Spiroheterocycle substituted pyrimidine compound as well as preparation method and application thereof

Abstract

The invention relates to a spiroheterocycle-substituted pyrimidine compound as well as a preparation method and application thereof, and particularly provides a spiroheterocycle-substituted pyrimidine compound as shown in a formula (I) or pharmaceutically acceptable salt thereof, which can be used for preparing medicines, especially medicines for preventing and / or treating CCR4-mediated diseases or symptoms. Each group in the formula (I) is as defined in the specification. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 202311273151X filed on September 28, 2023. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a spiroheterocyclic substituted pyrimidine compound, a preparation method and use thereof. Background Art

[0003] The successful operation of the host defense system is the result of several processes jointly eliminating foreign pathogens. The innate immune response and acquired immune response of coordination are needed, and many secretory factors and cell-related factors have been confirmed as important mediators for coordinating and regulating these two host defense weapons. Chemokines are a family of cytokines that guide leukocytes to move as chemical attractants. They are secreted by a variety of cells, and can be functionally divided into two categories: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are produced in certain tissues in a compositional manner, and control the cells of the immune system during the immune surveillance process, such as directing lymphocytes to lymph nodes so that they can screen for invasion of pathogens. Inflammatory chemokines are released by cell response pathological events (for example, proinflammatory stimulants, such as IL-1 or viruses). It mainly acts as a chemical attractant as a part of inflammatory response, and is used to guide the cells of the innate immune system and the adaptive immune system to the site of inflammation.

[0004] CC 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 extensive research and development interest as a 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, excellent and selective CCR4 small molecule antagonists.

[0005] The CCR4-related patents that have been disclosed so far include WO2019090272A1 and WO2019147862A1. Summary of the invention

[0006] The present disclosure provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in:

[0009] M is -O- or -NR 0 -;

[0010] R 0 H, C 1-6 Alkyl, C 1-6 A haloalkyl group or a 3- to 8-membered cycloalkyl group;

[0011] R a and R b The carbon atom to which it is connected forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 3- to 6-membered heterocyclic group is optionally selected from a deuterium atom, a halogen, a hydroxyl group, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkoxy group;

[0012] R 1 C 1-6 alkyl, 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group, wherein the C 1-6 The alkyl, 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclic groups are each independently optionally substituted with one or more R g replaced by;

[0013] Each R g are the same or different and are each independently halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, C(O)R g1 、-NHC(O)R g1 、-NHS(O)2R g2 、-S(O)2R g2 、-C(O)NR g3 R g4 、-S(O)2NR g3 R g4 、-NR g3 R g4 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 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 heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl, C(O)R g1 、-NHC(O)R g1、-C(O)NR g3 R g4 、-NR g3 R g4 and substituted by one or more substituents of a 3- to 8-membered cycloalkyl group;

[0014] R g1 C 1-6 Alkyl, C 1-6 Alkoxy or 3- to 8-membered cycloalkyl;

[0015] R g2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or 3- to 8-membered cycloalkyl;

[0016] R g3 and R g4 are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or 3- to 8-membered cycloalkyl;

[0017] R 2 and R 3 are the same or different and are each independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy, cyano, amino, oxo, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;

[0018] R 4 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)2R 4d NR 4a C(O)R 4e or NR 4a C(O)OR 4c , where the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups;

[0019] R 5 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)2R 5d NR 5a C(O)R 5e or NR 5a C(O)OR 5c , where the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups;

[0020] R 4a , R 4b , R 5a and R 5b are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

[0021] R 4c and R 5c are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

[0022] R 4d and R 5d are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

[0023] R 4e and R 5e are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group;

[0024] R 6 H, C 1-6 Alkyl, C 1-6 A haloalkyl group or a 3- to 8-membered cycloalkyl group;

[0025] or R 5 and R 6 The atoms to which it is attached together 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 selected from halogen, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group;

[0026] R 7 H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl;

[0027] Each R 8 are the same or different and are each independently H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, hydroxy, cyano or 3- to 8-membered cycloalkyl;

[0028] n is 0, 1, 2, 3, 4, 5 or 6;

[0029] m is 0, 1, 2, 3 or 4;

[0030] t is 0, 1, 2, 3, 4, or 5;

[0031] The heteroatoms in the 3- to 6-membered heterocyclyl, 3- to 8-membered heterocyclyl, 3- to 10-membered heterocyclyl, 5- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl or 5- to 6-membered heteroaryl are independently one or more of N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4.

[0032] 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 scheme of the present invention (this paragraph is hereinafter referred to as "in some embodiments") In the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the C 1-6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0033] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.

[0034] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the 3- to 10-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclobutyl, cyclopentyl or cyclohexyl.

[0035] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the 3- to 8-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl.

[0036] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the heteroatom in the 3- to 6-membered heterocyclic group, the 3- to 8-membered heterocyclic group, the 3- to 10-membered heterocyclic group or the 5- to 8-membered heterocyclic group is N, O or S, such as N; the number of the heteroatoms may be 1, 2 or 3, such as 1.

[0037] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the heteroatom in the 5- to 10-membered or 5- to 6-membered heteroaryl group is N, O or S, such as N; the number of the heteroatoms may be 1, 2 or 3, such as 2.

[0038] In some embodiments, in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the C 1-6 Alkoxy is C 1-4 Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0039] In some embodiments, the compound represented by formula (I) is a compound represented by formula (II) or formula (II-1),

[0040]

[0041] in:

[0042] R 4 H, halogen, C 1-6Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl;

[0043] R 5 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl;

[0044] R 6 H or C 1-6 alkyl;

[0045] R 1 , R 2 , R 3 , R 7 , R 8 , n, m and t are as defined in formula (I).

[0046] In some embodiments, the compound represented by formula (I) is a compound represented by formula (III) or formula (III-1) or a pharmaceutically acceptable salt thereof,

[0047]

[0048] in:

[0049] R 0 H or C 1-6 alkyl;

[0050] R 4 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl;

[0051] R 5 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl;

[0052] R 6 H or C 1-6 alkyl;

[0053] R 1 , R 2 , R 3 , R 7 , R 8 , n, m and t are as defined in formula (I).

[0054] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 5and R 6 Together with the atoms to which it is attached, it forms a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkylene group may be substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group.

[0055] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 1 Selected from 1, 2, 3 or 4 R g The replaced C 1-6 alkyl,

[0056] Each R g are the same or different and are each independently H, halogen, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)(3 to 8 membered cycloalkyl), -S(O)2C 1-6 Alkyl, -C(O)NR g3 R g4 、-NR g3 R g4 , 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, amino and carboxyl;

[0057] R g3 and R g4 are the same or different and are each independently selected from H or C 1-6 alkyl;

[0058] p is 0, 1, 2, 3 or 4.

[0059] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R1 for Preferably, R 1 for

[0060] In some embodiments, for or a mixture of the two; preferably, for

[0061] In some embodiments, for Or a mixture of the four.

[0062] In some embodiments, for or a mixture of the two; preferably, for

[0063] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 2 and R 3 are the same or different and are each independently selected from H, halogen and C 1-6 alkyl.

[0064] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 2 and R 3 Both are H.

[0065] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 4 is H, halogen or C 1-6 Alkyl; preferably, R 4 C 1-6 alkyl.

[0066] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 5 is H, halogen or C 1-6 Alkyl; preferably, R 5 It is a halogen.

