Chemokine receptor antagonist, pharmaceutical composition, and use

Abstract

Disclosed are a chemokine receptor antagonist, a pharmaceutical composition, and a use. Specifically, disclosed is a compound as represented by formula I, II, or III or a pharmaceutically acceptable salt thereof, or a deuterated compound thereof, or an optical isomer, a geometric isomer, a tautomer or an isomer mixture thereof, or a prodrug thereof, or a metabolite thereof. The compound of the present invention has better inhibitory activity on CCR4, and can be used for treating or preventing CCR4-mediated diseases.

Description

Chemokine receptor antagonist, pharmaceutical composition and application

[0001] This application claims priority to Chinese Patent Application No. 2023112023272 filed on September 15, 2023, Chinese Patent Application No. 2023115887144 filed on November 24, 2023, Chinese Patent Application No. 2023118690570 filed on December 29, 2023, Chinese Patent Application No. 2024100663944 filed on January 16, 2024, Chinese Patent Application No. 2024103865026 filed on March 29, 2024, Chinese Patent Application No. 2024107493569 filed on June 11, 2024, and Chinese Patent Application No. 2024110158509 filed on July 26, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a chemokine receptor antagonist, a pharmaceutical composition and an application. Background Art

[0003] Chemokines are a class of small cytokines whose primary function is to recruit leukocyte subsets under both steady-state and pathological conditions. They are also known as chemotactic cytokines. Based on the positions of the first two cysteine ​​(C) residues in their primary protein structure, chemokines are divided into four major subfamilies: C, CC, CXC, and CX3C chemokines. These subfamilies are primarily responsible for regulating physiological processes such as organ development, immune surveillance, host defense, and tissue renewal.

[0004] CCR4 belongs to the G protein-coupled receptor family, and its main ligands are thymic activation-regulated chemokine (TARC / CCL17) and macrophage chemokine (MDC / CCL22). CCR4 is mainly expressed in several subsets of T cells, such as Th2, Treg, Th17 and Th22. It is also expressed on the surface of platelets. Many tumor cells also highly express CCR4 on their surfaces. Diseases associated with 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 itching 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%, making it the skin disease with the highest disease burden among non-fatal diseases. Mechanistically, the immune response of atopic dermatitis is mainly Th2 type. Th2 cells express CCR3, CCR4, and CCR8 receptors, and can selectively inhibit the migration of Th2 cells to inflamed skin tissues by blocking the binding of CCR4 receptors to chemokine CCL17 / CCL22 ligands.

[0005] The first CCR4 antibody drug to be marketed in 2012 is moglizumab injection, used to treat adult patients with relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS) who have previously received at least one systemic therapy. Currently, there are no CCR4 small molecule drugs on the market. International patent application WO2019147862 A1 discloses RPT193, which is currently in Phase II clinical trials. Therefore, the development of highly active small molecule CCR4 antagonists is a key area of ​​research and development in this field.

[0006] Summary of the Invention

[0007] The present invention provides a chemokine receptor antagonist, a pharmaceutical composition and an application thereof. The compound of the present invention has a good antagonistic activity against CCR4.

[0008] The present invention provides a compound as shown in 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:

[0009] Among them, in the compound shown in Formula I, Formula II, or Formula III:

[0010] X 1 、X 2 、X 1’ 、X 2’ 、X 1” 、X 2” are each independently halogen, C2-C6 alkynyl or cyano;

[0011] Y 1 、Y 2 、Y 3 、Y 4 、Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ 、Y 1” 、Y 2” 、Y 3” 、Y 4” Each independently is N or CR 4 ;

[0012] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl, or one or more R 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, one or more R 4-2Substituted C1-C6 alkoxy, hydroxy, deuterated C1-C6 alkyl, -NH2, C2-C6 alkynyl, C2-C6 alkenyl, -O-C3-C8 cycloalkyl, substituted by one or more R 4-3 Substituted C3-C8 cycloalkyl, one or more R 4-4 Substituted C1-C6 alkoxy;

[0013] R 4-3 is halogen, -NH2, hydroxyl, C1-C6 alkyl or -OC(O)-C1-C6 alkyl;

[0014] R 4-4 is a halogen;

[0015] R 4-1 is halogen, cyano, or hydroxyl;

[0016] R 4-2 is a halogen;

[0017] R 1 、R 2 、R 1’ 、R 2’ 、R 1” 、R 2” are independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl;

[0018] R 1-1 is a halogen;

[0019] R 3 、R 3” is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0020] R 3-1 is a C3-C8 cycloalkyl group, which is occupied by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, one or more R 3- 1-2 Substituted C1-C6 alkyl, C3~C8 heterocycloalkyl, 3-1-3Substituted C3~C8 heterocycloalkyl, -COOH; the C3~C8 heterocycloalkyl or one or more R 3-1-3 The heteroatoms in the substituted C3-C8 heterocycloalkyl group are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0021] R 3-1-1 C1 to C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 , by one or more R 3-1-1-2 Substituted C1-C6 alkyl, -CONR 3-1-1-3 R 3-1-1-4 , cyano, NR 3-1-1-5 R 3-1-1-6 、

[0022] R 3-1-1-1 is a C1-C6 alkyl group;

[0023] R 3-1-1-2 is hydroxy or halogen;

[0024] R 3-1-1-3 、R 3-1-1-4 are independently H or C1-C6 alkyl;

[0025] R 3-1-1-5 、R 3-1-1-6 are independently H or C1-C6 alkyl;

[0026] R 3-1-1-7 is a hydroxyl group or a C1-C6 alkoxy group;

[0027] R 3-1-1-8 、R 3-1-1-9 are independently H, C1-C6 alkyl;

[0028] R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 , -COOH, -OSO3H, -OSO2NH2, -SO3H, two R 3-1-2 Forming C3~C8 cycloalkyl, two R 3-1-2 Formed by one or more R 3-1-2-5 Substituted C3-C8 cycloalkyl, -CONR 3-1- 2-6 R 3-1-2-7 , cyano;

[0029] R 3-1-2-1 、R 3-1-2-2 are independently hydrogen or -SO2R3-1-2-1-1 ;

[0030] R 3-1-2-1-1 -NH2, hydroxyl or C1-C6 alkyl;

[0031] R 3-1-2-3 C1 to C6 alkyl, -NR 3-1-2-3-1 R 3-1-2-3-2 ;

[0032] R 3-1-2-3-1 、R 3-1-2-3-2 are independently hydrogen, -COR 3-1-2-3-1-1 ;

[0033] R 3-1-2-3-1-1 is a C1-C6 alkyl group;

[0034] R 3-1-2-4 is -SO2NH2;

[0035] R 3-1-2-5 is a C1-C6 alkyl or halogen;

[0036] R 3-1-2-6 is hydrogen or a C1-C6 alkyl group;

[0037] R 3-1-2-7 is hydrogen or a C1-C6 alkyl group; R 3-1-3 is a C1-C6 alkyl or halogen;

[0038] R 3-2 、R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ;

[0039] R 3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; said 4-12 membered heterocycloalkyl or one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0040] R 3-2-1-1 is hydrogen or a C1-C6 alkyl group;

[0041] Among them, in the compound shown in formula II,

[0042] Ring A is a 7-12 membered spiroheterocycle or a 7-12 membered paraheterocycle or a phenyl group; the heteroatoms in the spiroheterocycle or paraheterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0043] R 3’ -NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1~C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4.

[0044] R 3’-1 、R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ;

[0045] R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1 Substituted 4-8 membered heterocycloalkyl; the heteroatoms in the 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0046] R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group;

[0047] R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1 substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0048] R 3’-3-1 is hydrogen or a C1-C6 alkyl group;

[0049] R 3’-4 is hydroxyl group;

[0050] R 3’-5 is a C1-C6 alkyl group or -COOH;

[0051] R 3’-6 is a C1-C6 alkyl group;

[0052] Among them, in the compound shown in formula III,

[0053] R 5” It is a halogen.

[0054] In a certain embodiment of the present invention, in the compound 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 metabolite thereof, certain groups have the following definitions, and the definitions of the groups not mentioned are as described in any embodiment of the present invention (this paragraph is hereinafter referred to as "in a certain embodiment of the present invention").

[0055] In a certain embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III or its pharmaceutically acceptable salt, or its deuterated product, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its prodrug or metabolite,

[0056] R 4-3 Halogen, -NH2, hydroxyl.

[0057] In a certain embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III or its pharmaceutically acceptable salt, or its deuterated product, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its prodrug or metabolite,

[0058] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl or one or more R 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, one or more R 4-2 Substituted C1-C6 alkoxy, hydroxy, deuterated C1-C6 alkyl, -NH2, C2-C6 alkynyl, C2-C6 alkenyl or -O-C3-C8 cycloalkyl;

[0059] R 3-1-2-1-1 It is -NH2 or a C1-C6 alkyl group.

[0060] In a certain embodiment of the present invention, the compound represented by Formula I, Formula II or Formula III or its pharmaceutically acceptable salt, or its deuterated product, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its prodrug or metabolite,

[0061] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl, or one or more R 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, hydroxy, deuterated C1-C6 alkyl, -NH2, C2-C6 alkynyl or C2-C6 alkenyl;

[0062] R 3-1-2-1-1It is -NH2 or a C1-C6 alkyl group.

[0063] In a certain embodiment of the present invention, the compound represented by Formula I or Formula II or its pharmaceutically acceptable salt, or its deuterated product, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its prodrug or metabolite,

[0064] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl, or one or more R 4-1 Substituted C1-C6 alkyl or C3-C8 cycloalkyl;

[0065] R 4-1 is halogen or cyano;

[0066] R 1 、R 2 、R 1’ 、R 2’ Each is independently hydrogen or a C1-C6 alkyl group;

[0067] R 3-1-1 C1 to C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 , by one or more R 3-1-1-2 Substituted C1-C6 alkyl, -CONR 3-1-1-3 R 3-1-1-4 , cyano or NR 3-1-1-5 R 3-1-1-6 ;

[0068] R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 , -COOH, two R 3-1-2 Forming C3~C8 cycloalkyl, two R 3-1-2 Formed by one or more R 3-1-2-5 Substituted C3-C8 cycloalkyl, -CONR 3-1-2-6 R 3-1-2-7 or cyano;

[0069] R 3-1-2-3 It is a C1-C6 alkyl group.

[0070] R 3-1-2-1-1 It is -NH2 or a C1-C6 alkyl group.

[0071] In one embodiment of the present invention, the compound represented by Formula I or 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:

[0072] in,

[0073] X 1 、X 2 、X 1’ 、X 2’ are each independently halogen or cyano;

[0074] Y 1 、Y 2 、Y 3 、Y 4 、Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ Each independently is N or CR 4 ;

[0075] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl or one or more R 4-1 Substituted C1-C6 alkyl;

[0076] R 4-1 is halogen or cyano;

[0077] R 1 、R 2 、R 1’ 、R 2’ Each is independently hydrogen or a C1-C6 alkyl group;

[0078] R 3 is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0079] R 3-1 is a C3-C8 cycloalkyl group, which is occupied by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, one or more R 3- 1-2 Substituted C1-C6 alkyl, C3~C8 heterocycloalkyl, 3-1-3 Substituted C3~C8 heterocycloalkyl; the C3~C8 heterocycloalkyl or one or more R 3-1-3The heteroatoms in the substituted C3-C8 heterocycloalkyl group are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0080] R 3-1-1 C1 to C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 , by one or more R 3-1-1-2 Substituted C1-C6 alkyl, -CONR 3-1-1-3 R 3-1-1-4 , cyano, NR 3-1-1-5 R 3-1-1-6 ;

[0081] R 3-1-1-1 is a C1-C6 alkyl group;

[0082] R 3-1-1-2 is hydroxy or halogen;

[0083] R 3-1-1-3 、R 3-1-1-4 are independently H or C1-C6 alkyl;

[0084] R 3-1-1-5 、R 3-1-1-6 are independently H or C1-C6 alkyl;

[0085] R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 , -COOH, two R 3-1-2 Forming C3~C8 cycloalkyl, two R 3-1-2 Formed by one or more R 3-1-2-5 Substituted C3-C8 cycloalkyl;

[0086] R 3-1-2-1 、R 3-1-2-2 are independently hydrogen or -SO2R 3-1-2-1-1 ;

[0087] R 3-1-2-1-1 -NH2 or C1-C6 alkyl;

[0088] R 3-1-2-3 is a C1-C6 alkyl group;

[0089] R 3-1-2-4 is -SO2NH2;

[0090] R 3-1-2-5 is a C1-C6 alkyl or halogen;

[0091] R 3-1-3is a C1-C6 alkyl or halogen;

[0092] R 3-2 、R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ;

[0093] R 3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; said 4-12 membered heterocycloalkyl or one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0094] R 3-2-1-1 is hydrogen or a C1-C6 alkyl group;

[0095] Among them, in the compound shown in formula II,

[0096] Ring A is a 7-12 membered spiroheterocycle or a 7-12 membered paraheterocycle or a phenyl group; the heteroatoms in the spiroheterocycle or paraheterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0097] R 3’ -NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1~C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4.

[0098] R 3’-1 、R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ;

[0099] R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1Substituted 4-8 membered heterocycloalkyl; the heteroatoms in the 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0100] R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group;

[0101] R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1 substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0102] R 3’-3-1 is hydrogen or a C1-C6 alkyl group;

[0103] R 3’-4 is hydroxyl group;

[0104] R 3’-5 is a C1-C6 alkyl group or -COOH;

[0105] R 3’-6 It is a C1-C6 alkyl group.

[0106] In one embodiment of the present invention, the compound represented by Formula I or 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:

[0107] Among them, X 1 、X 2 、X 1’ 、X 2’ are each independently halogen or cyano;

[0108] Y 1 、Y 2 、Y 3 、Y 4 、Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ Each independently is N or CR 4 ;

[0109] R 4 is hydrogen, halogen, cyano, C1-C6 alkyl or one or more R 4-1 Substituted C1-C6 alkyl;

[0110] R 4-1is halogen or cyano;

[0111] R 1 、R 2 、R 1’ 、R 2’ Each is independently hydrogen or a C1-C6 alkyl group;

[0112] R 3 is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl group are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0113] R 3-1 is a C3-C8 cycloalkyl group, which is occupied by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, one or more R 3- 1-2 Substituted C1-C6 alkyl,

[0114] R 3-1-1 is a C1-C6 alkyl, -COOH or hydroxyl group;

[0115] R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 or -COOH;

[0116] R 3-1-2-1 、R 3-1-2-2 are independently hydrogen or -SO2R 3-1-2-1-1 ;

[0117] R 3-1-2-1-1 -NH2 or C1-C6 alkyl;

[0118] R 3-1-2-3 is a C1-C6 alkyl group;

[0119] R 3-1-2-4 is -SO2NH2;

[0120] R 3-2 、R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ;

[0121] R3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; said 4-12 membered heterocycloalkyl or one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0122] R 3-2-1-1 is hydrogen or a C1-C6 alkyl group;

[0123] Among them, in the compound shown in formula II,

[0124] Ring A is a 7-12 membered spiroheterocycle or a 7-12 membered paraheterocycle or a phenyl group; the heteroatoms in the spiroheterocycle or paraheterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0125] R 3’ -NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1~C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4.

[0126] R 3’-1 、R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ;

[0127] R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1 Substituted 4-8 membered heterocycloalkyl; the heteroatoms in the 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0128] R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group;

[0129] R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1substituted 4-8 membered heterocycloalkyl; said 4-8 membered heterocycloalkyl or one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4;

[0130] R 3’-3-1 is hydrogen or a C1-C6 alkyl group;

[0131] R 3’-4 is hydroxyl group;

[0132] R 3’-5 is a C1-C6 alkyl group or -COOH;

[0133] R 3’-6 It is a C1-C6 alkyl group.

[0134] In one embodiment of the present invention, the compound of Formula I or Formula III or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0135] (1)R 3 、R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is independently a 5- or 6-membered heterocycloalkyl group;

[0136] (2)R 3 、R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is independently a 7 membered heterocycloalkyl group;

[0137] (3)R 3 wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl group are independently N, and the number of the heteroatoms is 1 or 2;

[0138] (4)R 3 、R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl group are independently N or O, and the number of heteroatoms is 1 or 2;

[0139] (5)R 3-1 、R 4 wherein the C3-C8 cycloalkyl group is replaced by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, one or more R 4-3The C3~C8 cycloalkyl group in the substituted C3~C8 cycloalkyl group and -O-C3~C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane;

[0140] (6)R 3-1 wherein the C1-C6 alkyl group is replaced by one or more R 3-1-2 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0141] (7)R 3-2-1 wherein the 4-12 membered heterocycloalkyl group and the one or more R 3-2-1-1 The 4-12-membered heterocycloalkyl group in the substituted 4-12-membered heterocycloalkyl group is independently a 5- or 6-membered heterocycloalkyl group;

[0142] (8)R 3-2-1 wherein the 4-12 membered heterocycloalkyl group and the one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl group are independently N, and the number of the heteroatoms is 1 or 2.

[0143] In one embodiment of the present invention, the compound of Formula I or Formula III or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0144] (1)R 3-1 In the C3-C8 heterocycloalkyl group, one or more R 3-1-3 Substituted C3~C8 heterocycloalkyl; the C3~C8 heterocycloalkyl or one or more R 3-1-3 The C3~C8 heterocycloalkyl in the substituted C3~C8 heterocycloalkyl is cyclobutane, cyclopentane or cyclohexane;

[0145] (2)R 3-1 In the C3-C8 heterocycloalkyl group, one or more R 3-1-3 Substituted C3~C8 heterocycloalkyl; the C3~C8 heterocycloalkyl or one or more R 3-1-3 The heteroatoms in the substituted C3-C8 heterocycloalkyl group are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0146] (3)R 3-1-3 、R 3-1-1-1 、R 3-1-1 、R 3-1-1-3 、R 3-1-1-4 、R 3-1-1-5 、R 3-1-1-6 、R 3-1-2-5 、R 3-1-2-6 、R 3-1-2-7wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;

[0147] (4)R 3-1-3 、R 3-1-1-2 、R 3-1-2-5 wherein the halogen is independently F, Cl, Br or I;

[0148] (5)R 3-1-2 Two R's 3-1-2 Forming a C3-C8 cycloalkyl group or two R 3-1-2 Formed by one or more R 3-1-2-5 The C3-C8 cycloalkyl group in the substituted C3-C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.

[0149] In one embodiment of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, R 3 wherein said one or more R 3-1 The substituted 4-8 membered heterocycloalkyl group is wherein n1 is 1, 2 or 3; preferably, the one or more R 3-1 The substituted 4-8 membered heterocycloalkyl group is Wherein n1 is 1, 2 or 3; preferably

[0150] In one embodiment of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, R 3 In the -NR 3- 2 R 3-3 for Where n2 is 1, 2 or 3.

[0151] In one embodiment of the present invention, the compound as shown in Formula I or a pharmaceutically acceptable salt thereof, R 1 is hydrogen, R 2 It is a methyl group.

[0152] In one embodiment of the present invention, the compound represented by Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0153] (1) In ring A, the 7-12 membered spiroheterocycle is a 7- or 8-membered spiroheterocycle, and the 7-12 membered heterocycle is an 8- or 9-membered heterocycle;

[0154] (2) In ring A, the heteroatom in the spiro heterocycle or fused heterocycle is nitrogen, and the number of nitrogen atoms is independently 1 or 2;

[0155] (3)R3'、R3’-1-1 、R 3’-3 wherein the 4-8 membered heterocycloalkyl group and the substituted 4-8 membered heterocycloalkyl group are independently 5- or 6-membered heterocycloalkyl groups;

[0156] (4)R3'、R 3’-1-1 、R 3’-3 wherein the heteroatoms in the 4-8 membered heterocycloalkyl and the substituted 4-8 membered heterocycloalkyl are independently N, and the number of the heteroatoms is 1 or 2;

[0157] (5)R 1’ is hydrogen, R 2’ It is a methyl group.

[0158] In one embodiment of the present invention, the compound represented by formula II or a pharmaceutically acceptable salt thereof, R 3’ In the -NR 3’-1 R 3’-2 for Where n2' is 1, 2 or 3.

[0159] In one embodiment of the present invention, the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0160] (1)X 1 、X 2 、X 1’ 、X 2’ 、R 4 、R 4-1 、R 1-1 、X 1” 、X 2” 、R 4-2 、R 4-3 、R 4-4 wherein the halogen is independently F, Cl, Br or I;

[0161] (2)R 4 、R 1 、R 2 、R 1’ 、R 2’ 、R 1” 、R 2” 、R 3-1 、R 3-1-1 、R 3-1-2-1-1 、R 3-1-2-3 、R 3-1-2-3-1-1 、R 3-2 、R 3-3 、R 3- 2-1-1 、R 3’ 、R 3’-1 、R 3’-2 、R3’-1-1-1 、R 3’-3-1 、R 3’-5 or R 3’-6 In the C1-C6 alkyl group and 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;

[0162] (3)X 1 、X 2 、X 1’ 、X 2’ wherein the C2-C6 alkynyl group is an ethynyl group;

[0163] (4)R 4 、R 3-1-1-7 wherein the C1-C6 alkoxy group is replaced by one or more R 4-4 The alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, or propoxy;

[0164] (5)R 4 In the above, the C2-C6 alkynyl group is ethynyl or propynyl;

[0165] (6)R 4 In the above, the C2-C6 alkenyl group is vinyl or propenyl.

[0166] In one embodiment of the present invention, the C1-C6 alkyl group in the -OC(O)-C1~C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, such as methyl.

[0167] In one embodiment of the present invention, X 1 、X 2 、X 1’ 、X 2’ 、X 1 ” and X 2 " are independently halogen.

[0168] In one embodiment of the present invention, R 1 、R 1’ and R 1” For hydrogen.

[0169] In one embodiment of the present invention, R 2 、R 2’ and R 2” are independently C1-C6 alkyl or deuterated C1-C6 alkyl; preferably, R 2 、R 2’ and R 2” are independently C1-C6 alkyl.

[0170] In one embodiment of the present invention, R 4 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or one or more R 4-1 Substituted C1-C6 alkyl or one or more R 4-2 Substituted C1-C6 alkoxy; preferably, R 4 is hydrogen, halogen, C1-C6 alkyl or one or more R 4-1 Substituted C1-C6 alkyl; more preferably, R 4 is hydrogen, halogen or C1-C6 alkyl; further preferably, R 4 is hydrogen or C1-C6 alkyl; most preferably, R 4 For hydrogen.

[0171] In one embodiment of the present invention, R 4 is C3-C8 cycloalkyl or is replaced by one or more R 4-3 Substituted C3-C8 cycloalkyl.

[0172] In one embodiment of the present invention, R 4 For one or more R 4-1 Substituted C1-C6 alkyl.

[0173] In one embodiment of the present invention, Y 1 is N or CH; preferably N.

[0174] In one embodiment of the present invention, Y 2 is N or CH.

[0175] In one embodiment of the present invention, Y 3 is N or CH.

[0176] In one embodiment of the present invention, Y 4 CR 4 .

[0177] In one embodiment of the present invention, R 4-1 is halogen or R 4-1 It is a hydroxyl group.

[0178] In one embodiment of the present invention, R 4-3 is halogen, -NH2, C1-C6 alkyl or -OC(O)-C1-C6 alkyl; preferably, R 4-3 It is halogen, C1~C6 alkyl or -OC(O)-C1~C6 alkyl.

[0179] In one embodiment of the present invention, R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said substituted one or more R 3-1The heteroatom of the 4- to 8-membered heterocycloalkyl group in the substituted 4- to 8-membered heterocycloalkyl group is nitrogen, and the number of the heteroatoms is independently 1 or 2.

[0180] In one embodiment of the present invention, each R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or one or more R 3-1-2 substituted C1-C6 alkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl or one or more R 3-1-2 Substituted C1-C6 alkyl; preferably, each R 3-1 Independently by one or more R 3-1-2 Substituted C1-C6 alkyl.

[0181] In one embodiment of the present invention, each R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 3-1 It is a C3-C8 heterocycloalkyl group, wherein the heteroatoms in the C3-C8 heterocycloalkyl group are independently one or more of nitrogen and oxygen, and the number of the heteroatoms is 1, 2, 3 or 4.

[0182] In one embodiment of the present invention, each R 3-1-1 are independently C1-C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 or -CONR 3- 1-1-3 R 3-1-1-4 Preferably, each R 3-1-1 are independently C1-C6 alkyl or -COOH.

[0183] In one embodiment of the present invention, each R 3-1-2 are independently -NR 3-1-2-1 R 3-1-2-2 、-CONR 3-1-2-6 R 3-1-2-7 , cyano, -OSO3H, -SO3H, -OSO2NH2 or -SO2R 3-1-2-3 Preferably, each R 3-1-2 are independently -NR 3-1-2-1 R 3-1-2-2 , -OSO3H or -OSO2NH2.

[0184] In one embodiment of the present invention, each R 3-1-2 are independently hydroxy or -COOH; preferably, each R 3-1-2 It is a hydroxyl group.

[0185] In one embodiment of the present invention, the compound represented by Formula I is a compound represented by Formula IA:

[0186] In one embodiment of the present invention, the compound shown in Formula I is not any of the following compounds

[0187] In a certain embodiment of the present invention, in the compound shown in Formula I,

[0188] X 1 and X 2 are independently halogen;

[0189] R 1 is hydrogen;

[0190] R 2 is a C1-C6 alkyl group;

[0191] Y 1 is N;

[0192] Y 2 is N or CH.

[0193] Y 3 is N or CH.

[0194] Y 4 N or CR 4 ;

[0195] R 4 is hydrogen, halogen or C1-C6 alkyl;

[0196] R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said substituted one or more R 3-1 The heteroatom of the 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is nitrogen, and the number of heteroatoms is independently 1 or 2;

[0197] Each R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl or one or more R 3-1-2 Substituted C1-C6 alkyl;

[0198] Each R 3-1-1C1 to C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 or -CONR 3-1-1-3 R 3-1-1-4 ;

[0199] R 3-1-1-1 is a C1-C6 alkyl group;

[0200] R 3-1-1-3 and R 3-1-1-4 are independently H or C1-C6 alkyl;

[0201] R 3-1-2 It is a hydroxyl group.

[0202] In a certain embodiment of the present invention, in the compound shown in Formula I,

[0203] X 1 and X 2 are independently halogen;

[0204] R 1 is hydrogen;

[0205] R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group;

[0206] Y 1 is N;

[0207] Y 2 is N or CH.

[0208] Y 3 is N or CH.

[0209] Y 4 N or CR 4 ;

[0210] R 4 is hydrogen, halogen or C1-C6 alkyl;

[0211] R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said substituted one or more R 3-1 The heteroatom of the 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is nitrogen, and the number of heteroatoms is independently 1 or 2;

[0212] Each R 3-1 Independently by one or more R 3-1-2 Substituted C1-C6 alkyl;

[0213] Each R 3-1-2 are independently -NR 3-1-2-1 R 3-1-2-2 、-CONR3-1-2-6 R 3-1-2-7 , cyano, -OSO3H, -SO3H, -OSO2NH2 or -SO2R 3-1-2-3 ;

[0214] R 3-1-2-1 、R 3-1-2-2 are independently hydrogen or -SO2R 3-1-2-1-1 ;

[0215] R 3-1-2-1-1 -NH2, hydroxyl or C1-C6 alkyl;

[0216] R 3-1-2-3 C1-C6 alkyl or -NR 3-1-2-3-1 R 3-1-2-3-2 ;

[0217] R 3-1-2-6 is hydrogen or a C1-C6 alkyl group;

[0218] R 3-1-2-7 is hydrogen or a C1-C6 alkyl group;

[0219] Preferably, each R 3-1-2 are independently -NR 3-1-2-1 R 3-1-2-2 , -SO3H or -OSO2NH2.

[0220] In a certain embodiment of the present invention, in the compound shown in Formula I,

[0221] X 1 and X 2 are independently halogen;

[0222] R 1 is hydrogen;

[0223] R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group;

[0224] Y 1 N or CH;

[0225] Y 2 is N or CH.

[0226] Y 3 N or CH;

[0227] Y 4 N or CR 4 ; R 4 is C3-C8 cycloalkyl or is replaced by one or more R 4-3 Substituted C3-C8 cycloalkyl;

[0228] R 4-3is halogen, -NH2, C1-C6 alkyl or -OC(O)-C1-C6 alkyl;

[0229] R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said substituted one or more R 3-1 The heteroatom of the 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is nitrogen, and the number of heteroatoms is independently 1 or 2;

[0230] Each R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or one or more R 3- 1-2 Substituted C1-C6 alkyl; the heteroatoms in the C3-C8 heterocycloalkyl group are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4;

[0231] Each R 3-1-1 are independently C1-C6 alkyl or -COOH;

[0232] Each R 3-1-2 are independently hydroxy or -COOH;

[0233] Preferably, R 4-3 is halogen or C1-C6 alkyl; each R 3-1-2 are independently hydroxyl.

[0234] In a certain embodiment of the present invention, in the compound shown in Formula I,

[0235] X 1 and X 2 are independently halogen;

[0236] R 1 is hydrogen;

[0237] R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group;

[0238] Y 1 N or CR 4 ;

[0239] Y 2 N or CR 4 .

[0240] Y 3 N or CR 4 ;

[0241] Y 4 CR 4 ;

[0242] R 4 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or one or more R 4-1 Substituted C1-C6 alkyl or one or more R 4-2 Substituted C1-C6 alkoxy;

[0243] R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said substituted one or more R 3-1 The heteroatom of the 4-8 membered heterocycloalkyl group in the substituted 4-8 membered heterocycloalkyl group is nitrogen, and the number of heteroatoms is independently 1 or 2;

[0244] Each R 3-1 Independently by one or more R 3-1-1 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4;

[0245] Each R 3-1-1 are independently C1-C6 alkyl or -COOH.

[0246] In a certain embodiment of the present invention, the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0247] (1)R 3 for

[0248] (2)R 3 for

[0249] (3)R 3 for

[0250] (4)R 3 for Preferably, R 3 for

[0251] (5) for

[0252] (6) for

[0253] (7) for

[0254] (8) for Preferably, for More preferably, for

[0255] (9) Ring A is

[0256] (10)R 3’ for

[0257] (11) for

[0258] (12) for

[0259] (13)R 3” for

[0260] (14) for

[0261] (15)X 1 is Cl or F, X 2 is Cl or F;

[0262] (16)X 1’ is Cl or F, X 2’ is Cl or F.

[0263] (17) R1 is hydrogen, R2 is methyl, -CDH2, -CHD2, -CD3, -CH2F, -CHF2, -CF3;

[0264] (18)R 1’ is hydrogen, R 2’ is methyl;

[0265] (19)R 1” is hydrogen, R 2” It is a methyl group.

[0266] In one embodiment of the present invention, the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0267] (1)R 3 for

[0268] (2)R 3 for

[0269] (3)R 3 for

[0270] (4) for

[0271] (5) for

[0272] (6) for

[0273] (7) Ring A is

[0274] (8)R 3’ for

[0275] (9) for

[0276] (10) for

[0277] (11)X 1 is Cl or F, X 2 is Cl or F;

[0278] (12)X 1 Cl, X 2 For Cl.

[0279] In one embodiment of the present invention, the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0280] (1)R 3 for

[0281] (2)R 3 for

[0282] (3) for

[0283] (4) for

[0284] (5) Ring A is

[0285] (6)R 3’ for

[0286] (7) for

[0287] (8) for

[0288] (9)X 1 is Cl or F, X 2 is Cl or F;

[0289] (10)X 1 Cl,X 2 For Cl.

[0290] In one embodiment of the present invention, the compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof satisfies one or more of the following conditions:

[0291] (1)R 3 for

[0292] (2) for

[0293] (3) Ring A is

[0294] (4)R 3’ for

[0295] (5) for

[0296] (6) for

[0297] (7)X 1 is Cl or F, X 2 is Cl or F;

[0298] (8)X 1 Cl,X 2 For Cl.

[0299] In one embodiment of the present invention, It can also be

[0300] In one embodiment of the present invention, R 3 for

[0301] Preferably, R 3 for

[0302] In one embodiment of the present invention, R 3 for

[0303] In one embodiment of the present invention, R 3 for

[0304] In one embodiment of the present invention, R 4 is F, Cl, methyl, -CF3, -CH2F, -CHF2, -O-CH2F or -CD3; preferably, R 4 is F, Cl or methyl.

[0305] In one embodiment of the present invention, for

[0306] In one embodiment of the present invention, for

[0307] In one embodiment of the present invention, for

[0308] In one embodiment of the present invention, for

[0309] In one embodiment of the present invention, R 1 For H.

[0310] In one embodiment of the present invention, R 2 is methyl or CD3; for example, R 2 It is a methyl group.

[0311] In one embodiment of the present invention, the compound represented by Formula I or a pharmaceutically acceptable salt thereof is any one of the following compounds:

[0312] In one embodiment of the present invention, the compound represented by Formula I may also be any of the following compounds:

[0313] The compound that elutes first under the following chromatographic conditions: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 μm); mobile phase consisting of mobile phase A and mobile phase B, mobile phase A being supercritical CO2, mobile phase B being EtOH containing 0.1% ethylenediamine, the percentage being the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase being 40%; flow rate: 80 mL / min; preferably, the retention time of the first-eluting compound is 13.5 min;

[0314] The compound eluting later under the following chromatographic conditions: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 μm); mobile phase consisting of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, the percentage is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80 mL / min; preferably, the retention time of the compound eluting later is 19 min;

[0315] The compound that elutes first under the following chromatographic conditions: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 μm); mobile phase consisting of mobile phase A and mobile phase B, mobile phase A being supercritical CO2, mobile phase B being EtOH containing 0.1% ethylenediamine, the percentage being the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase being 40%; flow rate: 80 mL / min; preferably, the retention time of the first-eluting compound is 12 min;

[0316] The compound that elutes later under the following chromatographic conditions, the chromatographic conditions are: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 um); the mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, the percentage is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80 mL / min; preferably, the retention time of the late-eluting compound is 18 min.

