N-diisopropylethylamine (409 mg, 3.18 mmol) in acetonitrile (2 mL) was heated to 80 ^° C and stirred for 3 hours. The reaction was completed. Cool, add water (10 mL) to the reaction solution, and extract with ethyl acetate (10 mL x 3). Combine the organic phases, wash with saturated brine (20 mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 3-2 (150 mg). MS m/z(ESI): 342.0(M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 3-2 (60 mg, 0.18 mmol), compound 1-4 (58 mg, 0.26 mmol) and anhydrous cesium carbonate (228 mg, 0.54 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred overnight. After the reaction was completed, the mixture was cooled, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 3 (29 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37 (dd, J = 2.1, 1.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.21 – 7.15 (m, 1H), 5.52 – 5.42 (m, 1H), 4.72 (s, 1H), 3.9 8 – 3.65 (m, 5H), 3.20 (s, 1H), 2.88 – 2.75 (m, 3H), 2.65 – 2.48 (m, 4H), 2.26 – 2.14 (m, 2H), 2.06 (dt, J = 20.7, 8.1 Hz, 4H), 2.00 (s, 2 H), 1.92 – 1.81 (m, 4H), 1.50 (d, J = 7.0 Hz, 3H). MS m/z(ESI): 490.2(M+H) ⁺ .

Example 4 (Compound 4)

first step

Under nitrogen protection, a solution of compound 4-1 (150 mg, 0.60 mmol), compound 1-6 (90 mg, 0.60 mmol) and N,N-diisopropylethylamine (232 mg, 1.81 mmol) in acetonitrile (2 mL) was stirred at room temperature for 3 hours. The reaction was completed. Water (10 mL) was added to the reaction solution, and ethyl acetate was extracted (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 4-2 (210 mg). MS m/z(ESI): 405.9 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 4-2 (100 mg, 0.25 mmol), compound 1-4 (220 mg, 0.25 mmol) and anhydrous cesium carbonate (250 mg, 0.75 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 - 10:1) and reverse phase preparative column purification to obtain compound 4 (35 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.31 (d, J = 1.7 Hz, 1H), 7.19 (s, 2H), 5.79 (d, J = 6.2 Hz, 1H), 5.38 (td, J = 6.8, 2.9 Hz, 1H), 3.90 – 3.57 (m, 6H), 3.03 – 2.97 (m, 1H), 2.65 (s, 2H), 2.35 (d, J = 2.7 Hz, 3H), 2.06 (dd, J = 12.6, 7.5 Hz, 1H), 1.90 (dd, J = 10.2, 5.5 Hz, 2H), 1.76 (dd, J = 13. 5, 7.5 Hz, 2H), 1.66 (s, 1H), 1.47 (d, J = 7.0 Hz, 3H). MS m/z(ESI):552.1 (M+H) ⁺ .

Example 5 (Compound 5)

first step

Under nitrogen protection, a solution of compound 5-1 (500 mg, 2.66 mmol), compound 1-6 (505 mg, 2.66 mmol) and N,N-diisopropylethylamine (1.03 g, 7.98 mmol) in acetonitrile (5 mL) was stirred at room temperature for 2 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 5-2 (210 mg). MS m/z(ESI): 341.1 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 5-2 (100 mg, 0.42 mmol), compound 1-4 (138 mg, 0.62 mmol) and anhydrous cesium carbonate (404 mg, 1.25 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 5 (40 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (d, J = 6.4 Hz, 1H), 7.23 – 7.16 (m, 1H), 5.71 (s, 1H), 5.33 (s, 1H), 4.13 (s, 3H), 3.99 (s, 2H), 3.24(s,5H) , 3.12 (s, 2H), 2.81 (s, 3H), 1.98 (d, J = 38.0 Hz, 3H), 1.65 (d, J = 8.5 Hz, 2H), 1.46 (d, J = 7.0 Hz, 3H). MS m/z(ESI): 489.2(M+H) ⁺ .

Example 6 (Compound 6)

first step

Under nitrogen protection, a solution of compound 6-1 (150 mg, 0.73 mmol), compound 1-6 (222 mg, 0.73 mmol) and N,N-diisopropylethylamine (282 mg, 2.19 mmol) in acetonitrile (2 mL) was stirred at room temperature for 3 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 6-2 (200 mg). MS m/z(ESI): 361.0 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 6-2 (150 mg, 0.42 mmol), compound 1-4 (138 mg, 0.63 mmol) and anhydrous cesium carbonate (546 mg, 1.68 mmol) in acetonitrile (2 mL) was heated to 80 ^° C and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 - 10:1) and reverse phase preparative column purification to obtain compound 6 (24 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.77 (s, 1H), 8.62 – 8.50 (m, 1H), 7.57 (dd, J = 8.3, 2.1 Hz, 2H), 7.38 (dd, J = 8.5, 2.2 Hz, 1H), 5.65 – 5.55 (m, 1H), 4.31 (t, J = 5.4 Hz, 1H), 3.85 – 3.72 (m, 2H), 3.72 – 3.57 (m, 2H), 3.45 (q, J = 6.1 Hz, 2H), 2.77 (q, J = 8.0 Hz, 1H), 2.39 (t, J = 6.5 Hz , 2H), 2.14 (s, 3H), 1.99 – 1.90 (m, 1H), 1.85 – 1.71 (m, 3H), 1.65 – 1.56 (m, 1H), 1.48 (d, J = 7.1 Hz, 3H), 1.45 – 1.39 (m, 1H). MS m/z(ESI): 507.1 (M+H) ⁺ .

Example 7 (Compound 7)

first step

Under nitrogen protection, a solution of compound 7-1 (500 mg, 2.42 mmol), compound 1-6 (459 mg, 2.42 mmol) and N,N-diisopropylethylamine (934 mg, 7.25 mmol) in acetonitrile (5 mL) was stirred at room temperature for 2 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 7-2 (770 mg). MS m/z(ESI): 360.1 (M+H) ⁺ .

Step 2

Under nitrogen protection, heat the acetonitrile (2 mL) solution of compound 7-2 (200 mg, 0.56 mmol), compound 1-4 (245 mg, 1.11 mmol) and anhydrous cesium carbonate (541 mg, 1.67 mmol) to 80 ^o C and stir to react overnight. The reaction is complete. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column (dichloromethane: methanol = 1:0-10:1) to obtain compound 7-3 (151 mg).

Step 3

Under nitrogen protection and 0 ^o C, add methyl magnesium bromide (4.00 mmol, 4 mL, 1 M) tetrahydrofuran solution to a solution of compound 7-3 (200 mg, 0.39 mmol) in anhydrous tetrahydrofuran (10 mL). After the addition, remove the cold bath, naturally raise the reaction solution to room temperature and stir overnight. The reaction is complete. Add saturated ammonium chloride aqueous solution (20 mL) to the reaction solution, extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated brine (20 mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane:methanol=1:0-10:1) to obtain compound 7 (80 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (d, J = 0.7 Hz, 1H), 7.28 (dd, J = 2.1, 1.4 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 7.07 (dd, J = 8.4, 2.1 Hz, 1H), 5.43 – 5.37 (m, 1H), 3.85 – 3.72 (m, 1H), 3.68 (t, J = 8.7 Hz, 1H), 3.55 (td, J = 5.3, 1.2 Hz, 3H), 2.86 (q, J = 8.0 Hz, 1H), 2.77 (q, J = 7.3 Hz, 1H ), 2.61 – 2.37 (m, 2H), 2.20 (d, J = 1.7 Hz, 3H), 1.94 (d, J = 5.7 Hz, 5H), 1.81 (td, J = 10.4, 9.1, 5.8 Hz, 2H), 1.75 – 1.60 (m, 2H), 1.50 (d, J = 4. 6 Hz, 6H), 1.40 (d, J = 7.0 Hz, 3H). MS m/z(ESI): 508.2(M+H) ⁺ .

Example 8 (Compound 8)

first step

Under nitrogen protection, a solution of compound 8-1 (250 mg, 1.21 mmol), compound 1-6 (230 mg, 1.21 mmol) and N,N-diisopropylethylamine (467 mg, 3.62 mmol) in acetonitrile (3 mL) was stirred at room temperature for 2 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 8-2 (380 mg). MS m/z(ESI): 360.1 (M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 8-2 (360 mg, 1.00 mmol), compound 1-4 (442 mg, 2.00 mmol) and anhydrous cesium carbonate (975 mg, 3.00 mmol) in acetonitrile (4 mL) was heated to 80 ^° C and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 8-3 (190 mg).

Step 3

Under nitrogen protection and 0 ^o C, add methyl magnesium bromide (2.00 mmol, 2 mL, 1 M) tetrahydrofuran solution to a solution of compound 8-3 (190 mg, 0.37 mmol) in anhydrous tetrahydrofuran (10 mL). After the addition, remove the cold bath, naturally raise the reaction solution to room temperature and stir overnight. The reaction is complete. Add saturated ammonium chloride aqueous solution (20 mL) to the reaction solution, extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated brine (20 mL x 1), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane:methanol=1:0-10:1) to give compound 8 (33 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.1 Hz, 1H), 5.49 (s, 1H), 4.00 – 3.70 (m, 5H), 3.63 (t, J = 5.3 Hz, 2H), 3.06 – 2.85 (m, 1H), 2.68 – 2.53 (m, 2H), 2.36 – 2.05 (m, 8H), 2.01 – 1.72 (m, 5H), 1.61 (t, J = 13.8 Hz, 2H), 1.4 9 (t, J = 6.8 Hz, 3H), 1.37 (s, 3H), 1.26 (d, J = 3.5 Hz, 6H). MS m/z(ESI): 508.1(M+H) ⁺ .