[0067] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 6 For H.

[0068] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 7 C 1-6 Alkyl or C 1-6 Preferably, R 7 C 1-6 alkyl.

[0069] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, R 8 It is a halogen.

[0070] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, for R 8A and R 8B are the same or different and are each independently H, halogen, C 1-6 alkyl.

[0071] In some embodiments, in the compounds of formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) or pharmaceutically acceptable salts thereof, for R 8A and R 8B are the same or different and are each independently halogen.

[0072] In some embodiments, the compound represented by formula (I) is the compound represented by formula (II-1-A) or (II-1-B) is

[0073]

[0074] In some embodiments, exemplary specific compounds of the present disclosure include, but are not limited to, the structures in Table A below: Table A

[0075]

[0076]

[0077] In some embodiments, the exemplary specific compounds of the present disclosure also include, but are not limited to, the structures in Table B below: Table B

[0078]

[0079]

[0080]

[0081] In some embodiments, the compound represented by formula (I) is any of the following compounds:

[0082] The compound that elutes first under the following chromatographic conditions: chromatographic column: Daicel OJ-3 25*250mm, 10μm; the mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is a methanol solution of NH3, the mobile phase B consists of a 7 mol / L ammonia methanol solution with a volume percentage of 0.2% and methanol with a volume percentage of 99.8%, the volume ratio of the mobile phase A to the mobile phase B is 9:1, and the flow rate is 3ml / min; preferably, the retention time of the first eluting compound is 0.947 minutes;

[0083] The compound that elutes later under the following chromatographic conditions: chromatographic column: Daicel OJ-3 25*250mm, 10μm; the mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is a methanol solution of NH3, the mobile phase B consists of a 7 mol / L ammonia methanol solution with a volume percentage of 0.2% and a methanol with a volume percentage of 99.8%, the volume ratio of the mobile phase A to the mobile phase B is 9:1, and the flow rate is 3ml / min; preferably, the retention time of the compound that elutes later is 1.111 minutes;

[0084]

[0085] A group of compounds that elute first under the following chromatographic conditions: chromatographic column: Daicel OD 25*250mm, 10um; mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is NH3 methanol solution, mobile phase B consists of 0.2% by volume of 7 mol / L ammonia methanol solution and 99.8% by volume of methanol, the volume ratio of mobile phase A to mobile phase B is 80:20, flow rate is 3ml / min; wavy lines in the four compounds Wedge-shaped solid key or both wedge-shaped and dashed keys Preferably, the retention time of the first eluting group of compounds is 1.290 minutes;

[0086] More preferably, the Depend on The compound that elutes first under the following chromatographic conditions is The chromatographic conditions are as follows: chromatographic column: Daicel OD25*250mm, 10um; the mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is a methanol solution of NH3, the mobile phase B consists of a 7 mol / L ammonia methanol solution with a volume percentage of 0.2% and a methanol with a volume percentage of 99.8%, the volume ratio of the mobile phase A to the mobile phase B is 80:20, and the flow rate is 3ml / min; preferably, the retention time of the first eluting compound is 2.057 minutes;

[0087]

[0088] A group of compounds that elute later under the following chromatographic conditions: chromatographic column: Daicel OD 25*250mm, 10um; mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is NH3 methanol solution, mobile phase B consists of 0.2% by volume of 7 mol / L ammonia methanol solution and 99.8% by volume of methanol, the volume ratio of mobile phase A to mobile phase B is 80:20, flow rate 3ml / min; wavy lines in the four compounds Wedge-shaped solid key or both wedge-shaped and dashed keys Preferably, the retention time of the group of compounds eluting later is 1.407 minutes;

[0089] More preferably, Depend on The compound that elutes first under the following chromatographic conditions is The chromatographic conditions are as follows: chromatographic column: Daicel OD 25*250mm, 10um; the mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is NH3 methanol solution, the mobile phase B consists of 0.2% by volume of a 7 mol / L ammonia methanol solution and 99.8% by volume of methanol, the volume ratio of the mobile phase A to the mobile phase B is 80:20, and the flow rate is 3 ml / min; preferably, the retention time of the first eluting compound is 2.057 min;

[0090]

[0091] A group of compounds that elute first under the following chromatographic conditions: chromatographic column: Daicel OD 25*250mm, 10um; mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is NH3 methanol solution, mobile phase B consists of 0.5% by volume of 7 mol / L ammonia methanol solution and 99.5% by volume of methanol, the volume ratio of mobile phase A to mobile phase B is 65:35, flow rate 3ml / min; wavy lines in the four compounds Wedge-shaped solid key or both wedge-shaped and dashed keys Preferably, the retention time of the first eluting group of compounds is 1.003 minutes;

[0092] More preferably, Depend on The compounds that elute later under the following chromatographic conditions are The chromatographic conditions are as follows: a chromatographic column: Daicel OD 25*250mm, 10um; the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is a methanol solution of NH3, the mobile phase B consists of a 7 mol / L ammonia methanol solution with a volume percentage of 0.2% and a methanol with a volume percentage of 99.8%, the volume ratio of the mobile phase A to the mobile phase B is 80:20, and the flow rate is 3ml / min; preferably, the retention time of the late peak compound is 2.325min;

[0093]

[0094] A group of compounds that elute later under the following chromatographic conditions: chromatographic column: Daicel OD 25*250mm, 10um; mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is NH3 methanol solution, mobile phase B consists of 0.5% by volume of 7 mol / L ammonia methanol solution and 99.5% by volume of methanol, the volume ratio of mobile phase A to mobile phase B is 65:35, flow rate 3ml / min; wavy lines in the four compounds Wedge-shaped solid key or both wedge-shaped and dashed keys Preferably, the retention time of the group of compounds eluting later is 1.290 min;

[0095] More preferably, Depend on The compounds that elute later under the following chromatographic conditions are The chromatographic conditions are as follows: a chromatographic column: Daicel OD 25*250mm, 10um; the mobile phase consists of a mobile phase A and a mobile phase B, the mobile phase A is supercritical CO2, the mobile phase B is a methanol solution of NH3, the mobile phase B consists of a 7 mol / L ammonia methanol solution with a volume percentage of 0.2% and a methanol with a volume percentage of 99.8%, the volume ratio of the mobile phase A to the mobile phase B is 80:20, and the flow rate is 3ml / min; preferably, the retention time of the late peak compound is 2.325min;

[0096] A group of compounds that elute first under the following chromatographic conditions: chromatographic column: YMC-Actus Triart-C18 150x 20mml.DS-5um, 12nm; mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is acetonitrile, the mobile phase B is an aqueous solution of NH4HCO3, the molar concentration of NH4HCO3 in the mobile phase B is 10mmol / L, and in the mobile phase, the volume percentage of mobile phase A increases from 40% to 60%; preferably, the retention time of the group of compounds that elute first is 1.71 minutes;

[0097] A group of compounds that elute later under the following chromatographic conditions: chromatographic column: YMC-Actus Triart-C18 150x 20mml.DS-5um, 12nm; the mobile phase consists of mobile phase A and mobile phase B, the mobile phase A is acetonitrile, the mobile phase B is an aqueous solution of NH4HCO3, the molar concentration of NH4HCO3 in mobile phase B is 10mmol / L, and in the mobile phase, the volume percentage of mobile phase A increases from 40% to 60%; preferably, the retention time of the group of compounds that elute later is 1.82 minutes.