[0317] In one embodiment of the present invention, the compound represented by Formula II or a pharmaceutically acceptable salt thereof is any one of the following compounds:

[0318] In one embodiment of the present invention, the compound represented by Formula III or a pharmaceutically acceptable salt thereof is any one of the following compounds:

[0319] The present invention also provides a pharmaceutical composition, comprising:

[0320] (1) any compound of formula I, formula II or formula III of the present invention, 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 thereof or a metabolite thereof; and

[0321] (2) Pharmaceutically acceptable excipients.

[0322] The present invention also provides a use of 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 metabolite thereof, or a pharmaceutical composition as described above, in the preparation of a CCR4 antagonist medicament, in particular, the medicament is used to treat or prevent a disease or condition mediated by CCR4.

[0323] The present invention also provides a use of a compound as shown in Formula I, Formula II or Formula III or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, in the preparation of a CCR4 antagonist medicament, particularly, the medicament is used to treat or prevent diseases or conditions mediated by CCR4.

[0324] In one embodiment of the present invention, 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.

[0325] In one embodiment of the present invention, the disease or condition mediated by CCR4 is one or more immune-related diseases selected from atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and drug eruption.

[0326] In one embodiment of the present invention, the drug rash is an exanthematous drug rash or an urticarial drug rash.

[0327] The present invention also provides 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 metabolite thereof, or the use of the pharmaceutical composition as described above in the preparation of a drug, wherein the drug is used to treat or prevent immune-related diseases or cancer.

[0328] In one embodiment of the present invention, the drug is used to treat or prevent immune-related diseases.

[0329] In one embodiment of the present invention, the immune-related disease is selected from one or more of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and drug eruption.

[0330] The cancer is selected from bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cancer, 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, neurilemoma and Wilms' tumor.

[0331] Unless otherwise specified, the terms used in this invention have the following meanings:

[0332] It will be understood by those skilled in the art that the structural formulas used in the present invention to describe groups are based on the conventions used in the art. It means that the corresponding group is connected to other fragments and groups in the compound through this site.

[0333] The term "geometric isomers" is also called cis-trans isomers, which are stereoisomers caused by the hindrance of free rotation of double bonds or bonds between atoms in a ring, resulting in different spatial arrangements. 3-1-1 In definition of Here, it means a cis isomer, a trans isomer, or a mixture of cis and trans isomers.

[0334] The term "optical isomer," also known as chiral isomer, refers to molecules that contain one or more chiral atoms, resulting in molecules not being completely superimposable on their mirror images. A key characteristic of optical isomers is their ability to deflect the direction of polarized light, making them optically active. For example, when a carbon atom is attached to four different groups, it is called a chiral carbon atom, and the resulting two structures are enantiomers, or chiral isomers.

[0335] The term "tautomer" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can rapidly convert into each other. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0336] As used herein, the term "prodrug" refers to a derivative of a compound that contains a bioreactive group such that, under biological conditions (in vitro or in vivo), the bioreactive group can be cleaved from the compound or otherwise reacted to provide the compound. Typically, the prodrug is inactive, or at least less active than the compound itself, such that its activity is not exerted until the compound is cleaved from the bioreactive group. The bioreactive group can be hydrolyzed or oxidized under biological conditions to provide the compound.

[0337] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0338] 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, a 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, an 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).

[0339] The term "pharmaceutical excipient" may refer to those excipients widely used in the field of pharmaceutical production. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They may also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients may be inert fillers, or may provide a function, such as stabilizing the overall pH value of the composition or preventing degradation of the active ingredient in the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0340] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0341] The pharmaceutical compositions of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention can also be controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0342] "Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, i.e., causing clinical symptoms of the disease not to develop; (2) inhibiting the disease, i.e., preventing the development of clinical symptoms; (3) alleviating the disease, i.e., causing the regression of clinical symptoms.

[0343] As used herein, "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0344] The expression "a group substituted with one or more substituents" means that one or more hydrogen atoms in a group are independently replaced by the substituents. When multiple substituents are present at the same time, unless otherwise specified, their definitions are independent of each other and do not affect each other. Therefore, if a group is replaced by one, two or three R 4-1 group substituted, that is, the group may be replaced by up to 3 R 4-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0345] The term "plurality" refers to 2, 3, 4 or 5, preferably 2 or 3.

[0346] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0347] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0348] The term "alkenyl" refers to a straight-chain or branched alkene having a specified number of carbon atoms (e.g., C2-C6) containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds may be internal or terminal. Examples of alkenes include vinyl, allyl, methylvinyl, and the like.

[0349] The term "alkynyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds with a specified number of carbon atoms (e.g., C2-C6, C2-C4 alkynyl). The one or more carbon-carbon triple bonds may be internal or terminal, such as ethynyl, propynyl with an internal triple bond, or a propynyl group with a triple bond at the terminal end wait.

[0350] The term "alkoxy" refers to the group -OR X , where R X is an alkyl group as defined above.

[0351] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 4-12, 4-8, 3-6, or 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified heteroatom species (one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium, or phosphorus; preferably one, two, or three of N, O, and S), which is a monocyclic, bridged, or spirocyclic ring, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, azetidine, azacyclohexane, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.

[0352] The term "cycloalkyl" refers to a non-aromatic, saturated, monovalent cyclic hydrocarbon group having a specified number of ring carbon atoms (e.g., C3-C8, C3-C6), which is a single ring. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0353] The term "spiroheterocycle" refers to a polycyclic heterocyclic group having a specified number (e.g., 7-12 members) of monocyclic rings sharing one atom (called a spiro atom), for example:

[0354] Preferably, "spiroheterocycle (e.g., 7-12 membered or 7-9 membered)" refers to a saturated polycyclic heterocycloalkyl group in which the rings share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. More preferably, a saturated "7-12 membered bispiroheterocycloalkyl" containing one or two nitrogen atoms.

[0355] The term "heterocyclic ring" refers to a ring having a specified number of members (e.g., 7-12 members) containing two or more heterocyclic rings, which are connected by sharing two atoms, for example:

[0356] Preferably, "half heterocyclic (e.g., 7-12 membered or 7-9 membered)" refers to a saturated polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or S, and the remaining ring atoms are carbon. More preferably, a saturated "7-12 membered bicyclic half heterocycloalkyl" containing 1 or 2 N atoms.

[0357] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0358] The reagents and raw materials used in the present invention are commercially available.

[0359] The positive improvement effect of the present invention is that the compound of the present invention has better antagonistic activity against CCR4. DETAILED DESCRIPTION

[0360] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0361] The structures of all compounds of the present invention can be determined by nuclear magnetic resonance ( 1 HNMR) and / or mass spectrometry (MS).

[0362] 1 H NMR chemical shifts (δ) are expressed in PPM (10 -6 ) were recorded. NMR was performed on a Bruker AVANCE-400 spectrometer.

[0363] LC-MS was determined by Agilent 1200 HPLC / 6120 mass spectrometer.

[0364] HPLC was performed on 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: Waters Xselect, 5 μm, 4.6×250 mm.

[0365] Thin layer silica gel plates are Liangchen Silicon Source HSGF254 or Qingdao GF254 silica gel plates. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as a carrier.

[0366] Example 1

[0367] first step:

[0368] (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline (I-1-a, see WO2013082429 for preparation) (5.4 g, 14 mmol), reduced iron powder (3.9 g, 69 mmol), and ammonium chloride (2.2 g, 42 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 100°C. LC-MS was used to monitor the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, 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 then separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-1-b) (5.2 g, 100%). LC-MS: 360.1 [M+H] + .

[0369] Step 2:

[0370] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-1-b) (1 g, 2.78 mmol) and sodium nitrite (211 mg, 3.06 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature. LC-MS monitored the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, added with saturated sodium bicarbonate solution (10 mL), and 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 column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-1-c) (730 mg, 71%). LC-MS: 371.0 [M+H] + .

[0371] Step 3:

[0372] Disperse (R)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (433 mg, 1.80 mmol), 1-methyl-3-oxocyclobutanecarboxylic acid (I-1-e) (300 mg, 2.34 mmol), and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (611 mg, 2.43 mmol) in toluene (5 mL). Stir the reaction mixture at 120°C for 4 hours. Monitor the reaction by LC-MS until the starting material is completely reacted. The reaction mixture was concentrated under reduced pressure, ethyl acetate (10 mL) was added, and the mixture was extracted with water (10 mL). The mixture was concentrated under reduced pressure to give the crude product (1R,3r)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-1-f) (724 mg, 114%), which was used directly in the next step. LC-MS: 353.3 [M+H] + .

[0373] Step 4:

[0374] (1R,3r)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-1-f) (724 mg, 2.05 mmol) was dissolved in dichloromethane (5 mL), and a 4N solution of hydrogen chloride in 1,4-dioxane (4 mL) was added. The reaction mixture was stirred at room temperature. LC-MS monitored the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, methanol (10 mL) was added, and the mixture was concentrated under reduced pressure again to obtain the crude product, methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g), as a hydrochloride salt (680 mg, 131%), which was used directly in the next step. LC-MS: 253.2 [M+H] + .

[0375] Step 5:

[0376] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate hydrochloride (I-1-g) (121 mg, 0.36 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-1-c) (120 mg, 0.32 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), BINAP (40 mg, 0.06 mmol), and Cs2CO3 (527 mg, 1.62 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (dichloromethane:methanol = 10:1) to obtain methyl (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-h) (32 mg, 18%). LC-MS: 556.2 [M+H]. + .

[0377] Step 6:

[0378] Methyl (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-h) (32 mg, 0.06 mmol) and lithium hydroxide (14 mg, 0.60 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-MS monitoring The reaction was continued until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-1) (30 mg, 96%). LC-MS: 542.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.75(d,J=9.0Hz,1H),7.54(d,J=2.0Hz,1H),7.32(dd,J=8.5, 1.9Hz,1H),7.25(d,J=8.5Hz,1H),6.66(dd,J=9.0,1.6Hz,1H),6.36(q,J=6.9Hz,1H) ,6.16(s,1H),4.07–3.89(m,2H),3.65(dt,J=19.7,6.5Hz,2H),3.37(s,1H),3.07(t ,J=11.3Hz,3H),2.66(d,J=4.2Hz,2H),2.46(d,J=7.2Hz,1H),2.08(d,J=7.0Hz,4H), 1.99–1.58(m,7H),1.36(s,3H).

[0379] Example 2

[0380] first step:

[0381] Tert-butyl azetidin-3-yl(methyl)carbamate (I-2-a) (100 mg, 0.44 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-1-c) (150 mg, 0.40 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol), and Cs2CO3 (659 mg, 2.02 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (dichloromethane:methanol = 10:1) to obtain tert-butyl (R)-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)(methyl)carbamate (I-2-b) (120 mg, 62%). LC-MS: 476.2 [M+H] + .

[0382] Step 2:

[0383] Tert-butyl (R)-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)(methyl)carbamate (I-2-b) (32 mg, 0.07 mmol) was dissolved in dichloromethane (5 mL), and a 4N solution of hydrogen chloride in 1,4-dioxane (4 mL) was added. The reaction mixture was stirred at room temperature. LC-MS monitoring was performed until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford (R)-(1-(1-(2-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)(methyl)carbamic acid (I-2) (10 mg, 35%). LC-MS: 420.1[M+H] + . 1 HNMR (400MHz, CDCl3) δ7.84(d,J=8.9Hz,1H),7.45(s,1H),7.18(dt,J=15.5,5.1Hz,2H),6.76(d,J=8.9Hz,1H),6.28(s,1H),6.22(q,J=7.1H z, 1H), 4.44 (q, J = 8.7Hz, 1H), 4.20 (dd, J = 15.4, 6.8Hz, 1H), 4.01 (d, J = 4.5Hz, 1H), 3.37 (s, 2H), 2.94 (d, J = 4.3Hz, 3H), 2.16 (d, J = 7.0Hz, 3H).

[0384] Example 3

[0385] first step:

[0386] Disperse (R)-3-(piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (300 mg, 1.25 mmol) (I-1-d), 2-bromoethanol (187 mg, 1.50 mmol), and potassium carbonate (518 mg, 3.75 mmol) in acetonitrile (5 mL). The reaction mixture was stirred at 70°C for 1 hour. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was filtered to obtain the crude product (R)-3-(1-(2-hydroxyethyl)piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-3-a) (355 mg, 100%), which was used directly in the next step. LC-MS: 285.2 [M+H] + .

[0387] Step 2:

[0388] Dissolve (R)-tert-butyl 3-(1-(2-hydroxyethyl)piperidin-3-yl)azetidine-1-carboxylate (I-3-a) (355 mg, 1.25 mmol) in dichloromethane (5 mL), and add 4N hydrogen chloride in 1,4-dioxane (4 mL). The reaction mixture was stirred at room temperature. LC-MS monitored the reaction until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-3-b) hydrochloride (430 mg, 134%), which was used directly in the next step. LC-MS: 185.2 [M+H] + .

[0389] Step 3:

[0390] (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol hydrochloride (114 mg, 0.44 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-1-c) (150 mg, 0.40 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol), and Cs2CO3 (659 mg, 2.02 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain 2-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-3) (20 mg, 10%). LC-MS: 474.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.84(d,J=8.9Hz,1H),7.44(d,J=1.8Hz,1H),7.22–7.09(m,2H),6.54(dd,J=9.0,1.9Hz,1H),6.20(q,J=7.0Hz,1H),6.02(d,J=1 .6Hz,1H),4.00(dt,J=11.5,7.6Hz,2H),3.74–3.53(m,4H),2.87(d,J=7.5H z,2H),2.65–2.48(m,3H),2.11(dd,J=19.8,9.3Hz,4H),1.98–1.41(m,6H).

[0391] Example 4

[0392] first step:

[0393] 3,5-Dibromopyrazin-2-amine (709 mg, 2.80 mmol) (I-4-a), (R)-1-(2,4-dichlorophenyl)ethanamine (532 mg, 2.80 mmol) (I-4-b), N,N-diisopropylethylamine (1.08 g, 8.4 mmol) were added to N,N-dimethylacetamide (10 mL) and microwaved at 150°C for 5 hours. The reaction solution was cooled to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with saturated brine (15 mL × 4). 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 = 0-7%) to obtain (R)-6-bromo-N 2 -(1-(2,4-dichlorophenyl)ethyl)pyrazine-2,3-diamine (I-4-c) (295 mg, 29%). LC-MS: 363.0 [M+H] + .

[0394] Step 2:

[0395] (R)-6-bromo-N 2 6-(1-(2,4-dichlorophenyl)ethyl)pyrazine-2,3-diamine (I-4-c) (172 mg, 0.475 mmol) was added to a mixed solution of acetic acid (6 mL) and water (4 mL). The mixture was cooled to 0°C and sodium nitrite (43 mg, 0.62 mmol) was added. The reaction solution was slowly warmed to room temperature and stirred for 4 hours. The reaction solution was extracted with ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL) was slowly added. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (10 mL × 3). 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 = 0-7%) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (110 mg, 62%). LC-MS: 373.9 [M+H] + .

[0396] Step 3:

[0397] (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (60 mg, 0.16 mmol), (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (96 mg, 0.36 mmol) were added to isopropanol (5 mL), cesium carbonate (156 mg, 0.48 mmol) was added, and the mixture was reacted at 80°C in a microwave for 1 hour. The reaction mixture was cooled to room temperature and concentrated, and then purified by silica gel column chromatography (methanol / dichloromethane = 0-7%) to give (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-4-e) (35 mg, 39.2%). LC-MS: 558.3 ​​[M+H] + .

[0398] Step 4:

[0399] Methyl (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-4-e) (35 mg, 0.063 mmol) was added to a mixed solvent of methanol: water: tetrahydrofuran (1:1:1, 6 mL), and lithium hydroxide monohydrate (5 mg, 0.12 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Saturated ammonium chloride solution (3 mL) was added to the reaction solution, and the mixture was concentrated to obtain a crude product, which was separated by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-4) (13 mg, 38%). LC-MS: 544.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.93 (s, 1H), 7.50 (d, J = 2.1Hz, 1H), 7.42 (t, J = 7.0Hz, 1H), 7.33 (dd, J=8.5,2.1Hz,1H),6.46(q,J=7.1Hz,1H),4.31(dd,J=19.2,10.1Hz,2H),4.12–3.94(m,2H) ,3.56–3.42(m,1H),3.26(d,J=12.0Hz,1H),2.82–2.61(m,3H),2.54(t,J=11.5Hz,1H),2.3 1(t,J=11.8Hz,1H),2.11–1.88(m,8H),1.83–1.64(m,1H),1.39(s,3H),1.22–1.09(m,1H).

[0400] Example 5

[0401] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (50 mg, 0.13 mmol) and (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-ol (I-3-b) hydrochloride (37 mg, 0.20 mmol) were added to tert-butanol (5 mL), and cesium carbonate (98 mg, 0.30 mmol) was added, and the mixture was reacted at 80°C in a microwave oven for 1 hour. Saturated ammonium chloride solution (3 mL) was added to the reaction mixture, and the mixture was concentrated to obtain a crude product, which was separated by silica gel chromatography (methanol:dichloromethane = 1:10) to obtain 2-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-5) (18 mg, 28.2%). LC-MS: 476.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.91 (s, 1H), 7.50 (s, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.33 (d ,J=8.4Hz,1H),6.46(d,J=7.0Hz,1H),4.36–4.20(m,2H),3.98(s,2H),3.71(t ,J=5.9Hz,2H),2.98(d,J=9.8Hz,2H),2.59(t,J=5.8Hz,3H),2.11(t,J=11.9H z, 1H), 2.04 (d, J = 7.0Hz, 3H), 1.95–1.53 (m, 5H), 0.93 (dd, J = 19.6, 8.8Hz, 1H).

[0402] Example 6

[0403] first step:

[0404] Compound (R)-1-(2,4-dichlorophenyl)ethylamine (I-4-b) (407 mg, 2.141 mmol) and potassium carbonate (592 mg, 4.283 mmol) were added to a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (I-6-a) (510 mg, 2.141 mmol) in acetonitrile (6 mL). The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the acetonitrile was evaporated under reduced pressure, and 40 mL of ethyl acetate was added to the reaction mixture. The mixture was then washed sequentially with 10 mL of water and 10 mL of saturated brine. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EA = 100 / 0 to 100 / 1, V / V) to obtain (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-fluoro-2-nitroaniline (I-6-b) as an orange powder (832 mg, 95.2% yield). 1 H NMR(400MHz, CDCl3)δ7.64(d,J=5.6Hz,1H),7.47(d,J=2.0Hz,1H),7.29–7.25(m,2H),6.65 (dd, J1=10.8Hz, J2=2.0Hz, 1H), 6.42 (s, 1H), 5.99 (q, J=6.8Hz, 1H), 1.60 (d, J=6.8Hz, 3H).

[0405] Step 2

[0406] Iron powder (551 mg, 9.865 mmol) and ammonium chloride (317 mg, 5.919 mmol) were slowly added to an ethanol / water solution (4:1, 10 mL) containing (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-fluoro-2-nitroaniline (I-6-b) (805 mg, 2.141 mmol). The reaction mixture was reacted at 90°C for 1 h. The reaction mixture was cooled to room temperature, filtered, and washed with ethanol. The ethanol was evaporated under reduced pressure, and the residue was added with 30 mL of ethyl acetate and 15 mL of saturated sodium carbonate solution. The aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue, (R)-5-bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-3-fluorobenzene-1,2-diamine (I-6-c), was directly used in the next reaction in a yield of 97.9%. M / Z=378.9(M+H) + ,1H NMR (400MHz, CDCl3) δ7.44(d,J=2.0Hz,1H),7.31(d,J=8.4Hz,1H),7.20(dd,J1=8.4Hz,J2=2.0Hz,1H),6.67(dd,J1= 9.2Hz,J2=2.0Hz,1H),6.16(t,J=2.0Hz,1H),4.85(q,J=6.8Hz,1H),4.16(s,1H),3.25(s,2H),1.55(d,J=6.8Hz,3H).

[0407] Step 3:

[0408] Sodium nitrite (200 mg, 2.896 mmol) was added to a solution of (R)-5-bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-3-fluorobenzene-1,2-diamine (I-6-c) (730 mg, 1.931 mmol) in acetic acid (10 mL). The reaction mixture was allowed to react at room temperature for 2 h. The acetic acid was evaporated under reduced pressure, and the residue was added with 15 mL of saturated sodium carbonate solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA = 100 / 0-20 / 1, V / V) to yield 563 mg of a viscous product (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-fluoro-1H-benzo[d][1,2,3]triazole (I-6-d) (832 mg, 75.0% yield). M / Z=389.9(M+H) +1H NMR(400MHz, CDCl3) δ7.48(d,J=2.0Hz,1H),7.36(d,J=1.6Hz,1H),7.25-7.1 9 (m, 2H), 7.16 (d, J = 8.4Hz, 1H), 6.31 (q, J = 7.2Hz, 1H), 2.18 (d, J = 7.2Hz, 3H).

[0409] Step 4:

[0410] Compound (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-fluoro-1H-benzo[d][1,2,3]triazole (I-6-d) (117 mg, 0.301 mmol), BrettPhosPd G3 (14 mg, 0.0150 mmol) and potassium acetate (62 mg, 0.632 mmol) were added to a solution of (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-3-b) hydrochloride (79 mg, 0.361 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was reacted at 100 ° C under argon overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by preparative TLC (DCM / MeOH = 10 / 1, V / V), further purified by preparative HPLC, and lyophilized to give a gray powder compound 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-f-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-6) (3 mg, yield 2.0%). M / Z = 492.2 (M+H) +1 H NMR (400MHz, CDCl3) δ7.45(d,J=2.0Hz,1H),7.20(dd,J1=8.4Hz,J2=2.0Hz,1H),7.15(d,J=8.4Hz,1H),6.20(d,J=1.6Hz,1H),6.17(q,J=6. 8Hz,1H),5.81(d,J=1.6Hz,1H),4.01(m,4H),3.77–3.49(m,4H),3.11(m,2H),2.59–2.43(m,2H),2.14(d,J=7.2Hz,3H),2.07–1.94(m,6H).

[0411] Example 7

[0412] first step:

[0413] 6-Bromo-2-fluoro-3-nitropyridine (267 mg, 1.21 mmol) (I-7-a), (R)-1-(2,4-dichlorophenyl)ethylamine (I-4-b) (230 mg, 1.21 mmol), and potassium carbonate (183 mg, 1.33 mmol) were added to N,N-dimethylformamide (10 mL) and reacted at room temperature for 5 hours. After the reaction, ethyl acetate (50 mL) was added and the mixture was washed with saturated brine (15 mL x 4). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography (methanol:dichloromethane = 0-5%) to obtain (R)-6-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-nitropyridine-2-amine (I-7-b) (483 mg, 99%). LC-MS: 391.9 [M+H] + .

[0414] Step 2:

[0415] (R)-6-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-nitropyridin-2-amine (395 mg, 1.01 mmol) (I-7-b), iron powder (564 mg, 10.1 mmol), and ammonium chloride (270 mg, 5.05 mmol) were added to ethanol (15 mL), and acetic acid (0.5 mL) was added dropwise. The mixture was refluxed for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness. Ethyl acetate (50 mL) and saturated sodium bicarbonate aqueous solution (15 mL) were added to the residual solid and stirred for 10 minutes. The organic phase was separated and washed with water (15 mL) and saturated brine (15 mL) in sequence. 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 = 0-5%) to obtain (R)-6-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-nitropyridin-2-amine. 2 -(1-(2,4-dichlorophenyl)ethyl)pyridine-2,3-diamine (I-7-c) (338 mg, 93%). LC-MS: 362.0 [M+H] + .

[0416] Step 3:

[0417] (R)-6-bromo-N 25-(1-(2,4-dichlorophenyl)ethyl)pyridine-2,3-diamine (I-7-c) (338 mg, 0.936 mmol) was added to a mixture of acetic acid (10 mL) and water (5 mL). The mixture was cooled to 0°C and sodium nitrite (97 mg, 1.4 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred for 4 hours. After the reaction was completed, ethyl acetate (25 mL) was added and saturated aqueous sodium bicarbonate solution (25 mL) was slowly added dropwise and stirred for 10 minutes. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 0-7%) to obtain (R)-5-bromo-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (I-7-d) (320 mg, 92%). LC-MS: 373.0 [M+H] + .

[0418] Step 4:

[0419] In a microwave tube, the raw materials (R)-5-bromo-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (I-7-d) (100 mg, 0.27 mmol) and (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-ol (I-3-b) hydrochloride (58 mg, 0.3 mmol) were dissolved in dimethyl sulfoxide (10 mL), and 55 mg (0.6 mmol) of sodium tert-butoxide was added and the mixture was heated at 150 ° C in a microwave tube. The reaction was allowed to proceed for 2 h, cooled, and diluted with ethyl acetate (100 mL). The product was washed with water (50 mL × 3) and saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated on a preparative plate (DCM:MeOH = 10:1) to afford 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-7) (15 mg) as a gray solid. Yield: 11.7%. LC-MS: M / Z = 476.3 [M+H]. + . 1H NMR(400MHz,CD3OD)δ7.98(d,J=8.7Hz,1H),7.50(s,1H),7.44(d,J=8.3Hz,1H),7.3 2(d,J=8.1Hz,1H),6.49(dd,J=17.9,7.9Hz,2H),4.17(d,J=7.4Hz,2H),3.86(s,2H), 3.73(s,2H),2.98(s,2H),2.58(d,J=20.6Hz,3H),2.09(dd,J=31.8,9.0Hz,4H),1.83 (d,J=8.5Hz,3H),1.64(d,J=11.4Hz,1H),1.40–1.26(m,2H),0.95(d,J=10.6Hz,1H).

[0420] Example 9

[0421] first step:

[0422] 5-Bromo-3-fluoro-2-nitropyridine (I-9-a) (460 mg, 2 mmol) and (R)-1-(2,4-dichlorophenyl)ethan-1-amine (I-4-b) (380 mg, 2 mmol) were dissolved in DMF (10 mL). Potassium carbonate (140 mg, 1 mmol) was added and the mixture was reacted at room temperature for 1 h. Ethyl acetate (120 ml) was added to dilute the mixture, washed with water (60 ml × 5), and then dried over saturated brine (60 ml × 1). The mixture was dried over anhydrous sodium sulfate and concentrated to give 0.76 g of a light yellow solid (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitropyridine-3-amine (I-9-b). LC-MS: 392.3 [M+H] + .

[0423] Step 2:

[0424] (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitropyridin-3-amine (I-9-b) (0.76 g, 1.94 mmol) was dissolved in ethanol (20 ml). 0.5 ml of glacial acetic acid, 2 ml of water, and 0.5 ml of saturated ammonium chloride solution were added, and the reaction mixture was heated to 70°C for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, adjusted to neutral with saturated sodium bicarbonate aqueous solution, and then added to celite, stirred for 5 minutes, and filtered. The filtrate was diluted with ethyl acetate (150 ml), washed with water (50 ml x 3), saturated brine (50 ml x 1), dried over anhydrous sodium sulfate, concentrated, and loaded onto a column. Purification by column chromatography afforded 700 mg of (R)-5-Bromo-N3-(1-(2,4-dichlorophenyl)ethyl)pyridine-2,3-diamine (I-9-c) as a light red solid. LC-MS: 362.3 [M+H] + .

[0425] Step 3:

[0426] (R)-5-Bromo-N3-(1-(2,4-dichlorophenyl)ethyl)pyridine-2,3-diamine (I-9-c) (700 mg, 1.94 mmol) was dissolved in glacial acetic acid (15 ml). Sodium nitrite (155 mg, 2.25 mmol) was slowly added at room temperature and stirred for 1 hour. After completion of the addition, the reaction mixture was concentrated, diluted with ethyl acetate (150 ml), and the pH was adjusted to neutral with saturated sodium bicarbonate aqueous solution. The mixture was washed with water (50 ml x 2) and brine (50 ml x 1), dried over anhydrous sodium sulfate, and concentrated. The sample was purified by column chromatography to obtain 360 mg of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (I-9-d). LC-MS: 373.3 [M+H] + .

[0427] Step 4:

[0428] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (I-9-d) (75 mg, 0.2 mmol), (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-ol hydrochloride (55 mg, 0.25 mmol), cesium carbonate (130 mg, 0.4 mmol), Pd2dba3 (18 mg, 0.02 mmol), XantPhos (23 mg, 0.04 mmol) were dissolved in 1,4-dioxane solution (10 ml), protected by argon, and refluxed for 8 h. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to obtain 8 mg of the product 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-9). LC-MS: 476.3 [M+H] + . 1H NMR(400MHz,MeOD)δ8.03(s,1H),7.56(s,1H),7.36(s,2H),6.62(s,1H),6.43(d,J=7.1Hz,1H),4.18–4.04(m,2H),3 .81(d,J=5.3Hz,4H),2.91(s,2H),2.65(s,1H),2.51(s,1H),2.24(d,J=11.0Hz,2H),2.11(d,J=6.7Hz,3H),1.89(s, 3H), 1.75 (d, J = 13.2Hz, 2H), 1.37 (d, J = 7.1Hz, 3H).

[0429] Example 10

[0430] first step:

[0431] 2,4-Dichloropyrimidin-5-amine (I-10-a) (1 g, 6.10 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (1.16 g, 6.10 mmol), and potassium carbonate (1.69 g, 12.2 mmol) were dispersed in DMF (10 mL). The reaction mixture was stirred at 120°C for 16 hours. The reaction was monitored by LC-MS until the starting materials were completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-2-chloro-N4-(1-(2,4-dichlorophenyl)ethyl)pyrimidine-4,5-diamine (I-10-b) (0.9 g, 46%). LC-MS: 317.0 [M+H] + .

[0432] Step 2:

[0433] (R)-2-chloro-N4-(1-(2,4-dichlorophenyl)ethyl)pyrimidine-4,5-diamine (I-10-b) (0.9 g, 2.83 mmol) and sodium nitrite (215 mg, 3.12 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature. LC-MS monitored the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (710 mg, 76%). LC-MS: 328.0 [M+H] + .

[0434] Step 3:

[0435] (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-3-b) hydrochloride (39 mg, 0.15 mmol), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (50 mg, 0.15 mmol), and sodium hydroxide (49 mg, 1.22 mmol) were dispersed in tert-butyl alcohol (5 mL) and water (5 mL). The reaction mixture was stirred at 95°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain 2-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-10) (3 mg, 4%). LC-MS: 476.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.07 (s, 1H), 7.68–7.44 (m, 2H), 7.36 (d, J = 8.1Hz, 1H), 6. 46(q,J=6.9Hz,1H),4.24(d,J=8.2Hz,2H),3.94(s,2H),3.74(t,J=5.8Hz,2H), 3.66(s,1H),3.01(s,2H),2.64(t,J=5.8Hz,2H),2.55(s,1H),2.22–2.10(m,1H ), 2.05 (d, J = 7.1Hz, 3H), 1.81 (dd, J = 27.3, 13.5Hz, 4H), 1.65 (d, J = 12.4Hz, 1H).

[0436] Example 14

[0437] first step:

[0438] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-1-b) (500 mg, 1.4 mmol) was dissolved in DCM (30 ml) and trifluoroacetic acid (6 ml) was added. The reaction mixture was allowed to react at 50°C for 48 h. After completion, the reaction mixture was concentrated to remove most of the solvent, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was diluted with ethyl acetate (150 ml) and washed with water (50 ml x 2) and brine (50 ml x 1). The mixture was dried over anhydrous sodium sulfate and concentrated. The sample was purified by column chromatography to obtain 590 mg of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole (I-14-a) as an anhydrous oily liquid. LC-MS: 439.2 [M+H] + .

[0439] Step 2:

[0440] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole (I-14-a) (100 mg, 0.23 mmol), (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-ol (I-3-b) hydrochloride (55 mg, 0.25 mmol), cesium carbonate (130 mg, 0.4 mmol), Pd2dba3 (35 mg, 0.038 mmol), XantPhos (40 mg, 0.07 mmol) were dissolved in 1,4-dioxane solution (10 ml), protected by argon, and refluxed for 8 h. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to obtain 10 mg of the product 2-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-14). LC-MS: 542.3 [M+H] + . 1H NMR(400MHz,MeOD)δ7.84(d,J=8.5Hz,1H),7.59–7.51(m,2H),6.58(d,J=8.8Hz,1H),6.18–6.0 8(m,1H),5.84(s,1H),4.58(s,1H),3.89(t,J=7.4Hz,1H),3.82(t,J=7.4Hz,1H),3.75(t,J=5. 9Hz,2H),3.53(t,J=6.7Hz,1H),3.10–2.95(m,2H),2.68(s,2H),2.27–2.18(m,1H),2.05(d,J= 6.9Hz, 3H), 1.90 (d, J = 12.2Hz, 1H), 1.80 (t, J = 12.7Hz, 3H), 1.63 (s, 2H), 1.37 (d, J = 8.1Hz, 3H).

