WO2022095971A1

WO2022095971A1 - Spiro heterocyclic compound, preparation method therefor and use thereof

Info

Publication number: WO2022095971A1
Application number: PCT/CN2021/129049
Authority: WO
Inventors: 王倩; 张冰宾; 石辰; 舒思杰; 霍国永; 向志军; 夏广新; 吴国胜; 梁涛; 赵永新; 李令文; 柯樱
Original assignee: 上海医药集团股份有限公司
Priority date: 2020-11-06
Filing date: 2021-11-05
Publication date: 2022-05-12
Also published as: CN114437096A

Abstract

Provided are a spiro heterocyclic compound, a preparation method therefor and use thereof. The spiro heterocyclic compound is represented by formula I. The compound has inhibitory activity on RORγt, can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the generation of IL-17, and then treating related autoimmune diseases mediated by RORγt.

Description

A kind of spiroheterocyclic compound, its preparation method and application

This application claims the priority of Chinese patent application 2020112298977 with a filing date of November 6, 2020. This application cites the full text of the above Chinese patent application.

technical field

The present invention relates to a spiro heterocyclic compound, its preparation method and application.

Background technique

Retinoic acid receptor-related orphan receptors (RORs) belong to the ligand-dependent transcription factor nuclear receptor superfamily and are involved in reproductive development, circadian rhythm regulation, metabolic disorders, inflammation, and It plays an important role in a series of physiological and pathological processes such as immune system regulation. RORs mainly include three members, RORα, RORβ, and RORγ. RORα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood. RORβ is mainly distributed in the central nervous system, including the brain, retina and pineal gland. RORγ is highly expressed in the thymus, and is also distributed in the kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas. It is divided into RORγ1 and RORγt (also known as RORγ2) according to different transcriptional splicing positions. The former is mainly expressed in thymus, testis, pancreas, heart, liver, skeletal muscle and kidney, while RORγt is only expressed in immune organs.

Th17 cells are a subtype of T helper cells, which are characterized by the secretion of interleukin 17 (IL-17) cytokines. It was initially thought to play an immune function mainly by recruiting neutrophils in resisting bacterial and fungal infections. Subsequent studies found that Th17 cells Plays a key role in many mouse models of autoimmune diseases, including in some human autoimmune diseases including psoriasis (Psoriasis), multiple sclerosis (MS), rheumatoid arthritis (RA) and inflammatory bowel disease Elevated levels of IL-17 can also be detected in IBD. Increased numbers of Th17 cells were found in tissue and peripheral blood samples from patients with autoimmune disease. Therefore, Th17 cells or the cytokine IL-17 produced by them are closely related to the pathogenesis of autoimmune diseases and inflammation, inhibiting the differentiation of Th17 cells, and can be used for the treatment of related diseases.

Studies have shown that RORγt is a key regulator of Th17 cell differentiation. Littman et al. first reported that RORγt is necessary for the differentiation of naive CD4+ T cells into Th17 cells. Mice lacking RORγt lack lymphoid organs such as lymph nodes and Peyer's nodes, and the development and maturation of T cells is also affected, and the number of various T cells is lower than that of normal mice. Regulating the activity of RORγt by small molecule compounds can directly affect the differentiation of Th17 cells, inhibiting RORγt, and the level of cytokine IL-17 secreted by Th17 is significantly reduced. Therefore, RORγt can be used as a new target for the treatment of autoimmune diseases, and it is of great significance to develop small molecule regulators of RORγt for the treatment of RORγt-mediated related diseases such as autoimmune diseases and inflammatory diseases.

At present, patent applications CN107522634, WO2012158784, WO2018145653, etc. disclose some RORγt small molecule modulators, but there are no related products on the market, and new RORγt small molecule modulators with better activity and higher safety are still needed in this field.

SUMMARY OF THE INVENTION

The present invention provides a spiro heterocyclic compound different from the prior art, a preparation method and application thereof. These compounds have inhibitory activity on RORγt and can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and then treating RORγt-mediated related autoimmune diseases, especially for psoriasis, Multiple sclerosis, atopic dermatitis, inflammatory bowel disease and other diseases.

The present invention provides a spiroheterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite or a predrug thereof body:

where 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 simultaneously CH or N;

Ring A and Ring B are independently C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl The heteroatoms in the cycloalkyl 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 1, 2, 3 or 4;

R ¹ is independently hydrogen, halogen, -OR ^1-1 , -SR ^1-2 , -CN, -NR ^1-3 R ^1-4 , -C(=O)R ^1-5 , -S(=O ) ₂ R ^1-6 , C ₁ -C ₇ alkyl or "R ^1-7 substituted C ₁ -C ₇ alkyl";

R ² is independently halogen, -OR ^2-1 , -SR ^2-2 , -CN, -NR ^2-3 R ^2-4 , -C(=O)R ^2-5 , -S(=O) ₂ R ^2-6 , C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₁ -C ₇ alkyl, "R ^{2 -7-} substituted C ₁ -C ₇ alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ³ is independently halogen, -OR ^3-1 , -SR ^3-2 , -CN, -NR ^3-3 R ^3-4 , -C(=O)R ^3-5 , -S(=O) ₂ R ^3-6 , C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, C ₁ -C ₇ alkyl, "R ^{3 -7-} substituted C ₁ -C ₇ alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4; or, the carbon to which any two non-adjacent R ³ are attached Atoms together form a 4-6 membered heterocycloalkyl, the heteroatoms in the heterocycloalkyl are O and/or N, and the number is 1 or 2 (that is, any two non-adjacent R ³ and One or more atoms to which they are bound, and any heteroatoms inserted into the ring, together form a 4-6 membered heterocycloalkyl; for example

for

When two non-adjacent R ³ together with the carbon atoms to which they are attached form a 4-6 membered heterocycloalkyl group which is an oxetanyl group

R ⁴ is independently halogen, -OR ^4-1 , -CN, -NR ^4-2 R ^4-3 , C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl base, 5-10-membered heteroaryl, C ₁ -C ₇ alkyl, "R ^4-4 substituted C ₁ -C ₇ alkyl" or oxo; the 3-14-membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl 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;

Alternatively, any two non-adjacent R ⁴ together with the carbon atoms to which they are connected form a 4-6-membered heterocycloalkyl group, and the heteroatom in the heterocycloalkyl group is N, and the number is 1;

R ^1-1 , R ^2-1 , R ^3-1 and R ^4-1 are independently hydrogen, "halogen substituted C ₁ -C ₇ alkyl", C ₁ -C ₇ alkyl, C ₃ -C ₁₄ Cycloalkyl, 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms in the base 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;

R ^1-2 , R ^2-2 and R ^3-2 are independently hydrogen, "halogen substituted C ₁ -C ₇ alkyl", C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3 -14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl or 5-10-membered heteroaryl; heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl 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;

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, C ₁ -C ₇ alkanes base, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl 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;

Alternatively, R ^1-3 and R ^1-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R ^1-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R ^1-3-2 substituted 3-14-membered heterocycloalkenyl"; said 3-14-membered heterocycloalkyl, "R ^1-3-1 substituted 3-14-membered heterocycle The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R ^1-3-2 substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R ^1-3-1 and R ^1-3-2 are independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^2-3 and R ^2-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl, "R ^2-3-1 substituted 3-14-membered heterocycloalkyl", a 3-14-membered heterocycloalkyl Heterocycloalkenyl or "R ^2-3-2 substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R ^2-3-1 substituted 3-14-membered heterocycloalkenyl" The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R ^2-3-2 substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R ^2-3-1 and R ^2-3-2 are independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^3-3 and R ^3-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R ^3-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R ^3-3-2 -substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R ^3-3-1 -substituted 3-14-membered heterocycloalkenyl" The heteroatoms in cycloalkyl", 3-14-membered heterocycloalkenyl and "R ^3-3-2 -substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R ^3-3-1 and R ^3-3-2 are independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^4-2 and R ^4-3 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R ^4-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkyl Heterocycloalkenyl or "R ^4-2-2 substituted 3-14-membered heterocycloalkenyl"; said 3-14-membered heterocycloalkyl, "R ^4-2-1 substituted 3-14-membered heterocycloalkenyl" The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R ^4-2-2 -substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R ^4-2-1 and R ^4-2-2 are independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

R ^1-5 is independently hydrogen, -OR ^1-5-1 , NR ^1-5-2 R ^1-5-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ^2-5 is independently hydrogen, -OR ^2-5-1 , NR ^2-5-2 R ^2-5-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ^3-5 is independently hydrogen, -OR ^3-5-1 , NR ^3-5-2 R ^3-5-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ^1-6 is independently hydrogen, -OR ^1-6-1 , NR ^1-6-2 R ^1-6-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ^2-6 is independently hydrogen, -OR ^2-6-1 , NR ^2-6-2 R ^2-6-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R ^3-6 is independently hydrogen, -OR ^3-6-1 , NR ^3-6-2 R ^3-6-3 , C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

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, C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and The heteroatoms in the 5-10-membered heteroaryl 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 or 2 , 3 or 4;

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, C ₁ -C ₇ alkyl, C ₃ -C ₁₄ -membered cycloalkyl, 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms in the aryl 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;

Alternatively, R ^1-5-2 and R ^1-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R ^{1 -5-2-1-} ^substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R ^1-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R ^1-5-2-1 and R ^{1-5-2-2 are} independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^2-5-2 and R ^2-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R ^{2 -5-2-1-} ^substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R ^2-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R ^2-5-2-1 and R ^{2-5-2-2 are} independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^3-5-2 and R ^3-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R ^{3 -5-2-1-} ^substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R ^3-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R ^3-5-2-1 and R ^{3-5-2-2 are} independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

R ^1-7 , R ^2-7 , R ^3-7 and R ^4-4 are independently halogen, hydroxy, amino, mercapto, cyano, C ₁ -C ₇ alkoxy, C ₃ -C ₁₄ cycloalkyl , 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms 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;

R ⁵ is independently C ₁ -C ₇ alkyl; alternatively, any two non-adjacent R ⁵ together with the carbon atom to which it is attached form a 4-10 membered cycloalkyl (ie, any two non-adjacent R ⁵ with One or more atoms to which they are bound together form a 4-10 membered cycloalkyl group; for example

for

When two non-adjacent R ⁵ together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group is a cycloheptyl group

Said R ^1-7 , said R ^2-7 , said R ^3-7 , said R ^4-4 , said R ^1-3-1 , said R ^{1-3- 2.} Said R ^2-3-1 , said R ^2-3-2 , said R ^3-3-1 , said R ^3-3-2 , said 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- The number of ¹ and said R ^3-5-2-2 is independently 1, ² , 3, 4, 5, 6 or 7; when said R ^1-7 , said R ^2-7 , said Said R ^3-7 , said R ^4-4 , said R ^1-3-1 , said R ^1-3-2 , said R ^2-3-1 , said R ^{2 -3-2} , said R ^3-3-1 , said R ^3-3-2 , said R ^1-5-2-1 , said R ^1-5-2-2 , said R ^1-5-2-2 , said The number of said R ^2-5-2-1 , said R ^2-5-2-2 , said R ^3-5-2-1 and said R ^3-5-2-2 is When there are more than one, said R ^1-7 , said R ^2-7 , said R ^3-7 , said R ^4-4 , said R ^1-3-1 , said R 1-3-1 ^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 said R ^{3-5-2-2 are} independently the same or different.

In the present invention, the definitions of certain substituents in the compound represented by formula I are as described in a certain preferred embodiment, and the definitions of unmentioned substituents are as described in any one of the embodiments of the present invention.

In a certain preferred embodiment, in the compound shown in the formula I:

n is 0 or 1;

Ring A and Ring B are independently C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl The heteroatoms in the cycloalkyl group and the 5-10-membered heteroaryl group 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 is independently -NR ^1-3 R ^1-4 , -C(=O)R ^1-5 , -S(=O) ₂ R ^1-6 , C ₁ -C ₇ alkyl or "R ^{1- 7} -substituted C ₁ -C ₇ alkyl";

R ² is independently halogen, -OR ^2-1 , -CN, -NR ^2-3 R ^2-4 , -C(=O)R ^2-5 , -S(=O) ₂ R ^2-6 , C ₃ -C ₁₄ -membered cycloalkyl, 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl, 5-10-membered heteroaryl, C ₁ -C ₇ alkyl, "R ^2-7 substituted C ₁ -C ₇ alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from a group consisting of oxygen, sulfur and nitrogen one or more, the number of heteroatoms is independently 1, 2 or 3;

R ³ is independently halogen, -OR ^3-1 , -CN, -NR ^3-3 R ^3-4 , -C(=O)R ^3-5 , -S(=O) ₂ R ^3-6 , C ₃ -C ₁₄ -membered cycloalkyl, 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl, 5-10-membered heteroaryl, C ₁ -C ₇ alkyl, "R ^3-7 substituted C ₁ -C ₇ alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen or Multiple, the number of heteroatoms is independently 1, 2 or 3; or, any two non-adjacent R ³ and the carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;

R ^1-5 is independently hydrogen, -OR ^1-5-1 , NR ^1-5-2 R ^1-5-3 or C ₁ -C ₇ alkyl;

R ^2-5 is independently hydrogen, -OR ^2-5-1 , NR ^2-5-2 R ^2-5-3 or C ₁ -C ₇ alkyl;

R ^3-5 is independently hydrogen, -OR ^3-5-1 , NR ^3-5-2 R ^3-5-3 or C ₁ -C ₇ alkyl;

R ^1-6 is independently hydrogen, -OR ^1-6-1 , NR ^1-6-2 R ^1-6-3 , C ₁ -C ₇ alkyl, C ₃ -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;

R ^2-6 is independently hydrogen, -OR ^2-6-1 , NR ^2-6-2 R ^2-6-3 , C ₁ -C ₇ alkyl, C ₃ -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;

R ^3-6 is independently hydrogen, -OR ^3-6-1 , NR ^3-6-2 R ^3-6-3 , C ₁ -C ₇ alkyl, C ₃ -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;

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, C ₁ -C ₇ alkyl or C ₃ -C ₁₄ cycloalkyl;

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, C ₁ -C ₇ alkyl, C ₃ -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 independent 1, 2 or 3 lands.

In a certain preferred embodiment, in the compound shown in the 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;

R ¹ is "C ₁ -C ₇ alkyl substituted by R ^1-7 ";

R ² is independently halogen, "R ^2-7 substituted C ₁ -C ₇ alkyl" or oxo;

R ³ is independently halogen, C ₁ -C ₇ alkyl, "R ^3-7 substituted C ₁ -C ₇ alkyl" or oxo, or, any two non-adjacent carbon atoms to which R ³ is attached together form a 4-6 membered heterocycloalkyl;

R ⁴ is independently halogen, C ₁ -C ₇ alkyl, "R ^4-4 substituted C ₁ -C ₇ alkyl" or oxo;

R ^1-7 , R ^2-7 , R ^3-7 and R ^4-4 are independently halogen or hydroxy.

In a certain preferred embodiment, in the compound shown in the 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, C ₆ -C ₁₀ -membered 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, the number of heteroatoms is independently 1, 2 or 3;

R ¹ is C ₁ -C ₇ alkyl substituted by R ^1-7 ;

R ² is independently halogen, "R ^2-7 substituted C ₁ -C ₇ alkyl" or oxo;

R ³ is independently halogen, C ₁ -C ₇ alkyl or oxo, alternatively, any two non-adjacent R ³ together with the carbon atom to which it is attached form a 4-6 membered heterocycloalkyl;

R ⁴ is independently halogen, -CN, -OR ^4-1 , C ₁ -C ₇ alkyl, "R ^4-4 substituted C ₁ -C ₇ 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 R5's together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl.

In a certain preferred embodiment, in the compound shown in the 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 C ₆ -C ₁₀ aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen. one or more, the number of heteroatoms is independently 1, 2 or 3;

R ¹ is C ₁ -C ₇ alkyl substituted by R ^1-7 ;

R ² is independently halogen or "R ^2-7 substituted C ₁ -C ₇ alkyl";

R ³ is independently halogen, C ₁ -C ₇ alkyl or oxo;

R ⁴ is independently halogen, -CN, -OR ^4-1 , C ₁ -C ₇ alkyl or oxo;

R ^1-7 , R ^2-7 and R ^4-4 are independently halogen or hydroxy;

R ^4-1 is hydrogen;

In a certain preferred embodiment, in the compound shown in the 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;

R ¹ is "C ₁ -C ₇ alkyl substituted by R ^1-7 ";

R ² is independently halogen or "R ^2-7 substituted C ₁ -C ₇ alkyl";

R ³ is independently halogen, C ₁ -C ₇ alkyl or oxo;

R ⁴ is independently halogen, C ₁ -C ₇ alkyl or oxo;

R ^1-7 and R ^2-7 are independently halogen or hydroxy.

In a certain preferred embodiment, 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;

R ¹ is C ₁ -C ₇ alkyl substituted by R ^1-7 ;

R ² is independently halogen, "R ^2-7 substituted C ₁ -C ₇ alkyl" or oxo;

R ^1-7 , R ^2-7 and R ^4-4 are independently halogen or hydroxy;

R ^4-1 is hydrogen;

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 C ₆ -C ₁₀ aryl or 5-10-membered heteroaryl; the heteroatom in the 5-10-membered heteroaryl is selected from one of oxygen, sulfur and nitrogen or Multiple, the number of heteroatoms is independently 1, 2 or 3;

R ¹ is "C ₁ -C ₇ alkyl substituted by R ^1-7 ";

R ² is independently halogen or "R ^2-7 substituted C ₁ -C ₇ alkyl";

R ³ is independently halogen or C ₁ -C ₇ alkyl; alternatively, any two non-adjacent R ³ and the carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;

R ⁴ is independently C ₁ -C ₇ alkyl;

R ^1-7 and R ^2-7 are independently halogen or hydroxy.

