A spiro heterocyclic compound, preparation method and application thereof

Abstract

The present invention provides a spiroheterocyclic compound, its preparation method, and application. The spiroheterocyclic compound of the present invention is shown in Formula I. This compound has inhibitory activity against RORγt, effectively inhibiting the RORγt protein receptor, thereby regulating the differentiation of Th17 cells and inhibiting the production of IL-17, thereby treating RORγt-mediated autoimmune diseases. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a spiro heterocyclic compound, a preparation method and application thereof. Background Art

[0002] Retinoic acid receptor-related orphan receptors (RORs) belong to the ligand-dependent nuclear receptor superfamily of transcription factors and play important roles in a range of physiological and pathological processes, including reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and immune system regulation. RORs primarily include RORα, RORβ, and RORγ. RORα is primarily distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain, and blood. RORβ is primarily distributed in the central nervous system, including the brain, retina, and pineal gland. RORγ is highly expressed in the thymus and also in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas. RORγ is divided into two subtypes, RORγ1 and RORγt (also known as RORγ2), based on the site of transcriptional splicing. RORγ1 is primarily expressed in the thymus, testis, pancreas, heart, liver, skeletal muscle, and kidney, while RORγt is exclusively expressed in immune organs.

[0003] Th17 cells are a subtype of T helper cells characterized by the secretion of the cytokine interleukin-17 (IL-17). Initially, they were thought to primarily contribute to immune responses against bacterial and fungal infections by recruiting neutrophils. Subsequent studies have revealed that Th17 cells play a key role in numerous mouse models of autoimmune diseases. Increased IL-17 levels have also been detected in several human autoimmune diseases, including psoriasis, multiple sclerosis (MS), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). Increased numbers of Th17 cells have been found in tissues and peripheral blood samples from patients with autoimmune diseases. Therefore, Th17 cells, or the cytokine IL-17 they produce, are closely linked to the pathogenesis of autoimmune diseases and inflammation. Inhibiting Th17 cell differentiation could be used to treat these conditions.

[0004] Studies have shown that RORγt is a key regulator of Th17 cell differentiation. Littman et al. were the first to report that RORγt is essential for the differentiation of initial CD4+ T cells into Th17 cells. Mice lacking RORγt lack lymph nodes and Peyer's patches, and the maturation of T cells is also affected, with the number of various T cells being lower than that of normal mice. Modulating RORγt activity through small molecule compounds can directly affect the differentiation of Th17 cells. Inhibiting RORγt significantly reduces the level of IL-17, a cytokine secreted by Th17. Therefore, RORγt can serve as a new target for the treatment of autoimmune diseases. The development of small molecule RORγt regulators for the treatment of RORγt-mediated diseases such as autoimmune diseases and inflammatory diseases is of great significance.

[0005] At present, patent applications CN107522634, WO2012158784, WO2018145653, etc. have disclosed some RORγt small molecule modulators, but no related products have yet been launched on the market. The field still needs to develop new RORγt small molecule modulators with better activity and higher safety. Summary of the Invention

[0006] The present invention provides a spiroheterocyclic compound, preparation method, and application thereof, which differ from the prior art. These compounds exhibit inhibitory activity against RORγt, effectively inhibiting the RORγt protein receptor, thereby regulating the differentiation of Th17 cells and suppressing the production of IL-17, thereby treating RORγt-mediated autoimmune diseases. They are particularly suitable for a variety of diseases, including psoriasis, multiple sclerosis, atopic dermatitis, and inflammatory bowel disease.

[0007] The present invention provides a spiroheterocyclic compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof:

[0008]

[0009] Wherein, m is 0, 1 or 2; n is 0, 1 or 2;

[0010] u is 0, 1, 2, 3, or 4;

[0011] v is 0, 1, 2, 3, or 4;

[0012] p is 1, 2, 3, or 4;

[0013] s is 1, 2, 3, or 4;

[0014] t is 0, 1, 2, or 3;

[0015] W, Q, Y and Z are independently CH or N, and W, Q, Y and Z are not CH or N at the same time;

[0016] Ring A and Ring B are independently C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0017] R 1 are independently hydrogen, halogen, -OR 1-1 、-SR 1-2 、-CN、-NR 1-3 R 1-4 、-C(=O)R 1-5 、-S(=O)2R 1-6 , C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl";

[0018] R 2 are independently halogen, -OR 2-1 、-SR 2-2 、-CN、-NR 2-3 R 2-4 、-C(=O)R 2-5 、-S(=O)2R 2-6 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C7 alkyl, "R 2-7 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0019] R 3 are independently halogen, -OR 3-1 、-SR 3-2 、-CN、-NR 3-3 R 3-4 、-C(=O)R 3-5 、-S(=O)2R 3-6 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C7 alkyl, "R 3-7substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; or, any two non-adjacent R 3 Together with the carbon atoms connected thereto, a 4-6 membered heterocycloalkyl is formed, wherein the heteroatoms in the heterocycloalkyl are O and / or N, and the number of the heteroatoms is 1 or 2 (i.e. any two non-adjacent R 3 Together with the atoms to which they are attached, and any heteroatoms inserted into the ring, they form a 4-6 membered heterocycloalkyl group; for example for When two non-adjacent R 3 The carbon atom to which it is connected forms a 4-6 membered heterocycloalkyl group, which is an oxetane group.

[0020] R 4 are independently halogen, -OR 4-1 、-CN、-NR 4-2 R 4-3 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C7 alkyl, "R 4-4 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0021] Or, any two non-adjacent R 4 Together with the carbon atom to which it is connected, it forms a 4-6 membered heterocycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is N and the number is 1;

[0022] R 1-1 、R 2-1 、R 3-1 and R 4-1 are independently hydrogen, "halogen-substituted C1-C7 alkyl", C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0023] R 1-2 、R 2-2 and R 3-2are independently hydrogen, "halogen-substituted C1-C7 alkyl", C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0024] R 1-3 、R 1-4 、R 2-3 、R 2-4 、R 3-3 、R 3-4 、R 4-2 and R 4-3 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0025] Or, R 1-3 and R 1-4 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 1-3-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 1-3-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, "R 1-3-1 Substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl and "R 1-3-2 The heteroatoms in the "substituted 3-14 membered heterocycloalkenyl" are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0026] The R 1-3-1 and R 1-3-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0027] Or, R 2-3 and R 2-4 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 2-3-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 2-3-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, "R 2-3-1Substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl and "R 2-3-2 The heteroatoms in the "substituted 3-14 membered heterocycloalkenyl" are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0028] The R 2-3-1 and R 2-3-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0029] Or, R 3-3 and R 3-4 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 3-3-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 3-3-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, "R 3-3-1 Substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl and "R 3-3-2 The heteroatoms in the "substituted 3-14 membered heterocycloalkenyl" are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0030] The R 3-3-1 and R 3-3-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0031] Or, R 4-2 and R 4-3 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 4-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 4-2-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, "R 4-2-1 Substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl and "R 4-2-2 The heteroatoms in the "substituted 3-14 membered heterocycloalkenyl" are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0032] The R 4-2-1 and R 4-2-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0033] R 1-5 are independently hydrogen, -OR 1-5-1 NR1-5-2 R 1-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0034] R 2-5 are independently hydrogen, -OR 2-5-1 NR 2-5-2 R 2-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0035] R 3-5 are independently hydrogen, -OR 3-5-1 NR 3-5-2 R 3-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0036] R 1-6 are independently hydrogen, -OR 1-6-1 NR 1-6-2 R 1-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0037] R 2-6 are independently hydrogen, -OR 2-6-1 NR 2-6-2 R 2-6-3 , C1-C7 alkyl, C3-C 14Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0038] R 3-6 are independently hydrogen, -OR 3-6-1 NR 3-6-2 R 3-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0039] R 1-5-1 、R 2-5-1 、R 3-5-1 、R 1-6-1 、R 2-6-1 and R 3-6-1 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0040] R 1-5-2 、R 1-5-3 、R 2-5-2 、R 2-5-3 、R 3-5-2 、R 3-5-3 、R 1-6-2 、R 1-6-3 、R 2-6-2 、R 2-6-3 、R 3-6-2 and R 3-6-3 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0041] Or, R 1-5-2 and R 1-5-3 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 1-5-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 1-5-2-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, the "R 1-5-2-1 substituted 3-14 membered heterocycloalkyl", the 3-14 membered heterocycloalkenyl and the "R 1-5-2-2 The heteroatoms in the substituted 3-14 membered heterocycloalkenyl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; the R 1-5-2-1 and R 1-5-2-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0042] Or, R 2-5-2 and R 2-5-3 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 2-5-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 2-5-2-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, the "R 2-5-2-1 substituted 3-14 membered heterocycloalkyl", the 3-14 membered heterocycloalkenyl and the "R 2-5-2-2 The heteroatoms in the substituted 3-14 membered heterocycloalkenyl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; the R 2-5-2-1 and R 2-5-2-2 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0043] Or, R 3-5-2 and R 3-5-3 The nitrogen atom connected thereto forms a 3-14 membered heterocyclic alkyl group, "R 3-5-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkenyl or "R 3-5-2-2 substituted 3-14 membered heterocycloalkenyl"; the 3-14 membered heterocycloalkyl, the "R 3-5-2-1 substituted 3-14 membered heterocycloalkyl", the 3-14 membered heterocycloalkenyl and the "R 3-5-2-2 The heteroatoms in the substituted 3-14 membered heterocycloalkenyl group are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4; the R 3-5-2-1 and R 3-5-2-2are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0044] R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen, hydroxy, amino, mercapto, cyano, C1-C7 alkoxy, C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0045] R 5 are independently C1-C7 alkyl; or, any two non-adjacent R 5 Together with the carbon atoms to which they are connected, they form a 4-10 membered cycloalkyl group (i.e. any two non-adjacent R 5 Together with the one or more atoms to which they are attached, they form a 4-10 membered cycloalkyl group; for example for When two non-adjacent R 5 The carbon atom to which it is connected forms a 4-10 membered cycloalkyl group, which is a cycloheptyl group.

[0046] The R 1-7 , the R 2-7 , the R 3-7 , the R 4-4 , the R 1-3-1 , the R 1-3-2 , the R 2-3-1 , the R 2-3-2 , the R 3-3-1 , the R 3-3-2 , the R 1-5-2-1 , the R 1-5-2-2 , the R 2-5-2-1 , the R 2-5-2-2 , the R 3-5-2-1 and the R 3-5-2-2 The number is independently 1, 2, 3, 4, 5, 6 or 7; when the R 1-7 , the R 2-7 , the R 3-7 , the R 4-4 , the R 1-3-1 , the R 1-3-2 , the R 2-3-1 , the R 2-3-2 , the R3-3-1 , the R 3-3-2 , the R 1-5-2-1 , the R 1-5-2-2 , the R 2-5-2-1 , the R 2-5-2-2 , the R 3-5-2-1 and the R 3-5-2-2 When the number of is multiple, the R 1-7 , the R 2-7 , the R 3-7 , the R 4-4 , the R 1-3-1 , the R 1-3-2 , the R 2-3-1 , the R 2-3-2 , the R 3-3-1 , the R 3-3-2 , the R 1 -5-2-1 , the R 1-5-2-2 , the R 2-5-2-1 , the R 2-5-2-2 , the R 3-5-2-1 and the R 3-5-2-2 independently the same or different.

[0047] In the present invention, the definitions of certain substituents in the compound represented by Formula I are as described in a preferred embodiment, and the definitions of substituents not mentioned are as described in any scheme of the present invention.

[0048] In a preferred embodiment, the compound as shown in Formula I:

[0049] n is 0 or 1;

[0050] Ring A and Ring B are independently C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0051] R 1 are independently -NR 1-3 R 1-4 、-C(=O)R 1-5 、-S(=O)2R 1-6 , C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl";

[0052] R 2 are independently halogen, -OR 2-1、-CN、-NR 2-3 R 2-4 、-C(=O)R 2-5 、-S(=O)2R 2-6 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C7 alkyl, "R 2-7 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0053] R 3 are independently halogen, -OR 3-1 、-CN、-NR 3-3 R 3-4 、-C(=O)R 3-5 、-S(=O)2R 3-6 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C1-C7 alkyl, "R 3-7 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; or, any two non-adjacent R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0054] R 1-5 are independently hydrogen, -OR 1-5-1 NR 1-5-2 R 1-5-3 or C1-C7 alkyl;

[0055] R 2-5 are independently hydrogen, -OR 2-5-1 NR 2-5-2 R 2-5-3 or C1-C7 alkyl;

[0056] R 3-5 are independently hydrogen, -OR 3-5-1 NR 3-5-2 R 3-5-3 or C1-C7 alkyl;

[0057] R 1-6 are independently hydrogen, -OR 1-6-1 NR 1-6-2 R 1-6-3, C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0058] R 2-6 are independently hydrogen, -OR 2-6-1 NR 2-6-2 R 2-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0059] R 3-6 are independently hydrogen, -OR 3-6-1 NR 3-6-2 R 3-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0060] R 1-5-1 、R 2-5-1 、R 3-5-1 、R 1-6-1 、R 2-6-1 and R 3-6-1 are independently hydrogen, C1-C7 alkyl or C3-C 14 Cycloalkyl;

[0061] R 1-5-2 、R 1-5-3 、R 2-5-2 、R 2-5-3 、R 3-5-2 、R 3-5-3 、R 1-6-2 、R 1-6-3 、R 2-6-2 、R 2-6-3 、R 3-6-2 and R 3-6-3 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3.

[0062] In a preferred embodiment, the compound as shown in Formula I:

[0063] m is 0 or 1;

[0064] n is 0 or 1;

[0065] u is 0 or 1;

[0066] v is 0, 1, or 2;

[0067] p is 1 or 2;

[0068] s is 1 or 2;

[0069] t is 0 or 2;

[0070] Ring A and Ring B are independently C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0071] R 1 For "R 1-7 "substituted C1-C7 alkyl";

[0072] R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo;

[0073] R 3 are independently halogen, C1-C7 alkyl, "R 3-7 Substituted C1-C7 alkyl" or oxo, or any two non-adjacent R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0074] R 4 are independently halogen, C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo;

[0075] R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen or hydroxy.

[0076] In a preferred embodiment, the compound as shown in Formula I:

[0077] m is 0 or 1;

[0078] n is 0 or 1;

[0079] u is 0 or 1;

[0080] v is 0, 1, or 2;

[0081] p is 1 or 2;

[0082] s is 1 or 2;

[0083] t is 0 or 2;

[0084] Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0085] R 1 R 1-7 Substituted C1-C7 alkyl;

[0086] R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo;

[0087] R 3 are independently halogen, C1-C7 alkyl or oxo, or any two non-adjacent R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0088] R 4 are independently halogen, -CN, -OR 4-1 、C1-C7 alkyl、"R 4-4 Substituted C1-C7 alkyl" or oxo;

[0089] R 1-7 、R 2-7 and R 4-4 are independently halogen or hydroxy;

[0090] R 4-1 is hydrogen;

[0091] Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group.

[0092] In a preferred embodiment, the compound as shown in Formula I:

[0093] m is 0 or 1;

[0094] n is 0 or 1;

[0095] u is 0 or 1;

[0096] v is 0, 1, or 2;

[0097] p is 1 or 2;

[0098] s is 1 or 2;

[0099] t is 0 or 2;

[0100] Ring A and Ring B are independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0101] R 1 R 1-7 Substituted C1-C7 alkyl;

[0102] R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl";

[0103] R 3 are independently halogen, C1-C7 alkyl or oxo;

[0104] R 4 are independently halogen, -CN, -OR 4-1 , C1-C7 alkyl or oxo;

[0105] R 1-7 、R 2-7 and R 4-4 are independently halogen or hydroxy;

[0106] R 4-1 is hydrogen;

[0107] Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group.

[0108] In a preferred embodiment, the compound as shown in Formula I:

[0109] m is 0 or 1;

[0110] n is 0 or 1;

[0111] u is 0 or 1;

[0112] v is 0, 1, or 2;

[0113] p is 1 or 2;

[0114] s is 1 or 2;

[0115] t is 0 or 2;

[0116] Ring A and Ring B are independently C6-C 10Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0117] R 1 For "R 1-7 "substituted C1-C7 alkyl";

[0118] R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl";

[0119] R 3 are independently halogen, C1-C7 alkyl or oxo;

[0120] R 4 are independently halogen, C1-C7 alkyl or oxo;

[0121] R 1-7 and R 2-7 are independently halogen or hydroxy.

[0122] In a preferred embodiment, the compound of formula I is as shown in formula II:

[0123]

[0124] m is 0 or 1;

[0125] u is 0 or 1;

[0126] v is 0, 1, or 2;

[0127] p is 1 or 2;

[0128] s is 1 or 2;

[0129] t is 0 or 2;

[0130] Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0131] R 1 R 1-7 Substituted C1-C7 alkyl;

[0132] R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo;

[0133] R 3are independently halogen, C1-C7 alkyl or oxo, or any two non-adjacent R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0134] R 4 are independently halogen, -CN, -OR 4-1 、C1-C7 alkyl、"R 4-4 Substituted C1-C7 alkyl" or oxo;

[0135] R 1-7 、R 2-7 and R 4-4 are independently halogen or hydroxy;

[0136] R 4-1 is hydrogen;

[0137] Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group.

[0138] In a preferred embodiment, the compound of formula I is as shown in formula II:

[0139]

[0140] m is 0 or 1;

[0141] u is 0 or 1;

[0142] v is 0, 1, or 2;

[0143] p is 1 or 2;

[0144] s is 1 or 2;

[0145] t is 0 or 2;

[0146] Ring A and Ring B are independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0147] R 1 For "R 1-7 "substituted C1-C7 alkyl";

[0148] R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl";

[0149] R 3 are independently halogen or C1-C7 alkyl; or, any two non-adjacent R 3Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0150] R 4 are independently C1-C7 alkyl;

[0151] R 1-7 and R 2-7 are independently halogen or hydroxy.

[0152] In a preferred embodiment, the compound of formula I is a compound as shown in formula III:

[0153]

[0154] Wherein, Ring A and Ring B are independently C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0155] R 1 are independently hydrogen, halogen, -OR 1-1 、-CN、-NR 1-3 R 1-4 、-C(=O)R 1-5 、-S(=O)2R 1-6 , C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl";

[0156] R 2 are independently halogen, -OR 2-1 、-CN、-NR 2-3 R 2-4 、-C(=O)R 2-5 、-S(=O)2R 2-6 、C3-C 14 Cycloalkyl, 3-14 membered heterocycloalkyl, C1-C7 alkyl "R 2-7 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0157] R 3 are independently halogen, -OR 3-1 、-CN、-NR 3-3 R 3-4 、-C(=O)R 3-5 、-S(=O)2R 3-6 、C3-C 14Cycloalkyl, 3-14 membered heterocycloalkyl, C1-C7 alkyl, "R 3-7 substituted C1-C7 alkyl" or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; or, any two non-adjacent R 3 Together with the carbon atom to which it is attached, it forms a 4-6 membered heterocycloalkyl group;

[0158] R 1-1 、R 2-1 and R 3-1 are independently hydrogen, "halogen-substituted C1-C7 alkyl", C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0159] R 1-3 、R 1-4 、R 2-3 、R 2-4 、R 3-3 and R 3-4 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl and 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0160] Or, R 1-3 and R 1-4 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 1-3-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and "R 1-3-1 The heteroatoms in the substituted 3-14 membered heterocycloalkyl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; the R 1-3-1 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0161] Or, R 2-3 and R 2-4 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 2-3-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and "R 2-3-1 The heteroatoms in the substituted 3-14 membered heterocycloalkyl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; the R 2-3-1are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0162] Or, R 3-3 and R 3-4 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 3-3-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and "R 3-3-1 The heteroatoms in the "substituted 3-14 membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2, 3 or 4; the R 3-3-1 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0163] R 1-5 are independently hydrogen, -OR 1-5-1 NR 1-5-2 R 1-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0164] R 2-5 are independently hydrogen, -OR 2-5-1 NR 2-5-2 R 2-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0165] R 3-5 are independently hydrogen, -OR 3-5-1 NR 3-5-2 R 3-5-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0166] R 1-6 are independently hydrogen, -OR 1-6-1 NR 1-6-2 R 1-6-3 , C1-C7 alkyl, C3-C 14Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0167] R 2-6 are independently hydrogen, -OR 2-6-1 NR 2-6-2 R 2-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0168] R 3-6 are independently hydrogen, -OR 3-6-1 NR 3-6-2 R 3-6-3 , C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0169] R 1-5-1 、R 2-5-1 、R 3-5-1 、R 1-6-1 、R 2-6-1 and R 3-6-1 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2, 3 or 4;

[0170] R 1-5-2 、R 1-5-3 、R 2-5-2 、R 2-5-3 、R 3-5-2 、R 3-5-3 、R 1-6-2 、R 1-6-3 、R 2-6-2 、R 2-6-3 、R 3-6-2 and R 3-6-3 are independently hydrogen, C1-C7 alkyl, C3-C 14 Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

[0171] Or, R 1-5-2 and R1-5-3 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 1-5-2-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and said "R 1-5-2-1 The heteroatoms in the substituted 3-14 membered heterocycloalkyl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; the R 1 -5-2-1 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0172] Or, R 2-5-2 and R 2-5-3 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 2-5-2-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and said "R 2-5-2-1 The heteroatoms in the substituted 3-14 membered heterocycloalkyl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; the R 2 -5-2-1 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0173] Or, R 3-5-2 and R 3-5-3 The nitrogen atom to which it is connected forms a 3-14 membered heterocycloalkyl group or "R 3-5-2-1 substituted 3-14 membered heterocycloalkyl"; said 3-14 membered heterocycloalkyl and said "R 3-5-2-1 The heteroatoms in the substituted 3-14 membered heterocycloalkyl group are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; the R 3 -5-2-1 are independently hydroxy, oxo, -CN, C1-C7 alkyl or C1-C7 alkoxy;

[0174] R 1-7 、R 2-7 and R 3-7 are independently halogen, hydroxy, amino, mercapto, cyano, C1-C7 alkoxy, C3-C 14 Cycloalkyl and 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3.

[0175] In a preferred embodiment, the compound of formula I is a compound as shown in formula IV:

[0176]

[0177] Where u is 0 or 1;

[0178] v is 0, 1, or 2;

[0179] Ring A is C6-C 10 aryl;

[0180] Ring B is independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1, 2 or 3;

[0181] R 1 For "R 1-7 "substituted C1-C7 alkyl";

[0182] R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl";

[0183] R 3 are independently halogen or C1-C7 alkyl;

[0184] R 1-7 and R 2-7 are independently halogen or hydroxy.

[0185] In a preferred embodiment, the compound shown in formula I is

[0186]

[0187] In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl group, the heteroatom in the 3-14 membered heterocycloalkyl group is not substituted by oxygen.

[0188] In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl group, the heterocycloalkyl group in the 3-14 membered heterocycloalkyl group is a heteromonocycloalkyl group or a heterobridged cycloalkyl group.

[0189] In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is connected to the ring B via a heteroatom.

[0190] In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is a 5-, 6- or 7-membered heterocycloalkyl group, and the heteroatoms are oxygen and / or nitrogen, and the number of the heteroatoms is 1 or 2.

[0191] In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is a piperidinyl or a piperazinyl, and more preferably

[0192] In a preferred embodiment, when the ring A is C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl, preferably phenyl.

[0193] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the heteroaryl group is a monocyclic ring.

[0194] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the heteroatom in the heteroaryl group is not substituted by oxygen. When the heteroatom is nitrogen, the heteroatom is not quaternized.

[0195] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is connected to the ring B via a carbon atom.

[0196] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, and the heteroatom is sulfur and / or nitrogen, and the number of the heteroatom is 1 or 2.

[0197] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, and the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2.

[0198] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a pyridyl group, a pyrimidyl group or a thienyl group, and more preferably

[0199] In a preferred embodiment, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is The right end is connected to the methylene group, and the left end is connected to ring B.

[0200] In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl group, the heteroatom in the 3-14 membered heterocycloalkyl group is not substituted by oxygen.

[0201] In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl group, the heterocycle in the 3-14 membered heterocycloalkyl group is a heteromonocycle.

[0202] In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is connected to the ring A via a heteroatom.

[0203] In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group, and the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2.

[0204] In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is a piperidinyl or piperazinyl, and more preferably Preferred The left end is connected to ring A, and the right end is connected to R 1 are connected.

[0205] In a preferred embodiment, when the ring B is C6-C 10 When the C6-C 10 Aryl is phenyl or naphthyl, preferably phenyl.