[0098] In another aspect, the present disclosure provides a compound represented by formula (A) or a pharmaceutically acceptable salt thereof (for preparing a compound represented by formula (I)),

[0099]

[0100] Among them, R a , R b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n, m and t are as defined in any one of the embodiments of formula (I).

[0101] In some embodiments, the compound represented by formula (A) includes but is not limited to the structures in Table C:

[0102] Table C

[0103]

[0104] In another aspect of the present disclosure, an isotope-labeled compound of formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (II-1-A) or (II-1-B), or a compound of Table A, Table B or Table C is provided, wherein the isotope label is preferably deuterium (D or 2 H) replaces hydrogen ( 1 H).

[0105] On the other hand, the present disclosure provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound (a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or a compound shown in Table A, Table B or Table C) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0106] On the other hand, the present disclosure also provides use of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for regulating CCR4.

[0107] On the other hand, the present disclosure also provides use of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicament for inhibiting CCR4.

[0108] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for preventing and / or treating a CCR4-mediated disease or condition.

[0109] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or a compound shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases and cancer; preferably, the medicament is used to prevent and / or treat one or more of the following diseases: arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.

[0110] 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 (III), Formula (III-1), Formula (II-1-A) or (II-1-B), shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0111] 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), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.

[0112] The present disclosure also provides a method for preventing and / or treating autoimmune diseases, inflammatory diseases and cancer, 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 (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or a compound shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0113] The present disclosure also provides a method for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease, 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 (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or a compound shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.

[0114] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a medicine.

[0115] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 modulator.

[0116] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 inhibitor.

[0117] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and / or treating CCR4-mediated diseases or conditions.

[0118] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), or shown in Table A, Table B or Table C, 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.

[0119] The present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (III), Formula (III-1), Formula (II-1-A) or (II-1-B), shown in Table A, Table B or Table C, 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 bowel disease.

[0120] In some embodiments, the CCR4-mediated disease is an autoimmune disease, an inflammatory disease or cancer.

[0121] In some embodiments, the CCR4-mediated disease is arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0122] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0123] 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 (III), formula (III-1), formula (II-1-A) or (II-1-B), Table A, Table B or Table C, or a pharmaceutically acceptable salt or an isotope-labeled substance thereof, based on the total weight of the composition.

[0124] In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (II-1-A) or (II-1-B), Table A, Table B or Table C, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.

[0125] In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (II-1-A) or (II-1-B), Table A, Table B or Table C, or a pharmaceutically acceptable salt or an isotope-labeled substance thereof.

[0126] In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound shown in the aforementioned formula (I), formula (II), formula (II-1), formula (III), formula (III-1), formula (II-1-A) or (II-1-B), Table A, Table B or Table C, or a pharmaceutically acceptable salt or an isotope-labeled substance thereof.

[0127] 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.

[0128] As a drug, the disclosed compounds can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes 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. It can be administered parenterally in a single bolus form, or it can be administered, for example, by a continuous infusion pump.

[0129] In preparing the compositions of the present disclosure, the active ingredient is typically mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, 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.

[0130] The "excipient" described in the present disclosure refers to ingredients other than active ingredients, for example, including one or more of diluents, fillers, absorbents, wetting agents, binders, disintegrants and lubricants.

[0131] 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 base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.

[0132] On the other hand, the compounds of the present invention 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 mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0133] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified. Indicates the absolute configuration, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations. Use wavy lines Indicates a wedge-shaped solid key or dotted wedge key

[0134] key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.

[0135] In addition, the compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. "Tautomer" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactimide isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure. The name of the compound named in a single manner does not exclude any tautomer.

[0136] The present disclosure also includes certain isotopically labeled compounds of the present disclosure having the same structure as described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P.32 P. 35 S. 18 F. 123 I. 125 I and 36 All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of the disclosure.

[0137] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium, or more. Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0138] The "therapeutically effective amount" of the present disclosure refers to the amount of active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by researchers, veterinarians, physicians or other clinicians, and includes one or more of the following: (1) Prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) Suppression of disease: for example, suppression of 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 further development of the pathology and / or symptoms). (3) Relief of disease: for example, relief of 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, a "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

[0139] The term "pharmaceutically acceptable" in the present disclosure refers to compounds, materials, compositions and / or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0140] The "patient" of the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0141] Definition and explanation of terms

[0142] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0143] In this disclosure It means that the corresponding group passes through Connect with other fragments and groups in the compound.

[0144] 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 (C 1-6 Alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-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 chain isomers thereof, etc. The alkyl group may be substituted or unsubstituted.

[0145] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferably, the alkoxy (C 2-alkyl) group contains from 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms. 1-12 Alkoxy), more preferably an alkoxy group containing 1 to 6 carbon atoms (C 1-6 Alkoxy). Non-limiting examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

[0146] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 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, 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 spirocyclic, condensed, and bridged rings.

[0147] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between each monocycle in the system, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. 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 of single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0148]

[0149] The term "condensed cycloalkyl" refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan). According to the number of the composition ring, dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, 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 of dicycloalkyl. The limiting examples of condensed cycloalkyl include:

[0150]

[0151] The term "bridged cycloalkyl" refers to a 5 to 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 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0152]

[0153] 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 The cycloalkyl group may be substituted or unsubstituted.

[0154] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being 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 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), 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 heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

[0155] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, in which one atom (called spiral atom) is shared between each monocyclic ring in the system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 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 single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0156]

[0157] The term "fused heterocyclic radical" refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system. The polycyclic heterocyclic group, 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, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a 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 radical. Non-limiting examples of fused heterocyclic radicals include:

[0158]

[0159] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing 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, the sulfur may be optionally oxoed (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 bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0160]

[0161] The heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0162] The heterocyclic group may be substituted or unsubstituted.

[0163] 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, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

[0164]

[0165] Aryl groups can be substituted or unsubstituted.

[0166] 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. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0167]

[0168] A heteroaryl group can be substituted or unsubstituted.

[0169] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "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 of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0170] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues 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".

[0171] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.

[0172] The term "heterocyclyloxy" refers to heterocyclyl-O- wherein heterocyclyl is as defined herein.

[0173] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.

[0174] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.

[0175] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.

[0176] The term "halogen" refers to F, Cl, Br or I.

[0177] The term "hydroxy" refers to -OH.

[0178] The term "amino" refers to -NH2.

[0179] The term "cyano" refers to -CN.

[0180] The term "nitro" refers to -NO2.

[0181] The term "oxo" or "oxo" refers to "=0".

[0182] The term "carbonyl" refers to C=O.

[0183] The term "carboxy" refers to -C(O)OH.

[0184] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined herein.

[0185] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and 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.

[0186] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0187] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0188] The reagents and raw materials used in the present invention are commercially available.

[0189] The positive and progressive effect of the present invention is that the present invention provides a spiroheterocyclic substituted pyrimidine compound which can be used as a CCR4 inhibitor, such as a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), or a compound shown in Table A or Table B. Such compounds or pharmaceutical compositions containing the same can be used to effectively treat or prevent CCR4-mediated diseases. DETAILED DESCRIPTION

[0190] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0191] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0192] The experimental methods in the following examples without specifying specific conditions were carried out according to conventional methods and conditions, or selected according to the product instructions.