In a certain preferred embodiment, the compound of formula I is a compound of formula III:

Wherein, ring A and ring B are independently C ₃ -C ₁₄ -membered cycloalkyl, 3-14-membered heterocycloalkyl, C ₆ -C ₁₀ -membered aryl or 5-10-membered heteroaryl; the 3-14 The heteroatoms in the 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 indivual;

R ¹ is independently hydrogen, halogen, -OR ^1-1 , -CN, -NR ^1-3 R ^1-4 , -C(=O)R ^1-5 , -S(=O) ₂ R ^1-6 , C ₁ -C ₇ alkyl or "R ^1-7 substituted C ₁ -C ₇ alkyl";

R ² is independently halogen, -OR ^2-1 , -CN, -NR ^2-3 R ^2-4 , -C(=O)R ^2-5 , -S(=O) ₂ R ^2-6 , C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₁ -C ₇ alkyl "C ₁ -C ₇ alkyl substituted by R ^2-7 " or oxo; the 3-14 membered The heteroatoms in the heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1, 2 or 3;

R ³ is independently halogen, -OR ^3-1 , -CN, -NR ^3-3 R ^3-4 , -C(=O)R ^3-5 , -S(=O) ₂ R ^3-6 , C ₃ -C ₁₄ cycloalkyl, 3-14 membered heterocycloalkyl, C ₁ -C ₇ alkyl, "R ^3-7 substituted C ₁ -C ₇ alkyl" or oxo; the 3-14 The heteroatoms in the 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 heteroatoms ^R3 together with the carbon atom to which it is attached forms a 4-6 membered heterocycloalkyl;

R ^1-1 , R ^2-1 and R ^3-1 are independently hydrogen, "halogen substituted C ₁ -C ₇ alkyl", C ₁ -C ₇ alkyl, C ₃ -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;

R ^1-3 , R ^1-4 , R ^2-3 , R ^2-4 , R ^3-3 and R ^3-4 are independently hydrogen, C ₁ -C ₇ alkyl, C ₃ -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;

Alternatively, R ^1-3 and R ^1-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R ^1-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R ^1-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3; the R ^1-3-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^2-3 and R ^2-4 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R ^2-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R ^2-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3; the R ^2-3-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^3-3 and R ^3-4 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R ^3-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R ^3-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2, 3 or 4; the R ^3-3-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy base;

R ^1-5 is independently hydrogen, -OR ^1-5-1 , NR ^1-5-2 R ^1-5-3 , C ₁ -C ₇ alkyl, C ₃ -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;

R ^2-5 is independently hydrogen, -OR ^2-5-1 , NR ^2-5-2 R ^2-5-3 , C ₁ -C ₇ alkyl, C ₃ -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;

R ^3-5 is independently hydrogen, -OR ^3-5-1 , NR ^3-5-2 R ^3-5-3 , C ₁ -C ₇ alkyl, C ₃ -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 heteroatoms the number of atoms is independently 1, 2 or 3;

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, C ₁ -C ₇ alkyl groups, C ₃ -C ₁₄ cycloalkyl groups or 3-14-membered heterocycloalkyl groups; the heteroatoms in the 3-14-membered heterocycloalkyl groups are independently selected from one of oxygen, sulfur and nitrogen or more, the number of heteroatoms is independently 1, 2, 3 or 4;

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, C ₁ -C ₇ alkyl, C ₃ -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 independent 1, 2 or 3 lands;

Alternatively, R ^1-5-2 and R ^1-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R ^1-5-2-1- substituted 3-14-membered heterocycloalkyl "; The heteroatoms in the 3-14-membered heterocycloalkyl and the "R ^1-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R ^1-5-2-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^2-5-2 and R ^2-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R ^2-5-2-1 substituted 3-14-membered heterocycloalkyl "; the heteroatoms in the 3-14-membered heterocycloalkyl and the "R ^2-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R ^2-5-2-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

Alternatively, R ^3-5-2 and R ^3-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R ^3-5-2-1 substituted 3-14-membered heterocycloalkyl "; the heteroatoms in the 3-14-membered heterocycloalkyl and the "R ^3-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R ^3-5-2-1 is independently hydroxyl, oxo, -CN, C ₁ -C ₇ alkyl or C ₁ -C ₇ alkoxy;

R ^1-7 , R ^2-7 and R ^3-7 are independently halogen, hydroxy, amino, mercapto, cyano, C ₁ -C ₇ alkoxy, C ₃ -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 indivual.

In a certain preferred embodiment, the compound of formula I is a compound of formula IV:

where u is 0 or 1;

v is 0, 1 or 2;

Ring A is C ₆ -C ₁₀ aryl;

Ring B is independently a C ₆ -C ₁₀ aryl group or a 5-10-membered heteroaryl group; the heteroatom in the 5-10-membered heteroaryl group is selected from one or more of oxygen, sulfur and nitrogen, The number of heteroatoms is 1, 2 or 3;

R ¹ is "C ₁ -C ₇ alkyl substituted by R ^1-7 ";

R ² is independently halogen or "R ^2-7 substituted C ₁ -C ₇ alkyl";

R ³ is independently halogen or C ₁ -C ₇ alkyl;

R ^1-7 and R ^2-7 are independently halogen or hydroxy.

In a certain preferred embodiment, the compound shown in formula I is

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

In a preferred embodiment, when the ring A is a 3-14-membered heterocycloalkyl, the heterocycloalkyl in the 3-14-membered heterocycloalkyl is a heteromonocycloalkyl or heterocycloalkyl Bridged cycloalkyl.

In a preferred embodiment, when the ring A is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is attached to the ring B through a heteroatom.

In a preferred embodiment, when the ring A is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is a 5-, 6- or 7-membered heterocycloalkyl, and a heteroatom For oxygen and/or nitrogen, the number is 1 or 2.

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

In a certain preferred embodiment, when the ring A is a C ₆ -C ₁₀ aryl group, the C ₆ -C ₁₀ aryl group is a phenyl group or a naphthyl group, preferably a phenyl group.

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

In a certain 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.

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

In a certain 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, the number is 1 or 2.

In a certain 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. 1 or 2.

In a preferred embodiment, when the ring A is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is pyridyl, pyrimidinyl or thienyl, more preferably

In a certain preferred embodiment, when the ring A is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is

The right end is connected with methylene, and the left end is connected with ring B.

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

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

In a preferred embodiment, when the ring B is a 3-14 membered heterocycloalkyl, the 3-14 membered heterocycloalkyl is attached to the ring A through a heteroatom.

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

In a preferred embodiment, when the ring B is a 3-14-membered heterocycloalkyl group, the 3-14-membered heterocycloalkyl group is piperidinyl or piperazinyl, more preferably

preferred

The left end is connected to ring ^A , and the right end is connected to R1.

In a certain preferred embodiment, when the ring B is a C ₆ -C ₁₀ aryl group, the C ₆ -C ₁₀ aryl group is phenyl or naphthyl, preferably phenyl.

In a certain preferred embodiment, when the ring B is a C ₆ -C ₁₀ aryl group, the C ₆ -C ₁₀ aryl group is

The left end is connected to ring A, and the right end is connected to R ¹ .

In a certain preferred embodiment, when the ring B is a 5-10 membered heteroaryl, the heteroaryl is a monocyclic heteroaryl.

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.

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

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 ortho to the point of attachment to ring A.

In a certain 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. 1 or 2.

In a certain preferred embodiment, when the ring B is a 5-10-membered heteroaryl group, the 5-10-membered heteroaryl group is a pyridyl group, more preferably a pyridyl group

In a certain preferred embodiment, when the ring B is a 5-10-membered heteroaryl, the 5-10-membered heteroaryl is

The left end is connected to ring A, and the right end is connected to R ¹ .

In ^a certain preferred embodiment, when R1 is independently halogen, said halogen is F, Br, Cl or I, preferably F.

In a certain preferred embodiment, when R ¹ is independently "C ₁ -C ₇ alkyl substituted by R ^1-7 ", the number of said R ^1-7 is 4, 5 or 6 or 7.

In a certain preferred embodiment, when R ¹ is independently "R ^1-7 substituted C ₁ -C ₇ alkyl", said C ₁ -C ₇ alkyl is C ₁ -C ₃ alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably isopropyl.

In a certain preferred embodiment, when R ^1-7 is halogen, the halogen is F, Br, Cl or I, preferably F.

In a certain preferred embodiment, when R ¹ is independently "R ^1-7 substituted C ₁ -C ₇ alkyl", the "R ^1-7 substituted C ₁ -C ₇ alkyl" is

^In a certain preferred embodiment, when R2 is independently halogen, said halogen is F, Br, Cl or I, preferably F.

In a preferred embodiment, when R ² is independently "C ₁ -C ₇ alkyl substituted by R ^2-7 ", the number of said R ^2-7 is three.

In a certain preferred embodiment, when R ² is independently "R ^2-7 substituted C ₁ -C ₇ alkyl", said C ₁ -C ₇ alkyl is C ₁ -C ₃ alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably methyl.

In a certain preferred embodiment, when R ^2-7 is halogen, said halogen is F, Br, Cl or I, preferably F.

In a certain preferred embodiment, when R ² is independently "R ^2-7 substituted C ₁ -C ₇ alkyl", the "R ^2-7 substituted C ₁ -C ₇ alkyl" is trifluoromethyl.

In a preferred embodiment, when ^R3 is independently halogen, said halogen is F, Br, Cl or I, preferably F or Cl.

In a certain preferred embodiment, when R ³ is independently C ₁ -C ₇ alkyl, said C ₁ -C ₇ alkyl is C ₁ -C ₃ alkyl (eg methyl, ethyl, n- propyl or isopropyl), more preferably methyl.

^In a certain preferred embodiment, when R4 is independently halogen, said halogen is F, Br, Cl or I, preferably Cl.

^In a certain preferred embodiment, when R4 is independently halogen, said halogen is preferably F or Cl.

In a certain preferred embodiment, when R ⁴ is independently C ₁ -C ₇ alkyl, said C ₁ -C ₇ alkyl is C ₁ -C ₃ alkyl (eg methyl, ethyl, n- propyl or isopropyl), more preferably methyl.

In a certain preferred embodiment, when R ⁴ is independently "C ₁ -C ₇ alkyl substituted by R ^4-4 ", the number of said R ^4-4 is three.

In a certain preferred embodiment, when R ⁴ is independently "R ^4-4 substituted C ₁ -C ₇ alkyl", said C ₁ -C ₇ alkyl is C ₁ -C ₃ alkyl ( For example, methyl, ethyl, n-propyl or isopropyl), more preferably methyl.

In a certain preferred embodiment, when R ^4-4 is halogen, said halogen is F, Br, Cl or I, preferably F.

In a certain preferred embodiment, when R ⁴ is independently "R ^4-4 substituted C ₁ -C ₇ alkyl", the "R ^4-4 substituted C ₁ -C ₇ alkyl" is trifluoromethyl.

In a preferred embodiment, when any two non-adjacent R ⁵ and the carbon atoms to which they are attached together form a 4-10 membered cycloalkyl group, the 4-10 membered cycloalkyl group is a 7-membered cycloalkyl group .

In a preferred embodiment, when Ring B is a 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl group, the substitution site for R ¹ is located at the para position to the bond to Ring A.

In a preferred embodiment, the substitution site on Ring B on Ring A is

Not adjacent.

In a certain preferred embodiment, m is 0 or 1, preferably 0.

In a certain preferred embodiment, n is 0 or 1, preferably 0.

In a certain preferred embodiment, u is 0 or 1.

In a certain preferred embodiment, v is 0, 1 or 2.

In a certain preferred embodiment, p is 1 or 2.

In a certain preferred embodiment, s is 1 or 2.

In a certain preferred embodiment, t is 0 or 2, preferably 0.

In a certain preferred embodiment, W is CH.

In a certain preferred embodiment, Z is CH.

In a certain preferred embodiment, Ring A is 3-14 membered heterocycloalkyl, _C6 - _C10 aryl or 5-10 membered heteroaryl, preferably _C6 - _C10 aryl or 5-10 membered Heteroaryl.

In a certain preferred embodiment, Ring B is a 3-14 membered heterocycloalkyl, a _C6 - _C10 aryl or a 5-10 membered heteroaryl, preferably a _C6 - _C10 aryl.

In a certain preferred embodiment, R ¹ is independently halogen or "R ^1-7 substituted C ₁ -C ₇ alkyl".

In a certain preferred embodiment, R ² is independently halogen, "R ^2-7 substituted C ₁ -C ₇ ^alkyl " or oxo, preferably halogen or "R ^2-7 substituted C ₁ -C ₇ . alkyl".

In a certain preferred embodiment, R ³ is independently halogen, C ₁ -C ₇ alkyl or oxo, preferably halogen or "R ^3-7 substituted C ₁ -C ₇ alkyl".

In a certain preferred embodiment, R ⁴ is independently halogen, -CN, -OR ^4-1 , C ₁ -C ₇ alkyl, "R ^4-4 substituted C ₁ -C ₇ alkyl" or oxo , R ^4-1 is H.

In a certain preferred embodiment, R ⁴ is independently halogen, C ₁ -C ₇ alkyl, "R ^4-4 substituted C ₁ -C ₇ alkyl" or oxo.

In a certain preferred embodiment, R ^1-7 , R ^2-7 , R ^3-7 and R ^4-4 are independently halogen or hydroxy.

In a certain preferred embodiment,

for

preferred

In a certain preferred embodiment,

for

and is connected with ring B through the right broken bond; preferably

In a certain preferred embodiment,

for

preferred

In a certain preferred embodiment, the compound shown in formula I is optionally any of the following compounds:

The present invention also provides a compound I-a:

Wherein, the definitions of m, n, p, s, t, Y, Z, W, Q, R ⁴ and R ⁵ are the same as above, and the compound Ia is not

The compound I-a is preferably any one of the following compounds:

More preferably, the retention time is 1.486min under the following chiral preparation conditions

or with a retention time of 2.705min

(i.e. compound

);

Described chiral preparation conditions: chromatographic column: chiral column CHIRALPAK IH-3; mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1ml/min; elution Conditions: eluted with 60% mobile phase A and 40% mobile phase B for 14min; flow rate: 1.0ml/min; detector wavelength: 220nm; temperature: room temperature, the "%" is volume percentage.

The present invention also provides the above-mentioned 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 or The preparation method of its prodrug, the preparation method is any of the following methods:

method one:

The preparation method of the compound shown in the formula I comprises the following steps: in a solvent, the compound I-a and the compound I-b are subjected to the reductive amination reaction of the following formula to obtain the compound shown in the formula I;

Wherein, 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 stated;

Method Two:

The preparation method of the compound shown in the formula I comprises the following steps: in the presence of a Pd catalyst, in a solvent, the compound I-d and the compound I-e are subjected to the Suzuki reaction of the following formula to obtain the compound I;

where ^R6 is

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 as defined above.

In the method one, the conditions and operations of the reductive amination can be the conventional conditions and operations of this type of reaction in this area, and the present invention particularly preferably the following conditions and operations:

In the first method, the solvent is preferably a halogenated hydrocarbon (eg, dichloromethane) and/or an amide solvent (eg, N,N-dimethylformamide).

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

In the first method, the reducing agent used in the reductive amination reaction is preferably sodium triacetyl borohydride and/or sodium acetyl borohydride. The molar ratio of the reducing agent to the compound I-a is preferably 5:1-2:1, such as 3:1.

In the first method, the molar ratio of the compound I-b to the compound I-a is preferably 0.9:1-3:1, for example, 1:1.

In the first method, the temperature of the reductive amination reaction is preferably carried out at room temperature.

In the first method, the progress of the reductive amination reaction can be monitored by conventional methods in the art (eg TLC or HPLC), and generally the end point of the reaction is that the compound I-a does not react or disappears. The time of the reductive amination reaction is preferably 12-36 hours.

In the first method, the post-processing steps after the reductive amination reaction are preferably as follows: concentration and column chromatography (for example, the eluent is methanol and dichloromethane with a volume content of 0-1:10).

In method 2, the condition and operation of described Suzuki can be the conventional condition and operation of this type of reaction in this area, and the present invention is particularly preferably the following condition and operation:

In the second method, the Pd catalyst is preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (Pd(dppf)Cl ₂ ) and/or [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex.

In the second method, the molar ratio of the Pd catalyst to the compound I-d is preferably 0.01:1-0.3:1, for example, 0.2:1.

In the second method, the solvent is preferably an ether solvent (eg dioxane).

In the second method, the alkaline reagent used in the Suzuki reaction is preferably an alkali metal carbonate (eg, potassium carbonate). The molar ratio of the basic reagent to the compound I-d is preferably 1.2:1-5:1, for example, 3:1.

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

In the second method, the temperature of the Suzuki reaction is preferably 80-110°C, for example, 100°C.

In the first method, the progress of the Suzuki reaction can be monitored by conventional methods in the art (eg, TLC or HPLC), and generally, the end point of the reaction is that the compound I-d does not react or disappears. The time of the Suzuki reaction is preferably 8-24 hours, such as 16 hours.

In the second method, the post-processing steps after the Suzuki reaction is preferably the following steps: concentration and column chromatography (for example, the eluent is methanol and dichloromethane with a volume content of 0-1:10).

The present invention also provides a pharmaceutical composition comprising the above-mentioned spiroheterocyclic compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable A solvate of a salt, its metabolite or its prodrug, with a pharmaceutically acceptable carrier.

The present invention also provides the use of a substance X in the preparation of a RORγt protein receptor modulator; the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, Its solvate, its solvate of a pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition.

The present invention also provides the application of a substance X in the preparation of medicine; the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, The solvate of its pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition.

The present invention also provides the application of a substance X in the preparation of a medicine; the medicine is used for preventing or treating diseases related to the RORγt protein receptor; the substance X is the spiro as shown in formula I. Heterocyclic compounds, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof, prodrugs thereof or the pharmaceutical composition thereof.

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

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

The present invention also provides the application of a substance X in the preparation of medicine; the substance X is the spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, The solvate of its pharmaceutically acceptable salt, its metabolite, its prodrug or said pharmaceutical composition; said medicine is used for preventing or treating psoriasis, multiple sclerosis, rheumatoid joints one or more of inflammatory bowel disease, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease, and chronic obstructive pulmonary disease.

The present invention also provides a method for preventing and/or treating a disease, the method comprising administering an effective amount of Substance X to a subject in need of treatment; wherein, the disease is a disease related to the RORγt protein receptor, and the Substance X is the spiroheterocyclic compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, its metabolite, its predrug body or the pharmaceutical composition.

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

The present invention also provides a method for preventing and/or treating a disease, the method comprising administering an effective amount of Substance X to a subject in need of treatment; wherein the disease is psoriasis, multiple sclerosis, rheumatoid One or more of arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease and chronic obstructive pulmonary disease; the substance X is the spiral as shown in formula I. Heterocyclic compounds, pharmaceutically acceptable salts thereof, solvates thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof, prodrugs thereof or the pharmaceutical composition thereof.

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

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acid includes inorganic acids, and the inorganic acids include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is 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, hydrogen tartrate, 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 (eg, glutamic acid, arginine), and the like. 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).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. Solvent molecules in solvates can exist in ordered or non-ordered arrangements. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

"Pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" are as described above and refer to Compound 1 of the present invention, and a relatively non-toxic, pharmaceutically acceptable 2. A substance formed by combining with a stoichiometric or non-stoichiometric amount of a solvent. The "solvates of pharmaceutically acceptable salts" include, but are not limited to, hydrochloric acid monohydrates of the compounds of the present invention.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" can exist in crystalline or amorphous forms. The term "crystal form" means that the ions or molecules in it are arranged in a strictly periodic manner in three-dimensional space in a certain manner, and have the regularity of periodic repetition at a certain distance; crystal form, or polymorphism. The term "amorphous" means that the ions or molecules are in a disordered distribution state, that is, there is no periodic arrangement between ions and molecules.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt", where stereoisomers exist, may be expressed as a single stereoisomer or their in the form of a mixture (eg, a racemate). The term "stereoisomer" refers to a cis-trans isomer or an optical isomer. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, spin chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.) It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or forming salts (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%.

The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt," if tautomers exist, may exist as a single tautomer or their mixtures, preferably in the form of more stable tautomers.

Atoms in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may exist in their natural or unnatural abundance. Taking a hydrogen atom as an example, its natural abundance form means that about 99.985% of it is protium and about 0.015% is deuterium; its unnatural abundance form, for example, about 95% of which is deuterium. That is, one or more atoms in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may be present in unnatural abundance Atoms that exist in the form.

When any variable (for example, R ^1-1-1 ) appears multiple times in the definition of a compound, the definition that appears in each position of the variable is independent of the definitions that appear in other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 R ^1-1-1 groups, that is, the group may be substituted with up to 3 R ^1-1-1 groups, the position R ¹ The definition of ^-1-1 is independent of the definition of the remaining positions R ^1-1-1 . Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

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

The term "alkyl" refers to a saturated straight or branched monovalent hydrocarbon radical having one to twelve carbon atoms (eg, _C1 - _C6 alkyl, eg, _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 base and 1-octyl.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group of two to twelve carbon atoms having at least one position of unsaturation, ie, a carbon-carbon sp ^double bond (eg, C2 _- _C6 alkenyl, and such as C2 _- _C4 alkenyl), and includes groups having "cis" and "trans" orientations or "E" and "Z" orientations. Examples include, but are not limited to, vinyl, allyl.

The term "cycloalkyl" refers to a saturated, non-aromatic, cyclic hydrocarbon radical (eg, C3 _- _C6 cycloalkyl) having three to twenty carbon atoms, including monocyclic cycloalkyls and polycyclic cycloalkanes base. Cycloalkyl groups contain 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms.

