Heterocycle-containing compound, pharmaceutical composition and application

Abstract

The invention discloses a heterocyclic ring-containing compound, a pharmaceutical composition and application. Specifically, the invention discloses a compound shown as a formula I, a formula II or a formula III or a pharmaceutically acceptable salt thereof. The compound provided by the invention has better inhibitory activity on CCR4, and can be used for treating or preventing diseases mediated by CCR4. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a heterocyclic-containing compound, a pharmaceutical composition and an application. Background Art

[0002] Chemokines are a class of small molecular weight cytokines, whose main function is to recruit leukocyte subsets under steady-state and pathological conditions, and are also known as chemotactic cytokines. According to the positions of the first two cysteine (C) residues in their main protein structures, chemokines are divided into four major subfamilies: C, CC, CXC and CX3C chemokines, which are mainly responsible for participating in the regulation of physiological processes such as organ development, immune surveillance, host defense and tissue renewal of the body.

[0003] CCR4 belongs to the G protein-coupled receptor family, and its main ligands are thymus activation-regulated chemokine (TARC / CCL17) and macrophage chemotactic factor (MDC / CCL22). CCR4 is mainly expressed in several subsets of T cells, such as Th2, Treg, Th17 and Th22, and is also expressed on the surface of platelets. Many tumor cells also highly express CCR4 on their surfaces. Diseases related to CCR4 are mainly autoimmune diseases such as asthma, rhinitis, dermatitis and T cell lymphoma. Atopic dermatitis is a chronic, recurrent, inflammatory skin disease characterized by pruritus and recurrent eczema, often accompanied by high serum IgE levels and eosinophilia. Data show that the 7-year recurrence rate of patients with atopic dermatitis is as high as 75.9%, which is the skin disease with the first disease burden among non-fatal diseases. Mechanistically, the immune response of atopic dermatitis is mainly of the Th2 type. Th2 cells express CCR3, CCR4, and CCR8 receptors, and the migration of Th2 cells to skin inflammatory tissues can be selectively inhibited by blocking the binding of the CCR4 receptor to the chemokine CCL17 / CCL22 ligands.

[0004] The CCR4 antibody drug mogamulizumab injection was launched in 2012 for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS) who have received at least one systemic therapy in the past. Currently, there is no CCR4 small molecule drug on the market. The international patent application WO2019147862 A1 discloses RPT193, which is currently in phase II clinical trials. Therefore, developing highly active CCR4 small molecule antagonists is the direction of research and development by researchers in this field. Summary of the Invention

[0005] The present invention provides a chemokine receptor antagonist, a pharmaceutical composition and an application. The compound of the present invention has good antagonistic activity against CCR4.

[0006] The present invention provides a compound represented by Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof:

[0007]

[0008] Wherein, in the compound represented by Formula I, Formula II or Formula III:

[0009] X 1 、X 3 and X 5 are each independently N or C;

[0010] X 2 、X 4 and X 6 are each independently N or CH;

[0011] Y 1 、Y 2 、Y 5 、Y 6 、Y 9 、Y 10 are each independently N or CR 25 ;

[0012] Y 3 、Y 7 、Y 11 are each independently CR 26 ;

[0013] Y 4 、Y 8 、Y 12 are each independently CR 27 or N;

[0014] Q 1 、Q 2 、Q 3 are each independently N, O, when Q 1 、Q 2 、Q 3 is O, R 1 、R 9 、R 17 does not exist;

[0015] Z 1 、Z 2 、Z 3 are each independently C or do not exist;

[0016] R 1 、R 9 、R 17 are each independently hydrogen or C1-C6 alkyl;

[0017] R 2 、R 3 、R 10 、R 11 、R 18 、R 19 Each independently is hydrogen, absent, or an alkyl group having 1 to 6 carbon atoms; R 4 、R 5 、R 6 、R 7 、R 8 、R 12 、R 13 、R 14 、R 15 、R 16 、R 20 、R 21 、R 22 、R 23 、R 24 Each independently is hydrogen or a halogen;

[0018] R 25 is an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms substituted by one or more R 25-1 ;

[0019] R 25-1 is a halogen;

[0020] R 26 is an alkyl group having 1 to 6 carbon atoms, hydrogen, or a cycloalkyl group having 3 to 8 carbon atoms;

[0021] R 27 is a halogen or

[0022] R 27-1 is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a 5- to 10-membered heteroaryl group, wherein the heteroatoms in the 5- to 10-membered heteroaryl group are independently one or more of nitrogen, oxygen, or sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0023] Alternatively, R 26 together with the C atom directly connected thereto and Y 2 form a 5- to 6-membered heteroaryl group or a 5- to 6-membered heteroaryl group substituted by one or more R 26-1 ; the heteroatoms in the 5- to 6-membered heteroaryl group are independently one or more of nitrogen, oxygen, or sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0024] Alternatively, R 26 together with the C atom directly connected thereto and Y 4 form a 5- to 6-membered heteroaryl group or a 5- to 6-membered heteroaryl group substituted by one or more R 26-2Substituted 5- or 6-membered heteroaryl; the heteroatoms in the 5- or 6-membered heteroaryl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0025] Each R 26-1 and R 26-2 are independently C1-C6 alkyl;

[0026] Ring A and ring B are independently 3- to 8-membered heterocycloalkyl or C3-C8 cycloalkyl, and ring A and ring B are connected in a fused-ring manner; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0027] Ring C and ring D are independently 3- to 8-membered heterocycloalkyl or C3-C8 cycloalkyl, and ring C and ring D are connected in a spiro-ring manner; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0028] Ring E is 3- to 8-membered heterocycloalkyl or C3-C8 cycloalkyl, and the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0029] L 1 is hydrogen, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted with one or more R I-2 , C1-C6 alkyl, C1-C6 alkyl substituted with one or more R I-3 , 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl substituted with one or more R I-4 or -NR I-5 R I-6 ; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0030] R I-1 is 3- to 8-membered heterocycloalkyl; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0031] Each R I-2 is independently -COOH, C1-C6 alkyl;

[0032] R I-3 is hydroxy;

[0033] Each R I-4Each independently is -COOH, a halogen, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted by one or more R I-4-1 substituted alkyl groups having 1 to 6 carbon atoms;

[0034] Each R I-4-1 is independently a hydroxyl group or -COOH;

[0035] R I-5 and R I-6 are independently hydrogen, an alkyl group having 1 to 6 carbon atoms, or

[0036] R I-5-1 is a heterocyclic alkyl group having 3 to 8 members, and the heteroatoms in the heterocyclic alkyl group having 3 to 8 members are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0037] L 3 is hydrogen, a cycloalkyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms substituted by one or more R II-1 substituted cycloalkyl groups having 3 to 8 carbon atoms, a heterocyclic alkyl group having 3 to 8 members, a heterocyclic alkyl group having 3 to 8 members substituted by one or more R II-2 substituted heterocyclic alkyl groups having 3 to 8 members, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted by one or more R II-3 substituted alkyl groups having 1 to 6 carbon atoms, -NR II-5 RI II-6 or -COOH, and the heteroatoms in the heterocyclic alkyl group having 3 to 8 members are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0038] Each R II-1 is independently an alkyl group having 1 to 6 carbon atoms, -COOH;

[0039] Each R II-2 is independently -COOH, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted by one or more R II-2-1 substituted alkyl groups having 1 to 6 carbon atoms;

[0040] R II-2-1 is a hydroxyl group;

[0041] Each R II-3 is independently a hydroxyl group or -COOH;

[0042] R II-4 is a heterocyclic alkyl group having 3 to 8 members, a heterocyclic alkyl group having 3 to 8 members substituted by one or more R II-4-1 substituted heterocyclic alkyl groups having 3 to 8 members, an alkenyl group having 2 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms substituted by one or more R II-4-2A substituted C1-C6 alkyl group, wherein the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0043] R II-4-1 is a C1-C6 alkyl group;

[0044] Each R II-4-2 is independently -COOH, and two R II-4-2 substituents can form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached;

[0045] R II-5 and R II-6 are independently hydrogen, a C1-C6 alkyl group,

[0046] R II-5-1 is a 3-8 membered heterocycloalkyl group, wherein the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0047] L 5 is -NR III-1 R III-2 a 3-8 membered heterocycloalkyl group, a 3-8 membered heterocycloalkyl group substituted with one or more R III-3 or a C1-C6 alkyl group;

[0048] R III-1 and R III-2 are independently hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group substituted with one or more R III-1-2 or a C1-C6 alkyl group substituted with one or more R III-1-3 ;

[0049] R III-1-1 is a 3-8 membered heterocycloalkyl group, a 3-8 membered heterocycloalkyl group substituted with one or more R III-1-1-1 a C1-C6 alkyl group, a C1-C6 alkyl group substituted with one or more R III-1-1-2 a 4-12 membered fused heterocycloalkyl group, a 4-12 membered fused heterocycloalkyl group substituted with one or more R III-1-1-3Substituted 4- to 12-membered fused heterocycloalkyl, 4- to 12-membered bridged heterocycloalkyl; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4- to 12-membered fused heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4- to 12-membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0050] Each R III-1-1-1 is independently an alkyl group having 1 to 6 carbon atoms, -NR III-1-1-1-1 R III-1-1-1-2 , hydroxyl, -COOH, an alkyl group having 1 to 6 carbon atoms substituted with one or more R III-1-1-1-3 , oxo, sulfinyl, halogen;

[0051] R III-1-1-1-1 , R III-1-1-1-2 are independently hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0052] Each R III-1-1-1-3 is independently hydroxyl, -COOH, a 4- to 10-membered heteroaryl group, and the heteroatoms in the 4- to 10-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0053] Each R III-1-1-2 is independently -COOH, two R III-1-1-2 The substituent may form a C3 - C8 cycloalkyl group, -NR III-1-1-2-1 R III-1-1-2-2 , a 3- to 8-membered heterocycloalkyl group with the C atom to which it is commonly attached;

[0054] R III-1-1-2-1 , R III-1-1-2-2 are independently hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0055] R III-1-1-3 is oxo;

[0056] Each R III-1-2 is independently an alkyl group having 1 to 6 carbon atoms, -COOH;

[0057] Each R III-1-3 is independently a 3- to 8-membered heterocycloalkyl group, hydroxyl;

[0058] Each R III-3 is independently -COOH, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with one or more R III-3-1 ;

[0059]

[0060] Each R III-3-1 is independently a hydroxyl group or NR III-3-1-1 R III-3-1-2 ;

[0061] R III-3-1-1 and R III-3-1-2 are each independently a C1-C6 alkyl group;

[0062] R III-3-2 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R III-3-2-1 substituents;

[0063] Each R III-3-2-1 is independently -COOH, and two R III-3-2-1 substituents can form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached;

[0064] L 2 is absent, hydrogen or a C1-C6 alkyl group;

[0065] L 4 is absent, hydrogen or a C1-C6 alkyl group;

[0066] L 6 is absent, hydrogen, a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more R III’-1 substituents;

[0067] R III’-1 is a hydroxyl group.

[0068] In one embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof:

[0069]

[0070]

[0071] wherein, in the compound represented by Formula I, Formula II or Formula III:

[0072] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 are each independently N or C;

[0073] Y 1, Y 2 , Y 5 , Y 6 , Y 9 , Y 10 Each independently is N or CR 25 ;

[0074] Y 3 , Y 7 , Y 11 Each independently is CR 26 ;

[0075] Y 4 , Y 8 , Y 12 Each independently is CR 27 or N;

[0076] Q 1 , Q 2 , Q 3 Each independently is N, O, when Q 1 , Q 2 , Q 3 is O, R 1 , R 9 , R 17 does not exist;

[0077] Z 1 , Z 2 , Z 3 Each independently is C, or does not exist;

[0078] R 1 , R 9 , R 17 Each independently is hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0079] R 2 , R 3 , R 10 , R 11 , R 18 , R 19 Each independently is hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0080] R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , R 14 , R 15 , R 16 , R 20 , R 21 , R 22 , R23 , R 24 are each independently hydrogen or a halogen;

[0081] R 25 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more R 25-1 substituents;

[0082] R 25-1 is a halogen;

[0083] R 26 is a C1-C6 alkyl group or hydrogen;

[0084] R 27 is a halogen or

[0085] R 27-1 is a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a 5- to 10-membered heteroaryl group, where the heteroatoms in the 5- to 10-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0086] Ring A and Ring B are independently 3- to 8-membered heterocycloalkyl groups or C3-C8 cycloalkyl groups, and Ring A and Ring B are fused; the heteroatoms in the 3- to 8-membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0087] Ring C and Ring D are independently 3- to 8-membered heterocycloalkyl groups or C3-C8 cycloalkyl groups, and Ring C and Ring D are spiro-fused; the heteroatoms in the 3- to 8-membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0088] Ring E is a 3- to 8-membered heterocycloalkyl group, where the heteroatoms in the 3- to 8-membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0089] L 1 is hydrogen, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group substituted by one or more R I-2 substituents, a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R I-3 substituents, a 3- to 8-membered heterocycloalkyl group, a 3- to 8-membered heterocycloalkyl group substituted by one or more R I-4 substituents, -NR I-5 R I-6 ; the heteroatoms in the 3- to 8-membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0090] R I-1 is a 3- to 8-membered heterocyclic alkyl group; the heteroatoms in the 3- to 8-membered heterocyclic alkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0091] R I-2 is -COOH or a C1-C6 alkyl group;

[0092] R I-3 is a hydroxyl group;

[0093] R I-4 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more R I-4-1 ;

[0094] R I-4-1 is a hydroxyl group;

[0095] R I-5 and R I-6 are independently hydrogen, a C1-C6 alkyl group, or

[0096] R I-5-1 is a 3- to 8-membered heterocyclic alkyl group; the heteroatoms in the 3- to 8-membered heterocyclic alkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0097] L 3 is hydrogen, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group substituted by one or more R II-1 ; a 3- to 8-membered heterocyclic alkyl group, a 3- to 8-membered heterocyclic alkyl group substituted by one or more R II-2 ; a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R II-3 ; -NR II-5 RI II-6 ; -COOH; the heteroatoms in the 3- to 8-membered heterocyclic alkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0098] R II-1 is a C1-C6 alkyl group or -COOH;

[0099] R II-2 is a C1-C6 alkyl group or a C1-C6 alkyl group substituted by one or more R II-2-1 ;

[0100] R II-2-1 is a hydroxyl group;

[0101] R II-3is hydroxy, -COOH;

[0102] R II-4 is a 3- to 8-membered heterocycloalkyl group, a 3- to 8-membered heterocycloalkyl group substituted by one or more R II-4-1 substituents, a C2-C6 alkenyl group, a C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more R II-4-2 substituents. The heteroatoms in the 3- to 8-membered heterocycloalkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0103] R II-4-1 is a C1-C6 alkyl group;

[0104] R II-4-2 is -COOH, two R II-4-2 substituents may form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached;

[0105] R II-5 and R II-6 are independently hydrogen, a C1-C6 alkyl group,

[0106] R II-5-1 is a 3- to 8-membered heterocycloalkyl group. The heteroatoms in the 3- to 8-membered heterocycloalkyl groups are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0107] L 5 is -NR III-1 R III-2 a 3- to 8-membered heterocycloalkyl group, a 3- to 8-membered heterocycloalkyl group substituted by one or more R III-3 substituents, or a C1-C6 alkyl group;

[0108] R III-1 and R III-2 are independently hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a C3-C8 cycloalkyl group substituted by one or more R III-1-2 substituents, or a C1-C6 alkyl group substituted by one or more R III-1-3 substituents;

[0109] R III-1-1 is a 3- to 8-membered heterocycloalkyl group, a 3- to 8-membered heterocycloalkyl group substituted by one or more R III-1-1-1 substituents, a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R III-1-1-2 substituents, a 4- to 12-membered fused heterocycloalkyl group, or a 4- to 12-membered fused heterocycloalkyl group substituted by one or more R III-1-1-3Substituted 4- to 12-membered fused heterocycloalkyl, 4- to 12-membered bridged heterocycloalkyl; the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4- to 12-membered fused heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4- to 12-membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0110] R III-1-1-1 is C1-C6 alkyl, -NR III-1-1-1-1 R III-1-1-1-2 , hydroxy, -COOH, C1-C6 alkyl substituted with one or more R III -1-1-1-3 substituents, oxo, sulfinyl, halogen;

[0111] R III-1-1-1-1 and R III-1-1-1-2 are each independently hydrogen, C1-C6 alkyl;

[0112] R III-1-1-1-3 is hydroxy, -COOH, 4- to 10-membered heteroaryl, and the heteroatoms in the 4- to 10-membered heteroaryl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0113] R III-1-1-2 is -COOH, two R III-1-1-2 substituents may form a C3-C8 cycloalkyl, -NR III-1-1-2-1 R III-1-1-2-2 with the C atom to which they are commonly attached, or a 3- to 8-membered heterocycloalkyl;

[0114] R III-1-1-2-1 and R III-1-1-2-2 are independently hydrogen, C1-C6 alkyl;

[0115] R III-1-1-3 is oxo;

[0116] R III-1-2 is C1-C6 alkyl, -COOH;

[0117] R III-1-3 is 3- to 8-membered heterocycloalkyl, hydroxy;

[0118] R III-3 is C1-C6 alkyl, C1-C6 alkyl substituted with one or more R III-3-1 substituents,

[0119] R III-3-1 is hydroxy, NR III-3-1-1 R III-3-1-2 ;

[0120] R III-3-1-1 and R III-3-1-2 are each independently a C1-C6 alkyl group;

[0121] R III-3-2 is a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R III-3-2-1 ;

[0122] R III-3-2-1 is -COOH, two R III-3-2-1 substituents can together with the C atom to which they are attached form a C3-C8 cycloalkyl group;

[0123] L 2 is hydrogen, a C1-C6 alkyl group;

[0124] L 4 is hydrogen, a C1-C6 alkyl group;

[0125] L 6 is hydrogen, a C1-C6 alkyl group, a C1-C6 alkyl group substituted by one or more R III’-1 ;

[0126] R III’-1 is hydroxy.

[0127] In one embodiment of the present invention, the compound of formula I as described above or its pharmaceutically acceptable salt, or its deuterated form, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its prodrug or its metabolite, wherein:

[0128] X 1 is N or C;

[0129] X 2 is N;

[0130] Y 1 is N;

[0131] Y 2 is N;

[0132] Y 3 is CR 26 ;

[0133] R 26 is hydrogen, a C1-C6 alkyl group or a C3-C8 cycloalkyl group;

[0134] Y 4 is CR 27 or N;

[0135] R 27 is a halogen,

[0136] R 27-1 is an alkyl group having 1 to 6 carbon atoms;

[0137] Alternatively, R 26 together with the C atom directly connected thereto and Y 2 together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered heteroaryl group substituted with one or more R 26-1 ; the heteroatoms in the 5- or 6-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0138] Alternatively, R 26 together with the C atom directly connected thereto and Y 4 together form a 5- or 6-membered heteroaryl group or a 5- or 6-membered heteroaryl group substituted with one or more R 26-2 ; the heteroatoms in the 5- or 6-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0139] Each R 26-1 and R 26-2 are independently an alkyl group having 1 to 6 carbon atoms;

[0140] Q 1 is N;

[0141] Z 1 is C;

[0142] R 1 is hydrogen;

[0143] R 2 is hydrogen;

[0144] R 3 is an alkyl group having 1 to 6 carbon atoms;

[0145] R 4 is a halogen;

[0146] R 6 is a halogen;

[0147] R 5 , R 7 , R 8 are hydrogen.