Example 9 (Compounds 9, 9-P1 and 9-P2)

first step

Under nitrogen protection, triethylamine (4.60 g, 45.54 mmol) was added to a solution of compound 9-1 (3.00 g, 15.19 mmol) and compound 1-6 (3.04 g, 15.99 mmol) in ethanol (140 mL). The resulting reaction solution was stirred at room temperature for 16 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using a silica gel column (petroleum ether: ethyl acetate = 1:0 - 10:1) to obtain compound 9-2 (4.70 g). MS m/z (ESI): 350.1 (M+1) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 9-2 (145 mg, 0.41 mmol), compound 1-4 (76 mg, 0.41 mmol) and cesium carbonate (400 mg, 1.23 mmol) in acetonitrile (4 mL) was heated to 80°C and stirred for 16 hours. The reaction was completed. After cooling, filtration, concentration, the crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 - 20:1) and reverse phase preparative column purification to obtain compound 9. Compound 9 was further chirally resolved to obtain 9-P1 (14 mg) and 9-P2 (11 mg).

SFC conditions: Chiral column: Daicel IG-25*250mm 10um; Mobile phase: CO ₂ /EtOH [1% NH ₃ (7 M in MeOH)] = 70/30; Flow rate: 100 mL/min

9-P1 (retention time: 1.055 min): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.55 – 7.52 (d, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.49 – 5.37 (m, 1H), 4.35 (s, 1H), 3.68 (t, J = 9.0 Hz, 2H), 3.63 – 3.42 (m, 4H), 2.91 – 2.73 (m, 1H), 2.45 – 2.37 (m, 2H), 2.18 (s, 3H), 2.14 (s, 3H), 1.98 – 1.90 (m, 1H), 1.83 – 1.72 (m, 2H), 1.70 – 1.64 (m, 1H), 1.62 – 1.52 (m, 1H), 1.43 (d, J = 7.1 Hz, 4H). MS m/z (ESI): 498.2(M+1) ⁺ .

9-P2 (retention time: 1.190 min): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.54 (d, J = 1.9 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 1.9 Hz, 1H), 7.30 (d, J = 7.1 Hz, 1H), 5.48 – 5.38 (m, 1H), 4.32 (s, 1H), 3.73 (d, J = 8.5 Hz, 1H), 3.64 (d, J = 8.4 Hz, 1H), 3.55 – 3.49 (m, 2H), 3.44 – 3.42 (m, 2H), 2.77 – 2.68 (m, 1H), 2.41 – 2.34 (m, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.93 – 1.84 (m, 1H), 1.78 – 1.65 (m, 3H), 1.61 – 1.52 (m, 1H), 1.43 (d, J = 7.1 Hz, 4H). MS m/z (ESI): 498.2(M+1) ⁺ .

Embodiment 10 (10-P1, 10-P2, 10-P3 and 10-P4)

first step

At room temperature, sodium cyanoborohydride (516 mg, 3.74 mmol) was added to a well-stirred methanol (5 mL) solution of compound 1-2 (300 mg, 1.25 mmol) and compound 10-1 (239 mg, 1.25 mmol). The resulting reaction solution was stirred at room temperature for 2 hours. The reaction was completed. The reaction mixture was slowly poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10-2 (400 mg). MS m/z (ESI): 353.3(M+1) ⁺ .

Step 2

Hydrogen chloride/1,4-dioxane (8 mL, 4 M) was added dropwise to a solution of compound 10-2 (380 mg, 1.10 mmol) in 1,4-dioxane (3 mL) at room temperature. The resulting reaction solution was stirred at room temperature for 2 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 10-3 (270 mg). MS m/z (ESI): 253.1(M+1) ⁺ .

Step 3

Under nitrogen protection, a mixed solution of compound 10-3 (288 mg, 1.00 mmol), compound 9-2 (351 mg, 1.00 mmol) and cesium carbonate (977 mg, 3.00 mmol) in acetonitrile (2 mL) and N,N-dimethylformamide (3 mL) was heated to 80 °C and stirred for 36 hours. The reaction was completed. Cool, filter, and concentrate the filtrate to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 - 1:1) and reverse phase preparative column purification to obtain two groups of compounds (12 mg) and (17 mg), each of which contained one or two structures of 10-P1, 10-P2, 10-P3 and 10-P4.

Preparation conditions: Reversed phase preparation column: waters XB-C18 19 x250 mm, 10 μm; Mobile phase: CH ₃ CN:H ₂ O (10mMNH ₄ HCO ₃ ) = 40-55%; UV: 214nM;

The first group of compounds (one or two structures of 10-P1, 10-P2, 10-P3 and 10-P4): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.52 (t, 1H), 7.48 (dd, J = 8.4, 1.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.30 (dd, J = 7.2, 2.2 Hz, 1H), 5.49 – 5.37 (m, 1H), 3.76 – 3.59 (m, 3H), 3.57 – 3.46 (m, 2H), 2.89 – 2.76 (m, 2H), 2.41 (dd, J = 11.2, 7.8 Hz, 2H), 2.17 (s, 3H), 1.94 (d, J = 1.6 Hz, 3H), 1.77 – 1.68 (m, 4H), 1.65 – 1.57 (m, 2H), 1.43 (d, J = 7.1 Hz, 4H), 1.24 (s, 3H). MS m/z (ESI): 566.2(M+1) ⁺ .

The second group of compounds (one or two structures of 10-P1, 10-P2, 10-P3 and 10-P4): ¹ H NMR (400 MHz, DMSO -d ₆ ) δ 7.53 (t, J = 2.2 Hz, 1H), 7.48 (dd, J = 8.4, 1.2 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.30 (dd, J = 5.6 Hz, 1H), 5.47 – 5.38 (m, 1H), 3.75 – 3.60 (m, 5H), 3.01 – 2.96 (m, 1H), 2.86 – 2.79 (m, 1H), 2.17 (s, 3H), 1.96 (d, J = 1.3 Hz, 3H), 1.89 – 1.83 (m, 2H), 1.81 – 1.51 (m, 6H), 1.43 (d, J = 7.1 Hz, 4H), 1.29 (s, 3H). MS m/z (ESI): 566.2(M+1) ⁺ .

Example 11 (Compound 11)

first step

Hydrogen chloride/1,4-dioxane (5 mL, 4 M) was added dropwise to a solution of compound 1-1 (1.00 g, 4.44 mmol) in 1,4-dioxane (5 mL) at room temperature. The resulting reaction solution was stirred at room temperature for 3 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain compound 11-1 (680 mg).

Step 2

Under nitrogen protection, compound 9-2 (1.40 g, 4.22 mmol), compound 11-1 (680 mg, 4.22 mmol) and anhydrous cesium carbonate (4.10 g, 12.67 mmol) were heated to 80 ^° C in acetonitrile (10 mL) solution and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0-0:1) to obtain compound 11-2 (1.19 g). MS m/z (ESI): 439.1 (M+H) ⁺ .

Step 3

At room temperature, sodium cyanoborohydride (29 mg, 0.46 mmol) was added to a well-stirred solution of compound 11-2 (100 mg, 0.23 mmol), compound 11-3 (46 mg, 0.46 mmol) and acetic acid (0.1 mL) in 1,2-dichloroethane (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. The reaction was completed. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 11 (29 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.55 (t, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.4, 1.8 Hz, 1H), 7.39 (dd, J = 8.4, 2.2 Hz, 1H), 7.29 (dd, J = 7.4, 3.0 Hz, 1H ), 5.47 – 5.40 (m, 1H), 3.72 – 3.66 (m, 2H), 3.51 (s, 2H), 3.00 (d, J = 13.9 Hz, 3H), 2.57 (d, J = 16.3 Hz, -1H), 2.45 (s, 1H), 2.19 (s, 3H) , 1.88 – 1.75 (m, 2H), 1.71 – 1.63 (m, 2H), 1.53 (d, J = 10.0 Hz, 2H), 1.45 (d, J = 7.1 Hz, 3H). MS m/z(ESI): 523.1 (M+H) ⁺ .

Example 12 (Compound 12)

The first step is to add hydrogen chloride/1,4-dioxane (2 mL, 4 M) dropwise to a solution of compound 12-1 (300 mg, 1.31 mmol) in 1,4-dioxane (2 mL) at room temperature. The resulting reaction solution is stirred at room temperature for 3 hours. The reaction is complete. The reaction solution is concentrated under reduced pressure to obtain compound 12-2 (205 mg). MS m/z(ESI):130.1 (M+H) ⁺ .

Step 2

At room temperature, sodium cyanoborohydride (60 mg, 0.91 mmol) was added to a well-stirred solution of compound 12-2 (150 mg, 0.91 mmol), compound 11-2 (200 mg, 0.46 mmol) and acetic acid (0.1 mL) in 1,2-dichloroethane (4 mL). The resulting reaction solution was stirred at room temperature for 4 hours. The reaction was completed. The reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 – 0:1) to obtain compound 12-3 (100 mg). MS m/z(ESI): 552.2 (M+H) ⁺ .

