Polycyclic compound as well as preparation method and medical application thereof

Abstract

The invention relates to a polycyclic compound, a preparation method thereof and application of the polycyclic compound in medicine. Specifically, the invention relates to a polycyclic compound as shown in a general formula (I), a preparation method of the polycyclic compound, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, especially application of the compound as a CCR4 inhibitor and application of the compound in preparation of drugs for treating and / or preventing CCR4-mediated or dependent diseases or symptoms. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a polycyclic compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, in particular, its use as a CCR4 inhibitor and its use in the preparation of a medicament for treating and / or preventing CCR4-mediated or dependent diseases or conditions. Background Art

[0002] Chemokines and chemokine receptors are key regulators of immune cell homing and migration. The CCR4 (CC motif chemokine receptor 4) chemokine receptor is primarily expressed on immune cells such as Th2, Treg, and skin-tropic CLA+ T cells. CCR4 is a G protein-coupled receptor. Binding of its corresponding ligands, such as CCL17 (TARC) and CCL22 (MDC), activates downstream G protein and β-arrestin signaling pathways, promoting immune cell migration and mediating immune responses.

[0003] CCR4 plays a crucial role in the development and progression of numerous autoimmune diseases, including atopic dermatitis, asthma, systemic lupus erythematosus, allergic rhinitis, and rheumatoid arthritis. At the site of lesions, chemokines such as CCL17 and CCL22 are highly expressed, guiding immune cell migration to that location and inducing and promoting autoimmune responses. CCR4 is highly expressed in various T-cell lymphomas, and the marketed humanized antibody Mogamulizumab, which enhances ADCC and targets CCR4, has demonstrated promising efficacy. In solid tumors, Treg cells with high CCR4 expression accumulate and mediate tumor immune escape and metastasis. Therefore, as a therapeutic target for both autoimmunity and tumor immunity, small molecule inhibitors of CCR4 hold great promise for application.

[0004] In addition to the marketed CCR4 monoclonal antibody mogamulizumab, RAPT's CCR4 small molecule inhibitors FLX475 and RPT193 have entered Phase II clinical trials for cancer and autoimmune diseases such as atopic dermatitis and asthma, respectively. The development of clinically viable small molecule CCR4 inhibitors is urgently needed.

[0005] Disclosed patent applications for compounds of CCR4 inhibitors include WO2019090272A1, WO2019147862A1, WO2023232130A1, WO2023205618A2, and WO2023196432A1. Summary of the Invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A is a cycloalkyl group or a heterocyclic group, and Ring A is optionally substituted by one or more R 1 replace;

[0010] X 1 Selected from N, N + -O - and CR X1 ;

[0011] X 2 Selected from N, N + -O - and CR X2 ;

[0012] X 3 Selected from N, N + -O - and CR X3 ;

[0013] W is C or N, V ​​is C or N;

[0014] Each R X1 、R X2 and R X3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa Rbb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0015] or R X2 、R X3 and the carbon atom to which it is attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, or, X 1 or X 3 With R 1 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 01 replaced by;

[0016] Each R 2a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0017] Each R 2bare the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0018] or R 2a 、R 2b and the carbon atom to which it is attached together form C=O, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 02 replaced by;

[0019] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0020] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0021] Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] L 1 Selected from bond, NR, O and (CR aa R bb ) x ;

[0023] L 2 is selected from the group consisting of a bond, NR, O, alkylene, alkenylene and alkynylene, each of which is independently optionally substituted by one or more R 03 replaced by;

[0024] L is selected from a bond, NR, O, C(O), C(O)O, S(O) v , alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by;

[0025] R 6 Selected from C(O)OR 14 , hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 NR 13 C(O)R 14 、C(O)R 14 、S(O) v R 14 、S(O) v NR 11 R 12 , OR 14 、(CR aa R bb )x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 04 replaced by;

[0026] Each R 1 、R3 、R 4 、R 5 、R 01 、R 02 、R 03 and R 04 are the same or different and are each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 、=CR 15 R 16 、=NR 13 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally replaced by one or more R * replaced by;

[0027] or R 4 、R 5 and the atoms connected to it and L 1 Together they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R * replaced by;

[0028] R aa and R bb are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R aa 、R bb and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by;

[0029] Each R, R 11 、R 12 、R 13 and R 14 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 NR 22C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally replaced by one or more R * Replaced by; or R 11 、R 12 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R * replaced by;

[0030] R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 20 R 21 、C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R 15 、R 16 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by;

[0031] Each R * are the same or different and are each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v OR 23 、S(O) v NR 20 R 21 、C(=NR 22 )R 23 、S(=NR 22 )R 23 、S(=NR 22 )(O)R 23 、P(O)R 20 R 21 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl;

[0032] Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl;

[0033] m is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3, 4, 5 or 6;

[0034] p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5 or 6;

[0035] Each x is the same or different and is independently 0, 1, 2, 3 or 4; and,

[0036] Each v is the same or different and is independently 0, 1 or 2.

[0037] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof,

[0038]

[0039] in,

[0040] Q is selected from the group consisting of a bond, (CR 1a R 1b ) y 、O、(CR 1a R 1b ) y O、O(CR 1a R 1b ) y , C(O) and NR 1e ;

[0041] Q 1 Selected from (CR 1c R 1d ) z 、O、(CR 1c R 1d ) z O、O(CR 1c R 1d ) z , C(O) and NR 1f ;

[0042] R 1a 、R 1b 、R 1c and R 1d When present, they are the same or different and are each independently a hydrogen atom or R 1 ; or, R 1a 、R 1b 、R 1c and R 1d Any two of them and the carbon atoms to which they are attached together form a bridge or ring E, which is optionally replaced by one or more R 1 replaced by;

[0043] Ring E is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0044] R 1e and R 1f are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group and a heterocyclic group;

[0045] n is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1, 2 or 3;

[0046] y is 0, 1, or 2; z is 1, 2, or 3;

[0047] Ring B, Ring C, Ring D, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,R4 ,p,R 1 、R 2a 、R 2b 、R 3 and m are as defined in the general formula (I).

[0048] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

[0049]

[0050] Wherein, ring E is a cycloalkyl group or a heterocyclic group;

[0051] n is 0, 1, 2, 3, 4, 5 or 6;

[0052] n1 is 0, 1, 2, 3 or 4; y is 0, 1 or 2; s is 0, 1, 2 or 3;

[0053] Ring B, Ring C, Ring D, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,R 4 ,p,R 1 、R 2a 、R 2b 、R 3 and m are as defined in the general formula (I).

[0054] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,

[0055]

[0056] in,

[0057] D 0 Selected from CR 5a R 5b 、O、C(O)、NR 5c , S, S(O) and S(O)2;

[0058] R 5a and R 5b are the same or different and are each independently a hydrogen atom or R 5 , or R 5a 、R 5b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; R 5c is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group;

[0059] T is CR 3c or N; R 3a 、R 3b and R 3c are the same or different and are each independently a hydrogen atom or R 3 ;

[0060] p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2;

[0061] Ring E, X 1 、X 2 、X 3 、R 6 , L, R 5 、R 4 、R 1 ,s,y,n,n1,R 2a 、R 2b and R 3 As defined in general formula (III).

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0063]

[0064] in,

[0065] Ring E, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in formula (IV).