[0148] In a certain embodiment of the present invention, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, wherein:

[0149] X 1 is N or C;

[0150] X 2 is N;

[0151] Y 1 is N;

[0152] Y 2 is N;

[0153] Y 3 is CR 26 ;

[0154] R 26 is hydrogen, C1-C6 alkyl;

[0155] Y 4 is CR 27 ;

[0156] R 27 is halogen,

[0157] R 27-1 is C1-C6 alkyl;

[0158] Q 1 is N;

[0159] Z 1 is C;

[0160] R 1 is hydrogen;

[0161] R 2 is hydrogen;

[0162] R 3 is C1-C6 alkyl;

[0163] R 4 is halogen;

[0164] R 6 is halogen;

[0165] R 5 、R 7 、R 8 are hydrogen.

[0166] In one embodiment of the present invention, the compound of formula II or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, wherein:

[0167] X 3 is N or C;

[0168] X4 is N;

[0169] Y 5 is N;

[0170] Y 6 is N;

[0171] Y 7 is CR 26 ;

[0172] R 26 is an alkyl group having 1 to 6 carbon atoms;

[0173] Y 8 is CR 27 ;

[0174] R 27 is a halogen;

[0175] Q 2 is N;

[0176] Z 2 is C;

[0177] R 10 is hydrogen;

[0178] R 11 is an alkyl group having 1 to 6 carbon atoms;

[0179] R 12 is a halogen;

[0180] R 14 is a halogen;

[0181] R 13 、R 15 、R 16 are hydrogen.

[0182] In one embodiment of the present invention, the compound represented by Formula III or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, wherein:

[0183] X 5 is C;

[0184] X 6 is N;

[0185] Y 9 is N;

[0186] Y 10 is N;

[0187] Y 11 is CR 26 ;

[0188] R 26 is hydrogen, C1-C6 alkyl;

[0189] Y 12 is CR 27 、 or N;

[0190] R 27-1 is C3-C8 cycloalkyl, 5-10 membered heteroaryl, the heteroatoms in the 5-10 membered heteroaryl are independently one or more of nitrogen, oxygen, sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0191] R 27 is halogen;

[0192] Q 3 is N or O;

[0193] Z 3 is C;

[0194] R 18 is hydrogen;

[0195] R 19 is C1-C6 alkyl;

[0196] R 20 is halogen;

[0197] R 22 is halogen;

[0198] R 21 、R 23 、R 24 are hydrogen.

[0199] In one embodiment of the present invention, a compound of formula III or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, wherein:

[0200] R 26 is C1-C6 alkyl;

[0201] L 5 is -NR III-1 R III-2 、3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R III-3 、C1-C6 alkyl;

[0202] R III-1 、R III-2 are independently C1-C6 alkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl substituted with one or more R III-1-2Substituted C3-C8 cycloalkyl, or C1-C6 alkyl substituted by one or more R III-1-3 Substituted C1-C6 alkyl;

[0203] R III-1-1 Is 3-8 membered heterocycloalkyl, or 3-8 membered heterocycloalkyl substituted by one or more R III-1-1-1 Substituted 3-8 membered heterocycloalkyl, C1-C6 alkyl, or C1-C6 alkyl substituted by one or more R III-1-1-2 Substituted C1-C6 alkyl, 4-12 membered fused heterocycloalkyl, or 4-12 membered fused heterocycloalkyl substituted by one or more R III-1-1-3 Substituted 4-12 membered fused heterocycloalkyl, 4-12 membered bridged heterocycloalkyl; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12 membered fused heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12 membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0204] Each R III-1-1-1 Is independently C1-C6 alkyl, -NR III-1-1-1-1 R III-1-1-1-2 Hydroxyl, -COOH, C1-C6 alkyl substituted by one or more R III-1-1-1-3 Substituted C1-C6 alkyl, oxo, sulfonyl, halogen;

[0205] R III-1-1-1-1 R III-1-1-1-2 Is independently hydrogen, C1-C6 alkyl;

[0206] R III-1-1-1-3 Is hydroxyl, -COOH, 4-10 membered heteroaryl, and the heteroatoms in the 4-10 membered heteroaryl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0207] Each R III-1-1-2 Is independently -COOH, or two R III-1-1-2 The substituent can form a C3-C8 cycloalkyl, -NR III-1-1-2-1 R III-1-1-2-2 3-8 membered heterocycloalkyl with the C atom to which it is commonly attached;

[0208] R III-1-1-2-1 R III-1-1-2-2 Is independently hydrogen, C1-C6 alkyl;

[0209] R III-1-1-3 Is oxo;

[0210] Each RIII-1-2 Each is independently an alkyl group of C1-C6 or -COOH;

[0211] Each R III-1-3 is independently a heterocyclic alkyl group of 3-8 members or a hydroxyl group;

[0212] Each R III-3 is independently -COOH, an alkyl group of C1-C6, an alkyl group of C1-C6 substituted by one or more R III-3-1 ;

[0213]

[0214] R III-3-1 is NR III-3-1-1 R III-3-1-2 ;

[0215] R III-3-1-1 and R III-3-1-2 are each independently an alkyl group of C1-C6;

[0216] R III-3-2 is an alkyl group of C1-C6, an alkyl group of C1-C6 substituted by one or more R III-3-2-1 ;

[0217] R III-3-2-1 is -COOH, and two R III-3-2-1 substituents may form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached;

[0218] L 6 is absent, hydrogen, an alkyl group of C1-C6, an alkyl group of C1-C6 substituted by one or more R III’-1 ;

[0219] R III’-1 is a hydroxyl group.

[0220] In one embodiment of the present invention, R III-3-1 is NR III-3-1-1 R III-3-1-2 .

[0221] In one embodiment of the present invention, R 26 is an alkyl group of C1-C6; L 5 is -NR III-1 R III-2 , a heterocyclic alkyl group of 3-8 members, a heterocyclic alkyl group of 3-8 members substituted by one or more R III-3 or an alkyl group of C1-C6.

[0222] In one embodiment of the present invention, R III-1 and R III-2 are independently an alkyl group of C1-C6, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted by one or more R III-1-2 or C1-C6 alkyl substituted by one or more R III-1-3 .

[0223] In one embodiment of the present invention, a compound represented by Formula III or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, wherein:

[0224] R 26 is C1-C6 alkyl;

[0225] L 5 is -NR III-1 R III-2 , 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted by one or more R III-3 or C1-C6 alkyl;

[0226] R III-1 , R III-2 are independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted by one or more R III-1-2 or C1-C6 alkyl substituted by one or more R III-1-3 ;

[0227] R III-1-1 is 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyl substituted by one or more R III-1-1-1 , C1-C6 alkyl, C1-C6 alkyl substituted by one or more R III-1-1-2 , 4-12 membered fused heterocycloalkyl, 4-12 membered fused heterocycloalkyl substituted by one or more R III-1-1-3 or 4-12 membered bridged heterocycloalkyl; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12 membered fused heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12 membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3;

[0228] R III-1-1-1 is C1-C6 alkyl, -NR III-1-1-1-1 R III-1-1-1-2 , hydroxy, -COOH, C1-C6 alkyl substituted by one or more R III -1-1-1-3 , oxo, sulfinyl, or halogen;

[0229] R III-1-1-1-1 、R III-1-1-1-2 Each independently represents hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0230] R III-1-1-1-3 is a hydroxyl group, -COOH, or a 4- to 10-membered heteroaryl group, wherein the heteroatoms in the 4- to 10-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4;

[0231] R III-1-1-2 is -COOH, and two R III-1-1-2 substituents can form a C3 - C8 cycloalkyl group, -NR III-1-1-2-1 R III-1-1-2-2 with the C atom to which they are commonly attached, or a 3- to 8-membered heterocycloalkyl group;

[0232] R III-1-1-2-1 、R III-1-1-2-2 Each independently represents hydrogen or an alkyl group having 1 to 6 carbon atoms;

[0233] R III-1-1-3 is oxo;

[0234] R III-1-2 is an alkyl group having 1 to 6 carbon atoms, -COOH;

[0235] R III-1-3 is a 3- to 8-membered heterocycloalkyl group, a hydroxyl group;

[0236] R III-3 is an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with one or more R III-3-1 substituents,

[0237] R III-3-1 is NR III-3-1-1 R III-3-1-2 ;

[0238] R III-3-1-1 、R III-3-1-2 Each independently represents an alkyl group having 1 to 6 carbon atoms;

[0239] R III-3-2 is an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with one or more R III-3-2-1 substituents;

[0240] R III-3-2-1 is -COOH, and two R III-3-2-1 substituents can form a C3 - C8 cycloalkyl group with the C atom to which they are commonly attached;

[0241] L 6is hydrogen, a C1-C6 alkyl group, or a C1-C6 alkyl group substituted by one or more R III’-1 substituted C1-C6 alkyl group;

[0242] R III’-1 is a hydroxyl group.

[0243] In one embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, wherein:

[0244] Ring A is a 3-8 membered heterocycloalkyl group or a C3-C8 cycloalkyl group; preferably a 5-membered heterocycloalkyl group, a 5-membered cycloalkyl group, or a 3-membered cycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1;

[0245] Ring B is a 3-8 membered heterocycloalkyl group; preferably a 5-membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1;

[0246] Ring C is a 3-8 membered heterocycloalkyl group or a C3-C8 cycloalkyl group; preferably a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, or a 4-membered cycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1;

[0247] Ring D is a 3-8 membered heterocycloalkyl group; preferably a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1;

[0248] Ring E is a 3-8 membered heterocycloalkyl group; preferably a 4-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1.

[0249] In one embodiment of the present invention, the compound represented by Formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, satisfies one or more of the following conditions:

[0250] (1) One or more of R 25 , R 26 , R 1 , R 2 , R 3 , R 27-1 , L 1 , R I-2 , R I-4 , R I-5 , R I-6 , R 25 is substituted by one or more R 25-1 , L 1 is substituted by one or more R I-3 , and R I-4 is substituted by one or more R I-4-1 in the C1-C6 alkyl group, and the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl;

[0251] (2) In R 25-1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 27 , the halogen is independently F, Cl, Br or I;

[0252] (3) In R 27-1 , ring A, ring B, L 1 , the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclopentane;

[0253] (4) In ring A, ring B, L 1 , R I-1 , R I-5-1 , R I-5-1 , the 3- to 8-membered heterocycloalkyl group is independently a 5- or 6-membered heterocycloalkyl group;

[0254] (5) In ring A, ring B, L 1 , R I-1 , R I-5-1 , R I-5-1Among them, the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2, or 3, preferably 1;

[0255] (6)R 27-1 is an alkyl group of C1-C6.

[0256] In a certain embodiment of the present invention, in the compound of formula I, R 26 Among them, the C3-C8 cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.

[0257] In a certain embodiment of the present invention, in the compound of formula I, the R 26 and the C atom directly connected thereto and Y 2 together form a 5- to 6-membered heteroaryl and a 5- to 6-membered heteroaryl substituted by one or more R 26-1 In the substituted 5- to 6-membered heteroaryl, the heteroatom in the 5- to 6-membered heteroaryl is selected from N; the 5- to 6-membered heteroaryl is preferably Preferably

[0258] In a certain embodiment of the present invention, in the compound of formula I, R 26 and the C atom directly connected thereto and Y 4 together form a 5- to 6-membered heteroaryl and a 5- to 6-membered heteroaryl substituted by one or more R 26-2 In the substituted 5- to 6-membered heteroaryl, the heteroatom in the 5- to 6-membered heteroaryl is selected from N; the 5- to 6-membered heteroaryl is preferably Preferably

[0259] In a certain embodiment of the present invention, in the compound of formula I, R 26-1 and R 26-2 Among them, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl.

[0260] In a certain embodiment of the present invention, R I-4 Among them, the halogens are independently F, Cl, Br or I; preferably F.

[0261] In a certain embodiment of the present invention, the compound of formula II or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, satisfies one or more of the following conditions:

[0262] (1)R 25 、R26 , R 9 , R 10 , R 11 , R 27-1 , L 3 , R II-1 , R II-2 , R II-4 , R II-4-1 , R II-5 , R II-6 , R 25 in which is substituted by one or more R 25-1 , L 3 in which is substituted by one or more R II-3 substituted C1-C6 alkyl, R II-2 in which is substituted by one or more R II-2-1 substituted C1-C6 alkyl, R II-4 in which is substituted by one or more R II-4-2 substituted C1-C6 alkyl, wherein the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl;

[0263] (2) R 25-1 , R 12 , R 13 , R 14 , R 15 , R 16 , R 27 in which the halogen is independently F, Cl, Br or I;

[0264] (3) R 27-1 , ring C, ring D, L 3 , L 3 in which is substituted by one or more R II-1 substituted C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclobutane;

[0265] (4) Ring C, ring D, L 3 , R II-4 , L 3 in which is substituted by one or more R II-2 substituted 3-8 membered heterocycloalkyl, R II-4 in which is substituted by one or more R II-4-1 substituted 3-8 membered heterocycloalkyl, wherein the 3-8 membered heterocycloalkyl is independently a 4, 5 or 6 membered heterocycloalkyl;

[0266] (5) Ring C, ring D, L 3 , R II-4 , L 3 in which is substituted by one or more R II-2Substituted 3- to 8-membered heterocycloalkyl, R II-4 in which one or more R II-4-1 substitute the 3- to 8-membered heterocycloalkyl, wherein the heteroatoms in the 3- to 8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2, or 3, preferably 1.

[0267] In one embodiment of the present invention, the compound of formula III as shown or its pharmaceutically acceptable salt, or its deuterated form, or its optical isomer, geometric isomer, tautomer, or isomer mixture, or its prodrug or its metabolite, satisfies one or more of the following conditions:

[0268] (1) R 25 , R 26 , R 17 , R 18 , R 19 , R 27-1 , L 5 , R III-1 , R III-2 , R III-1-1 , R III-1-1-1 , R III-1-1-1-1 , R III -1-1-1-2 , R III-1-1-2-1 , R III-1-1-2-2 , R III-1-2 , R III-3 , R III-3-1-1 , R III-3-1-2 , R III-3-2 , L 2 , L 4 , L 6 , R III-1 in which one or more R III-1-3 substitute the C1-C6 alkyl, R III-2 in which one or more R III-1-3 substitute the C1-C6 alkyl, R III-1-1 in which one or more R III-1-1-2 substitute the C1-C6 alkyl, R III-1-1-1 in which one or more R III-1-1-1-3 substitute the C1-C6 alkyl, R III-3 in which one or more R III-3-1 substitute the C1-C6 alkyl, R III-3-2 in which one or more R III-3-2-1 substitute the C1-C6 alkyl, L 6 in which one or more R III’-1Among the substituted C1-C6 alkyl groups, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl;

[0269] (2) R 25-1 , R 20 , R 21 , R 22 , R 23 , R 24 , R 27 , R III-1-1-1 Among them, the halogen is independently F, Cl, Br or I;

[0270] (3) R 27-1 , R III-1 , R III-2 , R III-1 In which the C3-C8 cycloalkyl group substituted by one or more R III-1-2 , R III-2 In which the C3-C8 cycloalkyl group substituted by one or more R III-1-2 , R III-1-1-2 In which two R III-1-1-2 Substituents can form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached, R III-3-2-1 In which two R III-3-2-1 Substituents can form a C3-C8 cycloalkyl group with the C atom to which they are commonly attached. Among them, the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane, cyclobutane;

[0271] (4) Ring E, L 5 , R III-1-1-2 , R III-1-3 , L 5 In which the 3- to 8-membered heterocycloalkyl group substituted by one or more R III-3 , R III-1-1 , R III-1-1 In which the 3- to 8-membered heterocycloalkyl group substituted by one or more R III-1-1-1 Among them, the 3- to 8-membered heterocycloalkyl group is independently a 4-, 5- or 6-membered heterocycloalkyl group;

[0272] (5) Ring E, L 5 , R III-1-1-2 , R III-1-3 , L 5 In which the 3- to 8-membered heterocycloalkyl group substituted by one or more R III-3 , R III-1-1 , R III-1-1 In which the 3- to 8-membered heterocycloalkyl group substituted by one or more R III-1-1-1In the substituted 3- to 8-membered heterocycloalkyl group, the heteroatoms in the 3- to 8-membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2, or 3, preferably 1;

[0273] (6)R III-1-1 in the 4- to 12-membered fused heterocycloalkyl group, R III-1-1 in the 4- to 12-membered fused heterocycloalkyl group substituted by one or more R III-1-1-3 in the 4- to 12-membered fused heterocycloalkyl group, the 4- to 12-membered fused heterocycloalkyl group is a C3-C8 cycloalkyl group fused to a 3- to 8-membered heterocycloalkyl group, preferably a cyclopropane fused to a 5-membered heterocyclic group;

[0274] (7)R III-1-1 in the 4- to 12-membered bridged heterocycloalkyl group, the 4- to 12-membered bridged heterocycloalkyl group is preferably a 6-membered bridged heterocyclic group.

[0275] In one embodiment of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or metabolite thereof, is characterized in that it satisfies one or more of the following conditions:

[0276] (1) wherein represents connection to L 1 connection, represents connection to L 2 connection;

[0277] (2)L 1 is H,

[0278]

[0279] (3)L 2 is H;

[0280] (4) wherein represents connection to X in ring B 2 connection.

[0281] In one embodiment of the present invention, in the compound of formula I, the L 1 is H,

[0282] In one embodiment of the present invention, in the compound of formula I, wherein represents connection to X in ring B 2 connection.

[0283] In one embodiment of the present invention, in the compound represented by Formula I,

[0284] In one embodiment of the present invention, the compound represented by Formula II or a pharmaceutically acceptable salt thereof, or a deuterated compound, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, satisfies one or more of the following conditions:

[0285] (1) Wherein represents connection to L 3 and represents connection to L 4 ;

[0286] (2) L 3 is

[0287]

[0288] (3) L 4 is H;

[0289] (4) Wherein represents connection to X of Ring D 4 ;

[0290] In one embodiment of the present invention, in the compound represented by Formula II, the L 3 is

[0291] In one embodiment of the present invention, in the compound represented by Formula II,

[0292] In one embodiment of the present invention, the compound represented by Formula III or a pharmaceutically acceptable salt thereof, or a deuterated compound, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, satisfies one or more of the following conditions:

[0293] (1) Wherein represents connection to L 5 and represents connection to L 6 ;

[0294] (2) L 5 is -NHCH3,

[0295]

[0296] (3)L 6 is H or -CH3, -CH2OH;

[0297] (4) wherein represents being connected to X of ring E 6 and is connected.

[0298] In a certain embodiment of the present invention, in the compound represented by formula III, L 5 is -NHCH3,

[0299]

[0300]

[0301] In a certain embodiment of the present invention, in the compound represented by formula III,

[0302] In a certain embodiment of the present invention, the compound represented by formula I is the compound represented by formula I-1:

[0303]

[0304] wherein, R 3 is an alkyl group having 1 to 6 carbon atoms,

[0305] L 1 、L 2 、ring A, ring B, X 1 、X 2 、Y 1 、Y 2 、Y 3 、Y 4 、Q 1 、R 1 、R 4 、R 5 、R 6 、R 7 and R 8 are defined as described in any one of the above.

[0306] In a certain embodiment of the present invention, the compound represented by formula II is the compound represented by formula II-1:

[0307]

[0308] Among them, R 11 is an alkyl group having 1 to 6 carbon atoms,

[0309] L 3 、L 4 、ring C, ring D, X 3 、X 4 、Y 5 、Y 6 、Y 7 、Y 8 、Q 2 、R 9 、R 12 、R 13 、R 14 、R 15 and R 16 are defined as described in any one of the above.