Step 3

At room temperature, a mixture of compound 12-3 (100 mg, 0.18 mmol) and lithium hydroxide (22 mg, 0.91 mmol) in tetrahydrofuran/water (v:v=1:1, 2 mL) was stirred overnight. The reaction was completed. Hydrochloric acid (1 N) was added dropwise to the reaction solution to adjust the pH of the reaction solution to 4 - 5. Solids precipitated and were filtered. The filter cake was washed with water (1 mL x 1) to obtain a crude product. The crude product was purified by reverse preparative column to give compound 12 (44 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (q, 1H), 7.50 (dd, J = 8.4, 2.5 Hz, 1H), 7.39 (dd, J = 8.4, 2.2 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 5.50 – 5.42 (m, 1H), 4.37 – 4.31 (m, 1H), 4.08 – 4.01 (m, 1H), 3.83 – 3.49 (m, 5H), 3.04 – 2.96 (m, 1H), 2.58 (d, J = 12.5 Hz, 2H), 2.33 – 2.24 (m, 1H), 2.19 (s, 3H), 1.95 – 1.82 (m, 2H), 1.80 – 1.68 (m, 2H), 1.60 – 1.50 (m, 1H), 1.44 (d, J = 7.1 Hz, 3H), 1.38 – 1.31 ( m, 1H). MS m/z(ESI): 538.1 (M+H) ⁺ .

Example 13 (Compounds 13, 13-P1, 13-P2, 13-P3, 13-P4, 13R-P1, 13R-P2, 13S-P1 and 13S-P2)

first step

At room temperature, sodium cyanoborohydride (29 mg, 0.46 mmol) was added to a well-stirred solution of compound 11-2 (100 mg, 0.23 mmol), compound 13-1 (53 mg, 0.46 mmol) and acetic acid (0.1 mL) in 1,2-dichloroethane (2 mL). The resulting reaction solution was stirred at room temperature for 4 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 – 10:1) to obtain compound 13 (27 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.5, 3.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.2 Hz, 1H), 7.33 – 7.25 (m, 1H), 5.48 – 5.39 (m, 1H), 3.74 – 3.67 (m, 2H), 2.84 – 2.66 (m, 3H), 2.39 – 2.31 (m, 3H), 2.18 (s, 3H), 1.95 – 1.81 (m, 4H), 1.77 – 1.59 (m, 4H), 1. 44 (d, J = 7.1 Hz, 3H). MS m/z(ESI):538.1 (M+H) ⁺ .

Compound 13R was synthesized by replacing compound 13-1 in Example 13 with (R)-pyrrolidine-3-carboxylic acid, and 13R-P1 (retention time 1.333 minutes) and 13R-P2 (retention time 1.651 minutes) were obtained by SFC separation.

SFC conditions: Chiral column: Daicel IG (25*250mm 10um); Mobile phase: CO ₂ /EtOH [0.2% NH ₃ (7 M in MeOH)]=60/40; Flow rate: 100 mL/min

Compound 13Z was synthesized by replacing compound 13-1 in Example 13 with (S)-methylpyrrolidine-3-methyl ester, and 13Z-P1 (retention time 1.671 minutes) and 13Z-P2 (retention time 2.221 minutes) were obtained by SFC separation.

SFC conditions: Chiral column: Daicel OJ (25*250mm 10um); Mobile phase: CO ₂ /EtOH [0.2% NH ₃ (7 M in MeOH)]=85/15; Flow rate: 100 mL/min

13Z-P1 and 13Z-P2 were hydrolyzed with LiOH to obtain 13S-P1 and 13S-P2, respectively. LiOH·H ₂ O (1M, 3.2 mL) was added to a solution of 13Z-P1 (440 mg, 0.80 mmol) in MeOH (10 mL) and stirred at room temperature for 4 hours. The pH of the reaction solution was adjusted to 6 with 2 mol/L dilute hydrochloric acid, the reaction solution was concentrated, and 13S-P1 (350 mg) was prepared by prep-HPLC (ACN/H ₂ O (0.1% FA)).

13S-P1 ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.54 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (d, J = 7.0 Hz, 1H), 5.42 (p, J = 7.0 Hz, 1H), 3.73 (d, J = 8.6 Hz, 1H), 3.66 (d, J = 8.4 Hz, 1H) , 3.54 (s, 3H), 2.92 – 2.83 (m, 1H), 2.71 (d, J = 9.0 Hz, 1H), 2.61 – 2.53 (m, 2H), 2.43 (d, J = 7.0 Hz, 1H), 2.18 (s, 3H), 1.94-1.88 (m, 3H), 1.78-1.63 (m, 4H), 1.50 – 1.38 (m, 4H ). MS m/z (ESI): 538.1 (M+1) ⁺ .

13S-P2 ¹ H NMR (400 MHz, DMSO- d6 ) δ 7.54 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.30 (d, J = 7.0 Hz, 1H), 5.44 (p, J = 7.0 Hz, 1H), 3.69 (d, J = 8.6 Hz, 2H), 3.67 – 3.38 (m, 3H), 2.91 – 2.85 (m, 1H), 2.71 (d, J = 9.0 Hz, 1H), 2.61 – 2.53 (m, 1H), 2.51 – 2.43 (m, 2H), 2.18 (s, 3H), 1.94-1.88 (m, 3H), 1.78-1.63 (m, 4H), 1.50 – 1.38 (m, 4H). MS m/z (ESI): 538.1 (M+1) ⁺ .

Example 14 (Compound 14)

first step

At room temperature, slowly add a solution of lithium hydroxide (1.74 g, 72.42 mmol) in water (130 mL) to a solution of compound 7-2 (13.00 g, 36.21 mmol) in tetrahydrofuran (130 mL). The resulting reaction solution was stirred at room temperature for 2 hours. The reaction was completed. The reaction solution was adjusted to pH = 4 - 5 with dilute hydrochloric acid (1 N), most of the tetrahydrofuran was evaporated under reduced pressure, and 2-methyltetrahydrofuran (50 mL x 3) was extracted. The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14-1 (12.30 g). MS m/z(ESI): 346.0(M+H) ⁺ .

Step 2

Under nitrogen protection, a solution of compound 14-1 (12.30 g, 35.65 mmol), diphenyl phosphate (9.80 g, 35.65 mmol) and triethylamine (3.60 g, 35.65 mmol) in anhydrous tetrahydrofuran (120 mL) was heated to 70 ^o C and stirred for 16 hours. The reaction was completed. After cooling and concentration, the crude product was directly purified by column chromatography (petroleum ether: ethyl acetate = 1:0 – 0:1) to obtain compound 14-2 (6.60 g). MS m/z (ESI): 343.0 (M+H) ⁺ .

Step 3

Under nitrogen protection and 0 ^° C, sodium hydroxide (280 mg, 7.02 mmol, 60%) was added in batches to a solution of compound 14-2 (2.00 g, 5.85 mmol) in N,N-dimethylformamide (20 mL). After the addition, the reaction solution was stirred at this temperature for 30 minutes, and then iodomethane (996 mg, 7.02 mmol) was added dropwise. After the addition, the cold bath was removed, the reaction solution was naturally raised to room temperature and the reaction was continued for 4 hours. The reaction was completed. Water (20 mL) was added to the reaction solution to quench the reaction, and extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated saline (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 14-3 (1.30 g). MS m/z (ESI): 357.0 (M+H) ⁺ .

Step 4

Under nitrogen protection, a solution of compound 14-3 (250 mg, 1.11 mmol), compound 14-4 (395 mg, 1.11 mmol) and cesium carbonate (1.08 g, 3.32 mmol) in acetonitrile (3 mL) was heated to 80 ^° C and stirred for 3 hours. The reaction was completed. After cooling, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (dichloromethane: methanol = 1:0 - 10:1) to obtain compound 14-5 (200 mg). MS m/z(ESI):547.2(M+H) ⁺ .

Step 5

Under nitrogen protection and 0 ^o C, sodium hydride (4 mg, 0.10 mmol, 60%) was added to a solution of compound 14-5 (50 mg, 0.091 mmol) in N,N-dimethylformamide (2 mL). After the addition, the reaction solution was stirred at this temperature for 30 minutes. Then, iodomethane (19 mg, 0.14 mmol) was added dropwise at this temperature. After the addition, the cold bath was removed, the reaction solution was naturally raised to room temperature and the stirring reaction was continued for 3 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 14-6 (56 mg).

Step 6

At 0 ^o C, add hydrogen chloride/1,4-dioxane solution (4 mL, 4 M) to a solution of compound 14-6 (220 mg, 0.39 mmol) in 1,4-dioxane (2 mL). After the addition, the reaction solution was stirred at this temperature for 3 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase preparative column to obtain compound 14-7 (140 mg).

Step 7

Under nitrogen protection, a solution of compound 14-7 (70 mg, 0.15 mmol), iodopropanol (31 mg, 0.17 mmol) and potassium carbonate (32 mg, 0.23 mmol) in acetonitrile (2 mL) was heated to 80 ^° C and stirred for 4 hours. The reaction was completed. After cooling, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0-10:1) and reverse phase preparative column purification to obtain compound 14 (9 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.38 (q, J = 1.6 Hz, 1H), 7.33 (d, J = 9.1 Hz, 1H), 5.96 (dd, J = 10.2, 6.8 Hz, 1H), 4.17 (m, J = 27.8, 10.9 Hz, 4H), 3.82 (d, J = 16.6 Hz, 2H), 3.71 (s, 3H), 3.56 (s, 2H), 3.35 (d, J = 4.1 Hz, 3H), 3.03 (s, 1H) , 2.43 (d, J = 9.4 Hz, 2H), 2.27 – 2.14 (m, 2H), 2.05 (d, J = 34.8 Hz, 3H), 1.94 – 1.85 (m, 3H), 1.36 (d, J = 47.3 Hz, 2H). MS m/z(ESI):520.47 (M+H) ⁺ .

Example 15 (Compound 15)

first step

Under nitrogen protection and 0 ^o C, sodium borohydride (300 mg, 8.11 mmol) was added in batches to a methanol (10 mL) solution of compound 1-1 (1.30 g, 5.78 mmol). After the addition, the cold bath was removed, the reaction solution was naturally raised to room temperature and the reaction was continued to stir for 1 hour. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 15-1 (1.10 g). MS m/z(ESI): 228.1 (M+H) ⁺ .