[0193] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0194] Mass spectra (MS) were measured by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0195] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0196] The thin layer chromatography silica gel plate used is GF254 silica gel plate produced by Chenghua (Shanghai) Co., Ltd. The specification of silica gel plate used in thin layer chromatography (TLC) is 0.2-0.25 mm, and the specification of thin layer chromatography separation and purification product is 0.4-0.5 mm.

[0197] Column chromatography generally uses 100-200 mesh silica gel as the carrier of Chenghua Chemical (Shanghai) Co., Ltd.

[0198] Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatography were used for high performance liquid preparation.

[0199] Gilson GX-281 preparative HPLC was used for chiral separation column chromatography.

[0200] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0201] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 liter.

[0202] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0203] Unless otherwise specified in the examples, the reaction temperature is room temperature, ranging from 20°C to 30°C.

[0204] Those skilled in the art should understand that the chiral compounds separated can be distinguished by the order of retention time in the chiral chromatographic column. Therefore, the chiral compounds separated according to the retention time are distinguished by corresponding number suffixes such as P1 and P2. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated 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 number suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with number suffixes P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.

[0205] The reagent names corresponding to the English abbreviations of the reagents are:

[0206]

[0207]

[0208] Example 1 (Compounds 1, 1-P1, 1-P2)

[0209]

[0210]

[0211] first step

[0212] 4-Chlorobutyryl chloride (5.60 g, 39.72 mmol) was dissolved in dichloromethane (50 mL), and NBS (10.60 g, 59.58 mmol), SOCl2 (473 mg, 3.97 mmol) and hydrobromic acid (0.5 ml, 40% acetic acid solution) were added and refluxed and stirred for 2 h. After the reaction was completed, the solid was completely dissolved, and a portion of DCM was evaporated off by rotary evaporation. N-hexane (100 mL) was added to produce solid, which was filtered, washed with n-hexane, filtered, and the filtrate was dried by rotary evaporation to obtain crude product 1-0 (9.6 g).

[0213] Step 2

[0214] Under nitrogen protection and 0°C, TMSCN (1.39 g, 14.01 mmol) was slowly added to a water (30 mL) solution of compound SM (2.00 g, 10.80 mmol) (purchased from Shanghai Shaoyuan) and acetic acid (0.65 g, 10.81 mmol). After the addition was complete, the cold bath was removed, the reaction solution was naturally warmed to room temperature and stirred for 16 hours. The reaction was completed. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (dichloromethane: methanol = 1: 0-10: 1) to obtain compound 1-1 (2.00 g).

[0215] MS m / z(ESI):213.2(M+1).

[0216] Step 3

[0217] 1-1 (2 g, 9.42 mmol) was dissolved in tetrahydrofuran (20 mL), and BH3.THF (18.44 mL, 1 M) was added at 0°C and stirred at room temperature for 2 h. After the reaction was completed, methanol was added to quench the reaction, and the mixture was directly concentrated and dried to obtain a crude product 1-2 (2.5 g).

[0218] MS m / z(ESI):161.1(M-55)

[0219] Step 4

[0220] The crude product of 1-2 (2.5 g, 9.42 mmol) was dissolved in methanol (30 mL), and 2,4-dimethoxybenzaldehyde (2.3 g, 13.87 mmol) and sodium acetate borohydride (4.9 g, 23.12 mmol) were added at 0°C and stirred at room temperature for 2 h. After the reaction was completed, the reaction solvent was dried by spin drying, saturated sodium bicarbonate was added to quench the reaction, and the aqueous phase was extracted with DCM (100 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent system (DCM: MeOH = 100: 0 to 10: 1) to obtain the title product 1-3 (3.22 g).

[0221] MS m / z(ESI):367.4(M+1).

[0222] Step 5

[0223] Dissolve 1-3 (3.11 g, 8.49 mmol) and triethylamine (4.29 mg, 42.43 mmol) in dichloromethane (50 mL), add 1-0 (3.70 g, 16.97 mmol) in an ice-water bath and stir at room temperature for 2 h. After the reaction is completed, add 50 mL of water to quench the reaction. The aqueous phase is then extracted with DCM (50 mL x 3). The organic phases are combined, dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography with an eluent system (PE: EA = 10: 1 to 1: 1) to obtain the title product 1-4 (2.60 g).

[0224] MS m / z(ESI):549.3(M+1).

[0225] Step 6

[0226] Potassium tert-butoxide (2.12 g, 18.91 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution (30 mL) of 1-4 (2.60 g, 4.73 mmol) was added at -78 °C and stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was poured into an aqueous solution of ammonium chloride (50 mL) to quench the reaction. The aqueous phase was then extracted with EA (50 mL x 3). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with an eluent system (DCM: MeOH = 100: 0 to 97: 3) to obtain the title product 1-5 (1.17 g).

[0227] MS m / z(ESI):433.3(M+1).

[0228] Step 7

[0229] 1-5 (1.17 g, 2.71 mmol) was dissolved in trifluoroacetic acid (5 mL) and heated and stirred at 60°C for 3 h. After the reaction was completed, the reaction solution was directly dried to obtain crude product 1-6 (1.1 g) which was used directly in the next step without purification.

[0230] MS m / z(ESI):183.2(M+1).

[0231] Step 8

[0232] The crude product of 1-6 (1.1 g, 2.71 mmol) and IM (0.95 g, 2.71 mmol) (the synthesis of IM can refer to method A on page 189 of the specification of patent CN111971279A, where 2,4-dichloro-5-methylpyrimidine is replaced by 2,4,5-trichloro-6-methylpyrimidine) are dissolved in DMSO (15 mL), and cesium carbonate (2.65 g, 8.13 mmol) is added. Heat and stir at 100°C for 16 h. After the reaction is completed, 50 mL of saturated brine is added to quench the reaction. The aqueous phase is then extracted with EA (100 mL x 3). The organic phases are combined, washed with saturated brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and the filtrate is concentrated under reduced pressure. The title product 1-7 (1.1 g) is purified by silica gel column chromatography with an eluent system (DCM: MeOH = 100: 0 to 10: 1) to obtain.

[0233] MS m / z(ESI):496.3(M+1).

[0234] Step 9

[0235] Compound 1-7 (1.0 g, 2.01 mmol) was dissolved in THF (20 mL), and LiAlH4 (6.03 mL, 1 M THF) was added under an ice-water bath. The reaction solution was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into a saturated aqueous ammonium chloride solution, and DCM (100 mL) was added. The mixture was extracted with DCM (100 x 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product 1-8 (434 mg) was purified using a CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100: 0 to 80: 20) to obtain the product.

[0236] MS m / z(ESI):482.3(M+1).

[0237] Step 10

[0238] 1-8 (40 mg, 0.08 mmol) was dissolved in toluene (3 mL), 3-carbonyl-1-methyl-cyclobutanecarboxylic acid (16 mg, 0.12 mmol) and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (25 mg, 0.10 mmol) were added, and the mixture was refluxed for 4 h under nitrogen protection at 120°C. After the reaction, the reaction solution was directly spin-dried to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with an eluent system (MeOH: DCM = 0: 100 to 10: 90) to obtain 50 mg of the crude product, and then purified by reverse phase preparation to obtain pure product 1 (38.57 mg).