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof,

[0067]

[0068] in,

[0069] D 0 Selected from CR 5a R 5b、O、C(O)、NR 5c , S, S(O) and S(O)2;

[0070] R 5a and R 5b are the same or different and are each independently a hydrogen atom or R 5 , or R 5a 、R 5b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; R 5c is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group;

[0071] T is CR 3c or N; R 3a 、R 3b and R 3c are the same or different and are each independently a hydrogen atom or R 3 ;

[0072] p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; n is 0, 1 or 2;

[0073] X 1 、X 2 、X 3 、R 6 , L, R 5 、R 4 、R 1 、R 2a 、R 2b and R 3 As defined in general formula (I).

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV-1) and (V) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof,

[0075]

[0076] in,

[0077] X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in formula (V).

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 1 is the key.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a bicyclic cycloalkyl or bicyclic heterocyclic group; in some embodiments, ring A is selected from spirocycloalkyl, spiroheterocyclic group, bridged cycloalkyl and bridged heterocyclic group; in some embodiments, ring A is a bridged heterocyclic group; in some embodiments, ring A is a spiroheterocyclic group; in some embodiments, ring A is a 7- to 10-membered spiroheterocyclic group; in some embodiments, ring A is a 7-, 8- or 9-membered spiroheterocyclic group; in some embodiments, ring A is selected from In some embodiments, Ring A is With X 1 The ring is fused, and the * end is connected to CR 2a R 2b In the above schemes, ring A is optionally connected with one or more R 1 Replacement, R 1 As defined in general formula (I).

[0080] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2; in some embodiments, t is 1.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein L 2 For key or C 2-6 Alkyne; in some embodiments, L 2 is a bond or ethynylene; in some embodiments, L 2 is the key.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q is (CR 1a R 1b ) y , R 1a and R 1b are the same or different and are each independently a hydrogen atom or R 1 ; R 1 and y are as defined in formula (II); in some embodiments, Q is (CH2) y , y is 0, 1 or 2; in some embodiments, Q is a bond.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein Q 1 CR 1cR 1d or CR 1c R 1d O, R 1c and R 1d and the carbon atom to which it is attached together form ring E, which is optionally substituted by one or more R 1 Replaced by; Ring E and R 1 As defined in formula (II); in some embodiments, Q 1 CR 1c R 1d or CR 1c R 1d O, R 1c and R 1d and the carbon atom to which it is attached together form ring E, ring E is as defined in formula (II); in some embodiments, Q 1 for In some embodiments, Q 1 CR 1c R 1d , R 1c and R 1d and the carbon atom to which it is attached together form ring E, which is optionally substituted by one or more R 1 Replaced by; Ring E and R 1 As defined in formula (II); in some embodiments, Q 1 CR 1c R 1d , R 1c and R 1d and the carbon atom to which it is attached together form ring E, ring E is as defined in formula (II); in some embodiments, Q 1 for

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 1c and R 1d Any two of them and the carbon atoms to which they are attached together form a bridge or ring E, which is optionally replaced by one or more R 1 replaced by the remaining R 1a 、R 1b 、R 1c and R 1d When present, they are the same or different and are each independently a hydrogen atom or R 1 ;

[0085] In some embodiments, R 1a 、R 1b and the same carbon atom to which it is attached together to form ring E, or R 1c、R 1d and the same carbon atom to which they are attached together form ring E, which is optionally replaced by one or more R 1 substituted; in some embodiments, R 1a 、R 1b and the same carbon atom to which they are attached together form ring E, which is optionally replaced by one or more R 1 substituted; in some embodiments, R 1c 、R 1d and the carbon atom to which it is attached together form ring E, which is optionally substituted by one or more R 1 Replaced by; Ring E and R 1 As defined in formula (II); in some embodiments, R 1c and R 1d and the same carbon atom to which they are attached together form ring E, ring E is as defined in formula (II); in some embodiments, R 1c and R 1d and the same carbon atom to which it is attached together form a cyclopropyl group.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein the remaining R 1a 、R 1b 、R 1c and R 1d When present, they are the same or different and are each independently a hydrogen atom or R 1 .

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b All are hydrogen atoms.

[0088] In some embodiments of the present disclosure, the compounds represented by general formula (II) to (IV), (IV-1) or pharmaceutically acceptable salts thereof, wherein y is 0 or 1; in some embodiments, y is 0.

[0089] In some embodiments of the present disclosure, the compounds represented by the general formula (II) to (IV), (IV-1) or pharmaceutically acceptable salts thereof, wherein s is 1 or 2; in some embodiments, s is 1.

[0090] In some embodiments of the present disclosure, the compounds represented by the general formula (II) to (IV), (IV-1) or their pharmaceutically acceptable salts, wherein y is 0, and / or s is 1 or 2; in some embodiments, y is 0, and / or s is 1.

[0091] In some embodiments of the present disclosure, the compounds represented by the general formula (III) to (IV), (IV-1) or pharmaceutically acceptable salts thereof, wherein n1 is 0, 1 or 2; in some embodiments, n1 is 0.

[0092] In some embodiments of the present disclosure, the compounds represented by the general formulae (II) to (V), (V-1) or their pharmaceutically acceptable salts, wherein each R 1 are the same or different and are each independently selected from oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; in some embodiments, each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl; in some embodiments, R 1 It is an oxo group.

[0093] In some embodiments of the present disclosure, the compounds represented by the general formula (II) to (V), (V-1) or pharmaceutically acceptable salts thereof, wherein n is 0, 1 or 2; in some embodiments, n is 1; in some embodiments, n is 0.

[0094] In some embodiments of the present disclosure, the compounds represented by the general formulae (II) to (V), (V-1) or their pharmaceutically acceptable salts, wherein each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 alkyl, and / or n is 0, 1 or 2.

[0095] In some embodiments of the present disclosure, the compounds represented by the general formula (II) to (V), (V-1) or pharmaceutically acceptable salts thereof, wherein ring E is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; in some embodiments, ring E is selected from In some embodiments, ring E is a 3- to 6-membered cycloalkyl group; in some embodiments, ring E is a 3- to 6-membered heterocyclyl group; in some embodiments, ring E is

[0096] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein ring C is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; in some embodiments, ring C is a 3- to 10-membered heterocyclic group; in some embodiments, ring C is a 4- to 7-membered heterocyclic group; in some embodiments, ring C is an azetidinyl group; in some embodiments, ring C is selected from In some embodiments,

[0097] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 4 are the same or different and are each independently selected from oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl.

[0098] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 4 are the same or different and are each independently selected from oxo, halogen and C 1-6 alkyl; and / or p is 0, 1 or 2.

[0099] In the present disclosure, general formulae (I) to (V) are general formulae (I), (II), (III), (IV), (V), (VI-1) or (V-1).

[0100] In some embodiments of the present disclosure, the compounds represented by general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein p is 0.

[0101] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein ring D is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; in some embodiments, ring D is a 3- to 10-membered heterocyclic group; in some embodiments, ring D is a 4- to 7-membered heterocyclic group; in some embodiments, ring D is a 6-membered heterocyclic group; in some embodiments, ring D is a piperidinyl or morpholinyl; in some embodiments, ring D is selected from In some embodiments, Ring D is In some embodiments, ring D is piperidinyl; in some embodiments, ring D is In some embodiments,

[0102] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 5 are the same or different and are each independently selected from oxo, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl.

[0103] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 5 are the same or different and are each independently selected from oxo, halogen and C 1-6 alkyl; and / or q is 0, 1 or 2.