[0206] In a preferred embodiment, when the ring B is C6-C 10 When the C6-C 10 Aryl The left end is connected to ring A, and the right end is connected to R 1 are connected.

[0207] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the heteroaryl group is a monocyclic heteroaryl group.

[0208] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the heteroatom in the heteroaryl group is not substituted by oxygen. When the heteroatom is nitrogen, the heteroatom is not quaternized.

[0209] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is connected to the ring A through a carbon atom.

[0210] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the heteroatom in the 5-10 membered heteroaryl group is located at the ortho position to the connection site of the ring A.

[0211] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, and the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2.

[0212] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a pyridyl group, and more preferably

[0213] In a preferred embodiment, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is The left end is connected to ring A, and the right end is connected to R 1 are connected.

[0214] In a preferred embodiment, when R 1 When independently halogen, the halogen is F, Br, Cl or I, preferably F.

[0215] In a preferred embodiment, when R 1 Independently for "R 1-7 When "substituted C1-C7 alkyl", the R 1-7 The number of is 4, 5, 6 or 7.

[0216] In a preferred embodiment, when R 1 Independently for "R 1-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and is more preferably isopropyl.

[0217] In a preferred embodiment, when R 1-7 When it is a halogen, the halogen is F, Br, Cl or I, preferably F.

[0218] In a preferred embodiment, when R 1 Independently for "R 1-7 substituted C1-C7 alkyl", the "R 1-7 Substituted C1-C7 alkyl" is

[0219] In a preferred embodiment, when R 2 When independently halogen, the halogen is F, Br, Cl or I, preferably F.

[0220] In a preferred embodiment, when R 2 Independently for "R 2-7 When "substituted C1-C7 alkyl", the R 2-7 The number of is 3.

[0221] In a preferred embodiment, when R 2 Independently for "R 2-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and is more preferably a methyl group.

[0222] In a preferred embodiment, when R 2-7 When it is a halogen, the halogen is F, Br, Cl or I, preferably F.

[0223] In a preferred embodiment, when R 2 Independently for "R 2-7 substituted C1-C7 alkyl", the "R 2-7 "Substituted C1-C7 alkyl" is trifluoromethyl.

[0224] In a preferred embodiment, when R 3 When independently halogen, the halogen is F, Br, Cl or I, preferably F or Cl.

[0225] In a preferred embodiment, when R 3 When they are independently C1-C7 alkyl, the C1-C7 alkyl is C1-C3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), more preferably methyl.

[0226] In a preferred embodiment, when R 4 When independently halogen, the halogen is F, Br, Cl or I, preferably Cl.

[0227] In a preferred embodiment, when R 4 When independently halogen, the halogen is preferably F or Cl.

[0228] In a preferred embodiment, when R 4 When they are independently C1-C7 alkyl, the C1-C7 alkyl is C1-C3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), more preferably methyl.

[0229] In a preferred embodiment, when R 4 Independently for "R 4-4 When "substituted C1-C7 alkyl", the R 4-4 The number of is 3.

[0230] In a preferred embodiment, when R 4 Independently for "R 4-4 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl (such as methyl, ethyl, n-propyl or isopropyl), and is more preferably a methyl group.

[0231] In a preferred embodiment, when R 4-4 When it is a halogen, the halogen is F, Br, Cl or I, preferably F.

[0232] In a preferred embodiment, when R 4 Independently for "R 4-4 substituted C1-C7 alkyl", the "R 4-4 "Substituted C1-C7 alkyl" is trifluoromethyl.

[0233] In a preferred embodiment, when any two non-adjacent R 5 When the carbon atom to which it is connected forms a 4-10 membered cycloalkyl group, the 4-10 membered cycloalkyl group is a 7-membered cycloalkyl group.

[0234] In a preferred embodiment, when ring B is a 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, said R 1 The substitution site is located at the para position relative to the bond connecting ring A.

[0235] In a preferred embodiment, the substitution position of ring B on ring A is Not adjacent.

[0236] In a preferred embodiment, m is 0 or 1, preferably 0.

[0237] In a preferred embodiment, n is 0 or 1, preferably 0.

[0238] In a preferred embodiment, u is 0 or 1.

[0239] In a preferred embodiment, v is 0, 1 or 2.

[0240] In a preferred embodiment, p is 1 or 2.

[0241] In a preferred embodiment, s is 1 or 2.

[0242] In a preferred embodiment, t is 0 or 2, preferably 0.

[0243] In a preferred embodiment, W is CH.

[0244] In a preferred embodiment, Z is CH.

[0245] In a preferred embodiment, ring A is a 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl, preferably C6-C 10 aryl or 5-10 membered heteroaryl.

[0246] In a preferred embodiment, ring B is a 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl, preferably C6-C 10 Aryl.

[0247] In a preferred embodiment, R 1 are independently halogen or "R 1-7 "substituted C1-C7 alkyl".

[0248] In a preferred embodiment, R 2are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo, preferably halogen or "R 2-7 "substituted C1-C7 alkyl".

[0249] In a preferred embodiment, R 3 are independently halogen, C1-C7 alkyl or oxo, preferably halogen or "R 3-7 "substituted C1-C7 alkyl".

[0250] In a preferred embodiment, R 4 are independently halogen, -CN, -OR 4-1 、C1-C7 alkyl、"R 4-4 Substituted C1-C7 alkyl" or oxo, R 4-1 For H.

[0251] In a preferred embodiment, R 4 are independently halogen, C1-C7 alkyl, "R 4-4 substituted C1-C7 alkyl" or oxo.

[0252] In a preferred embodiment, R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen or hydroxy.

[0253] In a preferred embodiment,

[0254] In a preferred embodiment, And connected to ring B through the right side of the broken bond; preferably

[0255] In a preferred embodiment, Preferred

[0256] In a preferred embodiment, the compound as shown in Formula I is any one of the following compounds:

[0257]

[0258]

[0259]

[0260] The present invention also provides a compound Ia:

[0261]

[0262] Among them, m, n, p, s, t, Y, Z, W, Q, R 4 and R 5 The definitions of are the same as above, and the compound Ia is not

[0263] The compound Ia is preferably any one of the following compounds:

[0264]

[0265] More preferably, under the following chiral preparation conditions, the retention time is 1.486 min or a retention time of 2.705 min (i.e. compound

[0266] The chiral preparation conditions are as follows: chromatographic column: chiral column CHIRALPAK IH-3; mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1 ml / min; elution conditions: elution with 60% mobile phase A and 40% mobile phase B for 14 minutes; flow rate: 1.0 ml / min; detector wavelength: 220 nm; temperature: room temperature, and the "%" refers to volume percentage.

[0267] The present invention also provides a method for preparing the spiroheterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof, wherein the preparation method is any of the following methods:

[0268] Method 1:

[0269] The method for preparing the compound of Formula I comprises the following steps: in a solvent, subjecting Compound Ia and Compound Ib to a reductive amination reaction according to the following formula to obtain the compound of Formula I;

[0270]

[0271] Among them, m, n, p, s, u, v, t, Y, Z, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 , Ring A and Ring B are defined as above;

[0272] Method 2:

[0273] The method for preparing the compound of formula I comprises the following steps: in the presence of a Pd catalyst, in a solvent, subjecting compound Id and compound Ie to a Suzuki reaction of the following formula to obtain compound I;

[0274]

[0275] Among them, R 6 for m, n, p, s, u, v, t, Y, Z, W, Q, R 1 、R 2 、R 3 、R 4 、R 5 The definitions of Ring A and Ring B are the same as those described above.

[0276] In method 1, the conditions and operations for the reductive amination may be conventional conditions and operations for such reactions in the art. The present invention particularly prefers the following conditions and operations:

[0277] In method 1, the solvent is preferably a halogenated hydrocarbon (such as dichloromethane) and / or an amide solvent (such as N,N-dimethylformamide).

[0278] In method 1, the reductive amination reaction is preferably carried out in the presence of a catalyst, preferably one or more of triethylamine, acetic acid and trifluoroacetic acid.

[0279] In method 1, the reducing agent used in the reductive amination reaction is preferably sodium triacetylborohydride and / or sodium acetylborohydride. The molar ratio of the reducing agent to the compound Ia is preferably 5:1-2:1, for example 3:1.

[0280] In method 1, the molar ratio of compound Ib to compound Ia is preferably 0.9:1-3:1, for example 1:1.

[0281] In method 1, the reductive amination reaction is preferably carried out at room temperature.

[0282] In Method 1, the progress of the reductive amination reaction can be monitored by conventional methods in the art (e.g., TLC or HPLC), with the end point generally being the disappearance or disappearance of Compound Ia. The reductive amination reaction preferably lasts 12-36 hours.

[0283] In method 1, the post-treatment steps after the reductive amination reaction are preferably the following steps: concentration and column chromatography (for example, the eluent is methanol and dichloromethane in a volume ratio of 0-1:10).

[0284] In method 2, the Suzuki conditions and operations may be conventional conditions and operations for such reactions in the art. The present invention particularly prefers the following conditions and operations:

[0285] In the second method, the Pd catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (Pd(dppf)Cl2) and / or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.

[0286] In method 2, the molar ratio of the Pd catalyst to the compound Id is preferably 0.01:1-0.3:1, for example 0.2:1.

[0287] In the second method, the solvent is preferably an ether solvent (such as dioxane).

[0288] In method 2, the alkaline reagent used in the Suzuki reaction is preferably an alkali metal carbonate (such as potassium carbonate). The molar ratio of the alkaline reagent to the compound Id is preferably 1.2:1-5:1, such as 3:1.

[0289] In method 2, the molar ratio of compound 1e to compound 1d is preferably 1.1:1-2:1, for example 1.5:1.

[0290] In method 2, the temperature of the Suzuki reaction is preferably 80-110°C, for example 100°C.

[0291] In method 1, the progress of the Suzuki reaction can be monitored by conventional methods in the art (e.g., TLC or HPLC), and the end point of the reaction is generally when the compound Id no longer reacts or disappears. The Suzuki reaction time is preferably 8-24 hours, for example, 16 hours.

[0292] In method 2, the post-treatment steps after the Suzuki reaction are preferably the following steps: concentration and column chromatography (for example, the eluent is methanol and dichloromethane in a volume ratio of 0-1:10).

[0293] The present invention also provides a pharmaceutical composition, which comprises the spiroheterocyclic compound shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a drug precursor thereof, and a pharmaceutically acceptable carrier.

[0294] The present invention also provides a use of a substance X in the preparation of a RORγt protein receptor modulator; the substance X is the spiroheterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a drug precursor thereof, or the pharmaceutical composition.

[0295] The present invention also provides a use of a substance X in the preparation of a drug; the substance X is the spiroheterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or the pharmaceutical composition.

[0296] The present invention also provides a use of a substance X in the preparation of a medicament; the medicament is used to prevent or treat diseases associated with the RORγt protein receptor; the substance X is the spiroheterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a drug precursor thereof, or the pharmaceutical composition.

[0297] The disease associated with the RORγt protein receptor is preferably an autoimmune disease.

[0298] The autoimmune disease is preferably one or more of psoriasis, multiple sclerosis (MS), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease and chronic obstructive pulmonary disease.

[0299] The present invention also provides a use of a substance X in the preparation of a medicament; the substance X is the spiroheterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or the pharmaceutical composition; the medicament is used to prevent or treat one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, and chronic obstructive pulmonary disease.

[0300] The present invention also provides a method for preventing and / or treating a disease, comprising administering an effective amount of a substance X to a subject in need of treatment; wherein the disease is a disease associated with the RORγt protein receptor, and the substance X is the spiroheterocyclic compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or the pharmaceutical composition thereof.

[0301] In the method, the diseases related to the RORγt protein receptor are the same as those described above.

[0302] The present invention also provides a method for preventing and / or treating a disease, comprising administering an effective amount of a substance X to a subject in need of treatment; wherein the disease is one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, and chronic obstructive pulmonary disease; and the substance X is the spiroheterocyclic compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, or the pharmaceutical composition.

[0303] The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

[0304] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention with a relatively nontoxic, pharmaceutically acceptable acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acid includes inorganic acids, including, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acid includes organic acids, including but not limited to acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, bitartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthoic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0305] The term "solvate" refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric solvent. The solvent molecules in the solvate may be present in an ordered or non-ordered arrangement. Such solvents include, but are not limited to, water, methanol, and ethanol.

[0306] As described above, the terms "pharmaceutically acceptable salt" and "solvate" in the term "pharmaceutically acceptable salt solvate" refer to compounds of the present invention that are prepared by: 1. combining with a relatively nontoxic, pharmaceutically acceptable acid or base; and 2. combining with a stoichiometric or non-stoichiometric amount of a solvent. Such "pharmaceutically acceptable salt solvate" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

[0307] The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" may exist in crystalline or amorphous forms. The term "crystalline form" refers to a compound in which the ions or molecules are arranged in a strictly periodic pattern in three-dimensional space, with a regular pattern of recurring appearance at intervals. Due to differences in this periodic arrangement, multiple crystalline forms may exist, also known as polymorphism. The term "amorphous form" refers to a compound in which the ions or molecules are distributed in a disordered manner, i.e., the ions or molecules do not have a regular periodic arrangement.

[0308] The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist as a single stereoisomer or a mixture thereof (e.g., a racemate) if stereoisomers exist. The term "stereoisomer" refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution by bonding with other chiral compounds (chemical bonding, etc.) or salt formation (physical bonding, etc.). The term "single stereoisomer" means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.

[0309] The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist as a single tautomer or a mixture thereof, if tautomers exist, preferably in a form in which the more stable tautomer predominates.

[0310] The atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "pharmaceutically acceptable salt solvate" may exist in their natural abundance or in a non-natural abundance form. For example, a hydrogen atom in its natural abundance form means that approximately 99.985% of it is protium and approximately 0.015% is deuterium; in its non-natural abundance form, for example, approximately 95% of it is deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "pharmaceutically acceptable salt solvate" may be atoms that exist in a non-natural abundance form.

[0311] When any variable (such as R 1-1-1 ) appears multiple times in the definition of a compound, the definition of each position of the variable is independent of the definition of the other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is replaced by 1, 2 or 3 R 1-1-1 group substituted, that is, the group may be replaced by up to 3 R 1-1-1 Replace, the position R 1-1-1 Definition and other positions R 1-1-1 In addition, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0312] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0313] The term "alkyl" refers to a saturated, linear or branched, monovalent hydrocarbon group having from one to twelve carbon atoms (e.g., C1-C6 alkyl, and also C1-C4 alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, and 1-octyl.

[0314] The term "alkenyl" refers to a group having at least one site of unsaturation, i.e., a carbon-carbon sp 2 A linear or branched monovalent hydrocarbon group of two to twelve carbon atoms having a double bond (e.g., C2-C6 alkenyl, or C2-C4 alkenyl), including groups with "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinyl and allyl.

[0315] The term "cycloalkyl" refers to a saturated, non-aromatic cyclic hydrocarbon radical (e.g., C3-C6 cycloalkyl) having three to twenty carbon atoms, including monocyclic cycloalkyl and polycyclic cycloalkyl. The cycloalkyl group contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0316] Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl.

[0317] Polycyclic cycloalkyl is a polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structure, including spirocyclic, fused and bridged cycloalkyl. Wherein, "spirocyclic cycloalkyl" refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between 5 to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl is divided into monospiroalkyl, bispiroalkyl or polyspiroalkyl according to the number of spiro atoms shared between rings, preferably monospiroalkyl and bispiroalkyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroalkyl. Examples of spiroalkyl include but are not limited to: "Fused-ring cycloalkyl" refers to a 5-20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused-ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Examples of fused-ring alkyl groups include, but are not limited to: "Bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, and more preferably a bicyclic or tricyclic group. Examples of bridged cycloalkyl groups include, but are not limited to:

[0318] The term "heterocycloalkyl" refers to a saturated carbocyclic group having 3 to 20 ring atoms, wherein at least one ring atom is a heteroatom independently selected from boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, and the remaining ring atoms are C. The group can be a carbon group or a heteroatom group (i.e. it can be a C-connected or N-connected, as long as it is possible). The example of heterocyclic radical includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thioalkyl and piperazinyl. Condensed ring moiety, spirocyclic moiety and bridged ring moiety are also included in the scope of this definition. For example, the group derived from tetrahydropyrrole can be tetrahydropyrrole-1-base (N-connected) or tetrahydropyrrole-3-base (C-connected). For example, a 3-7 membered monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S and Se, wherein N, B, P or Se is optionally replaced by one or more oxygen atoms to give groups such as NO, BOH, PO, PO2, SeO; N may be optionally quaternized; S atom may be optionally replaced by one or more oxygen atoms or nitrogen atoms to give groups such as SO, SO2, S(=O)(=NR a ),S(=NR b ) or S(=NR c )2 group, and at the same time, R a 、R b and R c are independently cyano, C1-C7 alkyl, C3-C 14 Cycloalkyl, "3-14 membered heterocycloalkyl group whose heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and whose heteroatoms are 1 to 4", "C1-C7 heteroaryl group whose heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and whose heteroatoms are 1 to 4", C6-C 10 Aryl or C1 to C7 alkoxy; at the same time, the -CH2- group can be optionally replaced by -C(=O)-, -C(=S)- or -C(=NR d )-substitution, R d are independently cyano, C1-C7 alkyl, C3-C 14 Cycloalkyl, "3-14 membered heterocycloalkyl group whose heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and whose heteroatoms are 1 to 4", "C1-C7 heteroaryl group whose heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and whose heteroatoms are 1 to 4", C6-C 10aryl or C1-C7 alkoxy; when the ring is a three-membered ring, there is only one heteroatom therein), or a bicyclic ring composed of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S, wherein N, S, B or P is optionally substituted by one or more oxygen atoms to give groups such as NO, BOH, SO, SO2, PO, PO2, SeO, and the -CH2- group may optionally be replaced by -C(=O)-). Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group, i.e., a heterocyclylene group.

[0319] The term "heterocycloalkenyl" refers to a monocyclic partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic hydrocarbon radical having three to twenty carbon atoms (eg, C3-C6 cycloalkenyl).

[0320] The term "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring having up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl units include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, or acenaphthyl. It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, attachment is via the aromatic ring.

[0321] The term "heteroaryl" refers to a stable monocyclic or bicyclic ring having up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Heteroaryl groups within this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, and tetrahydroquinoline. "Heteroaryl" is also understood to include N-oxide derivatives of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is through the aromatic ring. Heteroaromatic and bicyclic heteroaromatic ring systems may be fused to form a ring. In these, N, S, B, P, or Se may be optionally replaced by one or more oxygen atoms to form groups such as NO, SO, SO2, BOH, PO, PO2, and SeO. The nitrogen atom may be quaternized. A heteroaryl group may be attached to the main structure at any heteroatom or carbon atom to form a stable compound. Depending on the structure, a heteroaryl group may be a monovalent group or a divalent group, i.e., a heteroarylene group.

[0322] The term "alkoxy" refers to an alkyl group attached through an oxygen bridge; said alkyl group is as defined above.

[0323] The term "alkanethiol" refers to an alkyl group attached through a sulphur bridge; said alkyl group is as defined above.

[0324] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and in the preparation of prescriptions. These are all substances contained in pharmaceutical preparations, in addition to the active ingredient. For a complete list, see Part IV of the Pharmacopoeia of the People's Republic of China (2015 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).

[0325] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0326] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0327] The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

[0328] The term "patient" refers to any animal, preferably a mammal, and most preferably a human, that is about to receive or has received a compound or composition according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0329] The term "active ingredient" refers to the active ingredient in the pharmaceutical composition or combination kit of the present invention, i.e., Compound I, its pharmaceutically acceptable salt, its solvate, its solvate of a pharmaceutically acceptable salt, its metabolite or its prodrug, anticancer drug, or the above-mentioned combination formed therefrom.

[0330] In the present invention, "room temperature" refers to 15-35°C, and "overnight" refers to 10-18 hours.

[0331] 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.

[0332] The reagents and raw materials used in the present invention are commercially available.

[0333] The positive and progressive effects of the present invention are that the compounds of the present invention have inhibitory activity on RORγt, can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and further treating RORγt-mediated related autoimmune diseases. DETAILED DESCRIPTION

[0334] 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.

[0335] The structures of all compounds of the present invention can be determined by nuclear magnetic resonance ( 1 HNMR) and / or mass spectrometry (MS).

[0336] 1 H NMR chemical shifts (δ) are expressed in PPM (10 -6 ) were recorded. NMR was performed on a Bruker AVANCE-400 spectrometer.

[0337] LC-MS was determined by Agilent 1200 HPLC / 6120 mass spectrometer.

[0338] 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.

[0339] 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.

[0340] Preparation Example 1 (Preparation of Key Intermediates)

[0341]

[0342] first step:

[0343] To a solution of compound 1-a (20 g, 85.822 mmol, 1.00 equiv) and trifluoromethyltrimethylsilane (TMSCF3, 61.02 g, 429.111 mmol, 5.00 equiv) in tetrahydrofuran (200 mL) at 0°C was added tetrabutylammonium fluoride (54.15 g, 171.644 mmol, 2.00 equiv) and stirred at room temperature overnight. The reaction was monitored by LCMS until completion, then quenched by the addition of 1N HCl at 0°C. The reaction solution was extracted with ethyl acetate and dried over anhydrous Na2SO4 (sodium sulfate). The reaction solution was concentrated and separated by column chromatography (EA / PE, 15%-30%) to afford compound 1-b (11.80 g, 34.602 mmol, 40.32% yield) as a pale yellow oil. LCMS: (ESI, m / z): [M-1] - =338.75. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.66 (dd, J = 8.6, 7.0 Hz, 1H), 7.52 (dd, J = 9.6, 2.2 Hz, 1H), 7.45–7.33 (m, 1H), 3.56 (s, 1H).

[0344] Step 2:

[0345] To a solution of compound 1-b (11.80 g, 34.60 mmol, 1 eqiv) in 1,4-dioxane / water (4:1, 1 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (10.44 g, 44.98 mmol, 1.3 eq), tetrakistriphenylphosphine palladium (4.80 g, 4.15 mmol, 0.12 eq), and potassium carbonate (14.35 g, 103.81 mmol, 3 eq). The reaction was stirred at 95°C overnight under nitrogen. LCMS confirmed the reaction was complete, and the solvent was removed in vacuo. The residue was isolated by column chromatography (EA / PE, 10%-30%) to afford compound 1 (5.10 g, 13.93 mmol, 40.27% yield) as a white solid. LCMS: (ESI, m / z): [M-1] - =364.95. 1 H NMR (400MHz, DMSO-d6) δ10.08(s,1H),9.08(s,1H),8.03(d,J=8.3Hz,2H),7.84(dd,J=8.1,1.6Hz,2H),7.79(t,J=8.3Hz,1H),7.69–7.55(m,2H). 19 F NMR(377MHz, DMSO-d6)δ-73.95(s),-116.18(s).

[0346] Preparation Example 2 (Preparation of Key Intermediates)

[0347]

[0348] first step:

[0349] To a solution of compound 2-a (1 g, 3.86 mmol, 1 equiv) in N,N-dimethylformamide (DMF) (10 mL) at 0°C was added dropwise 2 mL of an aqueous solution of sodium nitrite (NaNO2) (293 mg, 4.24 mmol, 1.1 equiv), followed by the addition of HCl (6 M, 2 mL, 11.58 mmol, 3.0 equiv) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. KI (673 mg, 4.05 mmol, 1.05 eq) was added at 0°C and stirred overnight at room temperature. Upon completion of the reaction, LCMS was performed, and the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with saturated brine and concentrated to dryness. The residue was isolated by column chromatography (EA / PE, 10%-50%) to afford compound 2-b (912 mg, 2.46 mmol, 63.87% yield) as a yellow oil. LCMS:(ESI,m / z):[M-1] - =368.9.

[0350] Step 2:

[0351] To a solution of compound 2-b (23.00 g, 62.16 mmol, 1 equiv) in 1,4-dioxane (300 mL) were added pinacol diboronate (20.52 g, 80.80 mmol, 1.30 equiv), potassium acetate (18.30 g, 186.47 mmol, 3 equiv) and Pd(dppf)Cl2 (2.27 g, 3.11 mmol, 0.05 equiv). The reaction mixture was stirred at 95°C overnight under nitrogen protection. The reaction was monitored by LCMS. The solvent was removed in vacuo and the residue was purified by column chromatography (EA / PE, 10%-40%) to obtain compound 2 (28 g crude product, 69% purity ( 1 H NMR), white solid, LCMS: (ESI, m / z): [M-1] - =369.05. 1 H-NMR: 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.85–7.76(m,2H),7.75–7.67(m,2H),1.30(s,12H). 19 F NMR (377MHz, DMSO-d6) δ-73.85.

