Nitrogen-containing spiro heterocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention relates to a nitrogen-containing spiroheterocyclic compound as well as a pharmaceutical composition and application thereof, and particularly provides a 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 factor mediated diseases or symptoms. # imgabs0 #

Description

Technical Field

[0001] This application belongs to the field of medicine, and particularly relates to nitrogen-containing spiroheterocyclic compounds, their pharmaceutical compositions and uses thereof. Background Art

[0002] The successful operation of the host defense system is the result of several processes working together to eliminate foreign pathogens. Coordinated innate immune responses and acquired immune responses are required, and many secreted factors and cell-related factors have been identified as important mediators for coordinating and regulating these two host defense weapons. Chemokines are a family of cytokines that act as chemoattractants to guide the movement of leukocytes. They are secreted by a variety of cells and can be functionally divided into two categories: homeostatic chemokines and inflammatory chemokines. Homeostatic chemokines are constitutively produced in certain tissues and control the cells of the immune system during the process of immune surveillance, such as directing lymphocytes to lymph nodes so that they can screen for pathogen invasion. Inflammatory chemokines are released by cells in response to pathological events (e.g., pro-inflammatory stimuli such as IL-1 or viruses). They mainly act as chemoattractants as part of the inflammatory response and are used to direct the cells of the innate immune system and the adaptive immune system to the site of inflammation.

[0003] C-C chemokine receptor type 4 (CCR4), which is mainly expressed on Th2 cells, plays a major role in the progression of many allergic and inflammation-related diseases by regulating downstream cytokines such as IL4, IL5 and IL13. Although CCR4 has attracted extensive research and development interest as a highly potential drug development target, the development of small molecule compounds that regulate the function of CCR4 is an ongoing challenge. So far, no small molecule drug has entered the market. Therefore, there is still a need to actively explore new, excellent and selective CCR4 small molecule antagonists.

[0004] Currently, the CCR4-related patents that have been applied for include WO2019090272A1 and WO2019147862A1, etc. Summary of the Invention

[0005] To overcome the defect of the single structure of CCR4 inhibitors in the prior art, this application provides a small molecule compound with a spiroheterocyclic structure that can be used as a CCR4 inhibitor. This type of compound has a potent antagonistic effect on the CCR4 receptor and excellent pharmacokinetic properties, and can be used to effectively treat or prevent CCR4-mediated diseases.

[0006] This application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0007]

[0008] Wherein:

[0009] G 1 is CR 8 or N;

[0010] G 2 is CR 9 or N;

[0011] G 3 is CR 10 or N;

[0012] E is , , , , or ;

[0013] Z is O, S, Se or NR a ;

[0014] Y is O, S, NR a or CR b R c ;

[0015] R a is H, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl or 3- to 12-membered heterocyclic group;

[0016] R b and R c are the same or different and are each independently selected from the group consisting of H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3- to 12-membered heterocyclic group;

[0017] R 1 is L-R 12 ;

[0018] L is a chemical bond, O, S, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, C 1-6 alkylene, C 3-8 cycloalkylene or 3- to 12-membered heteroalkylene, wherein the C 1-6 alkylene, C 3-8The subcycloalkyl group and the 3- to 12-membered heterocycloalkyl group are each independently optionally substituted by one or more substituents selected from hydroxy, amino, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl, and 3- to 12-membered heterocycloalkyl;

[0019] R 12 is selected from H, halogen, hydroxy, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, -NR k2 R k3 -, -C(O)R k4 -, -S(O) x R k1 -, -S(O) x NR k2 R k3 -, -C(O)OR k4 -, -C(O)NR k2 R k3 -, -NR k2 SO2R k1 -, -NR k2 C(O)R k4 -, -NR k2 C(O)OR k4 -, C 3-8 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, where the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocycloalkyl, C 6-10 aryl, and 5- to 10-membered heteroaryl are each independently optionally substituted by one or more R g substituents;

[0020] R 1a is NR k2 R k3 ;

[0021] Each R g is the same or different and is independently halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, cyano, carboxy, -NHC(O)R g1 -, -NHS(O)2R g2 -, -S(O)2R g2 -, -C(O)NR g3 Rg4 、 -S(O)2NR g3 R g4 、 -NR g3 R g4 、 C 3-8 cycloalkyl, 3 - to 8 - membered heterocyclic group, C 6-10 aryl or 5 - to 10 - membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 - to 8 - membered heterocyclic group, C 6-10 aryl and 5 - to 10 - membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl, and C 3-8 cycloalkyl;

[0022] R 2 and R 3 are the same or different and each independently selected from H, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl;

[0023] R 4 is H, D, C 1-6 alkyl, or C 3-8 cycloalkyl;

[0024] R 5 and R 6 are the same or different and each independently selected from H, D, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, and C 3-8 cycloalkyl;

[0025] Each R 7 is the same or different and each independently selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 3-8 cycloalkyl;

[0026] R 8 , R 9 and R 10 are the same or different and are each independently selected from H, halogen, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Any of a cycloalkyl group and a 3-12-membered heterocyclic group;

[0027] R 11 Selected from H, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHC(O)NR k2 R k3 、-NR k2 R k3 、-P(O)R k2 R k3 、-SF5、-C(O)R k4 、- C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 S02R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 , , C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-10 Aryl and 5-10 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 and C 3-8 The cycloalkyl group is substituted by one or more substituents;

[0028] Alternatively, R 4 and R 11 together with the atom to which it is attached form a C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl, wherein the C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more R h substituents;

[0029] Alternatively, when G 3 is CR 10 , R 10 and R 11 together with the atom to which it is attached form a C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl, wherein the C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more R h substituents;

[0030] Each R h is the same or different and is independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O) x R k1 , -S(O) x NR k2 R k3 , -NHC(O)NR k2 R k3 , -NR k2 R k3 , -P(O)R k2 R k3 , -SF5, -C(O)R k4 , - C(O)OR k4 , -C(O)NR k2 R k3 , -NR k2 SO2R k1 , -NR k2 C(O)R k4 , -NR k2 C(O)OR k4 , - NR k2 OR k4 , , C 3-8Any of a cycloalkyl group and a 3-12-membered heterocyclic group;

[0031] R k1 , R k2 , R k3 , R k4 , R k5 , R g1 , R g2 , R g3 and R g4 are the same or different, each independently selected from H, halogen, carboxyl, cyano, amino, C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C(O)R v and any one of a 5-10 membered heteroaryl group, wherein the C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl and 5-10 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 and C 3-8 The cycloalkyl group is substituted by one or more substituents;

[0032] R v Selected from halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-8 Cycloalkyl;

[0033] s is 1 or 2;

[0034] t is 0, 1, or 2;

[0035] p is 0 or 1;

[0036] q is 0 or 1;

[0037] m is 0, 1, 2, 3, 4, 5 or 6;

[0038] n is 0, 1, 2, 3 or 4;

[0039] k is 0, 1, 2, 3, or 4;

[0040] x is 1 or 2;

[0041] v is 1, 2, or 3;

[0042] h is 0 or 1;

[0043] Among them, the heteroatoms in the said hetero-substituted cyclic group, heterocyclic group and heteroaryl group can each independently be selected from one or more of O, N and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5.

[0044] In some embodiments, in the compound represented by formula (I),

[0045] R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、R g3 and R g4 are the same or different and are each independently selected from H, halogen, carboxyl, cyano, amino, C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group and a 5- to 10-membered heteroaryl group, and the C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group and a 5- to 10-membered heteroaryl group are each independently optionally substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl and C 3-8 cycloalkyl;

[0046] The definitions of the remaining substituents are as defined in general formula (I).

[0047] In some embodiments, in the compound represented by formula (I), where E is 、 or ; Z, Y, R 1 、R 2 、R 3 、s, t, p, q, m and n are as defined in general formula (I);

[0048] R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、R g3 and R g4 are the same or different and are each independently selected from H, halogen, carboxyl, cyano, amino, C 1-6 alkyl, C 3-8Any one of a cycloalkyl group, a 3- to 8-membered heterocyclic group, and a 5- to 10-membered heteroaryl group, said C 1-6 alkyl group, C 3-8 cycloalkyl group, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, oxo, cyano, amino, carboxyl, and C 3-8 cycloalkyl group;

[0049] The definitions of the remaining substituents are as defined in general formula (I).

[0050] In some embodiments, in the compound represented by formula (I), wherein E is , or ;

[0051] Z, R 1a , R 1 , R 2 , R 3 , v, h, p, q, m, and n are as defined in general formula (I).

[0052] In some embodiments, in the compound represented by formula (I), among the substituents, each "C 3-8 cycloalkyl group" is independently a C 3-8 saturated cycloalkyl group, such as a C 4-6 monocyclic saturated cycloalkyl group, a C 5-8 spirocyclic saturated cycloalkyl group, a C 5-8 fused-ring saturated cycloalkyl group, or a C 5-8 bridged-ring saturated cycloalkyl group.

[0053] In some embodiments, in the compound represented by formula (I), among the substituents, each "C 3-8 cycloalkylene group" is independently a C 3-8 saturated cycloalkylene group, such as a C 4-6 monocyclic saturated cycloalkylene group, a C 5-8 spirocyclic saturated cycloalkylene group, a C 5-8 fused-ring saturated cycloalkylene group, or a C 5-8 bridged-ring saturated cycloalkylene group.

[0054] In some embodiments, in the compound represented by formula (I), among the substituents, each "C 4-8 cycloalkyl group" is independently a C 4-8 saturated cycloalkyl group, such as a C 4-6 monocyclic saturated cycloalkyl group, a C 5-8 spirocyclic saturated cycloalkyl group, a C 5-8Fused ring saturated cycloalkyl or C 5-8 Bridged ring saturated cycloalkyl.