Step 2

Under nitrogen protection and 0 ^o C, sodium hydride (80 mg, 2.00 mmol, 60%) was added in batches to a solution of compound 15-1 (227 mg, 1.00 mmol) in N,N-dimethylformamide (2 mL). After the addition, the reaction solution was stirred at this temperature for 10 minutes, and then compound 15-2 (230 mg, 1.10 mmol, 60%) was added. The cooling bath was removed, and the reaction solution naturally warmed to room temperature and continued to stir for 2 hours. The reaction was completed. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate = 1:0 - 0:1) to obtain compound 15-3 (120 mg).

Step 3

At room temperature, add hydrogen chloride/1,4-dioxane (1 mL, 4 M) dropwise to a solution of compound 15-3 (120 mg, 0.34 mmol) in 1,4-dioxane (1 mL). The resulting reaction solution was stirred at room temperature for 3 hours, and solids precipitated. The reaction was completed. Filter, wash the filter cake with 1,4-dioxane (1 mL x 1), and vacuum dry to obtain compound 15-4 (70 mg).

Step 4

Under nitrogen protection, a solution of compound 15-4 (70 mg, 0.29 mmol), compound 9-2 (70 mg, 0.20 mmol) and anhydrous cesium carbonate (146 mg, 0.45 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred overnight. The reaction was completed. Cool, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column separation (dichloromethane: methanol = 1:0 - 10:1) and reverse phase preparative column purification to obtain compound 15 (22 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (t, J = 1.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.4, 2.1 Hz, 1H), 5.49 (d, J = 6.3 Hz, 1H), 5.43 (td, J = 6.6, 2.2 Hz, 1H), 3.96 (t, J = 3.9 Hz, 1H), 3.91 – 3.60 (m, 5H), 3.48 (ddd, J = 6.0, 4.1, 1.7 Hz, 2H), 1.95 (dd, J = 5.8, 3.4 Hz, 2H), 1.81 – 1.72 (m, 1H), 1.61 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H). MS m/z(ESI):485.1 (M+H) ⁺ .

Example 16 (Compound 16)

first step

Under nitrogen protection, a solution of compound 14-7 (55 mg, 0.12 mmol), iodoethanol (23 mg, 0.13 mmol) and potassium carbonate (25 mg, 0.18 mmol) in acetonitrile (1 mL) was heated to 80 ^° C and stirred for 3 hours. The reaction was completed. After cooling, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by prep-HPLC to obtain compound 16 (3 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.89 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.5, 1.9 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.40 – 7.34 (m, 1H), 5.91 (m, J = 7. 3, 2.1 Hz, 1H), 3.94 – 3.74 (m, 4H), 3.68 (t, J = 6.2 Hz, 2H), 3.35 (s, 3H), 2.99 – 2.87 (m, 1H), 2.61 (t, J = 6.3 Hz, 1H), 2.43 (s, 1H), 2 .31 (s, 3H), 2.16 (m, J = 13.3, 7.0 Hz, 1H), 1.89 (d, J = 7.2 Hz, 3H), 1.80 – 1.72 (m, 1H), 1.68 – 1.47 (m, 1H), 1.39 – 1.22 (m, 1H). MS m/z(ESI):506.44(M+H) ⁺ .

Example 17 (Compound 19)

first step

Acetic acid (0.1 mL) was added to a solution of compound 11-2 (200 mg, 0.46 mmol) and methylamine (0.2 mL) in methanol (10 mL). After stirring for 30 min, sodium borohydride (70 mg, 1.85 mmol) was added to the reaction solution in batches. After the addition, the reaction was stirred at room temperature for 16 hours. After the reaction was completed, EtOAc (20 mL) and sodium bicarbonate aqueous solution (30 mL) were added to the reaction solution, and the organic phase was separated and collected. The aqueous phase was then extracted with EtOAc (20 mL × 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the obtained product 19-1 (150 mg) was purified by silica gel column chromatography with an eluent system (DCM:MeOH=10:1). MS m/z(ESI): 454.1 (M+H) ⁺ .

Step 2

Ethyl bromoacetate (110 mg, 0.66 mmol) was added to a solution of compound 19-1 (150 mg, 0.33 mmol) and DIEA (128 mg, 0.99 mmol) in acetonitrile (10 mL). After the addition, the reaction was stirred at room temperature for 16 hours until completion. The reaction solution was concentrated under reduced pressure and the obtained product 19-2 (130 mg) was purified by silica gel column chromatography with an eluent system (DCM:MeOH=10:1). MS m/z(ESI): 540.1 (M+H) ⁺ .

Step 3

Lithium hydroxide (31 mg, 1.29 mmol) was added to a solution of 19-2 (130 mg, 0.24 mmol) in water (1 mL) and methanol (3 mL). After the addition, the reaction was stirred at room temperature for 3 hours to complete. The reaction solution was concentrated under reduced pressure, dissolved in methanol and filtered, and the filtrate was purified by high-performance liquid chromatography to obtain product 19 (80.66 mg). ¹ H NMR (400 MHz, DMSO- d ₆ )) δ 7.54 (d, J = 1.7 Hz, 1H), 7.49 (dd, J = 8.4, 1.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.32 (d, J = 6.7 Hz, 1H), 5 .51 – 5.38 (m, 1H), 3.81 – 3.63 (m, 4H), 3.31 – 3.18 (m, 3H), 2.48 (s, 3H), 2.18 (s, 3H), 2.12 – 1.99 (m, 1H), 1.87 – 1.55 (m, 5H), 1.43 (d, J = 7.1 Hz, 3H).

Example 18 (Compound 24)

first step

Compound 24-1 (200 mg, 0.83 mmol) was added to a dry flask, and then a hydrogen chloride-1,4-dioxane solution (6 mL, 4M) was added and stirred at room temperature for 2 h. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure, and then dichloromethane was added to dissolve and concentrate to obtain a crude product 24-2 (115 mg). The obtained crude product was directly subjected to the next step. MS m/z(ESI): 140.1 (M+H) ⁺ .

Step 2

Compound 24-2 (115 mg, 0.83 mmol) was dissolved in DMSO (4 mL) and added to a solution of compound 9-2 (200 mg, 0.57 mmol) in CH ₃ CN (4 mL), and then Cs ₂ CO ₃ (557 mg, 1.71 mmol) was added and the temperature was raised to 80°C and stirred overnight. The reaction solution was concentrated under reduced pressure to remove most of the CH ₃ CN, and water (35 mL) was added, and then extracted with ethyl acetate (50 x 3 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent system (dichloromethane:methanol=1:0-20:1) to obtain compound 24-3 (150 mg). MS m/z(ESI): 453.1 (M+H) ⁺ .

Step 3

2-(Methylamino)ethanol (74 mg, 0.99 mmol) was added to a solution of compound 24-3 (150 mg, 0.33 mmol) in methanol (10 mL), stirred at room temperature for 5 min, then NaBH ₃ CN (104 mg, 1.65 mmol) was added, and the mixture was heated to 50°C and stirred for 12 h. The reaction solution was concentrated under reduced pressure to remove the organic solvent, diluted with water (10 mL), and then extracted with DCM (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent system (dichloromethane:methanol=1:0-10:1) and then prepared by reverse phase to give compound 24 (78.39 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53 (dd, J = 4.4, 2.0 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.37 (dd, J = 8.4, 1.2 Hz, 1H), 7.30 (dd, J = 7.2, 1.6 Hz, 1H), 5.48 – 5.38 (m, 1H), 4.26 (s, 1H), 3.82 – 3.33 (m, 6H), 2.47 – 2.37 (m, 2H), 2.29 (s, 1H), 2.18 (s, 6H), 1.79 (s, 1H), 1.64 (d, J = 9.2 Hz, 3H), 1.43 (d, J = 7.2 Hz, 3H), 1.34 – 1.04 (m, 4H). MS m/z (ESI): 512.1 (M+H) ⁺ .

Example 19 (Compounds 26-P1, 26-P2)

first step

At 0°C, add acetoxyacetyl chloride (614 mg, 5.20 mmol) to a solution of compound 19-1 (1.97 g, 4.33 mmol) and DIPEA (2.24 g, 17.32 mmol) in dichloromethane (15 mL) and stir for one hour. Dilute the reaction solution with ethyl acetate (60 mL), add water (80 mL) for separation, extract the organic phase with saturated brine (80 mL×2), dry with anhydrous sodium sulfate, concentrate, and then separate and purify on a silica gel column (MeOH:DCM=0~5%) to obtain compound 26-1 (2.3 g). MS m/z(ESI): 554.1 (M+H) ⁺ .

Step 2

Compound 26-1 was separated by SFC (equipment: SFC-150mgm (waters); column: Daicel OD (25*250mm, 10um); mobile phase: CO ₂ /MeOH [0.2% _{NH 3} (7M in MeOH)] = 65/35; flow rate: 100 mL/min) and concentrated under reduced pressure to obtain compound 26-1P1 (1.03 g), SFC retention time: 1.260 min; compound 26-1P2 (1.09 g), SFC retention time: 1.584 min. MS m/z (ESI): 553.9 (M+H) ⁺ .