[0239] 1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),7.54–7.43(m,2H),7.37(dd,J=8.4,2.0Hz ,1H),7.33(d,J=7.2Hz,1H),5.40(s,1H),3.84–3.47(m,4H),3.31–3.27(m,1H), 2.70–2.54(m,3H),2.46–2.31(m,2H),2.25–2.13(m,4H),2.09(d,J=11.0Hz,1H) ,1.78–1.60(m,2H),1.53–1.36(m,4H),1.27(d,J=2.6Hz,3H),0.76–0.37(m,4H).

[0240] MS m / z(ESI):594.3(M+1).

[0241] Step 11

[0242] Compound 1 was separated by SFC (equipment: UPCC, column: Daicel OJ-3 (25*250 mm, 10 μm); column temperature: 30° C.; mobile phase: CO 2 / MeOH [0.2% NH 3 (7M in MeOH)] = 90 / 10; total flow rate: 3 ml / min) to obtain compounds 1-P1 and 1-P2.

[0243] 1-P1: retention time 0.947 min, UV = 254 nm;

[0244] 1 H NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 7.49 (d, J = 4.0Hz, 1H), 7.46 (s, 1H), 7.39-7.36 (m, 1H ), 7.33(d,J=4.0Hz,1H), 5.40(s,1H), 3.79(t,J=8.0Hz,3H), 3.54-3.63(m,2H), 2.64-2.51( m,3H),2.50-2.41(m,2H),2.47(d,J=12.0Hz,1H),2.41(m,3H),2.14(d,J=12.0Hz,1H),1.74 -1.66(m,2H), 1.48(t,J=4.4Hz,1H), 1.43(d,J=4.4Hz,3H), 1.28(s,3H), 0.63-0.44(m,4H).

[0245] 1-P2, retention time 1.111 min, UV = 254 nm;

[0246] 1H NMR (400MHz, DMSO-d6) δ12.15 (s, 1H), 7.49 (d, J = 3.6, 1H), 7.47 (s, 1H), 7.39-7.36 (m, 1H), 7.3 3(d,J=3.6Hz,1H), 5.40(s,1H), 3.77(t,J=8.0Hz,3H), 3.52-3.59(m,2H), 2.67-2.64(m,3H), 2 .67-2.51(m,3H),2.48-2.35(m,2H),2.19-2.11(m,2H),2.17(m,3H),2.14(d,J=12.0Hz,1H),1 .73-1.65(m,2H), 1.44(t,J=3.6Hz,1H), 1.42(d,J=4.4Hz,3H), 1.27(s,3H), 0.69-0.43(m,4H).

[0247] Example 2 (Compounds 2, 2-P1, 2-P2)

[0248]

[0249] first step

[0250] 1-8 (40 mg, 0.08 mmol) was dissolved in acetonitrile (2 mL), iodoethanol (28 mg, 0.17 mmol) and DIPEA (32 mg, 0.25 mmol) were added, and stirred at 80 ° C for 16 h. After the reaction was completed, the reaction solution was directly spin-dried to obtain a crude product, which was purified by CombiFlash rapid preparation instrument with an eluent system (MeOH: DCM = 0: 100 to 10: 90) to obtain 45 mg of the crude product. Reverse phase preparation and purification gave pure product 2 (34.65 mg).

[0251] 1H NMR (400MHz, DMSO-d6) δ7.54–7.43(m,2H),7.40–7.35(m,1H),7.33(d,J=6.6Hz,1H) ,5.56–5.28(m,1H),4.41(s,1H),3.82–3.75(m,1H),3.72–3.45(m,5H),3.31(s,1H) ,2.78(d,J=10.6Hz,1H),2.62–2.52(m,1H),2.48–2.41(m,1H),2.41–2.30(m,2H),2 .26–2.12(m,4H),1.73(t,J=10.6Hz,1H),1.43(d,J=7.0Hz,3H),0.78–0.35(m,4H).

[0252] MS m / z(ESI):526.2(M+1).

[0253] Step 2

[0254] Compound 2 was separated by SFC to obtain compounds 2-P1 and 2-P2.

[0255] Example 3 (Compound 3)

[0256] Method 1

[0257]

[0258] first step

[0259] 1-8 (60 mg, 0.12 mmol) was dissolved in methanol (2 mL), and 1-methyl 3-oxocyclopentanecarboxylic acid ethyl ester (32 mg, 0.19 mmol) and NaBH3CN (23 mg, 0.37 mmol) were added and stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was spin-dried. Saturated brine (50 mL) was added to quench the reaction, extracted with EA (50 x 3 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product 3-1 (50 mg) was purified by CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100: 0 to 95: 5) to obtain the product.

[0260] MS m / z(ESI):636.3(M+1).

[0261] Step 2

[0262] 3-1 (50 mg, 0.08 mmol) was dissolved in THF / H2O (2 mL, 1:1), and lithium hydroxide (4 mg, 0.16 mmol) was added and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly added to 1 M dilute hydrochloric acid at pH = 7 to obtain a crude product, which was then purified by reverse phase preparation to obtain two components of compound 3, 3-1P (10.22 mg, two-step yield: 48.6%) and 3-2P (10.51 mg).

[0263] Preparation conditions:

[0264] Column information: YMC-Actus Triart-C18 150x 20mml.DS-5um,12nm

[0265] Mobile phase: ACN: H2O (10mM NH4HCO3) = 40-60%, UV: 214nm

[0266] Retention time: 3-1P: 1.71min; 3-2P: 1.82min.

[0267] 3-1P

[0268] 1H NMR (400MHz, DMSO-d6) δ12.04(s,1H),7.55–7.43(m,2H),7.37(dd,J=8.4,2.0Hz,1H),7.32(d,J=7.0Hz,1H),5.41(s,1H),3.92–3.39(m,5H),2.81– 2.69(m,1H),2.64–2.52(m,2H),2.39–2.12(m,6H),2.06–1.95(m,1H),1. 87–1.59(m,2H),1.57–1.37(m,5H),1.31–1.12(m,4H),0.77–0.36(m,4H).

[0269] MS m / z(ESI):608.3(M+1).

[0270] 3-2P

[0271] 1H NMR (400MHz, DMSO) δ7.55–7.44(m,2H),7.38(dd,J=8.4,2.0Hz,1H),7.33( d,J=7.2Hz,1H),5.41(s,1H),3.85–3.57(m,5H),2.83(s,1H),2.72–2.56(m ,2H),2.48–2.39(m,1H),2.29(s,1H),2.17(s,3H),2.12–1.88(m,2H),1.87 –1.50(m,4H),1.48–1.34(m,4H),1.16(d,J=2.2Hz,3H),0.77–0.38(m,4H).

[0272] MS m / z(ESI):608.3(M+1).

[0273] Method 2

[0274]

[0275]

[0276] first step

[0277] 3-Cyclopentenecarboxylic acid (5.0 g, 44.59 mmol) was dissolved in acetone (100 mL), potassium carbonate (8.39 g, 49.05 mmol) and benzyl bromide (12.33 g, 89.18 mmol) were added and stirred at 60°C for 4 h. After the reaction was completed, water (100 mL) was added to quench the reaction, extracted with DCM (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified using a CombiFlash rapid preparation instrument with an eluent system (PE: EA = 100: 0 to 93: 3) to obtain compound 3b (9.0 g).

[0278] 1 H NMR (400MHz, CDCl3) δ7.43–7.28(m,5H),5.66(s,2H),5.14(s,2H),3.26–3.08(m,1H),2.78–2.55(m,4H).