[0055] In some embodiments, in the compound of formula (I), among each substituent, each "3-12 membered heterocyclic group" is independently a 3-12 membered saturated heterocycloalkyl group, such as a 3-6 membered monocyclic saturated heterocycloalkyl group, a 5-12 membered spiro saturated heterocycloalkyl group, a 5-12 membered fused ring saturated heterocycloalkyl group or a 5-12 membered bridged ring saturated heterocycloalkyl group.

[0056] In some embodiments, in the compound of formula (I), among each substituent, each "3-12 membered heteroannular group" is independently a 3-12 membered saturated heteroannular alkyl group, such as a 3-6 membered monocyclic saturated heteroannular alkyl group, a 5-12 membered spiro saturated heteroannular alkyl group, a 5-12 membered fused ring saturated heteroannular alkyl group or a 5-12 membered bridged ring saturated heteroannular alkyl group.

[0057] In some embodiments, in the compound of formula (I), among each substituent, each "3-8 membered heterocyclic group" is independently a 3-8 membered saturated heterocycloalkyl group, such as a 3-6 membered monocyclic saturated heterocycloalkyl group, a 5-8 membered spiro saturated heterocycloalkyl group, a 5-8 membered fused ring saturated heterocycloalkyl group or a 5-8 membered bridged ring saturated heterocycloalkyl group.

[0058] In some embodiments, in the compound of formula (I), among each substituent, each "5-8 membered heterocyclic group" is independently a 5-8 membered saturated heterocycloalkyl group, such as a 5-6 membered monocyclic saturated heterocycloalkyl group, a 5-8 membered spiro saturated heterocycloalkyl group, a 5-8 membered fused ring saturated heterocycloalkyl group or a 5-8 membered bridged ring saturated heterocycloalkyl group.

[0059] In some embodiments, the compound of formula (I) is a compound of formula (II), formula (III), formula (IV) or formula (V),

[0060]

[0061] wherein, G 1 , G 2 , G 3 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 11 , s, t, k, m and n are as defined in formula (I).

[0062] In some embodiments, the compound of formula (I) is a compound of formula (II-1), formula (III-1), formula (IV-1) or formula (V-1),

[0063]

[0064] wherein G 1 、G 2 、G 3 、Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 11 、s, t, k, m and n are as defined in formula (I).

[0065] In some embodiments, the compound of formula (I), formula (II), formula (III), formula (IV) or formula (V) is selected from any of the following options:

[0066] Option 1, G 1 is N, G 2 is N, G 3 is CR 10 ;

[0067] Option 2, G 1 is N, G 2 is CR 9 ,G 3 is N;

[0068] Option 3, G 1 is CR 8 ,G 2 is CR 9 ,G 3 is CR 10 ;

[0069] wherein R 8 、R 9 and R 10 are as defined in formula (I).

[0070] In some embodiments, the compound of formula (I) is a compound of formula (VI), formula (VII) or formula (VIII),

[0071]

[0072] wherein, E, R 4 、R5 and R 7 and R 10 and R 11 and R h and k are as defined in formula (I).

[0073] In some embodiments, the compound represented by formula (I) is a compound represented by formula (VI-1), formula (VII-1) or formula (VIII-1),

[0074]

[0075] wherein E, R 4 and R 5 and R 7 and R 10 and R 11 and R h and k are as defined in formula (I).

[0076] In some embodiments, for the compound represented by formula (VI), formula (VI-1), formula (VIII) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, R 4 is H or C 1-6 alkyl; R 10 is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl; R 11 is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -P(O)(CH3)2 and -SF5.

[0077] In some embodiments, for the compound represented by formula (VII) or formula (VII-1) or a pharmaceutically acceptable salt thereof, R h is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -P(O)(CH3)2 and -SF5.

[0078] In some embodiments, for the compound represented by formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, wherein E is , , , , , , , , , , , , or ; R 1 , R 1a , R 2 , R 3 , R b , R c , m and n are as defined in formula (I).

[0079] In some embodiments, a compound of formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, wherein E is , , , , or ; R 1 , R 2 , R 3 , R b , R c , m and n are as defined in formula (I).

[0080] In some embodiments, a compound of formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, wherein E is or ; R 1 , R 2 , R 3 , m and n are as defined in formula (I).

[0081] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, wherein R 1 is L-R 12 ; L is a chemical bond, -C(O)-, C 1-6 alkylene, C 3-8 cycloalkylene or a 3-8 membered heteroalkylene;

[0082] R12 is H, halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally substituted with one or more R g substituents;

[0083] Each R g is the same or different and is each independently halogen, hydroxyl, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, carboxyl, C 3-8 cycloalkyl and a 3- to 8-membered heterocyclic group.

[0084] In some embodiments, a compound of formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1) or a pharmaceutically acceptable salt thereof, wherein E is , , , , , , or ; R 1 and R 1a are both NR k2 R k3 ; R k2 and R k3 are the same or different and are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group and a 5- to 10-membered heteroaryl group, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 8-membered heterocyclic group and a 5- to 10-membered heteroaryl group are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl and C 3-8 cycloalkyl; R 2 , R 3 , m and n are as defined above.

[0085] In some embodiments, a compound of formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein E is , , , , , , or , R 2 , R 3 , m and n are as defined in any one of the above aspects, R 1 or R 1a is , , , , , , , or .

[0086] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein R 1 is , , , , , , , or .

[0087] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), 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.

[0088] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are both H.

[0089] In some embodiments, a compound of formula (I), formula (VI), formula (VII), formula (VIII), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein E is , , , , , , , , , , and .

[0090] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein R 5 is H or C 1-6 alkyl.

[0091] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

[0092] In some embodiments, a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein For , R 7A and R 7B are the same or different and each independently is halogen, C 1-6 alkyl or C 1-6 haloalkyl.

[0093] In some embodiments, a compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein is , R 7A and R 7B are the same or different and each independently is halogen.

[0094] In some embodiments, a compound represented by formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or a pharmaceutically acceptable salt thereof, wherein is .

[0095] In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below or their stereoisomers:

[0096] Table A

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[0098] In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table B below:

[0099] Table B

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[0101] In one aspect of the present invention, the compound represented by formula (I) is any one of the following compounds:

[0102] A stereoisomer, where the carbon atom marked with "*" represents the chiral site that generates the stereoisomer, and its retention time under the following conditions is 2.007 minutes: Chiral column: Daicel OJ, 25*250mm, 10μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; Flow rate: 100 mL / min;

[0103] A stereoisomer, where the carbon atom marked with "*" represents the chiral site that generates the stereoisomer, and its retention time under the following conditions is 3.547 minutes: Chiral column: Daicel OJ, 25*250mm, 10μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; Flow rate: 100 mL / min.

[0104] The test conditions for the above retention times are not limitations on the compound. As long as the determination is carried out under the above test conditions, the obtained retention time is the same as or within the error range of the above records, and the compound is a stereoisomer of the compound defined by the above retention time, it falls within the protection scope of the present invention.

[0105] Another aspect of the present application provides an isotope-labeled compound of the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), or the compounds shown in the foregoing Table A or Table B, and the isotope labeling is preferably deuterium (D or 2 H) substituting hydrogen ( 1 H).

[0106] Another aspect of the present application provides a compound of formula (IIA) or a salt thereof,

[0107]

[0108] where G 1 、G 2 、G 3 、R 2 、R 3 、R 4 、R 5 、R 7 、R 11 、k, m and n are as defined in formula (II).

[0109] On the other hand, the present application provides a compound represented by formula (IIB) or formula (IIC) or a salt thereof,

[0110] or

[0111] wherein R w is an amino protecting group. Preferably, R w is tert-butoxycarbonyl (Boc);

[0112] G 1 、G 2 、G 3 、R 2 、R 3 、R 4 、R 5 、R 7 、R 11 、k, m and n are as defined in formula (II).

[0113] The present invention also provides a compound represented by formula (B) or a salt thereof,

[0114]

[0115] wherein E1 is 、 、 、 、 or ;

[0116] R w is an amino protecting group. Preferably, R w is tert-butoxycarbonyl (Boc);

[0117] R w1 and R w2 are each independently a C1-C6 alkyl group, such as methyl;

[0118] L1 is a C1-C6 alkylene group, such as methylene;

[0119] G 1 、G 2 、G 3 、R 2 、R 3 、R 4 、R 5 、R 7 、R 11 、R k2 、k, m and n are as defined in any aspect of the present invention.

[0120] On the other hand, the present application provides the following compound or a salt thereof,

[0121] 、 、 、 。

[0122] On the other hand, the present application provides a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound, or the aforementioned isotope-labeled compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0123] On the other hand, the present application also provides the use of the compound represented by the aforementioned formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compound shown in the aforementioned Table A or Table B, or the aforementioned isotope-labeled compound, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of a drug for regulating CCR4.

[0124] On the other hand, the present application also provides the use of the compound represented by the aforementioned formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compound shown in the aforementioned Table A or Table B, or the aforementioned isotope-labeled compound, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of a drug for antagonizing CCR4.

[0125] The present application also provides the use of the compound represented by the aforementioned formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compound shown in the aforementioned Table A or Table B, or the aforementioned isotope-labeled compound, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, in the preparation of a drug for preventing and / or treating CCR4-mediated diseases or disorders; preferably, the diseases and disorders are diseases or disorders with high CCR4 expression.

[0126] The present application also provides the use of the compounds shown by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compounds shown by the foregoing Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, in the preparation of a drug for preventing and / or treating an autoimmune disease, an inflammatory disease or cancer; preferably, the use in the preparation of a drug for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0127] The present application also provides a method for antagonizing CCR4, which comprises administering a therapeutically effective amount of the compounds shown by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compounds shown by the foregoing Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions to a patient in need thereof.