Step 3

Lithium hydroxide (234 mg, 5.58 mmol) was added to a solution of 26-1P1 (1.03 g, 1.86 mmol) in methanol (4 mL), and water (2 mL) was added, and the mixture was stirred for 2 hours. The reaction solution was concentrated and analyzed by Prep-HPLC (ACN/H ₂ O/0.1%/NH ₄ HCO ₃ =60~70%) to obtain compound 26-P2 (634.28 mg). Lithium hydroxide (23.4 mg, 0.56 mmol) was added to a solution of 26-1P2 (100 mg, 0.19 mmol) in methanol (2 mL), and water (1 mL) was added, and the mixture was stirred for two hours. The concentrated portion of the reaction solution was subjected to Prep-HPLC (ACN/H ₂ O/0.1%/NH ₄ HCO ₃ = 60-70%) to obtain compound 26-P1 (84 mg).

26-P2: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 5.49 – 5.40 (m, 1H), 4.89 – 3.90 (m, 4H), 3.79 – 3.46 (m, 4H), 2.70 (s, 3H), 2.18 (s, 3H), 2.04 – 1.82 (m, 2H), 1.79 – 1.50 (m, 4H), 1.43 (d, J = 7.1 Hz, 3H). MS m/z (ESI): 513.9 (M+H) ⁺ .

26-P1 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ7.54 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 5.53 – 5.36 (m, 1H), 4.84 – 4.75 (m, 1H), 4.48 – 4.30 (m, 1H), 4.15 – 4.00 (m, 2H), 3.80 (d, J = 8.6 Hz, 1H), 3.72 – 3.47 (m, 3H), 2.70 (s, 3H), 2.18 (s, 3H), 2.01 – 1.66 (m, 5H), 1.65 – 1.49 (m, 1H), 1.43 (d, J = 7.1 Hz, 3H). MS m/z (ESI): 513.9 (M+H) ⁺ .

Example 20 (Compound 31)

first step

DIPEA (323 mg, 2.5 mmol) was added to a DMF (10 mL) solution of compound 1-2 (200 mg, 0.83 mmol) and methoxyacetic acid (75 mg, 0.83 mmol) at room temperature, and then HATU (380 mg, 1 mmol) was added and stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction solution was diluted with ethyl acetate and extracted with saturated brine. The organic phase was collected and dried over anhydrous sodium sulfate, and the organic phase was concentrated. The residue was purified by column chromatography (PE/EA=2:1) to obtain compound 31-1 (150 mg).

Step 2

Add hydrogen chloride-1,4-dioxane solution (5 mL) to a methanol (5 mL) solution of compound 31-1 (150 mg, 0.49 mmol) and stir at room temperature for 1 hour. Concentrate the reaction solution to obtain crude compound 31-2 (90 mg). MS m/z(ESI): 213.3 (M+H) ⁺ .

Step 3

Cs ₂ CO ₃ (410 mg, 1.26 mmol) was added to a mixed solvent of CH ₃ CN (8 mL) and DMSO (4 mL) containing compound 31-2 (90 mg, 0.42 mmol) and compound 9-2 (74 mg, 0.21 mmol), and then refluxed at 80 ^° C for 22 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (DCM: MeOH = 10: 1) and then prepared to obtain compound 31 (7.84 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 5.50 – 5.40 (m, 1H ), 4.21 – 4.00 (m, 3H), 3.86 – 3.63 (m, 4H), 3.27 (s, 3H), 2.70 (d, J = 27.5 Hz, 3H), 2.18 (s, 3H), 2.05 – 1.62 (m, 6H), 1.44 (d, J = 7.1 Hz , 3H). MS m/z (ESI): 526.2 (M+H) ⁺ .

Example 21 (Compound 42)

first step

Acetic acid (0.2 mL) was added to a methanol (10 mL) solution of compound 11-2 (210 mg, 0.48 mmol) and D-proline methyl ester (119 mg, 0.72 mmol). After stirring for 30 min, sodium borohydride (73 mg, 1.93 mmol) was added to the reaction solution in batches. After the addition, the reaction was stirred at room temperature for 16 hours and the reaction was completed. Ethyl acetate (20 mL) and sodium bicarbonate aqueous solution (30 mL) were added to the reaction solution, and the organic phase was separated and collected. The aqueous phase was then extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography with an eluent system (DCM:MeOH=10:1) to obtain compound 42-1 (200 mg). MS m/z(ESI): 552.2 (M+H) ⁺ .

Step 2

Lithium hydroxide monohydrate (38 mg, 0.90 mmol) was added to a mixed solution of water (1 mL) and methanol (3 mL) containing compound 42-1 (90 mg, 0.16 mmol). The reaction solution was stirred at room temperature for 3 hours, and the reaction was completed by TLC monitoring. After the reaction solution was concentrated under reduced pressure, the filtrate was purified by high-performance liquid chromatography to obtain compound 42 (42.88 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.57 – 7.53 (m, 1H), 7.50 (dd, J = 8.4, 1.9 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.35 – 7.29 (m, 1H), 5.51 – 5. 40 (m, 1H), 3.84 – 3.55 (m, 6H), 2.91 – 2.79 (m, 1H), 2.18 (d, J = 1.1 Hz, 3H), 2.16 – 1.93 (m, 4H), 1.92 – 1.78 (m, 4H), 1.77 – 1.51 (m, 3 H), 1.43 (d, J = 7.0 Hz, 3H). MS m/z (ESI): 538.2 (M+H) ⁺ .

Example 22 (Compound 43)

Acetic acid (0.02 mL) was added to a methanol (5 mL) solution of compound 11-2 (70 mg, 0.16 mmol) and L-proline (36 mg, 0.31 mmol). After stirring for 30 min, sodium borohydride (49 mg, 1.30 mmol) was added to the reaction solution in batches. After the addition, the reaction was stirred at room temperature for 16 hours, and the reaction was terminated. Ethyl acetate (20 mL) and saturated sodium bicarbonate aqueous solution (30 mL) were added to the reaction solution, and the organic phase was separated and collected. The aqueous phase was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and concentrated. Purification was performed by silica gel column chromatography, and the eluent system (DCM: MeOH = 10:1) was used to obtain compound 43 (32.18 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.56 – 7.52 (m, 1H), 7.52 – 7.48 (m, 1H), 7.41 – 7.36 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 5.52 – 5.39 (m, 1H), 3. 82 – 3.55 (m, 6H), 2.90 – 2.80 (m, 1H), 2.22 – 2.17 (m, 3H), 2.17 – 2.06 (m, 2H), 2.06 – 1.79 (m, 6H), 1.79 – 1.50 (m, 3H), 1.43 (d, J = 7. 1 Hz, 3H). MS m/z (ESI): 538.2 (M+H) ⁺ .

Example 23 (Compound 44)

At room temperature, glacial acetic acid (0.04 mL) was added dropwise to a solution of compound 11-2 (100 mg, 0.23 mmol) and (S)-3-pyrrolidinol (30 mg, 0.34 mmol) in MeOH (8 mL). After stirring for half an hour, sodium borohydride (34 mg, 0.88 mmol) was added and stirring continued for one hour. The reaction solution was diluted with DCM (40 mL), and then saturated sodium bicarbonate solution (40 mL) was added to separate the two phases. The aqueous phase was extracted with DCM (40 mL×2), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was purified by column chromatography (DCM:MeOH=10:1) to obtain compound 44 (27.75 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.4, 2.9 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.30 (dd, J = 7.1, 2.5 Hz, 1H ), 5.48 – 5.38 (m, 1H), 4.66 (d, J = 2.3 Hz, 1H), 4.16 (s, 1H), 3.75 – 3.64 (m, 2H), 3.62 – 3.48 (m, 2H), 2.71 – 2.63 (m, 1H), 2.57 – 2.51 (m, 1H), 2.49 – 2.43 (m, 1H), 2.42 – 2.34 (m, 1H), 2.29 – 2.22 (m, 1H), 2.18 (s, 3H), 2.00 – 1.57 (m, 6H), 1.57 – 1.33 (m, 5H). MS m/z (ESI): 510.2 (M+H) ⁺ .

Example 24 (Compound 45)

Add glacial acetic acid (0.02 mL) dropwise into a MeOH (4 mL) solution of 11-2 (40 mg, 0.09 mmol) and (R)-3-pyrrolidinol (13 mg, 0.14 mmol), stir for half an hour, then add sodium borohydride (15 mg, 0.36 mmol), and continue stirring for one hour. The reaction solution was diluted with DCM (40 mL), and then saturated sodium bicarbonate solution (40 mL) was added to separate the two phases. The aqueous phase was extracted with DCM (40 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The residue was purified by column chromatography (DCM:MeOH=10:1) to obtain compound 45 (13.01 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.53 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 8.4, 2.9 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.30 (dd, J = 7.1, 2.5 Hz, 1H ), 5.48 – 5.38 (m, 1H), 4.66 (d, J = 2.3 Hz, 1H), 4.16 (s, 1H), 3.75 – 3.64 (m, 2H), 3.62 – 3.48 (m, 2H), 2.71 – 2.63 (m, 1H), 2.48 – 2.43 (m, 1H), 2.42 – 2.34 (m, 1H), 2.29 – 2.22 (m, 1H), 2.18 (s, 3H), 2.00 – 1.86 (m, 2H), 1.86 – 1.57 (m, 5H), 1.55 – 1.45 (m, 2H), 1.43 (d, J = 7.1 Hz, 3H). MS m/z (ESI): 510.2 (M+H) ⁺ .

Example 25 (Compound 46)

first step

Borane tetrahydrofuran (1 mol/L, 26 mL) was added to a tetrahydrofuran (30 mL) solution of compound 46-1 (2.30 g, 13.21 mmol). The reaction mixture was stirred at room temperature for 48 hours to complete. The reaction mixture was quenched by adding 100 mL of methanol, concentrated under reduced pressure to obtain a residue, and purified by silica gel column (PE: EA = 10:0-10:2) to obtain compound 46-2 (700 mg). MS m/z (ESI): 161.1 (M+H) ⁺ .