[0279] Step 2

[0280] Compound 3b (9.0 g, 44.50 mmol) was dissolved in tetrahydrofuran (100 mL). LDA (33.38 mL, 66.75 mmol, 2 M) was added at -78 °C and stirred for 0.5 h. Methyl iodide (9.47 g, 66.75 mmol) was added and the mixture was slowly heated to room temperature and stirred for 4 h. After the reaction was completed, water (100 mL) was added to quench the reaction, and the mixture was extracted with EA (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified using a CombiFlash rapid preparation instrument with an eluent system (PE: EA = 100: 0 to 98: 2) to obtain compound 3c (6.5 g).

[0281] 1 H NMR (400MHz, CDCl3) δ7.40–7.27(m,5H),5.60(s,2H),5.14(s,2H),2.99–2.86(m,2H),2.30–2.17(m,2H),1.32(s,3H).

[0282] Step 3

[0283] Compound 3c (6.7 g, 30.98 mmol) was dissolved in tetrahydrofuran (100 mL), and borane tetrahydrofuran (46.5 mL, 46.47 mmol, 1 M) was added at 0°C and stirred for 1.5 h. Sodium carbonate (98.50 g, 10% aqueous) was added at 0°C, followed by hydrogen peroxide (5.97 g, 30%), and stirred at room temperature for 16 h. After the reaction was completed, saturated sodium thiosulfate (100 mL) was added to quench the reaction, and the mixture was extracted with EA (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 3d (3.6 g) was obtained by purification using a CombiFlash rapid preparation instrument with an eluent system (PE: EA = 100: 0 to 85: 15).

[0284] MS m / z(ESI):235.2(M+1).

[0285] Step 4

[0286] Compound 3d (3.6 g, 15.36 mmol) was dissolved in dichloromethane (60 mL), and DMP (7.82 g, 18.44 mmol) was added at room temperature and stirred for 4 h. After the reaction was completed, the crude product was filtered. The crude product was purified by CombiFlash rapid preparation instrument with eluent system (PE: EA = 100: 0 to 85: 15), and then reverse phase purification (ACN: H2O (10 mmol NH4HCO3)) = (35: 65 to 50: 50) to obtain pure compound 3e (1.85 g).

[0287] MS m / z(ESI):250.2(M+18).

[0288] 1 H NMR (400MHz, CDCl3) δ7.44–7.29(m,5H),5.16(s,2H),2.79(d,J=18.2Hz,1H) ,2.46–2.29(m,3H),2.14(d,J=18.2Hz,1H),1.98–1.88(m,1H),1.41(s,3H).

[0289] Step 5

[0290] Compound 3e (300 mg, 1.29 mmol) was dissolved in methanol (5 mL), compound Pd / C (30 mg, 10%) was added, hydrogen was replaced three times, and the mixture was reacted at room temperature for 3 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated directly for the next reaction.

[0291] MS m / z(ESI):143.2(M+1).

[0292] 1 H NMR (400MHz, CDCl3) δ8.59(s,1H),2.80(d,J=18.2Hz,1H),2.52–2.29(m,3H),2.16(d,J=18.2Hz,1H),2.03–1.90(m,1H),1.43(s,3H).

[0293] Step 6

[0294] Compound 1-8 (560 mg, 1.13 mmol) was dissolved in THF (10 mL), and LiAlH4 (3.4 mL, 1M THF) was added under an ice-water bath. The reaction solution was stirred at room temperature for 4 h, and LCMS showed completion. The reaction solution was poured into a saturated aqueous ammonium chloride solution, DCM (100 mL) was added, and extracted with DCM (100 x 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified using a CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100: 0 to 80: 20), and then separated by SFC (SFC-150mgm (waters); column: Daicel OD (25*250mm, 10um); mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 80 / 20; flow rate: 3ml / min) to obtain 3g-P1 (75mg) and 3g-P2 (80mg).

[0295] MS m / z(ESI):482.3(M+1).

[0296] 3g-P1 retention time: 2.057min

[0297] 3g-P2 retention time: 2.325min

[0298] Step 7

[0299] Under nitrogen protection, 3g-P1 (70 mg, 0.14 mmol) was dissolved in toluene (3 mL), and 3f (31 mg, 0.22 mmol) and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (88 mg, 0.22 mmol) were added and refluxed at 120° C. for 4 h. After the reaction was completed, the crude product was obtained by concentration. The crude product was purified by CombiFlash rapid preparation instrument with eluent system (DCM: MeOH = 100: 0 to 80: 20), then purified by reverse phase preparation, and finally separated by SFC (SFC-150mgm (waters); column: Daicel OD (25*250mm, 10um); mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 80 / 20; flow rate: 3ml / min)) to obtain two groups of components 3-P3-A (21.92mg) and 3-P3-B (23.20mg). 3-P3-A is 2 of the 4 compounds, and 3-P3-B is the remaining 2 of the 4 compounds.

[0300] 3-P3-A, retention time: 1.290 min

[0301] 1 H NMR (400MHz, DMSO) δ12.11 (s, 1H), 7.53–7.43 (m, 2H), 7.37 (dd, J = 8.4, 2.0Hz, 1H),7.32(d,J=7.0Hz,1H),5.41(s,1H),4.00–3.37(m,5H),2.81–2.65(m,1H), 2.58(d,J=6.6Hz,1H),2.49–2.43(m,1H),2.41–2.11(m,6H),2.06–1.92(m,1H ),1.81–1.59(m,2H),1.53–1.36(m,5H),1.32–1.18(m,4H),0.73–0.34(m,4H).

[0302] MS m / z(ESI):608.1(M+1)

[0303] 3-P3-B, retention time: 1.407 minutes

[0304] 1H NMR (400MHz, DMSO) δ12.06 (s, 1H), 7.54–7.43 (m, 2H), 7.38 (dd, J = 8.4, 2.0Hz, 1H), 7.3 3(d,J=7.2Hz,1H),5.40(s,1H),3.86–3.41(m,5H),2.75(s,1H),2.58(d,J=6.8Hz,1H) ,2.49–2.43(m,1H),2.41–2.31(m,1H),2.28–2.13(m,5H),2.06–1.95(m,1H),1.87–1. 75(m,1H),1.71–1.59(m,1H),1.58–1.38(m,5H),1.27–1.16(m,4H),0.73–0.36(m,4H).

[0305] MS m / z(ESI):608.1(M+1)

[0306] Step 8

[0307] Under nitrogen protection, 3g-P2 (70 mg, 0.14 mmol) was dissolved in toluene (3 mL), and 3f (31 mg, 0.22 mmol) and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (88 mg, 0.22 mmol) were added and refluxed at 120° C. for 4 h. After the reaction was completed, the crude product was obtained by concentration. The crude product was purified by CombiFlash rapid preparation instrument with eluent system (DCM: MeOH = 100: 0 to 80: 20), then purified by reverse phase preparation, and finally separated by SFC (SFC-150mgm (waters); column: Daicel IG (25*250mm, 10um); mobile phase: CO2 / IPA [0.5% NH3 (7M in MeOH)] = 65 / 35; flow rate: 3ml / min)) to obtain two groups of components 3-P4-A (23.88mg) and 3-P4-B (17.62mg). 3-P4-A is 2 of the 4 compounds, and 3-P4-B is the remaining 2 of the 4 compounds.