[0128] The present application also provides a method for preventing and / or treating a CCR4-mediated disease or disorder, which comprises administering a therapeutically effective amount of the compounds shown by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compounds shown by the foregoing Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions to a patient in need thereof.

[0129] The present application also provides a method for preventing and / or treating an autoimmune disease, an inflammatory disease or cancer, which comprises administering a therapeutically effective amount of the compounds shown by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the compounds shown by the foregoing Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions to a patient in need thereof.

[0130] The present application also provides a method for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease, which comprises administering to a patient in need a therapeutically effective amount of the foregoing compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the foregoing compounds shown in Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions.

[0131] The present application also provides the foregoing compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the foregoing compounds shown in Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, for use as a medicament.

[0132] The present application also provides the foregoing compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the foregoing compounds shown in Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, for use as a CCR4 modulator.

[0133] The present application also provides the foregoing compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), the foregoing compounds shown in Table A or Table B, or the foregoing isotope-labeled substances, or pharmaceutically acceptable salts thereof, or the foregoing pharmaceutical compositions, for use as a CCR4 antagonist.

[0134] The present application also provides a use of a compound represented by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), a compound shown in the foregoing Table A or Table B, or the foregoing isotope-labeled substance, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, as a drug for preventing and / or treating CCR4-mediated diseases or disorders; preferably, the diseases and disorders are diseases or disorders with high CCR4 expression.

[0135] The present application also provides a use of a compound represented by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), a compound shown in the foregoing Table A or Table B, or the foregoing isotope-labeled substance, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, as a drug for preventing and / or treating autoimmune diseases, inflammatory diseases or cancers.

[0136] The present application also provides a use of a compound represented by the foregoing formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (II-1), formula (III-1), formula (IV-1), formula (V-1), formula (VI-1), formula (VII-1) or formula (VIII-1), a compound shown in the foregoing Table A or Table B, or the foregoing isotope-labeled substance, or a pharmaceutically acceptable salt thereof, or the foregoing pharmaceutical composition, as a drug for preventing and / or treating arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0137] In some embodiments, the CCR4-mediated disease is an autoimmune disease, an inflammatory disease or a cancer.

[0138] In some embodiments, the CCR4-mediated disease is arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

[0139] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0140] In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound, or its isotope-labeled compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound, or its isotope-labeled compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound, or its isotope-labeled compound, or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound, or its isotope-labeled compound, or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of one or more pharmaceutically acceptable excipients. 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.

[0142] When used as a drug, the compounds of the present application can be administered in the form of a pharmaceutical composition. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area being treated. They can be administered locally (e.g., transdermally, dermally, ophthalmically, and mucosally including intranasally, vaginally, and rectally), by the pulmonary route (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheally, intranasally, orally, or parenterally. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranially, e.g., intrathecally or intraventricularly. They can be administered parenterally in a single large dose form, or can be administered, for example, by means of a continuous perfusion pump.

[0143] In preparing the compositions of the present application, the active ingredient is usually admixed with excipients, and the compositions can be in the form of tablets, pills, powders, lozenges, cachets, capsules, 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.

[0144] The "excipients" referred to in the present application mean components other than the active ingredient, and include, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants, etc.

[0145] On the other hand, the pharmaceutically acceptable salts of the compounds described in the present application 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 (such as a carboxyl group) and a basic center (such as an amino group), they can also form inner salts.

[0146] On the other hand, the compounds of the present application may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereoisomers, (D)- isomers, (L)- isomers, racemic mixtures and other mixtures, as well as enantiomer- or diastereoisomer- enriched mixtures, all of these mixtures are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present application.

[0147] The "plural" indicating the number of substituents or heteroatoms means 2, 3, 4 or 5.

[0148] In the chemical structure of the compounds described in the present application, the bond " " indicates an unspecified configuration, and " " or " " indicates an absolute configuration. That is, if there are chiral isomers in the chemical structure, the bond " " can be " " or " ", or it can contain both " " and " " configurations.

[0149] The bond " " indicates an unspecified configuration, including cis (E) or trans (Z) configurations.

[0150] In addition, the compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present application are within the scope of the present application. The name of a compound named in a single way does not exclude any tautomer.

[0151] This application also includes isotopically labeled compounds of this application that have the same structures as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds of this application 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 Cl, etc. All isotopic compositions of the compounds of this application, whether radioactive or not, are included within the scope of this application.

[0152] Unless otherwise specified, when a position is specifically designated as deuterium (D), that position should be understood to have a deuterium abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 10% deuterium incorporation). The deuterium in the compounds of the examples can have an abundance greater than the natural abundance of deuterium by at least 1000-fold, at least 2000-fold, at least 3000-fold, at least 4000-fold, at least 5000-fold, at least 6000-fold, or higher. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in the preparation of deuterated compounds, or they can be synthesized using conventional techniques with deuterating reagents, including but not limited to deuterated borane, tetrahydrofuran solution of trideuterated borane, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, etc.

[0153] The "therapeutically effective amount" of the present application refers to the amount of an active compound or drug that a researcher, veterinarian, physician, or other clinician, etc. seeks in an organization, system, animal, individual, or human to cause a biological or medical response, and it includes one or more of the following: (1) Preventing diseases: For example, preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but has not yet experienced or shown the disease pathology or symptoms. (2) Suppressing diseases: For example, suppressing a disease, disorder, or condition in an individual who is experiencing or showing the pathology or symptoms of the disease, disorder, or condition (i.e., preventing the further development of the pathology and / or symptoms). (3) Alleviating diseases: For example, alleviating a disease, disorder, or condition in an individual who is experiencing or showing the pathology or symptoms of the disease, disorder, or condition (i.e., reversing the pathology and / or symptoms). For a drug or a pharmacological active agent, the "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to routine tests.

[0154] "Pharmaceutically acceptable" in the present application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with the tissues of a patient within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction, or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0155] The "patient" of the present application refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0156] Term Definitions and Explanations

[0157] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0158] In the present application, " " or " " means that the corresponding group is connected to other fragments and groups in the compound through this " ", " ".

[0159] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C1-6 alkyl). Non-limiting examples of alkyl 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 isomers thereof, etc. The alkyl can be substituted or unsubstituted.

[0160] The term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two H atoms from a saturated straight-chain or branched-chain hydrocarbon group, which may contain 1-20 carbon atoms, preferably includes 1-12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably includes 1-6 (e.g., 1, 2, 3, 4, 5, and 6) carbon atoms. Non-limiting examples include methylene (-CH2-), ethylene (-CH2CH2-), etc. The alkylene can be substituted or unsubstituted.

[0161] The term "alkoxy" refers to -O-(alkyl), where the alkyl is defined as described herein. Preferably, an alkoxy group contains 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C 1-12 alkoxy), and more preferably an alkoxy group contains 1 to 6 carbon atoms (C 1-6 alkoxy). Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, and butoxy. The alkoxy can be substituted or unsubstituted.

[0162] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring contains 3 to 20 carbon atoms, preferably contains 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0163] The term "spiroalkyl" refers to a polycyclic group having 5 to 20 members, in which each monocyclic ring in the system shares a carbon atom (referred to as a spiro atom), and which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spiroalkyls are classified into monospiroalkyls, dispiroalkyls, or polyspiroalkyls according to the number of spiro atoms shared between rings, and monospiroalkyls and dispiroalkyls are preferred. More preferably, they are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroalkyls. Non-limiting examples of spiroalkyls include:

[0164] .

[0165] The term "fused cycloalkyl" refers to a fully carbonaceous polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyls, with bicyclic or tricyclic being preferred, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic alkyls. Non-limiting examples of fused cycloalkyls include:

[0166] .

[0167] The term "bridged cycloalkyl" refers to a fully carbonaceous polycyclic group having 5 to 20 members, in which any two rings share two non-directly connected carbon atoms, and which may contain one or more double bonds. It is preferably 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 cycloalkyls, with bicyclic, tricyclic, or tetracyclic being preferred, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyls include:

[0168]

[0169] The cycloalkyl rings include cycloalkyls (including monocyclic, spiro, fused, and bridged) as described herein fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl. Non-limiting examples include , , , etc.; preferably and . The cycloalkyl may be substituted or unsubstituted.

[0170] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), but excluding ring moieties of -O-O-, -O-S- or -S-S-, 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, where 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), where 1 - 3 (e.g., 1, 2 and 3) are heteroatoms; still more preferably, it contains 3 to 6 ring atoms, where 1 - 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, where 1 - 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiroheterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.

[0171] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, where each monocyclic ring in the system shares one atom (called the spiro atom), one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, said sulfur being optionally oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). Spiroheterocyclic groups are classified into monospiroheterocyclic groups, dispiroheterocyclic groups or polyspiroheterocyclic groups according to the number of spiro atoms shared between rings, preferably monospiroheterocyclic groups and dispiroheterocyclic groups. More preferably, they are 3 - membered / 5 - membered, 3 - membered / 6 - membered, 4 - membered / 4 - membered, 4 - membered / 5 - membered, 4 - membered / 6 - membered, 5 - membered / 5 - membered or 5 - membered / 6 - membered monospiroheterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

[0172] 。

[0173] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 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 group. Non-limiting examples of fused heterocyclic groups include:

[0174] .

[0175] 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:

[0176] .

[0177] 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:

[0178] and wait.

[0179] The heterocyclic group may be substituted or unsubstituted.

[0180] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (fused polycyclic rings are rings that share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0181] and . The aryl may be substituted or unsubstituted.

[0182] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclic, or cycloalkyl ring as described herein, wherein the ring attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0183] and . The heteroaryl may be substituted or unsubstituted.

[0184] The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclic", "aryl", and "heteroaryl" etc. herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0185] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atoms, or residues derived by removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "subcycloalkyl", "subaryl", "subheterocyclic", "subheteroaryl".

