CN114437096A

CN114437096A - Spiro-heterocyclic compound, and preparation method and application thereof

Info

Publication number: CN114437096A
Application number: CN202111305935.7A
Authority: CN
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: Shanghai Pharmaceuticals Holding Co Ltd
Current assignee: Shanghai Pharmaceuticals Holding Co Ltd
Priority date: 2020-11-06
Filing date: 2021-11-05
Publication date: 2022-05-06
Also published as: WO2022095971A1

Abstract

The invention provides a spiro-heterocyclic compound, and a preparation method and application thereof. The spiro-heterocyclic compound is shown as a formula I. The compounds have inhibitory activity on ROR gamma t, and can effectively inhibit ROR gamma t protein receptors, thereby regulating and controlling the differentiation of Th17 cells, inhibiting the generation of IL-17, and further treating ROR gamma t-mediated related autoimmune diseases.

Description

Spiro-heterocyclic compound, and preparation method and application thereof

Technical Field

The invention relates to a spiro-heterocyclic compound, and a preparation method and application thereof.

Background

Retinoic acid receptor-Related Orphan Receptors (RORs) belong to a member of the ligand-dependent transcription factor nuclear receptor superfamily, and play an important role in a series of physiological and pathological processes such as reproductive development, circadian rhythm regulation, metabolic disturbance, inflammation generation and immune system regulation. RORs mainly include three members, ROR α, ROR β and ROR γ, and ROR α is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus, brain and blood. ROR β is distributed primarily in the central nervous system, including the brain, retina and pineal gland. ROR γ is highly expressed in thymus, and is distributed in kidney, liver, heart, skeletal muscle, adipose tissue, testis, prostate, and pancreas, and is classified into two subtypes, ROR γ 1 and ROR γ t (also referred to as ROR γ 2), which are mainly expressed in thymus, testis, pancreas, heart, liver, skeletal muscle, and kidney, and ROR γ t is expressed only in immune organs, depending on the transcriptional cleavage site.

Th17 cells, a subset of T helper cells, characterized by secretion of interleukin 17(IL-17) cytokines, were initially thought to exert immune function primarily through recruitment of neutrophils in response to bacterial fungal infections, and subsequent studies found that Th17 cells played a key role in many mouse models of autoimmune disease, with increased levels of IL-17 also detectable in some human autoimmune diseases including Psoriasis (Psoriasis), Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in both tissues and peripheral blood samples from patients with autoimmune disease is increased. Therefore, the Th17 cell or the cytokine IL-17 produced by the cell are closely related to the pathogenesis of autoimmune diseases and inflammations, and can inhibit the differentiation of the Th17 cell and be used for treating the diseases related to the Th17 cell.

Research shows that ROR gamma t is a key regulatory factor for Th17 cell differentiation. Littman et al first reported that ROR γ T was essential for the initial differentiation of CD4+ T cells into Th17 cells. Mice lacking ROR gamma T lack lymph organs such as lymph nodes and Peyer's patches, the development and maturation process of T cells is also affected, and the number of various T cells is reduced compared with that of normal mice. The small molecular compound can directly influence the differentiation of Th17 cells by regulating the activity of ROR gamma t, and the level of cytokine IL-17 secreted by ROR gamma t and Th17 is obviously reduced. Therefore, ROR gamma t can be used as a new target for treating autoimmune diseases, and the development of ROR gamma t small molecule regulators and the application of ROR gamma t small molecule regulators in treating related diseases such as autoimmune diseases, inflammatory diseases and the like have important significance.

At present, patent applications CN107522634, WO2012158784, WO2018145653 and the like disclose partial ROR γ t small molecule modulators, but related products are not on the market at present, and there is a need in the art to develop new ROR γ t small molecule modulators with better activity and higher safety.