[0310] In a certain embodiment of the present invention, the compound represented by Formula III is the compound represented by Formula III-1:

[0311]

[0312] Among them, R 19 is an alkyl group having 1 to 6 carbon atoms,

[0313] L 5 、L 6 、ring E, X 5 、X 6 、Y 9 、Y 10 、Y 11 、Y 12 、Q 3 、R 17 、R 20 、R 21 、R 22 、R 23 and R 24 are defined as described in any one of the above.

[0314] In a certain embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, is characterized in that the compound represented by Formula I, Formula II or Formula III is any one of the following compounds:

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324] The present invention also provides a pharmaceutical composition, which comprises:

[0325] (1) A compound represented by formula I, formula II or formula III as described in any one of the present invention, or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, geometric isomer, tautomer or mixture of isomers thereof, or a prodrug or metabolite thereof, and

[0326] (2) Pharmaceutically acceptable excipients.

[0327] The present invention also provides the use of a compound represented by formula I, formula II or formula III as described above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a drug for a CCR4 antagonist. In particular, the drug is used for treating or preventing a disease or disorder mediated by CCR4.

[0328] The disease or disorder mediated by CCR4 is selected from one or more immune-related diseases such as atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis; or the disease or disorder mediated by CCR4 is cancer.

[0329] The cancer is selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cell carcinoma, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, ependymoma, neuroblastoma, ganglioneuroma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma and Wilms tumor.

[0330] The present invention also provides the application of a compound represented by formula I, formula II or formula III as described above, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above in the preparation of a drug for treating or preventing a disease or disorder.

[0331] The disease or disorder is selected from one or more immune-related diseases such as atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis; or, the disease or disorder is cancer.

[0332] The cancer is selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cell carcinoma, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, ependymoma, neuroblastoma, ganglioneuroma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma, and Wilms tumor.

[0333] Unless otherwise specified, the terms used in the present invention have the following meanings:

[0334] Those skilled in the art can understand that, according to the convention used in the art, the in the structural formula of the group described in the present invention means that the corresponding group is connected to other fragments or groups in the compound through this site.

[0335] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0336] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, the base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0337] The term "pharmaceutical excipient" may be those excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after administration to a subject, or to promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipient may be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesive agent, glidant, wetting agent, gelling agent, absorption retardant, dissolution inhibitor, enhancer, adsorbent, buffer, chelating agent, preservative, coloring agent, flavoring agent and sweetening agent.

[0338] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0339] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be in a controlled-release or delayed-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, caplets, soft capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injection solutions, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the pharmaceutical composition include but are not limited to eye drops and other ophthalmic preparations; aerosols: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0340] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, that is, causing the symptoms of the clinical disease not to develop; (2) inhibiting the disease, that is, preventing the development of clinical symptoms; (3) alleviating the disease, that is, causing the clinical symptoms to subside.

[0341] "Prevention" as described in the present invention refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0342] The expression "a certain group substituted by one or more substituents" means that one or more hydrogen atoms in the certain group are independently replaced by the substituents. When multiple substituents appear simultaneously, unless otherwise specified, their definitions are independent of each other and do not affect each other. In addition, combinations of substituents and / or variables are only permitted if the combination results in a stable compound.

[0343] The term "plurality" means 2, 3, 4 or 5, preferably 2 or 3.

[0344] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0345] The term "alkyl" means a straight-chain or branched-chain, saturated monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl includes, but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0346] The term "heterocycloalkyl" means a cyclic group having a specified number of ring atoms (e.g., 3-8 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatoms (one, two or three of N, O and S), which is a monocyclic ring and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydropyrrolyl, tetrahydrofuryl, morpholinyl and piperidinyl, etc.

[0347] The term "cycloalkyl" means a non-aromatic, saturated monovalent cycloalkyl group having a specified number of ring carbon atoms (e.g., C3-C8), which is a monocyclic ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0348] The term "spiroheterocycle" refers to a polycyclic heterocyclic group having a specified number (e.g., 7-12 membered) of monocyclic rings sharing one atom (called a spiro atom), for example:

[0349] The term "fused heterocycle" refers to a heterocycle having a specified number (e.g., 4-12 membered) and containing two or more heterocyclic rings, which are connected by sharing two atoms, for example:

[0350] The term "bridged heterocycle" refers to a heterocycle having a specified number (e.g., 4-12 membered) and containing two or more heterocyclic rings, which are connected by sharing more than two atoms, for example:

[0351] On the basis of not violating the common knowledge in the art, the above preferred conditions can be arbitrarily combined to obtain various preferred examples of the present invention.

[0352] The reagents and raw materials used in the present invention are all commercially available.

[0353] The positive and progressive effects of the present invention are as follows: The compounds of the present invention have good antagonistic activity against CCR4. Detailed implementation manners

[0354] The present invention will be further illustrated below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0355] The structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 HNMR) and / or mass spectrometry (MS).

[0356] 1 The chemical shift (δ) of 1H NMR is recorded in PPM (10 -6 ). NMR is carried out by a Bruker AVANCE-400 spectrometer.

[0357] LC-MS is determined by an Agilent 1200 HPLC / 6120 mass spectrometer.

[0358] HPLC is determined by an Agilent 1260 high performance liquid chromatograph. Specific HPLC conditions: Mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; column time: 15 min; column type: Xselect from Waters company, 5 μm, 4.6×250 mm.

[0359] The thin layer silica gel plate is Liangchen Silica Source HSGF254 or Qingdao GF254 silica gel plate. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0360] Preparation Example 1

[0361]

[0362] First step:

[0363] Add (R)-1-(2,4-dichlorophenyl)ethylamine (1-a) (1.01 g, 5.31 mmol), 2,4,5-trichloro-6-methylpyrimidine (1.049 g, 5.31 mmol) (1-b), and triethylamine (800 mg, 7.92 mmol) into acetonitrile (10 mL), and stir at room temperature overnight. After the reaction is completed, the reaction solution is evaporated to dryness to obtain a crude product. The crude product is subjected to silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 35%) to obtain (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (965 mg, 52%). LC-MS: 351.9 [M+H] +。

[0364] Step 2:

[0365] Disperse (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (100 mg, 0.28 mmol) and tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-d) (200 mg, 0.94 mmol) in a mixed solvent of tert-butanol (5 mL) and water (5 mL). Add sodium hydroxide (140 mg, 3.5 mmol), and heat the system to 90 °C and stir overnight. After the reaction is completed, cool the system to room temperature, and add saturated ammonium chloride aqueous solution (5 mL). Evaporate the mixture to dryness to obtain the crude product, and obtain tert-butyl (3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-e) (92 mg, 62.4%) by silica gel column chromatography (methanol / dichloromethane = 0 - 6%). LC-MS: 526.1 [M+H] + 。

[0366] Step 3:

[0367] Add ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) to tert-butyl (3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-e) (92 mg, 0.174 mmol), and react at room temperature for 5 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, add 5 mL of dichloromethane to the residue, and concentrate again under reduced pressure to obtain the hydrochloride salt of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidin-4-amine (1-f) (86 mg). LC-MS: 426.1 [M+H] + 。

[0368] Preparation Example 2

[0369]

[0370] Step 1:

[0371] (R)-2,5-Dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (351 mg, 1.0 mmol) and the hydrochloride of tert-butyl azetidin-3-yl(methyl)carbamate (2-a) (222 mg, 1.0 mmol) were dispersed in a mixed solvent of tert-butanol (8 mL) and water (8 mL). Sodium hydroxide (280 mg, 7.0 mmol) was added, and the system was heated to 90 °C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, and saturated aqueous ammonium chloride solution (5 mL) was added. The mixture was evaporated to dryness to obtain a crude product, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain tert-butyl (R)-(1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamate (2-b) (480 mg, 96%). LC-MS: 500.2 [M+H] + .

[0372] Step 2:

[0373] A solution of hydrogen chloride in ethyl acetate (8 mL, 2 mol / L) was added to tert-butyl (R)-(1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamate (2-b) (480 mg, 0.96 mmol), and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was added with dichloromethane (5 mL), and then concentrated under reduced pressure again. The crude product was purified by column chromatography to obtain (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (2-c) (342 mg). LC-MS: 400.1 [M+H] + . 1 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.1 Hz, 1H), 5.50 (q, J = 7.1 Hz, 1H), 4.22 (dd, J = 9.8, 7.0 Hz, 1H), 4.08 (dd, J = 9.5, 7.2 Hz, 1H), 3.93–3.79 (m, 2H), 3.74 (dd, J = 9.9, 4.2 Hz, 1H), 2.56 (s, 3H), 2.29 (s, 3H), 1.50 (d, J = 7.1 Hz, 3H).

[0374] Preparation Example 3

[0375]

[0376] Step 1:

[0377] Add NaBH4 (126 mg, 3.329 mmol) to a methanol solution (6 mL) of tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-a) (500 mg, 2.22 mmol). The reaction mixture was reacted at room temperature and monitored by TLC. After completion of the reaction, methanol was evaporated under reduced pressure. The residue was added with 30 mL of ethyl acetate (30 mL), washed with water (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 500 mg of tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-b) with a yield of 99.1%.

[0378] Step 2:

[0379] Add an ethyl acetate solution of hydrogen chloride (10 mL, 2 mol / L) to tert-butyl (3aR,5r,6aS)-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-b) (500 mg, 2.20 mmol). The reaction mixture was stirred at room temperature and monitored by TLC. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain 363 mg of (3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ol (3-c), which could be directly used for the next step of the reaction.

[0380] Step 3:

[0381] Add compound (3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ol (3-c) (121 mg, 0.74 mmol), (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (260 mg, 0.74 mmol), sodium hydroxide (178 mg, 4.44 mmol), and water (6 mL) to tert-butanol (6 mL) in sequence. The reaction mixture was reacted at 90 °C for 16 hours. After completion of the reaction, tert-butanol was evaporated under reduced pressure. The residue was added with ethyl acetate (20 mL) and washed with water (20 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1 - 2 / 1, V / V) to obtain (3aR,5R,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-ol (3-d) (333 mg, with a yield of 85.7%), which was a white powder solid. LC-MS: 441.0 [M+H] + 。

[0382] Step 4:

[0383] At 0 °C, Dess-Martin reagent (454 mg, 1.069 mmol) was added to a solution of (3aR,5R,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-ol (3-d) (315 mg, 0.713 mmol) in dichloromethane (4 mL). The reaction mixture was stirred at 0 °C for 1.5 h and then at room temperature for 1.5 h. The reaction was quenched with aqueous Na2S2O3 (0.2 g dissolved in 2 mL of water) and saturated NaHCO3 (2 mL). The mixture was stirred for 15 min, extracted twice with ethyl acetate (15 mL), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1, V / V) to give the white powder (3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (3-e) (270 mg, yield 86.1%). LC-MS: 439.1, 441.1 [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.17 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.44 (q, J = 6.4 Hz, 1H), 3.73 (m, 1H), 3.54 (s, 1H), 3.33 (m, 1H), 3.21 (s, 1H), 2.92 (m, 2H), 2.46 (m, 2H), 2.13 (m, 2H), 1.51 (d, J = 6.4 Hz, 3H).

[0384] Step 5:

[0385] Methylamine hydrochloride (76 mg, 1.137 mmol), 1 drop of acetic acid and NaBH3CN (107 mg, 1.705 mmol) were successively added to a methanol solution (4 mL) of (3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydrocyclopenta[c]pyrrol-5(1H)-one (3-e) (250 mg, 0.568 mmol). The reaction mixture was reacted overnight at 80 °C. After completion of the reaction, the reaction mixture was cooled to room temperature, and methanol was evaporated under reduced pressure. The residue was added with ethyl acetate (20 mL), and the organic phase was washed successively with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 - 95 / 5, V / V) to obtain a white powder of (3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrol-5-amine (3-f) (200 mg, yield 77.4%). LC-MS: 454.1, 456.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 1.6 Hz, 1H), 7.27 - 7.17 (m, 2H), 5.95 (d, J = 6.0 Hz, 1H), 5.46 (q, J = 7.2 Hz, 1H), 3.51 (m, 4H), 2.82 (m, 2H), 2.62 (s, 3H), 2.40 (s, 3H), 2.07 (m, 2H), 1.78 (m, 1H), 1.67 (m, 1H), 1.57 (d, J = 7.2 Hz, 3H).

[0386] Preparation Example 4

[0387]

[0388] First step:

[0389] At room temperature, 2,4,5-trichloropyrimidine (4-a) (1 g, 5.452 mmol), 1-(2,4-dichlorophenyl)ethanol (4-b) (0.94 g, 4.907 mmol) and acetonitrile (10 mL) were successively added to a dry sample bottle; at 0 °C, potassium carbonate (1.36 g, 9.814 mmol) was added to the above solution in batches, and the reaction solution was stirred at 80 °C for 16 hours. After monitoring the reaction to completion by LC-MS, the reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the white solid compound (4-c) (889 mg, yield 48%). LCMS: 336.95 [M+H] + 。 1 HNMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.29–7.26 (m, 1H), 6.57 m, 1H), 1.69 (d, J = 6.5 Hz, 3H).

[0390] Example 1

[0391]

[0392] The first step:

[0393] Hydrochloride (86 mg) of 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidin-4-amine (Preparation Example 1-f), (tert-butoxycarbonyl)-D-proline (I-1-a) (37.5 mg, 0.174 mmol), 1-hydroxybenzotriazole (HOBT, 12 mg, 0.089 mmol) were dispersed in acetonitrile (8 mL), N,N-diisopropylethylamine (112 mg, 0.87 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 100 mg, 0.52 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, ethyl acetate (50 mL) was added, and the mixture was washed successively with saturated brine (15 mL × 1), saturated aqueous sodium bicarbonate (15 mL × 1), and water (15 mL × 1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain tert-butyl (R)-2-((3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyrrolidine-1-carboxylate (I-1-b) (45 mg). LC-MS: 623.2 [M+H] + .

[0394] Step 2:

[0395] A solution of hydrogen chloride in ethyl acetate (5 mL, 2 mol / L) was added to tert-butyl (R)-2-((3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyrrolidine-1-carboxylate (I-1-b) (45 mg, 0.072 mmol), and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the mixture was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain (3aR,6aS)-2-(D-propionyl)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (I-1) (6 mg). LC-MS: 523.2 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 8.40 (s, 2H), 7.41 (dd, J = 5.9, 2.1 Hz, 1H), 7.37 (dd, J = 8.4, 2.1 Hz, 1H), 7.24 (ddd, J = 8.4, 3.5, 2.1 Hz, 1H), 5.50 (p, J = 6.9 Hz, 1H), 4.46 (dd, J = 12.3, 7.4 Hz, 1H), 3.92–3.61 (m, 3H), 3.55–3.36 (m, 4H), 3.36–3.24 (m, 2H), 3.03 (ddd, J = 20.2, 16.7, 9.0 Hz, 2H), 2.48 (ddd, J = 19.5, 13.4, 8.6 Hz, 1H), 2.29 (s, 3H), 2.14–1.75 (m, 3H), 1.50 (d, J = 7.0 Hz, 3H).

[0396] Example 2

[0397]

[0398] First step:

[0399] 1-Methyl-3-oxocyclobutane-1-carboxylic acid (I-2-a) (157 mg, 1.23 mmol), tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-d) (200 mg, 0.94 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (320 mg, 1.26 mmol) were added to toluene (40 mL), and the mixture was heated to reflux with water separation for 4 h. After completion of the reaction, the reaction solution was evaporated to dryness to obtain a crude product. The crude product was added to methyl tert-butyl ether (15 mL) and water (15 mL), and the aqueous phase was concentrated to obtain (1R,3r)-3-((3aR,6aS)-5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-1-methylcyclobutane-1-carboxylic acid (I-2-b) (353 mg), which could be directly used in the next step. LC-MS: 325.2 [M+H] + .

[0400] Second step:

[0401] The product of the previous step, (1R,3r)-3-((3aR,6aS)-5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methylcyclobutane-1-carboxylic acid (I-2-b) (353 mg), was dispersed in a 1,4-dioxane solution of hydrogen chloride (8 mL, 2 mol / L), and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was added with dichloromethane (5 mL), and concentrated under reduced pressure again to obtain the hydrochloride of (1R,3r)-3-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methylcyclobutane-1-carboxylic acid (I-2-c) (324 mg), which could be directly used in the next reaction. LC-MS: 225.1 [M+H] + 。

[0402] Step 3:

[0403] The hydrochloride of the product of the previous step, (1R,3r)-3-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methylcyclobutane-1-carboxylic acid (I-2-c) (324 mg), and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (396 mg, 1.13 mmol) were dispersed in a mixed solvent of tert-butanol (8 mL) and water (8 mL). Sodium hydroxide (263 mg, 6.58 mmol) was added, and the system was heated to 90 °C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, and saturated ammonium chloride aqueous solution (5 mL) was added. The mixture was evaporated to dryness to obtain the crude product, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain (1R,3r)-3-((3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methylcyclobutane-1-carboxylic acid (I-2). LC-MS: 538.2 [M+H] + 。 11H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.40 (dd, J = 9.3, 2.1 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.0 Hz, 1H), 5.46–5.35 (m, 1H), 4.74–4.43 (m, 4H), 3.42 (td, J = 11.8, 6.9 Hz, 1H), 2.86–2.65 (m, 5H), 2.59–2.45 (m, 1H), 2.27 (d, J = 2.6 Hz, 3H), 2.15–2.03 (m, 2H), 1.90 (dd, J = 12.7, 7.3 Hz, 1H), 1.68–1.41 (m, 6H), 1.35 (d, J = 8.6 Hz, 1H), 1.16–1.02 (m, 1H).

[0404] Example 3

[0405]

[0406] The first step:

[0407] Disperse tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-d) (264 mg, 1.25 mmol) and (2-bromoethoxy)(tert-butyl)diphenylsilane (452 mg, 1.24 mmol) in acetonitrile (10 mL), add potassium carbonate (258 mg, 1.87 mmol), and stir at room temperature overnight. After the reaction is completed, add saturated ammonium chloride solution (10 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases and concentrate. The crude product is separated by column chromatography (methanol / dichloromethane = 0 - 6%) to obtain tert-butyl (3aR,6aS)-5-(2-((tert-butyldiphenylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (I-4-a) (416 mg, yield 67.6%). LC-MS: 495.3 [M+H] + .

[0408] The second step:

[0409] The ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) was added to tert-butyl (3aR,6aS)-5-(2-((tert-butyldiphenylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (I-4-a) (416 mg, 0.84 mmol), and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was added with dichloromethane (5 mL), and then concentrated under reduced pressure again to obtain the hydrochloride of (3aR,6aS)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)octahydropyrrolo[3,4-c]pyrrole (I-4-b) (408 mg). LC-MS: 395.3 [M+H] + 。

[0410] Step 3:

[0411] The hydrochloride of the product from the previous step, (3aR,6aS)-2-(2-((tert-butyldiphenylsilyl)oxy)ethyl)octahydropyrrolo[3,4-c]pyrrole (I-4-b) (168 mg), and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (150 mg, 0.43 mmol) were dispersed in a mixed solvent of tert-butanol (5 mL) and water (5 mL). Sodium hydroxide (134 mg, 3.35 mmol) was added, and the system was heated to 90 °C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, and saturated aqueous ammonium chloride (5 mL) was added. The mixture was evaporated to dryness to obtain the crude product, and the crude product was subjected to silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain 2-((3aR,6aS)-5-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethan-1-ol (I-4) (44 mg). LC-MS: 470.1 [M+H] + 。 1 HNMR(400MHz,CDCl3)δ7.36(d,J=2.1Hz,1H),7.23(d,J=8.4Hz,1H),7.17(dd,J=8.4,2.1Hz,1H),5.48–5.38(m,2H),3.67(t,J=5.2Hz,2H),3.56–3.43(m,2H),3.42–3.25(m,2H),3.03(d,J=6.6Hz,2H),2.90(d,J=3.2Hz,3H),2.74–2.66(m,2H),2.48(dd,J=9.4,4.3Hz,1H),2.36(d,J=6.8Hz,1H),2.30(s,3H),1.51(d,J=6.6Hz,3H).