[0352] Preparation Example 3 (Preparation of Key Intermediates)

[0353]

[0354] To a solution of compound 3-a (5 g, 13.512 mmol, 1.00 eqiv) in 1,4-dioxane / water (4:1, 100 mL) were added (4-formylphenyl)boronic acid (2.43 g, 16.215 mmol, 1.2 eqiv), tetrakistriphenylphosphine palladium (1.56 g, 1.351 mmol, 0.10 eqiv), and potassium carbonate (5.6 g, 40.537 mmol, 3.00 eqiv). The reaction mixture was stirred at 80°C overnight under nitrogen. LCMS monitored the reaction completion, and the solvent was removed in vacuo. The residue was separated by column chromatography (EA / PE, 0%-40%) to obtain the crude product. After purification with n-hexane slurry, compound 3 (2.491 g, 7.153 mmol, 52.94% yield) was obtained as a yellow solid. LCMS: (ESI, m / z): [M-1] - =347.00. 1 H NMR (400MHz, DMSO-d6) δ10.07(s,1H),8.84(s,1H),8.02(d,J=8.3Hz,2H),7.99–7.88(m,4H),7.82(d,J=8.3Hz,2H). 19 F NMR (377MHz, DMSO-d6) δ-73.89.

[0355] Preparation Example 4 (Preparation of Key Intermediates)

[0356]

[0357] The synthesis method of key intermediate 4 refers to patent WO2012077655A1.

[0358] Preparation Example 5 (Preparation of Key Intermediates)

[0359]

[0360] first step:

[0361] To a solution of compound 5-a (6.96 g, 74.74 mmol, 1.00 equiv) in methyl tert-butyl ether (75 mL) and water (100 mL) were added sodium dithionite (Na2S2O4) (15.61 g, 89.65 mmol, 1.20 equiv), sodium bicarbonate (NaHCO3) (7.53 g, 89.65 mmol, 1.20 equiv), and nBu4N.HSO4 (3.00 g, 8.84 mmol, 0.12 equiv). Heptafluoro-2-iodopropane (26.53 g, 89.65 mmol, 1.20 equiv) was then added. The reaction mixture was stirred at room temperature for 2 hours. Completion of the reaction was monitored by TLC. The organic phase was washed with 0.75N HCl (65 mL), then with saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography (EA / PE, 0%-20%) to give compound 5-b (11.70 g, 44.80 mmol, 59.95% yield) as a brown oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.43–7.34 (m, 2H), 6.79–6.70 (m, 2H), 3.94 (s, 2H).

[0362] Step 2:

[0363] To a solution of compound 5-b (11.70 g, 44.80 mmol, 1.00 equiv) in acetonitrile (200 mL) were added iodine (I2) (11.37 g, 44.80 mmol, 1.00 equiv), cuprous iodide (CuI) (9.39 g, 49.28 mmol, 1.10 equiv), and tert-butyl nitrite (6.93 g, 67.20 mmol, 1.50 equiv). The reaction mixture was stirred at 80°C for 1.5 hours. After completion of the reaction, the solvent was removed under reduced pressure. The residue was added with water and extracted with ethyl acetate. The insoluble material was filtered off. The organic phase was washed sequentially with 10% Na2S2O3 and water, dried over anhydrous sodium sulfate, and the solvent was removed in vacuo. The residue was separated by column chromatography (EA / PE, 0%-10%) to afford compound 5-c (11.10 g, 29.84 mmol, 66.60% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform d) δ 7.89–7.83 (m, 2H), 7.37–7.30 (m, 2H). 19 F NMR (377 MHz, chloroform-d) δ -75.69 (d, J = 7.1 Hz), -182.83 (p, J = 7.4 Hz).

[0364] Step 3:

[0365] To a solution of compound 5-c (10.00 g, 26.88 mmol, 1.00 equiv) in 1,4-dioxane (200 ml) were added pinacol diboronate (6.83 g, 26.88 mmol, 1.00 equiv), KOAc (7.91 g, 80.64 mmol, 3.00 equiv), and Pd(dppf)Cl2 (0.98 g, 1.34 mmol, 0.05 equiv). The reaction mixture was stirred at 90°C under nitrogen for 16 hours. The reaction was monitored for completion by TLC. The solvent was removed under reduced pressure, and the residue was isolated by column chromatography (EA / PE, 0%-20%) to afford compound 5 (3.50 g, 9.41 mmol, 34.99% yield) as a brown solid. 1 H NMR (400 MHz, chloroform-d) δ 7.94 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 1.35 (s, 12H). 19 F NMR (377 MHz, chloroform-d) δ -75.69 (d, J = 7.0 Hz), -182.83 (p, J = 7.3 Hz).

[0366] Preparation Example 6 (Preparation of Key Intermediates)

[0367]

[0368] To a solution of compound 6-a (2.50 g, 6.72 mmol, 1.00 equiv) in 1,4-dioxane / water (4:1, 50 ml) were added 4-formylphenylboronic acid (1.21 g, 8.06 mmol, 1.20 equiv), K₂CO₃ (2.79 g, 20.16 mmol, 3.00 equiv), and Pd(PPh₃)₄ (776.55 mg, 0.67 mmol, 0.10 equiv). The reaction mixture was stirred at 80°C for 16 hours. The reaction was monitored for completion by TLC. The solvent was removed under reduced pressure, and the residue was isolated by column chromatography (EA / PE, 0%-20%) to afford compound 6 (1.45 g, 4.14 mmol, 61.61% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.05(t,J=8.3Hz,4H),8.00(d,J=8.1Hz,2H),7.82(d,J=8.2Hz,2H). 19 FNMR (377MHz, DMSO-d6) δ -75.21 (t, J = 7.7Hz), -181.90 (p, J = 7.2Hz).

[0369] Preparation Example 7 (Preparation of Key Intermediates)

[0370]

[0371] first step:

[0372] To a solution of compound 4-a (8.0 g, 46.5 mmol, 1.00 equiv) in 100 mL of tetrahydrofuran was added NaHMDS (2 M, 25.58 mL, 51.16 mmol, 1.1 equiv) at -60°C. The reaction mixture was stirred at -15°C for 1 hour. BF₃.Et₂O (14.52 mL, 102.31 mmol, 2.20 equiv) and a solution of 1-tert-butoxycarbonyl-3-pyrrolidinone (7-a) (10.34 g, 55.81 mmol, 1.2 equiv) in THF (50 mL) were then added at -60°C. The reaction mixture was stirred at -60°C for 3 hours and then at room temperature for 3 hours. LCMS monitored the reaction for completion. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 x 300 mL). The organic phases were combined, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (MeOH / DCM, 0%-10%) to give compound 7-b (6.3 g, 46.5 mmol, 37.9% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =358.25.

[0373] Step 2:

[0374] To a solution of compound 7-b (6.3 g, 17.63 mmol, 1 equiv) in toluene (100 mL) were added CuI (355.86 mg, 1.76 mmol, 0.10 equiv), Cs2CO3 (4.8 g, 35.27 mmol, 2.00 equiv), and 8-hydroxyquinoline (511.98 mg, 3.53 mmol, 0.2 equiv). The reaction mixture was stirred at 115°C overnight. LCMS monitored the reaction for completion. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and the solvent removed under reduced pressure to yield compound 7-c, which was used directly in the next step without isolation. LCMS: (ESI, m / z): [M+1] + =277.34.

[0375] Step 3:

[0376] Compound 7-c (5 g, 18.09 mmol, 1 equiv) and HCl (4 M in 1,4-dioxane) (45 mL, 180.9 mmol, 10 equiv) were stirred at room temperature for 1.5 h. The reaction was complete as monitored by LCMS. The solvent was removed under reduced pressure, and the residue was diluted with water and basified with NaOH (2 M in H2O) to pH 8. Compound 7 (1.01 g, 5.73 mmol, 31% yield) was isolated by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (ACN in water) (3% NH3.H2O), 5% to 30%) to afford compound 7 as a yellow oil. LCMS: (ESI, m / z): [M+1] + =176.22; 1 H NMR(300MHz,DMSO-d6)δ8.07(d,J=4.5Hz,2H),7.28(dd,J=4.5,1.2Hz,1H),3.11–2.85(m,3H), 2.81(d,J=12.1Hz,1H), 2.10(dddd,J=13.3,7.5,4.4,1.2Hz,1H), 1.88(dt,J=13.4,8.2Hz,1H).

[0377]

[0378] Compound 7 was separated by chiral column (model: CHIRALPAK IH-3, column diameter: 4.600, analysis method: mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1 ml / min; elution conditions: elution with 60% mobile phase A and 40% mobile phase B for 14 minutes; flow rate: 1.0 ml / min; temperature: room temperature, "%" is volume percentage) to give Peak A (Peak A, RT = 1.486 min, wavelength 220, ee>95%) and Peak B (Peak B, RT = 2.705 min, wavelength 220, ee>95%).

[0379] Preparation Example 8 (Preparation of Key Intermediates)

[0380]

[0381] first step:

[0382] To compound 8-a (5 g, 24.22 mmol, 1.00 equiv) in 50 mL of THF at -78°C was added LDA (2 M, 14.53 mL, 29.06 mmol, 1.2 equiv). The reaction was stirred at -78°C for 30 minutes, followed by the addition of a solution of N-tert-butyloxycarbonyl-4-piperidone (5.79 g, 29.08 mmol, 1.2 equiv) in THF (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 3 hours. LCMS monitored the reaction for completion. The reaction was quenched with saturated aqueous NaHCO₃ and extracted with ethyl acetate (3 x 300 mL). The organic phases were combined and the solvent removed under reduced pressure. The residue was isolated by column chromatography (methanol / dichloromethane, 0%-10%) to afford compound 8-b (7.8 g, 19.23 mmol, 80% yield) as a yellow solid. LCMS (ESI, m / z): [M+1] + =405.05.

[0383] Step 2:

[0384] To a solution of compound 8-b (7.8 g, 19.23 mmol, 1 equiv) in 1,4-dioxane (100 mL) were added CuI (366.15 mg, 1.92 mmol, 0.10 equiv), Cs2CO3 (12.53 g, 38.45 mmol, 2.00 equiv), and 1,2-cyclohexanediamine (219.54 mg, 1.92 mmol, 0.1 equiv). The reaction was stirred at 100°C overnight. LCMS indicated the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were stripped of solvent under reduced pressure. The residue was isolated by column chromatography (methanol / dichloromethane, 0%-10%) to afford compound 8-c (2.1 g, 6.47 mmol, 33% yield) as a yellow solid. LCMS (ESI, m / z): [M+1] + =325.81.

[0385] Step 3:

[0386] To a solution of compound 8-c (2.1 g, 6.47 mmol, 1.00 eqiv) in 1,4-dioxane / water (4:1, 20 mL) were added methylboronic acid (464 mg, 7.78 mmol, 1.2 eqiv), Pd(PPh3)4 (747.1 mg, 7.76 mmol, 0.10 eqiv), and K2CO3 (1.79 g, 12.93 mmol, 2.00 eqiv). The reaction mixture was stirred at 100°C overnight under nitrogen. LCMS monitored the reaction completion, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether, 0%-40%) to afford compound 8-d (490 mg, 1.61 mmol, 25% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =305.28.

[0387] Step 4:

[0388] Compound 8-d (490 mg, 1.61 mmol, 1 equiv) and HCl (4 M 1,4-dioxane solution, 6.16 mL, 24.65 mmol, 15 equiv) were stirred at room temperature for 1.5 hours. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was diluted with water and basified with NaOH (2 M in H2O) to pH 8. Compound 8 (186 mg, 0.9 mmol, 56.56% yield) was isolated by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (3% NH3.H2O), 5% to 25%) as a white solid. LCMS (ESI, m / z): [M+1] + =205.28. 1 H NMR (300MHz, DMSO-d6) δ7.91(s,1H),7.10(s,1H),2.99(s,2H),2.88(m,2H),2.69–2.59(m,2H),2.36(s,3H),1.77–1.61(m,4H).

[0389] Preparation Example 9 (Preparation of Key Intermediates)

[0390]

[0391] first step:

[0392] 4-Bromobenzoic acid (1 g, 4.97 mmol, 1.00 equiv) and oxalyl chloride (883.94 mg, 6.96 mmol, 1.4 equiv) were added to a solution of DMF (18.18 mg, 0.248 mmol, 0.05 equiv) in dichloromethane (10 mL) at room temperature and stirred vigorously for 1 hour. The solvent was removed in vacuo, and the residue was dissolved in acetonitrile (10 mL). Compound 9-a (30.3 mg, 14.92 mmol, 3 equiv) and Ph3P (808 mg, 12.44 mmol, 2.5 equiv) were added. The reaction mixture was stirred at room temperature for 5 hours, cooled to room temperature, and water (20 mL) and pyridine were added. The mixture was stirred vigorously at 80°C for 1.5 hours, then cooled to room temperature. Water (50 mL) was added to the reaction system, and the mixture was extracted with methyl tert-butyl ether (3 × 50 mL). The organic phases were combined, dried over anhydrous Na2SO4, and the solvent removed in vacuo. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether, 10%-30%) to afford compound 9-b (500 mg, 1.74 mmol, 35% yield) as a brown solid. LCMS (ESI, m / z): [M-1] - =284.9.

[0393] Step 2:

[0394] To a solution of compound 9-b (500 mg, 1.74 mmol, 1 equiv) in 1,4-dioxane (8 mL) and water (2 mL) were added 4-formylphenylboronic acid (313.4 mg, 20.2 mmol, 1.2 equiv), K2CO3 (772.19 mg, 5.23 mmol, 3 equiv), and Pd(dppf)2Cl2 (142.25 mg, 0.174 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure, and the residue was isolated by silica gel column chromatography (EA / PE, 10%-30%) to afford compound 9 (230 mg, 0.73 mmol, 42% yield) as a brown solid. LCMS (ESI, m / z): [M-1] - =311.05; 1 H-NMR: 1 H NMR (300 MHz, chloroform-d) δ 10.07 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.71 (s, 4H), 6.14 (t, J = 54.4 Hz, 2H). 19 F NMR (282 MHz, chloroform-d) δ -130.11–-132.87 (m).

[0395] Preparation Example 10 (Preparation of Key Intermediates)

[0396]

[0397] first step:

[0398] To a solution of compound 10-a (25.00 g, 262.88 mmol, 1.00 equiv) in DMF (350 mL) at 0°C was added NaH (60%, 10.51 g, 262.88 mmol, 1.00 equiv). The reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of MOMCl (21.16 g, 262.88 mmol, 1.00 equiv). The reaction was allowed to warm to room temperature and continued stirring for 16 hours. LCMS indicated the reaction was complete. The product was quenched with saturated aqueous NH4Cl and water (700 mL) and extracted with ethyl acetate (3 x 400 mL). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to afford compound 10-b (22.70 g, 163.13 mmol, 62.05% yield) as a yellow oil. LCMS:(ESI,m / z):[M+1] + =140.15. 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (dd, J = 2.9, 0.7 Hz, 1H), 8.27 (dd, J = 4.7, 1.4 Hz, 1H), 7.37 (m, 1H), 7.22 (m, 1H), 5.20 (s, 2H), 3.49 (s, 3H).

[0399] Step 2:

[0400] To a solution of compound 10-b (15.00 g, 107.79 mmol, 1.00 equiv) in THF (300 ml) at -70°C was added s-BuLi (1.3 M, 124.38 ml, 161.69 mmol, 1.50 equiv). The reaction mixture was stirred at -70°C for 1 hour, followed by the addition of acetaldehyde (12.35 g, 280.27 mmol, 2.60 equiv) and stirring at this temperature for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl and water (300 ml) and extracted with ethyl acetate (3 x 300 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was isolated by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to afford compound 10-c (17.00 g, 92.79 mmol, 86.08% yield) as a yellow solid. LCMS:(ESI,m / z):[M+1] + =184.10.1 H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (s, 1H), 8.29 (d, J = 4.9 Hz, 1H), 7.40 (m, 1H), 5.27 (d, J = 0.5 Hz, 2H), 5.17 (q, J = 6.5 Hz, 1H), 3.51 (s, 3H), 1.49 (d, J = 6.5 Hz, 3H).

[0401] Step 3:

[0402] To a solution of compound 10-c (13.00 g, 70.96 mmol, 1.00 equiv) in DCM (100 ml) was added NaHCO₃ (17.88 g, 212.87 mmol, 3.00 equiv) and DMP (51.16 g, 120.63 mmol, 1.70 equiv) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction was quenched with saturated aqueous Na₂S₂O₃ and water (300 ml) and extracted with ethyl acetate (3 x 300 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was isolated by silica gel column chromatography (ethyl acetate / petroleum ether, 50% to 80%) to afford compound 10-d (8.80 g, 48.57 mmol, 68.45% yield) as a red oil. LCMS: (ESI, m / z): [M+1] + =182.10. 1 H NMR (400 MHz, chloroform-d) δ 8.64 (s, 1H), 8.38 (d, J = 4.9 Hz, 1H), 7.46 (dd, J = 4.8, 0.6 Hz, 1H), 5.33 (s, 2H), 3.54 (s, 3H), 2.64 (s, 3H).

[0403] Step 4:

[0404] To a solution of compound 10-d (10.55 g, 58.23 mmol) in MeOH (100 ml) was added HCl (50 ml) at room temperature, and the reaction mixture was stirred at 80°C for 3 hours. LCMS indicated the reaction was complete, and the reaction mixture was basified to pH 9 with NaOH (2 M aqueous solution) and the solvent removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to afford compound 10-e (5.95 g, 43.39 mmol, 74.51% yield) as a yellow oil. LCMS: (ESI, m / z): [M+1] + =138.20. 1HNMR (400 MHz, chloroform-d) δ 11.53 (s, 1H), 8.53 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 7.50 (dd, J = 5.1, 0.6 Hz, 1H), 2.68 (s, 3H).

[0405] Step 5:

[0406] To a solution of compound 10-e (5.95 g, 43.39 mmol, 1.00 equiv) in acetonitrile (90 ml) at room temperature were added pyrrolidine (9.26 g, 130.16 mmol, 3.00 equiv), acetic acid (7.82 g, 130.16 mmol, 3.00 equiv), and tert-butyl 3-oxoazetidine-1-carboxylate (11.14 g, 65.08 mmol, 1.50 equiv). The reaction mixture was stirred at 65°C for 4 hours. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 10-f (5.68 g, 19.56 mmol, 45.09% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =291.10. 1 H NMR (400MHz, chloroform-d) δ8.61 (s, 1H), 8.40 (d, J = 5.0Hz, 1H), 7.62 (d, J = 4.9Hz, 1 H), 4.12 (d, J = 9.5Hz, 2H), 3.98 (d, J = 9.6Hz, 2H), 3.12 (s, 2H), 1.45 (s, 9H).

[0407] Step 6:

[0408] To a solution of compound 10-f (3.00 g, 10.33 mmol, 1.00 equiv) in methanol (30 ml) at 0°C was added NaBH4 (781.87 mg, 20.67 mmol, 2.00 equiv). The reaction mixture was stirred at 50°C for 1 h. LCMS indicated the reaction was complete. The residue was purified by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 35% to 55%) to afford compound 10-g (2.60 g, 8.89 mmol, 86.07% yield) as a light yellow solid. LCMS: (ESI, m / z): [M+1] + =293.10. 1H NMR (400MHz, chloroform-d) δ8.27(s,1H),8.20(d,J=4.9Hz,1H),7.29(d,J=4.9Hz,1H),4.86(t,J=5.9Hz,1H),4.21(dd, J=9.6,1.0Hz,1H),4.11–4.04(m,2H),3.96(dd,J=9.4,1.1Hz,1H),2.48(s,1H),2.44–2.28(m,2H),1.45(s,9H).

[0409] Step 7:

[0410] To a solution of compound 10-g (1.30 g, 4.45 mmol, 1.00 equiv) in dichloromethane (25 mL) at 0°C was added Et3N (1.35 g, 13.34 mmol, 3.00 equiv). The mixture was stirred at 0°C for 30 minutes, and MsCl (764.05 mg, 6.67 mmol, 1.50 equiv) was added to the reaction system. The reaction mixture was stirred at room temperature for 16 hours, diluted with water (50 mL), and extracted with dichloromethane (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. DBU (13 mL) was added to the residue and stirred at 100°C for 4 hours. LCMS indicated the reaction was complete. The reaction mixture was separated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 10-h (700.00 mg, 2.55 mmol, 57.38% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =275.10. 1 H NMR (400 MHz, chloroform-d) δ 8.21 (s, 1H), 8.15 (d, J = 4.7 Hz, 1H), 6.89 (d, J = 4.8 Hz, 1H), 6.44 (d, J = 9.8 Hz, 1H), 6.15 (d, J = 9.9 Hz, 1H), 4.29–4.22 (m, 2H), 4.01 (m, 2H), 1.45 (s, 9H).

[0411] Step 8:

[0412] To a solution of compound 10-h (700.00 mg, 2.55 mmol) in methanol (10 ml) at room temperature was added Pd / C (10% Pd, 140 mg). The reaction mixture was stirred at room temperature for 1 hour. LCMS indicated the reaction was complete. The reaction system was filtered, and the filtrate was collected and the solvent removed under reduced pressure to yield compound 10-i (695.00 mg, 2.52 mmol, 98.56% yield) as a light yellow solid. LCMS: (ESI, m / z): [M+1]+ =277.15.

[0413] Step 9:

[0414] To a solution of compound 10-i (695.00 mg, 2.52 mmol) in dichloromethane (10 ml) was added HCl (4 M ethyl acetate, 10 ml). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was basified with NaOH (2 M aqueous solution) in methanol (10 ml) to pH = 11 and stirred at room temperature for 1 hour. LCMS indicated the reaction was complete, and the reaction mixture was purified by reverse phase column chromatography (C18 silica gel; acetonitrile / water (0.1% NH3.H2O), 25% to 45%) to afford compound 10 (290.00 mg, 1.65 mmol, 65.43% yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =177.10. 1 H NMR (400MHz, DMSO-d6) δ8.09(s,1H),7.99(d,J=4.8Hz,1H),7.09(d,J=4.8Hz,1H),3.5 6(d,J=8.7Hz,2H), 3.37(d,J=8.8Hz,2H), 2.77(t,J=6.5Hz,2H), 2.09(t,J=6.5Hz,2H).

[0415] Preparation Example 11 (Preparation of Key Intermediates)

[0416]

[0417] first step:

[0418] To a solution of compound 11-a (10.00 g, 48.43 mmol, 1.00 equiv) in tetrahydrofuran (80 ml) at -70°C was added LDA (2 M in n-hexane, 29.06 ml, 58.12 mmol, 1.20 equiv). The reaction mixture was stirred at -70°C for 30 minutes. Then, a solution of tert-butyl 4-oxopiperidine-1-carboxylate (11.58 g, 58.12 mmol, 1.20 equiv) in THF (20 ml) was added to the solution at the same temperature. The reaction mixture was stirred at -70°C for 3 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous NaHCO₃ and water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to give compound 11-b (13.82 g, 34.06 mmol, 70.33% yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =405.00. 1 H NMR (400MHz, chloroform-d) δ 8.20 (d, J = 4.9 Hz, 1H), 7.22 (d, J = 4.9 Hz, 1H), 3.90 (m, 2H), 3.11–3.01 (m, 4H), 1.76–1.64 (m, 4H), 1.44 (s, 9H).

[0419] Step 2:

[0420] To a solution of compound 11-b (13.82 g, 34.06 mmol, 1.00 equiv) in 1,4-dioxane (130 mL) were added CuI (648.73 mg, 3.41 mmol, 0.10 equiv), CsCO (22.20 g, 68.13 mmol, 2.00 equiv), and 1,2-diaminocyclohexane (388.97 mg, 3.41 mmol, 0.10 equiv) at room temperature. The reaction mixture was stirred at 100°C for 5 hours. LCMS indicated the reaction was complete. The reaction mixture was quenched with saturated aqueous NaHCO and water (200 mL) and extracted with ethyl acetate (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to afford the crude product (7.30 g). The crude product (1.00 g) was separated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 45% to 65%) to give compound 11 (0.55 g, 1.69 mmol) as a white solid. LCMS: (ESI, m / z): [M+1] + =325.05. 1 H NMR (400 MHz, chloroform-d) δ 7.92 (d, J = 4.7 Hz, 1H), 7.07 (d, J = 4.7 Hz, 1H), 3.77 (s, 2H), 3.52–3.40 (m, 2H), 3.08 (s, 2H), 2.00–1.91 (m, 2H), 1.73 (m, 2H), 1.47 (s, 9H).