[0104] In some embodiments of the present disclosure, the compounds represented by general formulae (I) to (V) or pharmaceutically acceptable salts thereof, wherein q is 0.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (VI-1) or (V-1) or a pharmaceutically acceptable salt thereof, wherein D 0 is CH2 or O; in some embodiments, D 0 is CH2; in some embodiments, is O.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (VI-1) or (V-1) or a pharmaceutically acceptable salt thereof, wherein r is 1.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, Ring C, Ring D, R 4 、R 5 、R 6 , L, p and q are as defined in the general formula (I).

[0108] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein ring B is a 6- to 10-membered aryl group or a 5- to 14-membered heteroaryl group; in some embodiments, ring B is a phenyl group or a 5- or 6-membered heteroaryl group; in some embodiments, ring B is a phenyl group or a 6-membered heteroaryl group; in some embodiments, ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl; in some embodiments, ring B is phenyl or pyridinyl; in some embodiments, ring B is selected from phenyl, Key and CR 2a R 2b Linkage; In some embodiments, Ring B is phenyl.

[0109] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein m is 0, 1, 2 or 3; in some embodiments, m is 2.

[0110] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein for T is CR 3c or N, R 3a 、R 3b and R 3c are the same or different and are each independently a hydrogen atom or R 3 In some embodiments, for R 3a and R 3b are the same or different and are each independently a hydrogen atom or R 3 ; R 3 As defined in formula (I); in some embodiments, for R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl; in some embodiments, for R 3a and R 3b are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, for

[0111] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 3 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl, and 3 to 6 membered heterocyclyl; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Olefin and C 2-6 Alkynyl; in some embodiments, each R 3 are the same or different and are each independently selected from halogen, cyano, C1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3 is halogen; in some embodiments, each R 3 are the same or different and are each independently selected from Cl, vinyl and ethynyl; in some embodiments, R 3 For Cl.

[0112] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein each R 3 are the same or different and are independently selected from halogen, cyano, C 1-6 Alkyl and C 1-6 haloalkyl, and / or m is 0, 1 or 2.

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3a 、R 3b and R 3c are the same or different and are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 3a 、R 3b and R 3c are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3a 、R 3b and R 3c are the same or different and are each independently a hydrogen atom or a halogen.

[0114] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are the same or different and are each independently selected from hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 3a and R 3b are the same or different and are each independently selected from hydrogen atom, halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R 3a and R 3b are the same or different and are each independently a hydrogen atom or a halogen.

[0115] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3a is halogen, and / or R 3b is halogen, and / or R 3c A hydrogen atom.

[0116] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 3a Selected from hydrogen atom, halogen, cyano, C 2-6 Olefin and C 2-6 Alkynyl; in some embodiments, R 3a is selected from hydrogen, Cl, vinyl, and ethynyl; in some embodiments, R 3a is halogen; in some embodiments, R 3a For Cl.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3b Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 3b Selected from hydrogen atom, halogen, cyano, C 2-6 Olefin and C 2-6Alkynyl; in some embodiments, R 3b is selected from hydrogen, Cl, vinyl, and ethynyl; in some embodiments, R 3b is halogen; in some embodiments, R 3b For Cl.

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein T is CR 3c , R 3c As defined in formula (IV); in some embodiments, T is CH.

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (IV), (V), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein R 3c Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R 3c Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 3c A hydrogen atom.

[0120] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 6 Selected from C(O)NR 11 R 12 NR 13 C(O)R 14 、C(O)R 14 、C(O)OR 14 、S(O) v R 14 、S(O) v OR 14 、S(O) v NR 11 R 12 , OR 14 and 5-membered heteroaryl, R 11 、R 12 、R 13 、R 14 and v are as defined in Formula (I); in some embodiments, R 6 Selected from C(O)NR 11 R 12 NR 13 C(O)R 14 、C(O)R14 、C(O)OR 14 、S(O) v R 14 、S(O) v OR 14 and OR 14 , R 11 、R 12 、R 13 and R 14 are the same or different and are each independently selected from hydrogen atom, C 1-6 Alkyl and 3- to 6-membered cycloalkyl;

[0121] In some embodiments, R 6 Selected from OR 14 、C(O)OR 14 and C(O)NR 11 R 12 , R 11 、R 12 and R 14 As defined in formula (I); in some embodiments, R 6 OR 14 or C(O)OR 14 , R 14 As defined in formula (I); in some embodiments, R 6 is OH or COOH; in some embodiments, R 6 C(O)OR 14 , R 14 As defined in formula (I); in some embodiments, R 6 is COOH.

[0122] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein L is a 3-6 membered cycloalkyl or C 1-6 Alkylene, the 3 to 6-membered cycloalkyl and C 1-6 Each alkylene group is independently optionally substituted with one or more R 03 Replaced by R 03 In some embodiments, L is a 3- to 6-membered cycloalkyl group or a C 1-6 Alkylene, the 3 to 6 membered cycloalkyl group is optionally substituted by one or more C 1-6 In some embodiments, L is cyclobutyl or C 1-6 Alkylene, cyclobutyl optionally replaced by one or more C 1-6 In some embodiments, L is methylcyclobutane or C 1-6Alkylene; in some embodiments, L is methylcyclobutane or CH2CH2; in some embodiments, L is methylcyclobutane; in some embodiments, L is C 1-6 Alkylene; in some embodiments, L is selected from and (CH2) x , x is 1, 2 or 3; in some embodiments, L is selected from and CH2CH2; in some embodiments, L is or CH2CH2, * end and R 6 Linked; in some embodiments, L is (CH2) u , u is 1, 2, 3 or 4; in some embodiments, L is CH2CH2.

[0123] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein Selected from In some embodiments, for In some embodiments, In some embodiments,

[0124] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (III), (IV), (V) or a pharmaceutically acceptable salt thereof, wherein for In some embodiments, for In some embodiments, R 2a and R 2b As defined in general formula (I).

[0125] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 2a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 2a C 1-6 alkyl or 3 to 6 membered cycloalkyl; in some embodiments, R 2a C 1-6 Alkyl; in some embodiments, R 2a It is a methyl group.

[0126] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 2bSelected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 haloalkyl and 3 to 6 membered cycloalkyl; in some embodiments, R 2b A hydrogen atom.

[0127] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 2a C 1-6 Alkyl, and / or R 2b is a hydrogen atom; in some embodiments, R 2a is methyl, and / or R 2b A hydrogen atom.

[0128] In some embodiments of the present disclosure, the compound represented by the general formula (IV-1) or (V-1) or a pharmaceutically acceptable salt thereof, wherein R 2b With R 2a different.

[0129] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein X 1 N or CR X1 , R X1 As defined in formula (I); in some embodiments, X 1 is N or CH; in some embodiments, X 1 is N.

[0130] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein X 2 N or CR X2 , R X2 As defined in formula (I); in some embodiments, X 2 is N or CH; in some embodiments, X 2 is N.

[0131] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein X 1 N, and / or X 2 is N.

[0132] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein X 3 N or CR X3 , R X3 As defined in formula (I); in some embodiments, X 3 CR X3 , R X3As defined in formula (I); in some embodiments, X 3 CR X3 , R X3 C 1-6 Alkyl; in some embodiments, X 3 It is C-methyl.

[0133] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R X1 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R X1 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0134] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R X2 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R X1 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0135] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R X3 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Olefin, C 2-6 alkynyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R X3 Selected from hydrogen atom, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Olefin, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl; in some embodiments, R X3Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 Alkynyl; in some embodiments, R X3 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R X3 C 1-6 Alkyl; in some embodiments, R X3 It is a methyl group.