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

Polycyclic cycloalkyls are polycyclic (eg, bicyclic and tricyclic) cycloalkyl structures, including spiro, fused, and bridged cycloalkyls. Among them, "spirocyclic cycloalkyl" refers to a polycyclic group with a single carbon atom (called a spiro atom) between 5 and 20 members, which may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between the rings, the spirocycloalkyl groups are divided into single spirocycloalkyl and double spirocycloalkanes. or polyspirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered Single/6-membered spirocycloalkyl. Examples of spirocycloalkyl include, but are not limited to:

"Fused-ring cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which may contain one or more double bonds , but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Examples of fused cycloalkyl groups include, but are not limited to:

"Bridged cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group with any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has Fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Examples of bridged cycloalkyl groups include, but are not limited to:

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, sulfur, selenium, nitrogen and phosphorus , and the remaining ring atoms are C. The group may be a carbon group or a heteroatom group (ie it may be C-attached or N-attached, as long as it is possible). Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thi oxanyl and piperazinyl. Fused ring moieties, spiro ring moieties and bridged ring moieties are also included within the scope of this definition. For example, a group derived from tetrahydropyrrole can be tetrahydropyrrol-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached). 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, where N, B, P or Se Optionally substituted by one or more oxygen atoms to give groups like NO, BOH, PO, _PO2 , SeO; N can optionally be quaternized; S atom can optionally be replaced by one or more oxygen atoms or nitrogen atom substituted to obtain groups like SO, SO ₂ , S(=O)(=NR ^a ), S(=NR ^b ) or S(=NR ^c ) ₂ , meanwhile, R ^a , R ^b and R ^c is independently cyano, C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, "heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. 3-14-membered heterocycloalkyl with 1 to 4 atoms", "heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C ₁ -C ₇ heteroaryl", C ₆ -C ₁₀ aryl or C ₁ -C ₇ alkoxy; meanwhile, the -CH ₂ - group can be optionally replaced by -C(=O)-, -C(=S)- or -C(=NR ^d )- replacement, R ^d is independently cyano, C ₁ -C ₇ alkyl, C ₃ -C ₁₄ cycloalkyl, "heteroatom is boron, silicon , one or more of oxygen, sulfur, selenium, nitrogen and phosphorus, 3-14-membered heterocycloalkyl with 1 to 4 heteroatoms", "heteroatoms are boron, silicon, oxygen, sulfur, selenium , one or more of nitrogen and phosphorus, C ₁ -C ₇ heteroaryl", C ₆ -C ₁₀ aryl or C ₁ -C ₇ alkoxy with 1-4 heteroatoms; When the said ring is a three-membered ring, in which there is only one heteroatom), or a bicyclic ring composed of 7-10 atoms (4-9 carbon atoms and 1- 3 heteroatoms, where N, S, B or P are optionally substituted with one or more oxygen atoms to give groups like NO, BOH, SO, SO2, PO, _PO2 , SeO, while, _- The CH2- group can optionally be replaced by _-C (=O)-). Depending on the structure, a heterocyclyl group can be a monoradical or a diradical, ie, a heterocyclylene.

The term "heterocycloalkenyl" refers to a monocyclic partially unsaturated (containing 1 or 2 double bond) non-aromatic cyclic hydrocarbon radical having _three to twenty carbon atoms (eg C3 _- C6cycloalkenyl) ).

The term "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring of up to 10 atoms in each ring, at least one of which is aromatic. Examples of the above-mentioned aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2,3-indenyl, biphenyl, phenanthrenyl, anthracenyl, or acenaphthyl. It will be appreciated that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through the aromatic ring.

The term "heteroaryl" refers to stable monocyclic or bicyclic rings of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 atoms selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus heteroatoms. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline. "Heteroaryl" should also be understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is non-aromatic or contains no heteroatoms, it is understood that the attachment is through the aromatic ring, respectively. Heteroaromatic and bicyclic heteroaromatic ring systems can be fused to form rings. where N, S, B, P or Se is optionally substituted with one or more oxygen atoms to give groups like NO, SO, SO2, BOH, PO, _PO2 , _SeO , the N atom can be quaternized . Heteroaryl groups can be attached to the main structure at any heteroatom or carbon atom to form stable compounds. Depending on the structure, a heteroaryl group can be a monoradical or a diradical, ie, a heteroarylene.

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

The term "alkylmercapto" refers to an alkyl group attached through a sulfur bridge; said alkyl group is as defined above.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, treatment refers to: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein. A "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.

The term "patient" refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is to be or has been administered according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

The term "active ingredient" refers to the active ingredient in the pharmaceutical composition or combination kit of the present invention, namely Compound I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, Its metabolites or prodrugs thereof, anticancer drugs, or the above-mentioned combinations formed by them.

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

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

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

The positive improvement effect of the present invention is that: the compound of the present invention has inhibitory activity on RORγt, and can effectively inhibit the RORγt protein receptor, thereby regulating the differentiation of Th17 cells, inhibiting the production of IL-17, and then treating RORγt-mediated related autoimmune diseases. disease.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

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

^<1 >H NMR chemical shifts ([delta]) are reported in PPM (10<" ⁶ >). NMR was performed on a Bruker AVANCE-400 spectrometer.

LC-MS was determined by an Agilent 1200 HPLC/6120 mass spectrometer.

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

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

Preparation Example 1 (Preparation of Key Intermediates)

first step:

To a solution of compound 1-a (20 g, 85.822 mmol, 1.00 equiv) and trifluoromethyltrimethylsilane (TMSCF ₃ , 61.02 g, 429.111 mmol, 5.00 eqiv) in tetrahydrofuran (200 mL) at 0° C. was added tetrabutyl Ammonium fluoride (54.15 g, 171.644 mmol, 2.00 equiv) was stirred at room temperature overnight. The reaction was monitored by LCMS until completion and was quenched by the addition of 1 N HCl at 0°C. The reaction solution was extracted with ethyl acetate and dried over anhydrous Na ₂ SO ₄ (sodium sulfate). The reaction solution was concentrated and separated by column chromatography (EA/PE, 15%-30%) to obtain 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).

Step 2:

To a solution of compound 1-b (11.80 g, 34.60 mmol, 1 eqiv) in 1,4-dioxane/water (4:1,1 mL) was added 4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)benzaldehyde (10.44g, 44.98mmol, 1.3eq), palladium tetrakistriphenylphosphine (4.80g, 4.15mmol, 0.12eq) and potassium carbonate (14.35 g, 103.81 mmol, 3 eq), the reaction system was stirred at 95°C overnight under nitrogen protection. The reaction was completed by LCMS, the solvent was removed in vacuo, and the residue was separated by column chromatography (EA/PE, 10%-30%) to obtain 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-d ₆ ) δ 10.08 (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=8.3 Hz, 1H), 7.69-7.55 (m, 2H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-73.95 (s), -116.18 (s).

Preparation Example 2 (Preparation of Key Intermediates)

first step:

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

Step 2:

To compound 2-b (23.00 g, 62.16 mmol, 1 equiv) in 1,4-dioxane solution (300 mL) was added pinacol biboronate (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. LCMS monitored the completion of the reaction, the solvent was removed in vacuo, and the residue was purified by column chromatography (EA/PE, 10%-40%) to give 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 (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H), 7.85–7.76 (m, 2H), 7.75–7.67 (m, 2H), 1.30 (s, 12H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-73.85.

Preparation Example 3 (Preparation of Key Intermediates)

To a solution of compound 3-a (5g, 13.512mmol, 1.00eqiv) in 1,4-dioxane/water (4:1, 100mL) was added (4-formylphenyl)boronic acid (2.43g, 16.215mmol, 1.2eqiv), tetrakistriphenylphosphine palladium (1.56g, 1.351mmol, 0.10eqiv) and potassium carbonate (5.6g, 40.537mmol, 3.00eqiv). The reaction mixture was stirred at 80°C overnight under nitrogen protection. The reaction was monitored by LCMS, the solvent was removed in vacuo, and the residue was separated by column chromatography (EA/PE, 0%-40%) to obtain a crude product, which was purified by n-hexane beating to obtain compound 3 (2.491 g, 7.153 mmol, 52.94% yield). rate), a yellow solid. LCMS: (ESI, m/z): [M-1] ^- = 347.00. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 8.84 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.99-7.88 (m, 4H), 7.82 (d, J=8.3 Hz, 2H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-73.89.

Preparation Example 4 (Preparation of Key Intermediates)

For the synthesis method of key intermediate 4, refer to patent WO2012077655A1.

Preparation Example 5 (Preparation of Key Intermediates)

first step:

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) was added sodium hydrosulfite (Na ₂ S ₂ O ₄ ) (15.61 g, 89.65 mmol, 1.20 equiv), sodium bicarbonate (NaHCO ₃ ) (7.53 g, 89.65 mmol, 1.20 equiv) and nBu ₄ N.HSO ₄ (3.00 g, 8.84 mmol, 0.12 equiv). Heptafluoro-2-iodopropane (26.53 g, 89.65 mmol, 1.20 equiv) was added to the above system. The reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by spot plate (TLC). The organic phase was washed with 0.75N HCl (65 ml), then with saturated aqueous sodium bicarbonate solution, 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).

Step 2:

To a solution of compound 5-b (11.70 g, 44.80 mmol, 1.00 equiv) in acetonitrile (200 mL) was added iodine (I ₂ ) (11.37 g, 44.80 mmol, 1.00 equiv), cuprous iodide (CuI) (9.39 g, 49.28 g 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. Dot plate (TLC) monitoring the completion of the reaction, remove the solvent under reduced pressure, add water to the residue, extract with ethyl acetate, filter off insoluble matter, wash the organic phase with 10% Na ₂ S ₂ O ₃ and water in turn, dry over anhydrous sodium sulfate, and vacuum The solvent was removed, and the residue was separated by column chromatography (EA/PE, 0%-10%) to give compound 5-c (11.10 g, 29.84 mmol, 66.60% yield) as a yellow oil. ¹ H NMR (400MHz, 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=7.4Hz).

third step:

To a solution of compound 5-c (10.00g, 26.88mmol, 1.00equiv) in 1,4-dioxane (200ml) was added pinacol biboronate (6.83g, 26.88mmol, 1.00equiv), KOAc (7.91g) , 80.64 mmol, 3.00 equiv) and Pd(dppf)Cl ₂ (0.98 g, 1.34 mmol, 0.05 equiv). The reaction mixture was stirred at 90°C for 16 hours under nitrogen protection. TLC monitored the completion of the reaction, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (EA/PE, 0%-20%) to obtain compound 5 (3.50 g, 9.41 mmol, 34.99% yield) as a brown solid. ¹ H NMR (400MHz, 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).

Preparation Example 6 (Preparation of Key Intermediates)

To a solution of compound 6-a (2.50g, 6.72mmol, 1.00equiv) in 1,4-dioxane/water (4:1,50ml) was added 4-formylphenylboronic acid (1.21g, 8.06mmol, 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 completion of the reaction was monitored by TLC, the solvent was removed under reduced pressure, and the residue was separated by column chromatography (EA/PE, 0%-20%) to obtain compound 6 (1.45 g, 4.14 mmol, 61.61% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 8.05 (t, J=8.3Hz, 4H), 8.00 (d, J=8.1Hz, 2H), 7.82 (d, J= 8.2 Hz, 2H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-75.21 (t, J=7.7 Hz), -181.90 (p, J=7.2 Hz).

Preparation Example 7 (Preparation of Key Intermediates)

first step:

To a solution of compound 4-a (8.0 g, 46.5 mmol, 1.00 equiv) in 100 mL of tetrahydrofuran was added NaHMDS (2M, 25.58 mL, 51.16 mmol, 1.1 equiv) at -60 °C. The reaction mixture was stirred at -15°C for 1 hour. Then BF ₃ .Et ₂ O (14.52 mL, 102.31 mmol, 2.20 equiv) and 1-tert-butoxycarbyl-3-pyrrolidone (7-a) (10.34 g, 55.81 mmol, 1.2 equiv) were added at -60°C of THF (50 mL). The reaction mixture was stirred at -60°C for 3 h, then at room temperature for 3 h, and the reaction was completed as monitored by LCMS. 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.

Step 2:

To a solution of compound 7-b (6.3 g, 17.63 mmol, 1 equiv) in toluene (100 mL) was added CuI (355.86 mg, 1.76 mmol, 0.10 eqiv), Cs ₂ CO ₃ (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 completion of the reaction. Saturated aqueous sodium bicarbonate was added to quench the reaction and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined, and the solvent was removed under reduced pressure to obtain compound 7-c, which was used in the next step without separation. LCMS: (ESI, m/z): [M+1] ⁺ = 277.34.

third step:

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 completed by LCMS, and the pressure was reduced. The solvent was removed, the residue was diluted with water, basified with NaOH (2M in _H2O ) to pH=8, and then subjected to reverse phase column chromatography (C18 silica gel; ACN in water) ( ₃ % NH3.H ₂ O), 5% to 30%) was isolated to give compound 7 (1.01 g, 5.73 mmol, 31% yield) as a yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ =176.22; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.07 (d, J=4.5Hz, 2H), 7.28 (dd, J=4.5, 1.2Hz, 1H), 3.11-2.85 (m, 3H), 2.81 ( d, J=12.1 Hz, 1H), 2.10 (dddd, J=13.3, 7.5, 4.4, 1.2 Hz, 1H), 1.88 (dt, J=13.4, 8.2 Hz, 1H).

Compound 7 was passed through a chiral column (model: CHIRALPAK IH-3, column diameter: 4.600, analytical method: mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1 ml/min; Elution conditions: use 60% mobile phase A and 40% mobile phase B to elute for 14 minutes; flow rate: 1.0ml/min; temperature: room temperature, "%" is volume percentage) to resolve peak A (Peak A, RT= 1.486min, wavelength 220, ee>95%) and peak B (Peak B, RT=2.705min, wavelength 220, ee>95%).

Preparation Example 8 (Preparation of Key Intermediates)

first step:

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

Step 2:

To compound 8-b (7.8 g, 19.23 mmol, 1 equiv) in 1,4-dioxane (100 mL) was added CuI (366.15 mg, 1.92 mmol, 0.10 eqiv), Cs ₂ CO ₃ (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 showed that the reaction was complete, the reaction was quenched with saturated aqueous NaHCO ₃ , extracted with ethyl acetate (3×30 mL), and the combined organic phases were removed under reduced pressure. The residue was separated by column chromatography (methanol/dichloromethane, 0%-10%) to obtain compound 8-c (2.1 g, 6.47 mmol, 33% yield) as a yellow solid. LCMS (ESI, m/z): [M+1] ⁺ =325.81.

third step:

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

the fourth step:

Compound 8-d (490 mg, 1.61 mmol, 1 equiv) and HCl (4M solution in 1,4-dioxane, 6.16 mL, 24.65 mmol, 15 equiv) were stirred at room temperature for 1.5 hours. LCMS showed the reaction was complete and the solvent was removed under reduced pressure. The residue was diluted with water and basified with NaOH (2M in _H2O ) to pH=8 and then subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water ( ₃ % NH3.H2O), ₅ % to 25 %) was isolated to give compound 8 (186 mg, 0.9 mmol, 56.56% yield) as a white solid. LCMS (ESI, m/z): [M+1] ⁺ = 205.28. ¹ H NMR (300MHz, DMSO-d ₆ )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).

Preparation Example 9 (Preparation of Key Intermediates)

first step:

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 DMF (18.18 mg, 0.248 mmol, 0.05 equiv) in dichloromethane (10 mL) at room temperature ) solution and vigorously stirred at room temperature for 1 hour, the solvent was removed in vacuo, the residue was dissolved in acetonitrile (10 mL), compound 9-a (30.3 mg, 14.92 mmol, 3 equiv), Ph ₃ P (808 mg, 12.44 mmol) were added. , 2.5equiv). After the reaction mixture was stirred at room temperature for 5 hours, cooled to room temperature, water (20 mL) and pyridine were added and vigorously stirred at 80°C for 1.5 hours, then cooled to room temperature. Water (50 mL) was added to the reaction system and extracted with methyl tert-butyl ether (3×50 mL). The organic phases were combined, dried over anhydrous Na ₂ SO ₄ , the solvent was removed in vacuo, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether, 10%-30%) to obtain compound 9-b (500 mg, 1.74 mmol, 35% yield), brown solid. LCMS (ESI, m/z): [M-1] ⁻ = 284.9.

Step 2:

To a solution of compound 9-b (500 mg, 1.74 mmol, 1 equiv) in 1.4-dioxane (8 mL) and water (2 mL) was added 4-formylbenzeneboronic acid (313.4 mg, 20.2 mmol, 1.2 equiv), K 2CO3 ( _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 protection. LCMS showed that the reaction was complete, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (EA/PE, 10%-30%) to give 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=8.1Hz, 2H), 7.71(s, 4H), 6.14(t, J=54.4Hz, 2H). ¹⁹ F NMR (282MHz, chloroform-d)δ-130.11–- 132.87(m).

Preparation Example 10 (Preparation of Key Intermediates)

first step:

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, then at this temperature, additional MOMCl (21.16 g, 262.88 mmol, 1.00 equiv) was added. The reaction was warmed to room temperature and stirred for 16 hours. LCMS showed the reaction was complete, 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 subjected to silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to give 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, 1 H), 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).

Step 2:

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, then at this temperature, acetaldehyde (12.35 g, 280.27 mmol, 2.60 equiv) was further added and stirred for 3 hours maintaining the temperature. LCMS showed that the reaction was complete, the reaction mixture was quenched with saturated aqueous NH ₄ Cl and water (300 ml), extracted with ethyl acetate (3×300 ml), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was filtered through silica gel Column chromatography (methanol/dichloromethane, 0% to 10%) isolated 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 (400MHz, chloroform-d) δ 8.41(s, 1H), 8.29(d, J=4.9Hz, 1H), 7.40(m, 1H), 5.27(d, J=0.5Hz, 2H), 5.17 (q, J=6.5 Hz, 1H), 3.51 (s, 3H), 1.49 (d, J=6.5 Hz, 3H).

third step:

To a solution of compound 10-c (13.00 g, 70.96 mmol, 1.00 equiv) in DCM (100 ml) was added NaHCO ₃ (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 showed the reaction was complete, the reaction was quenched with saturated aqueous _Na2S2O3 and water (300ml ₎ and extracted with ethyl acetate ( ₃ x 300ml). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated by silica gel column chromatography (ethyl acetate/petroleum ether, 50% to 80%) to obtain compound 10-d (8.80 g, 48.57 mmol, 68.45%) yield), red oil. LCMS: (ESI, m/z): [M+1] ⁺ = 182.10. ¹ H NMR (400MHz, 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).

the fourth step:

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 showed the reaction was complete, the reaction mixture was basified with NaOH (2M aq) to pH=9 and removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to obtain compound 10-e (5.95 g, 43.39 mmol, 74.51% yield) as a yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ = 138.20. ¹ H NMR (400MHz, chloroform-d) δ 11.53 (s, 1H), 8.53 (s, 1H), 8.27 (d, J=5.2Hz, 1H), 7.50 (dd, J=5.1, 0.6Hz, 1H ), 2.68(s, 3H).

the fifth step:

At room temperature, to a solution of compound 10-e (5.95g, 43.39mmol, 1.00equiv) in acetonitrile (90ml) was added pyrrolidine (pyrrolidine, 9.26g, 130.16mmol, 3.00equiv), acetic acid (7.82g, 130.16mmol, 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 showed the reaction was complete and the solvent was removed under reduced pressure. The residue was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM _NH4HCO3 ₎ , 40% to 60%) to give 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) δ 8.61 (s, 1H), 8.40 (d, J=5.0 Hz, 1H), 7.62 (d, J=4.9 Hz, 1H), 4.12 (d, J=9.5 Hz, 2H), 3.98 (d, J=9.6 Hz, 2H), 3.12 (s, 2H), 1.45 (s, 9H).