Disclosure of Invention

The invention provides a spiro-heterocyclic compound different from the prior art, and a preparation method and application thereof. The compounds have inhibitory activity on ROR gamma t, can effectively inhibit ROR gamma t protein receptors, thereby regulating and controlling the differentiation of Th17 cells, inhibiting the generation of IL-17, and further treating ROR gamma t mediated related autoimmune diseases, and are particularly suitable for various diseases such as psoriasis, multiple sclerosis, atopic dermatitis, inflammatory bowel disease and the like.

The invention provides a spiro-heterocyclic compound shown as a formula I, pharmaceutically acceptable salts thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof or prodrugs thereof:

wherein 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 both CH or N;

ring A and ring B are independently C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R¹independently hydrogen, halogen, -OR^1-1、-SR^1-2、-CN、-NR^1-3R^1-4、-C(＝O)R^1-5、-S(＝O)₂R^1-6、C₁-C₇Alkyl or "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently halogen, -OR^2-1、-SR^2-2、-CN、-NR^2-3R^2-4、-C(＝O)R^2-5、-S(＝O)₂R^2-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^2-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, the number of heteroatoms is independently 1,2, 3 or 4;

R³independently halogen, -OR^3-1、-SR^3-2、-CN、-NR^3-3R^3-4、-C(＝O)R^3-5、-S(＝O)₂R^3-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4; or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from O and/or N (i.e., any two non-adjacent R's)³Together with 1 or more atoms to which they are bound, and any heteroatoms inserted into the ring, form a 4-6 membered heterocycloalkyl; for example

Is composed of

When two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group being an oxetanyl group

R⁴Independently halogen, -OR^4-1、-CN、-NR^4-2R^4-3、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

or, any two non-adjacent R⁴Together with the carbon atoms connected with the heterocyclic ring form 4-6 membered heterocyclic alkyl, wherein the heteroatom in the heterocyclic alkyl is N, and the number of the heteroatoms is 1;

R^1-1、R^2-1、R^3-1and R^4-1Independently hydrogen, "halogen-substituted C₁-C₇Alkyl radical ", C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^1-2、R^2-2and R^3-2Independently hydrogen, "halogen-substituted C₁-C₇Alkyl radical ", C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^1-3、R^1-4、R^2-3、R^2-4、R^3-3、R^3-4、R^4-2and R^4-3Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

or, R^1-3And R^1-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^1-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^1-3-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl group, R^1-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl and "R^1-3-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4;

r is as described^1-3-1And R^1-3-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-3And R^2-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^2-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^2-3-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl group, R^2-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl and "R^2-3-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4;

said R^2-3-1And R^2-3-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-3And R^3-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^3-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^3-3-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl group, R^3-3-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl and "R^3-3-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4;

said R^3-3-1And R^3-3-2Independently is hydroxy, -CN, -C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^4-2And R^4-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^4-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^4-2-2Substituted 3-14 membered heterocycloalkenyl "; said 3-to 14-membered heterocycloalkyl group, "R^4-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenylAnd "R^4-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4;

r is as described^4-2-1And R^4-2-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-5independently hydrogen, -OR^1-5-1、NR^1-5-2R^1-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^2-5independently hydrogen, -OR^2-5-1、NR^2-5-2R^2-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^3-5independently hydrogen, -OR^3-5-1、NR^3-5-2R^3-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^1-6independently hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄A cycloalkyl group, a,3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^2-6independently hydrogen, -OR^2-6-1、NR^2-6-2R^2-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, the number of heteroatoms is independently 1,2, 3 or 4;

R^3-6independently hydrogen, -OR^3-6-1、NR^3-6-2R^3-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^1-5-1、R^2-5-1、R^3-5-1、R^1-6-1、R^2-6-1and R^3-6-1Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