[0136] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein W is C, and / or V is C.

[0137] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 01 are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 01 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0138] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 02 are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 02 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0139] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 03 are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6Halogenated alkoxy, C 1-6 Alkoxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 03 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R 03 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 03 C 1-6 Alkyl; in some embodiments, R 03 It is a methyl group.

[0140] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 04 are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R 04 are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0141] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R * are the same or different and are each independently selected from oxo, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkoxyalkyl and 3 to 6 membered cycloalkyl; in some embodiments, each R * are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0142] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 11 and R 12 are the same or different and are each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 11 and R 12are the same or different and are each independently a hydrogen atom or a methyl group; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0143] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 13 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 13 A hydrogen atom.

[0144] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 14 Selected from hydrogen atoms, C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic group, and NR 20 R 21 , R 20 and R 21 As defined in formula (I); in some embodiments, R 14 Selected from hydrogen atoms, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocyclyl; in some embodiments, R 14 C 1-6 alkyl or 3 to 6 membered heterocyclyl; in some embodiments, R 14 C 1-6 Alkyl; in some embodiments, R 14 is methyl; in some embodiments, R 14 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 14 is a hydrogen atom or a methyl group; in some embodiments, R 14 A hydrogen atom.

[0145] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or their pharmaceutically acceptable salts, wherein R is a hydrogen atom or C 1-6 Alkyl; in some embodiments, R is a hydrogen atom.

[0146] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen and C 1-6 Alkyl; in some embodiments, R 15 and R 16 are the same or different and are each independently a hydrogen atom or a halogen.

[0147] In some embodiments of the present disclosure, the compounds represented by the general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein each R 20 and R 21 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 20 and R 21 All are hydrogen atoms.

[0148] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 22 A hydrogen atom.

[0149] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein R 23 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 23 is a hydrogen atom; in some embodiments, R 23 C 1-6 alkyl.

[0150] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein v is 2; in some embodiments, it is 1.

[0151] In some embodiments of the present disclosure, the compounds represented by general formula (I) to (V) or pharmaceutically acceptable salts thereof, wherein x is 1 or 2.

[0152] In some embodiments of the present disclosure, the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein X 1 N, X 2 N; X 3 CR X3 , R X3 C 1-6 alkyl; y is 0, s is 1 or 2; ring E is cyclopropyl; n1 is 0; each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl, n is 0, 1 or 2; R 2a C 1-6 Alkyl; R 2b is a hydrogen atom; Ring B is a phenyl group, each R 3 are the same or different and are each independently selected from halogen, cyano, C 1-6 Alkyl and C 1-6 haloalkyl; m is 0, 1 or 2; p is 0; q is 0; ring C is a 3- to 10-membered heterocyclic group; ring D is a 3- to 10-membered heterocyclic group; L is selected from and (CH2)x , x is 1, 2 or 3; R 6 OR 14 or C(O)OR 14 , R 14 A hydrogen atom or C 1-6 alkyl.

[0153] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or (IV-1) or a pharmaceutically acceptable salt thereof, wherein X 1 N, X 2 N; X 3 CR X3 , R X3 C 1-6 alkyl; y is 0, s is 1 or 2; Ring E is a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclic group; n1 is 0; each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl, n is 0, 1 or 2; R 2a C 1-6 Alkyl; R 2b is a hydrogen atom; T is CR 3c , R 3c is a hydrogen atom; R 3a is halogen; R 3b is halogen; p is 0; q is 0; r is 1; D 0 is CH2 or O; L is methylcyclobutane or C 1-6 Alkylene; R 6 OR 14 or C(O)OR 14 , R 14 A hydrogen atom or C 1-6 alkyl.

[0154] In some embodiments of the present disclosure, the compound represented by the general formula (IV) or (IV-1) or a pharmaceutically acceptable salt thereof, wherein X 1 N, X 2 N; X 3 CR X3 , R X3 C 1-6 alkyl; y is 0, s is 1 or 2; ring E is cyclopropyl; n1 is 0; each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl, n is 0, 1 or 2; R 2a C 1-6 Alkyl; R 2b is a hydrogen atom; T is CR 3c , R 3c is a hydrogen atom; R 3a is halogen; R3b is halogen; p is 0; q is 0; r is 1; D 0 is CH2 or O; L is methylcyclobutane or C 1-6 Alkylene; R 6 OR 14 or C(O)OR 14 , R 14 A hydrogen atom or C 1-6 alkyl.

[0155] In some embodiments of the present disclosure, the compound represented by the general formula (V) or (V-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N or CH; X 2 is N or CH; X 3 N or CR X3 , R X3 A hydrogen atom or C 1-6 Alkyl; each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6 Alkyl, n is 0, 1 or 2; R 2a C 1-6 Alkyl; R 2b is a hydrogen atom; T is CR 3c , R 3c is a hydrogen atom; R 3a is halogen; R 3b is halogen; p is 0; q is 0; r is 1; D 0 is CH2 or O; L is methylcyclobutane or C 1-6 Alkylene; R 6 Selected from OR 14 、C(O)OR 14 and C(O)NR 11 R 12 , R 14 A hydrogen atom or C 1-6 Alkyl; R 11 and R 12 The same or different, and each independently a hydrogen atom or a C 1-6 alkyl.

[0156] In some embodiments of the present disclosure, the compound represented by the general formula (V) or (V-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N or CH; X 2 is N or CH; X 3 N or CR X3 , R X3 A hydrogen atom or C 1-6 Alkyl; each R 1 are the same or different and are each independently selected from oxo, halogen and C 1-6Alkyl, n is 0, 1 or 2; R 2a C 1-6 Alkyl; R 2b is a hydrogen atom; T is CR 3c , R 3c is a hydrogen atom; R 3a is halogen; R 3b is halogen; p is 0; q is 0; r is 1; D 0 is CH2 or O; L is methylcyclobutane or C 1-6 Alkylene; R 6 OR 14 or C(O)OR 14 , R 14 A hydrogen atom or C 1-6 alkyl.

[0157] Table A Typical compounds of the present disclosure include, but are not limited to:

[0158]

[0159]

[0160]

[0161] Another aspect of the present disclosure provides a compound represented by general formula (IVB) or (IV-1B) or a salt thereof,

[0162]

[0163] Wherein, X is a halogen, preferably Cl;

[0164] Ring E, X 1 、X 2 、X 3 、R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (IV) or (IV-1).

[0165] Another aspect of the present disclosure provides a compound represented by general formula (VB) or (V-1B) or a salt thereof,

[0166]

[0167] Wherein, X is a halogen, preferably Cl;

[0168] X 1 、X 2 、X 3 、R 1 、n、R 2a、R 2b , T, R 3a and R 3b As defined in general formula (V) or (V-1).

[0169] Table B Typical intermediate compounds or salts thereof disclosed herein include but are not limited to:

[0170]

[0171]

[0172] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0173]

[0174] The compound represented by general formula (IVA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by general formula (IVB) or its salt to obtain the compound represented by general formula (IV) or its pharmaceutically acceptable salt;

[0175] Wherein, X is a halogen, preferably Cl;

[0176] Ring E, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in formula (IV).

[0177] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (IV-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0178]

[0179] The compound represented by the general formula (IV-1A) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IV-1B) or its salt to obtain the compound represented by the general formula (IV-1) or its pharmaceutically acceptable salt;

[0180] Wherein, X is a halogen, preferably Cl;

[0181] Ring E, X 1 、X 2 、X 3 、R 6, L, R 5 ,q,r,D 0 、R 4 ,p,R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (IV-1).