Step 6:

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 NaBH ₄ (781.87 mg, 20.67 mmol, 2.00 equiv). The reaction mixture was stirred at 50°C for 1 h. LCMS showed the reaction was complete. The residue was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM NH ₄ HCO ₃ ), 35% to 55%) to give compound 10-g (2.60 g, 8.89 mmol, 86.07% yield) as a pale yellow solid . LCMS: (ESI, m/z): [M+1] ⁺ = 293.10. ¹ H NMR (400MHz, chloroform-d) δ 8.27(s, 1H), 8.20(d, J=4.9Hz, 1H), 7.29(d, J=4.9Hz, 1H), 4.86(t, J=5.9 Hz, 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).

Step 7:

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 above reaction system. The reaction mixture was stirred at room temperature for 16 hours, diluted with water (50ml) and extracted with dichloromethane (3x20ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was added with DBU (13 ml) and stirred at 100°C for 4 hours. LCMS showed that the reaction was complete. The reaction mixture was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM NH ₄ HCO ₃ ), 40% to 60%) to give compound 10-h (700.00 mg, 2.55 mmol, 57.38% yield), yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 275.10. ¹ H NMR (400MHz, chloroform-d) δ 8.21 (s, 1H), 8.15 (d, J=4.7Hz, 1H), 6.89 (d, J=4.8Hz, 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).

Step 8:

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

Step 9:

To a solution of compound 10-i (695.00 mg, 2.52 mmol) in dichloromethane (10 ml) was added HCl (4M in ethyl acetate, 10 ml). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was basified in methanol (10 ml) with NaOH (2M aq.) to pH=11 and stirred at room temperature for 1 hour. LCMS showed the reaction was complete and the reaction mixture was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (0.1% NH3.H2O), ₂₅ % to 45%) to give compound 10 (290.00 _mg , 1.65 mmol, 65.43% yield). rate), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 177.10. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.09(s,1H),7.99(d,J=4.8Hz,1H),7.09(d,J=4.8Hz,1H),3.56(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).

Preparation Example 11 (Preparation of Key Intermediates)

first step:

-70°C, LDA (2M n-hexane solution, 29.06 ml, 58.12 mmol, 1.20 equiv) was added to a solution of compound 11-a (10.00 g, 48.43 mmol, 1.00 equiv) in tetrahydrofuran (80 ml). The reaction mixture was stirred at -70°C for 30 minutes, then at this temperature, to the above solution was added tert-butyl 4-oxopiperidine-1-carboxylate, 11.58 g, 58.12 mmol, 1.20 equiv) in THF (20 ml). The reaction mixture was stirred for a further 3 hours at -70°C. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and water (100 ml) and extracted with ethyl acetate (3×100 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 obtain 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 (400 MHz, chloroform-d) δ 8.20 (d, J = 4.9 Hz, 1 H), 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).

Step 2:

At room temperature, to a solution of compound 11-b (13.82 g, 34.06 mmol, 1.00 equiv) in 1,4-dioxane (130 ml) was added CuI (648.73 mg, 3.41 mmol, 0.10 equiv), Cs ₂ CO ₃ ( 22.20 g, 68.13 mmol, 2.00 equiv) and 1,2-cyclohexanediamine (1,2-diaminocyclohexane, 388.97 mg, 3.41 mmol, 0.10 equiv). The reaction mixture was stirred at 100°C for 5 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and water (200 ml) and extracted with ethyl acetate (3×200 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 the crude product (7.30 g). The crude product (1.00 g) was isolated 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 (400MHz, chloroform-d) δ 7.92(d, J=4.7Hz, 1H), 7.07(d, J=4.7Hz, 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).

Preparation Example 12 (Preparation of Key Intermediates)

To a solution of compound 2 (10.1 g, 27.29 mmol, 1 equiv) in 1,4-dioxane (80 mL) and water (20 mL) was added 4-bromo-3,5-difluorobenzaldehyde (7.24 g, 32.75 mmol) , 1.2 equiv), K ₂ CO ₃ (11.31 g, 81.87 mmol, 3 equiv) and Pd(PPh ₃ ) ₄ (3.15 g, 2.73 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen protection. LCMS showed 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% FA (trifluoroacetic acid)), 45% to 75%) to give compound 12 (3.7 g, 9.63 mmol, 35.3% yield) as 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= 7.3Hz, 2H), 3.49(s, 1H).

Preparation Example 13 (Preparation of Key Intermediates)

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) was added 5-bromo-2-pyridinecarbaldehyde (5-bromopicolinaldehyde, 576.6 mg, 3.10 mmol, _1.2 equiv), K2CO3 (1.07 g, 7.74 mmol, ₃ equiv) and Pd( _PPh3 ) ₄ (268.3 mg, 0.26 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight under nitrogen protection. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was prepared by high performance liquid phase (column model: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; mobile phase A: water (10MMOL/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 25mL/min; Gradient: 10B to 10B in 2min, 10B to 41B in 2.5min, 41B to 65B in 10.5min, 220nm; retention time: 9.67min) isolated compound 13 (213.2mg, 0.58mmol, 23% yield) as a yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 368.00. ¹ H NMR (400MHz, chloroform-d) δ 10.15(s, 1H), 8.98(d, J=1.6Hz, 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.

Preparation Example 14 (Preparation of Key Intermediates)

To a solution of compound 2 (1.00 g, 2.7 mmol, 1 equiv) in 1,4-dioxane (8 mL) and water (2 mL) was added compound 14-a (660.96 mg, 3.24 mmol, 1.2 equiv), K ₂ CO ₃ (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 protection. LCMS showed that the reaction was completed, the solvent was removed under reduced pressure, and the residue was prepared by high-performance liquid phase (column model: Gemini-NX C18 AXAI Packed, 21.2*150mm 5um; mobile phase A: water (10MMOL/L NH ₄ HCO ₃ ), mobile phase B: acetonitrile; flow rate: 25mL/min; gradient: 10B to 10B in 2min, 10B to 41B in 2.5min, 41B to 65B in 10.5min, 220nm; retention time: 9.67min) separate to obtain compound 14 (202.2mg, 0.55mmol) , 20% yield), yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 368.00. ¹ H NMR (400MHz, chloroform-d) δ 10.27 (d, J=0.8Hz, 1H), 8.88 (m, 1H), 7.92 (d, J=8.2Hz, 2H), 7.82-7.73 (m, 2H) ), 7.77–7.70 (m, 1H), 3.69 (s, 1H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ-75.416, -123.758.

Preparation Example 15 (Preparation of Key Intermediates)

first step:

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. Keeping the temperature unchanged, a solution of compound 15-b (7.86 g, 34.88 mmol, 1.2 equiv) in tetrahydrofuran (20 mL) was added to the above reaction system, and the reaction mixture was stirred at -78 °C for 3 h. LCMS showed that the reaction was complete, the reaction system was quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate (3×300 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol/dichloromethane, 0%-10%) to obtain compound 15-c (3.2 g, 8.05 mmol, 28% yield) as a yellow solid. LCMS (ESI, m/z): [M+1] ⁺ =398.31.

Step 2:

To a solution of compound 15-c (1.0 g, 2.51 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added CuI (47.69 mg, 0.251 mmol, 0.10 eqiv), Cs ₂ CO ₃ (1.64 g, 5.02 mmol) , 2.00 equiv) and 1,2-cyclohexanediamine (1,2-cyclohexanediamine, 28.61 mg, 0.251 mmol, 0.1 equiv). The reaction mixture was stirred at 100°C overnight. LCMS showed the reaction was complete, quenched with saturated aqueous _NaHCO3 and extracted with ethyl acetate (3 x 30 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was separated by silica gel column chromatography (methanol/dichloromethane, 0%-10%) to give crude product 15-d (520 mg) which was used directly in the next step. LCMS (ESI, m/z): [M+1] ⁺ =317.31.

third step:

A mixture of compound 15-d (520 mg crude) and HCl (4M solution in 1,4-dioxane, 6.16 mL, 24.65 mmol) was stirred at room temperature for 1.5 hours. LCMS showed the reaction was complete and the solvent was removed under reduced pressure. The residue was diluted with water, basified with NaOH (2M in water) to pH=8 and separated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (3% NH ₃ .H ₂ O), 5% to 30% to) Compound 15 was obtained (340 mg, 1.57 mmol, 57% overall yield for 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, 3.6Hz, 2H), 1.83–1.72 (m, 2H).

Preparation Example 16 (Preparation of Key Intermediates)

first step:

At room temperature, to a solution of compound 16-a (5.00g, 36.46mmol, 1.00equiv) in acetonitrile (75ml) was added pyrrolidine (pyrrolidine, 7.78g, 109.38mmol, 3.00equiv), AcOH (6.57g, 109.38mmol, 3.00 equiv) and compound 16-b (11.24 g, 65.63 mmol, 1.80 equiv). The reaction mixture was stirred at 65°C for 5 hours. LCMS showed the reaction was complete and the solvent was removed under reduced pressure. The residue was separated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM NH ₄ HCO ₃ ), 40% to 60%) to give compound 16-c (1.60 g, 5.51 mmol, 15.12% yield), pale yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 291.10.

Step 2:

At 0°C, to a solution of compound 16-c (2.80 g, 9.64 mmol, 1.00 equiv) in methanol (30 ml) was added NaBH ₄ (729.74 mg, 19.29 mmol, 2.00 equiv). The reaction mixture was stirred at 50°C for 1.5 hours and LCMS showed 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 give 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) δ 8.49 (s, 1H), 8.33 (d, J=5.7Hz, 1H), 6.83 (d, J=5.7Hz, 1H), 4.96 (t, J=4.7 Hz,1H),4.33(d,J=9.8Hz,1H),4.13(d,J=9.5Hz,1H),4.01(d,J=9.7Hz,2H),2.44(dd,J=14.1,5.0 Hz, 1H), 2.28 (dd, J=14.1, 4.4 Hz, 1H), 1.45 (s, 9H).

third step:

At 0°C, to a solution of compound 16-d (1.50 g, 5.13 mmol, 1.00 equiv) in dichloromethane (30 mL) was added Et ₃ N (1.56 g, 15.39 mmol, 3.00 equiv). The reaction mixture was stirred at 0°C for 30 minutes and then MsCl (881.60 mg, 5.13 mmol, 1.50 equiv) was added and stirred at room temperature for 16 hours. The reaction system was diluted with water (50ml) and extracted with dichloromethane (3×20ml). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue was added DBU (15 ml) and stirred at 100°C for 4 hours. LCMS showed the reaction was complete. The reaction system was separated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM NH ₄ HCO ₃ ), 40% to 60%) to obtain compound 16-e (900.00 mg, 3.28 mmol, 63.94% yield), pale yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 275.15. ¹ H NMR (400MHz, chloroform-d) δ 8.28 (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).

the fourth step:

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 hydrogen atmosphere for 1 hour, LCMS showed the reaction was complete. The reaction mixture was filtered, the filtrate was collected and the solvent was 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.

the fifth step:

A mixture of compound 16-f (500.00 mg, 1.81 mmol) and HCl (4M 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 with NaOH (2M aq.) to pH=11 and stirred at room temperature for 1.5 hours. LCMS showed the reaction was complete and the reaction mixture was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM _NH4HCO3 ₎ , 15% to 35%) to give compound 16 (215.00 mg, 1.22 mmol, 67.43% yield) , white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 177.10. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.21 (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).

Preparation Example 17 (Preparation of Key Intermediates)

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

Preparation Example 18 (Preparation of Key Intermediates)

first step:

To a solution of compound 18-a (20.00 g, 114.94 mmol, 1.00 equiv) in 400 mL DMF at 0 °C was added NaH (60%, 9.19 g, 229.89 mmol, 2.00 equiv). After the reaction mixture was stirred at 0°C for 30 minutes, MOMCl (11.11 g, 137.93 mmol, 1.20 equiv) was added at this temperature, followed by stirring at room temperature for 2 hours. LCMS showed the reaction was complete, quenched with water (1000ml) and extracted with ethyl acetate (3*300ml). The organic phase was washed with saturated brine (2×200ml), 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%-10%) to obtain 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 H NMR (400MHz, DMSO-d ₆ ) 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).

Step 2:

Under nitrogen protection, to a solution of compound 18-b (10.40 g, 47.70 mmol, 1.00 equiv) in toluene (100 mL) was added tributyl(1-ethoxyethenyl) stannane, 25.84 g , 71.54 mmol, 1.50 equiv) and Pd(PPh ₃ ) ₄ (5.51 g, 4.77 mmol, 0.10 equiv). The reaction mixture was stirred at 110°C for 4 hours. LCMS showed 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 obtain compound 18-c (4.70 g, crude product) as a yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ = 210.10.

third step:

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 showed that the reaction was complete, concentrated under reduced pressure, the residue was neutralized to pH=8 and separated by silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to obtain compound 18-d (2.20 g, 16.04 mmol, 33.63 g) % 2 step overall yield), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 138.15. ¹ H NMR (400MHz, DMSO-d ₆ ) 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).

the fourth step:

Compound 18-d (2.20g, 16.04mmol, 1.00equiv) in methanol (40ml) solution was added pyrrolidine (pyrrolidine, 2.28g, 32.08mmol, 2.00equiv) and 4-oxopiperidine-1-carboxylate tert-butyl Ester (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. LCMS showed that the reaction was completed by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM _NH4HCO3 ₎ , 40% to 60%) to give compound 18-e (2.10 g, 6.60 mmol, 41.12% yield), 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) ).

the fifth step:

To a solution of compound 18-e (3.90 g, 12.25 mmol, 1.00 equiv) in methanol (40 ml) at 0 °C was added NaBH4 ( _926.88 mg, 24.50 mmol, 2.00 equiv). The reaction mixture was stirred at 50°C for 1.5 hours. LCMS showed that the reaction was complete, which was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM _NH4HCO3 ₎ , 40% to 60%) to give compound 18-f (3.50 g, 10.92 mmol, 89.18% yield) , white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 321.15. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.21 (d, J=5.6 Hz, 1H), 6.78 (d, J=5.6 Hz, 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).

Step 6:

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 and then MsCl (1.45 g, 12.64 mmol, 1.50 equiv) was added and stirred at room temperature for 16 hours. Add water (100ml) to dilute, extract with dichloromethane (3×50ml), dry the organic phase over anhydrous sodium sulfate, remove the solvent under reduced pressure, add DBU (28ml) to the residue and stir at 100°C for 4 hours. Compound 18-g (1.80 g, 5.95 mmol, 70.64% yield) was isolated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10 mM _NH4HCO3 ₎ , 45% to 65%) after LCMS showed the reaction was complete. , pale yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 303.10. ¹ H NMR (400MHz, chloroform-d) δ 8.25 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 6.72 (d, J=5.5 Hz, 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, 4.9 Hz, 2H), 1.47 (s, 9H).

Step 7:

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 for 1 hour under a hydrogen atmosphere. LCMS showed that the reaction was complete, the reaction mixture was filtered, the filtrate was collected and the solvent was removed under reduced pressure to give compound 18-h (890.00 mg, 2.92 mmol, 98.23% yield) as a white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 305.15.

Step 8:

A mixture of compound 18-h (890.00 mg, 2.92 mmol) and HCl (4M in ethyl acetate, 10.00 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 dissolved in NaOH (2N). Aqueous solution) was basified to pH=11 and stirred at room temperature for 1.5 hours. LCMS showed that the reaction was complete, which was separated by reverse phase column chromatography (C18 silica gel; acetonitrile/water (0.1% NH _{3 .} H ₂ O), 25% to 50%) Compound 18 (509.00 mg, 2.49 mmol, 85.22% yield) was obtained as a white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 205.10. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 8.13 (d, J=5.6Hz, 1H), 6.75 (d, J=5.6Hz, 1H), 2.80 (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).

Example 1

3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (50 mg, 0.263 mmol) and 4'-(1,1,1,3,3,3-hexa Fluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (3) (91 mg, 0.263 mmol) was dissolved in dichloromethane (10 ml), followed by addition of trifluoroacetic acid ( 50 μL). 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 21%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 2H), 7.85 (d, J=8.3 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.0 Hz) ,2H),7.50(d,J＝3.3Hz,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.

Example 2

3H-spiro[furo[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) was dissolved in dichloromethane (10 ml), then 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 52%. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.10(s, 2H), 7.73-7.41(m, 7H), 7.19(d, J=4.3Hz, 1H), 3.83(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.

Example 3

3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (50 mg, 0.263 mmol) and 4'-(perfluoropropan-2-yl)-[1,1 '-Biphenyl]-4-carbaldehyde (6) (92 mg, 0.263 mmol) was dissolved in dichloromethane (10 ml), then 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 18 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (methanol:dichloromethane=0-10%) to obtain 14 mg of the target compound as a yellow solid with a yield of 10%. 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.

Example 4

first step:

Under the protection of Ar gas, 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 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, followed by heating to -40°C and stirring for 1 hour. The temperature was lowered to -78°C again, 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, and the mixture was reacted at -60°C for 2 hours. After completion of the reaction monitored by TLC, the reaction system was quenched with saturated aqueous _NH4Cl (10 mL). Water (30 mL) and ethyl acetate (30 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 (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 4-((2,4-dichloropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-Butyl ester (I-4-b) (740 mg), pale yellow oil. LC-MS: m/z: (M-55) ⁺ = 305.0.

Step 2:

Under the protection of Ar gas, 4-((2,4-dichloropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I-4-b) (388 mg, 1.07 mmol) in dry DMF (10 mL), cooled to 0°C in an ice bath, added NaH (60%, 107 mg, 2.68 mmol), slowly warmed to room temperature and stirred for 16 hours. After completion of the reaction monitored by TLC, the reaction was cooled to 0 °C and quenched with saturated aqueous _NH4Cl (10 mL). 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 column chromatography (ethyl acetate:petroleum ether=1:2) to obtain 4-chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1 '-tert-butyl carboxylate (I-4-c) and tert-butyl 4-chloro-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate ( I-4-d) mixture (272 mg), pale yellow oil. LC-MS: m/z: (M+H) ⁺ =324.8.

third step:

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

the fourth step:

The previous step 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) mixture crude product (44mg), 4'-(1,1,1,3,3,3-hexafluoro-2- Hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (52 mg, 0.15 mmol) was dissolved in DMF (8 mL), followed by triethylamine (46 mg, 0.45 mmol), acetic acid (14 mg, 0.225 mmol) and 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 the reaction was complete, saturated aqueous _NH4Cl (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 column chromatography (dichloromethane:methanol=20:1) to obtain 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- Alcohol (I-4) (25 mg), white solid. LC-MS: m/z: (M+H) ⁺ = 557.0. 1H NMR (400MHz, CDCl3) δ 8.07 (d, J=5.5Hz, 1H), 7.80 (d, J=8.2Hz, 2H), 7.67(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,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).

Example 5

first step:

4-Chloro-3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (I-4-c) and 4-chloro-3H-spiro A mixture of [furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (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 _H2 atmosphere and stirred at room temperature for 16 hours. After the completion of the reaction monitored by TLC, Pd/C was removed by filtration, and the filtrate was evaporated to dryness. 3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (I-5-a) and 3H-spiro[furo[2,3 -b] A crude mixture of tert-butyl pyridine-2,4'-piperidine]-1'-carboxylate (I-5-b) (130 mg), yellow oil. LC-MS: m/z: (M+H) ⁺ = 290.8.