[0421] Preparation Example 12 (Preparation of Key Intermediates)

[0422]

[0423] To a solution of compound 2 (10.1 g, 27.29 mmol, 1 equiv) in 1,4-dioxane (80 mL) and water (20 mL) were added 4-bromo-3,5-difluorobenzaldehyde (7.24 g, 32.75 mmol, 1.2 equiv), K2CO3 (11.31 g, 81.87 mmol, 3 equiv), and Pd(PPh3)4 (3.15 g, 2.73 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (0.1% trifluoroacetic acid), 45% to 75%) to afford compound 12 (3.7 g, 9.63 mmol, 35.3% yield) as a white solid. LCMS: (ESI, m / z): [M-1]- =382.85. 1 H NMR (300 MHz, chloroform-d) δ 10.01 (s, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.3 Hz, 2H), 3.49 (s, 1H).

[0424] Preparation Example 13 (Preparation of Key Intermediates)

[0425]

[0426] To a solution of compound 13-a (1.00 g, 2.58 mmol, 1 equiv) in 1,4-dioxane (8 mL) and water (2 mL) were added 5-bromopicolinaldehyde (576.6 mg, 3.10 mmol, 1.2 equiv), KCO (1.07 g, 7.74 mmol, 3 equiv), and Pd(PPh) (268.3 mg, 0.26 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure. The residue was separated by preparative HPLC (column model: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10B to 10B in 2 min, 10B to 41B in 2.5 min, 41B to 65B in 10.5 min, 220 nm; retention time: 9.67 min) to afford compound 13 (213.2 mg, 0.58 mmol, 23% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =368.00. 1 H NMR (400 MHz, chloroform-d) δ 10.15 (s, 1H), 8.98 (d, J = 1.6 Hz, 1H), 8.17–8.04 (m, 2H), 7.75–7.54 (m, 3H), 4.03 (s, 1H). 19 F NMR (377 MHz, chloroform-d) δ -75.45, -115.15.

[0427] Preparation Example 14 (Preparation of Key Intermediates)

[0428]

[0429] To a solution of compound 2 (1.00 g, 2.7 mmol, 1 equiv) in 1,4-dioxane (8 mL) and water (2 mL) were added compound 14-a (660.96 mg, 3.24 mmol, 1.2 equiv), K2CO3 (1.11 g, 8.1 mmol, 3 equiv), and Pd(PPh3)4 (311.58 mg, 0.27 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure, and the residue was separated by preparative HPLC (column type: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10B to 10B in 2 min, 10B to 41B in 2.5 min, 41B to 65B in 10.5 min, 220 nm; retention time: 9.67 min) to afford compound 14 (202.2 mg, 0.55 mmol, 20% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =368.00. 1 H NMR (400 MHz, chloroform-d) δ 10.27 (d, J = 0.8 Hz, 1H), 8.88 (m, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.82–7.73 (m, 2H), 7.77–7.70 (m, 1H), 3.69 (s, 1H). 19 F NMR (377MHz, CDCl3) δ-75.416,-123.758.

[0430] Preparation Example 15 (Preparation of Key Intermediates)

[0431]

[0432] first step:

[0433] To a solution of compound 15-a (5 g, 29.07 mmol, 1.00 equiv) in 50 mL of tetrahydrofuran was added LDA (2 M, 17.44 mL, 34.88 mmol, 1.2 equiv) at -78°C. The reaction mixture was stirred at this temperature for 30 minutes. Maintaining the temperature, a solution of compound 15-b (7.86 g, 34.88 mmol, 1.2 equiv) in tetrahydrofuran (20 mL) was added to the reaction system, and the reaction mixture was stirred at -78°C for 3 hours. LCMS indicated the reaction was complete. The reaction system was quenched with saturated aqueous NaHCO₃ and extracted with ethyl acetate (3 x 300 mL). The organic phases were combined and the solvent removed under reduced pressure. The residue was isolated by silica gel column chromatography (methanol / dichloromethane, 0%-10%) to afford compound 15-c (3.2 g, 8.05 mmol, 28% yield) as a yellow solid. LCMS (ESI, m / z): [M+1] + =398.31.

[0434] Step 2:

[0435] To a solution of compound 15-c (1.0 g, 2.51 mmol, 1 equiv) in 1,4-dioxane (10 mL) were added CuI (47.69 mg, 0.251 mmol, 0.10 equiv), Cs2CO3 (1.64 g, 5.02 mmol, 2.00 equiv), and 1,2-cyclohexanediamine (28.61 mg, 0.251 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight. LCMS indicated the reaction was complete. The product was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane, 0%-10%) to afford crude product 15-d (520 mg), which was used directly in the next step. LCMS (ESI, m / z): [M+1] + =317.31.

[0436] Step 3:

[0437] A mixture of compound 15-d (520 mg crude product) and HCl (4 M 1,4-dioxane solution, 6.16 mL, 24.65 mmol) was stirred at room temperature for 1.5 hours. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was diluted with water, basified with NaOH (2 M aqueous solution) to pH 8, and then isolated by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (3% NH3.H2O), 5% to 30% to afford compound 15 (340 mg, 1.57 mmol, 57% yield over two steps) as a white solid. LCMS: (ESI, m / z): [M+1] + =217.28. 1 H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 4.7 Hz, 2H), 7.11–7.05 (m, 1H), 3.60 (m, 2H), 2.97 (d, J = 1.1 Hz, 2H), 2.38–2.24 (m, 2H), 2.10 (m, 2H), 1.92 (dd, J = 14.6, 3.6 Hz, 2H), 1.83–1.72 (m, 2H).

[0438] Preparation Example 16 (Preparation of Key Intermediates)

[0439]

[0440] first step:

[0441] To a solution of compound 16-a (5.00 g, 36.46 mmol, 1.00 equiv) in acetonitrile (75 ml) were added pyrrolidine (7.78 g, 109.38 mmol, 3.00 equiv), AcOH (6.57 g, 109.38 mmol, 3.00 equiv), and compound 16-b (11.24 g, 65.63 mmol, 1.80 equiv) at room temperature. The reaction mixture was stirred at 65°C for 5 hours. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 16-c (1.60 g, 5.51 mmol, 15.12% yield) as a pale yellow solid. LCMS: (ESI, m / z): [M+1] + =291.10.

[0442] Step 2:

[0443] To a solution of compound 16-c (2.80 g, 9.64 mmol, 1.00 equiv) in methanol (30 ml) at 0°C was added NaBH4 (729.74 mg, 19.29 mmol, 2.00 equiv). The reaction mixture was stirred at 50°C for 1.5 hours. LCMS indicated the reaction was complete. The residue was separated by reverse phase column chromatography (C18 silica gel, acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 16-d (2.30 g, 7.87 mmol, 81.58% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =293.10. 1 H NMR (300MHz, chloroform-d) δ8.49(s,1H),8.33(d,J=5.7Hz,1H),6.83(d,J=5.7Hz,1H),4.96(t,J=4.7Hz,1H),4.33(d,J=9.8Hz,1 H), 4.13 (d, J = 9.5Hz, 1H), 4.01 (d, J = 9.7Hz, 2H), 2.44 (dd, J = 14.1, 5.0Hz, 1H), 2.28 (dd, J = 14.1, 4.4Hz, 1H), 1.45 (s, 9H).

[0444] Step 3:

[0445] To a solution of compound 16-d (1.50 g, 5.13 mmol, 1.00 equiv) in dichloromethane (30 mL) at 0°C was added Et3N (1.56 g, 15.39 mmol, 3.00 equiv). The reaction mixture was stirred at 0°C for 30 minutes before the addition of MsCl (881.60 mg, 5.13 mmol, 1.50 equiv) and stirring at room temperature for 16 hours. The reaction system was diluted with water (50 mL) and extracted with dichloromethane (3 x 20 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. DBU (15 mL) was added to the residue and stirred at 100°C for 4 hours. LCMS indicated the reaction was complete. The reaction system was separated by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 16-e (900.00 mg, 3.28 mmol, 63.94% yield) as a pale yellow solid. LCMS: (ESI, m / z): [M+1] + =275.15. 1H NMR (400MHz, chloroform-d) δ8.28(d,J=5.6Hz,1H),8.17(s,1H),6.75(m,1H),6.50(dd,J=9.9,0.9Hz,1H ), 5.98 (d, J = 9.9 Hz, 1H), 4.24 (dd, J = 9.6, 1.1 Hz, 2H), 4.03 (dd, J = 9.6, 1.0 Hz, 2H), 1.46 (s, 9H).

[0446] Step 4:

[0447] To a solution of compound 16-e (900.00 mg, 3.28 mmol) in methanol (10 ml) was added Pd / C (200 mg) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and the solvent removed under reduced pressure to obtain compound 16-f (900.00 mg, 3.26 mmol, 99.27% ​​yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =277.10.

[0448] Step 5:

[0449] A mixture of compound 16-f (500.00 mg, 1.81 mmol) and HCl (4 M in ethyl acetate, 5.00 ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a solution of the residue in methanol (5 ml) was basified to pH 11 with NaOH (2 M aqueous solution) and stirred at room temperature for 1.5 hours. LCMS indicated the reaction was complete, and the reaction mixture was separated by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 15% to 35%) to afford compound 16 (215.00 mg, 1.22 mmol, 67.43% yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =177.10. 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.16(d,J=5.5Hz,1H),6.79(d,J=5.6Hz,1H),3.60–3.54(m,2H),3.39–3.34(m,2H),2.75(m,2H),2.10(m,2H).

[0450] Preparation Example 17 (Preparation of Key Intermediates)

[0451]

[0452] Compound 8-c (400 mg, 1.23 mmol, 1 equiv) and HCl (4 M solution in 1,4-dioxane, 4.62 mL, 18.47 mmol, 15 equiv) were stirred at room temperature for 1.5 hours. LCMS indicated the reaction was complete. The solvent was removed under reduced pressure, and the residue was diluted with water. The residue was basified to pH 8 with NaOH (2 M aqueous solution) and then purified by reverse-phase column chromatography (C18 silica gel; acetonitrile / water (3% NH3.H2O), 15% to 25%) to afford compound 17 (80 mg, 0.36 mmol, 29% yield) as a yellow solid. LCMS (ESI, m / z): [M+1] + =225.69. 1 H NMR (300 MHz, chloroform-d) δ 7.89 (s, 1H), 7.14 (m, 1H), 3.11 (m, 2H), 3.02 (d, J = 1.3 Hz, 2H), 2.96–2.82 (m, 2H), 2.00–1.86 (m, 2H), 1.76 (m, 2H).

[0453] Preparation Example 18 (Preparation of Key Intermediates)

[0454]

[0455] first step:

[0456] To a solution of compound 18-a (20.00 g, 114.94 mmol, 1.00 equiv) in 400 mL of DMF at 0°C was added NaH (60%, 9.19 g, 229.89 mmol, 2.00 equiv). The reaction mixture was stirred at 0°C for 30 minutes, followed by the addition of MOMCl (11.11 g, 137.93 mmol, 1.20 equiv) and stirring at room temperature for 2 hours. LCMS indicated the reaction was complete, and the mixture was quenched with water (1000 mL) and extracted with ethyl acetate (3 x 300 mL). The organic phase was washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was isolated by silica gel column chromatography (methanol / dichloromethane, 0%-10%) to afford compound 18-b (9.20 g, 42.19 mmol, 36.71% yield) as a pale yellow oil. LCMS:(ESI,m / z):[M+1] + =217.95. 1 HNMR (400MHz, DMSO-d6) δ 8.61 (s, 1H), 8.40 (d, J = 5.6Hz, 1H), 7.22 (d, J = 5.6Hz, 1H), 5.42 (s, 2H), 3.41 (s, 3H).

[0457] Step 2:

[0458] Under nitrogen, tributyl(1-ethoxyethenyl)stannane (25.84 g, 71.54 mmol, 1.50 equiv) and Pd(PPh3)4 (5.51 g, 4.77 mmol, 0.10 equiv) were added to a solution of compound 18-b (10.40 g, 47.70 mmol, 1.00 equiv) in toluene (100 mL). The reaction mixture was stirred at 110°C for 4 hours. LCMS indicated the reaction was complete, and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol / dichloromethane, 0%-10%) to afford compound 18-c (4.70 g, crude) as a yellow oil. LCMS: (ESI, m / z): [M+1] + =210.10.

[0459] Step 3:

[0460] To a solution of compound 18-c (4.70 g, crude product) in methanol (20 ml) was added HCl (12N, 50 ml, 27.00 equiv), followed by stirring at 70°C for 16 hours. LCMS indicated the reaction was complete, and the mixture was concentrated under reduced pressure. The residue was neutralized to pH 8 and then isolated by silica gel column chromatography (methanol / dichloromethane, 0% to 10%) to afford compound 18-d (2.20 g, 16.04 mmol, 33.63% overall yield over two steps) as a white solid. LCMS: (ESI, m / z): [M+1] + =138.15. 1 H NMR (400MHz, DMSO-d6) δ 11.83 (s, 1H), 8.15 (s, 1H), 7.67 (d, J = 7.4Hz, 1H), 6.32 (d, J = 7.5Hz, 1H), 2.53 (s, 3H).

[0461] Step 4:

[0462] To a solution of compound 18-d (2.20 g, 16.04 mmol, 1.00 equiv) in methanol (40 ml) were added pyrrolidine (2.28 g, 32.08 mmol, 2.00 equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (3.20 g, 16.04 mmol, 1.00 equiv). The reaction mixture was stirred at 80°C for 4 hours. After completion of the reaction, LCMS analysis revealed that the product was purified by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) to afford compound 18-e (2.10 g, 6.60 mmol, 41.12% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =319.10. 1 H NMR (300MHz, chloroform-d) δ9.01(s,1H),8.58(d,J=5.9Hz,1H),6.97(d,J=5.9Hz,1H),3.91(s,2H),3.24( t,J=12.6Hz,2H),2.80(s,2H),2.04(d,J=13.7Hz,2H),1.69(td,J=13.2,4.9Hz,2H),1.49(s,9H).

[0463] Step 5:

[0464] To a solution of compound 18-e (3.90 g, 12.25 mmol, 1.00 equiv) in methanol (40 ml) was added NaBH4 (926.88 mg, 24.50 mmol, 2.00 equiv) at 0°C. The reaction mixture was stirred at 50°C for 1.5 hours. LCMS indicated the reaction was complete. Compound 18-f (3.50 g, 10.92 mmol, 89.18% yield) was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 40% to 60%) as a white solid. LCMS: (ESI, m / z): [M+1] + =321.15. 1H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.21(d,J=5.6Hz,1H),6.78(d,J=5.6Hz,1H),5.56(d,J=6.0Hz,1H),4.78(d,J=8.6Hz,1H),3.67( s,2H),3.24(s,1H),3.09(s,1H),2.14(dd,J=13.7,5.9Hz,1H),1.85–1.75(m,2H),1.73–1.63(m,2H),1.63–1.53(m,1H),1.40(s,9H).

[0465] Step 6:

[0466] To a solution of compound 18-f (2.70 g, 8.43 mmol, 1.00 equiv) in dichloromethane (50 mL) at 0°C was added Et3N (2.56 g, 25.28 mmol, 3.00 equiv). The reaction mixture was stirred at 0°C for 30 minutes before the addition of MsCl (1.45 g, 12.64 mmol, 1.50 equiv) and stirring at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure. DBU (28 mL) was added to the residue and stirred at 100°C for 4 hours. LCMS indicated that the reaction was complete and the product was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile / water (10 mM NH4HCO3), 45% to 65%) to afford compound 18-g (1.80 g, 5.95 mmol, 70.64% yield) as a pale yellow solid. LCMS:(ESI,m / z):[M+1] + =303.10. 1 H NMR (400MHz, chloroform-d) δ8.25(d,J=5.6Hz,1H),8.15(s,1H),6.72(d,J=5.5Hz,1H),6.41(dd,J=10.0,0.8Hz,1H),5.59(d ,J=9.9Hz,1H),3.86(s,2H),3.28(s,2H),1.98(d,J=13.7Hz,2H),1.64(ddd,J=13.9,11.6,4.9Hz,2H),1.47(s,9H).

[0467] Step 7:

[0468] To a solution of compound 18-g (900.00 mg, 2.98 mmol) in methanol (10 ml) was added Pd(OH)2 / C (200 mg) at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was collected and the solvent removed under reduced pressure to yield compound 18-h (890.00 mg, 2.92 mmol, 98.23% yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =305.15.

[0469] Step 8:

[0470] A mixture of compound 18-h (890.00 mg, 2.92 mmol) and HCl (4 M ethyl acetate solution, 10.00 ml) was stirred at room temperature for 1 hour, and then the solvent was removed under reduced pressure. A solution of the residue in methanol (5 ml) was basified to pH = 11 with NaOH (2N aqueous solution) and stirred at room temperature for 1.5 hours. LCMS showed that the reaction was complete. The residue was purified by reverse phase column chromatography (C18 silica gel; acetonitrile / water (0.1% NH 3. H2O), 25% to 50%) to obtain compound 18 (509.00 mg, 2.49 mmol, 85.22% yield) as a white solid. LCMS: (ESI, m / z): [M+1] + =205.10. 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),8.13(d,J=5.6Hz,1H),6.75(d,J=5.6Hz,1H),2.8 0(m,4H),2.71(t,J=6.7Hz,2H),1.81(t,J=6.7Hz,2H),1.69–1.61(m,2H),1.56(m,2H).

[0471] Example 1

[0472]

[0473] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (4) (50 mg, 0.263 mmol) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (3) (91 mg, 0.263 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (167 mg, 0.788 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 29 mg of the target compound (I-1) as a yellow solid in a yield of 21%. 1 H NMR (400MHz, CDCl3) δ8.10(s,2H),7.85(d,J=8.3Hz,2H),7.69(d,J=8.7Hz,2H),7.62(d,J=8.0Hz,2H),7.50(d,J=3.3 Hz,2H),7.16(d,J=4.5Hz,1H),3.75(dd,J=14.0,7.0Hz,2H),3.05(s,2H),2.74(s,4H),2.01(s,4H).LC-MS:m / z:(M+H) + =523.1.

[0474] Example 2

[0475]

[0476] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (50 mg, 0.263 mmol) and 2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (96 mg, 0.263 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (167 mg, 0.788 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 74 mg of the target compound (I-2) as a yellow solid in a yield of 52%. 1 H NMR (400MHz, CDCl3) δ8.10 (s, 2H), 7.73-7.41 (m, 7H), 7.19 (d, J = 4.3Hz, 1H), 3.8 3(s,2H),3.06(s,2H),2.91(s,2H),2.79(s,2H),2.04(s,4H).LC-MS:m / z:(M+H)+ =541.1.

[0477] Example 3

[0478]

[0479] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (4) (50 mg, 0.263 mmol) and 4'-(perfluoropropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (6) (92 mg, 0.263 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (167 mg, 0.788 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 14 mg of the title compound as a yellow solid in a 10% yield. 1H NMR (400MHz, CDCl3) δ8.17(s,2H),7.72(q,J=8.6Hz,4H),7.62(d,J=8.2Hz,2H),7.51(d,J=8.1Hz,2H), 7.17(d,J=4.5Hz,1H),3.80(s,2H),3.06(s,2H),2.82(d,J=31.6Hz,4H),2.02(s,4H).LC-MS:m / z:(M+H) + =525.1.

[0480] Example 4

[0481]

[0482] first step:

[0483] Under Ar, anhydrous THF (20 mL) was added to a three-necked flask and cooled to -78°C. Phenyllithium solution (2.0 M / L, 5 mL) was slowly added, followed by diisopropylamine (17 mg, 0.17 mmol), and the mixture was stirred at this temperature for 10 minutes. 2,4-Dichloropyridine (I-4-a) (1.48 g, 10 mmol) was added dropwise to the reaction system, which was then heated to -40°C and stirred for 1 hour. The temperature was again lowered to -78°C, and a solution of N-Boc-1-oxa-6-azaspiro[2.5]octane (1.065 g, 5 mmol) in THF (5 mL) was added dropwise. The mixture was allowed to react at -60°C for 2 hours. After completion of the reaction, the reaction system was quenched with saturated aqueous NH4Cl (10 mL). Water (30 mL) and ethyl acetate (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to obtain tert-butyl 4-((2,4-dichloropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-4-b) (740 mg) as a light yellow oil. LC-MS: m / z: (M-55) + =305.0.

[0484] Step 2:

[0485] Under Ar, tert-butyl 4-((2,4-dichloropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-4-b) (388 mg, 1.07 mmol) was dissolved in dry DMF (10 mL) and cooled to 0°C in an ice bath. NaH (60%, 107 mg, 2.68 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 16 hours. After completion of the reaction as monitored by TLC, the reaction mixture was cooled to 0°C and quenched with saturated aqueous NH4Cl (10 mL). Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give a mixture of tert-butyl 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-c) and tert-butyl 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-d) (272 mg) as a light yellow oil. LC-MS: m / z: (M+H) + =324.8.

[0486] Step 3:

[0487] A mixture of tert-butyl 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-c) and tert-butyl 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-d) (150 mg, 0.46 mmol) was added to a dioxane hydrochloride solution (4 M / L, 8 mL). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, monitored by LC-MS, the reaction system was evaporated to dryness to afford a mixture of 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine] (I-4-e) and 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine] (I-4-f) (176 mg) as a white solid. The crude product was used directly in the next reaction. LC-MS:m / z:(M+H) + =224.6.

[0488] Step 4:

[0489] A crude mixture of 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine] (I-4-e) and 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine] (I-4-f) (44 mg) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (52 mg, 0.15 mmol) from the previous step was dissolved in DMF (8 mL). Triethylamine (46 mg, 0.45 mmol) and acetic acid (14 mg, 0.225 mmol) were added in sequence, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 2-(4'-((4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropyl-2-ol (I-4) (25 mg) as a white solid. LC-MS: m / z: (M+H) +=557.0.1H NMR (400MHz, CDCl3) δ8.07(d,J=5.5Hz,1H),7.80(d,J=8.2Hz,2H),7.67(d,J=8.4Hz,2H),7.58(d,J=8.0H z,2H),7.43(d,J=7.9Hz,2H),6.65(d,J=5.5Hz,1H),3.62(s,2H),3.02(s,2H),2.62(bs,4H),1.96(m,5H).

[0490] Example 5

[0491]

[0492] first step:

[0493] A mixture of tert-butyl 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-c) and tert-butyl 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-4-d) (125 mg, 0.385 mmol) was dissolved in methanol (10 mL). 10% Pd / C (30 mg) was added, and the system was placed under a H2 atmosphere and stirred at room temperature for 16 hours. After completion of the reaction, monitored by TLC, the Pd / C was removed by filtration, and the filtrate was evaporated to dryness. A crude mixture of tert-butyl 3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-5-a) and tert-butyl 3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-5-b) (130 mg) was obtained as a yellow oil. LC-MS: m / z: (M+H) + =290.8.

[0494] Step 2:

[0495] A crude mixture (130 mg) of tert-butyl 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-5-a) and tert-butyl 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-5-b) was added to a dioxane hydrochloride solution (4M / L, 8 mL). The mixture was stirred at room temperature for 4 hours. After completion of the reaction, monitored by LC-MS, the reaction system was evaporated to dryness to obtain a mixture (146 mg) of 3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine] (I-5-c) and 3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine] (I-5-d) as a white solid. The crude product was used directly in the next reaction. LC-MS: m / z: (M+H) + =190.7.

[0496] Step 3:

[0497] A mixture of 3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine] (I-5-c) and 3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine] (I-5-d) (146 mg) from the previous step and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (134 mg, 0.39 mmol) were dissolved in N,N-dimethylformamide (8 mL). Triethylamine (117 mg, 1.16 mmol) and acetic acid (35 mg, 0.58 mmol) were added sequentially, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (245 mg, 0.39 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 2-(4'-((3H-spiro[furo[2,3-b]pyridine-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-hexafluoropropyl-2-ol (I-5) (53 mg) as a white solid. LC-MS: m / z: (M+H) + =523.0. 1 H NMR (400MHz, CDCl3) δ7.98(d,J=4.5Hz,1H),7.82(d,J=8.3Hz,2H),7.62(d,J=8.6Hz,2H),7.55(d,J=8.0Hz,2H) ,7.45(t,J=7.0Hz,3H),6.79(dd,J=7.1,5.3Hz,1H),3.80(s,2H),3.03(s,2H),2.88(m,4H),2.14–1.95(m,4H).