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^3-6-2and R^3-6-3Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

or, R^1-5-2And R^1-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^1-5-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^1-5-2-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl, said "R^1-5-2-1Substituted 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkenyl and said "R^1-5-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4; said R^1-5-2-1And R^1-5-2-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-5-2And R^2-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^2-5-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^2-5-2-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl, said "R^2-5-2-1Substituted 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkenyl and said "R^2-5-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4; said R^2-5-2-1And R^2-5-2-2Independently is hydroxy, -CN, -C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-5-2And R^3-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group,“R^3-5-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^3-5-2-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl, said "R^3-5-2-1Substituted 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkenyl and said "R^3-5-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4; said R^3-5-2-1And R^3-5-2-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-7、R^2-7、R^3-7and R^4-4Independently halogen, hydroxy, amino, mercapto, cyano, C₁-C₇Alkoxy radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R⁵independently is C₁-C₇An alkyl group; or, any two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group (i.e., any two non-adjacent R's)⁵Together with 1 or more atoms to which they are bound form a 4-to 10-membered cycloalkyl group; for example

Is composed of

When two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-to 10-membered cycloalkyl group which is cycloheptyl

R is as described^1-7R is as described^2-7R is as described^3-7R is as described^4-4R is as described^1-3-1R is as described^1-3-2R is as described^2-3-1R is as described^2-3-2R is as described^3-3-1R is as described^3-3-2R is as described^1-5-2-1R is as described^1-5-2-2R is as described^2-5-2-1R is as described^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2Independently by number 1,2, 3, 4,5, 6 or 7; when said R is^1-7R is as described^2-7R is as described^3-7R is as described^4-4Said R^1-3-1R is as described^1-3-2R is as described^2-3-1R is as described^2-3-2Said R^3-3-1R is as described^3-3-2Said R^1-5-2-1R is as described^1-5-2-2R is as described^2-5-2-1R is as described^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2When the number of (A) is more than one, R is^1-7R is as described^2-7R is as described^3-7R is as described^4-4R is as described^1-3-1R is as described^1-3-2R is as described^2-3-1R is as described^2-3-2R is as described^3-3-1R is as described^3-3-2R is as described¹ ^-5-2-1R is as described^1-5-2-2R is as described^2-5-2-1R is as described^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2Independently the same or different.

In the present invention, certain substituents in the compounds of formula I are as defined in a preferred embodiment, and substituents not mentioned are as defined in any of the embodiments of the present invention.

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

n is 0 or 1;

ring A and ring B are independently C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; said 3-to 14-membered heterocycloalkyl group and saidThe heteroatoms in the 5-to 10-membered heteroaryl groups of (a) are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3;

R¹independently is-NR^1-3R^1-4、-C(＝O)R^1-5、-S(＝O)₂R^1-6、C₁-C₇Alkyl or "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently halogen, -OR^2-1、-CN、-NR^2-3R^2-4、-C(＝O)R^2-5、-S(＝O)₂R^2-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^2-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R³independently halogen, -OR^3-1、-CN、-NR^3-3R^3-4、-C(＝O)R^3-5、-S(＝O)₂R^3-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3; or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R^1-5independently hydrogen, -OR^1-5-1、NR^1-5-2R^1-5-3Or C₁-C₇An alkyl group;

R^2-5independently hydrogen, -OR^2-5-1、NR^2-5-2R^2-5-3Or C₁-C₇An alkyl group;

R^3-5independently hydrogen, -OR^3-5-1、NR^3-5-2R^3-5-3Or C₁-C₇An alkyl group;

R^1-6independently of one another is hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^2-6independently hydrogen, -OR^2-6-1、NR^2-6-2R^2-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^3-6independently hydrogen, -OR^3-6-1、NR^3-6-2R^3-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^2-6-1and R^3-6-1Independently of one another is hydrogen, C₁-C₇Alkyl or C₃-C₁₄A cycloalkyl group;

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^3-6-2and R^3-6-3Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocyclic alkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of the heteroatoms is independently 1,2 or 3.

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

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 C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R³independently of one another is halogen, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo, or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R⁴independently of one another, halogen, C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo;

R^1-7、R^2-7、R^3-7and R^4-4Independently halogen or hydroxy.