[0182] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0183]

[0184] The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (VB) or a salt thereof to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;

[0185] Wherein, X is a halogen, preferably Cl;

[0186] X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in formula (V).

[0187] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0188]

[0189] The compound represented by the general formula (IV-1A) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V-1B) or a salt thereof to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;

[0190] Wherein, X is a halogen, preferably Cl;

[0191] X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (V-1).

[0192] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (V) and shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0193] The present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of drugs for inhibiting CCR4 activity.

[0194] The present disclosure further relates to the use of the compounds represented by general formulae (I) to (V) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of CCR4 inhibitors.

[0195] The present disclosure further relates to the use of compounds of formula (I) to (V) and shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by or dependent on CCR4.

[0196] The present disclosure further relates to the use of the compounds of formula (I) to (V) and shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of medicaments for treating and / or preventing cancer, tumors, cardiovascular diseases, metabolic diseases, immune or inflammatory diseases or conditions; preferably, the use of the compounds of formula (I) to (V) and shown in Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of medicaments for treating and / or preventing immune or inflammatory diseases or conditions; the inflammatory diseases or conditions are preferably autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, 1 Type 2 diabetes mellitus, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, atopic dermatitis, and allergic rhinitis.

[0197] The present disclosure also relates to a method for treating and / or preventing diseases or conditions mediated by or dependent on CCR4, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0198] The present disclosure also relates to a method for inhibiting CCR4 activity, comprising administering to a patient in need thereof a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0199] The present disclosure also relates to a method for treating and / or preventing cancer, tumors, cardiovascular diseases, metabolic diseases, immune or inflammatory diseases or conditions, comprising administering to a patient in need thereof a compound of the aforementioned general formulae (I) to (V) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0200] The present disclosure further relates to a compound represented by the above-mentioned general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0201] The present disclosure further relates to a compound represented by the above general formula (I) to (V) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a CCR4 inhibitor.

[0202] The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting CCR4 activity.

[0203] The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for treating and / or preventing diseases or conditions mediated by or dependent on CCR4.

[0204] The present disclosure further relates to the compounds represented by the above general formulae (I) to (V) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in inhibiting CCR4 activity.

[0205] The present disclosure further relates to the compounds of the above-mentioned general formulae (I) to (V) or shown in Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating and / or preventing diseases or conditions mediated by or dependent on CCR4.

[0206] The present disclosure further relates to a compound of the above-mentioned general formula (I) to (V) or shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing cancer, tumors, cardiovascular diseases, metabolic diseases, immune or inflammatory diseases or conditions; preferably for treating and / or preventing immune or inflammatory diseases or conditions.

[0207] In some embodiments, the disease or condition mediated or dependent on CCR4 is selected from cancer, tumor, cardiovascular disease, metabolic disease, immune or inflammatory disease or condition; in some embodiments, is an immune or inflammatory disease or condition.

[0208] The term disease or condition refers to a state or health condition of a patient or individual that can be treated by the compounds or methods provided herein. The disease can be cancer, the disease can be an autoimmune disease, the disease can be an inflammatory disease, or the disease can be an infectious disease.

[0209] In some embodiments, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, and the like, including solid and lymphoid cancers, kidney, breast, lung, bladder, colon, ovary, prostate, pancreas, stomach, brain, head and neck, skin, uterus, testicles, gliomas, esophageal and liver cancers (including hepatocellular carcinoma), lymphomas (including B-acute lymphoblastic lymphoma), non-Hodgkin lymphomas (e.g., Burkitt's, small cell and large cell lymphomas), Hodgkin lymphomas, leukemias (including MDS, AML, ALL, ATLL and CML), or multiple myeloma.

[0210] As used herein, the term "inflammatory disease or disorder" refers to a disease or condition characterized by abnormal inflammation (eg, increased levels of inflammation compared to a control, such as a healthy person not suffering from the disease). Inflammatory diseases or conditions are preferably selected from autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, atopic dermatitis and allergic rhinitis. These conditions are often inseparable from other diseases, conditions and conditions. Non-limiting examples of inflammation-related diseases, disorders, and conditions that can be caused, for example, by inflammatory cytokines include arthritis, renal failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., where inflammatory cytokines prevent healing), anemia, and fibromyalgia. Other diseases and conditions that can be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infection, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczema, systemic sclerosis, transplantation, and multiple sclerosis. Compounds described herein (e.g., CCR4 inhibitors) that may be particularly effective for some of the above-mentioned diseases, disorders, and conditions are described in more detail below. Examples of inflammatory diseases include head injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

[0211] The term "cancer" as used herein refers to all types of cancers, tumors or malignancies found in mammals (e.g., humans), including leukemias, lymphomas, carcinomas and sarcomas. Cancers that can be treated with the compounds or methods provided herein include, for example, brain cancer, gliomas, glioblastomas, neuroblastomas, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, gastric cancer, ovarian cancer, lung cancer and head cancer. Cancers that can be treated with the compounds or methods provided herein include, for example, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, colorectal cancer, pancreatic cancer. Other examples include thyroid cancer, bile duct cancer, pancreatic cancer, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, primary brain tumor, cancer, malignant insulinoma, malignant carcinoid tumor, urinary bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic tumor, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0212] As used herein, the term "autoimmune disease" refers to a disease or condition in which an individual's immune system has an abnormal immune response to substances that do not normally elicit an immune response in a healthy individual. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome (APS), autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Barlow's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman disease, celiac disease, Chagas disease, disease), chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid / benign mucous membrane pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital heart block, coxsackievirus myocarditis, CREST disease, essential mixed cryoglobulinemia, demyelinating neuropathy, dermatitis herpetiformis, dermatomyositis, Devic's diseasedisease (neuromyelitis optica), discoid lupus, Dressler syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henoch-Schonlein purpura, herpes gestationis, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunomodulatory lipoproteins, inclusion body myositis, interstitial cystitis, juvenile Arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytodestructive vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease (LAD), systemic lupus erythematosus (SLE), Lyme disease, chronic Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neuromyelitis optica (Devic's), neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatic disease, PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococci), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria (PNH), Parry's disease Romberg syndrome, Parsonnage-Turner syndrome, pars planitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, autoimmune polyendocrine syndrome types I, II, and III, polymyalgia rheumatica, polymyositis, post-myocardial infarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, necrotic reflux disease Pyoderma gangrenosum, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless leg syndrome, retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, hard man syndrome, subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia, Takayasu's arteritisarteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome, transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, blistering skin disease, vitiligo, or Wegener's granulomatosis (also known as granulomatosis with polyangiitis [GPA]).

[0213] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure may be in the form of a tablet, capsule, cachet, bottled solution, powder, granules, lozenge, suppository, reconstituted powder, or liquid formulation.

[0214] As a general guide, suitable unit doses may be in the range of 0.1 to 1000 mg.

[0215] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0216] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0217] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0218] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0219] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives to provide a pleasing and palatable pharmaceutical formulation. Tablets contain the active ingredient and, in admixture, nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a longer period of time.

[0220] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0221] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0222] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents as described above may be added to provide a palatable formulation. These compositions may be preserved by the addition of antioxidants.