[0441] Example 16

[0442] first step:

[0443] To a two-necked flask were added (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridine (I-9-d) (100 mg, 0.27 mmol), (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (130 mg, 0.43 mmol), Pd2(dba)3 (27 mg, 0.003 mmol), XantPhos (30 mg, 0.0052 mmol), cesium carbonate (160 mg, 0.49 mmol), and 1,4-dioxane (15 mL). After replacing argon, the mixture was reacted at 135°C for 6 hours. After cooling, the mixture was filtered, and the filtrate was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to obtain 20 mg of the product, methyl 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-16-a). LC-MS: 557.3 [M+H] + . 1H(400MHz, CDCl3)8.02(d,J=2.5Hz,1H),7.45(d,J=1.9Hz,1H),7.21(dd,J=8.5Hz,1.9Hz,1H),7.17(d,J=8.5Hz,1H),6.29(d,J=2.4Hz,1H),6.22(q,J=6 .9Hz,1H),4.07(dd,J=17.4Hz,7.8Hz,2H),3.74(s,3H),3.71(d,J=6.6Hz,1 H),2.79(s,2H),2.62(d,J=5.3Hz,3H),2.15(d,J=7.0Hz,3H),1.83-1.75(br s,5H),1.72-1.57(br s,6H),1.42(s,3H).

[0444] Step 2:

[0445] 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-16-a) (15 mg, 0.027 mmol) was dissolved in methanol (3 mL), and lithium hydroxide monohydrate (5.5 mg, 0.135 mmol) and water (1 mL) were added. The reaction mixture was stirred at room temperature for 2 hours, the pH was adjusted to neutral with dilute hydrochloric acid, and then concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to obtain 10 mg of the product, 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-16). LC-MS: 543.3 [M+H] + .

[0446] 1H NMR (400MHz, CD3OD) δ8.03(d,J=2.4Hz,1H),7.55(d,J=1.8Hz,1H),7.40–7.32(m,2H),6.62(d,J=2.4Hz,1H),6 .43(q,J=7.0Hz,1H),4.11(dt,J=16.1,7.8Hz,2H),3.81(dd,J=13.3,7.0Hz,2H),3.52–3.39(m,1H),3.25(d,J= 10.6Hz,1H),2.79–2.69(m,2H),2.65(d,J=8.5Hz,1H),2.50(t,J=11.8Hz,1H),2.27(t,J=11.8Hz,1H),2.09(t, J=7.6Hz,3H),1.99(dd,J=23.1,13.5Hz,5H),1.75(t,J=13.3Hz,1H),1.38(d,J=5.5Hz,3H),1.32–1.29(m,2H).

[0447] Example 17

[0448] first step:

[0449] (R)-5-bromo-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (I-7-d) (76 mg, 0.20 mmol) and (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (50 mg, 0.20 mmol) were dissolved in dimethyl sulfoxide (5 mL), sodium tert-butoxide (48 mg, 0.50 mmol) was added, and the mixture was microwaved at 150°C for 2 hours. After the reaction solution was cooled to room temperature, ethyl acetate (30 mL) and saturated ammonium chloride solution (5 mL) were added and stirred for 10 minutes. The organic phase was separated, washed with saturated aqueous sodium chloride solution (10 mL x 3), dried, and filtered. The filtrate was evaporated to dryness to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane = 0-7%) to give (1R,3r)-3-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-17) (6 mg, 5.5%). LC-MS: 543.0 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 1H NMR (400MHz, CDCl3) δ7.98(d,J=8.9Hz,1H),7.40(dt,J=11.6,9.2Hz,2H),7.17(d,J =8.4Hz,1H),6.59–6.43(m,1H),6.27(d,J=9.0Hz,1H),4.22–4.03(m,2H),3.84(dd, J=19.1,11.5Hz,2H),3.10(s,4H),2.60(d,J=8.2Hz,2H),2.43(s,1H),2.35–2.10(m ,2H),2.04(d,J=7.1Hz,3H),1.97–1.50(m,5H),1.39(d,J=20.4Hz,3H),0.88(s,1H).

[0450] Example 25

[0451] first step:

[0452] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (229 mg, 0.756 mmol), Pd2(dba)3 (24 mg, 0.0262 mmol), BINAP (32 mg, 0.0514 mmol) and Cs2CO3 (345 mg, 1.059 mmol) were added to a solution of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-fluoro-1H-benzo[d][1,2,3]triazole (I-6-d) (196 mg, 0.504 mmol) in 1,4-dioxane (4 mL). The reaction mixture was replaced with argon three times and heated to 110°C for overnight reaction. The reaction was monitored by LC-MS, and the molecular ion peak of I-25-a was 574.1 [M+H] + and the molecular ion peak of the hydrolysis product I-25 is 560.1[M+H] + The system was cooled to room temperature and then filtered. The filter cake was washed with methanol. The filtrate was evaporated under reduced pressure and the residue was directly used for the next hydrolysis step.

[0453] Step 2:

[0454] The residue from the first step, sodium hydroxide (10 mg, 0.25 mmol), and water (1 mL) were added sequentially to methanol (3 mL). The reaction mixture was reacted at 40°C for 2 hours. The reaction mixture was cooled to room temperature, and the methanol was evaporated under reduced pressure. Water (6 mL) was added to the residue, and the pH was adjusted to approximately 6 with 2N hydrochloric acid. Ethyl acetate (8 mL x 3) was added for extraction. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol = 7 / 1, V / V). The crude product was further purified by HPLC and lyophilized to give compound (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-25) (15 mg, 5.3% yield over two steps). M / Z = 560.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.50(s,1H),7.56(s,1H),7.36(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),6.39(q,J=6.8Hz,1H),6.33(m,1H),5.97(s,1H),4.01( m,2H),3.71(m,2H),3.58(m,1H),3.38(m,4H),2.78(m,2H),2.59(m,2H),2 .38(m,1H),2.09(d,J=6.8Hz,3H),1.99(m,4H),1.75(m,1H),1.41(s,3H).

[0455] Example 29

[0456] first step:

[0457] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (248 mg, 0.67 mmol) and tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride (223 mg, 1.0 mmol) were added to tert-butanol (10 mL), and cesium carbonate (650 mg, 1.99 mmol) was added, and the reaction was carried out at 90°C overnight. The reaction mixture was cooled to room temperature, and saturated ammonium chloride solution (4 mL) was added to the reaction mixture. The mixture was concentrated to obtain a crude product, which was separated by silica gel chromatography (dichloromethane / methanol = 20:1) to obtain tert-butyl (R)-(1-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]piperidin-6-yl)azetidin-3-yl)(methyl)carbamate (I-29-a) (284 mg, 89.4%). LC-MS: 478.2 [M+H] + .

[0458] Step 2:

[0459] (R)-(1-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]piperidin-6-yl)azetidin-3-yl)(methyl)carbamic acid tert-butyl ester (I-29-a) (284 mg, 0.59 mmol) was dissolved in hexafluoroisopropanol (5 mL) and reacted at 120 ° C for 6 hours. After the reaction was completed, the reaction was concentrated to obtain a light yellow oil (R)-1-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-N-methylazetidin-3-amine (I-29-b) (crude product 235 mg), which can be used directly in the next step. LC-MS: 378.1 [M+H] + .

[0460] Step 3:

[0461] (R)-1-(1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-N-methylazetidin-3-amine (I-29-b) (72 mg, 0.19 mmol), (tert-butyloxycarbonyl)-D-proline (90 mg, 0.42 mmol), HOBt (36 mg, 0.27 mmol), EDCI (292 mg, 1.52 mmol), and DIPEA (369 mg, 2.86 mmol) were dispersed in acetonitrile (5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (dichloromethane:methanol = 10:1) to obtain (R)-tert-butyl 2-((1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (I-29-c) (80 mg, 73%). LC-MS: 575.0 [M+H] + .

[0462] Step 2:

[0463] Tert-butyl (R)-2-((1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylate (I-29-c) (80 mg, 0.14 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution (10 mL) was added, followed by extraction with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (dichloromethane:methanol = 10:1) to give (R)-N-(1-(1-(((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)-N-methylpyrrolidine-2-carboxamide (6 mg, 9%) (I-29). LC-MS: 475.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.90(s,1H),7.42(dd,J=5.2,3.1Hz,2H),7.22(dd,J=8.5,1.8Hz,1H),6.50(q,J=7.1Hz,1H),5.56–5.34(m,1H),4.48(dd,J =14.3,8.6Hz,2H),4.43–4.19(m,2H),4.08(d,J=7.8Hz,1H),3.35–3.10( m,4H),2.95(d,J=17.7Hz,1H),2.09(d,J=7.1Hz,3H),1.97–1.62(m,4H).

[0464] Example 47

[0465] first step:

[0466] 4-Bromo-6-chloropyridazin-3-amine (275 mg, 1.32 mmol) (I-47-a) and (R)-1-(2,4-dichlorophenyl)ethanamine (532 mg, 2.80 mmol) (I-4-b) were dispersed in water (2 mL), potassium carbonate (318 mg, 2.3 mmol) was added, and the reaction system was reacted in a microwave oven at 130°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with ethyl acetate (15 mL × 2). The organic phases were combined and concentrated, and the crude product was separated by column chromatography (dichloromethane: methanol = 15:1) to obtain (R)-6-chloro-N 4 -(1-(2,4-dichlorophenyl)ethyl)pyridazine-3,4-diamine (I-47-b) (85 mg). LC-MS: 319.1 [M+H] + .

[0467] Step 2:

[0468] (R)-6-chloro-N 4 -(1-(2,4-dichlorophenyl)ethyl)pyridazine-3,4-diamine (I-47-b) (110 mg, 0.35 mmol) was dispersed in water (2 mL), and dichloromethane (3 mL) and acetic acid (2 mL) were added. After the reaction system was cooled to 0°C, sodium nitrite (120 mg, 1.74 mmol) was added and stirred at room temperature until the starting material disappeared. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction system, followed by extraction with ethyl acetate (10 mL x 2). The organic phases were combined and concentrated, and the crude product was separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain 95 mg of (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridazine (I-47-c). LC-MS: 329.9 [M+H] +.

[0469] Step 3:

[0470] (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridazine (I-47-c) (50 mg, 0.15 mmol), (1R, 3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (64 mg) were added to tert-butanol (3 mL), cesium carbonate (230 mg, 0.62 mmol) was added, and the mixture was reacted at 110°C in a microwave oven for 4 hours. After the reaction was complete, the system was concentrated, and water (3 mL) was added to the residue. The pH was adjusted to approximately 3 with 1N hydrochloric acid solution, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phases were combined and concentrated to obtain 79 mg of crude product of methyl (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-47-d). LC-MS: 558.3 ​​[M+H] + .

[0471] Step 4:

[0472] The crude product (79 mg) of (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-47-d) was added to a mixed solvent of methanol (1 mL), water (1 mL) and tetrahydrofuran (1 mL), and lithium hydroxide monohydrate (115 mg) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the system was concentrated, and methyl tert-butyl ether (15 mL) and water (10 mL) were added. The aqueous phase was separated and the pH value was adjusted to 3 with 1N hydrochloric acid solution. After concentration, the product was prepared by HPLC to obtain 15 mg of (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid ((I-47). LC-MS: 544.1 [M+H] +. 1H NMR (400MHz, CD3OD) δ8.47(s,1H),7.56(d,J=1.8Hz,1H),7.42(qd,J=8.5,2.9Hz,2H),6.47 (s,1H),6.42(q,J=7.0Hz,1H),4.25(dd,J=17.5,8.8Hz,2H),4.02–3.89(m,2H),3.49(d,J= 7.5Hz,1H),3.34(s,1H),3.25(s,2H),2.80–2.63(m,3H),2.55(s,1H),2.34(s,1H),2.10(d ,J=7.0Hz,3H),2.06–1.91(m,4H),1.72(d,J=13.9Hz,1H),1.39(s,3H),1.25–1.10(m,1H).

[0473] Example 49

[0474] first step:

[0475] To a dry three-necked flask (250 mL) at room temperature under a nitrogen atmosphere, ethyl 3-oxocyclobutanecarboxylate (I-49-a) (10.0 g, 70.346 mmol), ethylene glycol (6.6 g, 105.519 mmol), toluene (100 mL), and p-toluenesulfonic acid (121.2 mg, 0.703 mmol) were added in sequence. The reaction mixture was stirred at 120° C. for 16 hours using a Dean-Stark apparatus under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium bicarbonate solution (200 mL) and methyl tert-butyl ether (200 mL). The organic phase was separated, and the aqueous phase was extracted with methyl tert-butyl ether (3×200 mL). The organic phases were combined, washed with saturated brine (2×200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 5,8-dioxaspiro[3.4]octane-2-carboxylic acid ethyl ester (I-49-b) (6.3 g, yield 48%). 1 H NMR (400MHz, CDCl3) δ4.15(m,2H),3.94–3.86(m,4H),2.89(m,1H),2.70–2.61(m,2H),2.58–2.48(m,2H),1.26(t,J=7.1Hz,3H).

[0476] Step 2:

[0477] Under a nitrogen atmosphere, diisopropylamine (5.1 g, 50.749 mmol), tetrahydrofuran (63 mL) and a 2.5 M n-butyllithium n-hexane solution (17.6 mL, 43.983 mmol) were added to a dry three-necked flask (250 mL) at -78 ° C. After stirring for 10 minutes, 5,8-dioxaspiro[3.4]octane-2-carboxylic acid ethyl ester (I-49-b) (6.3 g, 33.833 mmol) was added dropwise to the reaction solution, and stirring was continued at -78 ° C for 30 minutes. Iodoethane (7.9 g, 50.749 mmol) was diluted with tetrahydrofuran (21 mL), and then the iodoethane solution in tetrahydrofuran was added dropwise to the reaction mixture at -78 ° C and a nitrogen atmosphere. After the addition, the reaction mixture was kept at -20 ° C and a nitrogen atmosphere for 4 hours. After the reaction, ice water was added to the reaction mixture at 0°C to quench the reaction mixture. Ether (3 × 100 mL) was added for extraction. The organic phases were combined, washed with saturated brine (2 × 100 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain the compound 2-ethyl-5,8-dioxaspiro[3.4]octane-2-carboxylic acid ethyl ester (I-49-c) (6.1 g, yield 84%) as a yellow oil. LCMS: (ESI, m / z): [M+H] + =215.15.

[0478] Step 3:

[0479] To a dry round-bottom flask (250 mL) were added ethyl 2-ethyl-5,8-dioxaspiro[3.4]octane-2-carboxylate (I-49-c) (6.0 g, 28.004 mmol), acetone (60 mL) and aqueous hydrochloric acid (12 mL, 6N). The reaction mixture was stirred at 25 ° C for 4 hours. After the reaction was completed, it was concentrated under reduced pressure, the residue was diluted with water (100 mL), and ether (3×100 mL) was added for extraction. The organic phases were combined, washed with saturated brine (3×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) and concentrated under reduced pressure to give the compound 1-ethyl-3-oxocyclobutane-1-carboxylate (I-49-d) (3.0 g, yield 62%) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =171.15.

[0480] Step 4:

[0481] To a dry round-bottom flask (100 mL) were added 1-ethyl-3-oxocyclobutane-1-carboxylic acid ethyl ester (I-49-d) (3.0 g, 9.010 mmol), methanol (30 mL), water (30 mL), tetrahydrofuran (30 mL) and lithium hydroxide monohydrate (2.5 g, 45.050 mmol) in sequence. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed by liquid chromatography-mass spectrometry, the reaction solution was concentrated under reduced pressure, diluted with water (50 mL), and then adjusted to a pH of approximately 3 with aqueous hydrochloric acid (2 M). The mixture was diluted with water (100 mL), extracted with dichloromethane (3 × 100 mL), washed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-ethyl-3-oxocyclobutane-1-carboxylic acid (I-49-e) (1.8272 g, yield 65%) as a colorless oil. LCMS: (ESI, m / z): [MH] - =141.20.

[0482] Step 5:

[0483] Disperse (R)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (500 mg, 2.08 mmol), 1-ethyl-3-oxocyclobutane-1-carboxylic acid (I-49-e) (385 mg, 2.71 mmol), and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (706 mg, 2.81 mmol) in toluene (5 mL). Stir the reaction mixture at 120°C for 4 hours. Monitor the reaction by LC-MS until the starting material is completely reacted. The reaction mixture was concentrated under reduced pressure, ethyl acetate (10 mL) was added, and the mixture was extracted with water (10 mL). The aqueous layer was concentrated under reduced pressure to give the crude product (1R,3s)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid (I-49-f) (640 mg, 84%), which was used directly in the next step. LC-MS: 366.9 [M+H] + .

[0484] Step 6:

[0485] (1R, 3s)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid (I-49-f) (640 mg, 1.75 mmol) was dissolved in methanol (8 mL), and thionyl chloride (0.15 mL, 2.10 mmol) was added to the system. The reaction solution was stirred at room temperature for 24 hours. LC-MS monitored the reaction until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure, saturated sodium carbonate solution (10 mL) was added, and extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product (1R, 3s)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid methyl ester (I-49-g) (600 mg) of crude product, which was used directly in the next step. LC-MS: 281.0 [M+H] + .

[0486] Step 7:

[0487] Methyl (1R,3s)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylate (I-49-g) (111 mg, 0.29 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (100 mg, 0.27 mmol), and sodium carbonate (199 mg, 1.88 mmol) were dispersed in isopropanol (10 mL). The reaction mixture was stirred at 90°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol / dichloromethane = 1 / 10) to obtain (1R,3s)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid methyl ester (I-49-h) (110 mg, 72%). LC-MS: 571.8 [M+H] + .

[0488] Step 8:

[0489] (1R,3s)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid methyl ester (I-49-h) (110 mg, 0.19 mmol), Lithium hydroxide (46 mg, 1.92 mmol) was dispersed in methanol (5 mL) and water (0.5 mL), and the reaction mixture was stirred at room temperature for 4 hours. LC-MS monitored the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified using a GF254 preparative plate (methanol / dichloromethane = 1 / 10) to afford (1R,3s)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid (I-49) (70 mg, 65%). LC-MS: 557.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.92(s,1H),7.48(dd,J=16.3,5.3Hz,2H),7.33(dd,J=8.5,2.1Hz,1H),6.47(q,J=7.0Hz,1H),4.29(dd,J=18.9,9.5Hz,2H) ,4.12–3.92(m,2H),3.31–3.14(m,3H),2.75–2.53(m,3H),2.34(t,J=11 .5Hz,1H),2.15–1.83(m,10H),1.81–1.66(m,3H),0.83(t,J=7.3Hz,3H).

[0490] Example 51

[0491] Example 51 is the intermediate I-16-a used in the preparation of Example 16, namely, 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-16-a). LC-MS: 557.3 [M+H] + . 1H(400MHz, CDCl3)8.02(d,J=2.5Hz,1H),7.45(d,J=1.9Hz,1H),7.21(dd,J=8.5Hz,1.9Hz,1H),7.17(d,J=8.5Hz,1H),6.29(d,J=2.4Hz,1H),6.22(q, J=6.9Hz,1H),4.07(dd,J=17.4Hz,7.8Hz,2H),3.74(s,3H),3.71(d,J=6.6 Hz,1H),2.79(s,2H),2.62(d,J=5.3Hz,3H),2.15(d,J=7.0Hz,3H),1.79(br s,5H),1.67(br s,6H),1.42(s,3H).

[0492] Example 52

[0493] first step:

[0494] The specific synthesis method refers to the second step reaction in Example 14 to obtain methyl 3-(3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-52-a). LC-MS: 623.3 [M+H] + .

[0495] Step 2:

[0496] The specific synthesis method refers to the second step reaction in Example 16 to obtain 3-(3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-52); LC-MS: 609.3 [M+H] + . 1H NMR(400MHz,CD3OD)δ7.82(d,J=8.4Hz,1H),7.61–7.50(m,3H),6.58(dd,J=8.8,1.9Hz,1H),6 .13(q,J=6.9Hz,1H),5.88(d,J=1.6Hz,1H),3.90(t,J=7.5Hz,1H),3.81(t,J=7.5Hz,1H),3.6 4–3.53(m,2H),3.47–3.41(m,1H),3.38(d,J=8.8Hz,1H),3.25(d,J=11.0Hz,1H),2.76(dt,J= 21.7,10.9Hz,2H),2.63–2.50(m,2H),2.35(t,J=11.8Hz,1H),2.13(dd,J=21.2,11.4Hz,2H).

[0497] Example 53

[0498] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (104 mg, 0.31 mmol), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (100 mg, 0.31 mmol), and sodium carbonate (226 mg, 2.14 mmol) were dispersed in tert-butanol (10 mL). The reaction mixture was stirred at 95°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-53) (23 mg, 13%). LC-MS: 558.3 ​​[M+H] + . 1HNMR(400MHz, CDCl3) δ9.07(s,1H),7.46(d,J=8.5Hz,1H),7.42(d,J=2.1Hz,1H),7.23(dd,J=8.5,2.1Hz,1H),6.46(q,J=7.1Hz,1 H),4.24(s,2H),3.91(s,2H),3.73(s,3H),2.63(t,J=56.8Hz,6H),2.14–1.98(m,4H),1.78(dd,J=27.7,11.0Hz,7H),1.41(s,4H).

[0499] Example 54

[0500] Methyl (1R,3r)-3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-53) (15 mg, 0.03 mmol) and lithium hydroxide (6 mg, 0.27 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford (1R,3r)-3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-54) (8 mg, 55%). LC-MS: 544.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.06 (s, 1H), 7.51 (dd, J = 8.1, 5.3Hz, 2H), 7.36 (dd, J = 8.5, 2. 0Hz,1H),6.47(q,J=7.1Hz,1H),4.24(s,2H),3.92(s,2H),2.91(t,J=10.2Hz,2H),2 .76(dd,J=15.8,7.9Hz,1H),2.62(dd,J=11.0,7.4Hz,2H),2.51(d,J=8.1Hz,1H),2. 05(d,J=7.1Hz,3H),1.78(dd,J=16.8,11.4Hz,6H),1.64–1.47(m,2H),1.36(s,4H).

[0501] Example 55

[0502] first step:

[0503] (R)-tert-Butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (480 mg, 2 mmol), 3-thietanone (I-55-a) (364 mg, 3 mmol), and glacial acetic acid (0.1 mL) were dissolved in tetrahydrofuran (10 mL) and stirred at room temperature for 6 hours. Sodium acetate borohydride (850 mg, 4 mmol) was added portionwise. The reaction mixture was allowed to stand at room temperature overnight. The concentrated sample was then loaded onto a column (petroleum ether:ethyl acetate = 3:1) to afford 460 mg of tert-butyl (R)-3-(1-(thietan-3-yl)piperidin-3-yl)azetidine-1-carboxylate (I-55-b) as a light brown oily liquid. LC-MS: 313.3 [M+H] + .

[0504] Step 2:

[0505] Tert-butyl (R)-3-(1-(thietan-3-yl)piperidin-3-yl)azetidine-1-carboxylate (I-55-b) (155 mg, 0.5 mmol) was dissolved in dichloromethane (3 mL), and hydrogen chloride-dioxane (4 mol / L, 1 mL) was added and stirred for 1 hour. Concentration afforded 150 mg of the crude hydrochloride salt of (R)-3-(azetidin-3-yl)-1-(thietan-3-yl)piperidine (I-55-c). LC-MS: 213.3 [M+H] + .

[0506] Step 3

[0507] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (120 mg, 0.33 mmol), (R)-3-(azetidin-3-yl)-1-(thietidin-3-yl)piperidine (I-55-c) hydrochloride (100 mg, 0.33 mmol) were dissolved in isopropanol (5 mL), and sodium hydroxide (78 mg, 1.95 mmol) and water (1.5 mL) were added. The reaction mixture was stirred at 95°C for 3 hours, cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL × 3), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, mixed, and separated by column chromatography (dichloromethane:methanol = 100:4) to obtain 80 mg of 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(thiazole-3-yl)piperidin-3-yl)azetidin-1-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-55-d). LC-MS: 504.2 [M+H]. + .

[0508] Step 4:

[0509] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(thiazole-3-yl)piperidin-3-yl)azetidin-1-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-55-d) (40 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), and m-chloroperbenzoic acid (32.4 mg, 0.16 mmol) was added at room temperature. After the addition, the reaction solution was stirred at room temperature for 3 hours and quenched by adding saturated sodium thiosulfate solution. The mixture was quenched and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate separation (dichloromethane:methanol = 100:5) to obtain 11 mg of 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)thietane 1,1-dioxide (I-55). LC-MS: 537.2 [M+H] + . 1HNMR(400MHz,CD3OD)δ7.96(d,J=10.3Hz,1H),7.53(d,J=2.0Hz,1H),7.45(d,J=8.5Hz,1H),7.35 (dd,J=8.5,2.0Hz,1H),6.49(q,J=7.1Hz,1H),4.34-4.1(m,2H),4.13-4.11(m,1H),4.09(dd,J=8.9 ,5.6Hz,2H),3.45(dd,J=14.0,8.2Hz,1H),3.26(d,J=18.5Hz,1H),3.12–2.99(m,1H),2.78(t,J=11. 7Hz,1H),2.70–2.45(m,2H),2.24(dd,J=27.3,13.3Hz,1H),2.07(d,J=7.1Hz,3H),1.94(d,J=12.2Hz ,3H),1.83(d,J=14.3Hz,1H),1.39(dd,J=17.3,9.2Hz,3H),1.31(d,J=4.0Hz,3H),1.11-0.9(m,1H).

[0510] Example 56

[0511] 1-((R)-1-(2,4-dichlorophenyl)ethyl)-6-(3-((R)-1-(thiazole-3-yl)piperidin-3-yl)azetidin-1-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-55-d) (40 mg, 0.08 mmol), ammonium acetate (24 mg, 0.32 mmol), iodobenzene acetate (77 mg, 0.24 mmol) were dissolved in methanol ( The mixture was stirred at room temperature for 2 hours, concentrated, and then purified by preparative plate separation (dichloromethane:methanol = 100:5) to obtain 10 mg of 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-imino-116-thietane 1-oxide (I-56). LC-MS: 535.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.53(s,1H),7.46(d,J 8.2Hz,1H),7.35(d,J=8.6Hz,1H),6.53–6.43(m,1H),4.30(d,J=9.5Hz,2H),4.13(dd,J=21.7,13.5Hz,2H),4.09-4.01(m,3H),2.83( d,J=10.3Hz,2H),2.69(s,1H),2.07(d,J=7.0Hz,3H),1.93–1.69(m,4H),1.61(d,J=10.5Hz,1H),1.31(s,4H),1.01(d,J=12.7Hz,1H).

[0512] Example 57

[0513] first step:

[0514] (R)-6-Bromo-N2-(1-(2,4-dichlorophenyl)ethyl)pyrazine-2,3-diamine (I-4-c) (200 mg, 0.56 mmol) was dissolved in formic acid (3 mL) and heated to 100°C overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The mixture was diluted with ethyl acetate (80 mL) and washed with saturated sodium bicarbonate solution (50 mL × 1), water (50 mL × 3), and saturated brine (30 mL × 3). The mixture was dried over anhydrous sodium sulfate, concentrated, mixed, and loaded onto a column (petroleum ether:ethyl acetate = 2:1) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-imidazo[4,5-b]pyrazine (I-57-a) as a pale yellow solid (175 mg). LC-MS: 370.0 [M+H] + .

[0515] The second and third steps can be performed according to the procedures of Example 16 to obtain 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-imidazo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-57) as a white powder. LC-MS: 543.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.34(s,1H),7.69(s,1H),7.53(d,J=2.1Hz,1H),7.49(d,J=8.5Hz,1H),7.38(dd,J=8.5,2.1Hz,1H),6.17(q,J=7.2Hz,1H ),4.58(s,1H),4.18(q,J=8.5Hz,2H),3.88(t,J=5.9Hz,2H),3.51(t,J=7.4Hz,1H),2.77(dd,J=11.5,7.6Hz,2H),2.69~2.54(m,2H),2.35(t,J =11.5Hz,1H),2.09–1.93(m,7H),1.74(d,J=14.0Hz,1H),1.42(d,J=8.0Hz,3H),1.32(t,J=3.7Hz,3H),1.18(d,J=12.9Hz,1H).

[0516] Example 58

[0517] first step:

[0518] Dissolve (R)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (102 mg, 0.42 mmol) and 3-oxetanone (I-58-a) (46 mg, 0.64 mmol) in dry tetrahydrofuran (8 mL). The reaction system was cooled to 0°C in an ice bath, and acetic acid (20 mg, 0.33 mmol) was added dropwise, followed by sodium triacetoxyborohydride (270 mg, 1.27 mmol). The system was warmed to room temperature and stirred overnight. After the reaction was completed, saturated aqueous NaHCO₃ (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain 132 mg of crude (R)-tert-butyl 3-(1-(oxetane-3-yl)piperidin-3-yl)azetidine-1-carboxylate (I-58-b), which was used directly in the next reaction. LC-MS: 297.3 [M+H] + .

[0519] Step 2:

[0520] The (R)-3-(1-(oxetane-3-yl)piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-58-b) (132 mg, 0.44 mmol) obtained in the previous step was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added to the system. The reaction solution was stirred at room temperature. LC-MS monitored the reaction until the raw material reaction was complete. After the reaction solution was concentrated under reduced pressure, 166 mg of the trifluoroacetic acid salt of (R)-3-(azetidine-3-yl)-1-(oxetane-3-yl)piperidine (I-58-c) was obtained, and the crude product was directly used in the next reaction. LC-MS: 197.2 [M+H] + .

[0521] Step 3:

[0522] The trifluoroacetate (166 mg) of the product from the previous step (R)-3-(azetidin-3-yl)-1-(oxetane-3-yl)piperidine (I-58-c) was suspended in tert-butanol (8 mL), and water (8 mL), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (80 mg, 0.24 mmol) and cesium carbonate (410 mg, 1.25 mmol) were added in sequence, and the reaction system was heated to 100 ° C and stirred overnight. After the reaction was completed, the system was cooled to room temperature, saturated ammonium chloride solution (5 mL) was added, and the mixture was concentrated to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain 18 mg of 3-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-((R)-1-(oxetane-3-yl)piperidin-3-yl)azetidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-58) as an off-white solid. LC-MS: 488.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ9.04(s,1H),7.50(d,J=2.1Hz,1H),7.47(d,J=8.5Hz,1H),7.34(dd,J=8.5,2.1H z,1H),6.44(d,J=7.1Hz,1H),4.69(td,J=6.7,2.5Hz,2H),4.61(dt,J=12.7,6.3Hz,2H),4.28–4.13(m, 2H),3.91(d,J=5.7Hz,2H),3.49(p,J=6.5Hz,1H),2.72(d,J=7.6Hz,2H),2.53(dd,J=15.0,5.9Hz,1H), 2.03(d,J=7.1Hz,3H),1.91–1.71(m,3H),1.67–1.51(m,2H),1.33(d,J=3.0Hz,1H),1.03–0.91(m,1H).

[0523] Example 59

[0524] first step:

[0525] 5-Bromo-1-fluoro-3-methyl-2-nitrobenzene (I-59-a) (300 mg, 1.28 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (244 mg, 1.28 mmol), and potassium carbonate (354 mg, 2.56 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-2-nitroaniline (I-59-b) (260 mg, 50%).

[0526] Step 2:

[0527] (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methyl-2-nitroaniline (I-59-b) (260 mg, 0.64 mmol), reduced iron powder (180 mg, 3.22 mmol), and ammonium chloride (103 mg, 1.93 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 100°C. LC-MS was used to monitor the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, 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 column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methylbenzene-1,2-diamine (I-59-c) (160 mg, 66%). LC-MS: 373.0 [M+H] + .

[0528] Step 3:

[0529] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-3-methylbenzene-1,2-diamine (I-59-c) (210 mg, 0.56 mmol) and sodium nitrite (43 mg, 0.61 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, added with saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (I-59-d) (209 mg, 97%). LC-MS: 384.0 [M+H] + .

[0530] Step 4:

[0531] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (97 mg, 0.29 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (I-59-d) (100 mg, 0.26 mmol), Pd2(dba)3 (24 mg, 0.03 mmol), BINAP (32 mg, 0.05 mmol), and Cs2CO3 (423 mg, 1.30 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-59-e) (120 mg, 81%). LC-MS: 570.3 [M+H] + .

[0532] Step 5:

[0533] Methyl (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-59-e) (120 mg, 0.21 mmol) and lithium hydroxide (14 mg, 2.10 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to give (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-59) (70 mg, 60%). LC-MS: 556.3 [M+H]. + . 1H NMR (400MHz, CD3OD) δ7.55(d,J=2.1Hz,1H),7.32(dd,J=8.5,2.1Hz,1H),7.21(d,J=8.5Hz,1H),6.45(s,1H ),6.32(q,J=6.9Hz,1H),5.99(d,J=1.3Hz,1H),3.97(dt,J=18.5,7.7Hz,2H),3.74–3.59(m,2H),3.44–3.3 4(m,1H),3.24(dd,J=26.7,11.3Hz,2H),2.73(dd,J=11.5,7.3Hz,2H),2.64(s,3H),2.55–2.33(m,2H),2.1 6(t,J=12.0Hz,1H),2.08(d,J=7.0Hz,3H),2.05–1.84(m,5H),1.70(dd,J=26.8,13.2Hz,2H),1.39(s,3H).