[0186] The term "amino protecting group" refers to a group suitable for selectively blocking the reaction site of N in a compound so that chemical reactions can occur selectively during synthesis, and the amino protecting group can be removed in subsequent processes. Preferably, the amino protecting group is selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), formyl, acetyl, benzoyl, triphenylmethyl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn), etc.

[0187] The term "haloalkyl" means that an alkyl group is substituted by one or more halogen atoms, where the alkyl group is as defined herein.

[0188] The term "haloalkoxy" means that an alkoxy group is substituted by one or more halogen atoms, where the alkoxy group is as defined herein.

[0189] The term "hydroxyalkyl" means that an alkyl group is substituted by one or more hydroxyl groups, where the alkyl group is as defined herein.

[0190] The term "halogen" refers to F, Cl, Br or I.

[0191] The term "hydroxyl" refers to -OH.

[0192] The term "amino" refers to -NH2.

[0193] The term "cyano" refers to -CN.

[0194] The term "nitro" refers to -NO2.

[0195] The term "oxo group" or "oxo" refers to "=O".

[0196] The term "carboxyl" refers to -C(O)OH.

[0197] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclic alkyl group is substituted by an alkyl group and the case where the heterocyclic alkyl group is not substituted by an alkyl group.

[0198] "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.

[0199] In the present invention, the "modulator" or "antagonist" can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of CCR4 regulation or antagonism effects.

[0200] 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.

[0201] The reagents and raw materials used in the present invention are commercially available.

[0202] Beneficial Effects

[0203] The present application provides a small molecule compound with a spiroheterocyclic structure, which can be used as a CCR4 antagonist. This type of compound or pharmaceutical composition has a potent antagonistic effect on the CCR4 receptor and can be used to effectively treat or prevent CCR4-mediated diseases. DETAILED DESCRIPTION

[0204] 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.

[0205] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0206] 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.

[0207] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 MHz NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0208] Mass spectra (MS) were measured by Waters 2767 HPLC / Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC / Waters liquid chromatography-mass spectrometry.

[0209] Chiral HPLC analysis was performed using Shimadzu LC-20AD.

[0210] The thin layer chromatography silica gel plate uses GF254 silica gel plate produced by Chenghua (Shanghai) Co., Ltd. The specifications of the silica gel plate used in thin layer chromatography (TLC) are 0.2~0.25mm, and the specifications used for thin layer chromatography separation and purification products are 0.4~0.5mm.

[0211] Column chromatography generally uses 100~200 mesh silica gel as the carrier of Chenghua Chemical (Shanghai) Co., Ltd.

[0212] Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatography were used for high performance liquid preparation.

[0213] Gilson GX-281 preparative HPLC was used for chiral separation column chromatography.

[0214] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0215] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 liter.

[0216] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0217] Unless otherwise specified in the examples, the reaction temperature is room temperature, ranging from 20°C to 30°C.

[0218] Those skilled in the art should understand that the separated chiral compounds can be distinguished by the order of retention time in a chiral chromatographic column. Therefore, the chiral compounds separated according to the order of retention time are correspondingly distinguished by number suffixes such as P1, P2, etc. That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a 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 existing forms of the absolute configuration. The absolute configuration of the compounds with number suffixes P1 and P2 shall be subject to the absolute configuration objectively corresponding to a specific retention time.

[0219] English abbreviations and corresponding Chinese names:

[0220] Reagent Abbreviation Reagent Chinese Name <![CDATA[NaBH(OAc)3]]> Sodium triacetoxyborohydride <![CDATA[NaHCO3]]> Sodium bicarbonate FA Trifluoroformic acid <![CDATA[(Boc)2O]]> Di-tert-butyl dicarbonate DMP Dimethyl phthalate <![CDATA[Cs2CO3]]> Cesium carbonate Dess-Martin Dess-Martin THF Tetrahydrofuran <![CDATA[NH4Cl]]> Ammonium chloride ACN Acetonitrile <![CDATA[H2O]]> Water PE Petroleum ether EA / EtOAc Ethyl acetate MeOH Methanol <![CDATA[DCM / CH2Cl2]]> Dichloromethane DMSO Dimethyl sulfoxide TFA Trifluoroacetic acid DIEA N,N-Diisopropylethylamine SFC Supercritical fluid chromatography

[0221] Synthesis of Intermediate A

[0222]

[0223] The first step

[0224] Under nitrogen protection, triethylamine (4.60 g, 45.54 mmol) was added to a solution of compound A-1 (3.00 g, 15.19 mmol) and compound A-2 (3.04 g, 15.99 mmol) in ethanol (140 mL). The resulting reaction solution was stirred at room temperature for 16 hours. The reaction was completed. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a silica gel column (petroleum ether:ethyl acetate = 1:0 - 10:1) to obtain compound A (4.70 g, yield: 88%).

[0225] MS m / z (ESI): 352.1 [M+1] + 。

[0226] Example 1 (Compound 1)

[0227]

[0228] The first step

[0229] Under the condition of 0 °C, hydrochloric acid dioxane solution (30 mL) was added to compound 1-1 (3 g, 12.38 mmol), and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product of compound 1-2 (6 g).

[0230] MS m / z (ESI): 143.1 [M+1] +

[0231] The second step

[0232] At room temperature, dissolve compound 1-2 (2.21 g, 12.37 mmol) in dimethyl sulfoxide (15 mL). Add intermediate A (2.90 g, 8.25 mmol) and cesium carbonate (6.72 g, 20.62 mmol) thereto, and then stir the reaction at 120 °C for 16 h. After the reaction is completed, pour the reaction solution into water (100 mL) and filter. Extract the filtrate three times with dichloromethane (50 mL), wash it with saturated brine (100 mL), and then dry it over anhydrous sodium sulfate. After mixing the filter cake and the extract, concentrate under reduced pressure to obtain crude compound 1-3 (2.98 g).

[0233] MS m / z (ESI): 456.1 [M+1] + 。

[0234] The third step

[0235] At room temperature, dissolve compound 1-3 (2.98 g, 6.52 mmol) in tetrahydrofuran (30 mL), protect it with nitrogen and cool it to 0 °C. Then add borane dimethyl sulfide solution (12 mL), and then stir the reaction at room temperature for 16 h. After the reaction is completed, quench the reaction solution with methanol (20 mL), concentrate under reduced pressure to obtain a crude product, and purify it by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1-4 (900 mg).

[0236] MS m / z (ESI): 442.1 [M+1] + 。

[0237] The fourth step

[0238] At room temperature, dissolve compound 1-4 (88 mg, 0.2 mmol) in acetonitrile (3 mL). Add compound tert-butyl 2-(iodomethyl)azetidine-1-carboxylate (65 mg, 0.22 mmol) and potassium carbonate (83 mg, 0.6 mmol) thereto, and then stir the reaction at 80 °C for 16 h. After the reaction is completed, concentrate the reaction solution under reduced pressure to obtain a crude product, and then purify it by silica gel column chromatography (dichloromethane:methanol = 5:1) to obtain compound 1-5 (60 mg).

[0239] MS m / z (ESI): 611.2 [M+1] + 。

[0240] The fifth step

[0241] At 0 °C, hydrochloric acid dioxane solution (1 mL) was added to compound 1-5 (60 mg, 0.098 mmol), and the mixture was stirred at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain compound 1 (40 mg).

[0242] 1 H NMR (400 MHz, D2O) δ 7.48 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.26(d, J = 8.3 Hz, 1H), 5.43 (d, J = 7.2 Hz, 1H), 4.84 (s, 1H), 4.12 (dt, J =21.4, 10.2 Hz, 4H), 3.97 – 3.74 (m, 4H), 3.48 – 3.17 (m, 2H), 2.91 (d, J =43.6 Hz, 2H), 2.60 (s, 1H), 2.43 (t, J = 10.5 Hz, 1H), 2.32 (s, 3H), 1.50 (d,J = 7.0 Hz, 3H).

[0243] MS m / z (ESI): 511.3 [M+1] + 。

[0244] Example 2 (Compound 2)

[0245]

[0246] The first step

[0247] tert-Butyl 3-formylazetidine-1-carboxylate (35 mg, 0.19 mmol) was added to a solution of 1-4 (80 mg, 0.18 mmol) in methanol (3 mL), and the mixture was stirred for 2 h. Then, NaBH(OAc)3 (192 mg, 0.91 mmol) was added, and the mixture was stirred at 50 °C for 16 h. After the reaction was completed, the organic solvent was removed by concentration under reduced pressure. Then, DCM (20 mL) was added, and saturated NaHCO3 solution was added until the pH reached 6-7. Then, the mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by a CombiFlash rapid preparative instrument with an eluent system (MeOH:DCM = 5%) to obtain compound 2-1 (84 mg).

[0248] MS m / z (ESI): 611.3[M+1] + 。

[0249] The second step

[0250] Dissolve 2-1 (84 mg, 0.14 mmol) in DCM (2 mL), add TFA (1 mL) at 0 °C, and stir the reaction at 0 °C for 45 min. After the reaction is completed, concentrate the reaction solution under reduced pressure, combine the small-scale tests, adjust the pH to 7-8, and obtain the crude product. Compound 2 (32.68 mg) is obtained by Prep-HPLC (ACN:H2O (10 mM NH4HCO3) = 45-60%).

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 8.4Hz, 1H), 7.43 – 7.30 (m, 2H), 5.41 (q, J = 7.1 Hz, 1H), 3.89 – 3.46 (m, 10H),3.20 (s, 2H), 2.72 (d, J = 44.0 Hz, 1H), 2.48 (s, 1H), 2.33 (d, J = 41.6 Hz,4H), 2.19 (s, 3H), 1.44 (d, J = 7.0 Hz, 3H).