[0223] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0224] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solutions and microemulsions may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0225] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspensions for intramuscular and subcutaneous administration. The suspension can be prepared using known techniques with suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspending media. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

[0226] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0227] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0228] Terminology

[0229] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0230] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-10 Alkyl), preferably an alkyl group having 1 to 6 carbon atoms (ie, C 1-6Non-limiting examples 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0231] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 10 carbon atoms (i.e., C 1-10 Alkylene), preferably an alkylene group having 1 to 8 carbon atoms (ie, C 1-8 alkylene), more preferably an alkylene group having 2 to 7 carbon atoms (i.e., C 2-7 Alkylene) or an alkylene group having 1, 2 or 3 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0232] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0233] The term "alkenylene" refers to a divalent alkenyl group, wherein alkenyl is as defined above.

[0234] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0235] The term "alkynylene" refers to a divalent alkynyl group wherein alkynyl is as defined above.

[0236] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituent preferably being selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0237] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, propylthio, and butylthio. Alkylthio can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0238] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), most preferably a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered cycloalkyl group) or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group); and most preferably a cycloalkyl group having 5 or 6 ring atoms.

[0239] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0240] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0241] The term "spiroalkyl" refers to a polycyclic ring system having a common carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized to form nitrogen oxides; the sulfur may be optionally oxoed to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroalkyl). The spiroalkyl preferably has 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl), and more preferably has 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl). The spirocycloalkyl group includes a monospirocycloalkyl group and a polyspirocycloalkyl group (such as a bispirocycloalkyl group, etc.), preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 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 / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group. Non-limiting examples include:

[0242] Its connection point can be at any position;

[0243] wait.

[0244] The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl). The fused cycloalkyl is preferably a fused cycloalkyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered fused cycloalkyl). The fused cycloalkyl group includes bicyclic fused cycloalkyl groups and polycyclic fused cycloalkyl groups (such as tricyclic fused cycloalkyl groups, tetracyclic fused cycloalkyl groups, etc.), preferably bicyclic fused cycloalkyl groups or tricyclic fused cycloalkyl groups, 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 / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0245]

[0246] Its connection point can be at any position;

[0247]

[0248] wait.

[0249] The term "bridged cycloalkyl" refers to a full carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., a 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., a 6 to 14-membered bridged cycloalkyl), more preferably a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., a 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0250] Its connection point can be at any position.

[0251] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0252] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group) or a heterocyclic group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group), a heterocyclic group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclic group) or a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms.

[0253] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0254] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0255] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms in the ring, wherein the heterocyclic group is as defined above. Preferably, it is a 3- to 10-membered nitrogen-containing heterocyclic group, more preferably a 4- to 7-membered nitrogen-containing heterocyclic group, and most preferably a 5- or 6-membered nitrogen-containing heterocyclic group.

[0256] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) of 6 to 14 ring atoms, more preferably a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms. The spiro heterocyclic radical includes monospiro heterocyclic radical and polyspiro heterocyclic radical (such as dispiro heterocyclic radical etc.), preferably monospiro heterocyclic radical or dispiro heterocyclic radical, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0257]

[0258] wait.

[0259] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical preferably has a fused heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), more preferably a fused heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (such as tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), preferably bicyclic fused heterocyclic radicals or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples include:

[0260]

[0261] wait.

[0262] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered bridged heterocyclic group). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclic group), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclic group). According to the number of constituent rings, heterocyclic groups can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0263] wait.

[0264] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclic group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.

[0265] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 6 to 20-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 14 ring atoms (i.e., 6 to 14-membered aromatic group), more preferably an aromatic group having 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the point of attachment is on the phenyl group or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0266]

[0267] wait.

[0268] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0269] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl group), more preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl group), and most preferably a heteroaryl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl group).

[0270] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

[0271] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic groups, wherein the point of attachment is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0272]

[0273] wait.

[0274] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of a D atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0275] The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0276] The term "heterocyclyloxy" refers to an -O-heterocyclyl group wherein heterocyclyl is as defined above.

[0277] The term "aryloxy" refers to an -O-aryl group in which aryl is as defined above.

[0278] The term "heteroaryloxy" refers to an -O-heteroaryl group, wherein heteroaryl is as defined above.

[0279] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0280] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0281] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0282] The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0283] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0284] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0285] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0286] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0287] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0288] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

[0289] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0290] The term "hydroxy" refers to -OH.

[0291] The term "amino" refers to -NH2.

[0292] The term "cyano" refers to -CN.

[0293] The term "nitro" refers to -NO2.

[0294] The term "oxo" or "oxo" refers to "=0".

[0295] The term "carbonyl" refers to C=O.

[0296] TBS refers to tert-butyldimethylsilyl.

[0297] The term "amido" refers to -CONH2.

[0298] The term "acetyl" refers to C(O)CH3.

[0299] The term "alkyleneamino" refers to an -alkylene-amino group in which alkylene and amino are as defined above.

[0300] The term "alkyleneamido" refers to an -alkylene-amido group in which the alkylene and amido groups are as defined above.

[0301] The term "amino protecting group" refers to a group that is easily removed and introduced onto an amino group in order to keep the amino group unchanged while reacting other parts of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), and the like.

[0302] The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers having identical structures but different arrangements of atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). The substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), by forming a diastereomeric salt with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art to obtain the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

[0303] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0304] In the chemical structures of the compounds disclosed herein, "rac" is short for racemate (also known as raceme), which refers to an equimolar mixture of a pair of enantiomers. For example, when the compound has only one chiral center, "rac" refers to an equimolar mixture of the (R) configuration and the (S) configuration; when the compound has two chiral centers, "rac" refers to an equimolar mixture of the (R,R) configuration and the (S,S) configuration; or an equimolar mixture of the (R,S) configuration and the (S,R) configuration. Specifically, "rac-(1R,2R)" means that the compound is a racemate, which is an equimolar mixture of the (1R,2R) configuration and the (1S,2S) configuration.

[0305] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another. It includes all possible tautomers, i.e., existing in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. Examples of lactam-lactim equilibrium are shown below:

[0306]

[0307] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0308]

[0309] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0310] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 p、 33 p、 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0311] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0312] When a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (ie, at least 15% deuterium incorporation). Examples of compounds having a greater than natural abundance of deuterium may be at least 1000 times more abundant in deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times more abundant in deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times more abundant in deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times more abundant in deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times more abundant in deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times more abundant in deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 50 ...0% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in deuterium (i.e., at least 60% deuterium incorporation), at least 5000 times more abundant in de deuterium is incorporated at least 5000 times more abundant in deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times more abundant in deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times more abundant in deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times more abundant in deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times more abundant in deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times more abundant in deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times more abundant in deuterium (i.e., at least 99.5% deuterium incorporation), or more.

[0313] "Optional" or "optionally" means that the event or circumstances described below may but need not occur, and includes both situations where the event or circumstances occur or do not occur. For example, "C 1-6 The term "alkyl" includes both the case where the alkyl group is substituted by halogen or cyano and the case where the alkyl group is not substituted by halogen or cyano.

[0314] "Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1, 2 or 3, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of each other by a corresponding number of substituents. Those skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0315] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0316] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0317] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0318] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0319] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given for illustration purposes only and are not limiting.

[0320] Synthesis method of the disclosed compound

[0321] In order to achieve the purpose of this disclosure, the present disclosure adopts the following technical solutions:

[0322] Option 1

[0323] The method for preparing the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0324] The compound represented by general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by general formula (IVB) or a salt thereof under alkaline conditions to obtain the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof;

[0325] Wherein, X is a halogen, preferably Cl;

[0326] Ring E, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (IV).