Step 2:

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

third step:

Combine the previous step 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) mixture (146 mg), 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)- [1,1'-biphenyl]-4-carbaldehyde (134 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (8 mL), followed by the addition of triethylamine (117 mg, 1.16 mmol), acetic acid ( 35 mg, 0.58 mmol), 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 the reaction was complete, saturated aqueous _NH4Cl (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 column chromatography (dichloromethane:methanol=20:1) to obtain 2-(4'-((3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine) ]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-hexafluoropropyl-2-ol (1-5) (53 mg), 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).

Embodiment 6, 11

3H-spiro[furo[3,2-c]pyridine-2,4'-piperidine](I-5-c) and 3H-spiro[furo[2,3-b]pyridine-2,4 A mixture of '-piperidine](I-5-d) (80 mg), 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1 ,1'-biphenyl]-4-carbaldehyde (74mg, 0.20mmol) was dissolved in N,N-dimethylformamide (8mL), followed by adding triethylamine (61mg, 0.60mmol), acetic acid (18mg, 0.30 mmol) and 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 the reaction was complete, saturated aqueous _NH4Cl (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 phase to obtain 2-(4'-((3H-spiro[furo[3,2-c]pyridin-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]pyridin-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 (400MHz, MeOD) δ 8.23 (s, 1H), 8.18 (d, J=5.6Hz, 1H), 7.65–7.53 (m, 5H), 7.49 ( d, J=8.3Hz, 2H), 6.81(d, J=5.6Hz, 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 minutes. Compound 1-6: white solid. LC-MS: m/z: (M+H) ⁺ =541.0. 1H NMR (400MHz, CDCl3) δ 7.94 (d, J=4.5Hz, 1H), 7.63 (dd, J=16.2, 10.3Hz, 2H ), 7.44(m, 7H), 6.79(dd, J=7.1, 5.3Hz, 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 minutes.

Example 7

first step:

2-Bromo-5-aldolpyridine (I-7-a) (100 mg, 0.538 mmol), 1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)propyl-2-ol (398 mg, 1.075 mmol) was placed in N,N-dimethylformamide ( 20mL). Pd( _PPh3 ) _2Cl2 (74 _mg , 0.105 mmol), _K3PO4 (456 mg, 2.15 mmol) _were added. Ar gas protected the system, and the reaction was raised to 90°C for 16 hours. After the reaction was completed, 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, and 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 obtain 6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2- yl)phenyl)nicotinaldehyde (I-7-b) (140 mg), white solid. LC-MS: m/z: (M+H) ⁺ =350.0.

Step 2:

The previous step 6-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)phenyl)nicotinaldehyde (I-7-b) (140 mg, 0.40 mmol), 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (76 mg, 0.40 mmol) was dissolved in N,N-dimethylformamide (8 mL) , followed by adding triethylamine (122 mg, 1.20 mmol), acetic acid (36 mg, 0.60 mmol), and stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (254 mg, 1.20 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated aqueous _NH4Cl (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 column chromatography (dichloromethane:methanol=20:1) to obtain 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) , 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).

Example 9

first step:

3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (500 mg, 2.63 mmol), 4-bromo-3-fluorobenzaldehyde (1-9-a) ( 587 mg, 2.89 mmol) was 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 subjected to 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](1-9-b) (520 mg, 52.45% yield). LC-MS: 376.7 [M+1] ⁺ .

Step 2:

1'-(4-Bromo-3-fluorobenzyl)-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](1-9-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) was added to the reaction solution yl-1,3,2-dioxaboran-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), the reaction solution was heated to 100°C under nitrogen protection and stirred for 16 hours. The reaction solution was concentrated and then subjected to 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-hexa Fluoropropan-2-ol (I-9) (121 mg, 42.22%). LC-MS: 541.0 [M+1] ⁺ . 1H NMR (400 MHz, CDCl3) δ 8.14–8.05 (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=4.6 Hz, 0H), 2.82 (d, J=39.8 Hz, 2H), 2.02 (d, J=5.1 Hz, 2H), 0.89 (ddd, J=11.7, 8.1, 4.3 Hz, 1H).

Example 10

3H-spiro[furo[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) was added to 20 ml of dichloromethane, then Sodium borohydride acetate (130 mg, 0.62 mmol) was added and stirred overnight at room temperature. After the reaction solution was concentrated, 10 ml of saturated sodium carbonate solution was added, extracted twice with dichloromethane (2×25 ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated. Passed through column {7M ammonia methanol:(dichloromethane:ethyl acetate=12:2)=0-15%} to obtain 75 mg of white solid (I-10), yield 48%. LC-MS: m/z: (M+H) ⁺ = 526. 1H NMR (400MHz, CDCl3) δ 8.11–7.94 (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).

Compound (7 Peak A/B) (67 mg, 0.380 mmol) and 2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- [1,1'-Biphenyl]-4-carbaldehyde (1) (139 mg, 0.380 mmol) was dissolved in dichloromethane (10 ml), then 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 13%. ¹ H 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.

Compound (7 Peak B/A) (56 mg, 0.318 mmol) and 2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)- The [1,1'-biphenyl]-4-carbaldehyde compound (1) (116 mg, 0.318 mmol) was dissolved in dichloromethane (10 ml), and then 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 13%. ¹ H NMR (400MHz, DMSO) δ 9.04 (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.

Example 14

3H-spiro[furo[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) was dissolved in dichloromethane (10 ml), followed by addition of trifluoroacetic acid ( 50 μL). 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 15%. ¹ H NMR(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.

Example 15:

first step:

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

Step 2:

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-dioxaborane) -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(diphenylphosphine) ) ferrocene]dichloropalladium dichloromethane complex (6mg, 0.0074mmol) was added to 5ml of 1,4-dioxane, stirred at 100°C overnight under nitrogen protection. The reaction solution was filtered and concentrated with a thin Chromatography plate for separation {methanol: (dichloromethane: ethyl acetate = 10: 2) = 1: 10}. The obtained target product was dissolved in dichloromethane, 0.1 ml of 4M hydrochloric acid dioxane was added, and the solvent was evaporated After that, 3 mg of white solid (I-15) was obtained, with a yield of 10%. LC-MS: m/z: (M+H) ⁺ =525. 1H NMR (400 MHz, MeOD) δ 9.15 (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).

Example 16

3H-spiro[furo[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) was dissolved in dichloromethane (10 ml) , then 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 22%. ¹ H 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.

Example 17

first step:

1,4-Dibromobenzene (I-17-a) (5.72 g, 24.2 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), the reaction solution was cooled to -78°C, and n-butyllithium was added dropwise to the reaction solution After the dropwise addition, the reaction solution was stirred at -78°C for 0.5 hours, and ethyl 2,2-difluoroacetate (6.62 g, 53.3 mmol) was added to the reaction solution, After the addition, the reaction solution was stirred at -78 °C for 1 hour, and the dot plate showed that the reaction raw materials disappeared. A saturated aqueous ammonium chloride solution was added to the reaction solution to quench the reaction, and the reaction solution was warmed to room temperature. The organic phase was extracted with ethyl acetate. Washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 0-10%) to obtain the target compound 1-(4-bromophenyl)-2,2-di Fluoroethane-1-one (I-17-b) (4.0 g, 70%).

Step 2:

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 (4.8g, 34mmol) was added to the reaction solution, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (34mL, 1N) was slowly added dropwise, and the temperature was controlled to be lower than 5 ℃, after the dropwise addition, the reaction solution was stirred at room temperature for 16 hours, and the dot plate showed that the reaction raw materials disappeared, an aqueous solution was added to the reaction solution to quench the reaction, extracted with ethyl acetate, the organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered. , concentrated and subjected to silica gel column chromatography (petroleum ether/ethyl acetate=0～10%) to obtain the target compound 2-(4-bromophenyl)-1,1,1,3,3-pentafluoropropan-2-ol (I-17-c) (4.2 g, 81%).

third step:

2-(4-Bromophenyl)-1,1,1,3,3-pentafluoropropan-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-dioxaboran-2-yl)benzaldehyde (I-23) was added to the reaction solution -c) (295 mg, 1.97 mmol), potassium carbonate (690 mg, 4.92 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (240 mg, 0.33 mmol), reacted The solution was heated to 100°C and stirred for 16 hours. The reaction solution was concentrated and subjected to 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] ⁺ .

the fourth step:

4'-(1,1,1,3,3-Pentafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (I-17-d) (70 mg , 0.21 mmol) was dissolved in dichloromethane (10 mL), and 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (48 mg, 0.25 mmol) and triacetoxyl were added to the reaction solution. sodium borohydride (90 mg, 0.42 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to 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 (400 MHz, CDCl3) δ 8.07 (d, J=6.1 Hz, 2H), 7.80 (d, J=8.2 Hz, 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) ).

Example 18

first step:

2-Bromothiazole-5-carbaldehyde (I-28-a) (100 mg, 0.52 mmol) was dissolved in N,N-dimethylformamide (10 mL), and 1,1,1 was added to the reaction solution under nitrogen protection ,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenyl)propan-2 -Alcohol (2) (386.mg, 1.04mmol), potassium phosphate (442mg, 2.08mmol) and bistriphenylphosphonium palladium dichloride (73mg, 0.1mmol) The reaction solution was heated to 100°C and stirred for 16 hours, The reaction solution was concentrated and subjected to 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-hydroxypropane- 2-yl)phenyl)thiazole-5-carbaldehyde (I-18-b) (76 mg, 41.08%).

Step 2:

2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)thiazole-5-carbaldehyde (1-18-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 triacetyl were added to the reaction solution. Sodium oxyborohydride (91 mg, 0.43 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to 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) δ 8.92(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 = 20.6 Hz, 4H), 1.91–1.74 (m, 4H).

Example 20

first step:

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

Step 2:

3H-spiro[furo[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) was added to 20 ml of dichloromethane, then sodium borohydride acetate (0.23 g, 1.09 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, 10 ml of water and 10 ml of saturated aqueous sodium bicarbonate were added, extracted twice with dichloromethane (2×20 ml), the organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was passed through a column {methanol:(dichloromethane: Ethyl acetate = 12:2) = 0-15%) to obtain 110 mg of white solid (I-20-c) in 58% yield. LC-MS: m/z: (M+H) ⁺ =361.

third step:

1'-((5-Bromopyrimidin-2-yl)methyl)-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](1-20-c) (110 mg ,0.3mmol),1,1,1,3,3,3-hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- 2-yl)phenyl)propan-2-ol (130mg, 0.35mmol) (2), potassium carbonate (100mg, 0.72mmol), water (1ml) and [1,1'-bis(diphenylphosphine)di Ferrocene]palladium dichloride dichloromethane complex (25 mg, 0.03 mmol) was added to 8 ml of 1,4-dioxane, and stirred at 100°C overnight under nitrogen protection. The reaction solution was filtered and concentrated, and then separated by thin layer chromatography {7M ammonia methanol:(dichloromethane:ethyl acetate=12:2)=1:14}. 60 mg of white solid (I-20) was obtained in a yield of 37%. LC-MS: m/z: (M+H) ⁺ =525. 1H NMR (400MHz, CDCl3) δ 8.95(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).

Example 21

first step:

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-dioxaboran-2-yl)phenyl]propan-2-ol (2) (0.6 g, 2 mmol) and potassium carbonate (2M, 1.5 mL) ) was dissolved in 1,4-dioxane, then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.1 g, 0.1 mmol) was added and replaced with argon The air in the bottle was reacted at 90°C for 16 hours under the protection of argon. Thin layer chromatography on silica gel plate (TLC) (petroleum ether:ethyl acetate = 10:1) showed that the reaction was complete. LCMS showed product formation. The reaction solution was cooled in air and concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate 0-20%) to obtain a white solid product, 2,3-difluoro-4-[4-[2,2, 2-Trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]benzaldehyde (1-21-b) (0.4 g, 1 mmol). LC-MS: m/z (M+H) ⁺ =385.0.

Step 2:

2,3-Difluoro-4-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]benzaldehyde (I-21-b)( 100mg, 0.2603mmol), spiro[3H-furan[2,3-c]pyridine-2,4'-piperidine](4) (60mg, 0.31539mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), N,N-diethylethylamine (10 mg, 0.098824 mmol) and acetic acid (20 mg, 0.3331 mmol) were added, and after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (165 mg, 0.77852 mmol) was added. , and continue stirring for 16 hours. Thin layer chromatography on silica gel plates (petroleum ether:ethyl acetate = 3:1 and 0:1) showed the formation of new spots. LCMS showed product. The reaction solution was diluted with ethyl acetate (30 mL) and washed with water three times (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 obtain 2-[4-[2,3-difluoro-4-( Spiro[3H-furo[2,3-c]pyridine]-2,4'-piperidine]-1'-methyl)phenyl]phenyl]-1,1,1,3,3,3-hexa Fluoropropan-2-ol (I-21) (27 mg, 0.04834 mmol). ¹ H-NMR (CDCl ₃ ): δ 8.07 (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 = 13.2 Hz, 2H), 1.91–1.86 (m, 2H). LC-MS: m/z (M+H) ⁺ =559.2.

Example 22

3H-spiro[furo[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)pyridinecarbaldehyde (13) (50 mg, 0.136 mmol) was 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, followed by stirring at room temperature for 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 11%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.69 (s, 1H), 8.17-8.06 (m, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.2 Hz, 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=13.4 Hz, 4H). LC-MS: m/z: (M+H) ⁺ = 542.1.

Example 23

first step:

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 In tetrahydrofuran (10 mL), the reaction solution was cooled to 0°C, a solution of tetrabutylammonium fluoride in tetrahydrofuran (7.1 mL, 1N) was slowly added to the reaction solution, the temperature was raised to room temperature after the addition, and the reaction solution was stirred for 16 hours. The dot plate showed that the reaction was complete, the reaction solution was concentrated and subjected to 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-hexafluoropropan-2-ol (I-23-b) (820 mg, 59%).

Step 2:

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

third step:

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2'-(trifluoromethyl)-[1,1'-biphenyl]- 4-Carboxaldehyde (I-23-d) (120 mg, 0.29 mmol) was dissolved in dichloromethane (20 mL), and 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine was added to the reaction solution pyridine](4) (58 mg, 0.30 mmol) and sodium triacetoxyborohydride (122 mg, 0.58 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to 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 - Hexafluoropropan-2-ol (I-23) (45 mg, 26.43%). LC-MS: 591.2 [M+1] ⁺ . 1H NMR (400 MHz, CDCl3) δ 8.24 (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).

Example 24

2'-Fluoro-4'-((1,1,1,3,3,3-hexafluoro-2-hydroxypropan-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'-furan[2, 3-c]pyridine](15) (100mg, 0.46mmol) and sodium triacetoxyborohydride (196mg, 0.92mmol), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to 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'-furan[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 (400 MHz, CDCl3) δ 8.16–8.01 (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).

Example 25

first step:

5-Bromo-4-methylpyrimidine (I-25-a) (476mg, 2.75mmol) was placed in a there-necked flask, Ar gas protection, anhydrous THF (20mL) was added to the there-necked flask, cooled to -78 °C. Lithium diisopropylamide (LDA) (2.0 M/L, 1.65 mL) was slowly added dropwise, and the mixture was 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, and the reaction was incubated for 3 hours after the addition was completed. After completion of the reaction monitored by TLC, the reaction system was quenched with saturated aqueous _NH4Cl (8 mL). 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 (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-((5-bromopyrimidin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-25-b) (491 mg), pale yellow oil. LC-MS: m/z: (M-55) ⁺ = 316.0, 318.0.

Step 2:

4-((5-Bromopyrimidin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I-25-b) (206 mg, 0.554 mmol) was dissolved in toluene (15 mL) , and cuprous iodide (48 mg, 0.252 mmol), 8-hydroxyquinoline (72 mg, 0.50 mmol), and cesium carbonate (391 mg, 1.2 mmol) were added successively. The system was protected with argon, and the temperature was raised to 110°C for 16 hours. After completion of the reaction monitored by TLC, the reaction system was quenched with saturated aqueous _NH4Cl (8 mL). Water (20 mL) was 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 column chromatography (ethyl acetate:petroleum ether=1:1) to obtain tertiary 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylic acid Butyl ester (I-25-c) (105 mg), pale yellow oil. LC-MS: m/z: (M+H) ⁺ = 292.1.

third step:

7H-Spiro[furo[3,2-d]pyrimidine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester (I-25-c) (105 mg, 0.36 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (2 mL) was slowly added, and the mixture was stirred at room temperature for 5 hours. After the completion of the reaction monitored by LC-MS, the system was evaporated to dryness to obtain 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine] crude product (I-25-d) (125mg), yellow Oil. LC-MS: m/z: (M+H) ⁺ =192.0.

the fourth step:

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1)( 131mg, 0.36mmol), 7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine](1-25-d) crude (125mg) was dissolved in N,N-dimethylmethane To the amide (8 mL), triethylamine (101 mg, 1.0 mmol) and acetic acid (29 mg, 0.48 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated aqueous _NH4Cl (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 column chromatography (dichloromethane:methanol=20:1) to obtain 2-(4'-((7H-spiro[furo[3,2-d]pyrimidine-6,4'-piperidine) ]-1'-yl)methyl)-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropyl-2- Alcohol (I-25) (43 mg), 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).

Example 27

3-Fluoro-5-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)pyridinecarbaldehyde (14) (100 mg, 0.27 mmol) was dissolved in In dichloromethane (15 mL), 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (54 mg, 0.29 mmol) and triacetoxyboron were added to the reaction solution Sodium hydride (115 mg, 0.54 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to silica gel column chromatography (dichloromethane/methanol=0-10%) to obtain the target compound 2-(4-(6-((3H-spiro[furan[2,3-c]pyridine-2,4). '-Piperidin-1'-yl)methyl)-5-fluoropyridin-3-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-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).

Example 28

Compound (7 Peak A) (66 mg, 0.374 mmol) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-bi Benzene]-4-carbaldehyde (3) (130 mg, 0.374 mmol) was dissolved in dichloromethane (10 ml), then 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 18 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (methanol:dichloromethane=0-10%) to obtain the target compound (I-28A) mg, yellow solid, yield 18%. ¹ H 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.

Compound (7 Peak B) (70 mg, 0.397 mmol) and 4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-bi Benzene]-4-carbaldehyde (3) (138 mg, 0.396 mmol) was dissolved in dichloromethane (10 ml), then 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 18 hours. The reaction solution was concentrated, and the obtained 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, yield 18%. 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, 5.5 Hz, 1H). LC-MS: m/z: (M+H) ⁺ =509.1.

Example 29

4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropyl-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (1) (118 mg , 0.32 mmol), 5-methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](8) (66 mg, 0.32 mmol) in N,N-dimethyl Triethylamine (125 mg, 1.24 mmol) and acetic acid (50 mg, 0.83 mmol) were successively added to ethylformamide (10 mL), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (265 mg, 1.25 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, saturated aqueous _NH4Cl (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 column chromatography (dichloromethane:methanol=20:1) to obtain 1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4'-((5-methyl) (yl)-3H-spiro[furo[2,3-c]pyridin-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl) Propyl-2-ol (I-29) (45 mg), 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).

Example 30

first step:

2-Hydroxyisonotinaldehyde (I-30-a) (100 mg, 0.81 mmol) was dissolved in dichloromethane (15 mL), and 1,1,1,3,3,3 was added to the reaction solution under nitrogen protection - Hexafluoro-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-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), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to silica gel column chromatography (petroleum ether/ethyl acetate=100/0～50/50) 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 (1-30-b) (125 mg, 42.14%).

Step 2:

1-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-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[furo[2,3-c]pyridine-2,4'-piperidine]( 4) (98 mg, 0.52 mmol) and sodium triacetoxyborohydride (209 mg, 0.99 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to silica gel column chromatography (dichloromethane/methanol=0-10%) to obtain the target compound 4-((3H-spiro[furan[2,3-c]pyridine-2,4'-piperidine]- 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).