[0308] 3-P4-A, retention time: 1.003 minutes

[0309] 1H NMR (400MHz, DMSO) δ12.09(s,1H),7.55–7.44(m,2H),7.37(dd,J=8.4,2.0Hz,1H),7.31(d,J =7.0Hz,1H),5.40(s,1H),3.85–3.34(m,5H),2.77(d,J=10.4Hz,1H),2.63–2.53(m,1H),2.49 –2.43(m,1H),2.37(d,J=11.2Hz,1H),2.28–2.11(m,5H),2.06–1.95(m,1H),1.85–1.73(m,1 H),1.65(s,1H),1.58–1.37(m,5H),1.26–1.14(m,4H),0.74–0.62(m,1H),0.58–0.36(m,3H).

[0310] MS m / z(ESI):608.1(M+1).

[0311] 3-P4-B, retention time: 1.290 min

[0312] 1 H NMR (400MHz, DMSO) δ12.11 (s, 1H), 7.56–7.44 (m, 2H), 7.38 (dd, J = 8.4, 2.0Hz, 1H), 7.32(d,J=7.2Hz,1H),5.41(s,1H),3.91–3.34(m,5H),2.75(d,J=10.8Hz,1H),2.64 –2.54(m,1H),2.49–2.42(m,1H),2.40–2.26(m,2H),2.23–2.12(m,4H),2.06–1.94( m,1H),1.80–1.60(m,2H),1.52–1.37(m,5H),1.31–1.16(m,4H),0.76–0.36(m,4H).

[0313] MS m / z(ESI):608.1(M+1).

[0314] Example 4 (Compounds 4, 4-P1, 4-P2)

[0315]

[0316]

[0317] first step

[0318] 1-8 (45 mg, 0.09 mmol) was dissolved in toluene (3 mL), 1-methyl-4-oxocyclohexanecarboxylic acid (19 mg, 0.12 mmol) and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (35 mg, 0.14 mmol) were added, and the mixture was refluxed for 4 h under nitrogen protection at 120°C. After the reaction, the reaction solution was directly spin-dried to obtain a crude product, which was purified using a CombiFlash rapid preparation instrument with an eluent system (MeOH: DCM = 0: 100 to 20: 80) to obtain 50 mg of a crude product. Reverse phase preparation and purification gave pure product 4 (27.35 mg).

[0319] 1H NMR (400MHz, DMSO-d6) δ12.07(s,1H),7.48(d,J=9.2Hz,2H),7.40–7.35(m,1H),7.32(d ,J=7.1Hz,1H),5.52–5.27(m,1H),3.86–3.37(m,5H),2.77(d,J=10.7Hz,1H),2.64–2.51 (m,2H),2.20(d,J=11.2Hz,1H),2.17(s,3H),2.09(t,J=8.9Hz,1H),1.80(t,J=10.4Hz, 1H),1.57(d,J=7.2Hz,6H),1.49–1.35(m,5H),1.09(d,J=2.6Hz,3H),0.74–0.35(m,4H).

[0320] MS m / z(ESI):622.3(M+1).

[0321] Step 2

[0322] Compound 4 was separated by SFC to obtain compounds 4-P1 and 4-P2.

[0323] Example 5 (compound 5, 5-P1, 5-P2)

[0324]

[0325] first step

[0326] 1-8 (80 mg, 0.17 mmol) was dissolved in acetonitrile (3 mL), and N-Boc-bromoethylamine (56 mg, 0.25 mmol) and DIPEA (64 mg, 0.50 mmol) were added, and stirred at 60°C for 16 h. The reaction solution was directly spin-dried to obtain a crude product, which was purified using a CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100: 0 to 95: 5) to obtain the product 5-1 (90 mg).

[0327] MS m / z(ESI):625.3(M+1).

[0328] Step 2

[0329] 5-1 (75 mg, 0.12 mmol) was dissolved in HCl / dioxane (2 mL, 4 M) and stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated and dried to obtain crude product 5-2 (70 mg).

[0330] MS m / z(ESI):525.4(M+1).

[0331] Step 3

[0332] 5-2 (70 mg, 0.12 mmol) was dissolved in dichloromethane (2 mL), triethylamine (36 mg, 0.36 mmol) and cyclopropylcarbonyl chloride (14 mg, 1.1 mmol) were added, and stirred at room temperature for 1 h. Water (30 mL) was added directly to the reaction solution to quench the reaction, and DCM (30x3 mL) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product (50 mg) was purified by a CombiFlash rapid preparation instrument with an eluent system (DCM: MeOH = 100: 0 to 10: 10), and the pure product 5 (34.66 mg) was obtained by reverse phase preparation purification.

[0333] 1H NMR(400MHz,DMSO-d6)δ7.96(d,J=4.0Hz,1H),7.56–7.50(m,1H),7.49–7.44(m,1H) ),7.40–7.35(m,1H),7.35–7.29(m,1H),5.41(s,1H),3.92–3.36(m,5H),3.25–3.0 8(m,2H),2.77(d,J=10.8Hz,1H),2.61–2.53(m,1H),2.44–2.19(m,4H),2.17(s,3H ),1.79–1.63(m,1H),1.58–1.48(m,1H),1.43(d,J=7.0Hz,3H),0.76–0.38(m,8H).

[0334] MS m / z(ESI):593.3(M+1).

[0335] Step 4

[0336] Compound 5 was separated by SFC to obtain compounds 5-P1 and 5-P2.

[0337] Biological Testing

[0338] Test Example 1 HEK293-CCR4 Cell Calcium Flux Assay of the Disclosed Compounds

[0339] 20L of 50μg / mL coating solution was added to a 384-well cell plate (Greiner, 781090), and 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 1×106 cells / mL with culture medium (DMEM+10% FBS+300g / mL G418+BS2g / mL+1% PS), and 20L / well was added to the 384-well cell plate after the above washing; after incubation in a 5% CO2, 37°C incubator overnight, the cell culture medium was removed, and 20L of experimental buffer (20mM HEPES, 1×HBSS, 0.5% BSA) and 20L of 2×Fluo-4 detection reagent (Invitrogen, F10471, final concentration 4μM, containing 2.5mM Probenecid), incubate in a 37°C incubator for 50 min, and then stand at room temperature for 10 min. Place the agonist CCL17 (final concentration of 1M, 4-fold dilution, 10 concentrations) diluted in the experimental buffer gradient and the above cell plate and pipette tip into the FLIPR instrument, start the instrument, transfer 10L of agonist to the cell plate, read, and calculate EC80.

[0340] The compound to be tested was prepared to a final concentration of 3M, 10 concentrations, 3-fold dilution, double wells, and a final DMSO concentration of 0.5%; 20L of experimental buffer was added to the cell culture plate after removing the culture medium, and then 20L of 2×Fluo-4 detection reagent and 10L of compound were added, and the plate was incubated in a 37°C incubator for 50 minutes, and then allowed to stand at room temperature for 10 minutes, the FLIPR instrument was started, 10L of 6×EC80 agonist working solution was transferred to the cell plate, and the reading was performed. The inhibition rate IC of each compound was calculated according to the following formula 50 value:

[0341] Antagonist inhibition rate: inhibition rate % = 100-(RLU-LC) / (DMSO-LC)*100

[0342] RLU: relative light absorbance, 1 to the maximum allowed reading;

[0343] DMSO: average fluorescence signal of DMSO group; LC: average fluorescence signal of the highest antagonist concentration.