[0327] Option 2

[0328] The method for preparing the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0329] The compound represented by the general formula (IV-1A) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (IV-1B) or a salt thereof under alkaline conditions to obtain the compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof;

[0330] Wherein, X is a halogen, preferably Cl;

[0331] Ring E, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 ,s,y,n,n1,R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (IV-1).

[0332] Option 3

[0333] The method for preparing the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0334] The compound represented by the general formula (IVA) or its salt undergoes a nucleophilic substitution reaction with the compound represented by the general formula (VB) or its salt under alkaline conditions to obtain the compound represented by the general formula (V) or its pharmaceutically acceptable salt;

[0335] Wherein, X is a halogen, preferably Cl;

[0336] X 1 、X2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (V).

[0337] Option 4

[0338] The method for preparing the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof disclosed herein comprises the following steps:

[0339] The compound represented by the general formula (IV-1A) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V-1B) or a salt thereof under alkaline conditions to obtain the compound represented by the general formula (V-1) or a pharmaceutically acceptable salt thereof;

[0340] Wherein, X is a halogen, preferably Cl;

[0341] X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in general formula (V-1).

[0342] The reagents providing alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, potassium hydroxide and lithium hydroxide monohydrate; preferably cesium fluoride.

[0343] The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof. DETAILED DESCRIPTION

[0344] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0345] Example

[0346] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0347] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0348] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0349] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO QExactive)

[0350] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0351] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0352] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0353] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0354] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0355] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0356] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0357] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0358] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0359] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0360] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0361] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0362] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0363] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0364] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0365] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0366] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0367] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0368] Example 1

[0369] (1R,3r)-3-((R)-3-(1-(7'-((R)-1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid 1

[0370]

[0371]

[0372] first step

[0373] (R)-ethyl 2-(2-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-5-yl)acetate 1c

[0374] Ethyl 2-(2,4-dichloro-6-methylpyrimidin-5-yl)acetate 1a (1.2 g, 4.81 mmol, prepared by the method disclosed in Example 1 on page 2 of the specification of patent application "US3225047") and (R)-1-(2,4-dichlorophenyl)ethanamine 1b (915 mg, 4.81 mmol, Shanghai Hanhong) were dissolved in isopropanol (15 mL), and N,N'-dimethylethylenediamine (1.9 g, 14.7 mmol) was added. The reaction was stirred at 60°C for 16 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (1.2 g, yield: 61.8%).

[0375] MS m / z(ESI):402.2[M+1].

[0376] Step 2

[0377] (R)-2'-Chloro-7'-(1-(2,4-dichlorophenyl)ethyl)-4'-methylspiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one 1d

[0378] Compound 1c (1.2 g, 2.98 mmol) and 1,2-dibromoethane (1.4 g, 7.45 mmol) were dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.3 g, 9.4 mmol) was added. The reaction was stirred at 85°C for 3.5 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1d (630 mg, yield: 55.2%).

[0379] MS m / z(ESI):382.2[M+1].

[0380] Step 3

[0381] (R)-2'-chloro-7'-(1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]

[0382] Pyrimidine]1e

[0383] Compound 1d (200 mg, 522.6 μmol) was dissolved in tetrahydrofuran (10 mL), and a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (5 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1e (125 mg, yield: 64.8%).

[0384] MS m / z(ESI):368.2[M+1].

[0385] Step 4: (1R,3r)-3-((R)-3-(1-(7'-((R)-1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid 1

[0386] Compound 1e (90 mg, 244.1 μmol) and (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid 1f (90 mg, 356.6 μmol, prepared by the method disclosed in Method C on page 273 of the specification of patent application "WO2019147862") were dissolved in dimethyl sulfoxide (2 mL), and cesium fluoride (120 mg, 790 μmol) was added. The mixture was stirred at 85°C for 2 hours, and the reaction solution was cooled to room temperature and filtered. The filtrate was purified by preparative high performance liquid chromatography (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30×150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (42 mg, yield: 29.4%).

[0387] MS m / z(ESI):584.2[M+1].

[0388] 1 H NMR (500MHz, DMSO-d6): δ12.15(br,1H),7.60(s,1H),7.55-7.50(m,1H),7.44-7.40(m ,1H),5.51-5.39(m,1H),3.94-3.79(m,2H),3.60-3.44(m,3H),3.19-3.10(m,1H),2.67 -2.52(m,3H),2.45-2.22(m,3H),1.83(s,3H),1.73-1.52(m,6H),1.51-1.44(m,3H),1. 43-1.29(m,2H),1.26(s,3H),1.24-1.19(m,1H),1.16-1.08(m,1H),0.84-0.71(m,3H).

[0389] Example 2

[0390] 2-((R)-2-(1-(7'-((R)-1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo]

[0391] [2,3-d]pyrimidin-2'-yl)azetidin-3-yl)morpholin-1-ol

[0392]

[0393] MS m / z(ESI):518.2[M+1].

[0394] Example 3

[0395] 2-((R)-3-(1-(7'-((R)-1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo]

[0396] [2,3-d]pyrimidin-2'-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol 3

[0397]

[0398] MS m / z(ESI):516.2[M+1].

[0399] Example 4

[0400] (1R,3r)-3-((R)-3-(1-(7'-(R)-1-(2,4-dichlorophenyl)ethyl)-4'-methyl-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid

[0401]

[0402] Compound 1d (50 mg, 130.6 μmol) and compound 1f (50 mg, 198.1 μmol) were dissolved in dimethyl sulfoxide (2 mL), and cesium fluoride (60 mg, 395 μmol) was added. The mixture was stirred at 85°C for 2 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to give the title compound 4 (4.5 mg, yield: 5.7%).

[0403] MS m / z(ESI):598.2[M+1].

[0404] 1H NMR (500MHz, DMSO-d6): δ7.87-7.75(m,1H),7.47-7.30(m,2H),5.95-5.83(m,1H),4.17- 3.99(m,2H),3.86-3.76(m,1H),3.74-3.61(m,1H),3.48-3.37(m,1H),3.23-3.10(m,1H), 2.83-2.67(m,2H),2.54-2.42(m,2H),2.28-2.17(m,1H),2.10(s,3H),2.02-1.66(m,9H), 1.58-1.48(m,2H),1.38(s,3H),1.35-1.22(m,2H),1.18-1.05(m,1H),0.95-0.82(m,1H).

[0405] Biological evaluation

[0406] Test Example 1: Inhibitory effect of the compounds of the present invention on the chemotactic activity of CCRF-CEM cell lines

[0407] 1. Experimental Materials and Instruments

[0408]

[0409] 2. Experimental steps

[0410] CCRF-CEM cells were cultured in RPMI 1640 + 10% FBS medium. After cell counting, the supernatant was discarded and the cells were resuspended in 100% human serum to adjust the cell density to 2.67 × 10 6 cells / mL, and 100 μL of cells were seeded into a U-bottom 96-well plate. The test compound was prepared and diluted 3-fold to a total of 10 concentrations. The compound was added to the cell culture plate and incubated in a CO2 cell culture incubator for 30 minutes. Human CCL22 recombinant protein was prepared in 1× HBSS + 0.1% BSA buffer to a final concentration of 1 nM, and then 235 μL was added to each well of the HTS In the receiving plate, the negative control is 1×HBSS+0.1% BSA buffer. After the cell pre-incubation is completed, the cells are pipetted evenly and then 75μl per well is added to the HTS Place the upper chamber well of the culture chamber plate. Insert the upper chamber plate into the lower chamber plate and carefully place the cell culture plate in a 5% carbon dioxide cell culture incubator for 2 hours. Discard the upper chamber well plate, equilibrate the lower chamber receiving plate to room temperature, add 100 μL CellTiter-Glo reagent to each well, place it on a shaker to mix for 2 minutes, and then incubate at room temperature for 28 minutes. After the signal stabilizes, detect it on a PHERASTAR microplate reader. Use XLfit to analyze the data, perform four-factor curve fitting, and calculate the compound IC 50 value and Imax value.