Example 31

5-Chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](17) (40 mg, 0.19 mmol) was dissolved in dichloromethane (15 mL) and added to the reaction solution Add 2'-fluoro-4'-((1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde ( 1) (68mg, 0.19mmol) and sodium triacetoxyborohydride (75mg, 0.36mmol), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated by silica gel column chromatography (dichloromethane/methanol=0～10% ) to obtain the target compound 2-(4'-((5-chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidin]-1'-yl)methyl)-2- Fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-31) (55 mg, 53.74%). LC- MS: 575.1[M+1] ⁺ . 1H NMR (400MHz, CDCl3) δ 7.86(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) .

Example 32

4'-(1,1,3,3-Tetrafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (9) (100 mg, 0.32 mmol) was dissolved in Dichloromethane (15 mL), 3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine](4) (67 mg, 0.35 mmol) and triacetoxyboration were added to the reaction solution Sodium (136 mg, 0.64 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated and subjected to 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)-1,1,3,3-tetrafluoropropan-2-ol (I-32) (58mg , 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).

Example 33

first step:

(4-Formylphenyl)boronic acid (I-23-c) (120 mg, 0.47 mmol) and (S)-1-(4-bromophenyl)-2,2,2-trifluoroethane-1 - Alcohol (I-33-a) (84mg, 0.56mmol) was dissolved in dioxane (5ml) and water (5ml), then tetrakistriphenylphosphine palladium (55mg, 0.047mmol) and potassium carbonate (195mg) were added , 1.41 mmol). Stir at 100°C for 16 hours under nitrogen protection. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (ethyl acetate:petroleum ether=0-10%) to obtain 62 mg of the target compound (I-33-b) as a yellow solid with a yield of 47%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.09 (s, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.78 (d, J=8.2 Hz, 2H), 7.71 (d, J=8.3 Hz) , 2H), 7.63 (d, J=8.2 Hz, 2H), 5.14 (q, J=6.6 Hz, 1H). LC-MS: m/z: (M+H) ⁺ =281.1.

Step 2:

3H-spiro[furo[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) was dissolved in dichloromethane (10 ml), followed by the addition of trifluoroacetic acid ( 50 μL). After stirring at room temperature for 18 hours, sodium triacetylborohydride (191 mg, 0.9 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (methanol: dichloromethane). =0-10%) to obtain 13 mg of the target compound (I-33), yellow solid, yield 10%. ¹ H NMR (400 MHz, DMSO) δ 8.18-7.99 (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),6.86(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.

Example 34

first step:

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

Step 2:

3H-spiro[furo[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 (1-34-b) (81 mg, 0.428 mmol) was dissolved in dichloromethane (10 ml), followed by the addition of trifluoroacetic acid ( 50 μL). After stirring at room temperature for 18 hours, sodium triacetylborohydride (272 mg, 1.28 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (methanol: dichloromethane). Methane=0-10%) to obtain the target compound (I-34) 20 mg, yellow solid, yield 10%. ¹ H NMR (400 MHz, DMSO) δ 8.09 (d, J=9.4 Hz, 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.

Example 35

2'H,4'H-spiro[piperidine-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)pyridinecarbaldehyde (1) (89 mg, 0.243 mmol) was dissolved in dichloromethane (10 ml) and then added Trifluoroacetic acid (50 μL). 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 18 hours. The reaction solution was concentrated, and the obtained 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 with a yield of 9%. ¹ H 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.

Example 41

first step:

1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid (I-41-a) (10.00g, 43.62mmol) was dissolved in N,N-dimethylformamide (150ml), followed by adding 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). After stirring at room temperature for 10 minutes, 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 was completed, the system was diluted with ethyl acetate (600ml), the organic phase was washed with brine (2×300ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain 4-(methoxy(methyl)carbamoyl) Piperidine-1-carboxylate tert-butyl ester (I-41-b) (crude 13 g), yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ = 273.15.

Step 2:

4-(Methoxy(methyl)carbamoyl)piperidine-1-carboxylate tert-butyl ester (I-41-b) (6.00g, 22.03mmol) was dissolved in dichloromethane (24ml) at room temperature Trifluoroacetic acid (12 ml) was added and the reaction was stirred at this temperature for 1.5 hours. After the reaction was completed, it was concentrated under reduced pressure, the residue was dissolved in methanol (10 ml), and the pH was adjusted to 11 with ammonia water. After stirring at room temperature for ₁ hour, reverse phase preparation (C18 silica; acetonitrile:water (0.1% NH3.H2O), ₁₅ % to 35%) gave N-methoxy-N-methylpiperidine-4 - Formamide (I-41-c) (1.10 g, 6.39 mmol), pale yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ = 173.20.

third step:

N-Methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.00 g, 5.81 mmol) was dissolved in 1,4-dioxane (20 ml), tert-butyl group was added ((1,1,1,3,3,3-Hexafluoro-2-(4-iodophenyl)propan-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). The protective system was replaced with nitrogen, and then the temperature was raised to 90° C. for 18 hours. After the reaction was completed, the temperature was cooled and concentrated, and column chromatography (ethyl acetate: petroleum ether=1:1) was used to obtain 1-(4-(2-((tert-butyldimethylsilyl)oxy)-1,1 ,1,3,3,3-hexafluoropropan-2-yl)phenyl)-N-methoxy-N-methylpiperidine-4-carboxamide (I-41-d) (1.25g, 2.36 mmol), yellow oil. LCMS: (ESI, m/z): [M+1] ⁺ =529.35.

the fourth step:

Under nitrogen protection, 1-(4-(2-((tert-butyldimethylsilyl)oxy)-1,1,1,3,3,3-hexafluoropropan-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 (1.5M toluene solution, 2.08ml, 3.12mmol) 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 aqueous NH ₄ Cl solution, extracted with ethyl acetate (3×50 ml), the organic phases were combined, dried over Na ₂ SO ₄ , and concentrated. The concentrated residue was dissolved in tetrahydrofuran (10 ml), the system was protected by nitrogen replacement, cooled to 0°C, and tetrabutylammonium fluoride (TBAF, 1.0 M, 4.16 ml, 4.16 mmol) was added. After 30 minutes at 0°C, 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 Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated by column chromatography (dichloromethane:methanol=10:1) to obtain 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), white solid. LCMS: (ESI, m/z): [M+1] ⁺ =356.05. ¹ H NMR (400MHz, chloroform-d) δ 9.71(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, 3.9 Hz, 2H), 1.77 (m, 2H).

the fifth step:

3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (39 mg, 0.20 mmol), 1-(4-(1,1,1,3,3,3-hexafluoro -2-Hydroxypropan-2-yl)phenyl)piperidine-4-carbaldehyde (I-41-e) (72mg, 0.20mmol) was dissolved in dichloromethane (10mL), triethylamine (66mg, 0.65 mmol), acetic acid (30 mg, 0.50 mmol), 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 the reaction was completed, saturated aqueous _NH4Cl (10 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 column chromatography (dichloromethane:methanol=15:1) to obtain 2-(4-(4-((3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine). pyridin]-1'-yl)methyl)piperidin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (I-41) (69 mg), White solid. LCMS: (ESI, m/z): [M+1] ⁺ = 530.3. 1H NMR (400 MHz, DMSO) δ 8.34 (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, 2H), 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).

Example 50

Spirocyclic 3',4'-dihydrospiro[azetidine-3,2'-pyran[2,3-c]pyridine] (Preparation Example 10) (100 mg, 0.57 mmol) was dissolved in dihydro Chloromethane (10 mL), 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[ 1,1'-biphenyl]-4-carbaldehyde (Preparation Example 12) (262 mg, 0.68 mmol) and sodium triacetoxyborohydride (241 mg, 1.13 mmol), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated, evaporated to dryness, and subjected to silica gel column chromatography (dichloromethane/methanol=0/100～10/900) 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-hexafluoropropan-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).

Example 51

first step:

7-Chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (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 showed 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-trifluoroacetic acid Salt (I-51-a) (172 mg, 82.47%).

Step 2:

7-Chloro-3H-spiro[2,3-c]pyridine-2,4'-piperidine]2,2,2-trifluoroacetate (I-51-a) (172 mg, 0.51 mmol) Dissolved in dichloromethane (20 mL), 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl was added to the reaction solution at room temperature )-[1,1'-biphenyl]-4-carbaldehyde (234 mg, 0.61 mmol) and sodium triacetoxyborohydride (215 mg, 1.02 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated, evaporated to dryness, and subjected to silica gel column chromatography (dichloromethane/methanol=0/100～10/900) to obtain the target compound 2-(4'-((7-chloro-3H-spiro[fluoro[fluoro] 2,3-c]pyridin-2,4'-piperidin]-1'-yl)methyl)-2',6'-difluoro-[1,1'-biphenyl]-4-yl)- 1,1,1,1,3,3,3-hexafluoropropan-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=62.4 Hz, 2H).

Example 52

first step:

7-Chloro-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (11) (2.00 g, 6.16 mmol) was dissolved in 1, In 4-dioxane/water (5:1, 20 ml), methylboronic acid (442.30 mg, 7.39 mmol), K ₂ CO ₃ (1.70 g, 12.32 mmol) and Pd(PPh ₃ ) ₄ (711.56 mmol) were added successively mg, 0.62 mmol). After the system was protected by nitrogen replacement, the temperature was raised to 100° C. to react for 16 hours. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol=10:1) to obtain a crude product (1.20 g), which was further prepared by reverse phase (C18 silica gel, acetonitrile:water (10 mM) NH ₄ HCO ₃ ), 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), the product was a white solid. LC-MS: m/z: (M+H) ⁺ =305.10. 1H NMR (400MHz, chloroform-d) δ 8.01 (d, J=4.8Hz, 1H), 6.96 (d, J=4.6Hz, 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).

Step 2:

7-Methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-52-a) (460 mg, 1.51 mmol) Dissolved in dichloromethane (5ml), HCl in ethyl acetate solution (4mol/L, 5ml) was added. The reaction system was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated, and the residue was dissolved in methanol (5 ml) and adjusted to pH=11 with 2N aqueous NaOH. After stirring at room temperature for 1 hour, reverse phase preparation (C18 silica gel, acetonitrile:water (10 mM _NH4HCO3 ₎ , 45% to 65%) gave 7-methyl-3H-spiro[furan[2,3-c] Pyridine-2,4'-piperidine](1-52-b) (235 mg, 1.15 mmol), the product was a white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 205.10. H-NMR: 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J=4.7 Hz, 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).

third step:

7-Methyl-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine] (I-52-b) 62 mg, 0.30 mmol), 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), triethylamine (89 mg, 0.88 mmol) and acetic acid (28 mg, 0.47 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (290 mg, 1.37 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous _NH4Cl (10 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 column chromatography (dichloromethane:methanol=20:1) to obtain 2-(2',6'-difluoro-4'-((7-methyl-3H-spiro[furan[2, 3-c]pyridin-2,4'-piperidin]-1'-yl)methyl)-[1,1'-biphenyl]-4-yl)-1,1,1,3,3,3 - Hexafluoropropan-2-ol (I-52) (36 mg), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 573.8. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=4.8 Hz, 1H), 7.82 (d, J=8.3 Hz, 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).

Example 53

first step:

2,6-Diisopropylaniline (6.32 g, 62.50 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL), the reaction solution was cooled to -70°C, and n-butyllithium ( 25ml, 62.50mmol) the reaction solution was stirred at -70°C for 0.5 hours, 3-bromo-5-fluoropyridine (I-53-a) (10g, 56.82mmol) was added to the reaction solution, and the reaction solution was at -70°C After stirring for 0.5 hours, methyl iodide (9.68 g, 68.19 mmol) was added to the reaction solution, the reaction solution was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was quenched with water (300 mL), extracted with ethyl acetate (200 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and evaporated to dryness, and subjected to silica gel column chromatography (dichloromethane/petroleum ether=35/65～55/45) 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] ⁺ . 1H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (d, J=2.1 Hz, 3H).

Step 2:

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 the solution was added under nitrogen protection. Lithium diisopropylamide (13.40 ml, 26.84 mmol) was added to the reaction solution, and the reaction solution was stirred at -70° C. for 0.5 hours. The tetrahydrofuran solution of 4-oxypiperidine-1-carboxylate tert-butyl ester (5.35 g, 26.84 mmol) was added to the reaction solution, the reaction solution was stirred at -70°C for 3 hours, and water (100 mL) was added to the reaction solution to quench The reaction solution was extracted with ethyl acetate (100 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and concentrated by silica gel column chromatography (ethyl acetate/petroleum ether). =20/80～50/50) to obtain the target compound 4-(3-bromo-5-fluoropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate tert-butyl ester (I-53- c) (6.57 g, 62.88%). LC-MS: 389.05 [M+1] ⁺ . 1H NMR (400MHz, chloroform-d) δ8.56(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).

third step:

4-(3-Bromo-5-fluoropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate tert-butyl ester (I-53-c) (3.00 g, 7.71 mmol) was dissolved in Dioxane (30 mL), under nitrogen protection, cuprous iodide (146.78 mg, 0.77 mmol), cesium carbonate (5.02 g, 15.41 mmol) and 1,2-diaminocyclohexane (88.01 mmol) were added to the reaction solution mg, 0.77 mmol), the reaction solution was heated to 100 °C and stirred for 5 hours. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (80 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and concentrated by silica gel column chromatography (methanol/dichloromethane=0/100 ~10/90) to obtain the target compound 4-fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-53-d ) (2.26 g, 95.10%). LC-MS: 309.10 [M+1]+. 1H NMR (400MHz, 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).

the fourth step:

4-Fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-53-d) (700 mg, 2.27 mmol) Dissolve in dichloromethane (10 mL), add hydrochloric acid in ethyl acetate (10 mL, 4M) to the reaction solution, and stir the reaction solution at room temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, dissolved in methanol (10 mL), added with sodium hydroxide (2M aqueous solution) to adjust pH to 11 and stirred for 1 hour, evaporated to dryness under reduced pressure by reverse phase C18 silica gel column chromatography (acetonitrile/water (0.1% NH4OH)=27/73-47/53)) to obtain the target compound 4-fluoro-3H-spiro[fluoro[2,3-c]pyridine-2,4'-piperidine](I-53-e)( 290mg, 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).

the fifth step:

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), To the reaction solution was added 2,6-difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-bi Benzene]-4-carbaldehyde (266 mg, 0.69 mmol) and sodium triacetoxyborohydride (244 mg, 1.15 mmol), and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated, evaporated to dryness, and subjected to silica gel column chromatography (dichloromethane/methanol=0/100～10/900) 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-hexafluoropropan-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).

Example 54

first step:

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 added under nitrogen protection. Lithium diisopropylamide (14.53 mL, 29.06 mmol) was added to the reaction solution, and the reaction solution was stirred at -70° C. for 0.5 hours. The tetrahydrofuran solution of 4-oxypiperidine-1-carboxylate tert-butyl ester (5.79 g, 29.08 mmol) was added to the reaction solution, the reaction solution was stirred at -70°C for 3 hours, and water (100 mL) was added to the reaction solution to quench After the reaction, the reaction solution was extracted with ethyl acetate (300 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and concentrated by silica gel column chromatography (methanol/dichloromethane= 0/100～10/90) to obtain the target compound 4-(5-bromo-2-chloropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate tert-butyl ester (I-54-b ) (7.8 g, 80%). LC-MS: 405.05 [M+1] ⁺ .

Step 2:

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

third step:

4-(5-Bromo-2-chloropyridin-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate tert-butyl ester (I-54-c) (100 mg, 0.31 mmol) was dissolved in N , N-dimethylformamide (20 mL), under nitrogen protection, tetrakistriphenylphosphine palladium (71.16 mg, 0.06 mmol) and zinc cyanide (72.32 mg, 0.62 mmol) were added to the reaction solution, and the reaction solution was heated Stir to 120°C for 16 hours. TLC showed that the reaction was complete, the reaction solution was evaporated to dryness and concentrated by silica gel column chromatography (methanol/dichloromethane=0/100～10/90) to obtain the target compound 5-cyano-3H-spiro[furan[2,3- c] Pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-54-d) (52 mg, 53.55%).

the fourth step:

5-cyano-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-54-d) (32.00 mg, 0.10 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. The reaction solution was evaporated to dryness under reduced pressure to obtain the crude target compound 3H-spiro[2,3-c]pyridine-2,4'-piperidine]-5-carbonitrile-2,2,2-trifluoroacetate ( I-54-e) (30.00 mg, 89.79%). LC-MS: 216.2 [M+1] ⁺ .

the fifth step:

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-carbaldehyde (42.00 mg, 0.11 mmol) and sodium triacetoxyborohydride (38.62 mg, 0.11 mmol), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, concentrated, evaporated to dryness, and subjected to silica gel column chromatography (dichloromethane/methanol=0/100～10/900) 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).

Example 55

first step:

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

Step 2:

7-Cyano-3H-spiro[furo[2,3-c]pyridine-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (I-55-a) (580.00 mg, 1.84 mmol) Dissolve in dichloromethane (10ml) and slowly add trifluoroacetic acid (10ml) at room temperature. The reaction was stirred at room temperature for 1 hour. It was then concentrated under reduced pressure, and the residue was dissolved in methanol (10 ml), basified to pH=9 with aqueous ammonia, and stirred at room temperature for 1 hour. The obtained crude product was separated and purified by reverse-phase flash column chromatography (C18 silica gel; acetonitrile: water (0.1% NH ₃ .H ₂ O)=25-45%) to obtain compound (I-55-b) (210.00 mg, 0.98 mmol), off-white solid, yield 53.05%. ¹ H NMR (400MHz, chloroform-d) δ 8.18 (d, J=4.5Hz, 1H), 7.31 (dt, J=4.5, 1.3Hz, 1H), 3.16 (m, 2H), 3.09 (d, J = 1.3 Hz, 2H), 2.90 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H). LC-MS: m/z: (M+H) ⁺ =216.10.

third step:

3H-spiro[furo[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) was dissolved in dichloro Methane (10 ml) followed by trifluoroacetic acid (50 [mu]L). 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 18 hours. The reaction solution was concentrated, and the obtained crude product was separated and purified by flash column chromatography (methanol:dichloromethane=0-10%) to obtain 21 mg of the target compound (I-55) as a yellow solid with a yield of 16%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J=4.5 Hz, 1H), 7.83 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.4 Hz, 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.