Step 2

Pyridinium chlorochromate (PCC) (500 mg, 3.12 mmol) was added to a solution of 46-2 (500 mg, 3.12 mmol) in dichloromethane (20 mL). The reaction solution was stirred at room temperature for 16 hours, and the reaction was completed. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by a silica gel column (PE:EA =10:0-10:3) to obtain compound 46-3 (228 mg). MS m/z(ESI): 159.2 (M+H) ⁺ .

Step 3

Sodium acetate borohydride (960 mg, 4.53 mmol) was added to a solution of compound 46-3 (228 mg, 1.44 mmol), acetic acid (86 mg, 1.43 mmol) and 6-amino-2-azaspiro[3.4]octane-2-carboxylic acid tributyl ester (326 mg, 1.44 mmol) in 1,2-dichloroethane (20 mL). The reaction solution was stirred at room temperature for 16 hours, and the reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography with an eluent system (DCM:MeOH=100:0-100:3) to obtain compound 46-4 (100 mg).

Step 4

Compound 46-4 (90 mg, 0.29 mmol) was added to a solution of hydrogen chloride-1,4-dioxane (4M, 5 mL). After the addition, the reaction was stirred at room temperature for 1 hour until completion. The reaction solution was concentrated under reduced pressure to directly obtain a crude product 46-5 (60 mg). MS m/z(ESI): 211.2 (M+H) ⁺ .

Step 5

Csium carbonate (464 mg, 1.43 mmol) was added to a mixed solvent of acetonitrile (5 mL) solution of compound 46-5 (60 mg, 0.29 mmol) and compound 9-2 (101 mg, 0.29 mmol) and dimethyl sulfoxide (5 mL). After the addition, the reaction was heated to 80°C and stirred for 16 hours to complete. Ethyl acetate (20 mL) and aqueous solution (30 mL) were added to the reaction solution, and the organic phase was separated and collected. The aqueous phase was then extracted with ethyl acetate (10 mL × 3), and the organic phases were combined and washed with saturated saline (25 mL × 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by HPLC to obtain compound 46 (40.75 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (dd, J = 7.2, 2.0 Hz, 1H), 7.49 (dd, J = 8.4, 1.6 Hz, 1H), 7.41 – 7.35 (m, 1H), 7.32 (d, J = 7.2 Hz, 1H), 5.49 – 5.40 (m, 2H), 4.39 – 4.26 (m, 1H), 4.11 – 4.01 (m, 1H), 3.82 – 3.48 (m, 4H), 3.30 – 3.20 (m, 1H), 3.18 – 3.07 (m, 1H), 2.33 – 2.22 (m, 1 H), 2.18 (d, J = 0.6 Hz, 3H), 1.97 – 1.69 (m, 5H), 1.69 – 1.54 (m, 2H), 1.43 (d, J = 7.0 Hz, 3H). MS m/z (ESI): 524.2 (M+H) ⁺ .

Example 26 (Compound 47)

The starting material 46-1 in Example 46 was replaced with the R-configured material 47-1, and the product 47 was finally obtained after five steps of reaction. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ7.54 (dd, J = 7.0, 2.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 5.5 1 – 5.39 (m, 2H), 4.40 – 4.25 (m, 1H), 4.12 – 4.00 (m, 1H), 3.84 – 3.45 (m, 4H), 3.29 – 3.20 (m, 1H), 3.16 – 3.06 (m, 1H), 2.31 – 2.21 (m, 1H), 2.18 (s, 3H), 1.95 – 1.52 (m, 7H), 1.43 (d, J = 7.0 Hz, 3H). MS m/z (ESI): 524.2 (M+H) ⁺ .

Example 27 (Compound 48)

first step

( R )-1-(2,4-dichlorophenyl)ethylamine (492 mg, 2.59 mmol) and DIPEA (607 mg, 4.70 mmol) were added to a solution of compound 48-1 (470 mg, 2.35 mmol) in acetonitrile (10 mL) and stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure to remove the organic solvent, diluted with water (10 mL), and then extracted with DCM (15 x 3 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography with an eluent system (petroleum ether:ethyl acetate = 1:0-5:1) to obtain compound 48-2 (530 mg). MS m/z (ESI): 353.2 (M+H) ⁺ .

Step 2

85% m-CPBA (609 mg, 3.01 mmol) was added in batches to a solution of compound 48-2 (530 mg, 1.51 mmol) in dichloromethane (15 mL) and stirred at room temperature for 12 h. The reaction solution was quenched with sodium sulfite solution and then extracted with DCM (20 x 3 mL). The organic phases were combined and washed with saturated sodium carbonate aqueous solution and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Compound 48-3 (486 mg) was purified by silica gel column chromatography with an eluent system (petroleum ether: ethyl acetate = 1:0-5:1). MS m/z(ESI): 385.2 (M+H) ⁺ .

Step 3

Add a solution of 2-azaspiro[3.4]octan-6-one (236 mg, 1.89 mmol) in DMF (1 mL) to a solution of compound 48-3 (486 mg, 1.26 mmol) in DMF (4 mL), then add DIPEA (651 mg, 5.04 mmol), heat to 80 °C and stir overnight. Dilute with water (10 mL), then extract with ethyl acetate (15 x 3 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate = 1:0-5:1) to obtain compound 48-4 (363 mg). MS m/z(ESI): 430.2 (M+H) ⁺ .

Step 4

10 M methylamine ethanol solution (0.06 mL) and AcOH (2 drops) were added to a solution of compound 48-4 (80 mg, 0.19 mmol) in methanol (2 mL), stirred under nitrogen for 12 h, then NaBH(OAc) ₃ (201 mg, 0.95 mmol) was added, and stirred at room temperature for 3 h. The organic solvent was removed by concentration under reduced pressure, and then dichloromethane (10 mL) was added, and saturated sodium bicarbonate solution was added to pH = 8, and then extracted with dichloromethane (15 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 48-5 (80 mg). MS m/z(ESI): 446.1 (M+H) ⁺ .

Step 5

At 0 ℃, under nitrogen protection, DIPEA (152 mg, 0.72 mmol) was added to a dichloromethane (10 mL) solution of compound 48-5 (80 mg, 0.18 mmol), and then acetoxyacetyl chloride (30 mg, 0.22 mmol) was added dropwise. After the addition was completed, the mixture was returned to room temperature and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and purified by silica gel column (dichloromethane: methanol = 1:0-20:1) to obtain compound 48-6 (70 mg). MS m/z(ESI): 545.0 (M+H) ⁺ .

Step 6

Water (1 mL) and lithium hydroxide monohydrate (13 mg, 0.30 mmol) were added to a solution of compound 48-6 (80 mg, 0.15 mmol) in methanol (5 mL) and stirred at room temperature for 2 h. The organic solvent was removed by concentration under reduced pressure, and compound 48 (41.35 mg) was obtained after reverse phase preparation. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.93 (d, J = 6.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 5.59 – 5.39 (m, 1H), 4.88 – 3.98 (m, 4 H), 3.96 – 3.73 (m, 3H), 3.62 – 3.52 (m, 1H), 2.71 (s, 3H), 2.24 (s, 3H), 1.99 – 1.54 (m, 6H), 1.42 (d, J = 6.8 Hz, 3H). MS m/z (ESI): 503.1 (M+H) ⁺ .

Example 28 (Compound 49)

first step

Compound 49-1 (0.50 g, 5.88 mmol) and DMF (0.01 mL) were dissolved in dichloromethane (5 mL), and oxalyl chloride (895 mg, 7.05 mmol) was added in an ice-water bath and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was directly dried to obtain crude product 49-2 (0.71 g).

Step 2

Compound 19-1 (100 mg, 0.22 mmol) and triethylamine (67 mg, 0.66 mmol) were dissolved in dichloromethane (3 mL), and 49-2 (46 mg, 0.44 mmol) was added under an ice-water bath, and stirred at room temperature for 2 h. The mixture was extracted with dichloromethane (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was obtained by using a CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100:0 to 95:5) to obtain a crude product, and then purified by reverse phase preparation to obtain compound 49 (28.87 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.55 – 7.52 (m, 1H), 7.52 – 7.46 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 5.53 – 5.39 (m, 1H), 4.80 – 3.96 (m, 3H), 3.83 – 3.47 (m, 4H), 2.73 (d, J = 25.4 Hz, 3H), 2.18 (s, 3H), 2.07 – 1.65 (m, 5H), 1.65 – 1.50 (m, 1H), 1.44 (d, J = 7 .1 Hz, 3H). MS m/z (ESI): 520.9 (M+H) ⁺ .

Example 29 (Compound 60)

first step

Compound 60-1 (56 mg, 0.26 mmol) was added to a 4 M solution of 1,4-dioxane (5 mL). The reaction was stirred at room temperature for 1 hour and then completed. The reaction solution was concentrated under reduced pressure to directly obtain the crude product 60-2 (31 mg). MS m/z (ESI): 116.3 (M+H) ⁺ .

Step 2

Sodium cyanoborohydride (17 mg, 0.27 mmol) was added to a methanol (3 mL) solution of compound 24-3 (30 mg, 0.07 mmol) and compound 60-2 (31 mg, 0.19 mmol). After the addition, the reaction was stirred at room temperature for 16 hours, and the reaction was completed. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to obtain product 60 (25.4 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.57 – 7.51 (m, 1H), 7.49 (dd, J = 8.4, 4.6 Hz, 1H), 7.38 (dt, J = 8.4, 2.0 Hz, 1H), 7.30 (dd, J = 7.2, 2.4 Hz, 1H), 5.50 – 5.37 (m, 1H), 3.69 – 3.47 (m, 5H), 3.16 – 2.90 (m, 3H), 2.18 (s, 3H), 2.12 – 1.88 (m, 1H), 1.84 – 1.51 (m, 4H), 1.44 (d, J = 7.0 Hz , 3H), 1.38 (d, J = 4.0 Hz, 3H), 1.33 – 1.02 (m, 3H), 0.93 – 0.79 (m, 1H). MS m/z (ESI): 551.9 (M+H) ⁺ .