[0534] Example 60

[0535] first step:

[0536] 5-Bromo-1-chloro-3-fluoro-2-nitrobenzene (I-60-a) (300 mg, 1.18 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (224 mg, 1.18 mmol), and potassium carbonate (326 mg, 2.36 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-3-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline (I-60-b) (500 mg, 100%).

[0537] Step 2:

[0538] (R)-5-bromo-3-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline (I-60-b) (500 mg, 1.18 mmol), reduced iron powder (329 mg, 5.89 mmol), and ammonium chloride (189 mg, 3.53 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 100°C. LC-MS was used to monitor the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, 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 column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-3-chloro-N-(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-60-c) (410 mg, 88%). LC-MS: 393.0 [M+H] + .

[0539] Step 3:

[0540] (R)-5-Bromo-3-chloro-N1-(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-60-c) (410 mg, 1.04 mmol) and sodium nitrite (79 mg, 1.14 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, added with saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-6-bromo-4-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-60-d) (390 mg, 93%). LC-MS: 404.0 [M+H] + .

[0541] Step 4:

[0542] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (92 mg, 0.27 mmol), (R)-6-bromo-4-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-60-d) (100 mg, 0.25 mmol), Pd2(dba)3 (23 mg, 0.02 mmol), BINAP (31 mg, 0.05 mmol), and Cs2CO3 (402 mg, 1.23 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(4-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-60-e) (80 mg, 55%). LC-MS: 590.3 [M+H] + .

[0543] Step 5:

[0544] Methyl (1R,3r)-3-((R)-3-(1-(4-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-60-e) (80 mg, 0.14 mmol) and lithium hydroxide (32 mg, 1.35 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(4-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-60) (40 mg, 51%). LC-MS: 576.3 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.56(d,J=2.1Hz,1H),7.35(dd,J=8.5,2.1Hz,1H),7.27(d,J=8.5Hz,1H),6.69(d,J= 1.7Hz,1H),6.35(q,J=6.9Hz,1H),6.09(d,J=1.6Hz,1H),4.00(dt,J=20.7,7.8Hz,2H),3.74–3.62(m,2H), 3.41(d,J=8.3Hz,1H),3.30–3.16(m,2H),2.73(dd,J=11.6,7.8Hz,2H),2.54(s,1H),2.44(t,J=11.2Hz,1H ),2.27–2.14(m,1H),2.09(d,J=7.0Hz,3H),2.06–1.88(m,5H),1.71(dd,J=27.0,13.8Hz,2H),1.39(s,3H).

[0545] Example 61

[0546] first step:

[0547] Tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (330 mg, 1.37 mmol), 3-oxocyclobutane-1-carboxylic acid (I-61-a) (204 mg, 1.79 mmol), and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (466 mg, 1.85 mmol) were dispersed in toluene (10 mL). The reaction mixture was stirred at 120°C for 4 hours. LC-MS monitoring was performed until the reaction of the starting materials was complete. The reaction mixture was concentrated under reduced pressure, ethyl acetate (10 mL) was added, and the mixture was extracted with water (10 mL). The mixture was concentrated under reduced pressure to give the crude product (R)-3-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (I-61-b) (340 mg, 73%), which was used directly in the next step. LC-MS: 339.3 [M+H] + .

[0548] Step 2:

[0549] (R)-3-(3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (I-61-b) (340 mg, 1.00 mmol) was dissolved in methanol (8 mL), and thionyl chloride (0.09 mL, 1.21 mmol) was added to the system. The reaction solution was stirred at room temperature. LC-MS monitored the reaction until the starting material was completely reacted. The reaction solution was quenched by adding saturated sodium carbonate solution (5 mL), concentrated under reduced pressure, added with water (5 mL), and extracted with ethyl acetate (10 mL). The reaction solution was concentrated under reduced pressure to give the crude product (R)-3-(1-(3-(methoxycarbonyl)cyclobutyl)piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-61-c) (176 mg, 50%), which was used directly in the next step. LC-MS: 353.2 [M+H] + .

[0550] Step 3:

[0551] Dissolve (R)-tert-butyl 3-(1-(3-(methoxycarbonyl)cyclobutyl)piperidin-3-yl)azetidine-1-carboxylate (I-61-c) (176 mg, 0.50 mmol) in dichloromethane (5 mL), and add 4N hydrogen chloride in 1,4-dioxane (4 mL) to the system. The reaction solution was stirred at room temperature. LC-MS monitored the reaction until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-61-d) hydrochloride (168 mg, 103%), which was used directly in the next step. LC-MS: 253.2 [M+H] + .

[0552] Step 4:

[0553] (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid methyl ester (I-61-d) hydrochloride (79 mg, 0.24 mmol), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (80 mg, 0.24 mmol), and cesium carbonate (557 mg, 1.71 mmol) were dispersed in tert-butanol (8 mL). The reaction solution was stirred at 95°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain methyl 3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-61-e) (70 mg, 53%). LC-MS: 544.3 [M+H] + .

[0554] Step 5:

[0555] Methyl 3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-61-e) (70 mg, 0.13 mmol) and lithium hydroxide (31 mg, 1.29 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford 3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (I-61) (42 mg, 62%). LC-MS: 530.2 [M+H] + . 1H NMR (400MHz, CD3OD) δ9.08 (s, 1H), 7.51 (dd, J=18.3, 5.2Hz, 2H), 7.44–7.30 (m, 1H ),6.46(q,J=7.2Hz,1H),4.26(d,J=8.0Hz,2H),3.97(s,2H),3.51(s,1H),3.28–3. 10(m,2H),2.90(s,1H),2.53(d,J=36.7Hz,3H),2.33(d,J=10.4Hz,3H),2.22(d,J= 7.2Hz, 1H), 2.06 (d, J = 7.1Hz, 3H), 1.93 (d, J = 10.3Hz, 3H), 1.69 (d, J = 14.6Hz, 2H).

[0556] Example 62

[0557] first step:

[0558] (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid methyl ester (I-61-d) hydrochloride (77 mg, 0.24 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-1-c) (80 mg, 0.22 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), BINAP (27 mg, 0.04 mmol), and Cs2CO3 (351 mg, 1.08 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain methyl 3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-62-a) (110 mg, 94%). LC-MS: 542.3 [M+H] + .

[0559] Step 2:

[0560] Methyl 3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-62-a) (110 mg, 0.20 mmol) and lithium hydroxide (49 mg, 2.03 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford 3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (I-62) (3 mg, 3%). LC-MS: 528.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.77(d,J=9.0Hz,1H),7.56(d,J=2.0Hz,1H),7.34(dd,J=8.5,1.9H z,1H),7.23(d,J=8.4Hz,1H),6.69(d,J=9.0Hz,1H),6.37(q,J=6.9Hz,1H),6.18(s,1H),4 .02(dt,J=19.2,7.7Hz,2H),3.69(dt,J=23.9,12.0Hz,3H),3.21(dd,J=34.4,11.9Hz,2H ),2.91(s,1H),2.62–2.21(m,7H),2.10(d,J=6.9Hz,3H),1.96(s,3H),1.79–1.58(m,2H).

[0561] Example 63

[0562] Dissolve (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-4-e) (90 mg, 0.16 mmol) in dry tetrahydrofuran (8 mL) and cool to 0°C in an ice bath. Slowly add a solution of LiAlH4 in tetrahydrofuran (0.32 mL, 1 mol / L) dropwise to the reaction system, stirring in an ice bath after addition. Monitor the reaction by LC-MS until the reaction is complete. The reaction mixture was quenched with saturated NaHCO3 solution (2 mL) and concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain ((1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane)methanol (10 mg, 11.7%) (I-63). LC-MS: 530.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.92(s,1H),7.51(d,J=2.1Hz,1H),7.44(d,J=8.5Hz,1H),7.33(d d,J=8.5,2.0Hz,1H),6.47(q,J=7.1Hz,1H),4.35–4.19(m,2H),3.99(d,J=4.8Hz,2H),3 .43(s,2H),3.02–2.88(m,2H),2.79(s,1H),2.60(s,1H),2.19–2.09(m,2H),2.05(d,J= 7.1Hz, 3H), 1.94–1.75 (m, 4H), 1.75–1.50 (m, 4H), 1.12 (s, 3H), 0.97 (d, J = 11.2Hz, 1H).

[0563] Example 64

[0564] first step:

[0565] Methylamine hydrochloride (10 mg, 0.148 mmol), triethylamine (20 mg, 0.193 mmol), HATU (39 mg, 0.103 mmol), and DMF (2 mL) were added sequentially to compound (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-4) (50 mg, 0.0918 mmol). The reaction mixture was reacted at 30°C overnight. After the reaction was completed, ethyl acetate (20 mL) was added, and the mixture was washed sequentially with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, V / V) to give (1R,3r)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)-N,1-dimethylcyclobutane-1-carboxamide (I-64) (30 mg, 58.6% yield) as a white powder. LC-MS: 556.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.94 (s, 1H), 7.52 (d, J = 2.0Hz, 1H), 7.46(d,J=8.4Hz,1H),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.49(q,J=7.2Hz,1H),4.30(m,2H),4.02(m,2H),3.21(m,1H),3. 02(m,2H),2.77(s,3H),2.66(m,2H),2.07(d,J=7.2Hz,3H),2.14–1.99(m,5H),1.91–1.84(m,4H),1.69(m,1H),1.40(s,3H).

[0566] Example 69

[0567] first step:

[0568] 2,4-Dichloro-6-methylpyrimidin-5-amine (I-69-a) (1 g, 5.62 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (1.07 g, 6.10 mmol), and potassium carbonate (1.55 g, 11.2 mmol) were dispersed in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 120°C overnight. LC-MS monitoring was performed until the reaction of the starting materials was complete. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-2-chloro-N4-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-69-b) (460 mg, 25%). LC-MS: 330.7 [M+H] + .

[0569] Step 2:

[0570] (R)-2-chloro-N4-(1-(2,4-dichlorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-69-b) (460 mg, 1.39 mmol) and sodium nitrite (105 mg, 1.52 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (200 mg, 42%). LC-MS: 341.7 [M+H] + .

[0571] Step 3:

[0572] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (218 mg, 0.64 mmol), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (200 mg, 0.59 mmol), and cesium carbonate (1.33 g, 4.10 mmol) were dispersed in tert-butanol (10 mL). The reaction solution was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(3-((R,1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-69-d) (90 mg, 27%). LC-MS: 571.7 [M+H] + .

[0573] Step 4:

[0574] Methyl (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-69-d) (90 mg, 0.16 mmol) and lithium hydroxide (38 mg, 1.58 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. . The reaction was monitored by LC-MS until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R, 3r)-3-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-69) (20 mg, 23%). LC-MS: 557.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.51(d,J=2.0Hz,1H),7.46(d,J=8.5Hz,1H),7.35(dd,J=8.5,1. 9Hz,1H),6.42(q,J=7.0Hz,1H),4.24(d,J=8.5Hz,2H),3.95(s,2H),3.51–3.38(m,1H) ,3.28(dd,J=29.5,9.6Hz,2H),2.74(d,J=14.6Hz,5H),2.62–2.44(m,2H),2.26(t,J=1 1.6Hz, 1H), 2.15–1.99 (m, 6H), 1.95 (d, J = 8.9Hz, 3H), 1.80–1.67 (m, 1H), 1.40 (s, 3H).

[0575] Example 70

[0576] first step:

[0577] To a single-necked round-bottom flask (100 mL) were added 2,6-dichloro-4-methyl-3-nitropyridine (I-70-a) (0.3 g, 1.45 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (I-4-b) (276 mg, 1.46 mmol), DMF (15 mL), and DIPEA (0.26 mL, 1.5 mmol) in sequence and stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate (150 mL), washed with water (50 mL × 3), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether) to obtain (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-3-nitropyridine-2-amine (I-70-b) (310 mg, 60% yield) as a yellow oily liquid. LC-MS: 360.0 [M+H] + .

[0578] Step 2:

[0579] To a single-necked round-bottom flask (100 mL) were added (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-3-nitropyridine-2-amine (I-70-b) (300 mg, 0.83 mmol), ethanol (15 mL), reduced iron powder (187 mg, 3.3 mmol), glacial acetic acid (0.5 mL) and water (3 mL) in sequence and stirred at 70°C for 1.5 hours. The reaction mixture was cooled to room temperature, adjusted to alkalinity by adding saturated sodium bicarbonate solution, and filtered through celite. The filtrate was diluted with ethyl acetate (150 mL), washed with water (50 mL × 3), then with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain (R)-6-chloro-N2-(1-(2,4-dichlorophenyl)ethyl)-4-methylpyridine-2,3-diamine (I-70-c) (250 mg, 91.6% yield) as an oily liquid. LC-MS: 330.1 [M+H] + .

[0580] Step 3:

[0581] To a single-necked round-bottom flask (100 mL) were added (R)-6-chloro-N2-(1-(2,4-dichlorophenyl)ethyl)-4-methylpyridine-2,3-diamine (I-70-c) (250 mg, 0.76 mmol) and glacial acetic acid (3 mL) in sequence. Sodium nitrite (63 mg, 0.91 mmol) was added under ice-cooling and stirred for 0.5 hours. After the reaction was complete, most of the glacial acetic acid was removed by vortexing, and the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (50 mL × 3), and then washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to give (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-3-nitropyridine-2-amine (I-70-d) (230 mg, crude) as an oily liquid. LC-MS: 341.0 [M+H] + .

[0582] Step 4:

[0583] To a microwave tube, (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (106 mg, 0.352 mmol), (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-3-nitropyridin-2-amine (I-70-d) (100 mg, 0.293 mmol), potassium tert-butoxide (67 mg, 0.6 mmol), and DMSO (10 mL) were added sequentially. The reaction was carried out at 145°C under microwave conditions for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL × 3), and then washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then purified by preparative plate separation (dichloromethane:methanol = 100:10) to give a white powder (3-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-70) (13 mg, yield 6.2%). LC-MS: 557.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.51(d,J=1.8Hz,1H),7.41(d,J=8.4Hz,1H),7.37–7.30(m,1H),6.49(q,J =7.1Hz,1H),6.31(s,1H),4.18(dd,J=18.9,8.5Hz,2H),3.89(t,J=8.0Hz,2H),3.49(t,J=8.0Hz ,1H),3.27(d,J=12.5Hz,1H),2.76(t,J=8.0Hz,2H),2.58(m,2H),2.32(t,J=11.8Hz,1H),2.04( d,J=7.1Hz,3H),1.96(m,4H),1.74(m,1H),1.41(s,3H),1.38(s,1H),1.31(m,4H),1.16(m,1H).

[0584] Example 71

[0585] first step:

[0586] To a single-necked round-bottom flask (100 mL) were added tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (0.24 g, 1 mmol), N-(2-chloroethyl)methanesulfonamide (I-71-a) (190 mg, 1.2 mmol), potassium carbonate (180 mg, 1.3 mmol), and acetonitrile (20 mL) in sequence. The mixture was refluxed for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:10) to afford tert-butyl (R)-3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-71-b) (280 mg, 78% yield) as a colorless oil. LC-MS: 361.9 [M+H] + .

[0587] Step 2:

[0588] To a single-necked round-bottom flask (100 mL) were added tert-butyl (R)-3-(1-(2-(methylsulfonamido)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-71-b) (280 mg, 0.776 mmol), dichloromethane (5 mL), and a hydrogen chloride-dioxane solution (4 M, 5 mL) in sequence, and stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated to give a crude hydrochloride salt of (R)-N-(2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (I-71-c) (280 mg) as an oily liquid. LC-MS: 261.9 [M+H] + .

[0589] Step 3:

[0590] To a single-necked round-bottom flask (100 mL) were added (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (120 mg, 0.33 mmol), (R)-N-(2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (I-71-c) hydrochloride (100 mg, 0.38 mmol) and sodium hydroxide (51 mg, 1.28 mmol) in sequence, followed by isopropanol (10 mL) and water (2 mL). After the addition was complete, the mixture was stirred at 95°C for 2.5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), and then washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and then mixed and purified by column chromatography (dichloromethane:methanol = 100:8) to obtain N-(2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl))-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (I-71) (90 mg, yield 42.65%) as a white solid. LC-MS: 553.1 [M+H] + . 1 H NMR (400MHz, d-DMSO) δ7.99(s,1H),7.68(d,J=1.5Hz,1H),7.49(q,J=8.5Hz,2H),6.86(s,1H),6.34(q,J=6.9Hz,1H),4.23(s,2H),3.94(s,2H),3.07 (d,J=6.1Hz,2H),2.94(s,3H),2.77(s,2H),2.56(d,J=7.3Hz,1H),2.40(s ,2H),1.98(m,4H),1.81–1.58(m,4H),1.45(m,1H),0.86(d,J=11.0Hz,1H).

[0591] Example 72

[0592] first step:

[0593] 2,4-Dichloropyrimidin-5-amine (I-10-a) (410 mg, 2.50 mmol), (R)-1-(4-bromophenyl)ethane-1-amine (I-72-a) (480 mg, 2.40 mmol), and potassium carbonate (691 mg, 5.0 mmol) were dispersed in DMF (10 mL). The reaction solution was stirred at 120 ° C overnight. LC-MS monitored the reaction until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, and extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (ethyl acetate: petroleum ether = 25%) to obtain (R)-N 4 -(1-(4-bromophenyl)ethyl)-2-chloropyrimidine-4,5-diamine (I-72-b) (496 mg, 63.2%). LC-MS: 329.0 [M+H] + .

[0594] Step 2:

[0595] (R)-N 4 -(1-(4-bromophenyl)ethyl)-2-chloropyrimidine-4,5-diamine (I-72-b) (496 mg, 1.51 mmol) and sodium nitrite (210 mg, 3.04 mmol) were dispersed in a mixture of glacial acetic acid (8 mL) and water (2 mL). The reaction solution was stirred at room temperature. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, and the residue was added with saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (20 mL × 2). The organic phase was concentrated under reduced pressure to obtain the crude product (R)-3-(1-(4-bromophenyl)ethyl)-5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-72-c) (563 mg), which was used directly in the next reaction. LC-MS: 339.7 [M+H] + .

[0596] Step 3:

[0597] The crude product from the previous step, (R)-3-(1-(4-bromophenyl)ethyl)-5-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-72-c) (563 mg), the hydrochloride salt of (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) (468 mg, 1.55 mmol), and sodium carbonate (468 mg, 4.42 mmol) were dispersed in a mixture of tert-butyl alcohol (10 mL) and water (10 mL). The reaction mixture was stirred at 95°C overnight. LC-MS was used to monitor the reaction until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure, ethyl acetate (25 mL) was added, and the mixture was washed sequentially with saturated sodium bicarbonate solution (10 mL × 1), water (10 mL × 1), and saturated sodium chloride solution (10 mL × 1). The organic phase was concentrated to obtain a crude product, which was separated and purified by column chromatography (dichloromethane:methanol = 15:1) to afford methyl (1R,3r)-3-((R)-3-(1-(3-((R)-1-(4-bromophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-72-d) (291 mg, 33.83%). LC-MS: 568.1 [M+H] + .

[0598] Step 4:

[0599] Methyl (1R,3r)-3-((R)-3-(1-(3-((R)-1-(4-bromophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-72-d) (150 mg, 0.26 mmol) was dissolved in a mixture of methanol (3 mL), water (3 mL), and tetrahydrofuran (3 mL). Lithium hydroxide monohydrate (40 mg, 0.95 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS until the reaction of the starting material was complete. Aqueous hydrogen chloride solution (1 mL, 1 N) was added to the reaction system and concentrated. The residue was purified by preparative plate separation (dichloromethane:methanol = 100:10) to afford (1R,3r)-3-((R)-3-(1-(3-((R)-1-(4-bromophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-72) (45 mg, 30.76%). LC-MS: 554.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ9.07(s,1H),7.55–7.46(m,2H),7.34(d,J=8.5Hz,2H),6.07(q,J=7.1 Hz,1H),4.35–4.19(m,2H),3.99(d,J=5.3Hz,2H),3.51(dd,J=15.9,7.9Hz,1H),3.36(d,J=1 2.8Hz,1H),3.26(s,1H),2.76(dd,J=12.1,8.1Hz,2H),2.56(d,J=9.9Hz,2H),2.35(t,J=11. 8Hz,1H),2.12–1.87(m,8H),1.80–1.64(m,1H),1.39(s,3H),1.16(dd,J=21.9,11.8Hz,1H).

[0600] Example 73

[0601] first step:

[0602] To a single-necked round-bottom flask (100 mL) were added tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (360 mg, 1.5 mmol), bromoacetonitrile (235 mg, 1.95 mmol), sodium iodide (20 mg, 0.2 mmol), potassium carbonate (415 mg, 3 mmol), and acetonitrile (20 mL). Refluxed for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 100:3) to obtain tert-butyl (R)-3-(1-(cyanomethyl)piperidin-3-yl)azetidine-1-carboxylate (I-73-a) (410 mg, 98% yield) as an oily liquid. LC-MS: 280.0 [M+H] + .

[0603] Step 2:

[0604] To a single-necked round-bottom flask (50 mL) was added tert-butyl (R)-3-(1-(cyanomethyl)piperidin-3-yl)azetidine-1-carboxylate (I-73-a) (150 mg, 0.538 mmol), dichloromethane (5 mL), and hydrogen chloride-dioxane (4 M, 5 mL) in sequence and stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated to afford the hydrochloride salt of (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)acetonitrile (I-73-b) (160 mg, crude). LC-MS: 180.0 [M+H] + .

[0605] Step 3:

[0606] To a single-necked round-bottom flask (25 mL) were added R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine (I-4-d) (200 mg, 0.54 mmol), (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)acetonitrile (I-73-b) hydrochloride (160 mg, crude) and sodium hydroxide (67 mg, 1.68 mmol) in sequence, followed by isopropanol (10 mL) and water (2 mL). After the addition was complete, the mixture was stirred at 95°C for 2.5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and the sample was separated and purified on a column (dichloromethane:methanol = 100:8) to obtain 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetonitrile (I-73-c) (100 mg, yield 39.68%) as a white solid. LC-MS: 471.0 [M+H] + .

[0607] Step 4:

[0608] To a single-necked round-bottom flask (100 mL) were added 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetonitrile (I-73-c) (20 mg, 0.0425 mmol), methanol (5 mL), water (1 mL) and sodium hydroxide (40 mg, 1 mmol) in sequence and stirred at room temperature for 1.5 hours. After completion of the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid (1 mol / L). The product was concentrated and then purified by preparative plate separation (dichloromethane:methanol = 100:10) to afford 2-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetamide (I-73) (7 mg, 35% yield). LC-MS: 489.1 [M+H] + . 1H NMR(400MHz,d-DMSO)δ8.00(s,1H),7.68(d,J=1.8Hz,1H),7.55–7.43(m,2H),7.18 (d,J=10.9Hz,2H),6.34(q,J=7.0Hz,1H),4.17(d,J=49.6Hz,2H),4.04–3.80(m,2H) ,2.93(d,J=9.9Hz,2H),2.69(d,J=50.5Hz,3H),2.12(dd,J=35.4,12.1Hz,1H),1.9 8(d,J=7.0Hz,3H),1.87(s,2H),1.74–1.61(m,2H),1.53(m,1H),0.99–0.81(m,1H).

[0609] Example 74

[0610] first step:

[0611] 2,4-Dichloropyrimidin-5-amine (I-10-a) (500 mg, 3.05 mmol), (R)-1-(pyridin-2-yl)ethane-1-amine (I-74-a) (372 mg, 3.05 mmol), and potassium carbonate (843 mg, 6.10 mmol) were dispersed in DMF (10 mL). The reaction mixture was stirred at 120°C overnight. LC-MS monitored the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-2-chloro-N4-(1-(pyridin-2-yl)ethyl)pyrimidine-4,5-diamine (I-74-b) (340 mg, 45%). LC-MS: 249.9 [M+H] + .

[0612] Step 2:

[0613] (R)-2-chloro-N4-(1-(pyridin-2-yl)ethyl)pyrimidine-4,5-diamine (I-74-b) (340 mg, 1.39 mmol) and sodium nitrite (105 mg, 1.52 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-5-chloro-3-(1-(pyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-74-c) (290 mg, 82%). LC-MS: 260.8 [M+H] + .

[0614] Step 3:

[0615] The hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (417 mg, 1.23 mmol), (R)-5-chloro-3-(1-(pyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-74-c) (290 mg, 1.12 mmol), and cesium carbonate (2.54 g, 7.82 mmol) were dispersed in tert-butanol (10 mL). The reaction solution was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-1-methyl-3-((R)-3-(1-(3-(R)-1-(pyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid methyl ester (I-74-d) (110 mg, 20%). LC-MS: 490.9 [M+H] + .

[0616] Step 4:

[0617] Methyl (1R,3r)-1-methyl-3-((R)-3-(1-(3-(R)-1-(pyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-74-d) (110 mg, 0.22 mmol) and lithium hydroxide (54 mg, 2.24 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction solution was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford (1R,3r)-1-methyl-3-((R)-3-(1-(3-(R)-1-(pyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid (I-74) (90 mg, 84%). LC-MS: 476.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.09 (s, 1H), 8.50 (d, J = 4.5Hz, 1H), 7.81 (td, J = 7.8, 1.5Hz, 1H), 7.34 (dd, J =10.6,5.8Hz,2H),6.16(q,J=7.2Hz,1H),4.24(d,J=6.7Hz,2H),3.97(s,2H),3.52–3.38(m,1H), 3.34–3.17(m,2H),2.73(t,J=9.3Hz,2H),2.63–2.41(m,2H),2.24(t,J=11.7Hz,1H),2.14(d,J=7 .2Hz, 3H), 2.11–1.99 (m, 3H), 1.92 (d, J = 6.5Hz, 3H), 1.75 (dd, J = 26.7, 13.1Hz, 1H), 1.38 (s, 3H).

[0618] Example 75

[0619] first step:

[0620] Methyl (1R,3r)-3-((R)-3-(1-(3-((R)-1-(4-bromophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-72-d) (165 mg, 0.29 mmol), trimethylethynylsilane (560 mg, 5.7 mmol), cuprous iodide (41 mg, 0.22 mmol), and Pd(PPh3)2Cl2 (76 mg, 0.11 mmol) were dispersed in a mixture of triethylamine (3 mL) and DMF (4 mL). The system was replaced with argon three times, heated to 75°C, and stirred overnight. The reaction was monitored by LC-MS until the reaction of the starting material was complete. Ethyl acetate (30 mL) and saturated aqueous NaCl solution (5 mL) were added sequentially, and the mixture was filtered through celite. The filtrate was separated, and the organic phase was separated, washed with saturated aqueous NaCl solution (5 mL × 3), and concentrated. The residue was purified by HPLC to obtain (1R,3r)-1-methyl-3-((R)-3-(1-(3-((R)-1-(4-((trimethylsilyl)ethynyl)phenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylic acid methyl ester (I-75-a) (102 mg, 59.99%).

[0621] Step 2:

[0622] Methyl (1R,3r)-1-methyl-3-((R)-3-(1-(3-((R)-1-(4-((trimethylsilyl)ethynyl)phenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclobutane-1-carboxylate (I-75-a) (84 mg, 0.14 mmol) was dispersed in a mixture of methanol (1.5 mL), water (1.5 mL), and tetrahydrofuran (1.5 mL), and lithium hydroxide monohydrate (35 mg, 0.83 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction system was added with aqueous hydrogen chloride (0.85 mL, 1 mol / L) and concentrated. The residue was purified by HPLC to give (1R,3r)-3-((R)-3-(1-(3-((R)-1-(4-ethynylphenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-75) (23 mg, 32.11%). LC-MS: 500.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ9.08(d,J=3.8Hz,1H),7.45(d,J=8.3Hz,2H),7.40(d,J=8.3Hz,2H),6. 11(q,J=7.1Hz,1H),4.28(d,J=7.7Hz,2H),4.00(dd,J=8.7,5.6Hz,2H),3.64–3.50(m,2H),3 .40(d,J=11.4Hz,1H),3.31(s,1H),2.78(t,J=9.6Hz,2H),2.60(d,J=12.6Hz,2H),2.39(t,J =11.6Hz,1H),2.20–1.90(m,8H),1.76(d,J=11.9Hz,1H),1.41(s,3H),1.17(d,J=9.0Hz,1H).

[0623] Example 76 is the intermediate 2-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)azetidin-3-yl)piperidin-1-yl)acetonitrile (I-73-c) in the synthesis of Example 73. LC-MS: 471.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.93(s,1H),7.51(d,J=2.1Hz,1H),7.46(d,J=8.5Hz,1H),7.34(dd,J= 8.5,2.0Hz,1H),6.48(q,J=7.1Hz,1H),4.30(q,J=8.6Hz,2H),4.06–3.92(m,2H),3.67(s,2H) ,2.83(t,J=12.9Hz,2H),2.68(dd,J=15.2,8.8Hz,1H),2.38–2.24(m,1H),2.06(d,J=7.1Hz,3 H),2.04–1.97(m,1H),1.96–1.87(m,1H),1.85–1.76(m,2H),1.64(m,1H),1.06–0.95(m,1H).

[0624] Example 77

[0625] first step:

[0626] To a single-necked round-bottom flask (25 mL) were added (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (60 mg, 0.176 mmol), (R)-N-(2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (I-71-c) (80 mg, crude) and sodium hydroxide (35 mg, 0.88 mmol), followed by isopropanol (10 mL) and water (2 mL). After the addition, the mixture was stirred at 95 ° C for 2.5 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated aqueous sodium bicarbonate (50 mL × 3), saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 100:8) to obtain N-(2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethyl)methanesulfonamide (I-77) (20 mg, 20% yield) as a white solid. LC-MS: 567.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.58–7.41(m,2H),7.34(d,J=8.1Hz,1H),6.42(q,J=6.7Hz,1H ),4.22(s,2H),3.92(s,2H),3.25(t,J=6.3Hz,2H),2.99(s,3H),2.94(d,J=7.5Hz,2H ),2.75(s,3H),2.58(t,J=6.4Hz,2H),2.52(s,1H),2.10(d,J=10.5Hz,1H),2.04(d, J=7.0Hz,3H),1.88–1.70(m,4H),1.63-1.60(m,1H),1.30(s,1H),1.04–0.87(m,1H).

[0627] Example 78

[0628] first step:

[0629] To a single-necked round-bottom flask (100 mL) was added tert-butyl (R)-3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (0.5 g, 2.08 mmol) and dissolved in dichloromethane (20 mL). DIEA (0.54 mL, 3 mmol) and ethyl bromoacetate (0.45 g, 2.71 mmol) were then added sequentially, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated, diluted with ethyl acetate (100 mL), washed with water (50 mL x 2), washed with saturated brine (50 mL x 1), and dried over anhydrous sodium sulfate. The organic phase was filtered, the filtrate was concentrated and mixed, and then purified by column chromatography (dichloromethane:methanol = 100:4) to obtain (R)-tert-butyl 3-(1-(2-ethoxy-2-oxoethyl)piperidin-3-yl)azetidine-1-carboxylate (I-78-a) (0.61 g, 90% yield) as a colorless oily liquid. LC-MS: 327.0 [M+H] + .

[0630] Step 2:

[0631] To a two-necked round-bottom flask (50 mL) was added tert-butyl (R)-3-(1-(2-ethoxy-2-oxoethyl)piperidin-3-yl)azetidine-1-carboxylate (I-78-a) (0.41 g, 1.26 mmol). Anhydrous tetrahydrofuran (10 mL) was added under argon and the mixture was cooled to -78°C. LiHMDS (1.65 mL, 1 M) was slowly added and stirred at -78°C for 0.5 hours. A solution of 1,3,2-dioxazolothiophene-2,2-dioxide (I-78-b) (0.22 g, 1.8 mmol) in anhydrous tetrahydrofuran (3 mL) was added. After the addition, stirring was continued at -78°C for 1.5 hours. LiHMDS (1.65 mL, 1 M) was then added and the mixture was slowly warmed to room temperature overnight. After completion of the reaction, the reaction mixture was quenched with ethanol in an ice bath and diluted with ethyl acetate (100 mL). The organic phase was washed sequentially with water (50 mL x 2) and saturated brine (50 mL x 1), then dried over anhydrous sodium sulfate. The organic phase was filtered, the filtrate was concentrated, and the sample was purified by column chromatography (petroleum ether:ethyl acetate = 100:5) to obtain (R)-tert-butyl 3-(1-(1-(ethoxycarbonyl)cyclopropyl)piperidin-3-yl)azetidine-1-carboxylate (I-78-c) (106 mg, 24% yield) as a light yellow oil. LC-MS: 352.9 [M+H] + .

[0632] Step 3:

[0633] To a single-necked round-bottom flask (50 mL) was added tert-butyl (R)-3-(1-(1-(ethoxycarbonyl)cyclopropyl)piperidin-3-yl)azetidine-1-carboxylate (I-78-c) (106 mg, 0.3 mmol), dichloromethane (3 mL) and trifluoroacetic acid (2 mL) in sequence and stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated to give the trifluoroacetic acid salt of (R)-1-(3-(azetidin-3-yl)piperidin-1-yl)cyclopropane-1-carboxylate (I-78-d) (147 mg, crude product) as a brown oily liquid. LC-MS: 252.9 [M+H] + .