Example 56

first step:

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

Step 2:

Under nitrogen protection, tert-butyl 4-((6-bromo-2-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (I-56-b) (2.5g, 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 in portions. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the completion of the reaction monitored by LCMS, the reaction system was quenched with saturated aqueous ammonium chloride solution (40 mL), water (40 mL) was added, the system was extracted with ethyl acetate (3×100 mL), the organic phases were combined and concentrated, and the residue was subjected to column chromatography Separation (petroleum ether:ethyl acetate=1:1) to obtain tert-butyl 6-bromo-3H-spiro[furan[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate (I-56-c) (1.3 g, 3.22 mmol), the product was a yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 369.2.

third step:

6-Bromo-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-56-c) (950 mg, 2.57 mmol) was dissolved In a mixed solvent (15 mL) of dimethyl sulfoxide (DMSO)/water/tert-butanol (t-BuOH) (1:1:1), 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 was warmed to 120°C and stirred overnight. After the completion of the reaction monitored by LCMS, the reaction system was lowered to room temperature, concentrated under reduced pressure, and the residue was prepared in reverse phase (C18 silica gel; acetonitrile: water (0.1% trifluoroacetic acid (TFA)) = 40% to 60%) to obtain 6-hydroxy- 3H-Spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-56-d) (410 mg, 1.34 mmol) as a yellow solid. LCMS: (ESI, m/z): [M+23] ⁺ = 329.05.

the fourth step:

6-Hydroxy-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine]-1'-carboxylate tert-butyl ester (I-56-d) (410 mg, 1.34 mmol) was dissolved A solution of HCl in 1,4-dioxane (4M, 5.02 mL, 20.1 mmol) was stirred at room temperature for 1.5 hours. After monitoring the completion of the reaction by LCMS, the reaction mixture was concentrated under reduced pressure, water (5 mL) was added to the residue, pH=8 was adjusted with saturated aqueous sodium bicarbonate (NaHCO3) solution, the reaction system was concentrated under reduced pressure, and the residue was prepared in reverse phase (C18 silica gel; acetonitrile) : water ( ₃ % NH3.H2O, ₅ % to 25%) to give 6-hydroxy-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine](I-56 -e) (192 mg, 0.93 mmol, 70% yield), the product was a yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 207.00. 1H NMR (400 MHz, DMSO-d6) δ 6.90–6.70 (m, 1H), 5.30 (m, 1H), 2.82 (m, 2H), 2.71–2.54 (m, 4H), 1.71–1.47 (m, 4H).

the fifth step:

6-Hydroxy-3H-spiro[furo[2,3-b]pyridine-2,4'-piperidine](I-56-e) (57 mg, 0.28 mmol), 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) was dissolved in N, To N-dimethylformamide (10 mL), triethylamine (84 mg, 0.83 mmol) and acetic acid (25 mg, 0.42 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (177 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added. Water (20 mL) and ethyl acetate (30 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 (30 mL×3), anhydrous sulfuric acid Sodium dry. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 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), pale yellow solid. LCMS: (ESI, m/z): [M+1] ⁺ = 574.8. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.2 Hz, 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).

Example 57

first step:

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

Step 2:

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

third step:

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 under nitrogen protection at -75°C. 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 ether solution were added (1.93 g, 13.60 mmol). 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, concentrated, and passed through column (ethyl acetate: petroleum ether=35-55%) to obtain (I-57-d) 638 mg of pale yellow solid, yield 17%. LC-MS: m/z: (M+H) ⁺ =301.15.

the fourth step:

3-((2,6-Difluoropyridin-3-yl)methyl)-3-hydroxyazetidine-1-carboxylate tert-butyl ester (I-57-d) (638.00 mg, 2.12 mmol ) was added to 20ml of tetrahydrofuran, potassium tert-butoxide (1M in THF, 2.12ml, 2.12mmol) was added under nitrogen protection, stirred at room temperature for 2 hours, the reaction was quenched by adding 100ml of water, extracted with ethyl acetate (3×50ml ). The organic phase was dried over anhydrous sodium sulfate, concentrated, and passed through a column (methanol:dichloromethane=0-10%) to obtain 455 mg of yellow oil (I-57-e) in a yield of 76%. LC-MS: m/z: (M+H) ⁺ = 281.15.

the fifth step:

6'-Fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate tert-butyl ester (I-57-e) (300.00 mg, 1.07 mmol) was added to 6 ml of dichloromethane, then 3 ml of trifluoroacetic acid was added, stirred at room temperature for 1 hour, the reactant was concentrated and added to 6 ml of methanol, and the pH was adjusted to 2 mol/L aqueous sodium hydroxide solution. 10 or so. After stirring at room temperature for 1 hour, the reaction solution was passed through a reverse phase column (C18; acetonitrile: water (0.1% (NH ₃ .H ₂ O ammonia water)) = 15%-35%) to obtain 48 mg of white solid (I-57-f), Yield 25%. LC-MS: m/z: (M+H) ⁺ =181.20. 1H NMR (400MHz, Methanol-d4) δ 7.69 (t, J=7.8Hz, 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).

Step 6:

6'-Fluoro-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine](I-57-f) (20 mg, 0.11 mmol), 2,6 -Difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (40mg, 0.10 mmol) was added to 10 ml of dichloroethane, then sodium borohydride acetate (430 mg, 2.03 mmol) was added, and the mixture was stirred at room temperature overnight. After the reaction solution was concentrated, 10 ml of saturated sodium carbonate solution was added, extracted with dichloromethane three times (2×20 ml), the organic phase was dried over anhydrous sodium sulfate, and then concentrated through a column {methanol:(dichloromethane:ethyl acetate=2: 1)=0-15%} to obtain 30 mg of white solid (I-57) in a yield of 49%. LC-MS: m/z: (M+H) ⁺ =549. 1H NMR (400MHz, MeOD) δ 7.85 (d, J=8.4Hz, 2H), 7.71 (t, J=7.8Hz, 1H), 7.57(d,J=8.7Hz,2H),7.18-7.09(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).

Example 58

first step:

Trimethyl sulfoxide (I-58-a) (66.27 g, 301.13 mmol) was dissolved in dry dimethyl sulfoxide (250 mL), and 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. After dropping, it was slowly warmed to room temperature and stirred for 6 hours. After the completion of the reaction monitored by LCMS, the reaction system was quenched with water (50 mL), extracted with ethyl acetate (3×300 mL), the organic phases were combined and concentrated under reduced pressure, and the residue was purified and separated 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), which is a yellow oil. ¹ H NMR (400MHz, chloroform-d) δ 3.62 (m, 3H), 3.27 (m, 1H), 2.94 (d, J=5.5Hz, 2H), 2.26 (m, 1H), 1.92–1.78 (m , 1H), 1.47(s, 9H).

Step 2:

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

third step:

Under nitrogen protection, 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 in portions. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. After the completion of the reaction monitored by LCMS, the reaction system was quenched with saturated aqueous ammonium chloride solution (40 mL), water (40 mL) was added, the system was extracted with ethyl acetate (3×100 mL), the organic phases were combined and concentrated, and the residue was subjected to column chromatography Separation (petroleum ether:ethyl acetate=1:1) to obtain tert-butyl 6-fluoro-3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate (I-58-d) (1.2 g, 4.08 mmol), the product was a yellow solid. LCMS (ESI, m/z): [M+1-15] ⁺ =280.00.

the fourth step:

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

the fifth step:

6-(Benzyloxy)-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate tert-butyl ester (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 _H2 atmosphere and stirred at this temperature for 16 hours. After the reaction was monitored by LCMS, the insolubles were filtered off, the filter cake was washed with methanol, and the filtrates were combined and concentrated to obtain 6-hydroxy-3H-spiro[furan[2,3-b]pyridine-2,3'-pyrrolidine]-1' - Crude tert-butyl carboxylate (I-58-f) (370 mg), which can be directly used in the next reaction. LCMS (ESI, m/z): [M+1-15] ⁺ =278.00.

Step 6:

Crude 6-hydroxy-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate tert-butyl ester (I-58-f) (370 mg) was dissolved in bismuth In methyl chloride (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 2 hours. After the completion of the reaction monitored by LCMS, the reaction solution was concentrated, and the residue was purified by reverse-phase preparation (C18 silica gel; acetonitrile: water (3% NH ₃ .H ₂ O), 5% to 15%) to obtain a yellow solid 3H-spiro[furan [2,3-b]pyridin-2,3'-pyrrolidin]-6-ol (1-58-g) (186 mg, 0.967 mmol). LCMS: (ESI, m/z): [M+1] ⁺ = 193.1. ¹ H NMR (300 MHz, methanol-d ₄ ) δ 7.40 (m, 1H), 6.10 (d, J=8.0 Hz, 1H), 3.26 (dd, J=6.2, 2.5 Hz, 2H), 3.21 (m, 2H), 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).

Step 7:

3H-spiro[furo[2,3-b]pyridin-2,3'-pyrrolidin]-6-ol (I-58-g) (58 mg, 0.30 mmol), 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) was dissolved in N, To N-dimethylformamide (10 mL), triethylamine (91 mg, 0.90 mmol) and acetic acid (27 mg, 0.45 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (177 mg, 0.84 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added. Water (20 mL) and ethyl acetate (30 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 (30 mL×3), anhydrous sulfuric acid Sodium dry. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 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'-pyrrole Alkyl]-6-ol (I-58) (25 mg), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 560.8. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.5 Hz, 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=13.6Hz,2H), 3.20(q,J＝15.4Hz,2H),3.08(d,J＝10.6Hz,1H),2.96(dd,J＝16.3,7.2Hz,1H),2.84-2.72(m,2H),2.44-2.31 (m, 1H), 2.21–2.08 (m, 1H).

Example 59

first step:

6-Fluoro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine]-1'-carboxylate tert-butyl ester (I-58-d) (400 mg, 1.36 mmol) 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 monitored by LCMS, the reaction solution was concentrated, and the residue was purified by reverse-phase preparation (C18 silica gel; acetonitrile: water (3% NH ₃ .H ₂ O), 5% to 15%) to obtain 6-fluoro-3H as a yellow solid - Spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine](1-59-a) (240 mg, 1.24 mmol). LCMS: (ESI, m/z): [M+1] ⁺ = 195.1. ¹ H NMR (300MHz, methanol-d4)δ7.77(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).

Step 2:

6-Fluoro-3H-spiro[furo[2,3-b]pyridine-2,3'-pyrrolidine](1-59-a) (52 mg, 0.27 mmol), 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) was dissolved in N, To N-dimethylformamide (15 mL), triethylamine (82 mg, 0.81 mmol) and acetic acid (24 mg, 0.40 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (210 mg, 0.99 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added. Water (20 mL) and ethyl acetate (30 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 (30 mL×3), anhydrous sulfuric acid Sodium dry. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 2-(2',6'-difluoro-4'-((6-fluoro-3H-spiro[furan[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), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 562.8. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J=8.2 Hz, 2H), 7.66 (t, J=7.7 Hz, 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).

Example 60

first step:

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

Step 2:

6'-(Benzyloxy)-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate 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 monitored by LCMS, the insolubles were filtered off, the filter cake was washed with methanol, and the filtrates were combined and concentrated to obtain 6'-hydroxy-3'H-spiro[azetidine-3,2'-furan[2,3-b] ]Pyridine]-1-carboxylate tert-butyl ester (I-60-b) crude product (701mg), can be directly used in the next reaction. LCMS (ESI, m/z): [M+1] ⁺ = 279.10.

third step:

The crude 6'-hydroxy-3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-1-carboxylate tert-butyl ester (I-60-b) ( 180 mg) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was monitored by LCMS, the reaction solution was concentrated to obtain crude 3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-6'-ol trifluoroacetate ( I-60-c) (190 mg), can be used directly in the next reaction. LCMS: (ESI, m/z): [M+1] ⁺ = 179.20. 1H NMR (400 MHz, methanol-d4) δ 7.47 (d, J=8.0 Hz, 1H), 6.24 (d, J=8.0 Hz , 1H), 4.40 (q, J=11.9 Hz, 4H), 3.49 (s, 2H).

the fourth step:

3'H-spiro[azetidine-3,2'-furo[2,3-b]pyridine]-6'-ol trifluoroacetate (I-60-c) (50 mg), 2 ,6-Difluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1'-biphenyl]-4-carbaldehyde (92mg , 0.24 mmol) was dissolved in N,N-dimethylformamide (10 mL), triethylamine (73 mg, 0.72 mmol) and acetic acid (27 mg, 0.45 mmol) were added successively, 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 the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added. Water (20 mL) and ethyl acetate (30 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 (30 mL×3), anhydrous sulfuric acid Sodium dry. The organic phase was concentrated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 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]pyridin]-6'-ol (19 mg), white solid. LCMS: (ESI, m/z): [M+1] ⁺ = 547.1. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.1 Hz, 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).

With reference to above-mentioned embodiment, the compound shown in table 1 is prepared, and its structural characterization is as follows:

Table 1 List of compounds

Effect Example 1

1. Inhibitory activity of compounds on RORγt

1. Test method:

The compounds of the present invention use fluorescence resonance energy transfer (FRET) assay to determine the inhibitory activity of the compounds on RORγt.

2. Materials and reagents:

3. Experimental steps:

1) Prepare 4x serial dilutions of compounds in 1x buffer.

2) Add 5ul of the 4x serial dilution compound (prepared in step 1) to a 384 assay plate (784075, Greiner).

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

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

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

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

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

8) Centrifuge the 384 assay plates at 1000 g for 1 minute.

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

10) Read the 665nm and 615nm wavelength plates on an Envision 2104 plate reader.

4. Data analysis:

Relative Ratio (RR): Calculate the relative ratio (response at 665 nm/response at 615 nm - response at blank background) for each well.

Percent Inhibition:

Inhibition rate%=[1-(compound fluorescence detection value-positive compound fluorescence detection average value)/(negative control fluorescence detection average value-positive compound fluorescence detection average value)]x100

Calculate the IC50 and dose-response curve of the compound: By calculating the inhibition rate of the compound and the log value of the compound concentration, use Graphpad 8.0 to obtain the IC50 and dose-response curve of the compound.

Second, the test results data.

Table 2 Determination of RORγ Inhibitory Activity of Example Compounds

化合物编号Compound number	IC ₅₀ _IC50	化合物编号Compound number	IC ₅₀ _IC50	化合物编号Compound number	IC ₅₀ _IC50
I-1I-1	++++++	I-2I-2	++++++	I-3I-3	++++
I-6I-6	++	I-7I-7	++++	I-8I-8	++++++
I-9I-9	++++++	I-10I-10	++++	I-10AI-10A	++++
I-10BI-10B	++++	I-11I-11	++	I-12I-12	++++++
I-13I-13	++++++	I-14I-14	++++	I-15I-15	++++
I-16I-16	++++++	I-17I-17	++++++	I-18I-18	++++
I-19I-19	++++	I-20I-20	++++	I-21I-21	++++++
I-22I-22	++++++	I-23I-23	++++++	I-24I-24	++++
I-25I-25	++++	I-27I-27	++++	I-28AI-28A	++++
I-28BI-28B	++++	I-29I-29	++++	I-30I-30	++
I-31I-31	++	I-32I-32	++++	I-33I-33	++
I-34I-34	++	I-36I-36	++	I-41I-41	++
I-50I-50	++++++	I-51I-51	++	I-52I-52	++
I-53I-53	++++++	I-54I-54	++++	I-56I-56	++
I-57I-57	++	I-58I-58	++	I-59I-59	++
I-60I-60	++

Remarks: "+" means 1uM≤IC ₅₀ ≤10uM, "++" means 100nM≤IC ₅₀ ≤1uM, "+++" means 1nM≤IC ₅₀ ≤100nM,

Conclusion: It can be seen from Table 2 that the compound of the present invention has obvious inhibitory effect on RORγt.

Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims

A spiroheterocyclic compound shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite or a prodrug thereof:

where 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; and 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 simultaneously CH or N;

Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl The heteroatoms in the cycloalkyl 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 1, 2, 3 or 4;

R 1 is independently hydrogen, halogen, -OR 1-1 , -SR 1-2 , -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -S(=O ) 2 R 1-6 , C 1 -C 7 alkyl or "R 1-7 substituted C 1 -C 7 alkyl";

R 2 is independently halogen, -OR 2-1 , -SR 2-2 , -CN, -NR 2-3 R 2-4 , -C(=O)R 2-5 , -S(=O) 2 R 2-6 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 1 -C 7 alkyl, "R 2 -7- substituted C 1 -C 7 alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 3 is independently halogen, -OR 3-1 , -SR 3-2 , -CN, -NR 3-3 R 3-4 , -C(=O)R 3-5 , -S(=O) 2 R 3-6 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, C 1 -C 7 alkyl, "R 3 -7- substituted C 1 -C 7 alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, and the number of heteroatoms is independently 1, 2, 3, or 4; or, the carbon to which any two non-adjacent R 3 are attached The atoms together form a 4-6 membered heterocycloalkyl, and the heteroatoms in the heterocycloalkyl are O and/or N, and the number is 1 or 2;

R 4 is independently halogen, -OR 4-1 , -CN, -NR 4-2 R 4-3 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl base, 5-10-membered heteroaryl, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo; the 3-14-membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl 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;

R 1-1 , R 2-1 , R 3-1 and R 4-1 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -C 14 Cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms in the base 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;

R 1-2 , R 2-2 and R 3-2 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3 -14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl 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;

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, C 1 -C 7 alkanes base, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and the The heteroatoms in the 5-10-membered heteroaryl 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;

Alternatively, R 1-3 and R 1-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 1-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R 1-3-2 substituted 3-14-membered heterocycloalkenyl"; said 3-14-membered heterocycloalkyl, "R 1-3-1 substituted 3-14-membered heterocycle The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R 1-3-2 substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R 1-3-1 and R 1-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 2-3 and R 2-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl, "R 2-3-1 substituted 3-14-membered heterocycloalkyl", a 3-14-membered heterocycloalkyl Heterocycloalkenyl or "R 2-3-2 substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R 2-3-1 substituted 3-14-membered heterocycloalkenyl" The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R 2-3-2 substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R 2-3-1 and R 2-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 3-3 and R 3-4 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 3-3-1 substituted 3-14 membered heterocycloalkyl", a 3-14 membered heterocycloalkyl group Heterocycloalkenyl or "R 3-3-2 -substituted 3-14-membered heterocycloalkenyl"; the 3-14-membered heterocycloalkyl, "R 3-3-1 -substituted 3-14-membered heterocycloalkenyl" The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R 3-3-2 -substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R 3-3-1 and R 3-3-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 4-2 and R 4-3 together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl, "R 4-2-1 substituted 3-14 membered heterocycloalkyl", 3-14 membered heterocycloalkyl Heterocycloalkenyl or "R 4-2-2 substituted 3-14-membered heterocycloalkenyl"; said 3-14-membered heterocycloalkyl, "R 4-2-1 substituted 3-14-membered heterocycloalkenyl" The heteroatoms in "cycloalkyl", 3-14-membered heterocycloalkenyl and "R 4-2-2 -substituted 3-14-membered heterocycloalkenyl" are independently selected from boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

Said R 4-2-1 and R 4-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C6 - C10 aryl or 5-10 membered heteroaryl; heteroatoms in said 3-14 membered heterocycloalkyl and said 5-10 membered heteroaryl are independently One or more selected from boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1, 2, 3 or 4;

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, C 1 -C 7 alkyl, C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heterocycloalkyl and The heteroatoms in the 5-10-membered heteroaryl 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 or 2 , 3 or 4;

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, C 1 -C 7 alkyl, C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms in the aryl 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;

Alternatively, R 1-5-2 and R 1-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R 1 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 1-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R 1-5-2-1 and R 1-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 2-5-2 and R 2-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R 2 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 2-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R 2-5-2-1 and R 2-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 3-5-2 and R 3-5-3 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl, "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"; said 3-14-membered heterocycloalkyl, said "R 3 -5-2-1- substituted 3-14-membered heterocycloalkyl", said 3-14-membered heterocycloalkenyl and said "R 3-5-2-2- substituted 3-14-membered heterocycle The heteroatoms in "alkenyl" 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; Said R 3-5-2-1 and R 3-5-2-2 are independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen, hydroxy, amino, mercapto, cyano, C 1 -C 7 alkoxy, C 3 -C 14 cycloalkyl , 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl The heteroatoms 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;

R 5 is independently C 1 -C 7 alkyl; alternatively, any two non-adjacent R 5 and the carbon atoms to which they are attached together form a 4-10 membered cycloalkyl;

Said R 1-7 , said R 2-7 , said R 3-7 , said R 4-4 , said R 1-3-1 , said R 1-3- 2. Said R 2-3-1 , said R 2-3-2 , said R 3-3-1 , said R 3-3-2 , said 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- The number of 1 and said R 3-5-2-2 is independently 1, 2 , 3, 4, 5, 6 or 7; when said R 1-7 , said R 2-7 , said Said R 3-7 , said R 4-4 , said R 1-3-1 , said R 1-3-2 , said R 2-3-1 , said R 2 -3-2 , said R 3-3-1 , said R 3-3-2 , said R 1-5-2-1 , said R 1-5-2-2 , said R 1-5-2-2 , said The number of said R 2-5-2-1 , said R 2-5-2-2 , said R 3-5-2-1 and said R 3-5-2-2 is When there are more than one, said R 1-7 , said R 2-7 , said R 3-7 , said R 4-4 , said R 1-3-1 , said R 1-3-1 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 said R 3-5-2-2 are independently the same or different.
The spiroheterocyclic compound represented by formula I as claimed in claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a drug thereof The precursor is characterized in that the compound shown in the formula I is any of the following schemes:

plan 1:

In the described compound shown in formula I:

n is 0 or 1;

Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl The heteroatoms in the cycloalkyl group and the 5-10-membered heteroaryl group 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 is independently -NR 1-3 R 1-4 , -C(=O)R 1-5 , -S(=O) 2 R 1-6 , C 1 -C 7 alkyl or "R 1- 7 -substituted C 1 -C 7 alkyl";

R 2 is independently halogen, -OR 2-1 , -CN, -NR 2-3 R 2-4 , -C(=O)R 2-5 , -S(=O) 2 R 2-6 , C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, C 1 -C 7 alkyl, "R 2-7 substituted C 1 -C 7 alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from a group consisting of oxygen, sulfur and nitrogen one or more, the number of heteroatoms is independently 1, 2 or 3;

R 3 is independently halogen, -OR 3-1 , -CN, -NR 3-3 R 3-4 , -C(=O)R 3-5 , -S(=O) 2 R 3-6 , C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl, 5-10-membered heteroaryl, C 1 -C 7 alkyl, "R 3-7 substituted C 1 -C 7 alkyl" or oxo; the heteroatoms in the 3-14-membered heterocycloalkyl and the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen or Multiple, the number of heteroatoms is independently 1, 2 or 3; or, any two non-adjacent R 3 and the carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;

R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 or C 1 -C 7 alkyl;

R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 or C 1 -C 7 alkyl;

R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 or C 1 -C 7 alkyl;

R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -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;

R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -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;

R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -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;

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, C 1 -C 7 alkyl or C 3 -C 14 cycloalkyl;

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, C 1 -C 7 alkyl, C 3 -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 independent 1, 2 or 3 lands;

Scenario 2:

In the described 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;

Ring A and Ring B are independently C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; the 3-14 membered heteroaryl The heteroatoms in the cycloalkyl group and the 5-10-membered heteroaryl group 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 is "C 1 -C 7 alkyl substituted by R 1-7 ";

R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;

R 3 is independently halogen, C 1 -C 7 alkyl, "R 3-7 substituted C 1 -C 7 alkyl", or oxo; alternatively, any two non-adjacent R 3 carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;

R 4 is independently halogen, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo;

R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen or hydroxy;

Scenario 3:

In the described 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, C 6 -C 10 -membered 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, the number of heteroatoms is independently 1, 2 or 3;

R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;

R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;

R 3 is independently halogen, C 1 -C 7 alkyl or oxo, alternatively, any two non-adjacent R 3 together with the carbon atom to which it is attached form a 4-6 membered heterocycloalkyl;

R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 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 atoms to which they are attached form a 4-10 membered cycloalkyl;

Scenario 4:

In the described 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 C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen. one or more, the number of heteroatoms is independently 1, 2 or 3;

R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;

R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl";

R 3 is independently halogen, C 1 -C 7 alkyl or oxo;

R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 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 atoms to which they are attached form a 4-10 membered cycloalkyl;

Scenario 5:

In the described 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 C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatoms in the 5-10-membered heteroaryl are independently selected from one of oxygen, sulfur and nitrogen. one or more, the number of heteroatoms is independently 1, 2 or 3;

R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";

R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl";

R 3 is independently halogen, C 1 -C 7 alkyl or oxo, or any two non-adjacent R 3 and the carbon atom to which they are attached together form a 4-6 membered heterocycloalkyl;

R 4 is independently halogen, C 1 -C 7 alkyl or oxo;

R 1-7 and R 2-7 are independently halogen or hydroxy;

Scenario 6:

The compound of formula I is 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, C 6 -C 10 -membered 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, the number of heteroatoms is independently 1, 2 or 3;

R 1 is C 1 -C 7 alkyl substituted by R 1-7 ;

R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo;

R 3 is independently halogen, C 1 -C 7 alkyl or oxo, alternatively, any two non-adjacent R 3 together with the carbon atom to which it is attached form a 4-6 membered heterocycloalkyl;

R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 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 they are attached form a 4-10 membered cycloalkyl group

Scenario 7:

The compound of formula I is 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 C 6 -C 10 aryl or 5-10-membered heteroaryl; the heteroatom in the 5-10-membered heteroaryl is selected from one of oxygen, sulfur and nitrogen or Multiple, the number of heteroatoms is independently 1, 2 or 3;

R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";

R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl";

R 3 is independently halogen or C 1 -C 7 alkyl, or any two non-adjacent R 3 and the carbon atoms to which they are attached together form a 4-6 membered heterocycloalkyl;

R 4 is independently C 1 -C 7 alkyl;

R 1-7 and R 2-7 are independently halogen or hydroxy;

Scenario 8:

The compound of formula I is the compound shown in formula III:

Wherein, ring A and ring B are independently C 3 -C 14 -membered cycloalkyl, 3-14-membered heterocycloalkyl, C 6 -C 10 -membered aryl or 5-10-membered heteroaryl; the 3-14 The heteroatoms in the 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 indivual;

R 1 is independently hydrogen, halogen, -OR 1-1 , -CN, -NR 1-3 R 1-4 , -C(=O)R 1-5 , -S(=O) 2 R 1-6 , C 1 -C 7 alkyl or "R 1-7 substituted C 1 -C 7 alkyl";

R 2 is independently halogen, -OR 2-1 , -CN, -NR 2-3 R 2-4 , -C(=O)R 2-5 , -S(=O) 2 R 2-6 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 1 -C 7 alkyl, "R 2-7 substituted C 1 -C 7 alkyl" or oxo; the 3-14 The heteroatoms in the 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;

R 3 is independently halogen, -OR 3-1 , -CN, -NR 3-3 R 3-4 , -C(=O)R 3-5 , -S(=O) 2 R 3-6 , C 3 -C 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 1 -C 7 alkyl, "R 3-7 substituted C 1 -C 7 alkyl" or oxo; the 3-14 The heteroatoms in the 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 heteroatoms R3 together with the carbon atom to which it is attached forms a 4-6 membered heterocycloalkyl

R 1-1 , R 2-1 and R 3-1 are independently hydrogen, "halogen substituted C 1 -C 7 alkyl", C 1 -C 7 alkyl, C 3 -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;

R 1-3 , R 1-4 , R 2-3 , R 2-4 , R 3-3 and R 3-4 are independently hydrogen, C 1 -C 7 alkyl, C 3 -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;

Alternatively, R 1-3 and R 1-4 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R 1-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R 1-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3; the R 1-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 2-3 and R 2-4 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R 2-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R 2-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2 or 3; the R 2-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 3-3 and R 3-4 and the nitrogen atom to which they are attached together form a 3-14-membered heterocycloalkyl or "3-14-membered heterocycloalkyl substituted by R 3-3-1 "; the 3-14-membered heterocycloalkyl group The heteroatoms in -14-membered heterocycloalkyl and "R 3-3-1 substituted 3-14-membered heterocycloalkyl" are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms independently 1, 2, 3 or 4; the R 3-3-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy base;

R 1-5 is independently hydrogen, -OR 1-5-1 , NR 1-5-2 R 1-5-3 , C 1 -C 7 alkyl, C 3 -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;

R 2-5 is independently hydrogen, -OR 2-5-1 , NR 2-5-2 R 2-5-3 , C 1 -C 7 alkyl, C 3 -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;

R 3-5 is independently hydrogen, -OR 3-5-1 , NR 3-5-2 R 3-5-3 , C 1 -C 7 alkyl, C 3 -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 heteroatoms the number of atoms is independently 1, 2 or 3;

R 1-6 is independently hydrogen, -OR 1-6-1 , NR 1-6-2 R 1-6-3 , C 1 -C 7 alkyl, C 3 -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;

R 2-6 is independently hydrogen, -OR 2-6-1 , NR 2-6-2 R 2-6-3 , C 1 -C 7 alkyl, C 3 -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;

R 3-6 is independently hydrogen, -OR 3-6-1 , NR 3-6-2 R 3-6-3 , C 1 -C 7 alkyl, C 3 -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;

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, C 1 -C 7 alkyl groups, C 3 -C 14 cycloalkyl groups or 3-14-membered heterocycloalkyl groups; the heteroatoms in the 3-14-membered heterocycloalkyl groups are independently selected from one of oxygen, sulfur and nitrogen or more, the number of heteroatoms is independently 1, 2, 3 or 4;

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, C 1 -C 7 alkyl, C 3 -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 independent 1, 2 or 3 lands;

Alternatively, R 1-5-2 and R 1-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 1-5-2-1- substituted 3-14-membered heterocycloalkyl "; The heteroatoms in the 3-14-membered heterocycloalkyl and the "R 1-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R 1-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 2-5-2 and R 2-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 2-5-2-1 substituted 3-14-membered heterocycloalkyl "; the heteroatoms in the 3-14-membered heterocycloalkyl and the "R 2-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R 2-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

Alternatively, R 3-5-2 and R 3-5-3 together with the nitrogen atom to which they are attached form a 3-14-membered heterocycloalkyl or "R 3-5-2-1 substituted 3-14-membered heterocycloalkyl "; the heteroatoms in the 3-14-membered heterocycloalkyl and the "R 3-5-2-1 substituted 3-14-membered heterocycloalkyl" are independently selected from oxygen, sulfur and nitrogen One or more of, the number of heteroatoms is independently 1, 2 or 3; the R 3-5-2-1 is independently hydroxyl, oxo, -CN, C 1 -C 7 alkyl or C 1 -C 7 alkoxy;

R 1-7 , R 2-7 and R 3-7 are independently halogen, hydroxy, amino, mercapto, cyano, C 1 -C 7 alkoxy, C 3 -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 indivual;

Scenario 9:

The compound of formula I is the compound shown in formula IV:

where u is 0 or 1; v is 0, 1 or 2;

Ring A is C 6 -C 10 aryl;

Ring B is independently a C 6 -C 10 aryl group or a 5-10-membered heteroaryl group; the heteroatom in the 5-10-membered heteroaryl group is selected from one or more of oxygen, sulfur and nitrogen, The number of heteroatoms is 1, 2 or 3;

R 1 is "C 1 -C 7 alkyl substituted by R 1-7 ";

R 2 is independently halogen or "R 2-7 substituted C 1 -C 7 alkyl";

R 3 is independently halogen or C 1 -C 7 alkyl;

R 1-7 and R 2-7 are independently halogen or hydroxy;

Scenario 10:

The compound shown in the formula I is

and / or
The spiroheterocyclic compound represented by formula I according to claim 1 or 2, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or The prodrug thereof is characterized in that, 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, the heterocycloalkyl in the 3-14-membered heterocycloalkyl is a heteromonocycloalkyl or a heterobridged cycloalkyl ;

And/or, when the ring A is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is connected to the ring B through a heteroatom;

And/or, when the ring A is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is a 5-, 6- or 7-membered heterocycloalkyl, and the heteroatom is oxygen and/or or nitrogen, the number is 1 or 2;

And/or, when the ring A is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is a phenyl group;

And/or, when the ring A is a 5-10 membered heteroaryl group, the heteroaryl group is a single 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 through 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 heteroatom is sulfur and/or nitrogen, and the number of 1 or 2, preferably 5 or 6-membered heteroaryl, the heteroatom is nitrogen, and the number is 1 or 2;

And/or, when the ring B is a 3-14-membered heterocycloalkyl, the heteroatoms in the 3-14-membered heterocycloalkyl are not substituted by oxygen;

And/or, when the ring B is a 3-14-membered heterocycloalkyl, the heterocycle in the 3-14-membered heterocycloalkyl is a heteromonocycle;

And/or, when the ring B is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is a 5- or 6-membered heterocycloalkyl, the heteroatom is nitrogen, and the number is 1 or 2;

And/or, when the ring B is a C 6 -C 10 aryl group, the C 6 -C 10 aryl group is a phenyl group, preferably
Wherein the left end is connected with ring A, and the right end is connected with R 1 ;

And/or, when the ring B is a 5-10 membered heteroaryl, the heteroaryl is a monocyclic heteroaryl;

And/or, when the ring B is a 5-10 membered heteroaryl, the heteroatom in the heteroaryl is not substituted by oxygen;

And/or, when the ring B is a 5-10 membered heteroaryl, the 5-10 membered heteroaryl is connected to the ring A through 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 in the ortho position to the linking site of 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 is 1 or 2 indivual;

and/or, when R 1 is independently halogen, the halogen is F;

And/or, when R 1 is independently "C 1 -C 7 alkyl substituted by R 1-7 ", the number of R 1-7 is 4, 5, 6 or 7;

And/or, when R 1 is independently "C 1 -C 7 alkyl substituted by R 1-7 ", the C 1 -C 7 alkyl group is C 1 -C 3 alkyl group, more preferably iso- propyl;

And/or, when R 1-7 is halogen, the halogen is F;

and/or, when R 2 is independently halogen, the halogen is F;

And/or, when R 2 is independently "C 1 -C 7 alkyl substituted by R 2-7 ", the number of said R 2-7 is 3;

And/or, when R 2 is independently "C 1 -C 7 alkyl substituted by R 2-7 ", the C 1 -C 7 alkyl group is C 1 -C 3 alkyl group, more preferably methyl base;

And/or, when R 2-7 is halogen, the halogen is F;

and/or, when R is independently halogen, the halogen is F or Cl;

And/or, when R 3 is independently a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a C 1 -C 3 alkyl group, more preferably a methyl group;

and/or, when R4 is independently halogen, the halogen is preferably F or Cl, such as Cl;

And/or, when R 4 is independently a C 1 -C 7 alkyl group, the C 1 -C 7 alkyl group is a C 1 -C 3 alkyl group, more preferably a methyl group;

And/or, when R 4 is independently "C 1 -C 7 alkyl substituted by R 4-4 ", the number of said R 4-4 is 3;

And/or, when R 4 is independently "C 1 -C 7 alkyl substituted by R 4-4 ", the C 1 -C 7 alkyl group is C 1 -C 3 alkyl group, more preferably methyl base;

And/or, when R 4-4 is halogen, the halogen is F;

And/or, when any two non-adjacent R 5 and their connected carbon atoms together form 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.
The spiroheterocyclic compound represented by formula I according to any one of claims 1-3, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Its metabolite or its prodrug, characterized in that, when the ring A is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is piperidinyl or piperazinyl, more preferably

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, the 5-10-membered heteroaryl is pyridyl, pyrimidinyl or thiazolyl, more preferably
preferably

Wherein the right end is connected with methylene, and the left end is connected with ring B;

And/or, when the ring B is a 3-14-membered heterocycloalkyl, the 3-14-membered heterocycloalkyl is piperidinyl or piperazinyl, more preferably
The left end is connected with ring A, and the right end is connected with R 1 ;

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, more preferably
Wherein the left end is connected with ring A, and the right end is connected with R 1 ;

And/or, when R 1 is independently "R 1-7 substituted C 1 -C 7 alkyl", the "R 1-7 substituted C 1 -C 7 alkyl" is

And/or, when R 2 is independently "R 2-7 substituted C 1 -C 7 alkyl", the "R 2-7 substituted C 1 -C 7 alkyl" is trifluoromethyl ;

And/or, when R 4 is independently "R 4-4 substituted C 1 -C 7 alkyl", the "R 4-4 substituted C 1 -C 7 alkyl" is trifluoromethyl ;

And/or, when ring B is a 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, the substitution site of R 1 is located at the para position of the bond to ring A.
The spiroheterocyclic compound represented by formula I according to any one of claims 1-4, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Its metabolite or its prodrug, characterized in that m is 0 or 1, preferably 0;

and/or, n is 0 or 1, preferably 0;

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, preferably 0;

and/or, W is CH;

and/or, Z is CH;

And/or, Ring A is a 3-14-membered heterocycloalkyl group, a C 6 -C 10 -membered aryl group or a 5-10-membered heteroaryl group, preferably a C 6 -C 10 -membered aryl group or a 5-10-membered heteroaryl group;

And/or, ring B is a 3-14-membered heterocycloalkyl group, a C 6 -C 10 -membered aryl group or a 5-10-membered heteroaryl group, preferably a C 6 -C 10 -membered aryl group;

and/or, R 1 is independently halogen or "R 1-7 substituted C 1 -C 7 alkyl";

and/or, R 2 is independently halogen, "R 2-7 substituted C 1 -C 7 alkyl" or oxo, preferably halogen or "R 2-7 substituted C 1 -C 7 alkyl";

and/or, R 3 is independently halogen, C 1 -C 7 alkyl or oxo, preferably halogen or "R 3-7 substituted C 1 -C 7 alkyl";

and/or, R 4 is independently halogen, C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkyl" or oxo;

And/or, R 1-7 , R 2-7 , R 3-7 and R 4-4 are independently halogen or hydroxy.
The spiroheterocyclic compound represented by formula I according to any one of claims 1-4, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Its metabolite or its prodrug, characterized in that R 4 is independently halogen, -CN, -OR 4-1 , C 1 -C 7 alkyl, "R 4-4 substituted C 1 -C 7 alkane "base" or oxo, R 4-1 is H.
The spiroheterocyclic compound represented by formula I according to any one of claims 1-6, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt solvate, Its metabolites or prodrugs thereof, characterized in that,
for

preferred

and / or,
for

and is connected with ring B through the right broken bond; preferably

and / or,
for

preferred
The spiroheterocyclic compound represented by formula I as claimed in claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a drug thereof The precursor is characterized in that the compound shown in the formula I is optionally any of the following compounds:
One such as compound I-a:

Wherein, the definitions of m, n, p, s, t, Y, Z, W, Q, R 4 and R 5 are as described in any one of claims 1-8, and the compound Ia is not
The compound I-a of claim 9, wherein the compound I-a is any of the following compounds:

Preferably, the retention time is 1.486min under the following chiral preparation conditions
or with a retention time of 2.705min

Described chiral preparation conditions: chromatographic column: chiral column: CHIRALPAK IH-3; mobile phase A: n-hexane solution containing 0.1% ethylenediamine; mobile phase B: isopropanol; flow rate: 1ml/min; wash Decontamination conditions: eluted with 60% mobile phase A and 40% mobile phase B for 14 min; flow rate: 1.0 ml/min; detector wavelength: 220 nm; temperature: room temperature.
A pharmaceutical composition comprising the spiroheterocyclic compounds shown in formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, as described in any one of claims 1-8, A solvate of its pharmaceutically acceptable salt, its metabolite or its prodrug, and a pharmaceutically acceptable carrier.
A substance X is used in the preparation of RORγt protein receptor modulators or medicines;

Described substance X is the spiroheterocyclic compound shown in formula I as described in any one of claim 1-8, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable salt The solvate, its metabolite, its prodrug or the pharmaceutical composition of claim 11;

The medicine is used for preventing or treating diseases related to RORγt protein receptor;

The disease associated with the RORγt protein receptor is preferably an autoimmune disease;

The autoimmune disease is preferably one of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease and chronic obstructive pulmonary disease. one or more.
A method for preventing and/or treating a disease, the method comprising administering the spiroheterocyclic compound shown in formula I as described in any one of claims 1-8, and its pharmacy An acceptable salt, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof or the pharmaceutical composition according to claim 11; wherein the disease is associated with RORγt protein receptor-related diseases;

In the method, the disease associated with the RORγt protein receptor is preferably an autoimmune disease;

The autoimmune disease is preferably one of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, systemic lupus erythematosus, Behçet's disease and chronic obstructive pulmonary disease. one or more.