[0252] MS m / z (ESI): 511.3 [M+1] + 。

[0253] Example 3 (Compound 14-P1)

[0254]

[0255] The first step

[0256] At room temperature, add compound 14-1 (438 mg, 1.71 mmol) and DIEA (442 mg, 3.42mmol) to a solution of intermediate A (400 mg, 1.14 mmol) in dimethyl sulfoxide (5 mL). Stir the reaction at 80 °C for 16 h. After the reaction is completed, concentrate the reaction solution under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 14-2 (640 mg).

[0257] MS m / z (ESI): 571.1 [M+1] + 。

[0258] The second step

[0259] Under ice-water bath conditions, add dioxane hydrochloride solution (5 mL) to 1,4-dioxane (5 mL) of compound 14-2 (640 mg, 1.12 mmol), and stir the reaction at room temperature for 2 h. After the reaction is completed, the reaction solution is filtered and dried under reduced pressure to obtain crude compound 14-3 (450 mg). This crude compound is directly used in the next step without purification.

[0260] MS m / z (ESI): 471.1 [M+1] + 。

[0261] The third step

[0262] At room temperature, add tert-butyl (2S)-2-(bromomethyl)azetidine-1-carboxylate (85.04 mg, 0.34 mmol), potassium carbonate (46.99 mg, 0.34 mmol), and sodium iodide (0.025 g, 0.17 mmol) to a solution of compound 14-3 (80 mg, 0.17 mmol) in acetonitrile (2 mL). Stir the reaction mixture at 82 °C for 4 h. Concentrate the reaction solution, and purify the residue by silica gel column chromatography (PE:EA = 1:0~5:1) to obtain compound 14-4 (71 mg).

[0263] MS m / z (ESI): 639.2 [M+1] + 。

[0264] The fourth step

[0265] At room temperature, add hydrochloric acid / 1,4-dioxane (2.4 g, 65.83 mmol) to a solution of compound 14-4 (60 mg, 0.094 mmol) in 1,4-dioxane (2 mL). Stir the reaction mixture at 25 °C for 2 h. Concentrate the reaction solution to obtain a crude product (60 mg). Purify the residue by preparative high performance liquid chromatography (column: SunFire C18 19 x 250 mm, 10 μm; ACN:H2O (0.1% FA) = 30-60%, UV: 214 nm) to obtain compound 14-P1 (6.4 mg).

[0266] 11H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 5.38 (t, J = 7.0 Hz, 1H), 4.30–4.20 (m, 1H), 3.88–3.84 (m, 1H), 3.73–3.67 (m, 1H), 3.58 (m, 2H), 3.50–3.45 (m, 1H), 3.22–3.06 (m, 3H), 2.70 – 2.58 (m, 1H), 2.36 (dd, J = 13.1, 4.7 Hz, 3H), 2.30 – 2.23 (m, 2H), 2.19 (s, 3H), 2.16 (s, 1H), 2.09 – 2.00 (m, 1H), 1.68 – 1.55 (m, 2H), 1.44 (d, J = 7.1 Hz, 3H), 1.41 – 1.19 (m, 2H).

[0267] MS m / z (ESI): 539.2 [M+1] + 。

[0268] Example 4 (Compound 16)

[0269]

[0270] The first step

[0271] At room temperature, Compound 14-3 (0.5 g, 1.06 mmol) and methyl 2-oxocyclopentanecarboxylate (0.23 g, 1.59 mmol) were added to methanol (10 mL). Then sodium cyanoborohydride (0.20 g, 3.18 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 65 o °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 0 - 20%) to obtain Compound 16-1 (0.46 g).

[0272] MS m / z (ESI): 596.0 [M+1] + 。

[0273] The second step

[0274] At room temperature, compound 16-1 (0.5 g, 1.02 mmol) was added to a mixed solvent of THF (6 mL), MeOH (3 mL) and water (2 mL), and then lithium hydroxide (0.122 g, 5.1 mmol) was added. The mixed solution was stirred at 50 o °C for 12 hours. The reaction solution was acidified to about pH = 7 with 1M hydrochloric acid, extracted with ethyl acetate (15 mL×3), the combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude product. The crude product was separated and purified by reverse-phase column chromatography (waters XB-C18 19 x 250 mm, 10 μm; ACN:H2O (10 mM NH4HCO3) = 35 - 50%, UV:214 nm) to obtain two components of compound 16P1 (275.18 mg) and 16P2 (88.44 mg). 16P1 and 16P2 are mixtures that may contain 2 or 3 or 4 isomers among 16-P1, 16-P2, 16-P3 and 16-P4.

[0275] 16P1:

[0276] MS m / z (ESI): 582.00 [M+1] + 。

[0277] 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.55 (t, J = 4.2 Hz, 1H), 7.44 (dd, J = 8.5, 1.0 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 5.37 (td, J = 6.9, 2.0 Hz, 1H), 3.85 (dd, J = 12.9, 3.0 Hz, 2H), 3.57 (t, J = 4.0 Hz, 2H), 3.18 – 3.04 (m, 2H), 2.94 (q, J = 7.5 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.37 (dt, J = 17.9, 6.8 Hz, 2H), 2.28 – 2.11 (m, 5H), 1.89 – 1.52 (m, 7H), 1.51 – 1.17 (m, 6H).

[0278] 16P2:

[0279] MS m / z (ESI): 582.00 [M+1] + 。

[0280] 1 H NMR (400 MHz, DMSO-d6) δ 13.33 (d, J = 29.8 Hz, 1H), 7.55 (d, J =2.0 Hz, 1H), 7.46 (dd, J = 8.4, 4.7 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.29(dd, J = 6.6, 1.9 Hz, 1H), 5.40 (dd, J = 12.0, 6.9 Hz, 1H), 4.07 – 3.83 (m,2H), 3.71 – 3.54 (m, 2H), 3.17 – 3.00 (m, 2H), 2.89 (d, J = 4.1 Hz, 1H), 2.70– 2.53 (m, 2H), 2.26 – 2.09 (m, 4H), 2.01 – 1.90 (m, 1H), 1.89 – 1.47 (m,8H), 1.45 (d, J = 7.0 Hz, 3H), 1.39 – 1.15 (m, 3H).

[0281] The third step

[0282] Compound 16P2 (88.44 mg, 0.15 mmol) was resolved by SFC to obtain 16P2-P1 (25.95 mg) and 16P2-P2 (27.87 mg). 16P2-P1 and 16P2-P2 are single-configuration molecules corresponding to one of the structures of 16-P1, 16-P2, 16-P3, and 16-P4.

[0283] SFC conditions:

[0284] Chiral column: Daicel OJ 25*250mm, 10μm;

[0285] Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55;

[0286] Flow rate: 100 mL / min

[0287] 16P2-P1 (Retention time: 2.007 minutes):

[0288] 11H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H),7.45 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.27 (d, J = 7.0Hz, 1H), 5.39 (p, J = 7.0 Hz, 1H), 3.95 (d, J = 13.1 Hz, 2H), 3.70 – 3.55 (m,2H), 3.08 (dt, J = 31.8, 11.3 Hz, 2H), 2.87 (t, J = 5.9 Hz, 1H), 2.55 (d, J =7.6 Hz, 2H), 2.16 (d, J = 27.9 Hz, 4H), 1.92 (d, J = 12.9 Hz, 1H), 1.81 –1.63 (m, 4H), 1.54 (d, J = 8.0 Hz, 3H), 1.45 (d, J = 7.1 Hz, 3H), 1.26 (d, J= 17.3 Hz, 1H).

[0289] MS m / z (ESI): 582.1[M+1] + .

[0290] 16P2-P2 (Retention time: 3.547 minutes):

[0291] 11H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 5.40 (dd, J = 14.1, 7.1 Hz, 1H), 4.00 – 3.84 (m, 2H), 3.71 – 3.52 (m, 2H), 3.20 – 2.99 (m, 2H), 2.89 (t, J = 5.9 Hz, 1H), 2.60 (s, 2H), 2.47 – 2.38 (m, 1H), 2.22 (d, J = 20.4 Hz, 4H), 1.92 (d, J = 12.2 Hz, 1H), 1.82 – 1.49 (m, 7H), 1.45 (d, J = 7.1 Hz, 3H), 1.38 – 1.13 (m, 2H).

[0292] MS m / z (ESI): 582.1[M+1] + .

[0293] Example 5 (Compound 27)

[0294]

[0295] The first step

[0296] At room temperature, compound 27-1 (7.15 g, 99.15 mmol) was added to a solution of compound 1-Boc-piperidine-4-carbaldehyde (42.29 g, 198.3 mmol) in DCM (65 mL). The reaction mixture was cooled to 0 °C, and TFA (35 mL) was slowly added thereto. The mixture was stirred at 0 °C for 0.5 h and then at room temperature for 20 h. After the reaction was complete, the reaction mixture was concentrated, and the residue was dissolved in DCM (65 mL) and cooled to 0 °C. TEA (50.16 g, 495.75 mmol) was slowly added thereto and stirred for 0.5 h. The pH of the reaction mixture was adjusted to 8, and then (Boc)2O (43.28 g, 198.3 mmol) was added. The reaction mixture was stirred at room temperature for 20 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (65 mL), and K2CO3 (27.41 g, 198.3 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, water (300 mL) was added to the reaction system to quench the reaction. The reaction mixture was extracted with DCM (350 mL × 3), and the combined organic phases were washed with water (300 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 45%-90%) to obtain compound 27-2 (15.36 g).

[0297] MS m / z (ESI): 286.2 [M+1] + 。

[0298] The second step

[0299] At room temperature, compound 27-2 (15.12 g, 47.68 mmol) was added to a solution of dioxane (60 mL). The reaction mixture was cooled to 0 °C, and HCl / dioxane (60 mL, 4 mol / L) was slowly added thereto. The mixture was stirred at 0 °C for 0.5 h and then at room temperature for 20 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain crude compound 27-3 (9.68 g).