[0412] Example 4

[0413]

[0414] Step 1:

[0415] Disperse tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-a) (226 mg, 1 mmol) and (S)-pyrrolidin-2-ylmethanol (I-5-b) (152 mg, 1.5 mmol) in dichloromethane (10 mL), add acetic acid (90 mg, 1.5 mmol) dropwise, and add sodium triacetoxyborohydride (424 mg, 2.0 mmol) portionwise under stirring. Stir at room temperature overnight. After the reaction is completed, concentrate the system, add ethyl acetate (20 mL) and aqueous sodium bicarbonate solution (10 mL) to the residue. After separating the organic phase, concentrate and evaporate to dryness to obtain the crude product. The crude product is separated by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 35%) to obtain tert-butyl (3aR,6aS)-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-5-c) (295 mg, yield 95%). LC-MS: 311.1 [M+H] + 。

[0416] Step 2:

[0417] Dissolve tert-butyl (3aR,6aS)-5-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-5-c) (295 mg, 0.95 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and react at room temperature overnight. After the reaction is completed, concentrate the reaction solution under reduced pressure, add dichloromethane (5 mL) to the residue, and concentrate again under reduced pressure to obtain the trifluoroacetate salt (356 mg) of ((2S)-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)methanol (I-5-d), which can be used for the next reaction. LC-MS: 211.1 [M+H] + 。

[0418] Step 3:

[0419] The trifluoroacetate (356 mg) of the product of the previous step, ((2S)-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)methanol (I-5-d), and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (333 mg, 0.95 mmol) were dispersed in a mixed solvent of tert-butanol (8 mL) and water (8 mL). Sodium hydroxide (266 mg, 6.65 mmol) was added, and the system was heated to 90 °C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, and saturated aqueous ammonium chloride solution (5 mL) was added. The mixture was evaporated to dryness to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain ((2S)-1-((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)methanol (I-5). LC-MS: 524.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36 (t, J = 3.0 Hz, 1H), 7.24 (t, J = 6.8 Hz, 1H), 7.20–7.16 (m, 1H), 5.45 (dt, J = 19.3, 6.2 Hz, 2H), 3.91–3.59 (m, 4H), 3.57–3.44 (m, 3H), 3.33 (d, J = 9.4 Hz, 2H), 3.03–2.85 (m, 1H), 2.65 (d, J = 3.7 Hz, 2H), 2.39–2.22 (m, 5H), 2.19–1.87 (m, 5H), 1.76–1.65 (m, 1H), 1.59 (d, J = 7.5 Hz, 1H), 1.49 (dd, J = 14.6, 6.8 Hz, 3H).

[0420] Example 5

[0421]

[0422] First step:

[0423] Compound 5-bromo-2,4-dichloropyrimidine (I-9-a) (260 mg, 1.141 mmol), (R)-1-(2,4-dichlorophenyl)ethanamine (1-a) (217 mg, 1.141 mmol), and DIPEA (295 mg, 2.282 mmol) were successively added to isopropanol (3 mL), and the reaction mixture was reacted at 80 °C for 16 hours. After the reaction was completed, isopropanol was evaporated under reduced pressure. The residue was added with ethyl acetate (20 mL), washed with water (6 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 97 / 3 to 95 / 5, V / V) to obtain (R)-5-bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-9-b) as a pale yellow oil (333 mg, yield 76.5%). LC-MS: 381.9 [M+H] + 。

[0424] Step 2:

[0425] (R)-5-bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-9-b) (333 mg, 0.873 mmol), propyne (1.0 M in DMF, 0.9 mL, 0.873 mmol), triethylamine (265 mg, 2.619 mmol), CuI (17 mg, 0.0873 mmol), and Pd(PPh3)2Cl2 (333 mg, 0.873 mmol) were successively added to DMF (3 mL), and the reaction mixture was reacted at 80 °C under argon protection for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 97 / 3 to 95 / 5, V / V) to obtain (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-(prop-1-yn-1-yl)pyrimidin-4-amine (I-9-c) as a colorless oil (228 mg, yield 76.7%). LC-MS: 344.0 [M+H] + 。

[0426] Step 3:

[0427] (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-(prop-1-yn-1-yl)pyrimidin-4-amine (I-9-c) (144 mg, 0.423 mmol), tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-d) (90 mg, 0.174 mmol) and sodium hydroxide (85 mg, 2.114 mmol) were successively added to tert-butanol (5 mL) and water (5 mL), and the reaction mixture was reacted at 90 °C for 16 hours. After the reaction was completed, tert-butanol was evaporated under reduced pressure. The residue was added with ethyl acetate (15 mL), washed with water (5 mL), and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 97 / 3 - 95 / 5, V / V) to obtain a colorless oily compound tert-butyl (3aR,6aS)-5-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(prop-1-yn-1-yl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (I-9-d) (90 mg, yield 41.2%), LC-MS: 516.2 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.60 (d, J = 6.0 Hz, 1H), 5.48 (q, J = 6.4 Hz, 1H), 3.58 (m, 2H), 3.19 (m, 4H), 2.85 (m, 2H), 2.14 (s, 3H), 1.51 (d, J = 6.8 Hz, 3H), 1.45 (s, 9H), 1.27 (m, 2H).

[0428] Step 4:

[0429] The ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) was added to tert-butyl (3aR,6aS)-5-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(prop-1-yn-1-yl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (I-9-d) (90 mg, 0.174 mmol). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure. The residue was added with dichloromethane (5 mL) and concentrated under reduced pressure again to obtain the hydrochloride salt of N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(prop-1-yn-1-yl)pyrimidin-4-amine (I-9-e) (79 mg, yield 99.9%). LC-MS: 416.1 [M+H] + . 1 HNMR(400MHz,CD3OD)δ7.82(s,1H),7.51(d,J=1.2Hz,1H),7.46(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),5.70(q,J=6.4Hz,1H),3.87–3.51(m,6H),3.15(m,2H),2.17(s,3H),1.63(d,J=6.4Hz,3H),1.44-1.28(m,2H).

[0430] Step 5:

[0431] The hydrochloride (78 mg, 0.173 mmol) of compound N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(prop-1-yn-1-yl)pyrimidin-4-amine (I-9-e), (tert-butoxycarbonyl)-D-proline (I-1-a) (37 mg, 0.173 mmol), HATU (66 mg, 0.173 mmol) and triethylamine (37 mg, 0.363 mmol) were successively added to DMF (2 mL), and the reaction mixture was reacted at room temperature for 16 hours. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution, and it was washed successively with water (5 mL) and saturated brine (5 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 1 / 1, V / V) to obtain the white powder compound (R)-2-((3aR,6aS)-5-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(prop-1-yn-1-yl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-9-f) (90 mg, yield 85.0%), LC-MS: 613.3 [M+H] + .

[0432] Step 6:

[0433] The ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) was added to (R)-2-((3aR,6aS)-5-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(prop-1-yn-1-yl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-9-f) (88 mg, 0.143 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was obtained as a white powder compound (3aR,6aS)-2-(D-propionyl)-5-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(prop-1-yn-1-yl)pyrimidin-2-yl)octahydropyrrole[3,4-c]pyrrole (I-9) (45 mg, yield 61.1%). LC-MS: 513.2 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.81 (s, 1H), 7.44 (dd, J1 = 5.6 Hz, J2 = 2.0 Hz, 1H), 7.40 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.27 (m, 1H), 5.54 (q, J = 7.2 Hz, 1H), 4.47 (d, J = 4.8 Hz, 1H), 3.91 - 3.68 (m, 3H), 3.51 - 3.36 (m, 4H), 3.10 - 3.01 (m, 3H), 2.51 (m, 1H), 2.14 (s, 3H), 2.09 - 1.82 (m, 4H), 1.53 (d, J = 7.2 Hz, 3H).

[0434] Example 6

[0435]

[0436] Step 1:

[0437] Disperse (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (2-c) (100 mg, 0.25 mmol), (tert-butoxycarbonyl)-D-proline (I-1-a) (60 mg, 0.28 mmol), 1-hydroxybenzotriazole (HOBT, 15 mg, 0.11 mmol) in acetonitrile (10 mL), add N,N-diisopropylethylamine (129 mg, 1.0 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 100 mg, 0.52 mmol), and stir at room temperature overnight. After the reaction is completed, add ethyl acetate (30 mL), wash successively with saturated brine (15 mL × 1), saturated sodium bicarbonate (15 mL × 1), and water (15 mL × 1). Dry the organic phase over anhydrous sodium sulfate, filter, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain tert-butyl (R)-2-(((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (I-14-a) (120 mg). LC-MS: 597.2 [M+H] + .

[0438] Step 2:

[0439] The ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) was added to tert-butyl (R)-2-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (I-14-a) (120 mg), and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the solvent was evaporated to obtain the crude product, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain (R)-N-(1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (I-14). LC-MS: 497.1 [M+H] + 。 1 H NMR(400MHz,CD3OD)7.43 -7.31(m,2H),7.22(d,J=8.4Hz,

[0440] 1H),5.47(q,J=6.9Hz,1H),5.15 -4.89(m,1H),4.19(dt,J=32.1,8.9Hz,1H),4.10 -3.70(m,4H),3.13(td,J=12.3,6.3Hz,1H),3.01(d,J=31.7Hz,3H),2.81(dt,J=11.2,6.3Hz,1H),2.34 -2.08(m,4H),1.94 -1.55(m,3H),1.51(t,J=10.3Hz,3H).

[0441] Example 7

[0442]

[0443] The first step:

[0444] Compound (3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-N-methyloctahydrocyclopenta[c]pyrrol-5-amine (3-f) (100 mg, 0.220 mmol), (tert-butoxycarbonyl)-D-proline (I-1-a) (47 mg, 0.220 mmol), HATU (84 mg, 0.220 mmol) and triethylamine (47 mg, 0.462 mmol) were successively added to DMF (2 mL), and the reaction mixture was reacted overnight at room temperature. After completion of the reaction, ethyl acetate (20 mL) was added to the reaction solution, and it was washed successively with water (5 mL) and saturated brine (5 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 1 / 1, V / V) to obtain the white powder compound (2R)-2-(((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-15-a) (130 mg), LC-MS: 651.3, 653.3 [M+H] + .

[0445] Step 2:

[0446] A solution of hydrogen chloride in ethyl acetate (5 mL, 2 mol / L) was added to (2R)-2-(((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-15-a) (130 mg), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, and the residue was obtained as a white powder compound (2R)-N-((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)-N-methylpyrrolidine-2-carboxamide (I-15) (52 mg, yield 38.5%), LC-MS: 551.2, 553.2 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.42 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 5.49 (q, J = 7.2 Hz, 1H), 4.57 (m, 1H), 3.65–3.34 (m, 4H), 3.33 (s, 3H), 2.96 - 2.81 (m, 4H), 2.68 (m, 2H), 2.53 (m, 1H), 2.30 (s, 3H), 1.98 (m, 5H), 1.53 (d, J = 7.2 Hz, 3H), 1.49 - 1.24 (m, 2H).

[0447] Example 8

[0448]

[0449] Step 1:

[0450] 1-Methyl-3-oxocyclobutane-1-carboxylic acid (I-2-a) (42 mg, 0.33 mmol), ((R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (2-c) (100 mg, 0.25 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (84 mg, 0.33 mmol) were added to toluene (40 mL), and the mixture was heated to reflux with water separation for 4 hours. After completion of the reaction, the reaction solution was evaporated to dryness, methyl tert-butyl ether (15 mL) and water (15 mL) were added, and the aqueous phase was concentrated to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain (1R,3r)-3-(((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)amino)-1-methylcyclobutane-1-carboxylic acid (I-16). LC-MS: 512.1 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 7.43 - 7.31 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 5.47 (q, J = 6.9 Hz, 1H), 5.15 - 4.89 (m, 1H), 4.19 (dt, J = 32.1, 8.9 Hz, 1H), 4.10 - 3.70 (m, 4H), 3.13 (td, J = 12.3, 6.3 Hz, 1H), 3.01 (d, J = 31.7 Hz, 3H), 2.81 (dt, J = 11.2, 6.3 Hz, 1H), 2.34 - 2.08 (m, 4H), 1.94 - 1.55 (m, 3H), 1.51 (t, J = 10.3 Hz, 3H).

[0451] Example 9

[0452]

[0453] First step:

[0454] Dissolve tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (I-18-a) (165 mg, 0.83 mmol) and triethylamine (252 mg, 2.49 mmol) in dichloromethane (10 mL). Slowly add benzyl chloroformate (255 mg, 1.49 mmol). After addition, stir at room temperature overnight. After the reaction is completed, add saturated aqueous sodium bicarbonate solution (5 mL). Separate the organic phase and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 35%) to obtain tert-butyl (1R,5S,6s)-6-((tert-butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylate (I-18-b) (278 mg). LC-MS: 565.3 [2M - 99] + .

[0455] Second step:

[0456] (1R,5S,6s)-6-((tert-Butoxycarbonyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (I-18-b) (278 mg, 0.83 mmol) was dissolved in dry N,N-dimethylformamide (10 mL). After the system was protected by argon, it was cooled in an ice bath. Sodium hydride (60% w / w, 67 mg, 1.68 mmol) was added in portions. After the addition, the mixture was stirred for 1 hour and then methyl iodide (178 mg, 1.25 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (5 mL) and water (5 mL) were slowly added dropwise. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL × 3). The solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 35%) to obtain (1R,5S,6s)-6-((tert-butoxycarbonyl)(methyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (I-18-c) (242 mg). LC-MS: 593.3 [2M - 99] + .

[0457] Step 3:

[0458] (1R,5S,6s)-6-((tert-Butoxycarbonyl)(methyl)amino)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (I-18-c) (242 mg, 0.70 mmol) was dissolved in methanol (10 mL). Water (4 mL) and potassium hydroxide (4 g) were added. The temperature was raised to 100 °C and the mixture was stirred overnight. After the reaction was completed, the mixture was concentrated. The residue was added with methyl tert-butyl ether (40 mL) and water (20 mL). The organic phase was separated and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)(methyl)carbamic acid tert-butyl ester (I-18-d) (118 mg). LC-MS: 213.0 [M + H] + .

[0459] Steps 4 to 7:

[0460] Refer to the synthesis method of Example 1. Replace tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1-d) with tert-butyl ((1R,5S,6s)-3-azabicyclo[3.1.0]hexan-6-yl)(methyl)carbamate (I-18-d); replace (tert-butoxycarbonyl)-D-proline (I-1-a) with (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (I-18-g) to obtain the compound (R)-N-((1R,5S,6S)-3-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexan-6-yl)-N-methylpiperidine-2-carboxamide (I-18) as shown in the formula. LC-MS: 537.2 [M+H] + . 1 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.4, 1.9 Hz, 1H), 5.50 (q, J = 6.8 Hz, 1H), 4.06 (d, J = 10.6 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.68 (d, J = 10.8 Hz, 1H), 3.47 (dd, J = 11.2, 3.7 Hz, 1H), 3.24 (d, J = 13.2 Hz, 2H), 2.92 (s, 3H), 2.80 (t, J = 11.6 Hz, 1H), 2.47 (s, 1H), 2.26 (d, J = 9.6 Hz, 3H), 2.16 (s, 1H), 2.10 (d, J = 11.8 Hz, 1H), 2.04–1.88 (m, 2H), 1.79 (t, J = 12.6 Hz, 1H), 1.66–1.53 (m, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.42 (d, J = 13.1 Hz, 1H).

[0461] Example 10

[0462]

[0463] The first step:

[0464] PdCl2(dppf) (48 mg, 0.0656 mmol), sodium carbonate (278 mg, 2.623 mmol) and 1,4-dioxane (3 mL) were successively added to 2,4,5-trichloro-6-methyl-pyrimidine (1-b) (259 mg, 1.312 mmol) and 2,4-dichloroaniline (I-25-a) (213 mg, 1.312 mmol). The reaction mixture was stirred at 100 °C overnight under argon protection. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 2, V / V) to give the colorless oily compound 2,5-dichloro-N-(2,4-dichlorophenyl)-6-methylpyrimidin-4-amine (I-25-b) (260 mg, yield 61.4%). LC-MS: 322.0, 324.0 [M+H] + .

[0465] The second to fifth steps can be carried out with reference to the operating steps of Example 9 to obtain the compound (R)-N-(1-(5-chloro-4-((2,4-dichlorophenyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (I-25). 1 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J = 7.2 Hz, 1H), 7.62 (s, 1H), 7.42 (d, J = 7.2 Hz, 1H), 5.12 (m, 1H), 4.34 (m, 4H), 3.33 (s, 3H), 3.23 (m, 2H), 3.15 (m, 1H), 2.53 (s, 3H), 2.08 (m, 2H), 1.33 (m, 2H). LC-MS: 469.1, 471.1 [M+H] + .

[0466] Example 11

[0467]

[0468] The first step:

[0469] (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (100 mg, 0.28 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (I-28-a) (62 mg, 0.31 mmol), and sodium hydroxide (80 mg, 1.99 mmol) were dispersed in tert-butanol (5 mL) and water (5 mL). The reaction mixture was stirred at 95 °C overnight. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, the reaction mixture was added with water (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure to obtain the crude product tert-butyl (R)-6-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-28-b) (135 mg, 92%), which was directly used in the next step. LC-MS: 512.2 [M+H] + .

[0470] Step 2:

[0471] (R)-tert-Butyl 6-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (I-28-b) (135 mg, 0.26 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added to the system. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, the reaction mixture was added with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL). The organic layer was concentrated under reduced pressure to obtain the crude product, which was separated and purified by preparative TLC plate GF254 (methanol:dichloromethane = 10%) to give (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-amine (I-28-c) (90 mg, 83%). LC-MS: 412.1 [M+H] + .

[0472] Step 3:

[0473] (R)-5-Chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-4-amine (I-28-c) (90 mg, 0.22 mmol), (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (I-18-g) (60 mg, 0.26 mmol), HATU (124 mg, 0.33 mmol), and DIPEA (85 mg, 0.65 mmol) were dispersed in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC on GF254 (methanol:dichloromethane = 10%) to give tert-butyl (R)-2-(6-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carboxylate (I-28-d) (136 mg, 100%). LC-MS: 623.2 [M+H] + .

[0474] Step 4:

[0475] (R)-2-(6-(5-Chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (I-28-d) (136 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added to the system. The reaction mixture was stirred at room temperature. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC on GF254 (methanol:dichloromethane = 10%) to give (6-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(((R)-piperidin-2-yl)methanone (I-28) (100 mg, 88%). LC-MS: 523.2 [M+H] + . 11H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 1.9 Hz, 1H), 5.55 (d, J = 6.1 Hz, 1H), 5.50–5.35 (m, 1H), 4.42 (d, J = 9.1 Hz, 1H), 4.23 (d, J = 9.1 Hz, 1H), 4.18–4.03 (m, 4H), 3.92 (d, J = 8.9 Hz, 2H), 3.39–3.27 (m, 1H), 3.19 (d, J = 13.2 Hz, 1H), 2.70 (dd, J = 17.4, 7.3 Hz, 1H), 2.37 (s, 2H), 2.32 (s, 3H), 1.91 (s, 1H), 1.72 (s, 1H), 1.62 (d, J = 11.8 Hz, 1H), 1.53 (d, J = 6.9 Hz, 3H), 1.51–1.35 (m, 3H).