Example 30 (Compound 61)

NaBH ₃ CN (26 mg, 0.42 mmol) was added to a solution of compound 24-3 (30 mg, 0.07 mmol) and 3-azetidinecarboxylic acid (28 mg, 0.28 mmol) in methanol (5 mL), and stirred at room temperature overnight. The reaction solution was concentrated and purified by Prep-HPLC (ACN/H ₂ O/10 mM NH ₄ HCO ₃ ) to obtain compound 61 (23.32 mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.54 (dd, J = 4.2, 2.0 Hz, 1H), 7.48 (dd, J = 8.4, 3.6 Hz, 1H), 7.37 (dd, J = 8.4, 1.6 Hz, 1H), 7.30 (dd, J = 7.0, 2.6 Hz, 1H), 5.51 – 5.34 (m, 1H), 3.52 (dd, J = 16.0, 8.0 Hz, 3H), 3.10 (d, J = 0.6 Hz, 4H), 2.18 (s, 3H), 1.96-1.57 (m, 6H), 1.44 (d, J = 7.0 Hz, 3H), 1.34 – 0.76 (m, 5H). MS m/z (ESI): 537.9 (M+H) ⁺ .

Example 31 (Compound 80)

first step

At room temperature, compound 19-1 (50 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (2 mL), and (S)-1-Boc-piperidine-2-carboxylic acid (50 mg, 0.22 mmol), N,N-diisopropylethylamine (43 mg, 0.33 mmol), and HATU (84 mg, 0.22 mmol) were added thereto, and then stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse phase preparation to obtain compound 80-1 (36 mg). MS m/z (ESI): 665.3 (M+H) ⁺ .

Step 2

At 0°C, 4M hydrogen chloride-1,4-dioxane solution was added to compound 80-1 (36 mg, 0.05 mmol), and then stirred at room temperature for 3 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then prepared by reverse phase to obtain compound 80 (4.9 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 5.30 (m, 1H), 4.90 (m, 1 H), 4.28 – 3.84 (m, 5H), 3.38 (m, 2H), 2.88 (s, 3H), 2.80 (m, 1H), 2.28 (s, 3H), 2.05 (m, 1H), 1.98 – 1.80 (m, 5H), 1.73 (m, 2H), 1.60 (m, 4H), 1.44 (d, J = 6.8 Hz, 3H), 1.25 (s, 1H). MS m/z (ESI): 565.2 (M+H) ⁺ .

Biological tests

Test Example 1. HEK293-CCR4 Cell Calcium Flux Experiment

20 L of 50 μg/mL coating solution was added to a 384-well cell plate (Greiner, 781090). After pre-incubation at 37°C for 2 hours or at 4°C overnight, the coating solution was discarded and the plate was washed with sterile water. HEK293-CCR4 cells were diluted to 1 × 10 ⁶ cells/mL with culture medium (DMEM+10%FBS+ 300 g/mL G418+BS 2 g/mL+1%PS) and 20 L/well was added to the 384-well cell plate after washing as above. After incubation in a 37°C incubator with 5% CO ₂ overnight, the cell culture medium was removed and 20 L of experimental buffer (20 mM HEPES, 1×HBSS, 0.5% BSA) and 20 L of 2× Fluo-4 assay reagent (Invitrogen, F10471, final concentration 4 μM, containing 2.5 mM Probenecid) was placed in a 37°C incubator for 50 min, and then placed at room temperature for 10 min. The agonist CCL17 (final concentration of 1 M, 4-fold dilution, 10 concentrations) after gradient dilution of the experimental buffer and the above cell plate were placed in the FLIPR instrument, the instrument was started, 10 L of agonist was transferred to the cell plate, the number was read, and the EC80 was calculated.

The compound to be tested was prepared to a final concentration of 3 M, 10 concentrations, 3-fold dilution, duplicate wells, and a final DMSO concentration of 0.5%; 20 L of experimental buffer was added to the cell culture plate after removing the culture medium, and then 20 L of 2× Fluo-4 detection reagent and 10 L of compound were added, and the plate was placed in a 37°C incubator for 50 min, and then placed at room temperature for 10 min, the FLIPR instrument was started, 10 L of 6× EC80 agonist working solution was transferred to the cell plate, and the number was read. The inhibition rate of each compound was calculated according to the following formula: Antagonist inhibition rate: inhibition % = 100-(RLU-LC)/(DMSO-LC)*100 RLU: relative light absorbance, 1 to the maximum allowed reading; DMSO: average value of fluorescence signal in DMSO group; LC: average value of fluorescence signal at the highest concentration of antagonist.

The experimental test results are shown in the following table. Example No. Compound No. IC ₅₀ (nM) 1 1 47 2 2 19 3 3 10 4 4 94 5 5 28 6 6 5 9 9-P1 19 9 9-P2 16 13 13S-P1 29 14 14 95 16 16 44 18 twenty four 8 19 26-P2 32 twenty three 44 51 twenty four 45 75 25 46 20 27 48 63 28 49 20 30 61 65

The above data indicate that the compounds disclosed in the present disclosure have a potent antagonistic effect on CCR4 receptors.

without

without

Claims (20)