[0498] Examples 6 and 11

[0499]

[0500] A mixture of 3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine] (I-5-c) and 3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine] (I-5-d) (80 mg) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (74 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (8 mL). Triethylamine (61 mg, 0.60 mmol) and acetic acid (18 mg, 0.30 mmol) were added sequentially, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (127 mg, 0.60 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by high performance liquid chromatography to give 2-(4'-((3H-spiro[furo[3,2-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropyl-2-ol (I-11) (34 mg) and 2-(4'-((3H-spiro[furo[2,3-b]pyridine-2,4'-piperidin]-1'-yl)methyl)-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropyl-2-ol (I-6) (39 mg); Compound I-11: LC-MS: m / z: (M+H) + =541.0. 1H NMR (400 MHz, MeOD) δ 8.23 ​​(s, 1H), 8.18 (d, J = 5.6 Hz, 1H), 7.65–7.53 (m, 5H), 7.49 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 5.6 Hz, 1H), 3.67 (s, 2H), 3.10 (s, 2H), 2.67 (s, 4H), 1.99 (m, 2H), 1.95–1.83 (m, 2H). HPLC (Methods HCOOH 5–95 M), retention time (RT): 7.381 min. Compound I-6: white solid. LC-MS: m / z: (M+H) +=541.0. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 4.5 Hz, 1H), 7.63 (dd, J = 16.2, 10.3 Hz, 2H), 7.44 (m, 7H), 6.79 (dd, J = 7.1, 5.3 Hz, 1H), 3.77 (s, 2H), 3.02 (s, 2H), 2.84 (m, 4H), 2.07–1.91 (m, 4H). HPLC (Methods HCOOH 5–95 M), retention time: 9.326 min.

[0501] Example 7

[0502]

[0503] first step:

[0504] 2-Bromo-5-formylpyridine (I-7-a) (100 mg, 0.538 mmol) and 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl-2-ol (398 mg, 1.075 mmol) were placed in N,N-dimethylformamide (20 mL). Pd(PPh3)2Cl2 (74 mg, 0.105 mmol) and K3PO4 (456 mg, 2.15 mmol) were added. Under an Ar atmosphere, the temperature was raised to 90°C and the reaction was allowed to proceed for 16 hours. After completion of the reaction, water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), washed with water (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give 6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)phenyl)nicotinaldehyde (I-7-b) (140 mg) as a white solid. LC-MS: m / z: (M+H) + =350.0.

[0505] Step 2:

[0506] 6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)phenyl)nicotinaldehyde (I-7-b) (140 mg, 0.40 mmol) and 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (76 mg, 0.40 mmol) from the previous step were dissolved in N,N-dimethylformamide (8 mL). Triethylamine (122 mg, 1.20 mmol) and acetic acid (36 mg, 0.60 mmol) were added in sequence and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 2-(4-(5-((3H-spiro[furo[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)pyridin-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropyl-2-ol (I-7) (96 mg) as a white solid. LC-MS: m / z: (M+H) + =524.0. 1 H NMR (400MHz, CDCl3) δ8.63 (s, 1H), 8.15–7.65 (m, 8H), 7.14 (d, J = 4.4Hz, 1H), 3.72 (s, 2H), 2.99 (s, 2H), 2.71 (m, 4H), 1.96 (m, 4H).

[0507] Example 9

[0508]

[0509] first step:

[0510] 3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine] (4) (500 mg, 2.63 mmol) and 4-bromo-3-fluorobenzaldehyde (I-9-a) (587 mg, 2.89 mmol) were dissolved in dichloromethane (15 mL). Sodium triacetoxyborohydride (1.11 g, 5.26 mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography (dichloromethane / methanol 0-10%) to obtain the target compound 1'-(4-bromo-3-fluorobenzyl)-3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine] (I-9-b) (520 mg, 52.45% yield). LC-MS: 376.7 [M+1] + .

[0511] Step 2:

[0512] 1'-(4-Bromo-3-fluorobenzyl)-3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine](I-9-b) (200 mg, 0.53 mmol) was dissolved in 1,4-dioxane (15 mL), and 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (2) (294 mg, 0.80 mmol), potassium carbonate (223 mg, 1.59 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (78 mg, 0.11 mmol) were added to the reaction solution. The reaction solution was heated to 100 ° C under nitrogen protection and stirred for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol 0-10%) to obtain the target compound 2-(4'-(((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidin]-1'-yl]methyl)methyl)-2'-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-9) (121 mg, 42.22%). LC-MS: 541.0 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.14–8.05(m,2H),7.86(d,J=8.2Hz,2H),7.63(d,J=7.6Hz,2H),7.44(t,J=8.0Hz,1H),7.27–7 .21(m,1H),7.17(d,J=4.6Hz,0H),2.82(d,J=39.8Hz,2H),2.02(d,J=5.1Hz,2H),0.89(ddd,J=11.7,8.1,4.3Hz,1H).

[0513] Example 10

[0514]

[0515] 3H-spiro[furan[2,3-c]pyridine-2,3'-pyrrolidine] (52 mg, 0.295 mmol) (7), 2'-fluoro-4'-((1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (140 mg, 0.38 mmol) (1) were added to 20 ml of dichloromethane, followed by sodium acetate borohydride (130 mg, 0.62 mmol) and stirred at room temperature overnight. The reaction solution was concentrated and added with 10 ml of saturated sodium carbonate solution. The solution was extracted with dichloromethane twice (2×25 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated by column chromatography {7M ammonia methanol: (dichloromethane: ethyl acetate = 12:2) = 0-15%} to obtain 75 mg of a white solid (I-10) with a yield of 48%. LC-MS: m / z: (M+H) + =526.1H NMR (400MHz, CDCl3) δ8.11–7.94(m,2H),7.72–7.62(m,2H),7.59–7.49(m,3H),7.45(d,2H),7.17(d,1H),3. 85–3.71(m,2H),3.29(q,2H),3.06(d,1H),2.98(m,1H),2.85–2.71(m,2H),2.43(m,1H),2.19–2.04(m,1H).

[0516]

[0517] Compound (7-peak A / B) (67 mg, 0.380 mmol) and 2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (139 mg, 0.380 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (238 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 25 mg of the target compound (I-10A / B) as a yellow solid in a yield of 13%. 1H NMR (400MHz, MeOD) δ8.05(d,J=4.8Hz,1H),8.01(s,1H),7.67–7.47(m,7H),7.31(d,J=4.8Hz,1H),3.86(q,J=12.9Hz,2H),3.39(d,J =6.2Hz,2H),3.15(d,J=11.0Hz,1H),3.11–2.98(m,1H),2.92–2.80(m,2H),2.44–2.32(m,1H),2.25–2.14(m,1H).LC-MS:m / z:(M+H) + =527.2.

[0518] Compound (7-peak B / A) (56 mg, 0.318 mmol) and 2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (116 mg, 0.318 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (202 mg, 0.953 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 22 mg of the target compound (I-10B / A) as a yellow solid in a 13% yield. 1 HNMR(400MHz,DMSO)δ9.04(s,1H),8.17–8.00(m,2H),7.73(t,J=8.2Hz,1H),7.58(dd,J =15.0,8.3Hz,4H),7.47(d,J=8.1Hz,2H),7.27(d,J=4.6Hz,1H),3.71(s,2H),3.32(d,J= 5.8Hz,2H),2.95(d,J=10.5Hz,1H),2.84(dd,J=14.9,8.0Hz,1H),2.70(d,J=10.5Hz,1H ),2.62(dd,J=14.4,8.4Hz,1H),2.27–2.16(m,1H),2.16–2.05(m,1H).LC-MS:m / z:(M+H) + =527.2.

[0519] Example 14

[0520]

[0521] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (52 mg, 0.273 mmol) and 4-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyridin-2-yl)benzaldehyde (I-14-a) (95 mg, 0.273 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (174 mg, 0.821 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 21 mg of the target compound (I-14) as a yellow solid in a yield of 15%. 1 HNMR(400MHz,DMSO)δ9.13(s,1H),8.93(s,1H),8.09(dd,J=20.7,10.6Hz,5H),7.50(s,2H),7.28 (d, J=4.5Hz, 1H), 3.61 (s, 2H), 3.07 (s, 2H), 2.53 (s, 2H), 1.86 (s, 4H). LC-MS: m / z: (M+H)+=524.1.

[0522] Example 15:

[0523]

[0524] first step:

[0525] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (95 mg, 0.5 mmol) and 2-chloropyrimidine-5-carbaldehyde (71 mg, 0.5 mmol) (I-15-a) were added to 20 ml of dichloromethane, followed by sodium acetate borohydride (221 mg, 1.05 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated, 20 ml of water was added, and the mixture was extracted twice with dichloromethane (2 × 25 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated. The organic phase was separated by thin-layer chromatography (methanol:(dichloromethane:ethyl acetate=10:2)=1:12) to obtain 15 mg of a white solid (I-15-b) in a yield of 9%. LC-MS: m / z: (M+H) + =317.

[0526] Step 2:

[0527] 1'-(((2-chloropyrimidin-5-yl)methyl)-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (16 mg, 0.05 mmol) (I-15-b), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (22 mg, 0.06 mmol) (2), potassium carbonate (20 mg, 0. 14 mmol), water (0.1 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (6 mg, 0.0074 mmol) were added to 5 mL of 1,4-dioxane and stirred at 100°C overnight under nitrogen. The reaction mixture was filtered, concentrated, and separated using a thin-layer chromatography plate {methanol:(dichloromethane:ethyl acetate=10:2)=1:10}. The resulting target product was dissolved in dichloromethane and 0.1 mL of 4M hydrochloric acid in dioxane was added. The solvent was evaporated to yield 3 mg of a white solid (I-15), in a 10% yield. LC-MS: m / z: (M+H) + =525.1H NMR (400MHz, MeOD) δ9.15 (s, 2H), 8.61 (d, J = 8.9Hz, 2H), 8.43 (s, 2H), 7.97 (d ,J=5.4Hz,1H),7.92(d,J=8.5Hz,2H),4.61(s,2H),3.61(m,6H),2.40(m,4H).

[0528] Example 16

[0529]

[0530] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (4) (63 mg, 0.331 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (12) (127 mg, 0.331 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (210 mg, 0.991 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 40 mg of the target compound (I-16) as a yellow solid in a yield of 22%. 1H NMR (400MHz, DMSO) δ8.86 (s, 1H), 8.16-8.02 (m, 2H), 7.81 (d, J = 8.3Hz, 2H), 7.64 (d, J = 8.4Hz, 2H), 7.26 (dd, J=21.7,6.5Hz,3H),3.62(s,2H),3.08(s,2H),2.57(s,2H),1.87(dd,J=18.9,14.3Hz,4H).LC-MS:m / z:(M+H) + =559.1.

[0531] Example 17

[0532]

[0533] first step:

[0534] 1,4-Dibromobenzene (I-17-a) (5.72 g, 24.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and the reaction solution was cooled to -78 ° C. A solution of n-butyllithium in n-hexane (25.5 mL, 1N) was added dropwise to the reaction solution. After the addition was complete, the reaction solution was stirred at -78 ° C for 0.5 hour. Ethyl 2,2-difluoroacetate (6.62 g, 53.3 mmol) was added to the reaction solution. After the addition was complete, the reaction solution was stirred at -78 ° C for 1 hour. The plate showed that the reaction starting material disappeared. Saturated aqueous ammonium chloride was added to the reaction solution to quench the reaction, and the reaction solution was warmed to room temperature and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound 1-(4-bromophenyl)-2,2-difluoroethane-1-one (I-17-b) (4.0 g, 70%).

[0535] Step 2:

[0536] 1-(4-bromophenyl)-2,2-difluoroethane-1-one (I-17-b) (4.0 g, 17 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction solution was cooled to 0 ° C. Trimethyl (trifluoromethyl) silane (4.8 g, 34 mmol) was added to the reaction solution, and a tetrahydrofuran solution of tetrabutylammonium fluoride (34 mL, 1N) was slowly added dropwise. The temperature was controlled below 5 ° C during the addition. After the addition was completed, the reaction solution was stirred at room temperature for 16 hours. The plate showed that the reaction starting material disappeared. Aqueous solution was added to the reaction solution to quench the reaction. The reaction was extracted with ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound 2-(4-bromophenyl)-1,1,1,3,3-pentafluoropropane-2-ol (I-17-c) (4.2 g, 81%).

[0537] Step 3:

[0538] 2-(4-Bromophenyl)-1,1,1,3,3-pentafluoropropane-2-ol (I-17-c) (500 mg, 1.64 mmol) was dissolved in 1,4-dioxane (20 mL). Under nitrogen protection, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (I-23-c) (295 mg, 1.97 mmol), potassium carbonate (690 mg, 4.92 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (240 mg, 0.33 mmol) were added to the reaction solution, and the reaction solution was heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound 4'-(1,1,1,3,3-pentafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (I-17-d) (170 mg, 31.41%). LC-MS: 331 [M+1] + .

[0539] Step 4:

[0540] 4'-(1,1,1,3,3-Pentafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (I-17-d) (70 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), and 3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine] (48 mg, 0.25 mmol) and sodium triacetoxyborohydride (90 mg, 0.42 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4'-(((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl]-[1,1'-biphenyl]-4-yl)-1,1,1,3,3-pentafluoropropan-2-ol (I-17) (35 mg, 32.73%). LC-MS: 505.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.07(d,J=6.1Hz,2H),7.80(d,J=8.2Hz,2H),7.68(d,J=8.4Hz,2H),7.63–7.56(m,2H),7.44(d,J=8.0Hz,2H) ,7.14(d,J=4.4Hz,1H),6.24(t,J=54.4Hz,1H),3.64(s,1H),3.02(s,1H),2.65(s,2H),2.00(d,J=13.0Hz,1H),1.92–1.80(m,1H).

[0541] Example 18

[0542]

[0543] first step:

[0544] 2-Bromothiazole-5-carboxaldehyde (I-28-a) (100 mg, 0.52 mmol) was dissolved in N, N-dimethylformamide (10 mL), and 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (2) (386 mg, 1.04 mmol), potassium phosphate (442 The reaction mixture was heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound 2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazole-5-carbaldehyde (I-18-b) (76 mg, 41.08%).

[0545] Step 2:

[0546] 2-(4-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropane-2-yl)phenyl)thiazole-5-carbaldehyde (I-18-b) (76 mg, 0.21 mmol) was dissolved in dichloromethane (10 mL), and 3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine](4) (43 mg, 0.22 mmol) and sodium triacetoxyborohydride (91 mg, 0.43 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4-(5-((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)thiazol-2-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-18) (42 mg, 37.08%). LC-MS: 530.0 [M+1] + . 1H NMR (400MHz, DMSO) δ8.92 (s, 1H), 8.14–8.01 (m, 4H), 7.83 (s, 3H), 7.27 (d, J = 4.6Hz, 1H), 3.06 (s, 2H), 2.56 (d, J = 20.6Hz, 4H), 1.91–1.74 (m, 4H).

[0547] Example 20

[0548]

[0549] first step:

[0550] Dissolve ethyl 5-bromopyrimidine-2-carboxylate (0.46 g, 2 mmol) (I-20-a) in 10 ml of tetrahydrofuran, then add 1 mol / L diisobutylaluminum hydride in n-hexane (3.2 ml) at approximately -78°C. The reaction mixture is allowed to react for 1.5 hours. The reaction mixture is quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3 x 20 ml). The combined organic layers are washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to yield 0.12 g of a crude yellow solid (I-20-b), which is used directly in the next step with a yield of 32%. LC-MS: m / z: (M+H) + =187.

[0551] Step 2:

[0552] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (100 mg, 0.525 mmol) (4) and 5-bromopyrimidine-2-carbaldehyde (120 mg, 0.64 mmol) (I-20-b) were added to 20 ml of dichloromethane, followed by sodium acetate borohydride (0.23 g, 1.09 mmol) and stirred at room temperature overnight. The reaction solution was concentrated, and 10 ml of water and 10 ml of saturated sodium bicarbonate aqueous solution were added. The solution was extracted with dichloromethane twice (2 × 20 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography (methanol:(dichloromethane:ethyl acetate=12:2)=0-15%) to obtain 110 mg of a white solid (I-20-c) with a yield of 58%. LC-MS: m / z: (M+H) + =361.

[0553] Step 3:

[0554] 1'-((5-bromopyrimidin-2-yl)methyl)-3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine](I-20-c) (110 mg, 0.3 mmol), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (130 mg, 0.35 mmol) (2), potassium carbonate (100 mg, 0.72 mmol), water (1 ml) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) were added to 8 ml of 1,4-dioxane and stirred at 100°C overnight under nitrogen protection. The reaction mixture was filtered, concentrated, and separated using a thin-layer chromatography plate {7M ammonia methanol: (dichloromethane:ethyl acetate = 12:2) = 1:14}. 60 mg of a white solid (I-20) was obtained in a 37% yield. LC-MS: m / z: (M+H)+ =525.1H NMR (400MHz, CDCl3) δ8.95(s,2H),8.05(s,2H),7.97(d,J=8.3Hz,2H),7.66(d,J=8.6Hz ,2H),7.16(d,J=4.5Hz,1H),3.98(s,2H),3.04(s,2H),2.80(s,4H),2.12–1.92(m,4H).

[0555] Example 21

[0556]

[0557] first step:

[0558] 4-Bromo-2,3-difluorobenzaldehyde (I-21-a) (0.3 g, 1 mmol), 1,1,1,3,3,3-hexafluoro-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propan-2-ol (2) (0.6 g, 2 mmol), and potassium carbonate (2 M, 1.5 mL) were dissolved in 1,4-dioxane. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 g, 0.1 mmol) was then added. The atmosphere in the flask was replaced with argon, and the reaction was carried out at 90°C under argon protection for 16 hours. Thin layer chromatography (TLC) on silica gel (petroleum ether:ethyl acetate = 10:1) indicated the reaction was complete. LCMS showed the product was formed. The reaction mixture was cooled in air and concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate 0-20%) to give 2,3-difluoro-4-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]benzaldehyde (I-21-b) (0.4 g, 1 mmol) as a white solid. LC-MS: m / z (M+H) + =385.0.

[0559] Step 2:

[0560] 2,3-Difluoro-4-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]benzaldehyde (I-21-b) (100 mg, 0.2603 mmol) and spiro[3H-furo[2,3-c]pyridine-2,4'-piperidine](4) (60 mg, 0.31539 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL). N,N-diethylethanamine (10 mg, 0.098824 mmol) and acetic acid (20 mg, 0.3331 mmol) were added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (165 mg, 0.77852 mmol) was added and stirring was continued for 16 hours. Thin layer chromatography on silica gel plates (petroleum ether:ethyl acetate = 3:1 and 0:1) showed the formation of a new spot. LCMS showed the product. The reaction mixture was diluted with ethyl acetate (30 mL) and washed three times with water (20 mL × 3). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate 0-100% and dichloromethane / methanol 0-10%) to give 2-[4-[2,3-difluoro-4-(spiro[3H-furo[2,3-c]pyridine]-2,4'-piperidinyl]-1'-methyl)phenyl]phenyl]-1,1,1,3,3,3-hexafluoropropane-2-ol (I-21) (27 mg, 0.04834 mmol) as a white solid. 1 H-NMR (CDCl3): δ8.07 (d, 2H, J = 5.6Hz, 2H), 7.89 (d, 2H, J = 8.4Hz), 7.72–7.62 (m, 2H), 7.28–7.22 (m, 2H), 7.19–7. 13(m,1H),3.74(d,J=1.6Hz,2H),3.03(d,J=1.2Hz,2H),2.69(s,4H),2.02(d,J=13.2Hz,2H),1.91–1.86(m,2H). LC-MS:m / z(M+H) + =559.2.

[0561] Example 22

[0562]

[0563] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (26 mg, 0.136 mmol) and 5-(2-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinaldehyde (13) (50 mg, 0.136 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (86 mg, 0.406 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 8 mg of the target compound (I-22) as a yellow solid in an 11% yield. 1 H NMR (400MHz, CDCl3) δ8.69(s,1H),8.17-8.06(m,2H),7.92(d,J=8.0Hz,1H),7.67(d,J=8.2Hz,2H),7.62-7.48( m,2H),7.16(d,J=4.7Hz,1H),3.84(s,2H),3.06(s,2H),2.76(s,4H),2.04(d,J=13.4Hz,4H).LC-MS:m / z:(M+H) + =542.1.

[0564] Example 23

[0565]

[0566] first step:

[0567] Methyl 4-bromo-3-(trifluoromethyl)benzoate (I-23-a) (1.0 g, 3.5 mmol) and trimethyl(trifluoromethyl)silane (2.5 g, 18 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction solution was cooled to 0°C and a solution of tetrabutylammonium fluoride in tetrahydrofuran (7.1 mL, 1 N) was slowly added. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 hours. A spectrophotometer indicated that the reaction was complete. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound, 2-(4-bromo-3-(trifluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-23-b) (820 mg, 59%).

[0568] Step 2:

[0569] 2-(4-Bromo-3-(trifluoromethyl)phenyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-23-b) (600 mg, 1.53 mmol) was dissolved in 1,4-dioxane (20 mL). Under nitrogen protection, (4-formylphenyl)boric acid (I-23-c) (276 mg, 1.84 mmol), potassium carbonate (645 mg, 4.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (225 mg, 0.31 mmol) were added to the reaction solution. The reaction solution was heated to 100 ° C and stirred for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain the target compound 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde (I-23-d) (320 mg, 50.11%). LC-MS: 417.0 [M+1] + .

[0570] Step 3:

[0571] 4'-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropane-2-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]-4-carbaldehyde (I-23-d) (120 mg, 0.29 mmol) was dissolved in dichloromethane (20 mL), and 3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine] (4) (58 mg, 0.30 mmol) and sodium triacetoxyborohydride (122 mg, 0.58 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4'-(((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl]-2-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-23) (45 mg, 26.43%). LC-MS: 591.2 [M+1] + . 1HNMR(400MHz, CDCl3)δ8.24(s,1H),8.13–7.88(m,3H),7.43(dd,J=13.4,8.1Hz,3H),7.33(d,J=7.6Hz,3H), 7.19 (d, J = 4.1Hz, 1H), 3.66 (s, 2H), 3.06 (s, 2H), 2.67 (s, 4H), 2.03 (d, J = 12.8Hz, 2H), 1.90 (d, J = 6.4Hz, 2H).

[0572] Example 24

[0573]

[0574] 2'-Fluoro-4'-((1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (178 mg, 0.49 mmol) was dissolved in dichloromethane (20 mL), and 3'H-8-azaspiro[bicyclo[3.2.1]octane-3,2'-furo[2,3-c]pyridine] (15) (100 mg, 0.46 mmol) and sodium triacetoxyborohydride (196 mg, 0.92 mmol) were added to the reaction solution. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4'-(((3'H-8-aza][bicyclo[3.2.1]octane-3,2'-furo[2,3-c]pyridin]-8-yl)methyl)-2-fluoro-[[1,1'-biphenyl]-4-yl)-1,1,1,1,3,3,3-hexafluoropropane-2-ol (I-24) (185 mg, 70.64%). LC-MS: 567.2 [M+1] + . 1H NMR (400MHz, CDCl3) δ8.16–8.01(m,2H),7.68–7.53(m,6H),7.46(t,J=8.2Hz,1H),7.16(d, J=4.5Hz,1H),3.98(s,2H),3.64(s,2H),3.11(s,2H),2.67–2.43(m,4H),2.27–2.12(m,4H).

[0575] Example 25

[0576]

[0577] first step:

[0578] 5-Bromo-4-methylpyrimidine (I-25-a) (476 mg, 2.75 mmol) was placed in a three-necked flask under an argon atmosphere. Anhydrous THF (20 mL) was added to the flask and cooled to -78°C. Lithium diisopropylamide (LDA) (2.0 M / L, 1.65 mL) was slowly added dropwise and stirred at this temperature for 30 minutes. A solution of N-Boc-4-piperidone (657 mg, 3.3 mmol) in anhydrous tetrahydrofuran (THF) (5 mL) was added dropwise to the reaction system. After the addition, the reaction was incubated for 3 hours. After completion of the reaction, the reaction system was quenched with saturated aqueous NH4Cl (8 mL) by TLC monitoring. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:2) to give tert-butyl 4-((5-bromopyrimidin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-25-b) (491 mg) as a light yellow oil. LC-MS: m / z: (M-55) + =316.0,318.0.