[0476] Example 12

[0477]

[0478] First step:

[0479] Dissolve (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (300 mg, 0.85 mmol) and tert-butyl 2,6-diazaspiro[3.4]octane-6-carboxylate (I-31-a) (180 mg, 0.85 mmol) in a mixed solution of tert-butanol (15 mL) and water (15 mL), and add sodium hydroxide (204 mg, 5.1 mmol). Heat the reaction solution to 90 °C and react for 2 hours. Cool to room temperature and dilute with ethyl acetate (150 mL). Wash the organic phase with water (50 mL × 3) and saturated brine (50 mL × 3), dry over anhydrous sodium sulfate and filter. Concentrate the filtrate to obtain the crude product (R)-2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (I-31-b, 500 mg). LC-MS: 526.2 [M+H] + .

[0480] Second step:

[0481] The crude product of tert-butyl (R)-2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (I-31-b, 500 mg) obtained in the previous step was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. After the reaction mixture was stirred at room temperature for 2 hours, it was concentrated. After neutralizing to neutral with saturated sodium bicarbonate, it was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column (dichloromethane:methanol = 100:0 to 100:10) to obtain (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-amine (I-31-c, 320 mg) (88% yield). LC-MS: 426.1 [M+H] + 。 1 H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.22 (dd, J = 17.6, 8.3 Hz, 2H), 5.59 (d, J = 6.3 Hz, 1H), 5.45 (dd, J = 13.3, 6.6 Hz, 1H), 4.00 (d, J = 9.0 Hz, 1H), 3.95 (d, J = 9.1 Hz, 1H), 3.88 (d, J = 8.9 Hz, 1H), 3.78 (d, J = 8.9 Hz, 1H), 3.46–3.38 (m, 2H), 3.34 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 2.23 (t, J = 7.1 Hz, 2H), 1.53 (d, J = 6.9 Hz, 3H).

[0482] The third step:

[0483] The raw material (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-amine (I-31-c) (37 mg, 0.087 mmol) and 2-bromoethanol (22 mg, 0.17 mmol) were dissolved in acetonitrile (10 mL), and potassium carbonate (23 mg, 0.17 mmol) was added. The reaction mixture was reacted at 70 °C for 2 hours. After the system was cooled, it was filtered. The filtrate was concentrated and separated by preparative plate (DCM:MeOH = 100:10) to obtain (R)-2-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.4]oct-6-yl)ethan-1-ol (I-31, 13 mg), a white solid. The yield was 31.7%. LC-MS: 470.1 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 1.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 5.56 (d, J = 6.0 Hz, 1H), 5.47–5.37 (m, 1H), 3.97 (d, J = 8.9 Hz, 1H), 3.91 (d, J = 8.9 Hz, 1H), 3.85–3.72 (m, 4H), 3.15 (d, J = 7.0 Hz, 2H), 3.02 (s, 2H), 2.92 (s, 2H), 2.58 (s, 1H), 2.29 (s, 3H), 2.19 (t, J = 7.0 Hz, 2H), 1.51 (d, J = 6.9 Hz, 3H).

[0484] Example 13

[0485]

[0486] The first step:

[0487] 60% sodium hydride (37 mg, 0.55 mmol) was added to a DMF solution (2 mL) containing 2,5-dichloro-N-(2,4-dichlorophenyl)-6-methylpyrimidin-4-amine (I-25-b) (130 mg, 0.275 mmol). The mixture was stirred at room temperature for half an hour, then methyl iodide (47 mg, 0.330 mmol) was added, and the reaction mixture was reacted at 60 °C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, ethyl acetate (15 mL) was added, and it was washed successively with water (15 mL) and saturated sodium chloride aqueous solution (15 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 - 10 / 1, V / V) to obtain a colorless oily compound (1-(5-chloro-4-((2,4-dichlorophenyl)(methyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamic acid tert-butyl ester (I-34-a) (120 mg, yield 89.7%), LC-MS: 486.1, 488.1 [M+H] + .

[0488] The second to fourth steps can refer to the operating steps of Example 9 to obtain the compound (R)-N-(1-(5-chloro-4-((2,4-dichlorophenyl)(methyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (I-34). LC-MS: 483.0, 485.0 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 7.56 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5.24 (m, 1H), 4.39 (m, 2H), 4.22 (m, 2H), 3.35 (s, 3H), 3.34 (s, 3H), 3.22 (m, 2H), 2.53 (m, 1H), 2.30 (s, 3H), 1.98 (m, 4H).

[0489] Example 14

[0490]

[0491] First step:

[0492] Disperse tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate (I-37-a) (68 mg, 0.28 mmol) and (2-bromoethoxy)(tert-butyl)diphenylsilane (113 mg, 0.31 mmol) in acetonitrile (10 mL), add potassium carbonate (60 mg, 0.43 mmol), and stir at room temperature overnight. After the reaction is completed, add saturated ammonium chloride solution (10 mL), extract with ethyl acetate (15 mL × 3), combine the organic phases and concentrate. The crude product is separated by column chromatography (methanol / dichloromethane = 0 - 3%) to obtain tert-butyl (R)-3-(1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-37-b) (127 mg). LC-MS: 523.4 [M+H] + .

[0493] Second step:

[0494] Add ethyl acetate solution of hydrogen chloride (5 mL, 2 mol / L) to tert-butyl (R)-3-(1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-37-b) (127 mg, 0.24 mmol), and react at room temperature for 5 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure, add dichloromethane (5 mL) to the residue, and concentrate again under reduced pressure to obtain the hydrochloride salt of (R)-3-(azetidin-3-yl)-1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine (I-37-c) (121 mg). LC-MS: 423.3 [M+H] + .

[0495] Third step:

[0496] The hydrochloride (I-37-c) (121 mg) of the previous step product (R)-3-(azetidin-3-yl)-1-(2-((tert-butyldiphenylsilyl)oxy)ethyl)piperidine and 2,5-dichloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidine (4-c) were dispersed in a mixed solvent of tert-butanol (5 mL) and water (5 mL). Sodium hydroxide (85 mg, 2.12 mmol) was added, and the system was heated to 90 °C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, and saturated ammonium chloride aqueous solution (5 mL) was added. The mixture was evaporated to dryness to obtain the crude product, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain 2-((3R)-3-(1-(5-chloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-37) (56 mg). LC-MS: 485.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 3.1 Hz, 1H), 7.32 (dd, J = 8.4, 1.9 Hz, 1H), 6.43 (p, J = 6.4 Hz, 1H), 4.06 (t, J = 8.6 Hz, 1H), 3.97 (s, 1H), 3.82–3.51 (m, 4H), 2.94 (dd, J = 27.4, 9.8 Hz, 2H), 2.58 (t, J = 5.3 Hz, 2H), 2.42 (s, 1H), 2.09 (t, J = 11.1 Hz, 1H), 1.84–1.68 (m, 3H), 1.62 (d, J = 6.4 Hz, 4H), 0.90 (s, 1H).

[0497] Example 15

[0498]

[0499] The first step:

[0500] The synthesis method can refer to the synthesis of tert-butyl (R)-2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.4]octane-6-carboxylate (I-31-b) in Example 31. The product tert-butyl (R)-2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate (I-42-a, crude product 200 mg) was obtained. LC-MS: 540.2 [M+H] + 。

[0501] The second step:

[0502] The synthesis method can refer to the synthesis of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-4-amine (I-31-c) in Example 31. The product (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-amine (I-42-b, crude product 180 mg) was obtained. LC-MS: = 440.1 [M+H] + 。

[0503] The third step:

[0504] Dissolve the raw material (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-amine (I-42-b) (40 mg, 0.009 mmol) and ethyl bromoacetate (20 mg, 0.12 mmol) in dichloromethane (5 mL), and add triethylamine (15 mg, 0.15 mmol). The reaction solution was reacted at room temperature for 1 hour, and concentrated to obtain the crude product (R)-ethyl 2-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]non-6-yl)acetate (I-42-c, 60 mg). LC-MS: 526.2 [M+H] + 。

[0505] The fourth step:

[0506] Dissolve (R)-ethyl 2-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]non-6-yl)acetate (I-42-c) (60 mg, 0.11 mmol) in methanol (5 mL), then add lithium hydroxide monohydrate (10 mg, 0.23 mmol) and water (1 mL). The reaction solution was stirred overnight at room temperature, acidified with 1N dilute hydrochloric acid, and the mixture was concentrated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 100:10) to obtain 16 mg of white solid (R)-2-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]non-6-yl)acetic acid (I-42). LC-MS: 498.1 [M+H] + 。 11H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.4, 2.0 Hz, 1H), 5.54 (q, J = 7.0 Hz, 1H), 4.75–4.38 (m, 1H), 3.92 (d, J = 8.8 Hz, 1H), 3.74 (t, J = 8.5 Hz, 2H), 3.69–3.35 (m, 5H), 3.21 (s, 2H), 1.87 (d, J = 14.9 Hz, 4H), 1.52 (d, J = 7.1 Hz, 3H), 1.47–1.25 (m, 2H).

[0507] Example 16

[0508]

[0509] Step 1:

[0510] Dissolve (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(2,6-diazaspiro[3.5]non-2-yl)pyrimidin-4-amine (I-42-b) (50 mg) and ethyl acrylate (20 mg, 0.2 mmol) in ethanol (10 mL), and stir the reaction solution at 50 °C overnight. After the reaction is completed, concentrate it, and purify the residue by silica gel preparative plate (methylene chloride:methanol = 100:3) to obtain 40 mg of white solid methyl (R)-3-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]non-6-yl)propionate (I-43-a), with a yield of 67.8%. LC-MS: = 527.2 [M+H] + .

[0511] Step 2:

[0512] Methyl (R)-3-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]nonan-6-yl)propionate (I-43-a) (40 mg, 0.076 mmol) was dissolved in methanol (5 mL), and then lithium hydroxide monohydrate (10 mg, 0.234 mmol) and water (1 mL) were added. The reaction mixture was stirred at room temperature overnight, acidified with 1N dilute hydrochloric acid, and the filtrate was concentrated and purified by preparative thin-layer chromatography (dichloromethane:methanol = 100:10) to obtain 26 mg of white solid (R)-3-(2-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)-2,6-diazaspiro[3.5]nonan-6-yl)propionic acid (I-43) with a yield of 66.7%. LC-MS: 513.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.4, 2.1 Hz, 1H), 5.53 (q, J = 7.0 Hz, 1H), 3.85 (d, J = 8.9 Hz, 1H), 3.73 (s, 2H), 3.56 (d, J = 8.7 Hz, 1H), 3.35 (d, J = 12.3 Hz, 1H), 3.22 (dd, J = 23.2, 16.5 Hz, 4H), 3.10 (s, 2H), 2.57 (t, J = 6.6 Hz, 2H), 2.29 (s, 3H), 1.83 (s, 4H), 1.52 (d, J = 7.1 Hz, 3H).

[0513] Example 17

[0514]

[0515] The first step:

[0516] The compound (R)-5-bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-9-b) (1.019 g, 2.860 mmol), cyclopropylethyne (I-48-a) (189 mg, 2.860 mmol), triethylamine (579 mg, 5.720 mmol), CuI (54 mg, 0.286 mmol) and PdCl2(PPh3)2 (100 mg, 0.143 mmol) were successively added to DMF (10 mL). The reaction mixture was protected by argon and reacted at 80 °C for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 97 / 3 - 95 / 5, V / V) to obtain the yellow oily compound (R)-2-chloro-5-(cyclopropylethynyl)-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-48-b) (869 mg, yield 82.9%). LC-MS: 366.0, 368.0 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 7.46 (m, 2H), 7.32 (m, 1H), 5.59 (q, J = 6.8 Hz, 1H), 1.64 (m, 1H), 1.60 (d, J = 6.8 Hz, 3H), 0.98 (m, 2H), 0.87 (m, 2H).

[0517] The second to fourth steps can refer to the operation steps of Example 9 to obtain the compound (R)-2-((1-(5-(cyclopropylethynyl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-48-e). LC-MS: 613.3 [M+H] + 。

[0518] Step 5:

[0519] (R)-tert-Butyl 2-((1-(5-(cyclopropylethynyl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (I-48-e) (90 mg, 0.147 mmol) and zinc bromide (66 mg, 0.293 mmol) were successively added to dichloromethane (2 mL), and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, dichloromethane was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed with water (8 mL). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100 / 1 - 10 / 1, V / V) to give the white solid (R)-N-(1-(5-(cyclopropylethynyl)-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (I-48) (34 mg, yield 45.1%). LC-MS: 513.2 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.50 (q, J = 7.2 Hz, 1H), 5.12 (m, 1H), 4.59 (s, 2H), 4.24 (m, 1H), 4.06 (m, 2H), 3.88 (s, 1H), 3.32 (m, 2H), 3.07 (s, 3H), 2.48 (m, 1H), 1.96 (m, 2H), 1.79 (m, 1H), 1.59 (m, 1H), 1.55 (d, J = 7.2 Hz, 3H), 0.94 (m, 2H), 0.81 (m, 2H).

[0520] Example 18

[0521]

[0522] Step 1:

[0523] (R)-5-Bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-9-b) (600 mg, 1.573 mmol), 3-ethynylpyridine (195 mg, 1.887 mmol), triethylamine (318 mg, 3.145 mmol) and Pd(PPh3)4 (91 mg, 0.0786 mmol) were successively added to THF (8 mL), and the reaction mixture was reacted overnight at 100 °C under argon protection. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 - 2 / 1, V / V) to obtain the colorless oily compound (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-(pyridin-3-ylethynyl)pyrimidin-4-amine (I-56-a) (164 mg, yield 25.8%), LC-MS: 403.0, 405.0 [M+H] + 。

[0524] The synthesis of the second to fifth steps can be carried out with reference to the operating steps of Example 9 to obtain the compound (R)-N-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-(pyridin-3-ylethynyl)pyrimidin-2-yl)azetidin-3-yl)-N-methylpiperidine-2-carboxamide (I-56). LC-MS: 564.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 8.77 (s, 1H), 8.57 (s, 1H), 8.52 (dd, J1 = 4.8 Hz, J2 = 1.2 Hz, 1H), 8.05 (m, 2H), 7.53–7.41 (m, 2H), 7.30 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.58 (q, J = 6.8 Hz, 1H), 5.12 (m, 1H), 4.61 (m, 2H), 4.39–3.96 (m, 4H), 3.12 (s, 3H), 2.91 (m, 1H), 2.14–1.90 (m, 2H), 1.82–1.64 (m, 2H), 1.57 (d, J = 6.8 Hz, 3H), 1.50 (m, 2H).

[0525] Example 19

[0526]

[0527] The first step:

[0528] Dissolve tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-58-a) (120 mg, 0.5 mmol) and 3-thietanone (110 mg, 1.2 mmol) in methanol, add glacial acetic acid (30 mg), stir at room temperature overnight, then add sodium triacetoxyborohydride (320 mg, 1.5 mmol) and react for 3 hours. Filter the reaction solution, dilute it with ethyl acetate (100 mL), wash it with water (30 mL×2), wash it with saturated brine (30×2), dry it over anhydrous sodium sulfate, concentrate it, and purify it by silica gel column (petroleum ether:ethyl acetate = 100:0 - 50:50, V / V) to obtain tert-butyl 3-(1-(thiophen-3-yl)piperidin-3-yl)azetidine-1-carboxylate (I-58-b). The product is 100 mg of a brown oily liquid with a yield of 60%. LC-MS: 313.3 [M+H] + 。

[0529] Step 2:

[0530] Dissolve tert-butyl 3-(1-(thiophen-3-yl)piperidin-3-yl)azetidine-1-carboxylate (I-58-b) obtained in the previous step in dichloromethane (10 mL), and add trifluoroacetic acid (3 mL). Stir the reaction solution at room temperature for 2 hours and then concentrate it. Add saturated sodium bicarbonate solution (15 mL) to the residue, extract it with ethyl acetate (50 mL×3), wash the combined organic phases with saturated brine (50 mL×3), dry it over anhydrous sodium sulfate, concentrate it, and purify the residue by silica gel column (dichloromethane:methanol = 100:0 - 100:10) to obtain 3-(azetidin-3-yl)-1-(thiophen-3-yl)piperidine (I-58-c) 60 mg. LC-MS: 213.2 [M+H] + 。

[0531] Step 3:

[0532] (R)-2,5-Dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (100 mg, 0.28 mmol), 3-(azetidin-3-yl)-1-(thiophen-3-yl)piperidine (I-58-c) (60 mg, 0.28 mmol) were dissolved in a mixed solution of tert-butanol (10 mL) and water (10 mL), and sodium hydroxide (78 mg, 1.95 mmol) was added. The reaction solution was heated to 90 °C and reacted for 2 hours, cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (20 mL × 3), washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain 70 mg of the product 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(1-(thiophen-3-yl)piperidin-3-yl)azetidin-1-yl)pyrimidin-4-amine (I-58-d). LC-MS: 526.2 [M+H] + 。

[0533] Step 4:

[0534] 5-Chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(1-(thiophen-3-yl)piperidin-3-yl)azetidin-1-yl)pyrimidin-4-amine (I-58-d) (60 mg, 0.12 mmol), ammonium acetate (35 mg, 0.46 mmol), and diacetoxyiodobenzene (110 mg, 0.34 mmol) were dissolved in methanol (10 mL). The reaction solution was reacted at room temperature for 3 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL × 2), washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin-layer chromatography (methylene chloride:methanol = 100:10) to obtain 15 mg of the product 3-(3-(1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-imino-1λ 6 -thiophenylethane 1-oxide (I-58). LC-MS: 558.2 [M+H] + 。 11H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.23 (dd, J = 19.3, 8.4 Hz, 2H), 5.59 (s, 1H), 5.45 (dd, J = 11.5, 6.2 Hz, 1H), 4.16–3.81 (m, 6H), 3.71 (s, 1H), 3.51 (s, 1H), 3.35–3.10 (m, 2H), 2.69 (d, J = 37.6 Hz, 2H), 2.36 (s, 4H), 1.95 (s, 1H), 1.72 (s, 4H), 1.67–1.57 (m, 2H), 1.54 (d, J = 6.5 Hz, 3H).

[0535] Example 20

[0536]

[0537] Step 1:

[0538] Dissolve diethyl 1,1-cyclopropanedicarboxylate (I-60-a) (1.5 g, 8 mmol) in ethanol (20 mL), add lithium hydroxide monohydrate (340 mg, 8 mmol) and water (5 mL). Stir the reaction mixture at room temperature for 3 hours, neutralize with 1N dilute hydrochloric acid, extract with ethyl acetate (50 mL × 3), wash with saturated brine (50 mL × 3), dry over anhydrous sodium sulfate, and concentrate to obtain 1.1 g of crude 1-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (I-60-b) as a colorless oil (yield 86.6%). LC-MS: 159.1 [M+H] + .