A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein: G is CR ⁵ or N; R ¹ is LR ⁹ ; L is a chemical bond, NR ¹⁰ , O, S, -C(O)-, -S(O)- or -S(O) ₂ -; R ⁹ is H, C _1-6 alkyl, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocyclic group, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, NR ^9a R ^9b , C(O)NR ^9a R ^9b , S(O) ₂ R ^9c , C(O)CH ₂ CN, C(O)COOH, C(O)(3- to 8-membered heterocyclic group), C(O)OR ^9d , C(O)CH(CH ₃ )OR ^9d or C(O)CH ₂ OR ^9d , wherein the C R ¹⁰ is H, C 1-6 alkyl, deuterated C _1-6 alkyl or 3 to 8 membered cycloalkyl, wherein the C _1-6 alkyl and 3 to 8 membered cycloalkyl are optionally substituted by one or more ^substituents selected from halogen, hydroxyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, amino and 3 to 8 membered cycloalkyl; or when L is NR ¹⁰ , R ₉ and R ¹⁰ can be optionally combined _with the nitrogen atom to form ^a 4 to 8 membered heterocyclic group, and the 4 to 8 membered heterocyclic group is optionally substituted by one or more R ^g ; each R ^g are the same or different and are each independently halogen, hydroxyl, oxo, C _1-6 alkyl, C _1-6 alkoxy, cyano, carboxyl, -NHC(O)R ^g1 , -NHS(O) ₂ R ^g2 , -S(O) ₂ R ^g2 , -C(O)NR ^g3 R ^g4 , -S(O) ₂ NR ^g3 R ^g4 , -NR ^g3 R ^g4 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, C _1-6 alkoxy, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently and arbitrarily selected from halogen, hydroxyl, C _1-6 alkyl, C 1-6 ^Rg1 is C1-6 alkyl or C1-6 alkoxy; Rg2 is _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3 to 8 membered cycloalkyl; Rg3 _and ^Rg4 are the same or different and _are each independently H, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl or 3 to 8 membered cycloalkyl ^{; R2} and ^R3 are the same or different and ^are each independently H _, halogen, _C1-6 alkyl, _C1-6 halogenated alkyl, _C1-6 hydroxyalkyl _{, C1-6} alkoxy, _C1-6 R ⁴ is H, halogen, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, cyano, amino, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, NR ^4a R ^{4b , C(O)NR 4a R 4b} , C(O)OR ^4c , S(O) ₂ R ^4d , NR ^4a _C (O)R ^4e or NR ^4a C(O)OR ^4c , wherein the C _1-6 alkyl, C 1-6 alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group are each independently selected from ^halogen , hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, cyano, amino ^, oxo, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group. wherein R ⁵ is H _{, halogen, C 1-6 alkyl, C 1-6 alkoxy ,} hydroxyl, cyano, amino, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, NR _5a R 5b , C(O)NR ^5a R ^5b , C(O)OR 5c , S(O) ₂ R ^5d , NR ^5a C(O)R ^5e or NR ^5a C(O)OR ^5c , wherein the C _1-6 alkyl, C _1-6 alkoxy, ^hydroxyl , cyano ^, amino, 3 to 8 membered ^cycloalkyl , 3 _to 8 membered heterocyclic group wherein _{the 1-6} -membered alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group are each independently and optionally substituted by one or more substituents selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, C _1-6 hydroxyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group; R ⁶ is H, C _1-6 alkyl, C _1-6 halogenated alkyl or 3- to 8-membered cycloalkyl; or when G is CR ⁵ , R ⁴ and R ^{R 5} and the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl, a 5- to 8-membered heterocyclic group, a phenyl group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered cycloalkyl, the 5- to 8-membered heterocyclic group, the phenyl group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group; or R ⁵ and R ⁶ and the atoms to which they are attached form a 5- to 8-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 8-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C 1-6 wherein the alkyl radical is selected from the group consisting of H, D, halogen, C _1-6 alkyl or C _1-6 halogenated alkyl; R ⁸ is the same or different and is independently selected from the group consisting of H, halogen, C _1-6 alkyl _{, C 1-6 alkoxy, C 1-6 halogenated alkyl, C 1-6 halogenated alkoxy, C 1-6 hydroxyl , hydroxyl ,} cyano or 3 to ⁸ membered cycloalkyl; R ^4a , R ^4b , R ^5a , R 5b , R ^9a , R ^9b and R ^9d are the same or different and ^are independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 halogenated alkyl, C 1-6 ^R4c and ^R5c are the same or different and are each independently H, _C1-6 alkyl, _C1-6 halogenated alkyl, C1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group; ^R4d , ^R5d and ^R9c are the same or different and are each independently H, _C1-6 alkyl, C1-6 halogenated alkyl, _C1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group; ^R4e and ^R5e _{are the same or different and are each independently H, C1-6 alkyl, C1-6 halogenated alkyl} , _C1-6 hydroxyalkyl, ₃ to 8 membered cycloalkyl or 3 to 8 _membered heterocyclic group; n is 1 or 2; m is 1 or 2, provided that n and m are not 2 at the same time; k is 0, 1 or 2; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3, 4 or 5; the heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 8-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4. The compound of claim 1 as shown in formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of claim 1 as shown in formula (I) satisfies one or more of the following conditions: (1) G is CR ⁵ ; R ⁵ is as defined in claim 1; (2) in R ⁹ , R ^9a , R ^9b , R ^9d , R ¹⁰ and R ^g , the C _1-6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, dibutyl or tertiary butyl; (3) in R ⁹ , the 3- to 8-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl; (4) R In ^{R 9} , the heteroatom in the 3- to 8-membered heterocyclic group is N, O or S; the number of the heteroatom can be 1, 2 or 3; (5) In R ⁹ , the 3- to 8-membered heterocyclic group is a 3- to 6-membered heterocyclic group, such as azacyclobutane, pyrrolidinyl, piperidinyl, piperidine or imidazolidinyl; (6) In R ⁹ , the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S; the number of the heteroatom can be 1, 2 or 3; (7) In R ⁹ , the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group or an 8- to 10-membered condensed heteroaryl group; the 5- to 6-membered heteroaryl group can be pyrrolyl, pyrazolyl or imidazolyl; (8) R ⁹ and R R ¹⁰ and the nitrogen atom to which it is connected form a 4- to 8-membered heterocyclic group, wherein the heteroatom in the 4- to 8-membered heterocyclic group is N, O or S; the number of the heteroatom can be 1, 2 or 3; (9) R ⁹ and R ¹⁰ and the nitrogen atom to which they are connected form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group, such as azacyclobutane or pyrrolidinyl; (10) In R ^9a and R ^9b , the C _1-6 hydroxyalkyl group is independently a C _1-4 hydroxyalkyl group, such as -CH ₂ CH ₂ OH. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound of formula (I) is a compound of formula (II) or formula (II-1), or wherein: ^R4 is H, halogen, _C1-6 alkyl, _C1-6 alkoxy, hydroxyl, cyano, amine or 3 to 8-membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; the 3 to 8-membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, _C1-6 halogenated alkyl and cyano; ^R5 is H, halogen, C1-6 alkyl, hydroxyl, cyano, amine, C(O) _NH2 or 3 to 8-membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, C1-6 halogenated alkyl and cyano; wherein the 3 to 8- _{membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkoxy} , C _1-6 halogenated alkoxy, cyano, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; the 3 to 8-membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl and cyano; R ⁶ is H or C _1-6 alkyl; or R ⁴ and R ⁵ can optionally form a 5 to 6-membered cycloalkyl, a 5 to 6-membered heterocyclic group, a phenyl or a 5 to 6-membered heteroaryl together with the carbon atom to which they are connected, wherein the 5 to 6-membered cycloalkyl, a 5 to 6-membered heterocyclic group, a phenyl and a 5 to 6-membered heteroaryl are optionally selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 halogenated alkoxy, cyano, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group. R ^8A and R ^8B are the same or different and are each independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or C _1-6 hydroxyalkyl; R ¹ , R ² , R ³ , R ⁷ , n, m, p, q and k _are as defined in claim 1 or 2. The compound of claim 1 or 2 as shown in formula (I) or a pharmaceutically acceptable salt thereof, wherein G is CR ⁵ ; R ⁵ and R ⁶ together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted by one or more substituents selected from halogen, oxo, hydroxyl, C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, C _1-6 halogenated alkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2 or 4, wherein the compound of formula (I) is a compound of formula (III), formula (IV) or formula (V), , or wherein: ^R4 is H, halogen, _C1-6 alkyl, hydroxyl, cyano, amino or 3 to 8-membered cycloalkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, cyano, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group; the 3 to 8-membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl and cyano; ^R11 is H, _C1-6 alkyl or 3 to 8-membered cycloalkyl; ^R12 and ^R13 are the same or different and are each independently H, halogen, hydroxyl, _C1-6 alkyl, _C1-6 halogenated alkyl, C1-6 Preferably, R ¹² is H, halogen, C _1-6 alkyl, C _1-6 halogenated alkyl or cyano, and R ¹³ is H, halogen or C _1-6 alkyl; R ^8A and R ^8B are the same or different and are each independently H, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy or C _1-6 hydroxyalkyl; R ¹ , R ² , R ³ , R ⁷ , n, m, p, q and k are as defined in _any one of claim 1, ₂ or 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 4 and 5, wherein the compound of formula (I) is a compound of formula (III-1), formula (IV-1) or formula (V-1), , or , wherein: R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ^{8A , R 8B ,} R ¹¹ , R ¹² , R ¹³ , n, m, p, q and k are as defined in any one of claims 1, 2, 4 and 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein n is 1, m is 1, and k is 0, 1 or 2; or, n is 1, m is 2, and k is 0, 1 or 2; or, n is 2, m is 1, and k is 0, 1 or 2. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein Select from: , , , , , , , , and ; R ¹ , R ² , R ³ , p and q are as defined in any one of claims 1 to 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ¹ is NR ⁹ R ¹⁰ , OR ⁹ or C(O)NR ^9a R ^9b ; R ⁹ is H, C _1-6 alkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, 5 to 6-membered heteroaryl, C(O) C _1-6 alkyl, C(O)C(O)OH, C(O)(3 to 8-membered heterocyclic group) or C(O)CH ₂ OR ^9d , wherein the C _1-6 alkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group and 5 to 6-membered heteroaryl are each independently optionally substituted with one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ^9a is H or C _1-6 alkyl; R ^{R 9b} is H, C _1-6 alkyl, C _1-6 halogenated alkyl or C _1-6 hydroxyl alkyl; R ¹⁰ is H, C _1-6 alkyl, C _1-6 hydroxyl, deuterated C _1-6 alkyl or 3-8 membered cycloalkyl, wherein the 3-8 membered cycloalkyl is substituted by one or more halogens; or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group is optionally substituted by one or more R ^g ; each R ^g is the same or different and is independently halogenated, hydroxyl, oxo, C _1-6 alkyl, C _1-6 alkoxy, cyano, carboxyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclic group, wherein the C _1-6 alkyl, C 1-6 alkoxy, cyano, carboxyl, 3-8 membered cycloalkyl or 3-8 membered heterocyclic group _{The 1-6} -membered alkoxy group, the 3- to 8-membered cycloalkyl group and the 3- to 8-membered heterocyclic group are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C _1-6 alkyl, C _{1-6 halogenated alkyl, C 1-6 alkoxy} , C _1-6 halogenated alkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl group. According to any one of claims 1 to 6, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R ¹ is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ² and R ³ are the same or different and are each independently H, halogen or C _1-6 alkyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ⁷ is C _1-6 alkyl or C _1-6 halogenated alkyl. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ^8A and R ^8B are the same or different and are each independently halogen. A compound of claim 1 as shown in formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is NR ⁹ R ¹⁰ or OR ⁹ ; R ⁹ is H, C _1-6 alkyl, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclic group, C(O)CH ₂ OR ^9d , C(O)CH ₂ CN or C(O)(3 to 8-membered heterocyclic group), wherein the C _1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclic group are each independently optionally substituted by one or more R ^g ; R ^9d is H or C _1-6 alkyl; R ¹⁰ is H or C _1-6 alkyl; or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4 to 8-membered heterocyclic group, and the 4 to 8-membered heterocyclic group is optionally substituted by one or more R ^g ; Each ^Rg is the same or different and is independently halogen, hydroxyl, oxo, _C1-6 alkyl, carboxyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from cyano and carboxyl; ^R2 and ^R3 are the same or different and are independently H; ^R4 is H or _C1-6 alkyl, wherein the _C1-6 alkyl is optionally substituted by one or more substituents selected from halogen and hydroxyl; ^R5 is halogen, _C1-6 alkyl or cyano, wherein the _C1-6 alkyl is optionally substituted by hydroxyl; ^R6 is H; or ^R4 and R ^{R5 and R6} can be optionally taken together with the carbon atom to which they are attached to form a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered cycloalkyl, the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with a _C1-6 alkyl group; or when G is ^CR5 , ^R5 and ^R6 can be optionally taken together with the carbon atom to which they are attached to form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from oxo and _C1-6 alkyl; ^R7 is _C1-6 alkyl; R7 is the same or different and each is independently halogen; n is 1; m is 1; k is 1 or 2; p is 1; q is 1; t is 2; The heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4. A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein the compound is selected from any one of the following compounds, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or . A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the compound is selected from any one of the following compounds, , , , , , , , , , , , , , , , , or . A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. A use of a compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a drug for regulating CCR4. Use of a compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for preventing and/or treating a CCR4-mediated disease. Use of a compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a medicament for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer, for example, in the preparation of a medicament for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.