[0634] Step 4:

[0635] To a single-necked round-bottom flask (50 mL) were added (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (113 mg, 0.33 mmol), (R)-1-(3-(azetidin-3-yl)piperidin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (I-78-d) trifluoroacetate (147 mg, crude), and sodium carbonate (48 mg, 0.35 mmol) in sequence. Isopropyl alcohol (10 mL) and water (2 mL) were then added. The mixture was stirred at 95°C for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate aqueous solution (50 mL × 3), washed with saturated brine (50 mL × 3), and dried over anhydrous sodium sulfate. The organic phase was filtered, and the filtrate was concentrated and mixed, and purified by column chromatography (dichloromethane:methanol = 100:2) to obtain ethyl 1-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclopropane-1-carboxylate (I-78-e) (50 mg, 30% yield) as a light brown oily liquid. LC-MS: 558.7 [M+H] + .

[0636] Step 5:

[0637] To a single-necked round-bottom flask (50 mL) were added 1-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)cyclopropane-1-carboxylic acid ethyl ester (I-78-e) (50 mg, 0.09 mmol), methanol (5 mL), water (1 mL) and lithium hydroxide (15 mg, 0.36 mmol) in sequence and stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid (1N), and the product was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to obtain 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetic acid (I-78) (20 mg, 41.7% yield) as a white solid. LC-MS: 530.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.51(d,J=2.1Hz,1H),7.47(d,J=8.5Hz,1H),7.35(dd,J=8.5,2 .1Hz,1H),6.42(q,J=7.1Hz,1H),4.23(s,2H),3.92(s,2H),3.17(s,2H),3.07(s,1H), 2.75(s,3H),2.58(s,1H),2.04(d,J=7.1Hz,3H),1.90-1.82(m,3H),1.64(s,1H),1.3 8(d,J=21.1Hz,2H),1.27(d,J=24.1Hz,1H),1.14(d,J=8.0Hz,2H),1.11–1.02(m,1H).

[0638] Example 79

[0639] first step:

[0640] To a single-necked round-bottom flask (100 mL) were added 4,6-dichloro-2-methyl-3-nitropyridine (I-79-a) (0.5 g, 2.415 mmol), (R)-1-(2,4-dichlorophenyl)ethan-1-amine (I-4-b) (453 mg, 2.38 mmol), DMF (15 mL), and DIPEA (0.53 mL, 3 mmol) in sequence and stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate (150 mL), and the organic phase was washed with water (50 mL × 3) and saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 100:5) to obtain (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-3-nitropyridine-4-amine (I-79-b) (578 mg, 86.7% yield). LC-MS: 360.7 [M+H] + .

[0641] Step 2:

[0642] To a single-necked round-bottom flask (100 mL) were added (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-3-nitropyridine-4-amine (I-79-b) (300 mg, 0.83 mmol), ethanol (15 mL), reduced iron powder (187 mg, 3.3 mmol), glacial acetic acid (0.5 mL) and water (3 mL) in sequence and stirred at 70°C for 1.5 hours. The reaction solution was cooled to room temperature, adjusted to alkalinity by adding saturated sodium bicarbonate solution, and filtered through celite. The filtrate was diluted with ethyl acetate (150 mL), washed with water (50 mL × 3), saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain an oily liquid (R)-6-chloro-N4-(1-(2,4-dichlorophenyl)ethyl)-2-methylpyridine-3,4-diamine (I-79-c) (265 mg, 96.36% yield). LC-MS: 330.1 [M+H] + .

[0643] Step 3:

[0644] To a single-necked round-bottom flask (100 mL) were added (R)-6-chloro-N2-(1-(2,4-dichlorophenyl)ethyl)-4-methylpyridine-2,3-diamine (I-79-c) (250 mg, 0.76 mmol) and glacial acetic acid (3 mL). Sodium nitrate (63 mg, 0.91 mmol) was added under ice-cooling and stirred for 0.5 hours. After removing most of the glacial acetic acid, the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL × 3), then with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated to afford (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine (I-79-d) (245 mg, crude) as an oily liquid. LC-MS: 341.0 [M+H] + .

[0645] Step 4:

[0646] A microwave tube was added with (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (150 mg, 0.52 mmol), (R)-6-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine (I-79-d) (155 mg, 0.455 mmol), potassium tert-butoxide (67 mg, 0.6 mmol) and DMSO (10 mL). The reaction was carried out at 150°C under microwave for 3 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL × 3) and saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, concentrated, and purified by preparative plate separation (dichloromethane:methanol = 100:10) to give 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-79) (23 mg, 9.1% yield) as a white powder. LC-MS: 557.1 [M+H] +. 1H NMR(400MHz,CD3OD)δ7.55(d,J=1.9Hz,1H),7.40–7.34(m,1H),7.31(dd,J=8.5,3.1Hz,1H),6.32(q,J=6.9 Hz,1H),5.86(s,1H),4.16–4.02(m,2H),3.85–3.73(m,2H),3.63(dd,J=17.0,7.7Hz,1H),3.41(d,J=12.4Hz ,1H),3.27(s,1H),2.84–2.75(m,5H),2.72–2.52(m,3H),2.44(t,J=11.9Hz,1H),2.15(dd,J=21.8,12.3Hz, 2H), 2.08(d,J=7.0Hz,3H),2.04–1.92(m,3H),1.84–1.71(m,1H),1.44(q,J=8.6Hz,3H),1.21-1.16(m,1H).

[0647] Example 80

[0648] first step:

[0649] 2,4-Dichloropyrimidin-5-amine (I-10-a) (500 mg, 3.05 mmol), (R)-1-(3,5-dichloropyridin-2-yl)ethane-1-amine (I-80-a) (583 mg, 3.05 mmol), and potassium carbonate (843 mg, 6.10 mmol) were dispersed in DMF (10 mL). The reaction mixture was stirred at 120°C overnight. LC-MS monitored the reaction until the starting materials reacted completely. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-2-chloro-N4-(1-(3,5-dichloropyridin-2-yl)ethyl)pyrimidine-4,5-diamine (I-80-b) (670 mg, 69%). LC-MS: 317.7 [M+H] + .

[0650] Step 2:

[0651] (R)-2-chloro-N4-(1-(3,5-dichloropyridin-2-yl)ethyl)pyrimidine-4,5-diamine (I-80-b) (670 mg, 2.10 mmol) and sodium nitrite (160 mg, 2.31 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-5-chloro-3-(1-(3,5-dichloropyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-80-c) (485 mg, 70%). LC-MS: 328.7 [M+H] + .

[0652] Step 3:

[0653] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (318 mg, 0.94 mmol), (R)-5-chloro-3-(1-(3,5-dichloropyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-80-c) (280 mg, 0.85 mmol), and sodium carbonate (723 mg, 6.82 mmol) were dispersed in isopropanol (10 mL). The reaction solution was stirred at 90°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(3-((R,1-(3,5-dichloropyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-80-d) (54 mg, 11%). LC-MS: 558.7 [M+H] + .

[0654] Step 4:

[0655] Methyl (1R,3r)-3-((R)-3-(1-(3-((R,1-(3,5-dichloropyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-80-d) (54 mg, 0.10 mmol) and lithium hydroxide (23 mg, 0.97 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-MS monitoring The reaction was continued until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(3,5-dichloropyridin-2-yl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-80) (30 mg, 57%). LC-MS: 544.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.06 (s, 1H), 8.46 (d, J = 2.0Hz, 1H), 8.04 (d, J = 2.0Hz, 1H),6.48(q,J=6.9Hz,1H),4.21(s,2H),3.91(s,2H),3.37(s,2H),3.30–3. 08(m,3H),2.78–2.64(m,2H),2.53(d,J=7.0Hz,1H),2.30(t,J=11.7Hz,1H) ,2.10(d,J=7.0Hz,3H),2.02–1.84(m,5H),1.78–1.64(m,1H),1.38(s,3H).

[0656] Example 81

[0657] first step:

[0658] 1-Bromo-5-fluoro-2-methyl-4-nitrobenzene (I-81-a) (500 mg, 2.14 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (406 mg, 2.14 mmol), and potassium carbonate (591 mg, 4.27 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred at 100°C overnight. LC-MS monitoring was performed until the reaction of the starting materials was complete. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-2-nitroaniline (I-81-b) (810 mg, 94%).

[0659] Step 2:

[0660] (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-2-nitroaniline (I-81-b) (710 mg, 1.76 mmol), reduced iron powder (588 mg, 10.54 mmol), and ammonium chloride (282 mg, 5.27 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 100°C for 4 hours. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, added with water (10 mL), and 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 column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-methylbenzene-1,2-diamine (I-81-c) (360 mg, 55%). LC-MS: 372.6 [M+H] + .

[0661] Step 3:

[0662] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-4-methylbenzene-1,2-diamine (I-81-c) (360 mg, 0.96 mmol) and sodium nitrite (73 mg, 1.06 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, added with saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-5-methyl-1H-benzo[d][1,2,3]triazole (I-81-d) (205 mg, 55%). LC-MS: 383.6 [M+H] + .

[0663] Step 4:

[0664] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (199 mg, 0.58 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-5-methyl-1H-benzo[d][1,2,3]triazole (I-81-d) (205 mg, 0.53 mmol), Pd(dba) (49 mg, 0.05 mmol), BINAP (66 mg, 0.11 mmol), and CsCO (867 mg, 2.66 mmol) were dispersed in dioxane (5 mL) and stirred at 100°C overnight. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-5-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-81-e) (270 mg, 89%). LC-MS: 569.8 [M+H] + .

[0665] Step 5:

[0666] Methyl (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-5-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-81-e) (120 mg, 0.21 mmol) and lithium hydroxide (14 mg, 2.10 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to give (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-5-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-81) (70 mg, 26%). LC-MS: 555.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.65–7.51(m,2H),7.32(dt,J=21.9,5.3Hz,2H),6.40(q,J=6.9Hz, 1H),6.29(s,1H),4.04(dt,J=14.8,7.5Hz,2H),3.68(dt,J=20.7,6.7Hz,2H),3.26–3.06( m,3H),2.78–2.62(m,2H),2.41(d,J=7.7Hz,1H),2.34(s,3H),2.23(t,J=12.7Hz,1H),2. 09(d,J=7.0Hz,3H),2.04–1.95(m,2H),1.93(s,3H),1.86(d,J=12.1Hz,3H),1.37(s,3H).

[0667] Example 82

[0668] first step:

[0669] 2,4-Dichloro-6-methylpyrimidin-5-amine (I-69-a) (500 mg, 2.81 mmol), (R)-1-(2,4-difluorophenyl)ethane-1-amine (I-82-a) (441 mg, 2.81 mmol), and potassium carbonate (776 mg, 5.62 mmol) were dispersed in DMF (10 mL). The reaction mixture was stirred at 120°C overnight. LC-MS monitored the reaction until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to obtain (R)-2-chloro-N4-(1-(2,4-difluorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-82-b) (440 mg, 52%). LC-MS: 298.8 [M+H] + .

[0670] Step 2:

[0671] (R)-2-chloro-N4-(1-(2,4-difluorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-82-b) (440 mg, 1.47 mmol) and sodium nitrite (112 mg, 1.62 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 then purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-5-chloro-3-(1-(2,4-difluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-82-c) (216 mg, 47%). LC-MS: 309.8 [M+H] + .

[0672] Step 3:

[0673] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (261 mg, 0.77 mmol), (R)-5-chloro-3-(1-(2,4-difluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-82-c) (216 mg, 0.70 mmol), and sodium carbonate (593 mg, 5.60 mmol) were dispersed in isopropanol (10 mL). The reaction solution was stirred at 90°C overnight. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(3-((R,1-(2,4-difluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-82-d) (210 mg, 55%). LC-MS: 539.8 [M+H] + .

[0674] Step 4:

[0675] Methyl (1R,3r)-3-((R)-3-(1-(3-((R,1-(2,4-difluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-82-d) (210 mg, 0.39 mmol) and lithium hydroxide (93 mg, 3.89 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-MS monitoring The reaction was continued until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(2,4-difluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-82) (90 mg, 44%). LC-MS: 525.8 [M+H] + . 1H NMR(400MHz,CD3OD)δ7.54(dt,J=14.8,7.5Hz,1H),7.03–6.93(m,2H),6.31(q,J=7.1Hz,1H) ,4.23(t,J=8.8Hz,2H),3.95(dd,J=9.0,5.8Hz,2H),3.37(s,1H),3.29–3.09(m,3H),2.74(s, 3H),2.73–2.63(m,2H),2.49(d,J=7.5Hz,1H),2.27(t,J=11.2Hz,1H),2.05(d,J=7.2Hz,3H) ,2.03–1.92(m,4H),1.85(dd,J=19.2,9.7Hz,2H),1.71(td,J=13.1,4.0Hz,1H),1.37(s,3H).

[0676] Example 83

[0677] first step:

[0678] Under a nitrogen atmosphere, 3-iodopyridine (15.9 g, 77.708 mmol), tris(o-methylphenyl)phosphine (2.2 g, 7.064 mmol), N,N-dimethylformamide (200 mL), zinc powder (23.1 g, 353.220 mmol), iodine (3.6 g, 14.129 mmol), tris(dibenzylideneacetone)dipalladium (3.2 g, 3.532 mmol) and N-Boc-3-iodoazetidine (I-83-a) (20.0 g, 70.644 mmol) were added to a dry three-necked flask (500 mL) in sequence. Under a nitrogen atmosphere, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed by liquid chromatography-mass spectrometry, the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (3 × 500 mL). The organic phases were combined, saturated brine (3 × 500 mL) was added to wash the organic phase, and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by reverse phase liquid chromatography under the following conditions: column type: C18 column, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, gradient: 40%-60% over 20 minutes, wavelength 220 nm, and concentrated under reduced pressure to obtain the compound tert-butyl 3-(pyridin-3-yl)azetidine-1-carboxylate (I-83-b) (4.6 g, yield 27%) as a dark yellow oil. LCMS: (ESI, m / z): [M+H] + =235.25.

[0679] Step 2:

[0680] To a dry reaction kettle (500 mL) were added tert-butyl 3-(pyridin-3-yl)azetidine-1-carboxylate (I-83-b) (4.6 g, 19.632 mmol), ethanol (138 mL), platinum dioxide (460 mg, 1.963 mmol) and concentrated sulfuric acid (1.955 g, 19.632 mmol, 98%). The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (50 atm). After the reaction was complete as monitored by liquid chromatography-mass spectrometry, the reaction mixture was filtered, the filter cake was washed with ethanol (3×15 mL), and the filtrate was adjusted to pH 8 by adding saturated sodium bicarbonate solution at 0°C. The filtrate was concentrated under reduced pressure, and the resulting residue was diluted with ethanol (50 mL), filtered, and the filter cake was washed with ethanol (3×10 mL). The filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase liquid chromatography under the following conditions: column model: C18 column, mobile phase A: water, mobile phase B: acetonitrile, gradient: 40%-60% over 20 minutes, wavelength 220 nm, and concentrated under reduced pressure to obtain tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-83-c) (1.68 g, yield 35%) as a light yellow oil. LCMS: (ESI, m / z): [M+H] + =241.20.

[0681] Step 3:

[0682] The mixture tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-83-c) (1.6 g, 6.657 mmol) was separated by Prep-SFC under the following conditions: column model: CHIRAL ART Cellulose-SC, 5*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (20 mM NH3); flow rate: 100 mL / min; gradient: isocratic 35% B; column temperature (℃): 25; pressure (bar): 100; wavelength: 204 / 215 nm; (R)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) retention time: 4.75 min; (S)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-83-d) retention time: 6.52 min; Injection Volume: 0.7 mL; Number of Runs: 16, colorless oily (S)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-83-d) (543.5 mg, 30% yield, retention time: 6.52 min) was isolated. LCMS: (ESI, m / z): [M+H] + =241.05. 1H NMR (400MHz, CDCl3) δ3.94(m,2H),3.64(m,2H),3.07–2.92(m,2H),2.53(m,1H) ,2.29–2.14(m,2H),1.78–1.73(m,1H),1.62(m,2H),1.43(m,10H),0.96(m,1H).

[0683] Step 4:

[0684] Disperse (S)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-83-d) (173 mg, 0.72 mmol), 1-methyl-3-oxocyclobutanecarboxylic acid (I-1-e) (120 mg, 0.94 mmol), and diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (244 mg, 0.97 mmol) in toluene (5 mL). Stir the reaction mixture at 120°C for 4 hours. Monitor the reaction by LC-MS until the starting material is completely reacted. The reaction mixture was concentrated under reduced pressure, ethyl acetate (10 mL) was added, and the mixture was extracted with water (10 mL). The aqueous layer was concentrated under reduced pressure to give the crude product (1S,3r)-3-((S)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-83-e) (150 mg, 59%), which was used directly in the next step. LC-MS: 352.9 [M+H] + .

[0685] Step 5:

[0686] (1S,3r)-3-((S)-3-(1-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-83-e) (150 mg, 0.43 mmol) was dissolved in methanol (8 mL), and thionyl chloride (0.04 mL, 0.51 mmol) was added to the system. The reaction solution was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction solution was concentrated under reduced pressure, saturated sodium carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product tert-butyl 3-((S)-1-((1r,3S)-3-(methoxycarbonyl)-3-methylcyclobutyl)piperidin-3-yl)azetidine-1-carboxylate (I-83-f) (70 mg, 45%), which was used directly in the next step. LC-MS: 366.9 [M+H] + .

[0687] Step 6:

[0688] Tert-butyl 3-((S)-1-((1r,3S)-3-(methoxycarbonyl)-3-methylcyclobutyl)piperidin-3-yl)azetidine-1-carboxylate (I-83-f) (70 mg, 0.19 mmol) was dispersed in dichloromethane (5 mL), and a 4N solution of hydrogen chloride in 1,4-dioxane (2 mL) was added to the system. The reaction solution was stirred at room temperature for 2 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (1S,3r)-3-((S)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-83-g) hydrochloride (57 mg, 98%), which was used directly in the next step. LC-MS: 267.0 [M+H] + .

[0689] Step 7:

[0690] The hydrochloride salt of (1S,3r)-3-((S)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-83-g) (57 mg, 0.17 mmol), (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-10-c) (50 mg, 0.15 mmol), and sodium carbonate (129 mg, 1.22 mmol) were dispersed in isopropanol (10 mL). The reaction solution was stirred at 90°C for 16 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1S,3R)-3-((S)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-83-h) (32 mg, 38%). LC-MS: 558.7 [M+H] + .

[0691] Step 8:

[0692] Methyl (1S,3R)-3-((S)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-83-h) (32 mg, 0.06 mmol) and lithium hydroxide (14 mg, 0.57 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford (1S,3R)-3-((S)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-83) (18 mg, 58%). LC-MS: 544.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ9.08 (s, 1H), 7.52 (d, J = 2.1Hz, 1H), 7.47 (d, J = 8.5Hz, 1H), 7.36 (dd, J = 8. 5,2.1Hz,1H),6.46(q,J=7.1Hz,1H),4.26(t,J=8.3Hz,2H),3.98(s,2H),3.50–3.39(m,1H),3. 25(d,J=12.0Hz,1H),2.82–2.68(m,2H),2.64–2.44(m,2H),2.25(dd,J=22.6,10.7Hz,1H),2.0 5(d,J=7.1Hz,3H),2.04–1.86(m,6H),1.73(d,J=13.8Hz,1H),1.40(s,3H),1.22–1.08(m,1H).

[0693] Example 84

[0694] first step:

[0695] 2,4-Dichloro-6-methylpyrimidin-5-amine (I-69-a) (400 mg, 2.25 mmol), (R)-1-(4-chloro-2-fluorophenyl)ethane-1-amine (I-84-a) (472 mg, 2.81 mmol), and potassium carbonate (932 mg, 6.74 mmol) were dispersed in DMF (10 mL). The reaction mixture was stirred at 120°C for 16 hours. LC-MS monitoring was performed until the starting material reacted completely. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-2-chloro-N4-(1-(4-chloro-2-fluorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-84-b) (240 mg, 34%). LC-MS: 314.8 [M+H] + .

[0696] Step 2:

[0697] (R)-2-chloro-N4-(1-(4-chloro-2-fluorophenyl)ethyl)-6-methylpyrimidine-4,5-diamine (I-84-b) (240 mg, 0.76 mmol) and sodium nitrite (58 mg, 0.84 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-5-chloro-3-(1-(4-chloro-2-fluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-84-c) (200 mg, 81%). LC-MS: 325.7 [M+H] + .

[0698] Step 3:

[0699] The hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (230 mg, 0.68 mmol), (R)-5-chloro-3-(1-(4-chloro-2-fluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-84-c) (200 mg, 0.62 mmol), and sodium carbonate (522 mg, 4.92 mmol) were dispersed in isopropanol (10 mL). The reaction solution was stirred at 90°C for 16 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(3-((R,1-(4-chloro-2-fluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-84-d) (140 mg, 41%). LC-MS: 555.8 [M+H] + .

[0700] Step 4:

[0701] Methyl (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(4-chloro-2-fluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-84-d) (140 mg, 0.25 mmol) and lithium hydroxide (60 mg, 2.52 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-MS monitoring The reaction was continued until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(4-chloro-2-fluorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-84) (100 mg, 73%). LC-MS: 541.8 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.45 (dd, J=10.4, 6.4Hz, 1H), 7.23 (dq, J=6.7, 2.2Hz, 2H), 6.31 (q, J=7. 1Hz,1H),4.34–4.15(m,2H),3.95(s,2H),3.39(dd,J=14.4,6.3Hz,1H),3.32–3.19(m,2H),2.8 1–2.67(m,5H),2.51(dt,J=23.0,12.4Hz,2H),2.21(t,J=11.7Hz,1H),2.05(d,J=7.2Hz,3H), 2.04–1.86(m,5H),1.72(dd,J=26.6,13.1Hz,1H),1.39(s,3H),1.12(dd,J=23.0,11.1Hz,1H).

[0702] Example 89

[0703] first step:

[0704] 1-Bromo-2,5-difluoro-4-nitrobenzene (I-89-a) (500 mg, 2.10 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (399 mg, 2.10 mmol), and potassium carbonate (581 mg, 4.20 mmol) were dispersed in acetonitrile (10 mL). The reaction mixture was stirred at 100°C for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-fluoro-2-nitroaniline (I-89-b) (620 mg, 72%).

[0705] Step 2:

[0706] (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-fluoro-2-nitroaniline (I-89-b) (620 mg, 1.52 mmol), reduced iron powder (509 mg, 9.12 mmol), and ammonium chloride (244 mg, 4.56 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 100°C for 4 hours. LC-MS monitoring was performed until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure, added with water (10 mL), and 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 column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-4-fluorobenzene-1,2-diamine (I-89-c) (260 mg, 45%). LC-MS: 376.6 [M+H] + .

[0707] Step 3:

[0708] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-4-fluorobenzene-1,2-diamine (I-89-c) (260 mg, 0.69 mmol) and sodium nitrite (52 mg, 0.76 mmol) were dispersed in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-5-fluoro-1H-benzo[d][1,2,3]triazole (I-89-d) (150 mg, 56%). LC-MS: 387.6 [M+H] + .

[0709] Step 4:

[0710] The hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (144 mg, 0.42 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-5-fluoro-1H-benzo[d][1,2,3]triazole (I-89-d) (150 mg, 0.39 mmol), Pd2(dba)3 (35 mg, 0.04 mmol), BINAP (48 mg, 0.08 mmol), and Cs2CO3 (628 mg, 1.93 mmol) were dispersed in ultra-dry dioxane (5 mL). The reaction mixture was stirred at 100°C under argon for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-89-e) (54 mg, 24%). LC-MS: 573.7 [M+H] + .

[0711] Step 5:

[0712] Methyl (1R, 3r)-3-((R)-3-(1-(1-((R, 1-(2,4-dichlorophenyl)ethyl)-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-89-e) (54 mg, 0.09 mmol) and lithium hydroxide (23 mg, 0.94 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-MS monitoring The reaction was continued until the reaction of the raw materials was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R, 3r)-3-((R)-3-(1-(1-((R, 1-(2,4-dichlorophenyl)ethyl)-5-fluoro-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-89) (10 mg, 19%). LC-MS: 559.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.55(dd,J=10.9,6.9Hz,2H),7.35(dd,J=8.5,2.0Hz,1H),7.27(d, J=8.5Hz,1H),6.40(q,J=6.9Hz,1H),6.31(d,J=7.4Hz,1H),4.20–4.04(m,2H),3.80(d,J =7.2Hz,2H),3.53–3.42(m,1H),3.24(d,J=12.5Hz,2H),2.82–2.69(m,2H),2.53(d,J=12 .1Hz,2H),2.41–2.18(m,2H),2.10(d,J=6.9Hz,3H),1.98(t,J=10.0Hz,6H),1.40(s,3H).

[0713] Example 90

[0714] first step:

[0715] Compound (R)-1-(2,4-dichlorophenyl)ethanamine (I-4-b) (198 mg, 1.042 mmol) and triethylamine (211 mg, 2.085 mmol) were added to a solution of 2-chloro-4-fluoro-5-nitropyridine (I-90-a) (201 mg, 1.042 mmol) in acetonitrile (5 mL). The reaction mixture was allowed to react overnight at room temperature. After completion of the reaction, the acetonitrile was evaporated under reduced pressure, and ethyl acetate (20 mL) was added to the residue, which was then washed with water (5 mL) and then saturated brine (5 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 98 / 2 to 95 / 5, v / v) to obtain compound (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-nitropyridine-4-amine (I-90-b) as a yellow powder (323 mg, 89.5% yield). LC-MS: 346.0, 348.0 [M+H] + .

[0716] Step 2:

[0717] The hydrochloride salt (132 mg, 0.436 mmol) of the compound (1R, 3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g), DMF (2 mL) and sodium tert-butoxide (56 mg, 0.583 mmol) were added sequentially to the compound (R)-2-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-5-nitropyridin-4-amine (I-90-b) (100 mg, 0.289 mmol). The reaction mixture was reacted under microwave at 170°C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (5×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude methyl (1R,3r)-3-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-nitropyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-90-c), which was used directly in the next step. LC-MS: 576.1 [M+H] + .

[0718] Step 3:

[0719] The crude product of (1R,3r)-3-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-nitropyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-90-c) obtained in the previous step and sodium hydroxide (30 mg, 0.75 mmol) were added to a mixture of methanol (4 mL) and water (1 mL), and the reaction system was stirred at 40°C overnight. After the reaction was completed, the methanol was evaporated under reduced pressure, and ethyl acetate (6 mL) was added to the residue. The pH was adjusted to approximately 6 with hydrochloric acid (2N). The aqueous phase was extracted with ethyl acetate (5×10 mL). The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude product of (1R,3r)-3-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-nitropyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-90-d), which was directly used in the next step. LC-MS: 562.1 [M+H] + .

[0720] Step 4:

[0721] Iron powder (35 mg, 0.627 mmol) and ammonium chloride (17 mg, 0.318 mmol) were slowly added to a solution of crude (1R,3r)-3-((R)-3-(1-(4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-5-nitropyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-90-d) (90 mg, 0.160 mmol) in ethanol / water (4 mL / 1 mL). The reaction mixture was reacted at 90°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the filter cake was washed with methanol and dichloromethane in sequence. The filtrate was concentrated under reduced pressure to give a yellow crude product of (1R,3r)-3-((R)-3-(1-(5-amino-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-90-e), which was directly used in the next step. LC-MS: 532.1 [M+H] + .

[0722] Step 5:

[0723] Sodium nitrite (21 mg, 0.304 mmol) was added to a solution of crude (1R,3r)-3-((R)-3-(1-(5-amino-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyridin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-90-e) (70 mg, 0.132 mmol) in acetic acid (2 mL). The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, acetic acid was evaporated under reduced pressure, water (10 mL) was added to the residue, and the aqueous phase was adjusted to a pH of approximately 5 with hydrochloric acid (2N). The aqueous phase was concentrated under reduced pressure, and the residue was purified by preparative thin-layer silica gel chromatography (dichloromethane / methanol = 10 / 1, V / V) and then by preparative HPLC to afford (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-90) (4 mg, 5.3% yield). LC-MS: 542.8 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.92(s,1H),8.53(s,1H),7.57(d,J=1.6Hz,1H),7.40–7.34(m,1H),6.37(q,J=6.8Hz,1H),6.05(s,1H),5.36(m,1H), 4.12(m,2H),3.82(m,2H),2.78(m,2H),2.62(m,2H),2.21(m,1H),2.1 0(d,J=6.8Hz,3H),2.09–1.87(m,4H),1.47–1.31(m,5H),1.31(s,3H).

[0724] Example 91

[0725] first step:

[0726] (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (55 mg, 0.161 mmol) was placed in a single-necked bottle (10 mL). (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-3-b) hydrochloride (53 mg, 0.241 mmol), DMF (2 mL) and potassium carbonate (47 mg, 0.337 mmol) were added in sequence. The reaction mixture was reacted at 150°C overnight. After completion of the reaction, the mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, V / V) to afford 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-91) (18 mg, 22.9% yield) as a yellow powder. LC-MS: 489.8 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.52(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,1H),7.36(dd,J1=8.4Hz,J2=2.0Hz,1H),6.43(q,J=7.2Hz,1H),4.25(m,2H),3 .93(m,2H),3.77(t,J=6.0Hz,2H),3.13(m,2H),2.81–2.68(m,4H),2.0 4(d,J=7.2Hz,3H),1.93(s,3H),1.92–1.86(m,2H),1.84–1.68(m,4H).

[0727] Example 92

[0728] first step:

[0729] 2-Bromoethanol (289 mg, 2.313 mmol), 3-(piperidin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (I-92-a) (555 mg, 2.310 mmol) and potassium carbonate (383 mg, 2.771 mmol) were dispersed in acetonitrile (2 mL), and the reaction mixture was reacted at 80 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (30 mL) was added to the residue and washed with water (8 mL) and saturated brine (8 mL) in turn. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a colorless oily compound 3-(1-(2-hydroxyethyl)piperidin-4-yl)azetidine-1-carboxylic acid tert-butyl ester (I-92-b) (629 mg, yield 95.8%), which was directly put into the next step. LC-MS: [M+H] + .

[0730] Step 2:

[0731] A methanolic solution of hydrogen chloride (2 mL, 4 mol / L) was added to tert-butyl 3-(1-(2-hydroxyethyl)piperidin-4-yl)azetidine-1-carboxylate (I-92-b) (629 mg, 2.212 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 to obtain the hydrochloride salt of 2-(4-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-92-c) as a yellow oil (480 mg, yield 98.3%), LC-MS: 185.0 [M+H] + .

[0732] Step 3:

[0733] (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (65 mg, 0.190 mmol), DMF (2 mL) and potassium carbonate (55 mg, 0.398 mmol) were added sequentially to the hydrochloride salt of 2-(4-(azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-92-c) (63 mg, 0.285 mmol). The reaction mixture was reacted at 130°C overnight. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (20 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, V / V) to give (R)-2-(4-(1-(3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-92) (16 mg, 17.2% yield) as a yellow powder. LC-MS: 487.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.52(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,1H),7.35(dd,J 1=8.4Hz,J2=2.0Hz,1H),6.42(q,J=7.2Hz,1H),4.22(m,2H),3.90(m,2H),3.7 1(t,J=6.0Hz,2H),3.04(m,2H),2.76(s,3H),2.58(t,J=6.0Hz,2H),2.51(m,2 H), 2.14 (m, 2H), 2.04 (d, J = 7.2Hz, 3H), 1.76 (m, 2H), 1.56 (m, 1H), 1.36 (m, 1H).

[0734] Example 93

[0735] first step:

[0736] (S)-Morpholine-2-methanol (I-93-a) (160 mg, 1.366 mmol) was dispersed in 1,2-dichloroethane (3 mL) and methanol (1 mL). 3-Oxoazetidine-1-carboxylic acid tert-butyl ester (234 mg, 1.367 mmol) and acetic acid (82 mg, 1.366 mmol) were added sequentially. The reaction mixture was stirred at 30°C for 30 minutes, followed by the addition of sodium triacetoxyborohydride (434 mg, 2.0477 mmol). The reaction mixture was stirred at 30°C overnight. After the reaction was complete, the solvent was evaporated under reduced pressure, and the residue was added with ethyl acetate (15 mL), washed sequentially with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance (S)-tert-butyl 3-(2-(hydroxymethyl)morpholinyl)azetidine-1-carboxylate (I-93-b) (345 mg, yield 92.8%). LC-MS: 272.9 [M+H] + .

[0737] Step 2:

[0738] A methanolic solution of hydrogen chloride (2 mL, 4 mol / L) was added to tert-butyl (S)-3-(2-(hydroxymethyl)morpholinyl)azetidine-1-carboxylate (I-93-b) (345 mg), and the reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a yellow oil (S)-(4-(azetidin-3-yl)morpholin-2-yl)methanol hydrochloride (I-93-c) (260 mg, yield 98.3%), LC-MS: 172.8 [M+H] + .

[0739] Step 3:

[0740] (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (80 mg, 0.234 mmol), DMF (2 mL) and potassium carbonate (68 mg, 0.492 mmol) were added sequentially to (S)-(4-(azetidin-3-yl)morpholin-2-yl)methanol hydrochloride (I-93-c) (73 mg, 0.350 mmol). The reaction mixture was reacted at 130°C overnight. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (20 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 20 / 1, V / V) to give a yellow powder ((S)-4-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)morpholin-2-yl)methanol (I-93) (39 mg, 34.9% yield). LC-MS: 477.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.52(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,1H),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.43(q,J=7.2Hz,1H),4.24(m,2 H),4.05(m,2H),3.99–3.90(m,1H),3.72–3.50(m,4H),3.31(m,3H),2.89(m,1H),2.77(s,3H),2.79–2.72(m,1H),2.05(d,J=7.2Hz,3H).