[0579] Step 2:

[0580] Dissolve tert-butyl 4-((5-bromopyrimidin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-25-b) (206 mg, 0.554 mmol) in toluene (15 mL), and add cuprous iodide (48 mg, 0.252 mmol), 8-hydroxyquinoline (72 mg, 0.50 mmol), and cesium carbonate (391 mg, 1.2 mmol) in sequence. The system was protected by argon and heated to 110°C for 16 hours. After completion of the reaction, as monitored by TLC, the reaction system was quenched with saturated aqueous NH4Cl solution (8 mL). Water (20 mL) was added, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate:petroleum ether = 1:1) to give tert-butyl 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylate (I-25-c) (105 mg) as a light yellow oil. LC-MS: m / z: (M+H) + =292.1.

[0581] Step 3:

[0582] Dissolve tert-butyl 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylate (I-25-c) (105 mg, 0.36 mmol) in dichloromethane (10 mL), slowly add trifluoroacetic acid (2 mL), and stir at room temperature for 5 hours. After the reaction is completed, the system is evaporated to dryness to obtain crude 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine] (I-25-d) (125 mg) as a yellow oil. LC-MS: m / z: (M+H) + =192.0.

[0583] Step 4:

[0584] The above 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (131 mg, 0.36 mmol) and the crude product of 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine](I-25-d) (125 mg) were dissolved in N,N-dimethylformamide (8 mL). Triethylamine (101 mg, 1.0 mmol) and acetic acid (29 mg, 0.48 mmol) were added in sequence and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to obtain 2-(4'-((7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidin]-1'-yl)methyl)-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropyl-2-ol (I-25) (43 mg) as a white solid. LC-MS: m / z: (M+H) + =542.1. 1H NMR (400MHz, CDCl3) δ 8.69 (s, 1H), 8.16 (s, 1H), 7.53 (m, 7H), 3.69 (s, 2H), 3.13 (s, 2H), 2.72 (m, 4H), 2.03 (m, 4H).

[0585] Example 27

[0586]

[0587] 3-Fluoro-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinaldehyde (14) (100 mg, 0.27 mmol) was dissolved in dichloromethane (15 mL). 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (4) (54 mg, 0.29 mmol) and sodium triacetoxyborohydride (115 mg, 0.54 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4-(6-((3H-spiro[furano[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-5-fluoropyridin-3-yl)phenyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-27) (65 mg, 46.11%). LC-MS: 542.2 [M+1] + . 1H NMR (400MHz, DMSO) δ8.89(s,1H),8.81(s,1H),8.15–8.02(m,3H),7.97(d,J=8.7Hz,2H),7.82(d,J= 8.3Hz,2H),7.27(d,J=4.3Hz,1H),3.78(s,2H),3.04(s,2H),2.72–2.55(m,4H),1.88–1.75(m,4H).

[0588] Example 28

[0589]

[0590] Compound (7-peak A) (66 mg, 0.374 mmol) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (3) (130 mg, 0.374 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (238 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain the target compound (I-28A) as a yellow solid in an 18% yield. 1H NMR(400MHz,MeOD)δ8.05(d,J=4.8Hz,1H),8.01(s,1H),7.82(d,J=8.4Hz,2H),7.77–7 .71(m,2H),7.68(d,J=8.3Hz,2H),7.51(d,J=8.2Hz,2H),7.31(dd,J=4.8,0.8Hz,1H),3 .85(q,J=12.8Hz,2H),3.38(d,J=4.8Hz,2H),3.14(d,J=10.9Hz,1H),3.05(dt,J=9.4, 7.4Hz,1H),2.91–2.80(m,2H),2.44–2.33(m,1H),2.24–2.13(m,1H).LC-MS:m / z:(M+H) + =509.1.

[0591] Compound (7-peak B) (70 mg, 0.397 mmol) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (3) (138 mg, 0.396 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (252 mg, 1.19 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 35 mg of the target compound (I-28B) as a yellow solid in an 18% yield. 1 H NMR(400MHz,MeOD)δ8.05(d,J=4.8Hz,1H),8.01(s,1H),7.82(d,J=8.4Hz,2H),7.78– 7.71(m,2H),7.68(d,J=8.2Hz,2H),7.51(d,J=8.2Hz,2H),7.31(d,J=4.2Hz,1H),3.83 (q,J=12.8Hz,2H),3.39(d,J=5.2Hz,2H),3.12(d,J=11.0Hz,1H),3.08–2.97(m,1H), 2.88–2.74(m,2H),2.46–2.31(m,1H),2.19(dt,J=14.1,5.5Hz,1H).LC-MS:m / z:(M+H) + =509.1.

[0592] Example 29

[0593]

[0594] 4'-(1,1,1,3,3,3-Hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (118 mg, 0.32 mmol) and 5-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (8) (66 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (10 mL). Triethylamine (125 mg, 1.24 mmol) and acetic acid (50 mg, 0.83 mmol) were added in sequence and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added and stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous NH4Cl solution (5 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((5-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)propyl-2-ol (I-29) (45 mg) as a white solid. LC-MS: m / z: (M+H) + =555.2. 1 H NMR (400MHz, CDCl3) δ7.91(s,1H),7.54(m,7H),6.98(s,1H),3.65(s,2H),2.97(s,2H),2.65(s,4H),2.47(s,3H),1.94(m,4H).

[0595] Example 30

[0596]

[0597] first step:

[0598] 2-Hydroxyisonicotinaldehyde (I-30-a) (100 mg, 0.81 mmol) was dissolved in dichloromethane (15 mL), and 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (2) (361 mg, 0.97 mmol), copper acetate (221 mg, 1.22 mmol), pyridine (129 mg, 1.62 mmol) and triethylamine (164 mg, 1.62 mmol) were added to the reaction solution under nitrogen protection, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 50 / 50) to obtain the target compound 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (I-30-b) (125 mg, 42.14%).

[0599] Step 2:

[0600] 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)phenyl)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (I-30-b) (180 mg, 0.49 mmol) was dissolved in dichloromethane (15 mL), and 3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine](4) (98 mg, 0.52 mmol) and sodium triacetoxyborohydride (209 mg, 0.99 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 4-((3H-spiro[furo[2,3-c]pyridin-2,4'-piperidin]-1'-yl)methyl)-1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)pyridin-2(1H)-one (I-30) (67 mg, 25.2%). LC-MS: 540.2 [M+1] + . 1H NMR (400MHz, DMSO) δ8.09(d,J=11.4Hz,2H),7.82(d,J=7.7Hz,2H),7.65(dd,J=31.5,7.4Hz ,3H),7.30(s,1H),6.54–6.29(m,2H),3.44(s,2H),3.09(s,2H),2.57(s,2H),1.88(s,4H).

[0601] Example 31

[0602]

[0603] 5-Chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](17)(40 mg, 0.19 mmol) was dissolved in dichloromethane (15 mL), 2'-fluoro-4'-((1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde(1)(68 mg, 0.19 mmol) and sodium triacetoxyborohydride (75 mg, 0.36 mmol) were added to the reaction solution, and the mixture was stirred for 2 h. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4'-((5-chloro-3H-spiro[furano[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropane-2-ol (I-31) (55 mg, 53.74%). LC-MS: 575.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.64–7.51 (m, 5H), 7.45 (d, J = 8.0Hz, 2H), 7.14 (s, 1H), 3. 66(s,2H),3.03(s,2H),2.67(s,4H),2.01(d,J=12.9Hz,2H),1.91(dd,J=16.4,10.1Hz,2H).

[0604] Example 32

[0605]

[0606] 4'-(1,1,3,3-tetrafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (9) (100 mg, 0.32 mmol) was dissolved in dichloromethane (15 mL). 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (4) (67 mg, 0.35 mmol) and sodium triacetoxyborohydride (136 mg, 0.64 mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 0-10%) to obtain the target compound 2-(4'-((3H-spiro[furano[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,3,3-tetrafluoropropan-2-ol (I-32) (58 mg, 37.23%). LC-MS: 487.2 [M+1]. 1H NMR (400MHz, DMSO) δ8.19–8.01(m,2H),7.71(dd,J=22.8,7.8Hz,6H),7.44(d,J=6.9Hz,2H),7.28 (s,1H),7.05(s,1H),6.47(t,J=53.9Hz,2H),3.60(s,2H),3.06(s,2H),2.52(s,4H),1.86(s,4H).

[0607] Example 33

[0608]

[0609] first step:

[0610] (4-Formylphenyl)boronic acid (I-23-c) (120 mg, 0.47 mmol) and (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-ol (I-33-a) (84 mg, 0.56 mmol) were dissolved in dioxane (5 ml) and water (5 ml), followed by the addition of tetrakistriphenylphosphine palladium (55 mg, 0.047 mmol) and potassium carbonate (195 mg, 1.41 mmol). The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (ethyl acetate:petroleum ether = 0-10%) to afford 62 mg of the target compound (I-33-b) as a yellow solid in a 47% yield. 1 H NMR (400MHz, CDCl3) δ10.09(s,1H),7.99(d,J=8.2Hz,2H),7.78(d,J=8.2Hz,2H),7. 71(d,J=8.3Hz,2H),7.63(d,J=8.2Hz,2H),5.14(q,J=6.6Hz,1H).LC-MS:m / z:(M+H)+ =281.1.

[0611] Step 2:

[0612] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (84 mg, 0.3 mmol) and (S)-4'-((2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-4-carbaldehyde (I-33-b) (57 mg, 0.3 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (191 mg, 0.9 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction solution was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 13 mg of the target compound (I-33) as a yellow solid in a yield of 10%. 1 H NMR (400MHz, DMSO) δ8.18–7.99(m,2H),7.70(dd,J=16.7,7.3Hz,4H),7.58(d,J=8.1Hz,2H),7.45(s,2H),7.28(d,J=4.5Hz,1H),6.8 6(d,J=5.6Hz,1H),5.21(dd,J=13.3,6.9Hz,1H),3.59(s,2H),3.32(s,2H),3.08(s,2H),2.59(s,2H),1.87(s,4H).LC-MS:m / z:(M+H) + =455.2.

[0613] Example 34

[0614]

[0615] first step:

[0616] (4-Formylphenyl)boronic acid (I-23-c) (170 mg, 0.66 mmol) and (R)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1-ol (I-34-a) (120 mg, 0.8 mmol) were dissolved in dioxane (5 ml) and water (5 ml), followed by the addition of tetrakistriphenylphosphine palladium (77 mg, 0.066 mmol) and potassium carbonate (276 mg, 2.0 mmol). The mixture was stirred at 100°C under nitrogen for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash column chromatography (ethyl acetate:petroleum ether = 0-10%) to afford 120 mg of the target compound (I-34-b) as a yellow solid in a 64% yield. LC-MS: m / z: (M+H) + =281.1.

[0617] Step 2:

[0618] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine](4) (120 mg, 0.428 mmol) and (R)-4'-((2,2,2-trifluoro-1-hydroxyethyl)-[1,1'-biphenyl]-4-carbaldehyde (I-34-b) (81 mg, 0.428 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (272 mg, 1.28 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction solution was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 20 mg of the target compound (I-34) as a yellow solid in a yield of 10%. 1 H NMR (400MHz, DMSO) δ8.09(d,J=9.4Hz,2H),7.72(d,J=7.7Hz,4H),7.59(d,J=8.0Hz,2H),7.45(s,2H),7.29(d,J=3.8Hz,1H) ,6.88(d,J=5.5Hz,1H),5.29–5.13(m,1H),3.58(s,2H),3.09(s,2H),2.68(s,4H),1.89(d,J=22.2Hz,4H).LC-MS:m / z:(M+H) + =455.2.

[0619] Example 35

[0620]

[0621] 2'H,4'H-spiro[piperidin-4,3'-pyrano[3,2-c]pyridine] (18) (50 mg, 0.245 mmol) and 5-(2-fluoro-4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)picolinaldehyde (1) (89 mg, 0.243 mmol) were dissolved in dichloromethane (10 ml), and trifluoroacetic acid (50 μL) was added. After stirring at room temperature for 18 hours, sodium triacetylborohydride (155 mg, 0.731 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to obtain 12 mg of the target compound (I-35) as a yellow solid in a yield of 9%. 1H NMR (400MHz, DMSO) δ9.05 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 5.6Hz, 1H), 7.73 (t, J =8.3Hz,1H),7.64–7.52(m,4H),7.46(d,J=8.1Hz,2H),6.76(d,J=5.6Hz,1H),3. 58(s,2H),2.72(t,J=6.5Hz,2H),2.61(d,J=11.4Hz,2H),2.41(t,J=9.4Hz,2H), 1.83 (t, J=6.6Hz, 2H), 1.71 (dt, J=10.3, 8.6Hz, 4H). LC-MS: m / z: (M+H)+=555.2.

[0622] Example 41

[0623]

[0624] first step:

[0625] 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (I-41-a) (10.00 g, 43.62 mmol) was dissolved in N,N-dimethylformamide (150 ml). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 12.54 g, 65.42 mmol), 1-hydroxybenzotriazole (HOBt, 8.84 g, 65.42 mmol), and N,N-diisopropylethylamine (DIPEA, 22.55 g, 174.46 mmol) were added in sequence. The mixture was stirred at room temperature for 10 minutes, and N,O-dimethylhydroxylamine hydrochloride (5.11 g, 52.34 mmol) was added. The reaction system was stirred at room temperature for 92 hours. After the reaction is complete, ethyl acetate (600 ml) is added to dilute the system. The organic phase is washed with brine (2 x 300 ml), dried over anhydrous Na2SO4, and concentrated to afford tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (I-41-b) (crude product, 13 g) as a yellow oil. LCMS: (ESI, m / z): [M+1] + =273.15.

[0626] Step 2:

[0627] Tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (I-41-b) (6.00 g, 22.03 mmol) was dissolved in dichloromethane (24 ml) and trifluoroacetic acid (12 ml) was added at room temperature. The reaction system was stirred at this temperature for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml) and the pH was adjusted to 11 with aqueous ammonia. After stirring at room temperature for 1 hour, the mixture was prepared using a reverse phase method (C18 silica gel; acetonitrile:water (0.1% NH3.H2O), 15% to 35%) to afford N-methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.10 g, 6.39 mmol) as a pale yellow oil. LCMS: (ESI, m / z): [M+1] + =173.20.

[0628] Step 3:

[0629] N-methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.00 g, 5.81 mmol) was dissolved in 1,4-dioxane (20 ml), and tert-butyl ((1,1,1,3,3,3-hexafluoro-2-(4-iodophenyl)prop-2-yl)oxy)dimethylsilane (3.37 g, 6.97 mmol), RuPhos Pd G3 (0.49 g, 0.58 mmol), RuPhos (0.27 g, 0.58 mmol), and cesium carbonate (3.78 g, 11.61 mmol) were added. The system was purged with nitrogen and then heated to 90°C for 18 hours. After completion of the reaction, the reaction mixture was cooled and concentrated, and then separated by column chromatography (ethyl acetate:petroleum ether = 1:1) to give 1-(4-(2-((tert-butyldimethylsilyl)oxy)-1,1,1,3,3,3-hexafluoroprop-2-yl)phenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (I-41-d) (1.25 g, 2.36 mmol) as a yellow oil. LCMS: (ESI, m / z): [M+1] + =529.35.

[0630] Step 4:

[0631] Under nitrogen protection, 1-(4-(2-((tert-butyldimethylsilyl)oxy)-1,1,1,3,3,3-hexafluoroprop-2-yl)phenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (I-41-d) (1.10 g, 2.08 mmol) was dissolved in dry tetrahydrofuran (10 ml). After cooling to -70 ° C, diisobutylaluminum hydride (1.5 M toluene solution, 2.08 ml, 3.12 mmol) was slowly added dropwise, and the reaction system was kept at -70 ° C for 1 hour. After the reaction was detected, the system was quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate (3×50 ml). The organic phases were combined, dried over Na2SO4, and concentrated. The concentrated residue was dissolved in tetrahydrofuran (10 ml), the system was purged with nitrogen, cooled to 0°C, and tetrabutylammonium fluoride (TBAF, 1.0 M, 4.16 ml, 4.16 mmol) was added. After reacting at 0°C for 30 minutes, the reaction system was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (3 x 50 ml). The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol = 10:1) to afford 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)piperidine-4-carbaldehyde (I-41-e) (220 mg, 0.62 mmol) as a white solid. LCMS: (ESI, m / z): [M+1] + =356.05. 1 H NMR (400MHz, chloroform-d) δ9.71 (s, 1H), 7.55 (d, J = 8.6Hz, 2H), 6.98–6.91 (m, 2H), 3.71 (m, 2H), 3.28(s,1H),2.95(m,2H),2.52–2.38(m,1H),2.04(dd,J=13.4,3.9Hz,2H),1.77(m,2H).

[0632] Step 5:

[0633] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (39 mg, 0.20 mmol) and 1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)piperidine-4-carbaldehyde (I-41-e) (72 mg, 0.20 mmol) were dissolved in dichloromethane (10 mL). Triethylamine (66 mg, 0.65 mmol) and acetic acid (30 mg, 0.50 mmol) were added sequentially, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (130 mg, 0.61 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous NH4Cl solution (10 mL) was added. Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 15:1) to afford 2-(4-(4-((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)piperidin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-41) (69 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + =530.3.1H NMR (400MHz, DMSO) δ8.34(s,1H),8.18–7.99(m,2H),7.44(d,J=8.7Hz,2H),7.27(d,J=4.4Hz,1H),7.00(d,J=9.1Hz,2 H), 3.78 (d, J = 12.5Hz, 2H), 3.05 (s, 2H), 2.73 (t, J = 11.5Hz, 2H), 2.48 (m, 4H), 2.21 (s, 2H), 1.80 (m, 6H), 1.21 (m, 3H).

[0634] Example 50

[0635]

[0636] Spirocyclic 3',4'-dihydrospiro[azetidine-3,2'-pyrano[2,3-c]pyridine] (Preparation Example 10) (100 mg, 0.57 mmol) was dissolved in dichloromethane (10 mL), and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (Preparation Example 12) (262 mg, 0.68 mmol) and sodium triacetoxyborohydride (241 mg, 1.13 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was filtered, concentrated, evaporated to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 0 / 100 to 10 / 900) to obtain the target compound 2-(4'-((3',4'-dihydrospiro[3,2'-pyrano[2,3-c]pyridin]-1-yl)methyl)-2',6'-difluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3-hexafluoropropane-2-ol (I-50) (65 mg, 21.0%). LC-MS: 545.8 [M+1] + . 1H NMR (400MHz, MeOD) δ8.09 (s, 1H), 7.99 (d, J = 5.0Hz, 1H), 7.85 (d, J = 8.2Hz, 2H), 7.57 (d, J = 8.3Hz, 2H), 7.15 (dd, J = 17. 1, 6.7Hz, 3H), 3.84 (s, 2H), 3.55 (d, J = 8.9Hz, 2H), 3.42 (d, J = 8.7Hz, 2H), 2.91 (t, J = 6.5Hz, 2H), 2.25 (t, J = 6.5Hz, 2H).

[0637] Example 51

[0638]

[0639] first step:

[0640] Tert-butyl 7-chloro-3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (Preparation Example 11) (200 mg, 0.62 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (10 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. TLC indicated that the reaction was complete. The reaction solution was concentrated and evaporated to dryness to obtain the crude target compound, 7-chloro-3H-spiro[2,3-c]pyridine-2,4'-piperidine] 2,2,2-trifluoroacetate (I-51-a) (172 mg, 82.47%).

[0641] Step 2:

[0642] 7-Chloro-3H-spiro[2,3-c]pyridine-2,4'-piperidine] 2,2,2-trifluoroacetate (I-51-a) (172 mg, 0.51 mmol) was dissolved in dichloromethane (20 mL), and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (234 mg, 0.61 mmol) and sodium triacetoxyborohydride (215 mg, 1.02 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was filtered, concentrated, evaporated to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 0 / 100 to 10 / 900) to obtain the target compound 2-(4'-((7-chloro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-2',6'-difluoro-[1,1'-biphenyl]-4-yl)-1,1,1,1,3,3,3-hexafluoropropane-2-ol (I-51) (222 mg, 73.73%). LC-MS: 557.1 [M+1] + . 1H NMR (400MHz, CDCl3) δ7.87 (s, 3H), 7.60 (s, 2H), 7.07 (d, J = 8.5Hz, 3H), 3.62 (s, 1H), 3.12 (s, 1H), 2.69 (s, 2H), 1.98 (d, J = 62.4Hz, 2H).

[0643] Example 52

[0644]

[0645] first step:

[0646] Tert-butyl 7-chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidin]-1'-carboxylate (11) (2.00 g, 6.16 mmol) was dissolved in 1,4-dioxane / water (5:1, 20 ml). Methylboric acid (442.30 mg, 7.39 mmol), K2CO3 (1.70 g, 12.32 mmol), and Pd(PPh3)4 (711.56 mg, 0.62 mmol) were added in sequence. The system was purged with nitrogen and the reaction temperature was raised to 100°C for 16 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 10:1) to give a crude product (1.20 g). This was further purified by reverse phase chromatography (C18 silica gel, acetonitrile:water (10 mM NH4HCO3), 45% to 65%) to give tert-butyl 7-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-52-a) (460 mg, 1.51 mmol) as a white solid. LC-MS: m / z: (M+H)+ =305.10. 1H NMR (400 MHz, chloroform-d) δ8.01 (d, J=4.8 Hz, 1H), 6.96 (d, J=4.6 Hz, 1H), 3.77 (m, 2H), 3.48–3.36 (m, 2H), 2.99 (s, 2H), 2.42 (s, 3H), 1.95–1.85 (m, 2H), 1.75–1.64 (m, 2H), 1.47 (s, 9H).

[0647] Step 2:

[0648] Tert-butyl 7-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-52-a) (460 mg, 1.51 mmol) was dissolved in dichloromethane (5 ml) and HCl in ethyl acetate (4 mol / L, 5 ml) was added. The reaction system was stirred at room temperature for 1 hour. After completion of the reaction, the residue was concentrated and dissolved in methanol (5 ml) and the pH was adjusted to 11 using 2N aqueous NaOH. After stirring at room temperature for 1 hour, the reaction mixture was purified by reverse phase chromatography (C18 silica gel, acetonitrile:water (10 mM NH4HCO3), 45% to 65%) to afford 7-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (I-52-b) (235 mg, 1.15 mmol) as a white solid. LCMS: (ESI, m / z): [M+1] + =205.10.H-NMR:1H NMR(400MHz,DMSO-d6)δ7.90(d,J=4.7Hz,1H),7.08(d,J=4.7Hz,1H),3.01(s ,2H),2.94–2.84(m,2H),2.69–2.59(m,2H),2.29(s,3H),1.75–1.59(m,4H).

[0649] Step 3:

[0650] Dissolve 7-methyl-3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine] (I-52-b) (62 mg, 0.30 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (115 mg, 0.30 mmol) in N,N-dimethylformamide (10 mL). Add triethylamine (89 mg, 0.88 mmol) and acetic acid (28 mg, 0.47 mmol) sequentially, and stir at room temperature for 30 minutes. Then add sodium triacetoxyborohydride (290 mg, 1.37 mmol), and stir at room temperature for 16 hours. After completion of the reaction, add saturated aqueous NH4Cl solution (10 mL). Water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 2-(2',6'-difluoro-4'-((7-methyl-3H-spiro[furano[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-52) (36 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + =573.8.1H NMR (400MHz, CDCl3) δ7.97(d,J=4.8Hz,1H),7.82(d,J=8.3Hz,2H),7.57(d,J=8.5Hz,2H),7.05(d,J=8.5Hz,2H),6.97(d,J= 4.8Hz,1H),3.58(s,2H),3.01(s,2H),2.64(d,J=9.8Hz,4H),2.44(s,3H),2.05–1.94(m,2H),1.85(dd,J=17.4,9.7Hz,2H).

[0651] Example 53

[0652]

[0653] first step:

[0654] 2,6-Diisopropylaniline (6.32 g, 62.50 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL), and the reaction solution was cooled to -70 ° C. Under nitrogen protection, n-butyllithium (25 ml, 62.50 mmol) was slowly added to the reaction solution. The reaction solution was stirred at -70 ° C for 0.5 hours. 3-Bromo-5-fluoropyridine (I-53-a) (10 g, 56.82 mmol) was added to the reaction solution, and the reaction solution was stirred at -70 ° C for 0.5 hours. Iodomethane (9.68 g, 68.19 mmol) was added to the reaction solution, and the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with water (300 mL) and extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, evaporated to dryness, and purified by silica gel column chromatography (dichloromethane / petroleum ether = 35 / 65 to 55 / 45) to obtain the target compound 3-bromo-5-fluoro-4-methylpyridine (I-53-b) (5.10 g, 47.24%). LC-MS: 190.1 [M+1] + 1HNMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (d, J = 2.1 Hz, 3H).