[0539] Step 2:

[0540] Add (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (2-c) (142 mg, 0.35 mmol), 1-(ethoxycarbonyl)cyclopropane-1-carboxylic acid (I-60-b) (45 mg, 0.28 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) to dichloromethane (10 mL). Dropwise add 1-propylphosphonic anhydride (50 wt.% solution in ethyl acetate, 286 mg, 0.45 mmol) under ice bath, and stir at room temperature overnight. After completion of the reaction, evaporate the reaction mixture to dryness to obtain a crude product. The crude product is purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 - 35%) to obtain ethyl (R)-1-(((1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)cyclopropane-1-carboxylate (I-60-c) (155 mg). LC-MS: 540.1 [M+H]+ 。

[0541] Step 3:

[0542] Ethyl (R)-1-((1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)cyclopropane-1-carboxylate (I-60-c) (155 mg, 0.29 mmol) and lithium hydroxide monohydrate (30 mg, 0.71 mmol) were dispersed in a mixture of methanol (3 mL), tetrahydrofuran (3 mL) and water (3 mL), and the reaction mixture was stirred overnight at room temperature. After the raw materials reacted completely, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain 62 mg of (R)-1-((1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)cyclopropane-1-carboxylic acid (I-60). LC-MS: 512.1 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 7.42 (s, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 5.63–5.37 (m, 1H), 5.17–4.98 (m, 1H), 4.32–4.15 (m, 1H), 4.15–3.98 (m, 2H), 3.93 (dd, J = 34.6, 15.5 Hz, 1H), 3.04 (d, J = 57.7 Hz, 3H), 2.30 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H), 1.48–1.23 (m, 4H).

[0543] Example 21

[0544]

[0545] Step 1:

[0546] Sodium borohydride (166 mg, 4.388 mmol) was slowly added to a solution of tert-butyl 3-oxoazetidine-1-carboxylate (I-67-a) (500 mg, 2.921 mmol) in methanol (5 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction was confirmed by TLC, the reaction solution was concentrated under reduced pressure. The residue was added with ethyl acetate (20 mL) and washed successively with water (6 mL) and saturated brine (6 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 498 mg of tert-butyl 3-hydroxyazetidine-1-carboxylate (I-67-b) as a colorless oil, with a yield of 98.4%, which could be directly used in the next step of the reaction.

[0547] The second step:

[0548] A solution of hydrogen chloride in ethyl acetate (2 mL, 2 mol / L) was added to tert-butyl 3-hydroxyazetidine-1-carboxylate (I-67-b) (498 mg, 2.875 mmol). The reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of azetidin-3-ol (I-67-c) as a yellow oil (315 mg, yield 100.0%).

[0549] The third step:

[0550] The hydrochloride salt of compound azetidin-3-ol (I-67-c) (310 mg, 2.830 mmol), (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c) (993 mg, 2.828 mmol) and sodium hydroxide (453 mg, 11.33 mmol) were successively added to tert-butanol (5 mL) and water (5 mL). The reaction mixture was reacted at 100 °C overnight. After completion of the reaction, tert-butanol was distilled off under reduced pressure. The residue was added with ethyl acetate (30 mL) and washed with water (8 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1, V / V) to obtain 553 mg of white powder (R)-1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-ol (I-67-d), with a yield of 50.4%, LC-MS: 387.0, 389.0 [M+H] + 。 11H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.51 (q, J = 7.2 Hz, 1H), 4.51 (m, 1H), 4.15 (m, 2H), 4.04 (m, 1H), 3.74 (m, 1H), 3.60 (m, 1H), 2.29 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H).

[0551] Step 4:

[0552] At 0 °C, Dess-Martin reagent (903 mg, 2.129 mmol) was added to a solution of (R)-1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-ol (I-67-d) (550 mg, 1.419 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at 0 °C for 1.5 h and then at room temperature for 1.5 h. The reaction was quenched with Na2S2O3 (0.2 g dissolved in 2 mL of water) and saturated NaHCO3 (2 mL). The mixture was stirred for 15 min, extracted twice with ethyl acetate (15 mL), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1 - 10 / 1, V / V) to give the white powder (R)-1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-one (I-67-e) (346 mg, yield 63.2%). LC-MS: 385.1, 387.1 [M+H] + .

[0553] Step 5:

[0554] (3R)-3-Piperidinemethanol (I-67-f) (27 mg, 0.233 mmol), acetic acid (20 mg), and sodium triacetoxyborohydride (74 mg, 0.349 mmol) were successively added to a methanol solution (2 mL) of (R)-1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-one (I-67-e) (90 mg, 0.233 mmol). The reaction mixture was reacted overnight at room temperature and then at 90 °C overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, methanol was evaporated under reduced pressure. The residue was added with ethyl acetate (15 mL) and washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by a preparative TLC plate (dichloromethane / methanol = 10 / 1, V / V) to obtain (R)-1-(1-(5-chloro-4-((R)-1,4-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-3-yl)methanol (33 mg, yield 29.5%), LC-MS: 484.2, 486.2 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 7.44 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.49 (q, J = 7.2 Hz, 1H), 4.02 (m, 1H), 3.95 (m, 1H), 3.82 (m, 1H), 3.59 (m, 1H), 3.47 (m, 1H), 3.37 (m, 1H), 3.37 (m, 2H), 3.17 (m, 1H), 2.95 (m, 1H), 2.81 (m, 1H), 2.29 (s, 3H), 1.88 (m, 1H), 1.76 (m, 2H), 1.64 (m, 2H), 1.52 (d, J = 7.2 Hz, 3H).

[0555] Example 22

[0556]

[0557] (R)-5-Chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(4-(methylamino)piperidin-1-yl)pyrimidin-4-amine (I-77-a) can be prepared with reference to the preparation of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (2-c). LC-MS: 428.1 [M+H] + 。

[0558] Step 1:

[0559] tert-Butyl (R)-2-(((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (I-77-c) was prepared as follows: tert-Butyl (R)-2-formylpyrrolidine-1-carboxylate (I-77-b) (36 mg, 0.179 mmol), acetic acid (20 mg), and NaBH3CN (34 mg, 0.536 mmol) were successively added to a methanol solution (2 mL) of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(4-(methylamino)piperidin-1-yl)pyrimidin-4-amine (I-77-a) (83 mg, 0.179 mmol). The reaction mixture was stirred at 80 °C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, and methanol was removed under reduced pressure. The residue was taken up in ethyl acetate (15 mL), washed successively with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 1 - 10 / 1, V / V) to afford a white powder, tert-Butyl (R)-2-(((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (I-77-c) (79 mg, yield 72.2%). LC-MS: 611.3, 613.3 [M+H] + .

[0560] Step 2:

[0561] A solution of hydrogen chloride in ethyl acetate (2 mL, 2 mol / L) was added to tert-Butyl (R)-2-(((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)piperidin-4-yl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (I-77-c) (79 mg). The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to afford a white powder, 5-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-6-methyl-2-(4-(methyl((((R)-pyrrolidin-2-yl)methyl)amino)piperidin-1-yl)pyrimidin-4-amine (I-77) (82 mg). LC-MS: 511.2, 513.2 [M+H] + . 11H NMR (400 MHz, CD3OD) δ 7.54 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.64 (q, J = 6.8 Hz, 1H), 4.57 (s, 2H), 4.20 (s, 1H), 3.70 (m, 2H), 3.46 (m, 2H), 3.19 (m, 2H), 2.92 (s, 3H), 2.53 (s, 3H), 2.45 (m 1H), 2.24 (m, 5), 1.89 (m 2H), 1.62 (d, J = 6.8 Hz, 3H).

[0562] Example 23

[0563]

[0564] Step 1:

[0565] Disperse 2,5-dichloro-4-(1-(2,4-dichlorophenethyl)oxy)pyrimidine (4-c) (182 mg, 0.54 mmol) and tert-butyl (piperidin-4-yl)carbamate (115 mg, 0.54 mmol) in a mixed solvent of tert-butanol (5 mL) and water (5 mL). Add sodium hydroxide (152 mg, 3.8 mmol), and heat the system to 90 °C and stir overnight. After the reaction is completed, cool the system to room temperature and add saturated ammonium chloride aqueous solution (5 mL). Evaporate the mixture to dryness to obtain the crude product, and the crude product is purified by silica gel column chromatography (methanol / dichloromethane = 0 - 4%) to obtain tert-butyl (1-(5-chloro-4-(1-(2,4-dichlorophenethyl)oxy)pyrimidin-2-yl)piperidin-4-yl)(methyl)carbamate (I-78-b) (121 mg). LC-MS: 515.2 [M+H] + .

[0566] Step 2:

[0567] Dissolve tert-butyl (1-(5-chloro-4-(1-(2,4-dichlorophenethyl)oxy)pyrimidin-2-yl)piperidin-4-yl)(methyl)carbamate (I-78-b) (121 mg, 0.23 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature overnight. After the reaction is completed, concentrate the reaction solution under reduced pressure. Add dichloromethane (5 mL) to the residue and concentrate again under reduced pressure to obtain the trifluoroacetate salt (154 mg) of 1-(5-chloro-4-(1-(2,4-dichlorophenethyl)oxy)pyrimidin-2-yl)-N-methylpiperidin-4-amine (I-78-c).

[0568] Step 3:

[0569] The trifluoroacetate (145 mg) of 1-(5-chloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidin-2-yl)-N-methylpiperidin-4-amine (I-78-c) obtained in the previous step, (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (I-18-g) (65 mg, 0.28 mmol), 1-hydroxybenzotriazole (HOBT, 15 mg, 0.11 mmol) were dispersed in acetonitrile (10 mL), then N,N-diisopropylethylamine (250 mg, 1.94 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 220 mg, 1.15 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, ethyl acetate (50 mL) was added, and the mixture was washed successively with saturated brine (15 mL×1), saturated sodium bicarbonate (15 mL×1), and water (15 mL×1). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 5%) to obtain tert-butyl (2R)-2-(((1-(5-chloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidin-2-yl)piperidin-4-yl)(methyl)carbamoyl)piperidine-1-carboxylate (I-78-d) (102 mg). LC-MS: 626.2[M+H] + 。

[0570] Step 4:

[0571] tert-butyl (2R)-2-(((1-(5-chloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidin-2-yl)piperidin-4-yl)(methyl)carbamoyl)piperidine-1-carboxylate (I-78-d) (102 mg, 0.16 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was added with dichloromethane (5 mL), and concentrated under reduced pressure again to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0 - 6%) to obtain (2R)-N-(1-(5-chloro-4-(1-(2,4-dichlorophenyl)ethoxy)pyrimidin-2-yl)piperidin-4-yl)-N-methylpiperidine-2-carboxamide (I-78) (45 mg). 526.2[M+H] + 。 1HNMR (400 MHz, CD3OD) δ 8.08 - 8.02 (m, 1H), 7.49 - 7.42 (m, 1H), 7.38 (dd, J = 8.4, 3.2 Hz, 1H), 7.31 (dd, J = 8.4, 2.0 Hz, 1H), 6.36 (dd, J = 6.5, 4.5 Hz, 1H), 4.72 - 4.47 (m, 3H), 4.46 - 4.14 (m, 1H), 3.39 (d, J = 13.5 Hz, 1H), 3.02 (ddd, J = 28.8, 24.4, 11.6 Hz, 4H), 2.91 - 2.73 (m, 4H), 2.69 (s, 1H), 2.11 (dd, J = 33.0, 13.6 Hz, 1H), 1.88 (dd, J = 25.9, 12.0 Hz, 2H), 1.80 - 1.43 (m, 9H).

[0572] Example 24

[0573]

[0574] The first step:

[0575] Compound 2,4,5-trichloropyrimidine (I-79-a) (282 mg, 1.538 mmol) and triethylamine (312 mg, 3.075 mmol) were added to a solution of (R)-1-(2,4-dichlorophenyl)ethylamine (1-a) (293 mg, 1.542 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at room temperature overnight. After completion of the reaction, the acetonitrile was evaporated under reduced pressure. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed successively with water (6 mL) and saturated brine (6 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 97 / 3 - 95 / 5, V / V) to obtain a colorless oil, (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-79-b) (514 mg, yield 99.2%). LC-MS: 336.0, 338.0 [M+H] + .

[0576] The second step

[0577] The compound (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)pyrimidin-4-amine (I-79-b) (510 mg, 1.513 mmol), the hydrochloride salt of N-(azetidin-3-yl)-N-methylcarbamic acid tert-butyl ester (2-a) (371 mg, 1.666 mmol), and sodium hydroxide (242 mg, 6.050 mmol) were successively added to tert-butanol (6 mL) and water (6 mL), and the reaction mixture was reacted at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, and tert-butanol was distilled off under reduced pressure. The residue was added with ethyl acetate (20 mL) and washed with water (8 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 95 / 5 to 10 / 1, V / V) to obtain the white powder (R)-(1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamic acid tert-butyl ester (I-79-c) (703 mg, yield 95.4%). LC-MS: 486.1, 488.1 [M+H] + .

[0578] The third step

[0579] The methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to (R)-(1-(5-chloro-4-((1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamic acid tert-butyl ester (I-79-c) (698 mg, 1.434 mmol), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure. The residue was added with dichloromethane (5 mL) and concentrated under reduced pressure again to obtain the white powder compound (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (I-79-d) hydrochloride salt (602 mg, yield 99.2%), LC-MS: 386.1, 388.1 [M+H] + .

[0580] The fourth step

[0581] The hydrochloride salt of compound (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (I-79-d) (100 mg, 0.256 mmol), (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (I-18-g) (59 mg, 0.257 mmol), HATU (98 mg, 0.257 mmol) and triethylamine (54 mg, 0.534 mmol) were successively added to DMF (2 mL), and the reaction mixture was reacted overnight at room temperature. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution, and it was washed successively with water (5 mL) and saturated brine (5 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 0 / 1, V / V) to obtain a colorless oil, (R)-2-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (I-79-e) (95 mg, yield 65.7%), LC-MS: 597.3, 599.3 [M+H] + 。

[0582] Step 5

[0583] A methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to (R)-2-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (I-79-e) (90 mg, 0.151 mmol), and the reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain a white powder compound (R)-N-(1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)-N-methylpiperidine-2-carboxamide (I-79) (32 mg, yield 39.8%), LC-MS: 497.1, 499.1 [M+H] + 。 11H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 5.54 (q, J = 7.2 Hz, 1H), 5.08 (m, 1H), 4.23 (m, 2H), 4.17–4.00 (m, 2H), 3.96 (m, 2H), 3.41 (m, 1H), 3.07 (s, 3H), 2.21 (m, 1H), 1.93 (m, 2H), 1.74 (m, 2H), 1.61 (m, 1H), 1.54 (d, J = 7.2 Hz, 3H).

[0584] Example 25

[0585]

[0586] The first step:

[0587] Hydrochloride salt (100 mg) of (R)-5-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-amine (I-79-d), (tert-butoxycarbonyl)-D-proline (I-1-a) (56 mg, 0.260 mmol), HATU (98 mg, 0.258 mmol) and triethylamine (55 mg, 0.544 mmol) were successively added to DMF (2 mL), and the reaction mixture was reacted overnight at room temperature. After the reaction was completed, ethyl acetate (20 mL) was added to the reaction solution, and it was washed successively with water (5 mL) and saturated brine (5 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1 - 0 / 1, V / V) to obtain a colorless oil, (R)-2-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-80-a) (90 mg, yield 62.5%), LC-MS: 583.1, 585.1 [M+H] + .

[0588] The second step:

[0589] The methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to (R)-2-((1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (I-80-a) (86 mg, 0.147 mmol), and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain 50 mg of the white powder compound (R)-N-(1-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrimidin-2-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (I-80) with a yield of 65.3%. LC-MS: 483.1, 485.1 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.29 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 5.54 (q, J = 7.2 Hz, 1H), 5.12 (m, 1H), 4.65 (m, 1H), 4.32–4.15 (m, 1H), 4.06 (m, 2H), 3.87 (m, 1H), 3.42 (m, 2H), 3.09 (s, 3H), 2.09 (m, 2H), 1.97–1.82 (m, 2H), 1.54 (d, J = 7.2 Hz, 3H).

[0590] Example 26

[0591]

[0592] The first step:

[0593] Disperse methyl L - prolinate (I - 82 - a, 1.23 g, 7.43 mmol) and tert - butyl (3aR,6aS) - 5 - oxohexahydrocyclopenta[c]pyrrole - 2(1H) - carboxylate (3 - a, 1.11 g, 4.93 mmol) in dichloromethane (50 mL). After adding acetic acid (0.44 g, 7.33 mmol), stir at room temperature. Add sodium triacetoxyborohydride (5.62 g, 26.52 mmol) to the system in batches, and stir the reaction solution at room temperature for 24 hours. After concentrating the reaction solution under reduced pressure, add an aqueous solution of sodium bicarbonate (50 mL), and extract with ethyl acetate (30 mL×3). Combine the organic phases and concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (ethyl acetate: petroleum ether = 3:1) to obtain tert - butyl (3aR,6aS) - 5 - ((S) - 2 - (methoxycarbonyl)pyrrolidin - 1 - yl)hexahydrocyclopenta[c]pyrrole - 2(1H) - carboxylate (I - 82 - b, 0.85 g, 51%), LC - MS: 338.9[M + H] + .

[0594] The second step:

[0595] Disperse tert - butyl (3aR,6aS) - 5 - ((S) - 2 - (methoxycarbonyl)pyrrolidin - 1 - yl)hexahydrocyclopenta[c]pyrrole - 2(1H) - carboxylate (I - 82 - b, 0.85 g, 2.5 mmol) in dichloromethane (30 mL), and add trifluoroacetic acid (6 mL). Stir the reaction solution at room temperature for 4 hours. Monitor the reaction by TLC until the raw materials are completely reacted. After concentrating the reaction solution under reduced pressure, obtain the crude product ((3aR,6aS) - octahydrocyclopenta[c]pyrrol - 5 - yl) - L - prolinate methyl ester (I - 82 - c, 1.92 g). The crude product is directly used in the next step without purification. LC - MS: 238.9[M + H] + .

[0596] The third step:

[0597] The crude product of ((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)-L-proline methyl ester (I-82-c, 1.92 g, 2.27 mmol) and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c, 0.83 g, 2.4 mmol) were dispersed in isopropanol (40 mL) and water (2 mL), and lithium hydroxide monohydrate (0.36 g, 8.58 mmol) was added. The reaction mixture was stirred at 90 °C. The reaction was monitored by LC-MS until the raw materials were completely reacted. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added, and the pH was adjusted to 6 - 7 with hydrochloric acid, and then extracted with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative chromatography to obtain the formate salt (126 mg) of ((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)-L-proline (I-82). LC-MS: 538.0 [M+H] + , 1 H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.1 Hz, 1H), 5.54 (q, J = 7.0 Hz, 1H), 3.89 (dd, J = 9.9, 4.5 Hz, 1H), 3.68 (dtt, J = 14.1, 10.4, 4.9 Hz, 2H), 3.54 (ddd, J = 16.3, 11.9, 4.9 Hz, 2H), 3.13 (td, J = 10.9, 6.6 Hz, 1H), 2.73 (dq, J = 11.0, 7.5, 5.6 Hz, 2H), 2.45–2.34 (m, 2H), 2.32 (s, 3H), 2.30–2.25 (m, 1H), 2.18 (ddt, J = 12.6, 7.7, 4.1 Hz, 1H), 2.06 (dtt, J = 13.6, 6.8, 3.3 Hz, 1H), 1.88 (dtt, J = 13.5, 10.1, 7.0 Hz, 1H), 1.80–1.56 (m, 2H), 1.52 (d, J = 7.1 Hz, 3H).