[0741] Example 94

[0742] Example 94 can be synthesized by referring to the synthesis method of Example 93, replacing the starting material (S)-morpholine-2-methanol (I-93-a) with (R)-morpholine-2-methanol. LC-MS: 477.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.51(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,1H),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.43(q,J=7.2Hz,1H),4.2 3(m,2H),4.05(m,2H),3.93(m,1H),3.76–3.48(m,4H),3.32(m,3H),2.89(m,1H),2.82(m,1H),2.77(s,3H),2.05(d,J=7.2Hz,3H).

[0743] Example 97

[0744] Step 1: Dissolve tert-butyl 3-formylazetidine-1-carboxylate (I-97-a) (15.85 g, 85.57 mmol) in methanol (160 mL). Add triethylamine (24.0 mL, 172 mmol) under ice bath and argon protection and stir. Then, add nitromethane (19 mL, 353.9 mmol) dropwise. After the nitromethane is completely added, remove the ice bath and stir in a 25°C oil bath for 17 hours. Monitor the reaction by TLC until the reaction of the raw material is complete. The reaction solution is directly concentrated to obtain tert-butyl 3-(1-hydroxy-2-nitro-ethyl)azetidine-1-carboxylate (I-97-b) (22.1 g, 94.4%) as a waxy solid, which is used directly in the next reaction. LC-MS: 191.1 [M+H-tBu] + .

[0745] Step 2: Dissolve tert-butyl 3-(1-hydroxy-2-nitro-ethyl)azetidine-1-carboxylate (I-97-b) (22.1 g, 81.47 mmol) in methanol (165 mL) and add Pd / C (4.11 g, Pd content 10%). Replace the mixture with hydrogen three times and stir in a hydrogen atmosphere at 15-20°C for 20 hours. The reaction solution was filtered and concentrated to obtain crude tert-butyl 3-(2-amino-1-hydroxy-ethyl)azetidine-1-carboxylate (I-97-c) (19.9 g, 90.4%), which was used directly in the next reaction. LC-MS: 217.1 [M+H-tBu] + .

[0746] Step 3: Dissolve tert-butyl 3-(2-amino-1-hydroxy-ethyl)azetidine-1-carboxylate (I-97-c) (19.94 g, 73.76 mmol) in tetrahydrofuran (200 mL). Under stirring, water (100 mL) and sodium bicarbonate (21.57 g, 256.8 mmol) were added sequentially. Under ice bath and argon protection, 2-chloroacetyl chloride (10.5 mL, 132 mmol) was added dropwise. After the dropwise addition, the ice bath was removed and stirred at room temperature for 2 hours. The reaction solution was directly concentrated to remove the organic solvent, and the residual liquid was dissolved in ethyl acetate (100 mL), washed once with saturated sodium chloride aqueous solution (50 mL), and the resulting organic phase was concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (0-60% ethyl acetate-petroleum ether solution) was used to separate and purify the product to give tert-butyl 3-[2-[(2-chloroacetyl)amino]-1-hydroxy-ethyl]azetidine-1-carboxylate (I-97-d) (12.58 g, 58.26%). LC-MS: 237.1 [M+H-tBu] + . 1 H NMR (400MHz, CDCl3) δ7.08(s,1H),4.07(s,2H),3.96(t,J=8.5Hz,2H),3.92–3.84(m,2H),3.72(dd,J=8 .7,5.6Hz,1H),3.45(ddd,J=13.9,6.4,2.9Hz,1H),3.24–3.12(m,1H),2.65–2.49(m,1H),1.42(s,9H).

[0747] Step 4: Add tert-butyl alcohol (40 mL) and tert-butyl 3-[2-[(2-chloroacetyl)amino]-1-hydroxy-ethyl]azetidine-1-carboxylate (I-97-d) (2.32 g, 7.92 mmol) to the reaction flask. Under argon protection, heat to 40°C, and add potassium tert-butoxide (1.10 g, 9.51 mmol) after dissolution. Stir at 40°C for 1.5 hours. After the reaction is complete, cool to room temperature and quench with saturated aqueous ammonium chloride (11 mL). The reaction solution is extracted twice with ethyl acetate (30 mL × 2), the organic phases are combined, washed once with saturated aqueous sodium chloride (15 mL), and concentrated under reduced pressure to give crude tert-butyl 3-(5-oxomorpholin-2-yl)azetidine-1-carboxylate (I-97-e) (1.88 g, 74%), which is used directly in the next reaction. LC-MS: 201.1 [M+H-tBu] + .

[0748] Step 5: Add tert-butyl 3-(5-oxomorpholin-2-yl)azetidine-1-carboxylate (I-97-e) (1.156 g, 4.510 mmol) and dry tetrahydrofuran (35 mL) to the reaction flask. Under ice-salt bath and argon protection, add sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (3.9 mL, 14 mmol, 3.5 mol / L) dropwise. After completion of the dropwise addition, react at 0-5°C for 3 hours. Monitor the reaction by TLC. After the reaction is complete, slowly add 10% aqueous sodium hydroxide solution (1 mL) to quench the reaction. Add celite and stir for 10 minutes, then filter. The filtrate is directly concentrated under reduced pressure to give the crude product tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (I-97-f) (1.107 g, 96.2%). LC-MS: 187.1 [M+H-tBu] + .

[0749] Step 6: tert-Butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (I-97-f) (1.107 g, 4.340 mmol), tetrahydrofuran (12 mL), water (12 mL) and sodium bicarbonate (1.14 g, 13.6 mmol) were added to the reaction flask in sequence. Under ice bath and argon protection, benzyl chloroformate (1.30 mL, 8.83 mmol) was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 4 hours. TLC monitored the reaction. After the reaction was complete, water (30 mL) and ethyl acetate (30 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed once with saturated sodium chloride aqueous solution (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Silica gel column chromatography (0-30% ethyl acetate-petroleum ether solution) was used to separate and purify the mixture to give benzyl 4-(2-((1-tert-butoxycarbonyl)-3-azetidinyl)morpholinyl)carboxylate (I-97-g-1 and I-97-g-2) (1.026 g, 62.8%).

[0750] SFC preparative separation. SFC preparative chromatography conditions: 1. Instrument: Waters 150SFC; 2. Column: Chiralpak IC-H Column (150×30 mm, 5 μm particle size); 3. Flow rate: A for CO2 and B for MeOH; 4. Gradient: B 30%; 5. Flow rate: 80 mL / min. The fractions from Peak 1 (retention time: 3.3 min) were combined to give benzyl 4-(2-((1-tert-butoxycarbonyl)-3-azetidinyl)morpholinyl)carboxylate (one isomer of I-97-g-1 and I-97-g-2, 230 mg), and the fractions from Peak 2 (retention time: 5.0 min) were combined to give benzyl 4-(2-((1-tert-butoxycarbonyl)-3-azetidinyl)morpholinyl)carboxylate (one isomer of I-97-g-1 and I-97-g-2, 230 mg).

[0751] Step 7: Benzyl 4-(2-((1-tert-butyloxycarbonyl)-3-azetidinyl)morpholinyl)carboxylate (one of the isomers in I-97-g-1 and I-97-g-2, the fraction with a retention time of 5.0 min in the previous step, 97 mg) was dissolved in methanol (10 mL) and Pd / C (30 mg, 10% Pd content) was added. The gas was replaced with hydrogen three times and the mixture was stirred overnight under a hydrogen atmosphere at 15-20°C. After completion of the reaction, the reaction solution was filtered and concentrated to obtain crude tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (one of the isomers in I-97-h-1 and I-97-h-2) (67 mg), which was used directly in the next reaction. LC-MS: 187.1 [M+H-tBu] + .

[0752] Referring to the above procedure, the fraction with a retention time of 3.3 min from the previous step (the other isomer in I-97-g-1 and I-97-g-2, 96 mg) was used to obtain 116 mg of crude tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (one isomer in I-97-h-1 and I-97-h-2), which was used directly in the next reaction. LC-MS: 187.1 [M+H-tBu] + .

[0753] Step 8: The crude product of the previous step, tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (one of I-97-h-1 and I-97-h-2, obtained by chemical conversion of fraction 2 of 5.0 min) (67 mg) was dissolved in 1,2-dichloroethane (5 mL), and 1-methyl-3-oxocyclobutanecarboxylic acid (I-1-e) (39 mg) and acetic acid (20 mg) were added. After stirring at room temperature for 30 minutes, sodium acetate borohydride (210 mg) was added in batches and stirred at room temperature overnight. After completion of the reaction, ice water was added to quench the reaction. The organic phase of the mixed liquid was concentrated and removed, and the remaining aqueous phase was freeze-dried. The residue was extracted with 20 mL of a mixed solution (dichloromethane: methanol = 15: 1), filtered, and the filtrate was concentrated to give a crude product (one of I-97-i-1 and I-97-i-2, 162 mg), which can be used directly in the next reaction. LC-MS: 355.0 [M+H] + .

[0754] Referring to the above operation, 116 mg of the crude product tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (the other of I-97-h-1 and I-97-h-2, obtained by chemical conversion of fraction 1 at 3.3 min) from the previous step was used to obtain 188 mg of crude tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (one of I-97-i-1 and I-97-i-2), which was used directly in the next reaction. LC-MS: 355.0 [M+H] + .

[0755] Step 9: The crude product from the previous step (one of I-97-i-1 and I-97-i-2) (162 mg, obtained by chemical conversion of fraction 2 from 5.0 min) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated to obtain the crude trifluoroacetate salt of (one of I-97-j-1 and I-97-j-2) (240 mg), which was used directly in the next reaction. LC-MS: 254.9 [M+H] + .

[0756] Referring to the above procedure, 188 mg of the crude product tert-butyl 3-(morpholin-2-yl)azetidine-1-carboxylate (one of I-97-i-1 and I-97-i-2, obtained by chemical conversion from fraction 1 at 3.3 min) from the previous step was used to obtain 378 mg of the crude trifluoroacetate salt of (one of I-97-j-1 and I-97-j-2), which was used directly in the next reaction. LC-MS: 254.9 [M+H] + .

[0757] Step 10: The crude trifluoroacetate salt from the previous step (one of I-97-j-1 and I-97-j-2, obtained by chemical conversion of fraction 2 at 5.0 min, 240 mg) and (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (104 mg, 0.30 mmol) were dispersed in isopropanol (10 mL). Water (1.5 mL) and potassium carbonate (401 mg, 2.9 mmol) were added, and the reaction mixture was stirred at 90°C for 2 hours. The reaction was monitored by LC-MS until the reaction of the starting materials was complete. After the reaction was completed, the mixture was cooled to room temperature, water (5 mL) was added, the organic phase was concentrated and removed, and the remaining aqueous phase was lyophilized. The residue was extracted with 20 mL of a mixture (dichloromethane:methanol = 15:1) by slurrying, filtered, and the filtrate concentrated and purified by HPLC to obtain 33 mg of the formate salt of (one of I-97-1, I-97-2, I-97-3, and I-97-4). LC-MS: 560.1 [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.37(s,1H),7.51(d,J=2.1Hz,1H),7.45(s,1H),7.34(dd,J=8.5,2.1 Hz,1H),6.41(q,J=7.1Hz,1H),4.12(d,J=24.1Hz,3H),4.02(s,1H),3.95(d,J=9.8Hz,1H),3 .68(t,J=8.7Hz,2H),3.02–2.91(m,1H),2.91–2.76(m,3H),2.74(s,3H),2.65–2.57(m,2H) ,2.13(t,J=10.0Hz,1H),2.02(d,J=7.1Hz,3H),1.83(dd,J=26.2,15.2Hz,3H),1.38(s,3H).

[0758] 18 mg of the formate salt of another isomer (one of I-97-1, I-97-2, I-97-3 and I-97-4) was obtained. LC-MS: 560.1 [M+H] +. 1H NMR (400MHz, CD3OD) δ8.39(s,2H),7.51(d,J=2.1Hz,1H),7.45(d,J=8.5Hz,1H),7.34(dd,J=8.5 ,2.1Hz,1H),6.41(q,J=7.1Hz,1H),4.05(dd,J=40.3,28.0Hz,5H),3.82–3.70(m,2H),3.21–3.10 (m,1H),3.03(t,J=11.8Hz,2H),2.81(d,J=5.9Hz,1H),2.74(s,3H),2.51–2.40(m,2H),2.35(s,1H),2.17–1.96(m,6H),1.39(d,J=9.0Hz,3H).

[0759] Following the above procedure, using the crude trifluoroacetate from the previous step (one of I-97-j-1 and I-97-j-2, obtained by chemical conversion from fraction 1 at 3.3 min, 378 mg), 60 mg of the formate salt of (one of I-97-1, I-97-2, I-97-3, and I-97-4) was obtained. LC-MS: 560.1 [M+H] + . H NMR(400MHz,CD3OD)δ8.36(s,1H),7.51(d,J=2.1Hz,1H),7.46(d,J=8.5Hz,1H), 7.34(dd,J=8.5,2.1Hz,1H),6.41(q,J=7.1Hz,1H),4.05(dd,J=75.4,19.4Hz,5H) ,3.69(t,J=8.2Hz,2H),2.99(d,J=8.3Hz,1H),2.93–2.75(m,3H),2.69–2.56(m,5 H), 2.16 (d, J = 3.3Hz, 1H), 2.02 (d, J = 7.1Hz, 3H), 1.96–1.78 (m, 3H), 1.38 (s, 3H).

[0760] 25 mg of the formate salt of another isomer (one of I-97-1, I-97-2, I-97-3 and I-97-4) was obtained. LC-MS: 560.1 [M+H] +. H NMR (400MHz, CD3OD) δ8.39(s,1H),7.51(d,J=2.1Hz,1H),7.45(d,J=8.5Hz,1H),7.34(dd,J =8.5,2.1Hz,1H),6.41(q,J=7.1Hz,1H),4.08(dd,J=62.8,20.2Hz,5H),3.77(dd,J=20.8,1 1.4Hz,2H),3.20–3.11(m,1H),3.04(t,J=11.9Hz,2H),2.81(dd,J=13.9,7.9Hz,1H),2.74( s,3H),2.53–2.41(m,2H),2.36(t,J=10.3Hz,1H),2.23–1.97(m,6H),1.39(d,J=8.3Hz,3H).

[0761] Example 98

[0762] Step 1: Under a nitrogen atmosphere, to a dry three-necked flask (25 mL) were added (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (200 mg, 0.519 mmol) (I-59-d), carbon tetrachloride (2 mL), azobisisobutyronitrile (17.1 mg, 0.104 mmol), and N-bromosuccinimide (184.0 mg, 1.038 mmol). The reaction mixture was stirred at 80°C for 16 hours. After the reaction was complete as monitored by LCMS, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) and concentrated under reduced pressure to afford (R)-6-bromo-4-(bromomethyl)-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-98-a) (130 mg, 54%) as a yellow solid. LCMS: (ESI, m / z): [M+H] + =461.55.

[0763] Step 2: Under nitrogen, to a dry round-bottom flask (100 mL) were added (R)-6-bromo-4-(bromomethyl)-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-98-a) (850 mg, 1.832 mmol), dimethyl sulfoxide (8.5 mL), and water (4.2 mL). The reaction mixture was stirred at 80°C for 2 hours. After completion of the reaction as monitored by LCMS, the reaction solution was cooled to room temperature. The reaction mixture was purified by reverse phase liquid chromatography using a C18 column, mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 50%-70% over 20 minutes, and concentrated under reduced pressure to afford (R)-(6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (I-98-b) (540 mg, 73% yield) as a white solid. LCMS: (ESI, m / z): [M+H] + =399.75.

[0764] Step 3: (R)-(6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (I-98-b) (0.15 g, 0.37 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin oxidant (0.235 g, 0.56 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (80 mL), washed with saturated sodium bicarbonate solution (50 mL × 3), and then with saturated brine (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 100:10) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde (I-98-c) (0.14 g, 94% yield). LC-MS: 397.85 [M+H] + .

[0765] Step 4: Dissolve (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde (I-98-c) (0.14 g, 0.35 mmol) obtained in the previous step in dry dichloromethane (5 mL) and cool to 0°C in an ice bath under argon. Dissolve diethylaminosulfur trifluoride (DAST, 180 mg, 1.1 mmol) in anhydrous dichloromethane (2 mL) and slowly add to the reaction system. Allow to warm to room temperature and stir overnight. After completion of the reaction, saturated aqueous sodium bicarbonate solution was added for neutralization, followed by extraction with ethyl acetate (80 mL) and washing with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, mixed, and purified on a column (petroleum ether:ethyl acetate = 100:20) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole (I-98-d) (140 mg, 95.2% yield). LC-MS: 422.6 [M+H]+.

[0766] Step 5: To a two-necked round-bottom flask (50 mL) were added 3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (106 mg, 0.4 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazole (I-98-d) (0.14 g, 0.33 mmol), Pd2dba3 (35 mg, 0.038 mmol), BINAP (45 mg, 0.07 mmol), cesium carbonate (97 mg, 0.3 mmol) and 1,4-dioxane (10 mL), and stirred at 115 ° C for 16 hours under argon protection. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and washed with ethyl acetate (80 mL). The filtrate was concentrated, mixed, and purified by column chromatography (dichloromethane:methanol = 100:10) to obtain methyl 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-98-e) (10 mg, 5% yield) as a brown oily liquid. LC-MS: 507.7 [M+H] + .

[0767] Step 6: Methyl 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-98-e) (10 mg, 0.0165 mmol), methanol (3 ml), water (1 mL) and lithium hydroxide monohydrate (10 mg, 0.256 mmol) were added to a single-necked round-bottom flask (25 mL) and stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 5-6 with 1N dilute hydrochloric acid. The product was concentrated and then purified by preparative plate separation (dichloromethane:methanol = 100:10) to afford 3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-(difluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-98) (1.82 mg, 18.6% yield) as a brown solid. LC-MS: 592.1 [M+H] + .

[0768] 1 H NMR (400MHz, CDCl3) δ7.45 (s, 1H), 7.38 (s, 1H), 7.18 (d, J = 5.6Hz, 1H), 6.75 (s, 1H) ,6.23(d,J=6.4Hz,1H),6.11(br,1H),5.37(s,1H),4.03(s,2H),3.77-3.62(m,2H), 3.50-3.25(m,3H),2.73-2.63(m,2H),2.27–2.22(m,2H),2.14(d,J=6.3Hz,3H),2.0 7-2.0(m,3H),1.70-1.61(m,2H),1.54-1.47(m,2H),1.34(s,3H),0.94-085(m,2H).

[0769] Example 99

[0770] Step 1: Under a nitrogen atmosphere, (R)-(6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methanol (I-98-b) (400.0 mg, 0.997 mmol) and dichloromethane (4 mL) were added sequentially to a dry round-bottom flask (50 mL). Diethylaminosulfur trifluoride (176.8 mg, 1.097 mmol) was dissolved in dichloromethane (4 mL) at 0°C and then added dropwise to the reaction mixture. Under a nitrogen atmosphere, the reaction mixture was stirred at 0°C for 2 hours. The reaction was monitored by liquid chromatography-mass spectrometry. Under a nitrogen atmosphere at 0°C, the reaction mixture was poured into ice water to quench the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1). After concentration under reduced pressure, the compound (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-(fluoromethyl)-1H-benzo[d][1,2,3]triazole (I-99-a) (145.0 mg) was obtained as a white solid in a 36% yield. LCMS: (ESI, m / z): [M+H] + =401.95.

[0771] Step 2: Disperse the hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (93 mg, 0.27 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-(fluoromethyl)-1H-benzo[d][1,2,3]triazole (I-99-a) (100 mg, 0.25 mmol), Pd2(dba)3 (23 mg, 0.02 mmol), BINAP (31 mg, 0.05 mmol), and Cs2CO3 (404 mg, 1.24 mmol) in ultra-dry dioxane (5 mL). Stir the reaction mixture at 100°C under argon for 16 hours. Monitor the reaction by LC-MS until the starting material is completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to give methyl (1R,3r)-3-((R)-3-(1-(1-(((R)-1-(2,4-dichlorophenyl)ethyl)-4-(fluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-99-b) (66 mg, 45%). LC-MS: 587.7 [M+H] + .

[0772] Step 3: Methyl (1R,3r)-3-((R)-3-(1-(1-(((R)-1-(2,4-dichlorophenyl)ethyl)-4-(fluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-99-b) (66 mg, 0.11 mmol) and lithium hydroxide (17 mg, 0.70 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. LC-M The reaction was monitored by S until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-4-(fluoromethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-99) (40 mg, 62%). LC-MS: 573.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.55(d,J=2.1Hz,1H),7.33(dd,J=8.5,2.1Hz,1H),7.25(d,J=8.5Hz,1H),6.71(s,1H),6.37 (q,J=6.9Hz,1H),6.16(s,1H),5.88(s,1H),5.76(s,1H),4.02(dt,J=19.3,7.7Hz,2H),3.78–3.63(m,2H),3.39(d, J=8.2Hz,1H),3.30–3.16(m,2H),2.73(dd,J=11.5,7.6Hz,2H),2.53(s,1H),2.42(t,J=11.7Hz,1H),2.17(t,J=11 .4Hz, 1H), 2.10 (d, J = 7.0Hz, 3H), 1.97 (ddd, J = 19.4, 17.2, 9.7Hz, 6H), 1.70 (dd, J = 27.0, 13.2Hz, 1H), 1.38 (s, 3H).

[0773] Example 100

[0774] Step 1: Under a nitrogen atmosphere, methyltriphenylphosphonium bromide (852.64 mg, 2.386 mmol) and tetrahydrofuran (6 mL) were added sequentially to a dry three-necked flask (50 mL). Sodium hydride (127.29 mg, 3.182 mmol, 60%) was then slowly added in portions at 0°C and stirred for 0.5 hours. Under a nitrogen atmosphere, (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole-4-carbaldehyde (I-98-c) (635 mg, 1.591 mmol) was dissolved in tetrahydrofuran (6 mL) and slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by liquid chromatography-mass spectrometry, the reaction mixture was quenched by adding ice water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8 / 1) and concentrated under reduced pressure to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-vinyl-1H-benzo[d][1,2,3]triazole (I-100-a) (375.0 mg, 58% yield) as a colorless oil. LCMS: (ESI, m / z): [M+H] + =396.10.

[0775] Step 2: Under a nitrogen atmosphere, a solution of potassium hydroxide (4397.5 mg, 78.352 mmol) in water (67.5 mL) was slowly added dropwise to a solution of N-methyl-N-nitrosourea (1168.1 mg, 11.328 mmol) in diethyl ether (112.5 mL) at -20°C. The reaction mixture was allowed to react at -20°C for 0.5 hours, then allowed to stand and separate the organic layer. The organic phase was then added dropwise to a solution of (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-vinyl-1H-benzo[d][1,2,3]triazole (I-100-a) (375 mg, 0.944 mmol) in diethyl ether (18.75 mL) at 0°C. After the addition was complete, palladium acetate (21.20 mg, 0.094 mmol) was added and the reaction continued at 0°C for 2 hours. After the reaction was complete, as monitored by liquid chromatography-mass spectrometry, the reaction mixture was filtered, and the filter cake was washed twice with acetonitrile (3 x 25 mL). The filtrate was concentrated under reduced pressure to obtain a residue, which was then purified by reverse-phase liquid chromatography using the following conditions: C18 column, mobile phase A: water (0.1% ammonium bicarbonate), mobile phase B: acetonitrile, gradient: 80%-95% over 20 minutes, wavelength 220 nm, to obtain compound (R)-6-bromo-4-cyclopropyl-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-100-b) as a white solid (159.0 mg, 43% yield). LCMS: (ESI, m / z): [M+H]+ =409.85.

[0776] Step 3: Disperse the hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (91 mg, 0.26 mmol), (R)-6-bromo-4-cyclopropyl-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-100-b) (100 mg, 0.24 mmol), Pd2(dba)3 (22 mg, 0.02 mmol), BINAP (30 mg, 0.05 mmol), and Cs2CO3 (396 mg, 1.21 mmol) in ultra-dry dioxane (5 mL). Stir the reaction mixture at 100°C under argon for 16 hours. Monitor the reaction by LC-MS until the reaction is complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to afford methyl (1R,3r)-3-((R)-3-(1-(4-cyclopropyl-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-100-c) (60 mg, 41%). LC-MS: 595.7 [M+H] + .

[0777] Step 4: Methyl (1R,3r)-3-((R)-3-(1-(4-cyclopropyl-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-100-c) (60 mg, 0.10 mmol) and lithium hydroxide (24 mg, 1.01 mmol) were dispersed in methanol (5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(4-cyclopropyl-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-100) (30 mg, 51%). LC-MS: 581.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.55(d,J=1.9Hz,1H),7.32(dd,J=8.5,1.8Hz,1H),7.21(d,J=8.5Hz,1H),6 .31(q,J=7.0Hz,1H),6.19(s,1H),5.95(s,1H),4.05–3.84(m,2H),3.76–3.55(m,2H),3.37(s,1H) ,3.25(dd,J=24.3,11.7Hz,2H),2.72(d,J=6.6Hz,2H),2.50(td,J=8.2,4.1Hz,1H),2.47–2.32(m, 2H), 2.24–1.80 (m, 9H), 1.77–1.61 (m, 1H), 1.38 (s, 3H), 1.13 (d, J = 8.3Hz, 2H), 1.09–0.94 (m, 3H).

[0778] Example 101

[0779] Example 101 can be synthesized by referring to the synthesis method of Example 93, except that the starting material (S)-morpholine-2-methanol (I-93-a) is replaced with (S)-piperidine-3-methanol. LC-MS: 475.8 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.50(s,1H),7.47(d,J=8.4Hz,1H),7.34(d,J=8.4Hz,1H),6.43(q,J=7.2Hz,1H),4.27(m,2H),4.07(m,2H) ,3.50(m,1H),3.40(m,2H),3.33(m,2H),3.08(m,1H),2.96(m,1H),2.76(s,3H),2.04(d,J=7.2Hz,3H),1.99(m,1H),1.80(m,4H).

[0780] Example 102

[0781] first step:

[0782] To a single-necked round-bottom flask (100 mL) were added tert-butyl (R)-3-(1-(2-ethoxy-2-oxoethyl)piperidin-3-yl)azetidine-1-carboxylate (I-78-a) (200 mg, 0.6 mmol), dichloromethane (3 mL), and a hydrogen chloride-dioxane solution (2 mL, 4 M) in sequence, and stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated to afford the hydrochloride salt of (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethyl acetate (I-102-a) (180 mg, crude product) as a light brown, transparent oily liquid. LC-MS: 227.0 [M+H] + .

[0783] Step 2:

[0784] To a single-necked round-bottom flask (25 mL) were added (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (200 mg, 0.58 mmol), (R)-ethyl 2-(3-(azetidin-3-yl)piperidin-1-yl)acetate (I-102-a) hydrochloride (180 mg, crude), and sodium carbonate (70 mg, 0.65 mmol). Isopropyl alcohol (10 mL) and water (2 mL) were then added. The mixture was stirred at 95°C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), and washed with saturated sodium bicarbonate solution (50 mL × 3) and saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (dichloromethane:methanol = 100:4) to afford ethyl 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetate (I-102-b) (140 mg, 44% yield) as a light yellow oily liquid. LC-MS: 531.7 [M+H] + .

[0785] Step 3:

[0786] To a single-necked round-bottom flask (50 mL) was added ethyl 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetate (I-102-b) (20 mg, 0.0377 mmol), methanol (3 mL), water (1 mL) and lithium hydroxide (5 mg, 0.125 mmol) in sequence and stirred at room temperature for 1.5 hours. After completion of the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid (1N). The product was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to afford 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetic acid (I-102) (10 mg, 52.6% yield) as a white solid. LC-MS: 504.0 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.51(d,J=1.8Hz,1H),7.46(d,J=8.5Hz,1H),7.35(dd,J =8.5,2.1Hz,1H),6.42(q,J=7.1Hz,1H),4.34–4.16(m,2H),3.97(s,2H),3.60 -3.52(m,4H),2.91(s,1H),2.76(s,3H),2.59(s,1H),2.25–2.11(m,2H),2.04 (d,J=7.1Hz,3H),1.96-1.93(m,3H),1.35(d,J=2.6Hz,1H),1.26–1.12(m,1H).

[0787] Example 103

[0788] first step:

[0789] To a two-necked round-bottom flask (50 mL) was added ethyl 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetate (I-102-b) (140 mg, 0.264 mmol), anhydrous tetrahydrofuran (10 mL) was added under argon protection and the mixture was cooled to -78 ° C. LiHMDS (0.34 mL, 1 M) was slowly added and stirred at -78 ° C for 0.5 hours. Add 1,3,2-dioxazolidinone-2,2-dioxide (I-78-b) (50 mg, 0.396 mmol, anhydrous tetrahydrofuran (3 mL) solution, continue stirring at -78 ° C for 1 hour, then add LiHMDS (0.34 mL, 1 M), and naturally warm to room temperature overnight. After the reaction is completed, quench with ethanol, dilute with ethyl acetate (100 mL), wash the organic phase with water (50 mL × 2), wash with saturated brine (50 mL × 1), The organic phase was dried over anhydrous sodium sulfate. Sodium sulfate was removed from the organic phase by filtration, and the filtrate was concentrated and separated by column chromatography (dichloromethane:methanol = 100:5) to afford ethyl 2-((R)-3-(1-(7-cyclopropyl-3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetate (I-103-a) (45 mg, 30.6% yield) as a light yellow oily liquid. LC-MS: 558.7 [M+H] + .

[0790] Step 2:

[0791] To a single-necked round-bottom flask (50 mL) were added ethyl 2-((R)-3-(1-(7-cyclopropyl-3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetate (I-103-a) (45 mg, 0.081 mmol), methanol (5 mL), water (1 mL) and lithium hydroxide (10 mg, 0.24 mmol) in sequence and stirred at room temperature overnight. After completion of the reaction, the pH was adjusted to 5-6 with dilute hydrochloric acid (1N). The product was concentrated and purified by preparative plate separation (dichloromethane:methanol = 100:10) to afford 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)acetic acid (I-103) (15 mg, 35.7% yield) as a white solid. LC-MS: 530.1 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.50(d,J=2.0Hz,1H),7.43(d,J=8.5Hz,1H),7.34(dd,J=8.5,2.1Hz,1H) ,6.40(q,J=7.1Hz,1H),4.19(dt,J=18.8,7.0Hz,2H),3.92(dd,J=9.2,5.6Hz,2H),3.64(d,J=2 6.4Hz,4H),2.93(s,1H),2.68(ddd,J=12.7,8.2,4.6Hz,2H),2.54(s,1H),2.22–2.09(m,1H),2 .06–2.01(m,3H),2.00–1.81(m,3H),1.45–1.39(m,2H),1.28–1.23(m,2H),1.20-1.18(m,1H).

[0792] Example 104

[0793] first step:

[0794] Under nitrogen atmosphere, compound (1R, 3r)-3-((R)-3-(1-(3-((R, 1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-69-d) (120 mg, 0.210 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), cooled to -78 ° C, and lithium bistrimethylsilylamide (0.6 mL, 0.6 mmol, 1.0 mol / L tetrahydrofuran solution) was slowly added dropwise. After the addition was complete, the reaction was continued at -78 ° C for 30 minutes. 1,3,2-dioxazolidinone-2,2-dioxide (I-78-b) (39 mg, 0.314 mmol) l) was added to the above reaction solution and the reaction was continued at -78°C for 30 minutes, then slowly warmed to room temperature overnight. After completion of the reaction, water (10 mL) was added to quench the reaction and extracted with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product (1R,3R)-3-((R)-3-(1-(7-cyclopropyl-3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-104-a) (100 mg), which was used directly in the next reaction without purification. LC-MS: 597.7 [M+H] + .

[0795] Step 2:

[0796] Sodium hydroxide (30 mg, 0.75 mmol), water (0.5 mL) and methanol (2 mL) were added sequentially to the crude product (1R,3R)-3-((R)-3-(1-(7-cyclopropyl-3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-104-a) (100 mg), and the reaction mixture was reacted at 40°C overnight. The reaction mixture was cooled to room temperature, and the methanol was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 7 / 1, V / V) to obtain a yellow powder compound (1R,3R)-3-((R)-3-(1-(7-cyclopropyl-3-((R)-1-(2,4-dichlorophenyl)ethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-104) (35 mg, 35.8% yield). LC-MS: 583.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.51(d,J=2.4Hz,1H),7.45(d,J=8.4Hz,1H),7.35(dd, J1=8.4Hz, J2=2.4Hz,1H),6.41(q,J=7.2Hz,1H),4.19(m,2H),3.89(m,2H),3 .19(m,2H),2.70(m,2H),2.48(m,1H),2.31(m,1H),2.03(d,J=7.2Hz,3H),1. 91(m,6H),1.68(m,2H),1.42(m,2H),1.38(s,3H),1.30(m,2H),1.26(m,2H).

[0797] Example 105

[0798] first step:

[0799] 1-Bromo-2-chloro-5-fluoro-4-nitrobenzene (I-105-a) (1.00 g, 3.93 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (745 mg, 3.92 mmol), and potassium carbonate (1.09 g, 7.77 mmol) were dispersed in acetonitrile (20 mL). The reaction mixture was stirred at 100°C for 24 hours. The reaction was monitored by LC-MS until the starting materials were completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 10%) to obtain (R)-5-bromo-4-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline (I-105-b) (1.61 g, 96.8%).