[0300] MS m / z (ESI): 186.1 [M+1] + 。

[0301] The third step

[0302] At room temperature, intermediate A (450.6 mg, 1.16 mmol) was added to a DMSO (8 mL) solution of compound 27-3 (430.3 mg, 2.32 mmol). DIEA (450.1 mg, 3.48 mmol) was slowly added to the reaction mixture, and the mixture was stirred at 120 °C for 20 hours. The reaction was monitored by LCMS until completion. The reaction mixture was cooled to room temperature, and then water (10 ml) was added to quench the reaction. The reaction mixture was extracted with EtOAc (25 mL x 3), and the combined organic phases were washed with water (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to obtain compound 27-4 (600.3 mg).

[0303] MS m / z (ESI): 499.1 [M+1] + 。

[0304] The fourth step

[0305] At room temperature, compound 27-4 (770.6 mg, 1.39 mmol) was added to a DCM (8 mL) solution. The reaction mixture was cooled to 0 °C, and DMP (2.95 g, 6.95 mmol) was slowly added thereto. After the addition was complete, the reaction mixture was stirred at 0 °C for 0.5 hour and then at room temperature for 35 hours. The reaction was monitored by LCMS until completion. A saturated aqueous solution of sodium thiosulfate (25 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with EtOAc (35 mL x 3), and the combined organic phases were washed with water (35 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 27-5 (580.9 mg).

[0306] MS m / z (ESI): 497.1 [M+1] + 。

[0307] The fifth step

[0308] At room temperature, compound 27-5 (400.8 mg, 0.72 mmol) was added to a solution of methylamine hydrochloride (68.3 mg, 2.16 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (140.3 mg, 2.16 mmol) was slowly added to the reaction solution and stirred at room temperature for 20 hours. The complete reaction was monitored by LCMS. Water (10 mL) was added to the reaction solution to quench the reaction. The reaction solution was extracted with EtOAc (35 mL x 3). The combined organic phases were washed with water (35 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (DCM:MeOH = 8:1) to obtain compound 27-6 (320.6 mg).

[0309] MS m / z (ESI): 512.2 [M+1] + 。

[0310] Step 6

[0311] At room temperature, compound 27-6 (110.25 mg, 0.19 mmol) was added to a solution of 3-oxocyclobutanecarboxylic acid (65.15 mg, 0.57 mmol) in methanol (6 mL). The reaction mixture was stirred for 2 hours. The reaction solution was cooled to 0 °C. Sodium cyanoborohydride (36.61 mg, 0.57 mmol) was slowly added to the above reaction solution. The mixture was stirred at 0 °C for 0.5 hour and then at room temperature for 20 hours. The complete conversion of the reaction was monitored by LCMS. Water (5 ml) was added to the reaction system to quench the reaction. The reaction mixture was concentrated under reduced pressure until a solid precipitated, and then DMF (7 ml) was added to obtain a clear solution. The reaction solution was purified by reverse-phase chromatography column (H2O:MeOH = 65%-68%) to obtain a crude product. The crude product was further purified by preparative high-performance liquid chromatography (column: XBridge-C18 19 x 250 mm, 10 μm; mobile phase: ACN:H2O (10 mM NH4HCO3); gradient: 40-55%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 27 (33.08 mg).

[0312] MS m / z (ESI): 610.2 [M+1] + 。

[0313] 11H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 4.6Hz, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.23 (d, J = 6.7Hz, 1H), 5.35 (q, J = 7.1Hz, 1H), 4.43 (t, J = 15.5 Hz, 2H), 3.93 – 3.82 (m, 1H), 3.20 (d, J = 11.1Hz, 1H), 3.09 – 3.00 (m, 1H), 2.88 (s, 1H), 2.72 – 2.51 (m, 4H), 2.19 (s,5H), 1.97 (d, J = 33.4 Hz, 5H), 1.62 (d, J = 12.7 Hz, 1H), 1.44 (d, J = 7.1Hz, 8H), 1.18 – 0.52 (m, 3H).

[0314] Example 6 (Compound 26)

[0315]

[0316] The first step

[0317] Dissolve tert-butyl 3-formylazetidine-1-carboxylate (500 mg, 2.7 mmol) and 3-buten-1-ol (194 mg, 2.7 mmol) in dichloromethane (20 mL). Slowly add TFA (10 mL) under nitrogen protection and stir at room temperature for 16 h. Concentrate the solvent. Then add DCM (20 mL), Boc2O (601 mg, 2.75 mmol) and triethylamine (1.37 g, 13.5 mmol), and stir at room temperature for 3 h. After concentrating the DCM, add 10 mL of methanol and potassium carbonate (373 mg, 2.7 mmol), and stir at room temperature overnight. Monitor the reaction by LCMS until completion. Quench the reaction by adding water (50 mL), extract with DCM (50 x 3 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue with a CombiFlash rapid preparative instrument using an eluent system (PE:EA = 100:0 to 80:20) to obtain Compound 26-2 (500 mg).

[0318] MS m / z (ESI): 258.1 [M+1] + .

[0319] The second step

[0320] Compound 26-2 (420 mg, 1.63 mmol) was dissolved in DCM (5.0 mL), and TFA (1.0 mL) was added thereto. The reaction was stirred at room temperature for 3 h. After the reaction solution was concentrated under reduced pressure, crude product 26-3 (724 mg) was obtained and directly subjected to the next step.

[0321] MS m / z (ESI): 158.1 [M+1] + 。

[0322] The third step

[0323] Compound 26-3 (257 mg, 1.63 mmol) and intermediate A (516 mg, 1.47 mmol) were dissolved in DMSO (20.0 mL), and Cs2CO3 (2.7 g, 8.16 mmol) was added thereto. The reaction was stirred at 120 °C for 1 h and then at 100 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with water, and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by CombiFlash rapid preparative instrument with an eluent system (EtOAc: PE = 20-95%) to obtain compound 26-4 (505 mg).

[0324] MS m / z (ESI): 471.1 [M+1] + 。

[0325] The fourth step

[0326] Compound 26-4 (505 mg, 1.07 mmol) was dissolved in DCM (5.0 mL), and Dess-Martin (908 mg, 2.14 mmol) was added thereto. The reaction was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. Then it was purified by CombiFlash rapid preparative instrument with an eluent system (MeOH: CH2Cl2 = 0-10%) to obtain compound 26-5 (853 mg).

[0327] MS m / z (ESI): 469.1 [M+1] + 。

[0328] The fifth step

[0329] At room temperature, dissolve compound 26-5 (300 mg, 0.64 mmol) in methanol (1 mL), add methylamine hydrochloride (65 mg, 0.96 mmol) and sodium cyanoborohydride (100 mg, 1.6 mmol) thereto, and then stir the reaction at 20 °C for 16 h. Pour the reaction solution into water, extract with ethyl acetate (50 mL×3), combine the organic layers, wash, dry, and concentrate under reduced pressure to obtain compound 26-6 (306 mg).

[0330] MS m / z (ESI): 512.2[M+1] + 。

[0331] Step 6

[0332] At room temperature, dissolve compound 26-6 (80 mg, 0.16 mmol) in methanol (1 mL), add compound 3-oxo-1-methyl-cyclobutanecarboxylic acid (41 mg, 0.32 mmol) and sodium cyanoborohydride (20 mg, 0.32 mmol) thereto. Stir the reaction mixture at 60 °C for 16 h. After the reaction is completed, concentrate the reaction solution under reduced pressure and purify it by preparative high performance liquid chromatography (Prep-HPLC: XBridge-C18 19 x 250 mm, 10 μm; ACN:H2O (10 mM NH4HCO3)=35-50%, UV: 214 nm) to obtain compound 26 (66 mg).

[0333] MS m / z (ESI): 596.1 [M+1] + 。

[0334] 11H NMR (400 MHz, DMSO-d6) δ 7.56 – 7.45 (m, 2H), 7.40 – 7.29 (m, 2H), 5.42 (t, J = 7.2 Hz, 1H), 3.97 – 3.74 (m, 3H), 3.64 (s, 2H), 3.51 (s, 1H), 3.10 (s, 1H), 2.83 (s, 1H), 2.67 (s, 1H), 2.42 (s, 1H), 2.18 (d, J = 1.4 Hz, 4H), 2.01 (q, J = 7.5, 5.8 Hz, 3H), 1.91 – 1.77 (m, 1H), 1.72 (s, 1H), 1.60 (s, 1H), 1.43 (d, J = 7.0 Hz, 5H), 1.32 (d, J = 2.2 Hz, 1H), 1.30 – 1.21 (m, 3H), 0.99 (d, J = 12.3 Hz, 1H).

[0335] Example 7 (Compound 39)

[0336]

[0337] The first step

[0338] At room temperature, dissolve Compound 26-6 (70 mg, 0.14 mmol) in methanol (1 mL), add Compound 3-oxo-1-cyclohexanecarboxylic acid (59.70 mg, 0.42 mmol) and acetic acid (8.41 mg, 0.14 mmol) thereto, stir at 60 °C for 30 minutes, then add sodium cyanoborohydride (26.39 mg, 0.42 mmol) and continue to stir at 60 °C for 16 hours. Concentrate the reaction solution under reduced pressure and purify it by reverse-phase separation (water (0.5% FA): methanol = 1:1) to obtain the crude product. The crude product is purified by preparative high-performance liquid chromatography (column: YMC-Actus Triart C18 150 x 20.0 mm I.D.; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 35 - 50%; wavelength: 214 nm) to obtain Compound 39 (7.48 mg).

[0339] MS m / z (ESI): 610.2 [M+1] + .