[0655] Step 2:

[0656] 3-Bromo-5-fluoro-4-methylpyridine (I-53-b) (3 g, 7.71 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL), the reaction solution was cooled to -70 ° C, and lithium diisopropylamide (13.40 ml, 26.84 mmol) was added to the reaction solution under nitrogen protection. The reaction solution was stirred at -70 ° C for 0.5 hours. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.35 g, 26.84 mmol) in tetrahydrofuran was added to the reaction solution, and the reaction solution was stirred at -70°C for 3 hours. Water (100 mL) was added to the reaction solution to quench the reaction. The reaction solution was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 20 / 80 to 50 / 50) to obtain the target compound tert-butyl 4-(3-bromo-5-fluoropyridin-4-ylmethyl)-4-hydroxypiperidine-1-carboxylate (I-53-c) (6.57 g, 62.88%). LC-MS: 389.05 [M+1] + 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (s, 1H), 8.37 (s, 1H), 3.92 (s, 2H), 3.07 (m, 4H), 1.81–1.68 (m, 2H), 1.57 (m, 2H), 1.46 (s, 9H).

[0657] Step 3:

[0658] Dissolve tert-butyl 4-(3-bromo-5-fluoropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-53-c) (3.00 g, 7.71 mmol) in dioxane (30 mL). Under nitrogen protection, add cuprous iodide (146.78 mg, 0.77 mmol), cesium carbonate (5.02 g, 15.41 mmol) and 1,2-diaminocyclohexane (88.01 mg, 0.77 mmol) to the reaction solution, and heat the reaction solution to 100 ° C and stir for 5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and concentrated. The mixture was purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 to 10 / 90) to obtain the target compound, tert-butyl 4-fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-53-d) (2.26 g, 95.10%). LC-MS: 309.10 [M+1]+. 1H NMR (400 MHz, chloroform-d) δ8.04 (s, 2H), 3.90–3.74 (m, 2H), 3.44–3.29 (m, 2H), 3.04 (s, 2H), 1.98–1.86 (m, 2H), 1.78–1.67 (m, 2H), 1.46 (s, 9H).

[0659] Step 4:

[0660] Tert-butyl 4-fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-53-d) (700 mg, 2.27 mmol) was dissolved in dichloromethane (10 mL). A 4M solution of hydrochloric acid in ethyl acetate (10 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness under reduced pressure, dissolved in methanol (10 mL), and sodium hydroxide (2M aqueous solution) was added to adjust the pH to 11. The mixture was stirred for 1 hour, evaporated to dryness under reduced pressure, and then chromatographed on a reverse-phase C18 silica gel column (acetonitrile / water (0.1% NH4OH) = 27 / 73 to 47 / 53) to obtain the target compound 4-fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine] (I-53-e) (290 mg, 61.35%). LC-MS: 209.15 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 8.00 (d, J = 2.0Hz, 1H), 3.13 (s, 2H), 2.93–2.81 (m, 2H), 2.70–2.61 (m, 2H), 1.79–1.66 (m, 4H).

[0661] Step 5:

[0662] 4-Fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine](I-53-e) (120 mg, 0.58 mmol) was dissolved in dichloromethane (10 mL), and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (266 mg, 0.69 mmol) and sodium triacetoxyborohydride (244 mg, 1.15 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was filtered, concentrated, evaporated to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 0 / 100 to 10 / 900) to obtain the target compound 2-(2',6'-difluoro-4'-((4-fluoro-3H-spiro[fluoro[2,3-c]pyridin-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,1,3,3,3-hexafluoropropane-2-ol (I-53) (131.0 mg, 39.44%). LC-MS: 576.8 [M+1] + . 1H NMR (400MHz, DMSO) δ8.86 (s, 1H), 8.06 (d, J = 20.7Hz, 2H), 7.81 (d, J = 8.1Hz, 2H), 7.63 (d, J = 8 .1Hz,2H),7.22(d,J=8.5Hz,2H),3.61(s,2H),3.17(s,2H),2.56(s,4H),2.00–1.79(m,4H).

[0663] Example 54

[0664]

[0665] first step:

[0666] 5-Bromo-2-chloro-4-methylpyridine (I-54-a) (5 g, 24.22 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), the reaction solution was cooled to -70 ° C, and lithium diisopropylamide (14.53 mL, 29.06 mmol) was added to the reaction solution under nitrogen protection. The reaction solution was stirred at -70 ° C for 0.5 hours. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.79 g, 29.08 mmol) in tetrahydrofuran was added to the reaction mixture, and the reaction mixture was stirred at -70°C for 3 hours. Water (100 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 to 10 / 90) to obtain the target compound, tert-butyl 4-(5-bromo-2-chloropyridin-4-ylmethyl)-4-hydroxypiperidine-1-carboxylate (I-54-b) (7.8 g, 80%). LC-MS: 405.05 [M+1] + .

[0667] Step 2:

[0668] Dissolve tert-butyl 4-(5-bromo-2-chloropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-54-b) (7.8 g, 19.23 mmol) in dioxane (100 mL). Under nitrogen protection, add cuprous iodide (366.15 mg, 1.92 mmol), cesium carbonate (12.53 g, 38.45 mmol) and 1,2-diaminocyclohexane (219.54 mg, 1.92 mmol) to the reaction solution, and heat the reaction solution to 100 ° C and stir for 5 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and concentrated. The mixture was then purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 to 10 / 90) to obtain the target compound, tert-butyl 4-(5-bromo-2-chloropyridin-4-ylmethyl)-4-hydroxypiperidine-1-carboxylate (I-54-c) (2.1 g, 33%). LC-MS: 325.81 [M+1] + .

[0669] Step 3:

[0670] Tert-butyl 4-(5-bromo-2-chloropyridin-4-ylmethyl)-4-hydroxypiperidine-1-carboxylate (I-54-c) (100 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (20 mL). Tetrakistriphenylphosphine palladium (71.16 mg, 0.06 mmol) and zinc cyanide (72.32 mg, 0.62 mmol) were added to the reaction mixture under nitrogen. The reaction mixture was heated to 120°C and stirred for 16 hours. TLC indicated that the reaction was complete. The reaction mixture was evaporated to dryness and concentrated, and then purified by silica gel column chromatography (methanol / dichloromethane = 0 / 100 to 10 / 90) to obtain the target compound, tert-butyl 5-cyano-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-54-d) (52 mg, 53.55%).

[0671] Step 4:

[0672] Dissolve tert-butyl 5-cyano-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidin]-1'-carboxylate (I-54-d) (32.00 mg, 0.10 mmol) in dichloromethane (10 mL). Add trifluoroacetic acid (10 mL) to the reaction mixture, and stir at room temperature for 1 hour. Evaporate the reaction mixture to dryness under reduced pressure to obtain the crude target compound, 3H-spiro[2,3-c]pyridine-2,4'-piperidin]-5-carbonitrile-2,2,2-trifluoroacetate (I-54-e) (30.00 mg, 89.79%). LC-MS: 216.2 [M+1] + .

[0673] Step 5:

[0674] 3H-spiro[2,3-c]pyridine-2,4'-piperidine]-5-carbonitrile-2,2,2-trifluoroacetate (I-54-e) (30.0 mg, 0.09 mmol) was dissolved in dichloromethane (10 mL), and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropane-2-yl)-[1,1'-biphenyl]-4-carboxaldehyde (42.00 mg, 0.11 mmol) and sodium triacetoxyborohydride (38.62 mg, 0.11 mmol) were added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was filtered, concentrated, evaporated to dryness, and purified by silica gel column chromatography (dichloromethane / methanol = 0 / 100 to 10 / 900) to obtain the target compound 1'-(2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-(1,1'-biphenyl]-4-yl)methyl)-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-5-carbonitrile (I-54) (35.00 mg, 65.81%). LC-MS: 583.5 [M+1] +. 1H NMR (400MHz, DMSO) δ8.86 (s, 1H), 8.27 (s, 1H), 8.02–7.72 (m, 3H), 7.62 (d, J = 6.8Hz, 2H) ,7.21(d,J=7.9Hz,2H),3.61(s,2H),3.41(s,2H),2.53(d,J=15.4Hz,4H),1.91(s,4H).

[0675] Example 55

[0676]

[0677] first step:

[0678] Tert-butyl 7-chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (2.00 g, 6.16 mmol) was dissolved in N,N-dimethylformamide (20 ml). Zn(CN)2 (4.34 g, 36.95 mmol), Zn (402.58 mg, 6.16 mmol), DPPF (682.74 mg, 1.23 mmol), and Pd2(dba)3 (567.75 mg, 0.62 mmol) were added under nitrogen. The reaction was stirred at 100°C for 4 hours. After completion of the reaction, water (200 ml) was added to the system, and the mixture was extracted three times with ethyl acetate (3 × 100 ml). The organic phase was washed with saturated brine (2 × 100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol:dichloromethane = 0-10%). The resulting crude product was further purified by reverse-phase flash column chromatography (C18 silica gel; ACN:H2O (0.1% FA) = 40-60%) to afford compound (I-55-a) (1.17 g, 3.71 mmol) as an off-white solid in a 60.25% yield. LC-MS: m / z: (M+H) + =316.3.

[0679] Step 2:

[0680] Tert-butyl 7-cyano-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate (I-55-a) (580.00 mg, 1.84 mmol) was dissolved in dichloromethane (10 ml) and trifluoroacetic acid (10 ml) was slowly added at room temperature. The reaction was stirred at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml) and basified with aqueous ammonia to pH 9. The mixture was stirred at room temperature for 1 hour. The crude product was isolated and purified by reverse phase flash column chromatography (C18 silica gel; acetonitrile: water (0.1% NH3.H2O) = 25-45%) to afford compound (I-55-b) (210.00 mg, 0.98 mmol) as an off-white solid in a yield of 53.05%. 1 H NMR (400MHz, chloroform-d) δ8.18(d,J=4.5Hz,1H),7.31(dt,J=4.5,1.3Hz,1H),3.16(m,2H ),3.09(d,J=1.3Hz,2H),2.90(m,2H),1.97(m,2H),1.80(m,2H).LC-MS:m / z:(M+H) + =216.10.

[0681] Step 3:

[0682] 3H-spiro[furano[2,3-c]pyridine-2,4'-piperidine]-7-carbonitrile (I-55-b) (50 mg, 0.23 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (90 mg, 0.23 mmol) were dissolved in dichloromethane (10 ml), followed by the addition of trifluoroacetic acid (50 μL). After stirring at room temperature for 18 hours, sodium triacetylborohydride (148 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated, and the resulting crude product was isolated and purified by flash column chromatography (methanol:dichloromethane = 0-10%) to afford 21 mg of the target compound (I-55) as a yellow solid in a 16% yield. 1 HNMR (400MHz, CDCl3) δ8.22(d,J=4.5Hz,1H),7.83(d,J=8.2Hz,2H),7.60(d,J=8.4Hz,2H),7.34(d,J=4.5Hz,1H),7. 07(d,J=8.3Hz,2H),3.64(s,2H),3.13(s,2H),2.72(s,4H),2.15–2.06(m,2H),2.01–1.86(m,2H).LC-MS:m / z:(M+H) + =584.2.

[0683] Example 56

[0684]

[0685] first step:

[0686] Under nitrogen, 2,2,6,6-tetramethylpiperidine (5.22 g, 51.58 mmol) was dissolved in dry tetrahydrofuran (20 mL), cooled to -78°C, and n-butyllithium (2.5 M, 20.63 mL, 51.58 mmol) was slowly added dropwise. The mixture was stirred at this temperature for 30 minutes. A solution of 2-bromo-6-fluoropyridine (9.08 g, 51.58 mmol) in dry tetrahydrofuran (50 mL) was added dropwise at -78°C. The mixture was stirred at this temperature for 30 minutes, followed by a solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (I-56-a) (10 g, 46.89 mmol) in dry tetrahydrofuran (50 mL). After completion of the reaction, as monitored by LCMS, the reaction system was quenched with saturated aqueous ammonium chloride (NH4Cl) (40 mL), water (40 mL) was added, and the system was extracted with ethyl acetate (3×300 mL). The organic phases were combined and concentrated, and the residue was separated by column chromatography (dichloromethane:methanol = 30:1 to 10:1) to obtain tert-butyl 4-((6-bromo-2-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-56-b) (2.5 g, 6.42 mmol) as a yellow solid. LCMS: (ESI, m / z): [M-15+1] + =373.95.

[0687] Step 2:

[0688] Under nitrogen, tert-butyl 4-((6-bromo-2-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-56-b) (2.5 g, 6.42 mmol) was dissolved in dry tetrahydrofuran (50 ml). The system was cooled to 0°C, and NaH (60%, 513.4 mg, 12.84 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction system was quenched with saturated aqueous ammonium chloride (40 mL), water (40 mL) was added, and the system was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined and concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford tert-butyl 6-bromo-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-56-c) (1.3 g, 3.22 mmol) as a yellow solid. LCMS:(ESI,m / z):[M+1] + =369.2.

[0689] Step 3:

[0690] Dissolve tert-butyl 6-bromo-3H-spiro[furano[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-56-c) (950 mg, 2.57 mmol) in a mixture of dimethyl sulfoxide (DMSO) / water / tert-butyl alcohol (t-BuOH) (1:1:1) (15 mL). Add cuprous iodide (49 mg, 0.257 mmol), 2-((2,6-dimethylphenyl)amino)-2-oxoacetic acid (248.53 mg, 1.29 mmol), and potassium hydroxide (288.69 mg, 5.15 mmol). The reaction mixture is heated to 120°C and stirred overnight. After completion of the reaction, as monitored by LCMS, the reaction system was cooled to room temperature and concentrated under reduced pressure. The residue was then subjected to reverse phase purification (C18 silica gel; acetonitrile:water (0.1% trifluoroacetic acid (TFA)) = 40% to 60%) to afford tert-butyl 6-hydroxy-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-56-d) (410 mg, 1.34 mmol) as a yellow solid. LCMS: (ESI, m / z): [M+23] + =329.05.

[0691] Step 4:

[0692] Tert-butyl 6-hydroxy-3H-spiro[furan[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-56-d) (410 mg, 1.34 mmol) was dissolved in 4M HCl in 1,4-dioxane (5.02 mL, 20.1 mmol) and stirred at room temperature for 1.5 hours. After completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure, the residue was added with water (5 mL), and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate (NaHCO). The reaction system was concentrated under reduced pressure, and the residue was subjected to reverse phase purification (C18 silica gel; acetonitrile:water (3% NH3.H2O), 5% to 25%) to afford 6-hydroxy-3H-spiro[furan[2,3-b]pyridine-2,4'-piperidine] (I-56-e) (192 mg, 0.93 mmol, 70% yield) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =207.00. 1H NMR (400MHz, DMSO-d6) δ6.90–6.70(m,1H),5.30(m,1H),2.82(m,2H),2.71–2.54(m,4H),1.71–1.47(m,4H).

[0693] Step 5:

[0694] Dissolve 6-hydroxy-3H-spiro[furano[2,3-b]pyridine-2,4'-piperidine] (I-56-e) (57 mg, 0.28 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (117 mg, 0.31 mmol) in N,N-dimethylformamide (10 mL). Add triethylamine (84 mg, 0.83 mmol) and acetic acid (25 mg, 0.42 mmol) sequentially, and stir at room temperature for 30 minutes. Then add sodium triacetoxyborohydride (177 mg, 0.84 mmol), and stir at room temperature for 16 hours. After completion of the reaction, add saturated aqueous ammonium chloride (10 mL). Water (20 mL) and ethyl acetate (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 1'-((2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidin]-6-ol (I-56) (22 mg) as a light yellow solid. LCMS: (ESI, m / z): [M+1] + =574.8.1H NMR (400MHz, MeOD) δ7.83(d,J=8.3Hz,2H),7.56(d,J=8.2Hz,2H),7.41(d,J=8.0Hz,1H),7.13(d,J=8.3Hz ,2H),6.09(d,J=8.0Hz,1H),3.66(s,2H),2.94(s,2H),2.68(s,4H),2.10–1.95(m,2H),1.95–1.77(m,2H).

[0695] Example 57

[0696]

[0697] first step:

[0698] 3-Methyleneazetidine-1-carboxylic acid tert-butyl ester (I-57-a) (20.00 g, 118.19 mmol) was added to 100 ml of dimethyl sulfoxide, and then N-bromosuccinimide (NBS, 42.07 g, 236.37 mmol) and water (4.26 g, 236.37 mmol) were slowly added under ice bath. The reaction mixture was stirred at room temperature overnight. 600 ml of water was added to the reaction solution and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and column chromatography (methanol: dichloromethane = 0-10%) was used to obtain 24 g of a colorless oil (I-57-b) with a yield of 76%. LC-MS: m / z: (M+H) + =266.

[0699] Step 2:

[0700] tert-Butyl 3-(bromomethyl)-3-hydroxyazetidine-1-carboxylate (I-57-b) (12.00 g, 45.09 mmol) was added to 360 ml of tetrahydrofuran, and then sodium hydride (60%, 1.98 g, 49.60 mmol) was slowly added under an ice bath and nitrogen protection. Stir at room temperature for 5 hours, add 400 ml of saturated aqueous ammonium chloride solution, and extract with ethyl acetate (3×200 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated, and filtered through a column (ethyl acetate: petroleum ether = 15-45%) to obtain 4.92 g of a light yellow oil (I-57-c) in a yield of 59%. LC-MS: m / z: (M+H) + =186.20.

[0701] Step 3:

[0702] 3-Bromo-2,6-difluoropyridine (2.40 g, 12.36 mmol) was added to 20 ml of tetrahydrofuran, and n-butyllithium (5.44 ml, 13.60 mmol) was added at -75°C under nitrogen protection. After stirring for 0.5 hours, tert-butyl 1-oxa-5-azaspiro[2.3]hexane-5-carboxylate (I-57-c) (2.29 g, 12.36 mmol) and boron trifluoride in ether (1.93 g, 13.60 mmol) were added. After stirring for 2 hours, the reaction was quenched with water and extracted with ethyl acetate (3 x 60 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated, and purified by column chromatography (ethyl acetate:petroleum ether = 35-55%) to afford (I-57-d) as a light yellow solid (638 mg, 17% yield). LC-MS: m / z: (M+H) + =301.15.

[0703] Step 4:

[0704] Tert-butyl 3-((2,6-difluoropyridin-3-yl)methyl)-3-hydroxyazetidine-1-carboxylate (I-57-d) (638.00 mg, 2.12 mmol) was added to 20 ml of tetrahydrofuran. Potassium tert-butoxide (1M in THF, 2.12 ml, 2.12 mmol) was added under nitrogen. The mixture was stirred at room temperature for 2 hours. 100 ml of water was added to the reaction mixture to quench the mixture. The mixture was extracted with ethyl acetate (3 x 50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated. The mixture was purified by column chromatography (methanol:dichloromethane = 0-10%) to afford 455 mg of a yellow oil (I-57-e) in a 76% yield. LC-MS: m / z: (M+H) + =281.15.

[0705] Step 5:

[0706] 6'-Fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylic acid tert-butyl ester (I-57-e) (300.00 mg, 1.07 mmol) was added to 6 ml of dichloromethane, followed by 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and added to 6 ml of methanol. The pH was adjusted to approximately 10 with 2 mol / L aqueous sodium hydroxide solution. After stirring at room temperature for 1 hour, the reaction solution was filtered through a reverse phase column (C18; acetonitrile:water (0.1% (NH3.H2O ammonia)) = 15%-35%) to obtain 48 mg of a white solid (I-57-f) in a 25% yield. LC-MS: m / z: (M+H) + =181.20. 1H NMR (400MHz, Methanol-d4) δ7.69 (t, J = 7.8 Hz, 1H), 6.52 (d, J = 7.9 Hz, 1H), 4.06 (d, J = 10.7 Hz, 2H), 3.77 (d, J = 10.2 Hz, 2H), 3.52 (s, 2H).

[0707] Step 6:

[0708] 6'-Fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine] (I-57-f) (20 mg, 0.11 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (40 mg, 0.10 mmol) were added to 10 ml of dichloroethane, followed by sodium acetate borohydride (430 mg, 2.03 mmol), and stirred at room temperature overnight. The reaction solution was concentrated, and 10 ml of saturated sodium carbonate solution was added. The product was extracted with dichloromethane three times (2 × 20 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated by column chromatography (methanol:(dichloromethane:ethyl acetate=2:1)=0-15%) to afford 30 mg of (I-57) as a white solid in a 49% yield. LC-MS:m / z:(M+H) + =549.1H NMR(400MHz,MeOD)δ7.85(d,J=8.4Hz,2H),7.71(t,J=7.8Hz,1H),7.57(d,J=8.7Hz,2H),7.1 8–7.09(m,2H),6.53(dd,J=7.8,0.9Hz,1H),3.82(s,2H),3.64(q,J=9.2Hz,4H),3.54(s,2H).

[0709] Example 58

[0710]

[0711] first step:

[0712] Trimethylsulfoxide iodide (I-58-a) (66.27 g, 301.13 mmol) was dissolved in dry dimethylsulfoxide (250 mL). Potassium tert-butoxide (33.79 g, 301.13 mmol) was added at room temperature and stirred at this temperature for 30 minutes. The system was cooled to 0°C and a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (50 g, 250.94 mmol) in ethylene glycol dimethyl ether (DME) (250 mL) was added dropwise. The mixture was slowly warmed to room temperature and stirred for 6 hours. After completion of the reaction, as monitored by LCMS, the reaction system was quenched with water (50 mL) and extracted with ethyl acetate (3 × 300 mL). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain tert-butyl 1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (I-58-b) (4.1 g) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 3.62 (m, 3H), 3.27 (m, 1H), 2.94 (d, J = 5.5 Hz, 2H), 2.26 (m, 1H), 1.92–1.78 (m, 1H), 1.47 (s, 9H).

[0713] Step 2:

[0714] Under nitrogen, 3-bromo-2,6-difluoropyridine (3.34 g, 17.22 mmol) was dissolved in dry tetrahydrofuran (30 mL), cooled to -78°C, and n-butyllithium (n-BuLi) (2.5 M, 8.26 mL, 20.66 mmol) was slowly added. The reaction system was stirred at -78°C for 30 minutes, and then a solution of tert-butyl 1-oxa-5-azaspiro[2.4]heptane-5-carboxylate (I-58-b) (4.1 g, 17.22 mmol) in dry tetrahydrofuran (20 mL) was added dropwise, followed by the dropwise addition of boron trifluoride etherate (BF3.EtO) (5.1 mL, 20.66 mmol). The reaction system was reacted at -78°C for 2 hours. After completion of the reaction, the system was quenched with saturated ammonium chloride (15 mL), water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 300 mL). The organic phases were combined and concentrated under reduced pressure. The residue was purified and separated by column chromatography (dichloromethane:methanol = 15:1) to obtain tert-butyl 3-((2,6-difluoropyridin-3-yl)methyl)-3-hydroxypyrrolidine-1-carboxylate (I-58-c) (2.2 g, 7.0 mmol) as a yellow solid. LCMS (ESI, m / z): [M+1-15] + =300.1.

[0715] Step 3:

[0716] Under nitrogen, tert-butyl 3-((2,6-difluoropyridin-3-yl)methyl)-3-hydroxypyrrolidine-1-carboxylate (I-58-c) (1.9 g, 6.04 mmol) was dissolved in dry tetrahydrofuran (20 ml). The system was cooled to 0°C, and potassium tert-butoxide (678.3 mg, 6.04 mmol) was added portionwise. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After completion of the reaction, as monitored by LCMS, the reaction system was quenched with saturated aqueous ammonium chloride (40 mL), water (40 mL) was added, and the system was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined and concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate = 1:1) to give tert-butyl 6-fluoro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-d) (1.2 g, 4.08 mmol) as a yellow solid. LCMS (ESI, m / z): [M+1-15] +=280.00.

[0717] Step 4:

[0718] Dissolve tert-butyl 6-fluoro-3H-spiro[furano[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-d) (500 mg, 1.7 mmol) and benzyl alcohol (BnOH) (270.5 mg, 2.04 mmol) in dry tetrahydrofuran (10 mL). Sodium hydride (NaH) (60%, 135.9 mg, 3.4 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, as monitored by LCMS, water (20 mL) was added to quench the reaction. The system was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were concentrated under reduced pressure, and the residue was purified by reverse phase preparative purification (C18 silica gel; acetonitrile:water (3% NH3.H2O), 35% to 55%) to obtain tert-butyl 6-(benzyloxy)-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-e) (550 mg, 1.44 mmol) as a yellow solid. LCMS (ESI, m / z): [M+1] + =383.1.