[0800] Step 2:

[0801] (R)-5-bromo-4-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline (I-105-b) (1.45 g, 3.40 mmol), reduced iron powder (1.19 g, 21.3 mmol), and ammonium chloride (680 mg, 12.7 mmol) were dispersed in ethanol (50 mL) and glacial acetic acid (4.5 mL). The reaction solution was stirred at 100°C for 1 hour. After the reaction of the raw materials was complete, the reaction solution was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (ethyl acetate: petroleum ether = 10%) to obtain (R)-5-bromo-4-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-nitroaniline. 1 -(1-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-105-c) (1.05 g, 78%). LC-MS: 395.0 [M+H] + .

[0802] Step 3:

[0803] (R)-5-Bromo-4-chloro-N 11-(2,4-dichlorophenyl)ethyl)benzene-1,2-diamine (I-105-c) (380 mg, 0.96 mmol) was dispersed in glacial acetic acid (8 mL). The temperature was lowered to below 10°C, and a solution of sodium nitrite (73 mg, 1.1 mmol) in water (0.5 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 then separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to give (R)-6-bromo-5-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-105-d) (350 mg, 90%). LC-MS: 407.5 [M+H] + .

[0804] Step 4:

[0805] Methyl (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) hydrochloride (150 mg, 0.59 mmol), (R)-6-bromo-5-chloro-1-(1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazole (I-105-d) (250 mg, 0.62 mmol), Pd(dba) (65 mg, 0.06 mmol), BINAP (78 mg, 0.13 mmol), and CsCO (1000 mg, 2.83 mmol) were dispersed in ultra-dry dioxane (10 mL). The reaction mixture was stirred at 100°C under argon for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was filtered and concentrated under reduced pressure to give 1 g of crude (1R,3r)-3-((R)-3-(1-(5-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-105-e), which was used directly in the next step. LC-MS: 589.7 [M+H] + .

[0806] Step 5:

[0807] 1 g of crude (1R,3r)-3-((R)-3-(1-(5-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-105-e) obtained in step 4 was dissolved in methanol (5 mL) and water (0.5 mL) with lithium hydroxide (130 mg, 5.4 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to 5-6 with 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 column chromatography (dichloromethane:methanol = 97:3) to obtain (1R,3r)-3-((R)-3-(1-(5-chloro-1-(R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-105) (10 mg). LC-MS: 576.1 [M+H]. + . 1 H NMR (400MHz, CD3OD) δ7.87 (s, 1H), 7.55 (d, J = 2.0Hz, 1H), 7.34 (s, 1H), 7.29 (d, J = 8.5Hz, 1H), 6.40 (d, J=6.4Hz, 1H), 4.18 (q, J=8.1Hz, 1H), 3.85 (dd, J=14.0, 8.2Hz, 1H), 3.75–3. 62(m,1H),3.47–3.33(m,1H),2.80(dd,J=11.9,8.0Hz,1H),2.69(s,1H),2.57–2.40(m,1 H),2.24–1.92(m,4H),1.77(d,J=13.7Hz,1H),1.41(d,J=10.1Hz,1H),1.26–1.13(m,1H).

[0808] Example 106

[0809] first step:

[0810] Methyl (1R,3s)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylate (I-49-g) (104 mg, 0.29 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazole (I-59-d) (100 mg, 0.26 mmol), Pd2(dba)3 (24 mg, 0.03 mmol), BINAP (32 mg, 0.05 mmol), and Cs2CO3 (423 mg, 1.30 mmol) were dispersed in ultra-dry dioxane (5 mL). The reaction mixture was stirred at 100°C under argon for 16 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol / dichloromethane = 1:10) to obtain (1R,3s)-3-((R)-3-(1-(1-((R,1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid methyl ester (I-106-a) (70 mg, 46%). LC-MS: 583.8 [M+H] + .

[0811] Step 2:

[0812] Methyl (1R, 3s)-3-((R)-3-(1-(1-((R, 1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylate (I-106-a) (70 mg, 0.12 mmol) and lithium hydroxide (29 mg, 1.20 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature for 4 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified using a GF254 preparative plate (methanol / dichloromethane = 1:10) to obtain (1R,3s)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-ethylcyclobutane-1-carboxylic acid (I-106) (44 mg, 64%). LC-MS: 569.8 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.54(d,J=2.1Hz,1H),7.32(dd,J=8.5,2.1Hz,1H),7.22(d,J=8.5Hz,1H),6.45(s,1H ),6.32(q,J=7.0Hz,1H),5.99(s,1H),3.96(dt,J=19.1,7.7Hz,2H),3.74–3.57(m,2H),3.32–3.13(m,3H),2 .68(d,J=8.1Hz,2H),2.64(s,3H),2.45(d,J=7.2Hz,1H),2.37(t,J=11.9Hz,1H),2.08(d,J=7.0Hz,4H),2. 03–1.82(m,5H),1.73(ddd,J=39.2,19.5,9.5Hz,3H),1.02(dd,J=22.9,10.9Hz,1H),0.85(t,J=7.3Hz,3H).

[0813] Example 107

[0814] first step:

[0815] To a single-necked round-bottom flask (25 mL) were added 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-91) (52 mg, 0.1 mmol), DMA (3 mL) and chlorosulfonamide (40 mg, 0.35 mmol) in sequence, and the mixture was stirred at 85°C for 4 hours without opening. After completion of the reaction, the reaction mixture was cooled and separated using a C-18 reverse phase column (H2O:MeOH = 100:65) to obtain 2-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethyl hydrogen sulfate (I-107) (12 mg, 19.5% yield) as a white solid. LC-MS: 570.0 [M+H] + . 1H NMR (400MHz, d-DMSO) δ = 9.27 (s, 1H), 7.68 (s, 1H), 7.49 (q, J = 8.5, 2H), 6.30 (q, J = 7.1, 1H), 4.27-4.02(m,4H),3.98-3.78(m,2H),3.67-3.44(m,2H),3.42-3.36(m,1H),3.10(dd,J=14 .5,7.1,1H),2.96-2.77(m,1H),2.70(s,3H),2.65-2.57(m,1H),2.09-1.97(m,1H),1.96(d ,J=7.1,3H),1.93-1.77(m,2H),1.74-1.63(m,1H),1.19(t,J=7.3,1H),1.12–0.96(m,1H).

[0816] Example 108

[0817] first step:

[0818] To a single-necked round-bottom flask (50 mL) were added (R)-tert-butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (150 mg, 0.625 mmol), 2-(1,3-dioxoindole-2-yl)acetaldehyde (I-108-a) (155 mg, 0.81 mmol) and DCE (20 mL) in sequence, and the mixture was stirred at room temperature for 0.5 hours, followed by the addition of sodium triacetoxyborohydride (265 mg, 1.25 mmol) overnight. After completion of the reaction, the mixture was concentrated and diluted with ethyl acetate (100 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL x 2) and saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and concentrated to afford tert-butyl (R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-b) (320 mg) as a reddish-brown crude product. LC-MS: 413.9 [M+H] + .

[0819] Step 2:

[0820] To a single-necked round-bottom flask (50 mL) was added crude (320 mg) of tert-butyl (R)-3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-b) and methanol (3 mL). After the solution clarified, hydrazine hydrate (0.5 mL, 85%) was added and stirred at room temperature overnight. A large amount of white solid precipitated from the reaction solution, which was filtered and the filter cake washed with dichloromethane. The filtrate was concentrated to afford tert-butyl (R)-3-(1-(2-aminoethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-c) (150 mg, crude) as a colorless, transparent oil. LC-MS: 284.0 [M+H] + .

[0821] Step 3:

[0822] To a two-necked round-bottom flask 1 (25 mL) was added tert-butyl alcohol (93 mg, 1.25 mmol) and anhydrous DCM (5 mL). Under argon protection, chlorosulfonyl isocyanate (177 mg, 1.25 mmol) was slowly added dropwise under ice-cooling. After addition, the mixture was heated to room temperature and stirred for 1 hour.

[0823] To another two-necked round-bottom flask (25 mL) was added tert-butyl (R)-3-(1-(2-aminoethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-c) (150 mg, 0.53 mmol), triethylamine (0.18 mL, 0.13 mmol), and anhydrous DCM (5 mL). The system was protected by argon and then cooled in an ice bath. The reaction solution in two-necked flask 1 was added dropwise, and the temperature was slowly raised to room temperature and stirred overnight. After completion of the reaction, the mixture was concentrated, and the residue was separated by column chromatography (dichloromethane:methanol = 100:10) to obtain tert-butyl (R)-3-(1-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-d) (200 mg, yield 82%) as a white solid. LC-MS: 463.1 [M+H] + .

[0824] Step 4:

[0825] To a single-necked round-bottom flask (50 mL) were added tert-butyl (R)-3-(1-(2-((N-(tert-butoxycarbonyl)sulfamoyl)amino)ethyl)piperidin-3-yl)azetidine-1-carboxylate (I-108-d) (100 mg, 0.22 mmol), dichloromethane (3 mL), and trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated to give the crude trifluoroacetate salt of (3R)-3-(azetidin-3-yl)-1-[2-(sulfamoylamino)ethyl]piperidine (I-108-e) (120 mg). LC-MS: 558.7 [M+H] + .

[0826] Step 5:

[0827] To a single-necked round-bottom flask (25 mL) were added (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (45 mg, 0.13 mmol), (3R)-3-(azetidin-3-yl)-1-[2-(aminosulfonylamino)ethyl]piperidine (I-108-e) trifluoroacetate crude product (120 mg) and sodium carbonate (50 mg, 0.36 mmol), followed by isopropanol (10 mL) and water (2 mL). After the addition was complete, the mixture was stirred at 95°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated directly. The residue was purified on a preparative plate (dichloromethane:methanol = 100:10) to afford 3-[(1R)-1-(2,4-dichlorophenyl)ethyl]-7-methyl-5-[3-[(3R)-1-[2-(sulfamoylamino)ethyl]-3-piperidinyl]azetidin-1-yl]triazolo[4,5-d]pyrimidine (I-108) (10 mg, 13.6% yield) as a white solid. LC-MS: 568.0 [M+H] + . 1H NMR (400MHz, d-DMSO) δ = 10.13 (s, 1H), 7.68 (d, J = 1.2, 1H), 7.56–7.45 (m, 2H), 6.94 (s, 1H), 6.75 (s,1H),6.29(q,J=6.9,1H),4.25-4.05(m,2H),4.02-3.78(m,2H),3.52-3.42(m,2H),3.19(q,J =4.8,2H),2.92-2.78(m,1H),2.70(s,3H),2.67–2.58(m,1H),2.54(s,1H),2.48–2.40(m,1H),2 .22-2.08(m,1H),1.96(d,J=7.1,3H),1.88-1.73(m,3H),1.28-1.22(m,1H),1.15-0.99(m,1H).

[0828] Example 109

[0829] first step:

[0830] Dissolve (R)-3-(piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-1-d) (134 mg, 0.558 mmol) in ethanol (2 mL), add methyl acrylate (48 mg, 0.558 mmol), and heat to 50°C for 5 hours. After completion of the reaction, cool to room temperature and concentrate the reaction solution under reduced pressure to obtain a colorless oil (R)-3-(1-(3-methoxy-3-oxopropyl)piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-109-a) (180 mg, yield 98.9%). LC-MS: 326.9 [M+H] + .

[0831] Step 2:

[0832] A methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to tert-butyl (R)-3-(1-(3-methoxy-3-oxopropyl)piperidin-3-yl)azetidine-1-carboxylate (I-109-a) (180 mg, 0.552 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 to obtain the hydrochloride salt of methyl (R)-3-(3-(azetidin-3-yl)piperidin-1-yl)propanoate (I-109-b) (140 mg, yield 96.6%) as a yellow oil. LC-MS: 227.0 [M+H] + .

[0833] Step 3:

[0834] (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (86 mg, 0.251 mmol) was dispersed in DMF (2 mL), and (R)-methyl 3-(3-(azetidin-3-yl)piperidin-1-yl)propanoate (I-109-b) (99 mg, 0.377 mmol) and potassium carbonate (73 mg, 0.528 mmol) were added sequentially. The reaction mixture was stirred at 140°C overnight. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (15 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product (15 mg) of methyl 3-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propanoate (I-109-c). LC-MS: 532.7 [M+H] + .

[0835] Step 4:

[0836] Sodium hydroxide (10 mg, 0.25 mmol), water (0.5 mL) and methanol (2 mL) were added sequentially to the crude product (15 mg) of methyl 3-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propanoate (I-109-c), and the reaction mixture was stirred at 50°C overnight. The reaction mixture was cooled to room temperature, and the methanol was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 7 / 1, V / V) and then purified by HPLC to give 3-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propanoic acid (I-109) (6 mg). LC-MS: 517.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ7.52(d,J=2.0Hz,1H),7.46(d,J=8.4Hz,1H),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.42(d,J=7.2Hz,1H),4 .58(m,2H),4.28(m,2H),3.98(m,2H),3.50(m,2H),3.22(m,2H),2.77(s,3H),2.62(m,2H),2.04(d,J=7.2Hz,3H),1.33(m,6H).

[0837] Example 110

[0838] first step:

[0839] (R)-tert-Butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (146 mg, 0.608 mmol) was dissolved in acetonitrile (2 mL), and methyl 4-bromobutyrate (I-110-a) (110 mg, 0.608 mmol) and potassium carbonate (101 mg, 0.731 mmol) were added. The mixture was heated to 70°C and reacted for 5 hours. After cooling to room temperature, the acetonitrile was removed by vortexing under reduced pressure. Ethyl acetate (15 mL) was added to the residue, which was then washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate (I-110-b) (206 mg, 99.6% yield) as a yellow oil. LC-MS: 341.3 [M+H] + .

[0840] Step 2:

[0841] A methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to tert-butyl (R)-3-(1-(4-methoxy-4-oxobutyl)piperidin-3-yl)azetidine-1-carboxylate (I-110-b) (206 mg, 0.605 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 to obtain a colorless oil (R)-4-(3-(azetidin-3-yl)piperidin-1-yl)butanoate (I-110-c) hydrochloride (167 mg, yield 99.7%), LC-MS: 241.2 [M+H] + .

[0842] Step 3:

[0843] (R)-4-(3-(azetidin-3-yl)piperidin-1-yl)butanoic acid methyl ester (I-110-c) hydrochloride (104 mg, 0.376 mmol), acetonitrile (2 mL) and potassium carbonate (73 mg, 0.528 mmol) were added sequentially to (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (86 mg, 0.251 mmol). The reaction mixture was stirred at 140°C overnight. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate (15 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude methyl 4-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)butanoate (I-110-d) (50 mg). LC-MS: 546.1 [M+H] + .

[0844] Step 4:

[0845] Sodium hydroxide (20 mg, 0.500 mmol), water (0.5 mL) and methanol (2 mL) were added sequentially to the crude product (50 mg) of methyl 4-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)butanoate (I-110-d), and the reaction mixture was reacted at 50°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 10 / 1, V / V) to obtain 4-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)butanoic acid (I-110) (18 mg, 36.9% yield) as a white powder. LC-MS: 531.7 [M+H] + . 1H NMR (400MHz, CD3OD) δ8.52(s,1H),7.52(d,J=2.0Hz,1H),7.45(d,J=8.4Hz,1H ),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.42(q,J=7.2Hz,1H),4.26(m,2H),3.99 (m,2H),3.49(m,2H),3.13(t,J=6.0Hz,2H),2.77(s,3H),2.62(m,2H),2.51(m, 2H), 2.12 (m, 1H), 2.04 (d, J = 7.2Hz, 3H), 2.00–1.75 (m, 4H), 1.36–1.21 (m, 3H).

[0846] Example 111

[0847] first step:

[0848] 5-Bromo-1-fluoro-3-methoxy-2-nitrobenzene (I-111-a) (530 mg, 2.120 mmol) was dispersed in DMF (6 mL). (R)-1-(2,4-dichlorophenyl)ethanamine (I-4-b) (443 mg, 2.331 mmol) and potassium carbonate (352 mg, 2.547 mmol) were added sequentially. The reaction mixture was reacted at 125°C overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and ethyl acetate (25 mL) was added to the residue, which was then washed 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 = 100 / 0-100 / 2, V / V) to give a yellow powder compound (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methoxy-2-nitroaniline (I-111-b) (850 mg, yield 95.5%). 1 H NMR (400MHz, CDCl3) δ7.41(d,J=2.0Hz,1H),7.26(t,J=4.2Hz,1H),7.21(dd,J=8.4,2.0Hz,1H),6.61(d,J=5. 0Hz, 1H), 6.41 (d, J = 1.7Hz, 1H), 6.17 (d, J = 1.7Hz, 1H), 4.96–4.86 (m, 1H), 3.85 (s, 3H), 1.52 (d, J = 6.7Hz, 3H).

[0849] Step 2:

[0850] (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methoxy-2-nitroaniline (I-111-b) (830 mg, 1.976 mmol) was dispersed in a mixture of ethanol (8 mL) and water (2 mL). Iron powder (552 mg, 9.884 mmol) and ammonium chloride (212 mg, 3.963 mmol) were slowly added. The reaction mixture was reacted at 90°C for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to obtain a brown powder (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-3-methoxy-2-nitroaniline. 1 -(1-(2,4-dichlorophenyl)ethyl)-3-methoxybenzene-1,2-diamine (I-111-c) (765 mg) can be used directly in the next reaction. LC-MS: 390.6 [M+H] + .

[0851] Step 3:

[0852] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-3-methoxybenzene-1,2-diamine (I-111-c) (765 mg) was dissolved in dichloromethane (8 mL) and acetic acid (3 mL). Sodium nitrite (203 mg, 2.940 mmol) was added, and the reaction mixture was allowed to react at room temperature overnight. After completion of the reaction, the acetic acid was evaporated under reduced pressure, and the residue was added to a saturated sodium carbonate solution (15 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1-10 / 1, v / v) to obtain (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazole (I-111-d) (560 mg) as a white powder. LC-MS: 401.6 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.46 (d, J = 2.0Hz, 1H), 7.20 (dd, J1 = 8.4Hz, J2 = 2.0Hz, 1H), 7.11 (d, J = 8.4Hz, 1H), 7.10(d,J=1.2Hz,1H), 6.81(d,J=1.2Hz,1H), 6.26(q,J=7.2Hz,1H), 4.13(s,3H), 2.16(d,J=7.2Hz,3H).

[0853] Step 4:

[0854] (R)-6-Bromo-1-(1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazole (I-111-d) (100 mg, 0.249 mmol) was dispersed in 1,4-dioxane (8 mL) solution, and (1R, 3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) hydrochloride (113 mg, 0.373 mmol), Pd2(dba)3 (12 mg, 0.0131 mmol), BINAP (16 mg, 0.0257 mmol) and Cs2CO3 (171 mg, 0.525 mmol) were added in sequence. The reaction system was replaced with argon three times and heated to 110°C for overnight reaction. After the reaction is completed, the mixture is cooled to room temperature and filtered. The filter cake is washed with methanol, and the filtrate is concentrated under reduced pressure to give a brown crude product (90 mg) of (1R,3r)-3-((R)-3-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-111-e), which is used directly in the next reaction. LC-MS: 586.2 [M+H] + .

[0855] Step 5:

[0856] Water (0.5 mL), methanol (2 mL) and sodium hydroxide (20 mg, 0.500 mmol) were added sequentially to the crude product (90 mg) of (1R, 3r)-3-((R)-3-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-111-e), and the reaction mixture was stirred at 50°C overnight. After completion of the reaction, the mixture was cooled to room temperature, and the methanol was evaporated under reduced pressure. The residue was purified by preparative silica gel chromatography (dichloromethane / methanol = 10 / 1, V / V) to give (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-111) (60 mg). LC-MS: 572.3 [M+H]. + . 1H NMR (400MHz, CD3OD) δ7.54 (d, J=2.0Hz, 1H), 7.32 (dd, J1=8.4Hz, J2=2.0Hz, 1H), 7 .21(d,J=8.4Hz,1H),6.27(q,J=6.8Hz,1H),6.01(s,1H),5.72(s,1H),4.02(s,3H ),3.97(m,1H),3.68(m,2H),3.28–3.16(m,2H),2.72(m,2H),2.49(m,2H),2.22(m ,1H),2.09(m,2H),2.07(d,J=6.8Hz,3H),1.93(m,5H),1.71(m,2H),1.39(s,3H).

[0857] Example 112

[0858] Step 1: Compound (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-methoxy-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-111) (75 mg, 0.131 mmol) was dissolved in dichloromethane (3 mL), cooled to 0°C, and aluminum chloride (75 mg, 0.562 mmol) was added. The reaction mixture was reacted at room temperature overnight. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative silica gel chromatography (DCM / MeOH = 5 / 1, V / V) and then purified by HPLC to give the formate salt of (1R,3r)-3-((R)-3-(1-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-4-hydroxy-1H-[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-112) (12 mg, 16.4% yield) as an off-white powder. LCMS: 557.7 (M+H)+. 1HNMR (400MHz, CD3OD) δ8.44 (s, 1H), 7.55 (d, J = 2.0Hz, 1H), 7.33 (dd, J1 = 8.4Hz, J2 = 2.0Hz, 1 H),7.19(d,J=8.4Hz,1H),6.25(d,J=7.2Hz,1H),5.95(s,1H),5.36(t,J=4.8Hz,1H),4.10–3 .97(m,2H),3.73–3.61(m,2H),3.50(m,1H),3.22(m,2H),2.79(m,2H),2.22(m,2H),2.07(d, J=7.2Hz,3H),2.01(m,1H),1.75–1.71(m,2H),1.49–1.46(m,2H),1.34(s,3H),1.30(m,3H).

[0859] Example 113

[0860] Step 1: Disperse 2,4-dichlorobenzaldehyde (I-113-a) (1 g, 5.71 mmol), (R)-2-methylpropane-2-sulfamide (1.25 g, 10.29 mmol), and isopropyl titanate (8.12 g, 28.57 mmol) in ultra-dry tetrahydrofuran (8 mL). The reaction mixture was stirred at 70°C under argon for 16 hours. LC-MS monitored the reaction until the starting materials reacted completely. The reaction mixture was concentrated under reduced pressure and then added with saturated brine (10 mL). The precipitated solid was filtered and the filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R,E)-N-(2,4-dichlorobenzylidene)-2-methylpropane-2-sulfamide (I-113-b) (1.1 g, 69%). LC-MS: 277.8 [M+H] + .

[0861] Step 2: Disperse (R,E)-N-(2,4-dichlorobenzylidene)-2-methylpropane-2-sulfamide (I-113-b) (1.1 g, 4.0 mmol) in ultra-dry tetrahydrofuran (8 mL) and cool to -40°C under argon. Add deuterated iodomethane in ether (5.9 mL, 5.9 mmol, 1 mol / L) dropwise. Maintain the reaction mixture at -40°C with stirring for 3 hours and gradually warm to room temperature. Monitor the reaction by LC-MS until complete reaction is complete. The reaction mixture was quenched by adding water (10 mL) and 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 column chromatography (ethyl acetate:petroleum ether = 20%) to afford 1 g of a mixture of (R)-N-((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cA) and (R)-N-((S)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cB). SFC preparative separation afforded (R)-N-((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cA) (350 mg, 29%). LC-MS: 277.8 [M+H] + .

[0862] SFC preparative chromatography separation conditions: 1. Instrument: Waters 150SFC; 2. Column: Chiralpak AD-H-Column (250×19 mm, 5 μm particle size); 3. Flow rate: A for CO2 and B for EtOH; 4. Gradient: B 20%; 5. Flow rate: 50 mL / min. Fractions from Peak 1 (retention time: 2.16 min) were combined to yield 600 mg of (R)-N-((S)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cB), and fractions from Peak 2 (retention time: 3.20 min) were combined to yield 350 mg of (R)-N-((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cA).

[0863] Step 3: Disperse (R)-N-((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-2-methylpropane-2-sulfamide (I-113-cA) (350 mg, 1.18 mmol) in dichloromethane (7 mL), and then add a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 mol / L). The reaction mixture was stirred at room temperature for 6 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction mixture was filtered to obtain the crude product (R)-1-(2,4-dichlorophenyl)ethane-2,2-d3-amine (I-113-d) hydrochloride (216 mg, 80%), which was used directly in the next step. LC-MS: 192.9 [M+H] + .

[0864] Step 4: Disperse 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (I-59-a) (220 mg, 0.94 mmol), (R)-1-(2,4-dichlorophenyl)ethane-2,2-d3-amine (I-113-d) hydrochloride (216 mg, 0.94 mmol), and potassium carbonate (390 mg, 2.82 mmol) in DMF (10 mL). Stir the reaction at 120°C for 16 hours. Monitor the reaction by LC-MS until the starting material is completely reacted. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added, followed by extraction with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (ethyl acetate: petroleum ether = 10%) to give (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-3-methyl-2-nitroaniline (I-113-e) (240 mg, 63%).

[0865] Step 5: Disperse (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-3-methyl-2-nitroaniline (I-113-e) (240 mg, 0.59 mmol) and hydrosulfite (2.05 g, 11.79 mmol) in ethanol (5 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 24 hours. LC-MS was used to monitor the reaction until the starting material reacted completely. The reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (ethyl acetate:petroleum ether = 30%) to afford (R)-5-bromo-N-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-3-methylbenzene-1,2-diamine (I-113-f) (170 mg, 76%). LC-MS: 375.7 [M+H] + .

[0866] Step 6: Disperse (R)-5-bromo-N1-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-3-methylbenzene-1,2-diamine (I-113-f) (260 mg, 0.45 mmol) and sodium nitrite (34 mg, 0.49 mmol) in glacial acetic acid (5 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS monitoring was performed until the reaction of the starting material was complete. The reaction mixture was concentrated under reduced pressure, added with saturated sodium bicarbonate solution (10 mL), and extracted with ethyl acetate (10 mL). The organic phase was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (ethyl acetate:petroleum ether = 20%) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-4-methyl-1H-benzo[d][1,2,3]triazole (I-113-g) (80 mg, 46%). LC-MS: 386.7 [M+H] + .

[0867] Step 7: Disperse the hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (77 mg, 0.23 mmol), (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-4-methyl-1H-benzo[d][1,2,3]triazole (I-113-g) (80 mg, 0.21 mmol), Pd2(dba)3 (19 mg, 0.02 mmol), BINAP (26 mg, 0.04 mmol), and Cs2CO3 (336 mg, 1.04 mmol) in ultra-dry dioxane (5 mL). Stir the reaction mixture at 100°C under argon for 16 hours. Monitor the reaction by LC-MS until the reaction is complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol:dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-(((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-113-h) (40 mg, 34%). LC-MS: 572.7 [M+H]. + .

[0868] Step 8: (1R,3r)-3-((R)-3-(1-(1-(((R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-113-h) (40 mg, 0.07 mmol) and lithium hydroxide (17 mg, 0.70 mmol) were dispersed in methanol (5 mL) and water (0.5 mL), and the reaction solution was stirred at room temperature. 4 hours. LC-MS monitored the reaction until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by GF254 preparative plate (methanol: dichloromethane = 10%) to obtain (1R,3r)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl-2,2,2-d3)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-113) (30 mg, 77%). LC-MS: 558.7 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.55(d,J=2.1Hz,1H),7.32(dd,J=8.5,2.1Hz,1H),7.21(d,J=8.5H z,1H),6.45(s,1H),6.30(s,1H),5.99(d,J=1.3Hz,1H),3.98(dt,J=18.7,7.7Hz,2H),3.7 4–3.58(m,2H),3.48–3.38(m,1H),3.24(dd,J=20.3,12.6Hz,2H),2.74(dd,J=11.7,7.6H z,2H),2.64(s,3H),2.54–2.38(m,2H),2.30–2.15(m,1H),2.09–1.85(m,5H),1.71(dd,J= 26.9,13.4Hz,2H),1.39(s,3H).

[0869] Example 115

[0870] first step:

[0871] To a three-necked round-bottom flask (25 mL) were added 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (I-91) (100 mg, 0.2 mmol) and DMA (3 mL) in sequence. The system was protected by argon and then cooled in an ice bath. Chlorosulfonamide (115.5 mg, 1 mmol) was added. After the addition, the temperature was slowly raised to room temperature and stirred overnight. After completion of the reaction, separation was performed using a C-18 reverse phase column (H2O:MeOH = 100:65 to 100:85) to obtain ethyl 2-((R)-3-(1-(3-((R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)sulfamate (I-115) (25 mg, 22% yield) as a white solid. LC-MS: 569.0 [M+H] + . 1 H NMR(400MHz,d-DMSO)δ7.66(dd,J=16.1,3.4Hz,1H),7.50(d,J=13.6Hz,2H),6 .34–6.22(m,1H),5.35-4.35(m,2H),4.3-3.65(m,8H),3.55-3.42(m,1H),3.2 1-3.02(m,1H),2.70(dd,J=5.4,3.6Hz,3H),2.42-2.26(m,1H),2.01–1.94(m, 3H),1.92-1.74(m,3H),1.73-1.54(m,1H),1.25(d,J=6.5Hz,1H),1.11(m,1H).

[0872] Example 116

[0873] Step 1: Disperse 5-bromo-1-fluoro-3-methyl-2-nitrobenzene (I-59-a) (0.50 g, 2.1 mmol), (2,4-dichlorophenyl)methanamine (I-116-a) (0.38 g, 2.22 mmol), and potassium carbonate (0.60 g, 4.3 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at 100°C for 24 hours. The reaction was monitored by LC-MS until the starting materials were completely reacted. The reaction mixture was concentrated under reduced pressure, added with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 99:1) to afford 5-bromo-N-(2,4-dichlorobenzyl)-3-methyl-2-nitroaniline (I-116-b) (0.49 g, 59%) as a brown solid.

[0874] Step 2: Disperse 5-bromo-N-(2,4-dichlorobenzyl)-3-methyl-2-nitroaniline (I-116-b) (0.49 g, 1.256 mmol), reduced iron powder (0.352 g, 6.304 mmol), and ammonium chloride (0.202 g, 3.776 mmol) in ethanol (20 mL) and glacial acetic acid (1 mL). The reaction mixture was stirred at 100°C for 2 hours. TLC was used to monitor the reaction until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, added with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate:petroleum ether = 1:30) to afford 5-bromo-N-(2,4-dichlorobenzyl)-3-methylbenzene-1,2-diamine (I-116-c) (0.33 g, 73%) as a brown oil. LC-MS: 358.6 [M+H] + .

[0875] Step 3: Dissolve 5-bromo-N1-(2,4-dichlorobenzyl)-3-methylbenzene-1,2-diamine (I-116-c) (330 mg, 0.92 mmol) in glacial acetic acid (6 mL) and cool to below 10°C. Dissolve sodium nitrite (70 mg, 1.01 mmol) in water (0.5 mL) and add dropwise to the reaction mixture. Stir the mixture at room temperature for 3 hours. Monitor the reaction by LC-MS until the reaction is complete. The reaction mixture is concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL x 3). The organic phase is concentrated under reduced pressure to obtain the crude product, which is then purified by column chromatography (ethyl acetate:petroleum ether = 3:97) to afford 6-bromo-1-(2,4-dichlorobenzyl)-4-methyl-1H-benzo[d][1,2,3]triazole (I-116-d) (240 mg, 71%). LC-MS: 371.6 [M+H] + .

[0876] Step 4: Disperse the hydrochloride salt of (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-1-g) (196 mg, 0.776 mmol), 6-bromo-1-(2,4-dichlorobenzyl)-4-methyl-1H-benzo[d][1,2,3]triazole (I-116-d) (240 mg, 0.65 mmol), Pd2(dba)3 (102.4 mg, 0.11 mmol), BINAP (123.3 mg, 0.198 mmol), and Cs2CO3 (1485 mg, 4.58 mmol) in ultra-dry dioxane (10 mL). Stir the reaction mixture at 100°C under argon for 16 hours. Monitor the reaction by LC-MS until the reaction is complete. The reaction mixture was filtered and concentrated under reduced pressure to give the crude product (1R,3r)-3-((R)-3-(1-(1-(2,4-dichlorobenzyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-116-e). The crude product was used directly in the next step without purification. LC-MS: 557.8 [M+H] + .

[0877] Step 5: Disperse the crude product of (1R,3r)-3-((R)-3-(1-(1-(2,4-dichlorobenzyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-116-e) with lithium hydroxide (136 mg, 5.68 mmol) in methanol (6 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The pH was adjusted to 4-5 with 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 purified by TLC (dichloromethane:methanol=5:1) to give (1R,3r)-3-(1R,3r)-3-((R)-3-(1-(1-(2,4-dichlorobenzyl)-4-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-116) (2.13 mg). LC-MS: 544.1 [M+H]. + , 1H NMR (400MHz, CD3OD) δ7.56(d,J=2.1Hz,1H),7.28(dd,J=8.4,2.1Hz,1H),6.94(d,J=8.4Hz,1H),6 .46(s,1H),6.12(d,J=1.5Hz,1H),5.84(s,2H),4.00(dd,J=17.4,7.8Hz,2H),3.67(dd,J=13.1,6. 7Hz,2H),3.45(d,J=22.4Hz,2H),3.22(d,J=11.4Hz,1H),2.78–2.69(m,2H),2.69–2.40(m,5H),2. 25(s,1H),1.97(dd,J=19.2,10.5Hz,5H),1.77–1.66(m,1H),1.38(s,3H),1.13(d,J=11.3Hz,1H).