[0340] 11H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.39 – 7.30 (m, 2H), 5.41 (m, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 3.67 (m, 2H), 3.56 (m, 2H), 2.67 (m, 3H), 2.28 (m, 1H), 2.17 (m, 3H), 2.16 – 2.07 (m, 3H), 1.79 (m, 3H), 1.58 (s, 5H), 1.43 (d, J = 7.2 Hz, 3H), 1.38 – 1.12 (m, 4H), 0.97 (m, 1H).

[0341] Example 8 (Compound 40)

[0342]

[0343] The first step

[0344] At room temperature, dissolve Compound 26-6 (70 mg, 0.14 mmol) in methanol (1 mL), add S-3-oxocyclopentanecarboxylic acid (53.81 mg, 0.42 mmol) and acetic acid (8.41 mg, 0.14 mmol), stir at 60 °C for 2 hours, add sodium cyanoborohydride (26.39 mg, 0.42 mmol), and continue to stir at 60 °C for 16 hours. After the reaction is completed, pour the reaction solution into water (10 mL), extract with ethyl acetate (10 mL × 3), wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated by silica gel column chromatography (methylene chloride:methanol = 5:3) to obtain crude Compound 40, and then purified by preparative high performance liquid chromatography (column: YMC-Actus Triart C18 150 x 20.0 mm I.D.; mobile phase: acetonitrile-water (0.1% ammonium bicarbonate); gradient: 30-50%; wavelength: 214 nm) to obtain two components, 40P1 (3.55 mg) and 40P2 (9.0 mg). 40P1 and 40P2 are mixtures that may contain 2 or 3 or 4 isomers among 40-P1, 40-P2, 40-P3, 40-P4, 40-P5, 40-P6, 40-P7 and 40-P8.

[0345] 40P1:

[0346] MS m / z (ESI): 596.19 [M+1] + 。

[0347] 1 1H NMR (400 MHz, CDCl3) δ 7.38–7.32 (m, 1H), 7.21 (m, 1H), 7.18 (m, 1H), 5.53 (m, 1H), 5.43 (m, 1H), 4.08 (m, 1H), 3.82 (m, 2H), 3.65–3.54 (m, 2H), 3.39 (m, 1H), 3.19 (m, 1H), 3.06 (m, 1H), 2.95 (m, 1H), 2.61 (s, 1H), 2.41 (d, J = 2.4 Hz, 2H), 2.29 (d, J = 0.8 Hz, 3H), 2.03 (s, 4H), 1.72 (m, 5H), 1.51 (d, J = 6.8 Hz, 3H).

[0348] 40P2:

[0349] MS m / z (ESI): 596.19 [M+1] + 。

[0350] 1 1H NMR (400 MHz, DMSO-d6) δ 7.52 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 – 7.30 (m, 2H), 5.41 (m, 1H), 3.90 (s, 1H), 3.81 (m, 1H), 3.68 (m, 2H), 3.00 (m, 1H), 2.82 (m, 1H), 2.66 (m, 1H), 2.54 (m, 1H), 2.17 (s, 3H), 2.11 (d, J = 6.0 Hz, 2H), 1.97 (m, 1H), 1.82 – 1.69 (m, 3H), 1.64 – 1.48 (m, 4H), 1.43 (d, J = 7.2 Hz, 3H), 1.05 (m, 1H).

[0351] Example 9 (Compound 41)

[0352]

[0353] The first step

[0354] At room temperature, dissolve compound 26-6 (50 mg, 0.1 mmol) in dichloromethane (2 mL), add compound acetoxyacetyl chloride (27 mg, 0.20 mmol) and triethylamine (30 mg, 0.30 mmol), and then stir the reaction at 20 °C for 16 h. Pour the reaction solution into water, extract it with ethyl acetate (5 mL×3), combine the organic layers, wash, dry, and concentrate under reduced pressure to obtain compound 41-1 (60 mg).

[0355] MS m / z (ESI): 584.2[M+1] + 。

[0356] The second step

[0357] At room temperature, dissolve compound 41-1 (80 mg, 0.16 mmol) in a mixed solvent of THF:H2O = 1:1 (1 mL), add lithium hydroxide (41 mg, 0.32 mmol), and then stir the reaction at 20 °C for 16 h. After the reaction is completed, concentrate the reaction solution under reduced pressure. Purify the residue by high performance liquid chromatography to obtain compound 41 (9.2 mg).

[0358] MS m / z (ESI): 542.1 [M+1] + 。

[0359] 1 1H NMR (400 MHz, DMSO-d6) δ 7.53 (dd, J = 5.1, 2.1 Hz, 1H), 7.48 (dd,J = 8.3, 1.2 Hz, 1H), 7.41 – 7.30 (m, 2H), 5.42 (s, 1H), 4.55 – 4.34 (m, 2H),4.15 (s, 1H), 4.04 (d, J = 5.4 Hz, 1H), 3.92 (s, 1H), 3.81 (t, J = 8.6 Hz,1H), 3.70 (s, 3H), 2.71 (t, J = 3.3 Hz, 3H), 2.56 (s, 1H), 2.17 (s, 3H), 1.57(d, J = 59.2 Hz, 2H), 1.43 (d, J = 7.1 Hz, 4H), 1.33 – 1.18 (m, 2H).

[0360] Biological test

[0361] Test Example 1 Calcium flux experiment of HEK293-CCR4 cells of the compounds disclosed in the present invention

[0362] Add 20 μL of the coating solution at 50 μg / mL to a 384-well cell plate (Greiner, 781090). After pre-incubating at 37°C for 2 hours or overnight at 4°C, discard the coating solution and wash with sterile water. Dilute HEK293-CCR4 cells to 1 × 106 cells / mL with the culture medium (DMEM + 10% FBS + 300 μg / mL G418 + BS 2 μg / mL + 1% PS), and add 20 μL per well to the above-washed 384-well cell plate. Incubate overnight in a 5% CO2, 37°C incubator, then remove the cell culture medium. Add 20 μL of the experimental buffer (20 mM HEPES, 1×HBSS, 0.5% BSA) and 20 μL of the 2× Fluo-4 detection reagent (Invitrogen, F10471, final concentration 4 μM, containing 2.5 mM Probenecid) to each well in sequence, place it in a 37°C incubator for 50 min, and then let it stand at room temperature for 10 min. Gradient-dilute CCL17 (also known as thymus and activation-regulated chemokine (TARC), purchased from GenScript) (final concentration 1 μM, 4-fold dilution, 10 concentrations) with the experimental buffer and the above cell plate, place the pipette tips into the FLIPR instrument respectively, start the instrument, transfer 10 μL of the agonist to the cell plate, read the value, and calculate the EC80.

[0363] Prepare the test compound at a final concentration of 3 μM, 10 concentrations, 3-fold dilution, in duplicate wells, with the final concentration of DMSO being 0.5%. Add 20 μL of the experimental buffer to the cell culture plate from which the medium has been removed, then add 20 μL of the 2× Fluo-4 detection reagent and 10 μL of the test compound, place it in a 37°C incubator for 50 min, and then let it stand at room temperature for 10 min. Start the FLIPR instrument, transfer 10 μL of the 6× EC80 agonist working solution to the cell plate, read the value, and calculate the inhibition rate IC of each compound according to the following formula 50 :

[0364] Antagonist inhibition rate: Inhibition rate % = 100 - (RLU - LC) / (DMSO - LC) * 100

[0365] RLU: Relative light absorption value, from 1 to the maximum allowable reading value;

[0366] DMSO: Average fluorescence signal value of the DMSO group; LC: Average fluorescence signal value of the highest concentration point of the antagonist.

[0367] The experimental test results are shown in the following table:

[0368]

[0369] The above data indicate that the compounds of the present disclosure have a potent antagonistic effect on the CCR4 receptor.

[0370] Test Example 2 CCR4-mediated CCRF-CEM chemokine inhibition experiment

[0371] Experimental procedure

[0372] Centrifuge the CCRF-CEM cells, remove the supernatant, resuspend them in human serum, and adjust the cell density to 2.5x10 6 / mL. Aliquot the cells into a 96-well cell culture plate, 100 μL per well. Prepare a stock solution of the compound at a concentration of 10 mM using DMSO as the solvent, and then serially dilute the sample with DMSO as needed. Transfer 25 μL of the test compound to each well of the cells in the 96-well plate and incubate in a cell culture incubator at 37 °C and 5% carbon dioxide for 0.5 hour. Prepare a solution of hCCL22 at a concentration of 1 nM using 0.1% HBSS as the solvent. Take out the Multiscreen Ⓡ Transport Receiver Plate and add 330 μL of the hCCL22 solution. Place it in the upper chamber of the MultiScreen® Filter Plates. Take out the cells from the incubator and transfer 100 μL of the cells to each well. Cover the lid and incubate in a cell culture incubator at 37 °C and 5% carbon dioxide for 1 hour. Aspirate the liquid in the upper chamber, remove the upper chamber, and place it in another Millpore Multiscreen Ⓡ Transport Receiver Plate containing 330 μL of Cell / Tissue Dissociation Solution. Incubate together with the previous lower chamber receiving solution in a cell culture incubator at 37 °C and 5% carbon dioxide for another 0.5 hour, and then take out the lower chamber receiving solution. Take 50 μL of the lower chamber receiving solution from both times and mix them in a white opaque 96-well plate. Add 50 μL of CellTiter-Glo reagent and incubate in the dark for 30 minutes. Then, read the luminescence signal using a Molecular Devices SpectraMax i3x microplate reader. Use Graphpad software to fit the data to obtain the inhibition rate of the compound on cell migration, and calculate the IC 50 .

[0373] The compounds of the present invention have good activity in inhibiting CCR4-mediated CCRF-CEM chemokines.