[0344] The experimental test results are shown in the following table.

[0345] A:IC 50 <100nM; B:100nM <IC 50 <500nM; C:500nM <IC50

[0346] Example No. Compound No. <![CDATA[IC 50 (nM)]]> 1 1 132 2 2 213 3 3-1P 65 3 3-2P 47 3 3-P4-A 24 3 3-P4-B 16 4 4 84 5 5 79

[0347] The above data indicate that the compounds disclosed herein have a potent antagonistic effect on CCR4 receptors.

Claims

1. A compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, in: M is -O- or -NR 0 -; R 0 H, C 1-6 Alkyl, C 1-6 A haloalkyl group or a 3- to 8-membered cycloalkyl group; R a and R b The carbon atom to which it is connected forms a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered cycloalkyl or the 3- to 6-membered heterocyclic group is optionally selected from a deuterium atom, a halogen, a hydroxyl group, a C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkoxy group; R 1 C 1-6 alkyl, 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group, wherein the C 1-6 The alkyl, 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclic groups are each independently optionally substituted with one or more R g replaced by; Each R g are the same or different and are each independently halogen, hydroxy, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, C(O)R g1 、-NHC(O)R g1 、-NHS(O)2R g2 、-S(O)2R g2 、-C(O)NR g3 R g4 、-S(O)2NR g3 R g4 、-NR g3 R g4 , 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 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 heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, oxo, cyano, amino, carboxyl, C(O)R g1 、-NHC(O)R g1 、-C(O)NR g3 R g4 、-NR g3 R g4 and substituted by one or more substituents of a 3- to 8-membered cycloalkyl group; R g1 C 1-6 Alkyl, C 1-6 Alkoxy or 3- to 8-membered cycloalkyl; R g2 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or 3- to 8-membered cycloalkyl; R g3 and R g4 are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or 3- to 8-membered cycloalkyl; R 2 and R 3 are the same or different and are each independently H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, hydroxy, cyano, amino, oxo, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl; R 4 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)2R 4d NR 4a C(O)R 4e or NR 4a C(O)OR 4c , where the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; R 5 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)2R 5d NR 5a C(O)R 5e or NR 5a C(O)OR 5c , where the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 substituted by one or more substituents selected from hydroxyalkyl, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic groups; R 4a , R 4b , R 5a and R 5b are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group; R 4d and R 5d are the same or different and are each independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, 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 Haloalkyl, C 1-6 Hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclic group; R 6 H, C 1-6 Alkyl, C 1-6 A haloalkyl group or a 3- to 8-membered cycloalkyl group; or R 5 and R 6 The atoms to which it is attached together 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 selected from halogen, oxo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group; R 7 H, D, halogen, C 1-6 Alkyl or C 1-6 Haloalkyl; Each R 8 are the same or different and are each independently H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, hydroxy, cyano or 3- to 8-membered cycloalkyl; n is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3 or 4; t is 0, 1, 2, 3, 4, or 5; The heteroatoms in the 3- to 6-membered heterocyclyl, 3- to 8-membered heterocyclyl, 3- to 10-membered heterocyclyl, 5- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl or 5- to 6-membered heteroaryl are independently one or more of N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) satisfies one or more of the following conditions: (1) C 1-6 Alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) The halogen is fluorine, chlorine, bromine or iodine, for example fluorine or chlorine; (3) The 3- to 10-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclobutyl, cyclopentyl or cyclohexyl; (4) The 3- to 8-membered cycloalkyl group is a 3- to 6-membered cycloalkyl group, such as cyclopropyl, cyclobutyl or cyclopentyl; (5) The heteroatom in the 3- to 6-membered heterocyclic group, the 3- to 8-membered heterocyclic group, the 3- to 8-membered heterocyclic group or the 5- to 8-membered heterocyclic group is N, O or S, such as N; the number of the heteroatoms can be 1, 2 or 3, such as 1; (6) The heteroatom in the 5- to 10-membered or 5- to 6-membered heteroaryl group is N, O or S, such as N; the number of the heteroatoms can be 1, 2 or 3, such as 2; (7) C 1-6 Alkoxy is C 1-4 Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

3. 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), in: R 4 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl; R 5 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl; R 6 H or C 1-6 alkyl; R 1 , R 2 , R 3 , R 7 , R 8 , n, m and t are as defined in claim 1 or 2.

4. 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 (III) or formula (III-1), in: R 0 H or C 1-6 alkyl; R 4 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl; R 5 H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, hydroxy, cyano, amino or 3- to 8-membered cycloalkyl; R 6 H or C 1-6 alkyl; R 1 , R 2 , R 3 , R 7 , R 8 , n, m and t are as defined in claim 1 or 2.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 Together with the atoms to which it is attached, it forms a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkylene group may be substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from 1, 2, 3 or 4 R g The replaced C 1-6 alkyl, Each R g are the same or different and are each independently H, halogen, hydroxyl, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, cyano, carboxyl, C(O)C 1-6 Alkyl, -NHC(O)C 1-6 Alkyl, -NHC(O)(3 to 8 membered cycloalkyl), -S(O)2C 1-6 Alkyl, -C(O)NR g3 R g4 、-NR g3 R g4 , 3 to 8 membered cycloalkyl or 3 to 8 membered heterocyclic group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic groups are each independently optionally selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, amino and carboxyl; R g3 and R g4 are the same or different and are each independently selected from H or C 1-6 alkyl; p is 0, 1, 2, 3 or 4.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R 1 for Preferably, R 1 for More preferably, for or a mixture of both; e.g. for or, for or a mixture of the four; or, for or a mixture of both; e.g. for 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same or different and are each independently selected from H, halogen and C 1-6 Alkyl; preferably, R 2 and R 3 Both are H.

9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 7 C 1-6 Alkyl or C 1-6 Preferably, R 7 C 1-6 alkyl.

10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 8 It is a halogen.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which satisfies one or more of the following conditions: (1)R 4 is H, halogen or C 1-6 Alkyl; preferably, R 4 C 1-6 alkyl; (2)R 5 is H, halogen or C 1-6 Alkyl; preferably, R 5 is a halogen; (3)R 6 is H; (4) for R 8A and R 8B are the same or different and are each independently H, halogen, C 1-6 Alkyl; preferably, R 8A and R 8B are each independently a halogen; (5) The compound represented by formula (I) is: The compound represented by formula (II-1-A) or (II-1-B) is:

12. A compound as shown in formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the compound as shown in formula (I) is selected from any of the following compounds, Preferably, the compound represented by formula (I) is selected from any of the following compounds:

13. A compound represented by formula (A) or a pharmaceutically acceptable salt thereof, in, R a , R b , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , n, m and t as described in any one of claims 1-12.

14. The compound of formula (A) or a pharmaceutically acceptable salt thereof according to claim 13, wherein the compound of formula (A) has the following structure:

15. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

16. Use of the compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 15 in the preparation of a medicament for regulating CCR4.

17. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating a CCR4-mediated disease; preferably, the CCR4-mediated disease is an autoimmune disease, an inflammatory disease or cancer, more preferably arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

18. Use of a compound of formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 15 in the preparation of a medicament for preventing and / or treating autoimmune diseases, inflammatory diseases and cancer; preferably, the medicament is used to prevent and / or treat one or more of the following diseases: arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.

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