[0878] Example 117

[0879] Step 1: (R)-tert-Butyl 3-(piperidin-3-yl)azetidine-1-carboxylate (I-1-d) (224 mg, 0.932 mmol) was dissolved in acetonitrile (3 mL), and ethylenesulfonamide (100 mg, 0.933 mmol) was added. The reaction mixture was allowed to react at 30°C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure to afford tert-butyl 3-(1-(2-sulfamoylethyl)piperidin-3-yl)azetidine-1-carboxylate (I-117-a) (323 mg, 99.7%) as a yellow oil, which was used directly in the next step. LCMS: 347.9 (M+H)+.

[0880] Step 2: A methanol solution of hydrogen chloride (2 mL, 4 mol / L) was added to the compound (R)-3-(1-(2-sulfamoylethyl)piperidin-3-yl)azetidine-1-carboxylic acid tert-butyl ester (I-117-a) (323 mg, 0.930 mmol). The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride salt of (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide (I-117-b) as a yellow oil (260 mg, yield 98.6%), LCMS: 248.2 (M+H)+.

[0881] Step 3: Compound (R)-5-chloro-3-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (I-69-c) (90 mg, 0.263 mmol), DMSO (2 mL) and potassium carbonate (76 mg, 0.550 mmol) were added sequentially to the hydrochloride salt (110 mg, 0.388 mmol) of compound (R)-2-(3-(azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide (I-117-b). The reaction mixture was reacted at 120°C overnight. After the reaction was completed, the mixture was cooled to room temperature, ethyl acetate (15 mL) was added, and the mixture was washed with water (5 mL) and saturated brine (5 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1, V / V) to give a yellow powder compound 2-((R)-3-(1-(3-(R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethane-1-sulfonamide (I-117) (18 mg, yield 12.4%). LCMS: 553.0 (M+H)+ 1 H NMR (400MHz, CD3OD) δ7.52(d,J=2.0Hz,1H),7.48(d,J=8.4Hz,1H),7.35(dd,J1=8.4Hz,J2=2.0Hz,1H),6.42(q,J=7.2Hz,1H),4.22(m,2H ),3.93(m,2H),3.34(m,2H),3.31(m,2H),2.92(m,4H),2.76(s,3H),2.11(m,1H),2.04(d,J=7.2Hz,3H),1.87–1.70(m,4H),1.61(m,1H).

[0882] Example 118

[0883] first step:

[0884] 1-Bromo-3-fluoro-2-methyl-4-nitrobenzene (I-118-a) (0.50 g, 2.14 mmol), (R)-1-(2,4-dichlorophenyl)ethane-1-amine (I-4-b) (406 mg, 2.14 mmol), and potassium carbonate (0.59 g, 4.27 mmol) were dispersed in acetonitrile (4 mL). The reaction mixture was stirred at 100°C for 24 hours. The reaction was monitored by TLC until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (ethyl acetate:petroleum ether = 99:1) to obtain (R)-3-bromo-N-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-nitroaniline (I-118-b) (350 mg, 40.54%).

[0885] Step 2:

[0886] (R)-3-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-nitroaniline (I-118-b) (0.35 g, 0.87 mmol), reduced iron powder (0.25 g, 4.48 mmol), and ammonium chloride (140 mg, 2.62 mmol) were dispersed in ethanol (10 mL) and glacial acetic acid (0.5 mL). The reaction mixture was stirred at 90°C for 4 hours. LC-MS monitoring was performed until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate:petroleum ether = 97:3) to afford (R)-5-Bromo-N-(1-(2,4-dichlorophenyl)ethyl)-6-methylbenzene-1,2-diamine (I-118-c) (0.27 g, 83%). LC-MS: 374.1[M+H] + .

[0887] Step 3:

[0888] (R)-5-Bromo-N1-(1-(2,4-dichlorophenyl)ethyl)-6-methylbenzene-1,2-diamine (I-118-c) (270 mg, 0.72 mmol) was dispersed in glacial acetic acid (5 mL) and cooled to below 10°C. Sodium nitrite (70 mg, 1.16 mmol) was dissolved in water (0.5 mL) and then added dropwise to the acetic acid solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by LC-MS until the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate solution (10 mL) was added, 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 then purified by column chromatography (ethyl acetate:petroleum ether = 97:3) to afford (R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-1H-benzo[d][1,2,3]triazole (I-118-d) (200 mg, 70%). LC-MS: 385.6 [M+H] + .

[0889] Step 4:

[0890] The hydrochloride of methyl ((1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylate (I-1-g) (167 mg, 0.63 mmol), ((R)-6-bromo-1-(1-(2,4-dichlorophenyl)ethyl)-7-methyl-1H-benzo[d][1,2,3]triazole (I-118-d) (200 mg, 0.52 mmol), Pd2(dba)3 (75 mg, 0.082 mmol), BINAP (98 mg, 0.157 mmol), Cs2CO3 (1.18 g, 3.62 mmol) was dispersed in ultra-dry dioxane (10 mL), and the reaction solution was stirred at 100°C under argon protection for 16 hours. The reaction was monitored by LC-MS until the reaction of the raw materials was complete. After filtration, the reaction solution was concentrated under reduced pressure to obtain the crude product, (1R,3r)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-118-e). The crude product was used directly in the next step without purification. LC-MS: 571.8 [M+H] + .

[0891] Step 5:

[0892] The crude product (1R,3r)-3-((R)-3-(1-(1-(R)-1-(2,4-dichlorophenyl)ethyl)-7-methyl-1H-benzo[d][1,2,3]triazol-6-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid methyl ester (I-118-e) from the previous step was dispersed in methanol (5 mL). Lithium hydroxide (300 mg, 13 mmol) and water (1 mL) were added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LC-MS until the reaction of the starting material was complete. The reaction solution was concentrated under reduced pressure, and water (10 mL) was added. The mixture was extracted with eth...

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 2 , X 1’ , X 2’ , X 1” , X 2” Each is independently halogen, C2-C6 alkynyl or cyano; Y 1 、Y 2 、Y 3 、Y 4 、Y 1’ 、Y 2’ 、Y 3’ 、Y 4’ 、Y 1” 、Y 2” 、Y 3” 、Y 4” each independently represents N or CR 4 ; R 4 is hydrogen, halogen, cyano, C1-C6 alkyl, or one or more R 4-1 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, substituted by one or more R 4-2 Substituted C1-C6 alkoxy, hydroxy, deuterated C1-C6 alkyl, -NH2, C2-C6 alkynyl, C2-C6 alkenyl, -O-C3-C8 cycloalkyl, substituted by one or more R 4-3 Substituted C3-C8 cycloalkyl, one or more R 4-4 Substituted C1-C6 alkoxy; R 4-1 is halogen, cyano, hydroxyl; R 4-2 is a halogen; R 4-3 is halogen, -NH2, hydroxyl, C1-C6 alkyl or -OC(O)-C1-C6 alkyl; R 4-4 is a halogen; R 1 , R 2 , R 1’ , R 2’ , R 1” , R 2” are independently hydrogen, deuterium, C1-C6 alkyl, deuterated C1-C6 alkyl, 1-1 Substituted C1-C6 alkyl; R 1-1 is a halogen; R 3 , R 3” is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; R 3-1 is a C3-C8 cycloalkyl group, 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, substituted by one or more R 3- 1-2 Substituted C1-C6 alkyl, C3~C8 heterocycloalkyl, 3-1-3 Pick substituted C3-C8 heterocycloalkyl, -COOH; the C3-C8 heterocycloalkyl may be replaced by one or more R 3-1-3 The heteroatoms in the substituted C3-C8 heterocycloalkyl are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; R 3-1-1 C1-C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 , by one or more R 3-1-1-2 Substituted C1-C6 alkyl, -CONR 3-1-1-3 R 3-1-1-4 , cyano, NR 3-1-1-5 R 3-1-1-6 , R 3-1-1-1 is a C1-C6 alkyl group; R 3-1-1-2 is hydroxyl or halogen; R 3-1-1-3 , R 3-1-1-4 are independently H or C1-C6 alkyl; R 3-1-1-5 , R 3-1-1-6 are independently H or C1-C6 alkyl; R 3-1-1-7 is a hydroxyl group or a C1-C6 alkoxy group; R 3-1-1-8 , R 3-1-1-9 are independently H, C1-C6 alkyl; R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 , -COOH, -OSO3H, -OSO2NH2, -SO3H, two R 3-1-2 Forming C3-C8 cycloalkyl, two R 3-1-2 Formed by one or more R 3-1-2-5 Substituted C3-C8 cycloalkyl, -CONR 3-1- 2-6 R 3-1-2-7 , cyano; R 3-1-2-1 , R 3-1-2-2 independently hydrogen or -SO2R 3-1-2-1-1 ; R 3-1-2-1-1 is -NH2, hydroxyl or C1-C6 alkyl; R 3-1-2-3 is a C1-C6 alkyl group, -NR 3-1-2-3-1 R 3-1-2-3-2 ; R 3-1-2-3-1 , R 3-1-2-3-2 are independently hydrogen, -COR 3-1-2-3-1-1 ; R 3-1-2-3-1-1 is a C1-C6 alkyl group; R 3-1-2-4 is -SO2NH2; R 3-1-2-5 is a C1-C6 alkyl or halogen; R 3-1-2-6 is hydrogen or a C1-C6 alkyl group; R 3-1-2-7 is hydrogen or a C1-C6 alkyl group; R 3-1-3 is a C1-C6 alkyl or halogen; R 3-2 , R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ; R 3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; the 4-12 membered heterocycloalkyl may be replaced by one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3-2-1-1 is hydrogen or a C1-C6 alkyl group; Among them, in the compound shown in formula II, Ring A is a 7-12 membered spiro heterocycle or a 7-12 membered para-heterocycle or a phenyl group; the heteroatoms in the spiro heterocycle or para-heterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’ For-NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1-C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted by one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4. R 3’-1 , R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ; R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1 Substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl The heteroatoms are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group; R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-3-1 is hydrogen or a C1-C6 alkyl group; R 3’-4 is hydroxyl group; R 3’-5 It is a C1-C6 alkyl group or -COOH; R 3’-6 is a C1-C6 alkyl group; Among them, in the compound shown in formula III, R 5” It is a halogen.

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 or Formula II: X 1 , X 2 , X 1’ , X 2’ are each independently halogen or cyano; Y 1 , Y 2 , Y 3 , Y 4 , Y 1’ , Y 2’ , Y 3’ , Y 4’ Each independently is N or CR 4 ; R 4 is hydrogen, halogen, cyano, C1-C6 alkyl or is replaced by one or more R 4-1 Substituted C1-C6 alkyl; R 4-1 is halogen or cyano; R 1 , R 2 , R 1’ , R 2’ Each is independently hydrogen or a C1-C6 alkyl group; R 3 is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; R 3-1 is a C3-C8 cycloalkyl group, 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, substituted by one or more R 3- 1-2 Substituted C1-C6 alkyl, C3~C8 heterocycloalkyl, 3-1-3 Substituted C3-C8 heterocycloalkyl; the C3-C8 heterocycloalkyl may be replaced by one or more R 3-1-3 The heteroatoms in the substituted C3-C8 heterocycloalkyl are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; R 3-1-1 C1-C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 , by one or more R 3-1-1-2 Substituted C1-C6 alkyl, -CONR 3-1-1-3 R 3-1-1-4 , cyano, NR 3-1-1-5 R 3-1-1-6 ; R 3-1-1-1 is a C1-C6 alkyl group; R 3-1-1-2 is hydroxyl or halogen; R 3-1-1-3 , R 3-1-1-4 are independently H or C1-C6 alkyl; R 3-1-1-5 , R 3-1-1-6 are independently H or C1-C6 alkyl; R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 , -COOH, two R 3-1-2 Forming C3-C8 cycloalkyl, two R 3-1-2 Formed by one or more R 3-1-2-5 Substituted C3-C8 cycloalkyl; R 3-1-2-1 , R 3-1-2-2 independently hydrogen or -SO2R 3-1-2-1-1 ; R 3-1-2-1-1 is -NH2 or a C1-C6 alkyl group; R 3-1-2-3 is a C1-C6 alkyl group; R 3-1-2-4 is -SO2NH2; R 3-1-2-5 is a C1-C6 alkyl or halogen; R 3-1-3 is a C1-C6 alkyl or halogen; R 3-2 , R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ; R 3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; the 4-12 membered heterocycloalkyl may be replaced by one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3-2-1-1 is hydrogen or a C1-C6 alkyl group; Among them, in the compound shown in formula II, Ring A is a 7-12 membered spiro heterocycle or a 7-12 membered para-heterocycle or a phenyl group; the heteroatoms in the spiro heterocycle or para-heterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’ For-NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1-C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted by one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4. R 3’-1 , R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ; R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1 Substituted 4-8 membered heterocycloalkyl; the heteroatoms in the 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group; R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-3-1 is hydrogen or a C1-C6 alkyl group; R 3’-4 is hydroxyl group; R 3’-5 It is a C1-C6 alkyl group or -COOH; R 3’-6 is a C1-C6 alkyl group; Preferably, in the compound as shown in Formula I or Formula II: X 1 , X 2 , X 1’ , X 2’ are each independently halogen or cyano; Y 1 , Y 2 , Y 3 , Y 4 , Y 1’ , Y 2’ , Y 3’ , Y 4’ Each independently is N or CR 4 ; R 4 is hydrogen, halogen, cyano, C1-C6 alkyl or is replaced by one or more R 4-1 Substituted C1-C6 alkyl; R 4-1 is halogen or cyano; R 1 , R 2 , R 1’ , R 2’ Each is independently hydrogen or a C1-C6 alkyl group; R 3 is a 4-8 membered heterocycloalkyl group, 3-1 Substituted 4-8 membered heterocycloalkyl, -NR 3-2 R 3-3 The 4-8 membered heterocycloalkyl group may be replaced by one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are independently one or more of nitrogen, oxygen, sulfur, boron, silicon, selenium or phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; R 3-1 is a C3-C8 cycloalkyl group, 3-1-1 Substituted C3-C8 cycloalkyl, C1-C6 alkyl, substituted by one or more R 3- 1-2 Substituted C1-C6 alkyl, R 3-1-1 It is a C1-C6 alkyl, -COOH or hydroxyl group; R 3-1-2 Hydroxyl, -NR 3-1-2-1 R 3-1-2-2 、-SO2R 3-1-2-3 、-OR 3-1-2-4 or -COOH; R 3-1-2-1 , R 3-1-2-2 independently hydrogen or -SO2R 3-1-2-1-1 ; R 3-1-2-1-1 is -NH2 or a C1-C6 alkyl group; R 3-1-2-3 is a C1-C6 alkyl group; R 3-1-2-4 is -SO2NH2; R 3-2 , R 3-3 are independently hydrogen, C1-C6 alkyl, -COOH or -CO-R 3-2-1 ; R 3-2-1 is a 4-12 membered heterocycloalkyl group, 3-2-1-1 substituted 4-12 membered heterocycloalkyl; the 4-12 membered heterocycloalkyl may be replaced by one or more R 3-2-1-1 The heteroatoms in the substituted 4-12 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3-2-1-1 is hydrogen or a C1-C6 alkyl group; Among them, in the compound shown in formula II, Ring A is a 7-12 membered spiro heterocycle or a 7-12 membered para-heterocycle or a phenyl group; the heteroatoms in the spiro heterocycle or para-heterocycle are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’ For-NR 3’-1 R 3’-2 、-CO-R 3’-3 , C1-C6 alkyl, one or more R 3’-4 Substituted C1-C6 alkyl, C3-C8 cycloalkyl, substituted by one or more R 3’-5 Substituted C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl or one or more R 3’-6 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-6 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4. R 3’-1 , R 3’-2 are independently hydrogen, C1-C6 alkyl or -CO-R 3’-1-1 ; R 3’-1-1 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-1-1-1 Substituted 4-8 membered heterocycloalkyl; the heteroatoms in the 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-1-1-1 is hydrogen or a C1-C6 alkyl group; R 3’-3 is a 4-8 membered heterocycloalkyl group or is replaced by one or more R 3’-3-1 substituted 4-8 membered heterocycloalkyl; the 4-8 membered heterocycloalkyl may be replaced by one or more R 3’-3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are each independently one or more of nitrogen, oxygen or sulfur, and the number of heteroatoms is each independently 1, 2, 3 or 4; R 3’-3-1 is hydrogen or a C1-C6 alkyl group; R 3’-4 is hydroxyl group; R 3’-5 It is a C1-C6 alkyl group or -COOH; R 3’-6 It is a C1-C6 alkyl group.

3. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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 compounds represented by Formula I and Formula III independently satisfy one or more of the following conditions: (1)R 3 , R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is independently a 5- or 6-membered heterocycloalkyl; (2)R 3 , R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is independently a 7-membered heterocycloalkyl; (3)R 3 wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are independently N, and the number of the heteroatoms is 1 or 2; (4)R 3 , R 3” wherein the 4-8 membered heterocycloalkyl group and the one or more R 3-1 The heteroatoms in the substituted 4-8 membered heterocycloalkyl are independently N or O, and the number of heteroatoms is 1 or 2; (5)R 3-1 , R 4 wherein the C3-C8 cycloalkyl group is replaced by one or more R 3-1-1 Substituted C3-C8 cycloalkyl, one or more R 4-3 The C3-C8 cycloalkyl in the substituted C3-C8 cycloalkyl and -O-C3-C8 cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane; (6)R 3-1 In the above, the C1-C6 alkyl group is replaced by one or more R 3-1-2 The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (7)R 3-2-1 wherein the 4-12 membered heterocycloalkyl and the 3-2-1-1 The 4-12-membered heterocycloalkyl in the substituted 4-12-membered heterocycloalkyl is independently a 5- or 6-membered heterocycloalkyl; (8)R 3-2-1 wherein the 4-12 membered heterocycloalkyl and the 3-2-1-1 The heteroatom in the substituted 4-12 membered heterocycloalkyl group is independently N, and the number of the heteroatom is 1 or 2.

4. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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 as shown in Formula I or Formula III independently satisfies one or more of the following conditions: (1)R 3-1 In the present invention, C3-C8 heterocycloalkyl, one or more R 3-1-3 Substituted C3-C8 heterocycloalkyl; the C3-C8 heterocycloalkyl may be replaced by one or more R 3-1-3 The C3-C8 heterocycloalkyl in the substituted C3-C8 heterocycloalkyl is cyclobutane, cyclopentane or cyclohexane; (2)R 3-1 In the present invention, C3-C8 heterocycloalkyl, one or more R 3-1-3 Substituted C3-C8 heterocycloalkyl; the C3-C8 heterocycloalkyl may be replaced by one or more R 3-1-3 The heteroatoms in the substituted C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is independently 1, 2, 3 or 4; (3)R 3-1-3 , R 3-1-1-1 , R 3-1-1 , R 3-1-1-3 , R 3-1-1-4 , R 3-1-1-5 , R 3-1-1-6 , R 3-1-2-5 , R 3-1-2-6 , R 3-1-2-7 wherein the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (4)R 3-1-3 , R 3-1-1-2 , R 3-1-2-5 wherein the halogen is independently F, Cl, Br or I; (5)R 3-1-2 Two R's 3-1-2 Forming a C3-C8 cycloalkyl group or two R 3-1-2 Formed by one or more R 3-1-2-5 The C3~C8 cycloalkyl group in the substituted C3~C8 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, preferably cyclopropane.

5. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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 as shown in Formula I, R 3 In the above, the one or more R 3-1 The substituted 4-8 membered heterocycloalkyl is wherein n1 is 1, 2 or 3; preferably, the 3- 1 The substituted 4-8 membered heterocycloalkyl is Wherein n1 is 1, 2 or 3; preferably 6. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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 as shown in Formula I, R 3 In the above, the -NR 3-2 R 3-3 for Where n2 is 1, 2 or 3.

7. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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) In ring A, the 7-12 membered spiro heterocycle is a 7- or 8-membered spiro heterocycle, and the 7-12 membered heterocycle is an 8- or 9-membered heterocycle; (2) In ring A, the heteroatom in the spiro heterocyclic ring or the fused heterocyclic ring is nitrogen, and the number of N atoms is independently 1 or 2; (3) R3', R 3’-1-1 , R 3’-3 wherein the 4-8 membered heterocycloalkyl and the substituted 4-8 membered heterocycloalkyl are independently 5- or 6-membered heterocycloalkyl; (4) R3', R 3’-1-1 , R 3’-3 In the 4-8 membered heterocycloalkyl group and the substituted 4-8 membered heterocycloalkyl group, the heteroatoms are independently N, and the number of the heteroatoms is 1 or 2; (5)R 1’ is hydrogen, R 2’ It is methyl.

8. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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, R 3’ In the above, the -NR 3’-1 R 3’-2 for Where n2' is 1, 2 or 3.

9. The compound of formula I, formula II or formula III as claimed in claim 1 or 2, 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)X 1 , X 2 , X 1’ , X 2’ , R 4 , R 4-1 , R 1-1 , X 1” , X 2” , R 4-2 , R 4-3 , R 4-4 wherein the halogen is independently F, Cl, Br or I; (2)R 4 , R 1 , R 2 , R 1’ , R 2’ , R 1” , R 2” , R 3-1 , R 3-1-1 , R 3-1-2-1-1 , R 3-1-2-3 , R 3-1-2-3-1-1 , R 3-2 , R 3-3 , R 3- 2-1-1 , R 3’ , R 3’-1 , R 3’-2 , R 3’-1-1-1 , R 3’-3-1 , R 3’-5 or R 3’-6 In the C1-C6 alkyl group and 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; (3)X 1 , X 2 , X 1’ , X 2’ In, the C2-C6 alkynyl group is ethynyl; (4)R 4 , R 3-1-1-7 In the above, the C1-C6 alkoxy group is replaced by one or more R 4-4 The alkoxy group in the substituted C1-C6 alkoxy group is methoxy, ethoxy, or propoxy; (5)R 4 In the above, the C2-C6 alkynyl group is ethynyl or propynyl; (6)R 4 In the above, the C2-C6 alkenyl group is vinyl or propenyl; (7) The C1-C6 alkyl group in the -OC(O)-C1-C6 alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl.

10. The compound of formula I, formula II or formula III as described 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: It meets one or more of the following conditions: (1)X 1 , X 2 , X 1’ , X 2’ , X 1 ” and X 2 ” are independently halogen; (2)R 1 , R 1’ and R 1” is hydrogen; (3)R 2 , R 2’ and R 2” are independently C1-C6 alkyl or deuterated C1-C6 alkyl; preferably, R 2 , R 2’ and R 2” are independently C1-C6 alkyl; (4)R 4 Choose from any of the following options: Option 1: R 4 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or one or more R 4-1 Substituted C1-C6 alkyl or one or more R 4-2 Substituted C1-C6 alkoxy; preferably, R 4 is hydrogen, halogen, C1-C6 alkyl or is replaced by one or more R 4-1 substituted C1-C6 alkyl; more preferably, R 4 is hydrogen, halogen or C1-C6 alkyl; or R 4 For one or more R 4-1 substituted C1-C6 alkyl; further preferably, R 4 is hydrogen or C1-C6 alkyl; most preferably, R 4 is hydrogen; Option 2: R 4 is C3-C8 cycloalkyl or is replaced by one or more R 4-3 Substituted C3-C8 cycloalkyl (5)R 4-1 is halogen or R 4-1 is hydroxyl group; (6)R 4-3 is halogen, -NH2, C1-C6 alkyl or -OC(O)-C1-C6 alkyl; preferably, R 4-3 is halogen, C1-C6 alkyl or -OC(O)-C1-C6 alkyl; (7)Y 4 CR 4 ; (8)R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said 3-1 The heteroatom of the 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is nitrogen, and the number of the heteroatom is independently 1 or 2; (9) Each R 3-1 Independently for one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or one or more R 3-1-2 substituted C1-C6 alkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; preferably, R 3-1 Independently for one or more R 3-1-1 Substituted C3-C8 cycloalkyl or one or more R 3-1-2 Substituted C1-C6 alkyl, or each R 3-1 Independently for one or more R 3-1-1 substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; preferably, each R 3-1 Independently for one or more R 3-1-2 Substituted C1-C6 alkyl, or, R 3-1 is a C3-C8 heterocycloalkyl group, wherein the heteroatoms in the C3-C8 heterocycloalkyl group are independently one or more of nitrogen and oxygen, and the number of the heteroatoms is 1, 2, 3 or 4; (10) Each R 3-1-1 are independently C1-C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 or-CONR 3-1-1-3 R 3-1-1-4 Preferably, each R 3-1-1 are independently C1-C6 alkyl or -COOH; (11) Each R 3-1-2 Independently -NR 3-1-2-1 R 3-1-2-2 、-CONR 3-1-2-6 R 3-1-2-7 , cyano, -OSO3H, -SO3H, -OSO2NH2 or-SO2R 3-1-2-3 Preferably, each R 3-1-2 Independently -NR 3-1-2-1 R 3-1-2-2 , -OSO3H or -OSO2NH2; Alternatively, each R 3-1-2 are independently hydroxyl or -COOH; preferably, each R 3-1-2 is hydroxyl group; (12) The compound as shown in formula I is a compound as shown in formula IA: (13) The compound as shown in formula I is not any of the following compounds 11. 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: The compound shown in Formula I is the following Scheme 1, Scheme 2, Scheme 3 or Scheme 4: Option 1: X 1 and X 2 are independently halogen; R 1 is hydrogen; R 2 is a C1-C6 alkyl group; Y 1 is N; Y 2 N or CH; Y 3 N or CH; Y 4 N or CR 4 ; R 4 is hydrogen, halogen or C1-C6 alkyl; R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said 3-1 The heteroatom of the 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is nitrogen, and the number of the heteroatom is independently 1 or 2; Each R 3-1 Independently for one or more R 3-1-1 Substituted C3-C8 cycloalkyl or one or more R 3-1-2 Substituted C1-C6 alkyl; Each R 3-1-1 C1-C6 alkyl, -COOH, hydroxyl, -COOR 3-1-1-1 or-CONR 3-1-1-3 R 3-1-1-4 ; R 3-1-1-1 is a C1-C6 alkyl group; R 3-1-1-3 and R 3-1-1-4 are independently H or C1-C6 alkyl; R 3-1-2 is hydroxyl group; Scenario 2: X 1 and X 2 are independently halogen; R 1 is hydrogen; R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Y 1 is N; Y 2 N or CH; Y 3 N or CH; Y 4 N or CR 4 ; R 4 is hydrogen, halogen or C1-C6 alkyl; R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said 3-1 The heteroatom of the 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is nitrogen, and the number of the heteroatom is independently 1 or 2; Each R 3-1 Independently for one or more R 3-1-2 Substituted C1-C6 alkyl; Each R 3-1-2 Independently -NR 3-1-2-1 R 3-1-2-2 、-CONR 3-1-2-6 R 3-1-2-7 , cyano, -OSO3H, -SO3H, -OSO2NH2 or -SO2R 3-1-2-3 ; R 3-1-2-1 , R 3-1-2-2 independently hydrogen or -SO2R 3-1-2-1-1 ; R 3-1-2-1-1 is -NH2, hydroxyl or C1-C6 alkyl; R 3-1-2-3 C1-C6 alkyl or -NR 3-1-2-3-1 R 3-1-2-3-2 ; R 3-1-2-6 is hydrogen or a C1-C6 alkyl group; R 3-1-2-7 is hydrogen or a C1-C6 alkyl group; Preferably, each R 3-1-2 Independently -NR 3-1-2-1 R 3-1-2-2 , -SO3H or -OSO2NH2; Scenario 3: X 1 and X 2 are independently halogen; R 1 is hydrogen; R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Y 1 N or CH; Y 2 N or CH; Y 3 N or CH; Y 4 N or CR 4 ; R 4 is C3-C8 cycloalkyl or is replaced by one or more R 4-3 Substituted C3-C8 cycloalkyl; R 4-3 is halogen, -NH2, C1-C6 alkyl or -OC(O)-C1-C6 alkyl; R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said 3-1 The heteroatom of the 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is nitrogen, and the number of the heteroatom is independently 1 or 2; Each R 3-1 Independently for one or more R 3-1-1 Substituted C3-C8 cycloalkyl, C3-C8 heterocycloalkyl or one or more R 3- 1-2 Substituted C1-C6 alkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; Each R 3-1-1 are independently C1-C6 alkyl or -COOH; Each R 3-1-2 are independently hydroxyl or -COOH; Preferably, R 4-3 is halogen or C1-C6 alkyl; each R 3-1-2 are independently hydroxyl groups; Option 4: X 1 and X 2 are independently halogen; R 1 is hydrogen; R 2 is a C1-C6 alkyl group or a deuterated C1-C6 alkyl group; Y 1 N or CR 4 ; Y 2 N or CR 4 ; Y 3 N or CR 4 ; Y 4 CR 4 ; R 4 is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, or one or more R 4-1 Substituted C1-C6 alkyl or one or more R 4-2 Substituted C1-C6 alkoxy; R 3 For one or more R 3-1 substituted 4-8 membered heterocycloalkyl; said 3-1 The heteroatom of the 4-8-membered heterocycloalkyl in the substituted 4-8-membered heterocycloalkyl is nitrogen, and the number of the heteroatom is independently 1 or 2; Each R 3-1 Independently for one or more R 3-1-1 Substituted C3-C8 cycloalkyl or C3-C8 heterocycloalkyl; the heteroatoms in the C3-C8 heterocycloalkyl are independently one or more of nitrogen and oxygen, and the number of heteroatoms is 1, 2, 3 or 4; Each R 3-1-1 are independently C1-C6 alkyl or -COOH.

12. 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: It meets one or more of the following conditions: (1)R 3 For Option 1, Option 2, or Option 3: Option 1: R 3 for Preferably, R 3 for Option 2: R 3 for Option 3: R 3 for (3)R 4 is F, Cl, methyl, -CF3, -CH2F, -CHF2, -O-CH2F or -CD3; preferably, R 4 is F, Cl or methyl; (4) For Option 1, Option 2, or Option 3: Scenario 1: for Scenario 2: for Scenario 3: for Solution 4: for (5)R 1 is H; (6)R 2 is methyl or CD3; for example, R 2 It is methyl.

13. A compound as described in any one of claims 1 to 12, 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, characterized in that: It meets one or more of the following conditions: (1)R 3 for (2)R 3 for (3)R 3 for (4)R 3 for (5) for (6) for (7) for (8) for (9) Ring A is (10)R 3’ for (11) for (12) for (13)R 3” for (14) for (15)X 1 Cl or F, X 2 Cl or F; (16)X 1’ Cl or F, X 2’ Cl or F; (17)R 1 is hydrogen, R 2 is methyl, -CDH2, -CHD2, -CD3, -CH2F, -CHF2, -CF3; for example, R 1 is hydrogen, R 2 is methyl; (18)R 1’ is hydrogen, R 2’ is methyl; (19)R 1” is hydrogen, R 2” It is methyl.

14. 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: The compound as shown in formula I is any of the following compounds: The compound shown in formula II is any of the following compounds: The compound shown in formula III is any of the following compounds: Preferably, the compound as shown in formula I is any of the following compounds: The compound that elutes first under the following chromatographic conditions, the chromatographic conditions are: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 um); the mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, the percentage is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80 mL / min; preferably, the retention time of the first eluting compound is 13.5 min; The compound that eluted later under the following chromatographic conditions: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 um); the mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, the percentage is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80 mL / min; preferably, the retention time of the compound that eluted later is 19 min; The compound that first elutes under the following chromatographic conditions: chromatographic column: Whelk-01 (SS) (150×30 mm, 5 um); mobile phase consisting of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, percentage The number is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80mL / min; preferably, the retention time of the first peak compound is 12min; The compound that elutes later under the following chromatographic conditions, the chromatographic conditions are: chromatographic column: Whelk-01 (SS) (150×30mm, 5um); the mobile phase consists of mobile phase A and mobile phase B, mobile phase A is supercritical CO2, mobile phase B is EtOH containing 0.1% ethylenediamine, the percentage is the volume percentage of ethylenediamine in mobile phase B, and the volume percentage of mobile phase B in the mobile phase is 40%; flow rate: 80mL / min; preferably, the retention time of the late-eluting compound is 18min.

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 any one of claims 1 to 14 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 metabolite thereof, or a pharmaceutical composition as claimed in claim 15 in the preparation of a CCR4 antagonist drug, preferably, the drug is used to treat or prevent a disease or condition mediated by CCR4; More preferably, the disease or condition mediated by CCR4 is selected from one or more immune-related diseases among atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and drug eruption; further preferably, the disease or condition mediated by CCR4 is selected from one or more immune-related diseases among atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis; or, the disease or condition mediated by CCR4 is cancer; the drug eruption may be an exanthematous drug eruption or an urticarial drug eruption.

17. A use of a compound as shown in Formula I, Formula II or Formula III as described in any one of claims 1 to 14, 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, or a pharmaceutical composition as described in claim 16 in the preparation of a drug, wherein the drug is used to treat or prevent immune-related diseases or cancer; preferably, the drug is used to treat or prevent immune-related diseases, and the immune-related diseases can be selected from one or more of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus, rheumatoid arthritis and drug eruption; the drug eruption can be an exanthematous drug eruption or an urticarial drug eruption.

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