[0374] The above is a description of specific embodiments of the present invention. It should be understood that the present invention is not limited to the limitations of the above embodiments, and the above embodiments and the descriptions in the specification are only for explaining the principles of the present invention. Without departing from the concept of the present invention, those skilled in the art will also make various non-substantial changes and improvements, and all of these fall within the scope of the present invention claimed.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: G 1 is CR 8 or N; G 2 is CR 9 or N; G 3 is CR 10 or N; E is , , , , or ; Z is O, S, Se or NR a ; Y is O, S, NR a or CR b R c ; R a is H, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl or a 3- to 12-membered heterocyclic group; R b and R c are the same or different and each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and any group selected from 3- to 12-membered heterocyclic groups; R 1 is L-R 12 ; L is a chemical bond, O, S, -C(O)-, -C(O)O-, -S(O)-, -S(O)2-, C 1-6 alkylene, C 3-8 cycloalkylene or a 3- to 12-membered heterocycloalkylene, wherein said C 1-6 alkylene, C 3-8 cycloalkylene and 3- to 12-membered heterocycloalkylene are each independently optionally substituted by one or more substituents selected from hydroxy, amino, halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and 3- to 12-membered heterocycloalkyl; R 12 selected from H, halogen, hydroxyl, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, -NR k2 R k3 , -C(O)R k4 , -S(O) x R k1 , -S(O) x NR k2 R k3 , - C(O)OR k4 , -C(O)NR k2 R k3 , -NR k2 SO2R k1 , -NR k2 C(O)R k4 , -NR k2 C(O)OR k4 , C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted by one or more R g substituents; R 1a is NR k2 R k3 ; Each R g is the same or different and each independently is halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkoxy, cyano, carboxy, -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 、C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxy and C 3-8 cycloalkyl; R 2 and R 3 are the same or different and each independently selected from H, halogen, hydroxy, cyano, amino, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 3-8 cycloalkyl; R 4 is H, D, C 1-6 alkyl or C 3-8 cycloalkyl; R 5 and R 6 are the same or different and each independently selected from H, D, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and C 3-8 cycloalkyl; Each R 7 is the same or different and is independently selected from H, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 3-8 cycloalkyl; R 8 、R 9 and R 10 are the same or different and each independently selected from H, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-8 cycloalkyl and any group selected from 3- to 12-membered heterocyclic groups; R 11 selected from H, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHC(O)NR k2 R k3 、-NR k2 R k3 、-P(O)R k2 R k3 、-SF5, -C(O)R k4 、-C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、 、C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3- to 12-membered heterocyclic group, C 6-10 aryl and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl, and C 3-8 cycloalkyl; Alternatively, R 4 and R 11 together with the atom(s) to which it is attached form a C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl, wherein the C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more R h substituents; Alternatively, when G 3 is CR 10 , R 10 and the atom to which R 11 is attached together form a C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl, and the C 4-8 cycloalkyl, 5- to 8-membered heterocyclic group, C 6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted by one or more R h substituents; Each R h is the same or different and each independently selected from halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -S(O) x R k1 、-S(O) x NR k2 R k3 、-NHC(O)NR k2 R k3 、-NR k2 R k3 、-P(O)R k2 R k3 、-SF5, -C(O)R k4 、- C(O)OR k4 、-C(O)NR k2 R k3 、-NR k2 SO2R k1 、-NR k2 C(O)R k4 、-NR k2 C(O)OR k4 、- NR k2 OR k4 、 、C 3-8 any group selected from cycloalkyl and 3- to 12-membered heterocyclic group; R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、R g3 and R g4 are the same or different and each independently selected from H, halogen, carboxyl, cyano, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, C(O)R v and 5- to 10-membered heteroaryl, and the C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl and C 3-8 cycloalkyl; R v Selected from halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 3-8 cycloalkyl; s is 1 or 2; t is 0, 1 or 2; p is 0 or 1; q is 0 or 1; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; x is 1 or 2; v is 1, 2 or 3; h is 0 or 1; Among them, The heteroatoms in the said heteroalkyl group, heterocyclic group and heteroaryl group may each independently be selected from one or more of O, N and S, and the number of heteroatoms is each independently 1, 2, 3, 4 or 5.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that R k1 、R k2 、R k3 、R k4 、R k5 、R g1 、R g2 、R g3 and R g4 are the same or different and each independently selected from H, halogen, carboxyl, cyano, amino, C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl, and the C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl, and C 3-8 cycloalkyl.

3. The compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, wherein E is , or .

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The compound of formula (I) is a compound of formula (II), formula (III), formula (IV) or formula (V), wherein, G 1 、G 2 、G 3 、Y, R 1 、R 2 、R 3 、R 4 、R 5 、R 7 、R 11 、s, t, k, m and n are as defined in any one of claims 1 - 3.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, It is selected from any of the following schemes: Solution 1, G 1 is N, G 2 is N, G 3 is CR 10 ; Solution 2, G 1 is N, G 2 is CR 9 , G 3 is N; Solution 3, G 1 is CR 8 , G 2 is CR 9 , G 3 is CR 10 ; wherein R 8 , R 9 and R 10 are as defined in any one of claims 1-4.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, The compound of formula (I) is a compound of formula (VI), formula (VII) or formula (VIII), wherein, E, R 4 , R 5 , R 7 , R 10 , R 11 , R h and k are as defined in any one of claims 1 - 3; preferably, R 4 is H or C 1-6 alkyl; R 11 is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl; R 11 is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -P(O)(CH3)2, and -SF5; R h is selected from any one of H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, -P(O)(CH3)2, and -SF5.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1, 2, 5 and 6, wherein E is , , , , , , , , , , , , or ; R 1 , R 1a , R 2 , R 3 , R b , R c , m and n are as defined in claims 1, 2, 5 or 6.

8. The compound of formula (I) according to any one of claims 1, 2, 3, 5 and 6, or a pharmaceutically acceptable salt thereof, wherein E is , , , , or ; preferably, E is or ; R 1 , R 1a , R 2 , R 3 , R b , R c , m and n are as defined in any one of claims 1, 2, 3, 5 and 6; Further preferably, E is , , , , , , , , , , and .

9. The compound of formula (I) according to claim 7 or a pharmaceutically acceptable salt thereof, wherein E is 、 、 、 、 、 、 or ; R 1 and R 1a are both NR k2 R k3 ; R k2 and R k3 are the same or different and are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocyclic group, and 5- to 10-membered heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, oxo, cyano, amino, carboxyl, and C 3-8 cycloalkyl, R 2 , R 3 , m, and n are as defined in claim 7; preferably, R 1 or R 1a is 、 、 、 、 、 、 、 or .

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R 1 is L-R 12 ; L is a chemical bond, -C(O)-, C 1-6 alkylene, C 3-8 cycloalkylene or a 3-8 membered heteroalkylene; R 12 is H, halogen, hydroxy, cyano, carboxy, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl and the 3- to 8-membered heterocyclic group are each independently optionally substituted by one or more R g substituents; Each R g is the same or different and each independently is halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, carboxy, C 3-8 cycloalkyl and 3- to 8-membered heterocyclic group; Preferably, R 1 is , , , , , , , or .

11. A compound of formula (I) as claimed in any one of claims 1 - 10 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are the same or different and each independently selected from H, halogen and C 1-6 alkyl; preferably, R 2 and R 3 are H.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein R 5 is H or C 1-6 alkyl, preferably methyl.

13. The compound of formula (I) according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein is , R 7A and R 7B are the same or different and each independently is halogen, C 1-6 alkyl or C 1-6 haloalkyl, preferably halogen; Preferably, is .

14. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound of formula (I) has the following structure or their stereoisomers: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, The compound of formula (I) has the following structure: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Or is the following compound: A stereoisomer thereof, wherein the carbon atom marked with "*" represents the chiral site that generates the stereoisomer, and its retention time under the following conditions is 2.007 minutes: Chiral column: Daicel OJ, 25 * 250 mm, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; Flow rate: 100 mL / min; A stereoisomer thereof, wherein the carbon atom marked with "*" represents the chiral site that generates the stereoisomer, and its retention time under the following conditions is 3.547 minutes: Chiral column: Daicel OJ, 25 * 250 mm, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7 M in MeOH)] = 45 / 55; Flow rate: 100 mL / min.

16. A compound of formula (IIA), formula (IIB), formula (IIC) or of formula (B) or a salt thereof, Among them, E1 is , , , , or ; R w is an amino protecting group. Preferably, R w is tert - butyloxycarbonyl (Boc); R w1 and R w2 each independently is a C1-C6 alkyl group, such as methyl; L1 is a C1-C6 alkylene group, such as a methylene group; G 1 、 G 2 、 G 3 、 R 2 、 R 3 、 R 4 、 R 5 、 R 7 、 R 11 、 R k2 、 k, m and n are as defined in any one of claims 1 - 15.

17. A compound or a salt thereof as described below: 。 18. An isotope-labeled compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, and the said isotope labeling is preferably deuterium substitution for hydrogen.

19. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, or the isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 18, and one or more pharmaceutically acceptable excipients.

20. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, or the isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 18, or the pharmaceutical composition according to claim 19, in the preparation of a drug for modulating CCR4.

21. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, or the isotope-labeled compound or a pharmaceutically acceptable salt thereof according to claim 18, or the pharmaceutical composition according to claim 19, in the preparation of a drug for preventing and / or treating CCR4-mediated diseases, preferably, the said CCR4-mediated diseases are autoimmune diseases, inflammatory diseases or cancers; more preferably, the said CCR4-mediated diseases are arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

22. Use of a compound of formula (I) as claimed in any one of claims 1 - 15 or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance as claimed in claim 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 19, in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease, an inflammatory disease or cancer, for example in the manufacture of a medicament for the prevention and / or treatment of arthritis, psoriasis, systemic lupus erythematosus or inflammatory bowel disease.

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