[0411] Table 1 Inhibition of chemotactic activity of CCRF-CEM cell lines

[0412] Compound number <![CDATA[IC 50 / nM]]> 1 73.75

[0413] Conclusion: The disclosed compounds have an inhibitory effect on the chemotactic activity of CCRF-CEM cell lines.

Claims

1. A compound represented by general formula (I), or a pharmaceutically acceptable salt thereof: in: Ring A is a cycloalkyl group or a heterocyclic group, and Ring A is optionally substituted by one or more R 1 replace; X 1 Selected from N, N + -O - and CR X1 ; X 2 Selected from N, N + -O - and CR X2 ; X 3 Selected from N, N + -O - and CR X3 ; W is C or N, V ​​is C or N; Each R X1 、R X2 and R X3 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by; or R X2 、R X3 and the carbon atom to which it is attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, or, X 1 or X 3 With R 1 and the atoms to which they are attached together form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R 01 replaced by; Each R 2a are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by; Each R 2b are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by; or R 2a 、R 2b and the carbon atom to which it is attached together form C=O, cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R 02 replaced by; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; L 1 Selected from bond, NR, O and (CR aa R bb ) x ; L 2 is selected from the group consisting of a bond, NR, O, alkylene, alkenylene and alkynylene, each of which is independently optionally substituted by one or more R 03 replaced by; L is selected from a bond, NR, O, C(O), C(O)O, S(O) v , alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 03 replaced by; R 6 Selected from C(O)OR 14 , hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 NR 13 C(O)R 14 、C(O)R 14 、S(O) v R 14 、S(O) v NR 11 R 12 , OR 14 、(CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 04 replaced by; Each R 1 、R 3 、R 4 、R 5 、R 01 、R 02 、R 03 and R 04 are the same or different and are each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa R bb ) x C(O)NR 11 R 12 、(CR aa R bb ) x NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 、(CR aa R bb ) x C(O)R 14 、C(O)OR 14 、OC(O)R 14 、OC(O)OR 14 、(CR aa R bb ) x S(O) v R 14 、S(O) v OR 14 、OS(O) v R 14 、(CR aa R bb ) x S(O) v NR 11 R 12 NR 13 S(O) v R 14 、(CR aa R bb ) x C(=NR 13 )R 14 、S(=NR 13 )R 14 、S(=NR 13 )(O)R 14 、P(O)R 11 R 12 、(CR aa R bb ) x OR 14 、=CR 15 R 16 、=NR 13 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally replaced by one or more R * replaced by; or R 4 、R 5 and the atoms connected to it and L 1 Together they form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted by one or more R * replaced by; R aa and R bb are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R aa 、R bb and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by; Each R, R 11 、R 12 、R 13 and R 14 are the same or different and are each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 NR 22 C(O)R 23 、C(O)R 23 、C(O)OR 23 、OC(O)R 23 、OC(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl are each independently optionally replaced by one or more R * Replaced by; or R 11 、R 12 and the nitrogen atom to which it is attached together form a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more R * replaced by; R 15 and R 16 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 20 R 21 、C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v NR 20 R 21 , cycloalkyl, heterocyclic, aryl and heteroaryl; the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally replaced by one or more R * Replaced by; or R 15 、R 16 and the carbon atoms to which they are attached together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl and heterocyclic groups are each independently optionally substituted by one or more R * replaced by; Each R * are the same or different and are each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 20 R 21 、C(O)NR 20 R 21 、Alkylene NR 20 R 21 、alkylene C(O)NR 20 R 21 、C(O)R 23 、C(O)OR 23 , OR 23 、S(O) v R 23 、S(O) v OR 23 、S(O) v NR 20 R 21 、C(=NR 22 )R 23 、S(=NR 22 )R 23 、S(=NR 22 )(O)R 23 、P(O)R 20 R 21 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; Each R 20 、R 21 、R 22 and R 23 are the same or different and are each independently selected from hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; m is 0, 1, 2, 3, 4, 5 or 6; t is 0, 1, 2, 3, 4, 5 or 6; p is 0, 1, 2, 3, 4, 5 or 6; q is 0, 1, 2, 3, 4, 5 or 6; Each x is the same or different and is independently 0, 1, 2, 3 or 4; and, Each v is the same or different and is independently 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof: in, Ring E is a cycloalkyl group or a heterocyclic group; n is 0, 1, 2, 3, 4, 5 or 6; n1 is 0, 1, 2, 3 or 4; y is 0, 1 or 2; s is 0, 1, 2 or 3; Ring B, Ring C, Ring D, X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,R 4 ,p,R 1 、R 2a 、R 2b 、R 3 and m as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V), or a pharmaceutically acceptable salt thereof: in, D 0 Selected from CR 5a R 5b 、O、C(O)、NR 5c , S, S(O) and S(O)2; R 5a and R 5b are the same or different and are each independently a hydrogen atom or R 5 , or R 5a 、R 5b and the carbon atom to which it is attached together form a cycloalkyl or heterocyclic group; R 5c is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and a heterocyclic group; T is CR 3c or N; R 3a 、R 3b and R 3c are the same or different and are each independently a hydrogen atom or R 3 ; p is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; n is 0, 1 or 2; X 1 、X 2 、X 3 、R 6 , L, R 5 、R 4 、R 1 、R 2a 、R 2b and R 3 As defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: R 6 OR 14 or C(O)OR 14 , R 14 As defined in claim 1, and / or L is a 3 to 6-membered cycloalkyl group or C 1-6 Alkylene, the 3 to 6 membered cycloalkyl group is optionally substituted by one or more C 1-6 Alkyl substituted; and / or R 2a C 1-6 Alkyl, and / or R 2b is a hydrogen atom; R 6 Preferably, it is OH or COOH, and / or L is methylcyclobutane or CH2CH2.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

6. A compound represented by general formula (VB), or a salt thereof: in, X is a halogen, preferably Cl; X 1 、X 2 、X 3 、R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in claim 3.

7. A method for preparing the compound represented by general formula (V) or a pharmaceutically acceptable salt thereof according to claim 3, the method comprising: The compound represented by the general formula (IVA) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (VB) or a salt thereof to obtain the compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof; Wherein, X is a halogen, preferably Cl; X 1 、X 2 、X 3 、R 6 , L, R 5 ,q,r,D 0 、R 4 ,p,R 1 、n、R 2a 、R 2b , T, R 3a and R 3b As defined in claim 3.

8. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of the compound represented by general formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a CCR4 inhibitor.

10. Use of the compound represented by the general formula (I) according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing cancer, tumors, cardiovascular diseases, metabolic diseases, immune or inflammatory diseases or conditions; preferably in the preparation of a medicament for treating and / or preventing immune or inflammatory diseases or conditions; the inflammatory diseases or conditions are preferably autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile diabetes Diabetes mellitus, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, vasculitis, glomerulonephritis, autoimmune thyroiditis, Behçet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, pelvic inflammatory disease, reperfusion injury, ischemia-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, atopic dermatitis, and allergic rhinitis.

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