[0598] Example 27

[0599]

[0600] The first step:

[0601] Methyl (S)-2-(pyrrolidin-2-yl)acetate (I-83-a, 100 mg, 0.70 mmol), tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-a, 189 mg, 0.84 mmol), and sodium triacetoxyborohydride (592 mg, 2.79 mmol) were dispersed in dichloromethane (5 mL). The reaction mixture was stirred at room temperature. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, the reaction mixture was added with ethyl acetate (10 mL) and extracted with water (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product tert-butyl 5-((S)-2-(2-methoxy-2-oxoethyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-83-b, 250 mg), which was directly used in the next step. LC-MS: 352.9 [M+H] + 。

[0602] Step 2:

[0603] tert-Butyl 5-((S)-2-(2-methoxy-2-oxoethyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate ((I-83-b, 250 mg, 0.70 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL) was added to the system. The reaction mixture was stirred at room temperature for 6 hours. The reaction was monitored by LC-MS until the starting materials were completely reacted. After concentration under reduced pressure, the crude product trifluoroacetate of methyl 2-((2S)-1-(octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)acetate (I-83-c) (150 mg) was obtained, which was directly used in the next step. LC-MS: 253.0 [M+H] + 。

[0604] Step 3:

[0605] (R)-2,5-Dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c, 100 mg, 0.28 mmol), the trifluoroacetate of 2-((2S)-1-(octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)acetic acid methyl ester (I-83-c) (110 mg, 0.30 mmol), and lithium hydroxide (27 mg, 1.14 mmol) were dispersed in isopropanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at 95 °C for 16 h. The reaction was monitored by LC-MS until the raw materials were completely reacted. After concentration under reduced pressure, water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain 2-((2S)-1-(2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)pyrrolidin-2-yl)acetic acid (I-83, 10 mg). LC-MS: 551.7 [M+H] + 。 1 H NMR (400 MHz, CD3OD) δ 7.45 (s, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 5.58–5.46 (m, 1H), 3.85–3.64 (m, 2H), 3.56 (d, J = 11.0 Hz, 2H), 3.43 (s, 2H), 3.24 (s, 2H), 2.86–2.34 (m, 6H), 2.30 (s, 3H), 2.21 (s, 1H), 2.12–1.96 (m, 2H), 1.85 (d, J = 7.3 Hz, 1H), 1.50 (t, J = 13.9 Hz, 5H).

[0606] Example 28

[0607]

[0608] The first step:

[0609] The hydrochloride salt of methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate (I-92-a) (0.60 g, 3.1 mmol) and tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3-a, 0.50 g, 2.22 mmol) were dispersed in dichloromethane (30 mL). After adding acetic acid (0.21 g, 3.50 mmol), the mixture was stirred at room temperature, and sodium triacetoxyborohydride (2.83 g, 13.0 mmol) was added in portions. The reaction mixture was stirred at room temperature for 24 hours. After concentration under reduced pressure, an aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (dichloromethane solution of 0 - 5% methanol) to obtain tert-butyl (3aR,6aS)-5-((2S,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-92-b, 0.79 g, 2.1 mmol, 95%). LC-MS: 357.3 [M+H] + .

[0610] Step 2:

[0611] tert-Butyl (3aR,6aS)-5-((2S,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-92-b, 0.79 g, 2.1 mmol) was dispersed in dichloromethane (30 mL), and trifluoroacetic acid (5 mL) was added. The reaction mixture was stirred at room temperature. The reaction was monitored by LCMS until the raw materials were completely reacted. After concentration under reduced pressure, the crude product methyl (2S,4R)-4-fluoro-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrole-2-carboxylate (I-92-c, 1.50 g, 94.8%) was obtained. The crude product was directly used in the next step without purification. LC-MS: 257.2 [M+H] + .

[0612] Step 3:

[0613] The crude product of the previous step, methyl (2S,4R)-4-fluoro-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrole-2-carboxylate (I-92-c, 0.475 g, 0.667 mmol), and (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c, 0.286 g, 0.815 mmol) were dispersed in isopropanol (12 mL) and water (6 mL). Lithium hydroxide monohydrate (0.155 g, 6.47 mmol) was added, and the reaction mixture was stirred at 90 °C overnight. The reaction was monitored by LC-MS until the raw materials were completely reacted. After the reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the pH was adjusted to 6 - 7 with 4 M hydrochloric acid. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was concentrated under reduced pressure to obtain the crude product. Ethyl acetate (25 mL) was added to the obtained crude product, and the mixture was stirred at room temperature. A precipitate formed and was filtered to obtain an off-white solid (140 mg). It was dissolved in methanol (20 mL) and filtered. The filtrate was concentrated to obtain (2S,4R)-1-((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)-4-fluoropyrrole-2-carboxylic acid (I-92, 18 mg). LCMS: 556.0 [M+H] + 。

[0614] 1 H NMR (400 MHz, d-DMSO) δ 7.54 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.5, 2.1 Hz, 1H), 7.23 (d, J = 6.9 Hz, 1H), 5.51–5.41 (m, 1H), 3.65–3.53 (m, 3H), 3.12–3.04 (m, 2H), 2.93 (dd, J = 26.4, 12.5 Hz, 2H), 2.19 (s, 3H), 2.15–2.04 (m, 2H), 2.00 (dd, J = 14.3, 6.9 Hz, 2H), 1.44 (d, J = 7.1 Hz, 3H), 1.29–1.20 (m, 6H).

[0615] Example 29

[0616]

[0617] The first step:

[0618] At room temperature, the hydrochloride salt (0.50 g, 3.02 mmol) of (2S,5R)-5-methylpyrrolidine-2-carboxylic acid (I-93-a) and methanol (30 mL) were added to a single-neck flask (50 mL). Under ice bath conditions, thionyl chloride (0.3 mL, 4 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature. After the reaction was complete, the reaction solution was directly concentrated to dryness to obtain the hydrochloride salt (0.60 g, 3.02 mmol) of methyl (2S,5R)-5-methylpyrrolidine-2-carboxylate (I-93-b). The crude product was used directly in the next step without purification.

[0619] The second step

[0620] The hydrochloride salt (0.48 g, 2.66 mmol) of methyl (2S,5R)-5-methylpyrrolidine-2-carboxylate (I-93-b) and tert-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.40 g, 1.78 mmol) (3-a) were dispersed in dichloromethane (30 mL). After adding acetic acid (0.16 g, 2.66 mmol), the mixture was stirred at room temperature, and sodium triacetoxyborohydride (2.02 g, 9.55 mmol) was added in batches. The reaction solution was stirred at room temperature for 24 hours. After the reaction solution was concentrated under reduced pressure, an aqueous sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (dichloromethane solution of 0 - 5% methanol) to obtain tert-butyl (3aR,6aS)-5-((2S,5R)-2-(methoxycarbonyl)-5-methylpyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-93-c, 296 mg, 0.84 mmol). LCMS: 353.3 [M+H] + 。

[0621] The third step:

[0622] tert-Butyl (3aR,6aS)-5-((2S,5R)-2-(methoxycarbonyl)-5-methylpyrrolidin-1-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (I-93-c, 296 mg, 0.84 mmol) was dispersed in dichloromethane (50 mL), and trifluoroacetic acid (4.6 mL) was added. The reaction solution was stirred at room temperature. The reaction was monitored by LCMS until the raw materials were completely reacted. After the reaction solution was concentrated under reduced pressure, the crude product methyl (2S,5R)-5-methyl-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrole-2-carboxylate (I-93-d, 520 mg, 0.84 mmol) was obtained. The crude product was used directly in the next step without purification. LC-MS: 252.9 [M+H] + 。

[0623] The fourth step:

[0624] The crude product methyl (2S,5R)-5-methyl-1-((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)pyrrole-2-carboxylate (I-93-d, 520 mg, 0.84 mmol), (R)-2,5-dichloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (1-c, 310 mg, 0.882 mmol) were dispersed in isopropanol (12 mL) and water (6 mL), lithium hydroxide (476.5 mg, 19.9 mmol) was added, and the reaction mixture was stirred at 90 °C. The reaction was monitored by LC-MS until the raw materials were completely reacted. After the reaction mixture was concentrated under reduced pressure, water (20 mL) was added, the pH was adjusted to 6 - 7 with 4 M hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative chromatography to obtain the formate salt (134.1 mg) of (2S,5R)-1-((3aR,6aS)-2-(5-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)-5-methylpyrrolidine-2-carboxylic acid (I-93), LC-MS: 554.0 [M+H] + 。 1 H NMR (400 MHz, d-DMSO) δ 7.57 (d, J = 2.1 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.5, 2.1 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 5.56–5.49 (m, 1H), 2.55 (s, 1H), 2.21 (s, 3H), 2.05–1.95 (m, 3H), 1.89 (s, 2H), 1.70 (d, J = 11.6 Hz, 2H), 1.46 (d, J = 7.0 Hz, 3H), 1.25 (s, 9H), 1.17 (d, J = 6.6 Hz, 3H).

[0625] Example 30

[0626]

[0627] The first step:

[0628] 5-Bromo-2,4-dichloro-6-methylpyrimidine (I-96-a, 400 mg, 1.65 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (1-a, 310 mg, 1.64 mmol) and triethylamine (0.25 g, 2.47 mmol) were dispersed in acetonitrile (6 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by LC-MS until the raw materials were completely reacted. The reaction mixture was concentrated to obtain a crude product, which was separated and purified by column chromatography (ethyl acetate: petroleum ether = 95:5) to give (R)-5-bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (I-96-b, 670 mg, 81.96%), LC-MS: 395.6 [M+H] + .

[0629] Step 2:

[0630] (R)-5-Bromo-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidin-4-amine (I-96-b, 670 mg, 1.69 mmol) and the crude product of ((3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl)-L-proline methyl ester (I-82-c, 0.87 g) were dispersed in isopropanol (40 mL), lithium hydroxide (500 mg, 20 mmol) and water (1.5 mL) were added, and the reaction mixture was stirred at 90 °C overnight. The reaction was monitored by LC-MS until the raw materials were completely reacted. After the reaction mixture was concentrated to dryness under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The aqueous phase was adjusted to pH 6-7 with hydrochloric acid and concentrated under reduced pressure to obtain a crude product, which was separated and purified by HPLC to give ((3aR,6aS)-2-(5-bromo-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)octahydrocyclopenta[c]pyrrol-5-yl)-L-proline (I-96, 400 mg), LC-MS: M / Z = 584.0 [M+H] + . 11H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.26 (dd, J = 8.4, 2.0 Hz, 1H), 5.50 (q, J = 7.0 Hz, 1H), 3.89 (dd, J = 9.8, 4.4 Hz, 1H), 3.75–3.59 (m, 2H), 3.51 (ddd, J = 24.2, 11.8, 4.8 Hz, 2H), 3.41–3.32 (m, 2H), 3.13 (td, J = 10.8, 6.5 Hz, 1H), 2.77–2.62 (m, 2H), 2.45–2.23 (m, 6H), 2.23–1.98 (m, 3H), 1.90 (dt, J = 17.6, 5.8 Hz, 1H), 1.79–1.54 (m, 2H), 1.51 (d, J = 7.0 Hz, 3H).

[0631] Referring to the above embodiments, the compounds shown in Table I were prepared, and their structural characterizations are as follows:

[0632] Table 1 Compound List

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647] Effect Example 1

[0648] I. In Vitro FLIPR Calcium Flux Assay

[0649] 1. Research Purpose

[0650] FLIPR calcium flux assay is a common method for measuring intracellular calcium changes. The detection principle is that after the lipophilic acetoxymethyl (AM) carries a Ca 2+ sensitive indicator dye into the cell, it is cleaved by cytoplasmic enzymes to release free Ca 2+ sensitive indicator dye. When the channel opens, a large amount of calcium ions flow into the cell and bind to the indicator dye, emitting a strong fluorescence signal. The blocking effect of the drug on the channel at different concentrations reduces the calcium ion influx, thereby reducing the fluorescence signal intensity, and thus reflecting the strength of the blocking effect of the drug on the channel.

[0651] In this experiment, the inhibitory effect of the compound on the CCR4 receptor was detected by using the FLIPR calcium flux experiment.

[0652] 2. Experimental Method

[0653] Experimental Materials

[0654] Reagent Name Catalog Number Brand DMEM Medium 11965 Gibco Fetal Bovine Serum (FBS) FSP500 Excell Geneticin (G418) 10131-027 Gibco Penicillin-Streptomycin (PS) SV30010 Hyclone Blasticidin S (BS) A11139 Invitrogen Fluo-4 Calcium Assay Kit (Fluo-4 Direct) F10471 Invitrogen 384-Well Cell Culture Plate 781090 Greiner

[0655] Experimental Instruments

[0656]

[0657] Experimental Procedures

[0658] 1. The cell line stably expressing CCR4 (CCR4-HEK293) was cultured using DMEM medium supplemented with fetal bovine serum, G418, and BS, penicillin-streptomycin. The cells were diluted to 1×10*6 cells / mL with the medium and added to a 384-well cell plate at 20 μL / well, and the cells were cultured overnight.

[0659] 2. The next day, prepare 250 mM FLIPR assay buffer and 2×Fluo-4 Direct TM loading buffer.

[0660] 3. For the agonist reference compound CCL17 (refers to the natural ligand CCL17), dilute the 123 μM stock solution to 5 μM with the assay buffer and perform 3-fold serial dilutions to 10 concentration points. For the reference and test compound plates: the test compounds and reference compounds were serially diluted 4-fold to 10 concentration points using Echo, and then 900 nL of the compound was transferred to the destination plate. 30 μL / well of the assay buffer was added.

[0661] 4. Discard the supernatant from the cell reaction plate, add 20 μL of experimental buffer and 20 μL of Fluo-4 Direct TM loading buffer, incubate at 37 °C in a 5% carbon dioxide environment for 50 minutes, and then incubate at room temperature for 10 minutes.

[0662] 5. Transfer 10 μL of the CCL17 serial dilution from the agonist reference compound plate to the cell plate, read the values, calculate and prepare the EC 80 .

[0663] 6. Transfer 10 μL of the test compound dilution from the compound plate to the cell reaction plate, incubate at 37 °C in a 5% carbon dioxide environment for 50 minutes, and then incubate at room temperature for 10 minutes.

[0664] 7. Transfer the reaction plate to FLIPR (Molecular Devices). Take 10 μL of 6×EC 80 recombinant human CCL17 dilution and add it to the cell reaction plate. Read the fluorescence values, analyze the data using Graphpad software, and calculate the IC 50 of the compound's inhibitory activity on CCR4 receptor calcium flux.

[0665] 3. Experimental Results

[0666] The results of the calcium flux assay are shown in Table 2

[0667] Table 2 Inhibitory activity of the test compounds on calcium flux

[0668] Compound Number <![CDATA[IC 50 (nM)]]> Compound Number <![CDATA[IC 50 (nM)]]> I-1 51.05 I-5 93.5 I-6 114.7 I-14 11.67 I-15 142.8 I-20 154 I-21 63.28 I-26 44.65 I-28 32.79 I-29 79.43 I-31 87.57 I-33 49.36 I-44 87.05 I-45 85.14 I-46 20.82 I-47 113.8 I-49 207.7 I-50 27.18 I-51 19.58 I-55 49.36 I-58 62.16 I-59 80.04 I-61 74.62 I-65 74.57 I-66 16.66 I-76 104.8 I-81 36.96 I-82 13.59 I-83 24.3 I-92 25.78 I-93 36.4 I-96 30.33 .

Claims

1. A compound as shown in Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof: in, In the compound shown in Formula I, Formula II or Formula III: X 1 , X 3 and X 5 Each independently is N or C; X 2 , X 4 and X 6 are each independently N or CH; Y 1 , Y 2 , Y 5 , Y 6 , Y 9 , Y 10 Each independently is N or CR 25 ; Y 3 , Y 7 , Y 11 Each independently is CR 26 ; Y 4 , Y 8 , Y 12 Each independently is CR 27 or N; Q 1 , Q 2 , Q 3 Each independently is N or O, when Q 1 , Q 2 , Q 3 When R is 0, 1 , R 9 , R 17 does not exist; Z 1 , Z 2 , Z 3 Each independently is C or does not exist; R 1 , R 9 , R 17 Each is independently hydrogen or a C1-C6 alkyl group; R 2 , R 3 , R 10 , R 11 , R 18 , R 19 Each is independently hydrogen, absent or a C1-C6 alkyl group; R 4 , R 5 , R 6 , R 7 , R 8 , R 12 , R 13 , R 14 , R 15 , R 16 , R 20 , R 21 , R 22 , R 23 , R 24 are each independently hydrogen or halogen; R 25 is a C1-C6 alkyl group or is replaced by one or more R 25-1 Substituted C1-C6 alkyl; R 25-1 is a halogen; R 26 is C1-C6 alkyl, hydrogen or C3-C8 cycloalkyl; R 27 Halogen or R 27-1 is a C1-C6 alkyl, a C3-C8 cycloalkyl or a 5-10 membered heteroaryl, wherein the heteroatoms in the 5-10 membered heteroaryl are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Or, R 26 and the C atoms and Y atoms directly connected to it 2 Together they form a 5-6 membered heteroaryl group or are replaced by one or more R 26-1 A substituted 5-6 membered heteroaryl group; the heteroatoms in the 5-6 membered heteroaryl group are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Or, R 26 and the C atoms and Y atoms directly connected to it 4 Together they form a 5-6 membered heteroaryl group or are replaced by one or more R 26-2 A substituted 5-6 membered heteroaryl group; the heteroatoms in the 5-6 membered heteroaryl group are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Each R 26-1 and R 26-2 Each is independently a C1-C6 alkyl group; Ring A and Ring B are independently 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl, and Ring A and Ring B are connected in a cyclic manner; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Ring C and ring D are independently 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl, and ring C and ring D are connected in a spiro ring manner; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Ring E is a 3-8 membered heterocycloalkyl or a C3-C8 cycloalkyl, wherein the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; L 1 For hydrogen, C3~C8 cycloalkyl, I-2 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, substituted by one or more R I-3 Substituted C1-C6 alkyl, 3-8 membered heterocycloalkyl, substituted by one or more R I-4 Substituted 3-8 membered heterocycloalkyl or -NR I-5 R I-6 The heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; R I-1 is a 3-8 membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is independently 1, 2 or 3; Each R I-2 Each is independently -COOH or a C1-C6 alkyl group; R I-3 is hydroxyl group; Each R I-4 Each independently represents -COOH, halogen, C1-C6 alkyl or one or more R I-4-1 Substituted C1-C6 alkyl; Each R I-4-1 Each independently is hydroxyl or -COOH; R I-5 and R I-6 are independently hydrogen, C1-C6 alkyl or R I-5-1 is a 3-8 membered heterocycloalkyl group, wherein the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is independently 1, 2 or 3; L 3 is hydrogen, C3-C8 cycloalkyl, or one or more R II-1 Substituted C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, substituted by one or more R II-2 Substituted 3-8 membered heterocycloalkyl, C1-C6 alkyl, substituted by one or more R II-3 Substituted C1-C6 alkyl, -NR II-5 RI II-6 or -COOH, wherein the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is independently 1, 2 or 3; Each R II-1 Each is independently a C1-C6 alkyl or -COOH; Each R II-2 Each independently is -COOH, C1-C6 alkyl or one or more R II-2-1 Substituted C1-C6 alkyl; R II-2-1 is hydroxyl group; Each R II-3 Each independently is hydroxyl or -COOH; R II-4 is a 3-8 membered heterocycloalkyl group, II-4-1 Substituted 3-8 membered heterocycloalkyl, -C2-C6 alkenyl, C1-C6 alkyl or one or more R II-4-2 Substituted C1-C6 alkyl, wherein the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; R II-4-1 is a C1-C6 alkyl group; Each R II-4-2 Each independently is -COOH or two R II-4-2 The substituents can form a C3-C8 cycloalkyl group with the C atom to which they are connected; R II-5 , R II-6 are independently hydrogen, C1-C6 alkyl, R II-5-1 is a 3-8 membered heterocycloalkyl group, wherein the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is independently 1, 2 or 3; L 5 For-NR III-1 R III-2 , 3-8 membered heterocycloalkyl, III-3 Substituted 3-8 membered heterocycloalkyl or C1-C6 alkyl; R III-1 , R III-2 are independently hydrogen, C1-C6 alkyl, C3~C8 cycloalkyl, III-1-2 Substituted C3-C8 cycloalkyl or one or more R III-1-3 Substituted C1-C6 alkyl; R III-1-1 is a 3-8 membered heterocycloalkyl group, III-1-1-1 Substituted 3-8 membered heterocycloalkyl, C1-C6 alkyl, one or more R III-1-1-2 Substituted C1-C6 alkyl, 4-12 membered heterocyclic alkyl, substituted by one or more R III -1-1-3 Substituted 4-12-membered heterocycloalkyl, 4-12-membered bridged heterocycloalkyl; the heteroatoms in the 3-8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12-membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; Each R III-1-1-1 are each independently a C1-C6 alkyl group, -NR III-1-1-1-1 R III-1-1-1-2 , hydroxyl, -COOH, one or more R III-1-1-1-3 Substituted C1-C6 alkyl, oxo, disulfide, halogen; R III-1-1-1-1 , R III-1-1-1-2 Each is independently hydrogen, C1-C6 alkyl; Each R III-1-1-1-3 Each is independently hydroxyl, -COOH, or 4-10 membered heteroaryl, wherein the heteroatoms in the 4-10 membered heteroaryl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4; Each R III-1-1-2 Each independently is -COOH, two R III-1-1-2 The substituents can form C3-C8 cycloalkyl, -NR III-1-1-2-1 R III-1-1-2-2 or a 3-8 membered heterocycloalkyl; R III-1-1-2-1 , R III-1-1-2-2 are independently hydrogen or C1-C6 alkyl; R III-1-1-3 For oxygen generation; Each R III-1-2 Each is independently a C1-C6 alkyl or -COOH; Each R III-1-3 Each is independently a 3-8 membered heterocycloalkyl or hydroxyl group; Each R III-3 Each independently represents -COOH, a C1-C6 alkyl group, one or more R III-3-1 Substituted C1-C6 alkyl, Each R III-3-1 Each independently is hydroxyl or NR III-3-1-1 R III-3-1-2 ; R III-3-1-1 , R III-3-1-2 Each is independently a C1-C6 alkyl group; R III-3-2 is a C1-C6 alkyl group or is replaced by one or more R III-3-2-1 Substituted C1-C6 alkyl; Each R III-3-2-1 Each independently is -COOH, two R III-3-2-1 The substituents can form a C3-C8 cycloalkyl group with the C atom to which they are connected; L 2 is absent, hydrogen, or a C1-C6 alkyl group; L 4 is absent, hydrogen or a C1-C6 alkyl group; L 6 is absent, hydrogen, C1-C6 alkyl, or is replaced by one or more R III’-1 Substituted C1-C6 alkyl; R III’-1 It is hydroxyl.