[0719] Step 5:

[0720] tert-Butyl 6-(benzyloxy)-3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-e) (550 mg, 1.44 mmol) was dissolved in methanol (10 mL) and 10% Pd / C (55 mg) was added at room temperature. The reaction system was replaced with an H2 atmosphere and stirred at this temperature for 16 hours. After the reaction was completed, the insoluble material was filtered off, the filter cake was washed with methanol, and the filtrates were combined and concentrated to give crude tert-butyl 6-hydroxy-3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-f) (370 mg), which was used directly in the next reaction. LCMS (ESI, m / z): [M+1-15] + =278.00.

[0721] Step 6:

[0722] Crude tert-butyl 6-hydroxy-3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-f) (370 mg) was dissolved in dichloromethane (6 mL) and trifluoroacetic acid (2 mL) was added. The mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated and the residue was purified using reverse phase preparative purification (C18 silica gel; acetonitrile:water (3% NH3.H2O), 5% to 15%) to obtain 3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-6-ol (I-58-g) (186 mg, 0.967 mmol) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =193.1. 1 H NMR (300MHz, methanol-d4) δ7.40(m,1H),6.10(d,J=8.0Hz,1H),3.26(dd,J=6.2,2.5Hz,2H),3.21(m,2 H), 3.12 (ddd, J=11.2, 8.8, 3.9Hz, 1H), 2.91 (d, J=12.5Hz, 1H), 2.38–2.25 (m, 1H), 2.01 (m, 1H).

[0723] Step 7:

[0724] Dissolve 3H-spiro[furano[2,3-b]pyridine-2,3'-pyrrolidin]-6-ol (I-58-g) (58 mg, 0.30 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (127 mg, 0.33 mmol) in N,N-dimethylformamide (10 mL). Add triethylamine (91 mg, 0.90 mmol) and acetic acid (27 mg, 0.45 mmol) sequentially, and stir at room temperature for 30 minutes. Then add sodium triacetoxyborohydride (177 mg, 0.84 mmol), and stir at room temperature for 16 hours. After completion of the reaction, add saturated aqueous ammonium chloride (10 mL). Water (20 mL) and ethyl acetate (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 1'-((2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidino]-6-ol (I-58) (25 mg) as a white solid. LCMS: (ESI, m / z): [M+1] +=560.8.1H NMR (400MHz, MeOD) δ7.83(d,J=8.3Hz,2H),7.55(d,J=8.5Hz,2H),7.41(d,J=8.1Hz,1H),7.14(d,J=8.5Hz,2H),6.11(d,J=8.0Hz,1H),3.77(q,J=1 3.6Hz,2H),3.20(q,J=15.4Hz,2H),3.08(d,J=10.6Hz,1H),2.96(dd,J=1 6.3,7.2Hz,1H),2.84–2.72(m,2H),2.44–2.31(m,1H),2.21–2.08(m,1H).

[0725] Example 59

[0726]

[0727] first step:

[0728] Dissolve tert-butyl 6-fluoro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-d) (400 mg, 1.36 mmol) in dichloromethane (6 mL), add trifluoroacetic acid (2 mL), and react at room temperature for 2 hours. After completion of the reaction, the reaction solution is concentrated and the residue is purified using reverse phase preparative purification (C18 silica gel; acetonitrile:water (3% NH3.H2O), 5% to 15%) to obtain 6-fluoro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine] (I-59-a) (240 mg, 1.24 mmol) as a yellow solid. LCMS: (ESI, m / z): [M+1] + =195.1. 1 H NMR (300 MHz, methanol-d4) δ 7.77 (m, 1H), 6.60 (m, 1H), 3.75 (m, 1H), 3.70–3.51 (m, 2H), 3.49–3.38 (m, 3H), 2.55 (m, 1H), 2.30 (m, 1H).

[0729] Step 2:

[0730] Dissolve 6-fluoro-3H-spiro[furano[2,3-b]pyridine-2,3'-pyrrolidine] (I-59-a) (52 mg, 0.27 mmol) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (124 mg, 0.32 mmol) in N,N-dimethylformamide (15 mL). Add triethylamine (82 mg, 0.81 mmol) and acetic acid (24 mg, 0.40 mmol) sequentially, and stir at room temperature for 30 minutes. Then add sodium triacetoxyborohydride (210 mg, 0.99 mmol), and stir at room temperature for 16 hours. After completion of the reaction, add saturated aqueous ammonium chloride (10 mL). Water (20 mL) and ethyl acetate (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 2-(2',6'-difluoro-4'-((6-fluoro-3H-spiro[furano[2,3-b]pyridin-2,3'-pyrrolidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-59) (32 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + =562.8.1H NMR (400MHz, MeOD) δ7.82(d,J=8.2Hz,2H),7.66(t,J=7.7Hz,1H),7.55(d,J=8.6Hz,2H),7.14(d,J=8.5Hz,2H),6.48(d,J=7.8Hz,1H),3.77(d,J=3 .9Hz,2H),3.35(d,J=16.3Hz,2H),3.09(d,J=10.7Hz,1H),2.97(dd,J=15 .4,6.8Hz,1H),2.87–2.74(m,2H),2.47–2.34(m,1H),2.23–2.09(m,1H).

[0731] Example 60

[0732]

[0733] first step:

[0734] Under nitrogen, tert-butyl 6'-fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate (I-57-e) (1.00 g, 3.57 mmol) was dissolved in dry tetrahydrofuran (20 ml) and cooled to 0°C. Sodium hydride (60%, 285.38 mg, 7.14 mmol) and benzyl alcohol (424.38 mg, 3.92 mmol) were added portionwise at room temperature. The reaction system was heated to 60°C for 2 hours. After completion of the reaction, the reaction was cooled to room temperature and quenched with water (20 mL). The system was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined and concentrated under reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol = 20:1) to obtain tert-butyl 6'-(benzyloxy)-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate (I-60-a) (1.23 g, 3.34 mmol) as a bright yellow liquid. LCMS: (ESI, m / z): [M+1] + =369.20.

[0735] Step 2:

[0736] 6'-(Benzyloxy)-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylic acid tert-butyl ester (I-60-a) (1.23 g, 3.34 mmol) was dissolved in methanol (15 mL) and 10% Pd / C (200 mg) was added at room temperature. The reaction system was replaced with a hydrogen atmosphere and stirred at this temperature for 16 hours. After the reaction was completed, the insoluble matter was filtered off, the filter cake was washed with methanol, and the filtrates were combined and concentrated to give tert-butyl 6'-hydroxy-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate (I-60-b) crude product (701 mg), which was used directly in the next reaction. LCMS (ESI, m / z): [M+1] + =279.10.

[0737] Step 3:

[0738] The crude product of tert-butyl 6'-hydroxy-3'H-spiro[azetidine-3,2'-furan[2,3-b]pyridine]-1-carboxylate (I-60-b) (180 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product 3'H-spiro[azetidine-3,2'-furan[2,3-b]pyridine]-6'-ol trifluoroacetate (I-60-c) (190 mg), which was directly used in the next reaction. LCMS: (ESI, m / z): [M+1] +=179.20. 1H NMR (400MHz, methanol-d4) δ7.47 (d, J = 8.0Hz, 1H), 6.24 (d, J = 8.0Hz, 1H), 4.40 (q, J = 11.9Hz, 4H), 3.49 (s, 2H).

[0739] Step 4:

[0740] 3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-6'-ol trifluoroacetate (I-60-c) (50 mg) and 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (92 mg, 0.24 mmol) were dissolved in N,N-dimethylformamide (10 mL). Triethylamine (73 mg, 0.72 mmol) and acetic acid (27 mg, 0.45 mmol) were added sequentially, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (227 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (10 mL) was added. Water (20 mL) and ethyl acetate (30 mL) were added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 3), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol = 20:1) to give 1-((2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-yl)methyl)-3'H-spiro[azetidine-3,2'-fluoro[2,3-b]pyridine]-6'-ol (19 mg) as a white solid. LCMS: (ESI, m / z): [M+1] + =547.1.1H NMR (400MHz, MeOD) δ7.83(d,J=8.2Hz,2H),7.54(d,J=8.1Hz,2H),7.43(d,J=8.0Hz,1H),7. 10(d,J=8.2Hz,2H), 6.15(d,J=8.0Hz,1H), 3.80(s,2H), 3.61(q,J=8.5Hz,4H), 3.40(s,2H).

[0741] With reference to the above examples, the compounds shown in Table 1 were prepared, and their structural characterizations are shown below:

[0742] Table 1 Compound list

[0743]

[0744]

[0745] Effect Example 1

[0746] 1. Inhibitory activity of compounds against RORγt

[0747] 1. Test method:

[0748] The compounds of the present invention are assayed using fluorescence resonance energy transfer (FRET) assay to determine their inhibitory activity on RORγt.

[0749] 2. Materials and Reagents:

[0750]

[0751] 3. Experimental steps:

[0752] 1) Prepare 4x serial dilutions of compound in 1x buffer.

[0753] 2) Add 5ul of 4x serially diluted compound (prepared in step 1) to a 384 assay plate (784075, Greiner).

[0754] 3) Prepare 4x RORgt-LBD in 1x buffer.

[0755] 4) Add 5ul of 4x RORgt-LBD (prepared in step c) to the 384 assay plate (prepared in step b).

[0756] 5) Incubate the assay plate at room temperature for 15 minutes, protected from light.

[0757] 6) Prepare 2x SRC, anti-GST Eu and streptavidin-d2 mix in 1x freezing buffer.

[0758] 7) Add 10 ul of the 2x mix (prepared in step f) to the 384 assay plate (prepared in step d).

[0759] 8) Centrifuge the 384 test plates at 1000 g for 1 minute.

[0760] 9) Incubate at room temperature for 3 h, protected from light.

[0761] 10) Read the plate at 665 nm and 615 nm wavelengths on an Envision 2104 plate reader.

[0762] 4. Data Analysis:

[0763] Relative ratio (RR): Calculate the relative ratio of each well (665nm response value / 615nm response value-blank background response value).

[0764] Percent inhibition rate:

[0765] Inhibition rate % = [1-(fluorescence detection value of compound-average fluorescence detection value of positive compound) / (average fluorescence detection value of negative control-average fluorescence detection value of positive compound)] x 100

[0766] Calculation of IC50 and dose-effect curve of the compound: The IC50 and dose-effect curve of the compound were obtained by calculating the inhibition rate of the compound and the log value of the compound concentration using Graphpad 8.0.

[0767] 2. Test result data.

[0768] Table 2 Determination of RORγ inhibitory activity of the compounds in the examples

[0769]

[0770]

[0771] Note: “+” means 1uM≤IC 50 ≤10uM, “++” means 100nM≤IC 50 ≤1uM, "+++" means 1nM≤IC 50 ≤100nM,

[0772] Conclusion: It can be seen from Table 2 that the compounds of the present invention have a significant inhibitory effect on RORγt.

[0773] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A spiroheterocyclic compound of Formula I or a pharmaceutically acceptable salt thereof: in, m is 0, 1 or 2; n is 0, 1 or 2; u is 0, 1, 2, 3 or 4; v is 0, 1, 2, 3 or 4; p is 1, 2, 3 or 4; s is 1, 2, 3 or 4; t is 0, 1, 2 or 3; W, Q, Y and Z are independently CH or N, and W, Q, Y and Z are not CH or N at the same time; Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2, 3 or 4; R 1 are independently hydrogen, halogen, C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen, C1-C7 alkyl, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl, "R 3-7 Substituted C1-C7 alkyl" or oxo; R 4 are independently halogen, -OR 4-1 、-CN、C1-C7 alkyl、"R 4-4 Substituted C1-C7 alkyl" or oxo; R 4-1 is hydrogen; R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen or hydroxy; R 5 are independently C1-C7 alkyl; or, any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group; The R 1-7 , the R 2-7 , the R 3-7 and the R 4-4 The number is independently 1, 2, 3, 4, 5, 6 or 7; when the R 1-7 , the R 2-7 , the R 3-7 and the R 4-4 When the number of is multiple, the R 1-7 , the R 2-7 , the R 3-7 and the R 4-4 independently the same or different.

2. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound shown in Formula I is any of the following: Option 1: In the compound shown in formula I: n is 0 or 1; Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 are independently C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen, C1-C7 alkyl, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl, "R 3-7 Substituted C1-C7 alkyl" or oxo; Option 2: In the compound shown in formula I: m is 0 or 1; n is 0 or 1; u is 0 or 1; v is 0, 1 or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 For "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl, "R 3-7 Substituted C1-C7 alkyl" or oxo; R 4 are independently halogen, C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo; R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen or hydroxy; Option 3: In the compound shown in formula I: m is 0 or 1; n is 0 or 1; u is 0 or 1; v is 0, 1, or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 R 1-7 Substituted C1-C7 alkyl; R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl or oxo; R 4 are independently halogen, -CN, -OR 4-1 , C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo; R 1-7 、R 2-7 and R 4-4 are independently halogen or hydroxy; R 4-1 is hydrogen; Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group; Option 4: In the compound shown in formula I: m is 0 or 1; n is 0 or 1; u is 0 or 1; v is 0, 1, or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 R 1-7 Substituted C1-C7 alkyl; R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl"; R 3 are independently halogen, C1-C7 alkyl or oxo; R 4 are independently halogen, -CN, -OR 4-1 , C1-C7 alkyl or oxo; R 1-7 and R 2-7 are independently halogen or hydroxy; R 4-1 is hydrogen; Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group; Option 5: In the compound shown in formula I: m is 0 or 1; n is 0 or 1; u is 0 or 1; v is 0, 1 or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 For "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl"; R 3 are independently halogen, C1-C7 alkyl or oxo; R 4 are independently halogen, C1-C7 alkyl or oxo; R 1-7 and R 2-7 are independently halogen or hydroxy; Option 6: The compound of formula I is as shown in formula II: m is 0 or 1; u is 0 or 1; v is 0, 1, or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 R 1-7 Substituted C1-C7 alkyl; R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl or oxo; R 4 are independently halogen, -CN, -OR 4-1 , C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo; R 1-7 、R 2-7 and R 4-4 are independently halogen or hydroxy; R 4-1 is hydrogen; Any two non-adjacent R 5 Together with the carbon atom to which it is attached, it forms a 4-10 membered cycloalkyl group Option 7: The compound of formula I is as shown in formula II: m is 0 or 1; u is 0 or 1; v is 0, 1 or 2; p is 1 or 2; s is 1 or 2; t is 0 or 2; Ring A and Ring B are independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 For "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl"; R 3 are independently halogen or C1-C7 alkyl; R 4 are independently C1-C7 alkyl; R 1-7 and R 2-7 are independently halogen or hydroxy; Option 8: The compound of formula I is a compound as shown in formula III: Wherein, ring A and ring B are independently 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3; R 1 are independently hydrogen, halogen, C1-C7 alkyl or "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen, C1-C7 alkyl, "R 2-7 Substituted C1-C7 alkyl" or oxo; R 3 are independently halogen, C1-C7 alkyl, "R 3-7 Substituted C1-C7 alkyl" or oxo; R 1-7 、R 2-7 and R 3-7 are independently halogen or hydroxy; Option 9: The compound of formula I is a compound as shown in formula IV: Where u is 0 or 1; v is 0, 1 or 2; Ring A is C6-C 10 aryl; Ring B is independently C6-C 10 Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1, 2 or 3; R 1 For "R 1-7 "substituted C1-C7 alkyl"; R 2 are independently halogen or "R 2-7 "substituted C1-C7 alkyl"; R 3 are independently halogen or C1-C7 alkyl; R 1-7 and R 2-7 are independently halogen or hydroxy; Option 10: The compound shown in formula I: and / or 3. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: When the ring A is a 3-14 membered heterocycloalkyl, the heteroatom in the 3-14 membered heterocycloalkyl is not substituted by oxygen; and / or, when the ring A is a 3-14 membered heterocycloalkyl group, the heterocycloalkyl group in the 3-14 membered heterocycloalkyl group is a heteromonocycloalkyl group or a heterobridged cycloalkyl group; and / or, when the ring A is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is connected to the ring B via a heteroatom; and / or, when the ring A is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is a 5-, 6- or 7-membered heterocycloalkyl group, and the heteroatoms are oxygen and / or nitrogen, and the number of the heteroatoms is 1 or 2; And / or, when the ring A is C6-C 10 When the C6-C 10 Aryl is phenyl; and / or, when the ring A is a 5-10 membered heteroaryl group, the heteroaryl group is a monocyclic ring; and / or, when the ring A is a 5-10 membered heteroaryl group, the heteroatom in the heteroaryl group is not substituted by oxygen; and / or, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is connected to the ring B via a carbon atom; and / or, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, and the heteroatoms are sulfur and / or nitrogen, and the number of the heteroatoms is 1 or 2; and / or, when the ring B is a 3-14 membered heterocycloalkyl group, the heteroatom in the 3-14 membered heterocycloalkyl group is not substituted by oxygen; and / or, when the ring B is a 3-14 membered heterocycloalkyl group, the heterocycle in the 3-14 membered heterocycloalkyl group is a heteromonocycle; and / or, when the ring B is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is a 5- or 6-membered heterocycloalkyl group, the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2; And / or, when the ring B is C6-C 10 When the C6-C 10 Aryl is phenyl; and / or, when the ring B is a 5-10 membered heteroaryl group, the heteroaryl group is a monocyclic heteroaryl group; and / or, when the ring B is a 5-10 membered heteroaryl group, the heteroatom in the heteroaryl group is not substituted by oxygen; and / or, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is connected to the ring A via a carbon atom; and / or, when the ring B is a 5-10 membered heteroaryl group, the heteroatom in the 5-10 membered heteroaryl group is located at the ortho position to the site of attachment to the ring A; and / or, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2; and / or, when R 1 When independently halogen, the halogen is F; and / or, when R 1 Independently "R 1-7 When "substituted C1-C7 alkyl", the R 1-7 The number of is 4, 5, 6 or 7; and / or, when R 1 Independently "R 1-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl; and / or, when R 1-7 When halogen, the halogen is F; and / or, when R 2 When independently halogen, the halogen is F; and / or, when R 2 Independently "R 2-7 When "substituted C1-C7 alkyl", the R 2-7 The number of is 3; and / or, when R 2 Independently "R 2-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl; and / or, when R 2-7 When halogen, the halogen is F; and / or, when R 3 When independently halogen, the halogen is F or Cl; and / or, when R 3 When they are independently C1-C7 alkyl, the C1-C7 alkyl is C1-C3 alkyl; and / or, when R 4 When independently halogen, the halogen is F or Cl; and / or, when R 4 When they are independently C1-C7 alkyl, the C1-C7 alkyl is C1-C3 alkyl; and / or, when R 4 Independently "R 4-4 When "substituted C1-C7 alkyl", the R 4-4 The number of is 3; and / or, when R 4 Independently "R 4-4 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is a C1-C3 alkyl; and / or, when R 4-4 When halogen, the halogen is F; And / or, when any two non-adjacent R 5 When the carbon atom to which it is connected forms a 4-10 membered cycloalkyl group, the 4-10 membered cycloalkyl group is a 7-membered cycloalkyl group; and / or, the substitution site of ring B on ring A is Not adjacent.

4. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein: When the ring A is a 5-10 membered heteroaryl group, the heteroatom of the 5- or 6-membered heteroaryl group is nitrogen, and the number of the heteroatom is 1 or 2; And / or, when the ring B is C6-C 10 When the C6-C 10 Aryl The left end is connected to ring A, and the right end is connected to R 1 connected; and / or, when R 1 Independently "R 1-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is isopropyl; and / or, when R 2 Independently "R 2-7 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is methyl; and / or, when R 3 When they are independently C1-C7 alkyl, the C1-C7 alkyl is methyl; and / or, when R 4 When independently halogen, the halogen is Cl; and / or, when R 4 When they are independently C1-C7 alkyl, the C1-C7 alkyl is methyl; and / or, when R 4 Independently "R 4-4 When the term "substituted C1-C7 alkyl" is used, the C1-C7 alkyl is methyl.

5. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, wherein: When the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 5- or 6-membered heteroaryl group, and the heteroatom is nitrogen, and the number of the heteroatom is 1 or 2.

6. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein: When the ring A is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is a piperidinyl or piperazinyl; and / or, when the ring A is a 5-10 membered heteroaryl group, and the heteroatom in the heteroaryl group is nitrogen, the heteroatom is not quaternized; and / or, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a pyridyl group, a pyrimidinyl group or a thiazolyl group; and / or, when the ring B is a 3-14 membered heterocycloalkyl group, the 3-14 membered heterocycloalkyl group is a piperidinyl group or a piperazinyl group; and / or, when the ring B is a 5-10 membered heteroaryl group, and the heteroatom in the heteroaryl group is nitrogen, the heteroatom is not quaternized; and / or, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a pyridyl group; and / or, when R 1 Independently "R 1-7 When "substituted C1-C7 alkyl", the "R 1-7 Substituted C1-C7 alkyl" is and / or, when R 2 Independently "R 2-7 When "substituted C1-C7 alkyl", the "R 2-7 "substituted C1-C7 alkyl" is trifluoromethyl; and / or, when R 4 Independently "R 4-4 When "substituted C1-C7 alkyl", the "R 4-4 "substituted C1-C7 alkyl" is trifluoromethyl; And / or, when ring B is a 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, said R 1 The substitution site is located at the para position relative to the bond connecting ring A.

7. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 6, wherein: When the ring A is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is And / or, when the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is The right end is connected to the methylene group, and the left end is connected to ring B; And / or, when the ring B is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is The left end is connected to ring A, and the right end is connected to R 1 connected; And / or, when the ring B is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is The left end is connected to ring A, and the right end is connected to R 1 are connected.

8. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 7, wherein: When the ring A is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is 9. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: m is 0 or 1; and / or, n is 0 or 1; and / or, u is 0 or 1; and / or, v is 0, 1, or 2; and / or, p is 1 or 2; and / or, s is 1 or 2; and / or, t is 0 or 2; and / or, W is CH; and / or, Z is CH; and / or, Ring A is a 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; and / or, Ring B is a 3-14 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; and / or, R 1 are independently halogen or "R 1-7 "substituted C1-C7 alkyl"; and / or, R 2 are independently halogen, "R 2-7 Substituted C1-C7 alkyl" or oxo; and / or, R 3 are independently halogen, C1-C7 alkyl or oxo; and / or, R 4 are independently halogen, C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo; and / or, R 1-7 、R 2-7 、R 3-7 and R 4-4 are independently halogen or hydroxy.

10. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 9, wherein: m is 0; and / or, n is 0; and / or, t is 0; and / or, Ring A is C6-C 10 Aryl or 5-10 membered heteroaryl; and / or, Ring B is C6-C 10 aryl; and / or, R 2 are independently halogen, "R 2-7 "substituted C1-C7 alkyl"; and / or, R 3 are independently halogen or "R 3-7 "substituted C1-C7 alkyl".

11. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R 4 are independently halogen, -CN, -OR 4-1 , C1-C7 alkyl, "R 4-4 Substituted C1-C7 alkyl" or oxo, R 4-1 For H.

12. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: for and / or, for And it is connected to ring B through the broken bond on the right side; and / or, for 13. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 12, wherein: for and / or, for and / or, for 14. The spiroheterocyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound as shown in formula I is any one of the following compounds:

15. A compound Ia: in, m,n,p,s,t,Y,Z,W,Q,R 4 and R 5 The definitions are as described in any one of claims 1 to 13, and the compound Ia is not 16. Compound Ia according to claim 15, characterized in that The compound Ia is any one of the following compounds:

17. The compound Ia according to claim 16, characterized in that Under the following chiral preparation conditions, the retention time is 1.486 min. or a retention time of 2.705 min The chiral preparation conditions are as follows: chromatographic column: CHIRALPAK IH-3; mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1 ml / min; elution conditions: elution with 60% mobile phase A and 40% mobile phase B for 14 minutes; flow rate: 1.0 ml / min; detector wavelength: 220 nm; temperature: room temperature.

18. A pharmaceutical composition comprising the spiroheterocyclic compound of formula I according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. Use of a substance X in the preparation of a RORγt protein receptor modulator or drug; The substance X is a spiroheterocyclic compound of formula I according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18; The medicine is used for preventing or treating diseases related to RORγt protein receptor.

20. The use according to claim 19, characterized in that The disease associated with the RORγt protein receptor is an autoimmune disease.

21. The use according to claim 20, characterized in that The autoimmune disease is one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease and chronic obstructive pulmonary disease.

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