2. The compound of formula I, formula II or formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: In the compound shown in formula I, X 1 N or C; X 2 is N; Y 1 is N; Y 2 is N; Y 3 CR 26 ; R 26 is hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl; Y 4 CR 27 or N; R 27 For halogen, R 27-1 is a C1-C6 alkyl group; Or, R 26 and the C atoms and Y atoms directly connected to it 2 Together they form a 5-6 membered heteroaryl group or are replaced by one or more R 26-1 A substituted 5-6 membered heteroaryl group; the heteroatoms in the 5-6 membered heteroaryl group are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Or, R 26 and the C atoms and Y atoms directly connected to it 4 Together they form a 5-6 membered heteroaryl group or are replaced by one or more R 26-2 A substituted 5-6 membered heteroaryl group; the heteroatoms in the 5-6 membered heteroaryl group are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; Each R 26-1 and R 26-2 Each is independently a C1-C6 alkyl group; Q 1 is N; Z 1 is C; R 1 is hydrogen; R 2 is hydrogen; R 3 is a C1-C6 alkyl group; R 4 is a halogen; R 6 is a halogen; R 5 , R 7 , R 8 For hydrogen.

3. The compound of formula I, formula II or formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: In the compound shown in Formula II, X 3 N or C; X 4 is N; Y 5 is N; Y 6 is N; Y 7 CR 26 ; R 26 is a C1-C6 alkyl group; Y 8 CR 27 ; R 27 is a halogen; Q 2 is N; Z 2 is C; R 10 is hydrogen; R 11 is a C1-C6 alkyl group; R 12 is a halogen; R 14 is a halogen; R 13 , R 15 , R 16 For hydrogen.

4. The compound of formula I, formula II or formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated substance thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: In the compound shown in formula III, X 5 is C; X 6 is N; Y 9 is N; Y 10 is N; Y 11 CR 26 ; R 26 is hydrogen, C1-C6 alkyl; Y 12 CR 27 , or N; R 27-1 is a C3-C8 cycloalkyl group or a 5-10-membered heteroaryl group, wherein the heteroatoms in the 5-10-membered heteroaryl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatoms is independently 1, 2, or 3; R 27 is a halogen; Q 3 N or O; Z 3 is C; R 18 is hydrogen; R 19 is a C1-C6 alkyl group; R 20 is a halogen; R 22 is a halogen; R 21 , R 23 , R 24 For hydrogen.

5. The compound of formula I, formula II or formula III as claimed in claim 1 or claim 4, or a pharmaceutically acceptable salt thereof, or a deuterated substance thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: In the compound shown in formula III, R 26 is a C1-C6 alkyl group; L 5 For-NR III-1 R III-2 , 3-8 membered heterocycloalkyl, III-3 Substituted 3-8 membered heterocycloalkyl or C1-C6 alkyl; R III-1 , R III-2 are independently C1-C6 alkyl, C3~C8 cycloalkyl, III -1-2 Substituted C3-C8 cycloalkyl, one or more R III-1-3 Substituted C1-C6 alkyl; R III-1-1 is a 3-8 membered heterocycloalkyl group, III-1-1-1 Substituted 3-8 membered heterocycloalkyl, C1-C6 alkyl, substituted by one or more R III-1-1-2 Substituted C1-C6 alkyl, 4-12 membered heterocyclic alkyl, substituted by one or more R III -1-1-3 Substituted 4-12-membered heterocycloalkyl, 4-12-membered bridged heterocycloalkyl; the heteroatoms in the 3-8-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12-membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatoms in the 4-12-membered bridged heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; Each R III-1-1-1 are each independently a C1-C6 alkyl group, -NR III-1-1-1-1 R III-1-1-1-2 , hydroxyl, -COOH, one or more R III-1-1-1-3 Substituted C1-C6 alkyl, oxo, disulfide, halogen; R III-1-1-1-1 , R III-1-1-1-2 Each is independently hydrogen, C1-C6 alkyl; R III-1-1-1-3 is hydroxyl, -COOH, or 4-10 membered heteroaryl, wherein the heteroatoms in the 4-10 membered heteroaryl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, 3, or 4; Each R III-1-1-2 Each independently is -COOH, two R III-1-1-2 The substituents can form C3-C8 cycloalkyl, -NR III-1-1-2-1 R III-1-1-2-2 , 3-8 membered heterocycloalkyl; R III-1-1-2-1 , R III-1-1-2-2 are independently hydrogen, C1-C6 alkyl; R III-1-1-3 For oxygen generation; Each R III-1-2 Each is independently a C1-C6 alkyl or -COOH; Each R III-1-3 Each is independently a 3-8 membered heterocycloalkyl or hydroxyl group; Each R III-3 Each independently represents -COOH, a C1-C6 alkyl group, one or more R III-3-1 Substituted C1-C6 alkyl, R III-3-1 NR III-3-1-1 R III-3-1-2 ; R III-3-1-1 , R III-3-1-2 Each is independently a C1-C6 alkyl group; R III-3-2 is a C1-C6 alkyl group, with one or more R III-3-2-1 Substituted C1-C6 alkyl; R III-3-2-1 -COOH, two R III-3-2-1 The substituents can form a C3-C8 cycloalkyl group with the C atom to which they are connected; L 6 is absent, hydrogen, C1-C6 alkyl, III’-1 Substituted C1-C6 alkyl; R III’-1 is hydroxyl group; Preferably, the compound as shown in formula III satisfies one or more of the following conditions: (1)R III-3-1 NR III-3-1-1 R III-3-1-2 ; (2)R 26 is a C1-C6 alkyl group; L 5 For-NR III-1 R III-2 , 3-8 membered heterocycloalkyl, III-3 a substituted 3-8 membered heterocycloalkyl group or a C1-C6 alkyl group; and (3)R III-1 , R III-2 are independently C1-C6 alkyl, C3~C8 cycloalkyl, III-1-2 Substituted C3-C8 cycloalkyl, one or more R III-1-3 Substituted C1-C6 alkyl.

6. The compound of formula I, formula II or formula III as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a deuterated substance thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: It meets one or more of the following conditions: (1) Ring A is a 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; preferably a 5-membered heterocycloalkyl, a 5-membered cycloalkyl or a 3-membered cycloalkyl; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1; (2) Ring B is a 3-8 membered heterocycloalkyl group; preferably a 5 membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen and sulfur, and the number of heteroatoms is independently 1, 2 or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1; (3) Ring C is a 3-8 membered heterocycloalkyl or C3-C8 cycloalkyl; preferably a 4-membered heterocycloalkyl, a 5-membered heterocycloalkyl, a 6-membered heterocycloalkyl, or a 4-membered cycloalkyl; the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of heteroatoms is preferably 1; (4) Ring D is a 3-8 membered heterocycloalkyl group; preferably a 4-membered heterocycloalkyl group, a 5-membered heterocycloalkyl group, or a 6-membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, and sulfur, and the number of the heteroatoms is independently 1, 2, or 3; the heteroatom is preferably nitrogen, and the number of the heteroatoms is preferably 1; and (5) Ring E is a 3-8 membered heterocycloalkyl group; preferably a 4-membered heterocycloalkyl group or a 6-membered heterocycloalkyl group; the heteroatoms in the 3-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen and sulfur, and the number of the heteroatoms is independently 1, 2 or 3; the heteroatom is preferably nitrogen, and the number of the heteroatoms is preferably 1.

7. The compound of formula I, formula II or formula III according to claim 1, claim 2 or claim 6, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound as shown in Formula I satisfies one or more of the following conditions: (1)R 25 , R 26 , R 1 , R 2 , R 3 , R 27-1 , L 1 , R I-2 , R I-4 , R I-5 , R I-6 , R 25 One or more R 25-1 Replaced by L 1 One or more R I-3 Replaced, R I-4 One or more R I-4-1 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl; (2)R 25-1 , R 4 , R 5 , R 6 , R 7 , R 8 , R 27 wherein the halogen is independently F, Cl, Br or I; (3)R 27-1 , Ring A, Ring B, L 1 In the above, the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane or cyclopentane; (4) Ring A, Ring B, L 1 , R I-1 , R I-5-1 , R I-5-1 wherein the 3-8-membered heterocycloalkyl is independently a 5- or 6-membered heterocycloalkyl; (5) Ring A, Ring B, L 1 , R I-1 , R I-5-1 , R I-5-1 In the 3-8 membered heterocycloalkyl, the heteroatoms are independently one or more of nitrogen, oxygen and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2 or 3, preferably 1; (6)R 27-1 is a C1-C6 alkyl group; (7)R 26 wherein the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane; (8) R 26 and the C atoms and Y atoms directly connected to it 2 together to form a 5-6 membered heteroaryl group and is represented by one or more R 26-1 In the substituted 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heteroaryl is selected from N; the 5-6 membered heteroaryl is preferably Preferably (9)R 26 and the C atoms and Y atoms directly connected to it 4 together to form a 5-6 membered heteroaryl group and is represented by one or more R 26-2 In the substituted 5-6 membered heteroaryl, the heteroatom in the 5-6 membered heteroaryl is selected from N; the 5-6 membered heteroaryl is preferably Preferably (10)R 26-1 and R 26-2 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl; (11)R I-4 wherein the halogen is independently F, Cl, Br or I; preferably F.

8. The compound of formula I, formula II or formula III according to claim 1, claim 3 or claim 6, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound as shown in formula II satisfies one or more of the following conditions: (1)R 25 , R 26 , R 9 , R 10 , R 11 , R 27-1 , L 3 , R II-1 , R II-2 , R II-4 , R II-4-1 , R II-5 , R II-6 , R 25 One or more R 25-1 Replaced by L 3 One or more R II-3 Substituted C1-C6 alkyl, R II-2 One or more R II-2-1 Substituted C1-C6 alkyl, R II-4 One or more R II-4-2 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl; (2)R 25-1 , R 12 , R 13 , R 14 , R 15 , R 16 , R 27 wherein the halogen is independently F, Cl, Br or I; (3)R 27-1 , Ring C, Ring D, L 3 , L 3 One or more R II-1 In the substituted C3-C8 cycloalkyl group, the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclobutane; (4) Ring C, Ring D, L 3 , R II-4 , L 3 One or more R II-2 Substituted 3-8 membered heterocycloalkyl, R II-4 One or more R II-4-1 In the substituted 3-8-membered heterocycloalkyl, the 3-8-membered heterocycloalkyl is independently a 4-, 5- or 6-membered heterocycloalkyl; (5) Ring C, Ring D, L 3 , R II-4 , L 3 One or more R II-2 Substituted 3-8 membered heterocycloalkyl, R II-4 One or more R II-4-1 In the substituted 3-8 membered heterocycloalkyl, the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2 or 3, preferably 1.

9. The compound of formula I, formula II or formula III according to claim 1, claim 4, claim 5 or claim 6, or a pharmaceutically acceptable salt thereof, or a deuterated substance thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound shown in formula III satisfies one or more of the following conditions: (1)R 25 , R 26 , R 17 , R 18 , R 19 , R 27-1 , L 5 , R III-1 , R III-2 , R III-1-1 , R III-1-1-1 , R III-1-1-1-1 , R III-1-1-1-2 , R III-1-1-2-1 , R III-1-1-2-2 , R III-1-2 , R III-3 , R III-3-1-1 , R III-3-1-2 , R III-3-2 , L 2 , L 4 , L 6 , R III-1 One or more R III-1-3 Substituted C1-C6 alkyl, R III-2 One or more R III-1-3 Substituted C1-C6 alkyl, R III-1-1 One or more R III-1-1-2 Substituted C1-C6 alkyl, R III-1-1-1 One or more R III-1-1-1-3 Substituted C1-C6 alkyl, R III-3 One or more R III-3-1 Substituted C1-C6 alkyl, R III-3-2 One or more R III -3-2-1 Substituted C1-C6 alkyl, L 6 One or more R III’-1 In the substituted C1-C6 alkyl group, the C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; preferably methyl; (2)R 25-1 , R 20 , R 21 , R 22 , R 23 , R 24 , R 27 , R III-1-1-1 wherein the halogen is independently F, Cl, Br or I; (3)R 27-1 , R III-1 , R III-2 , R III-1 One or more R III-1-2 Substituted C3-C8 cycloalkyl, R III-2 One or more R III-1-2 Substituted C3-C8 cycloalkyl, R III-1-1-2 Two R's III-1-1-2 The substituents can form a C3-C8 cycloalkyl group with the carbon atoms they are connected to. III-3-2-1 Two R's III-3-2-1 The substituents can form a C3-C8 cycloalkyl group with the C atom they are connected to, wherein the C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane or cyclobutane; (4) Ring E, L 5 , R III-1-1-2 , R III-1-3 , L 5 One or more R III-3 Substituted 3-8 membered heterocycloalkyl, R III-1-1 , R III-1-1 One or more R III-1-1-1 In the substituted 3-8-membered heterocycloalkyl, the 3-8-membered heterocycloalkyl is independently a 4-, 5- or 6-membered heterocycloalkyl; (5) Ring E, L 5 , R III-1-1-2 , R III-1-3 , L 5 One or more R III-3 Substituted 3-8 membered heterocycloalkyl, R III-1-1 , R III-1-1 One or more R III-1-1-1 In the substituted 3-8 membered heterocycloalkyl, the heteroatoms in the 3-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, and sulfur, preferably nitrogen, and the number of heteroatoms is independently 1, 2 or 3, preferably 1; (6)R III-1-1 4-12 membered heterocyclic alkyl, R III-1-1 One or more R III-1-1-3 In the substituted 4-12-membered heterocycloalkyl, the 4-12-membered heterocycloalkyl is a C3-C8 cycloalkyl and a 3-8-membered heterocycloalkyl, preferably a cyclopropane and a 5-membered heterocycloalkyl; (7)R III-1-1 In the 4-12-membered bridged heterocycloalkyl, the 4-12-membered bridged heterocycloalkyl is preferably a 6-membered bridged heterocycloalkyl.

10. The compound of formula I, formula II or formula III according to claim 1, claim 2, claim 6 or claim 7, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound as shown in formula I satisfies one or more of the following conditions: (1) for in Indicates that L 1 connect, Indicates that L 2 connect; (2)L 1 For H. (3)L 2 is H; (4) for in Indicates that X in ring B 2 Connected; (5) for 11. The compound of formula I, formula II or formula III according to claim 1, claim 3, claim 6 or claim 8, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound as shown in formula II satisfies one or more of the following conditions: (1) for in Indicates that L 3 connect, Indicates that L 4 connect; (2)L 3 for (3)L 4 is H; (4) for in Represents X with ring D 4 Connected; (5) for 12. The compound of formula I, formula II or formula III according to claim 1, claim 4, claim 5, claim 6 or claim 9, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, characterized in that: The compound shown in formula III satisfies one or more of the following conditions: (1) for in Indicates that L 5 connect, Indicates that L 6 connect; (2)L 5 is -NHCH3, (3)L 6 is H or -CH3 or -CH2OH; (4) for in Represents X with ring E 6 Connected; (5) for 13. The compound of formula I, formula II or formula III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It is the following scheme 1, scheme 2 or scheme 3: Scheme 1: The compound shown in formula I is a compound shown in formula I-1: Among them, R 3 is a C1-C6 alkyl group, L 1 , L 2 , Ring A, Ring B, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Q 1 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 The definition as in any one of claims 1 to 12; Scheme 2: The compound shown in formula II is a compound shown in formula II-1: Among them, R 11 is a C1-C6 alkyl group, L 3 , L 4 , Ring C, Ring D, X 3 , X 4 , Y 5 , Y 6 , Y 7 , Y 8 , Q 2 , R 9 , R 12 , R 13 , R 14 , R 15 and R 16 The definition as in any one of claims 1 to 12; Scheme 3: The compound shown in formula III is the compound shown in formula III-1: Among them, R 19 is a C1-C6 alkyl group, L 5 , L 6 , Ring E, X 5 , X 6 , Y 9 , Y 10 , Y 11 , Y 12 , Q 3 , R 17 , R 20 , R 21 , R 22 , R 23 and R 24 The definition as described in any one of claims 1 to 12.

14. The compound of formula I, formula II or formula III or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound shown in Formula I, Formula II or Formula III is any of the following compounds:

15. A pharmaceutical composition, comprising: (1) a compound of any one of claims 1 to 14 as represented by formula I, formula II or formula III, or a pharmaceutically acceptable salt thereof, or a deuterated product thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a prodrug or a metabolite thereof, and (2) Pharmaceutically acceptable excipients.

16. Use of a compound of formula I, formula II or formula III or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing a disease or condition mediated by CCR4, or for treating or preventing a disease or condition.

17. The use according to claim 16, wherein the disease or condition mediated by CCR4 is selected from one or more immune-related diseases selected from atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, and rheumatoid arthritis; or, the disease or condition mediated by CCR4 is cancer; The disease or condition is selected from one or more immune-related diseases selected from atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, and rheumatoid arthritis; or, the disease or condition is cancer.

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