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

m is 0 or 1;

n is 0 or 1;

u is 0 or 1;

v is 0, 1 or 2;

p is 1 or 2;

s is 1 or 2;

t is 0 or 2;

ring A and ring B are independently 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of the heteroatoms is independently 1,2 or 3;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R³independently of one another, halogen, C₁-C₇Alkyl or oxo, or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R⁴independently halogen, -CN, -OR^4-1、C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is hydrogen;

any two non-adjacent R⁵Together with the carbon atoms to which they are attached form a 4-10 membered cycloalkyl group.

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

m is 0 or 1;

n is 0 or 1;

u is 0 or 1;

v is 0, 1 or 2;

p is 1 or 2;

s is 1 or 2;

t is 0 or 2;

ring A and ring B are independently C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently of one another, halogen, C₁-C₇Alkyl or oxo;

R⁴independently halogen, -CN, -OR^4-1、C₁-C₇Alkyl or oxo;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is hydrogen;

any two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-to 10-membered cycloalkyl group.

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

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;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently of one another, halogen, C₁-C₇Alkyl or oxo;

R⁴independently of one another, halogen, C₁-C₇Alkyl or oxo;

R^1-7and R^2-7Independently halogen or hydroxy。

In a preferred embodiment, the compound of formula I is represented by formula II:

m is 0 or 1;

u is 0 or 1;

v is 0, 1 or 2;

p is 1 or 2;

s is 1 or 2;

t is 0 or 2;

ring A and ring B are independently 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is 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 C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 5-10 membered heteroaryl are selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently is halogen or C₁-C₇An alkyl group; or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R⁴independently is C₁-C₇An alkyl group;

R^1-7and R^2-7Independently halogen or hydroxy.

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

wherein ring A and ring B are independently C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R¹independently of each other hydrogen or halogenElement, -OR^1-1、-CN、-NR^1-3R^1-4、-C(＝O)R^1-5、-S(＝O)₂R^1-6、C₁-C₇Alkyl or "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently halogen, -OR^2-1、-CN、-NR^2-3R^2-4、-C(＝O)R^2-5、-S(＝O)₂R^2-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₁-C₇Alkyl radical "R^2-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R³independently halogen, -OR^3-1、-CN、-NR^3-3R^3-4、-C(＝O)R^3-5、-S(＝O)₂R^3-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3; or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R^1-1、R^2-1and R^3-1Independently hydrogen, "halogen-substituted C₁-C₇Alkyl radical ", C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^3-3and R^3-4Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl and 3-14 membered heterocycloalkyl; hetero in said 3-to 14-membered heterocycloalkylThe atoms are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

or, R^1-3And R^1-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^1-3-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and "R^1-3-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; r is as described^1-3-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-3And R^2-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^2-3-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and "R^2-3-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R^2-3-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-3And R^3-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^3-3-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and "R^3-3-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2, 3 or 4; said R^3-3-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-5independently hydrogen, -OR^1-5-1、NR^1-5-2R^1-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^2-5independently hydrogen, -OR^2-5-1、NR^2-5-2R^2-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^3-5independently hydrogen, -OR^3-5-1、NR^3-5-2R^3-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R^1-6independently hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^2-6-1and R^3-6-1Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2, 3 or 4;

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^3-6-2and R^3-6-3Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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;

or, R^1-5-2And R^1-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^1-5-2-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and said "R^1-5-2-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R¹ ^-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-5-2And R^2-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^2-5-2-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and said "R^2-5-2-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; r is as described² ^-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-5-2And R^3-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^3-5-2-1Substitution3-14 membered heterocycloalkyl group of (a); said 3-to 14-membered heterocycloalkyl group and said "R^3-5-2-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R³ ^-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-7、R^2-7and R^3-7Independently halogen, hydroxy, amino, mercapto, cyano, C₁-C₇Alkoxy radical, C₃-C₁₄Cycloalkyl and 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocyclic alkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of the heteroatoms is independently 1,2 or 3.

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

wherein u is 0 or 1;

v is 0, 1 or 2;

ring A is C₆-C₁₀An aryl group;

ring B is independently C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatom in the 5-10 membered heteroaryl is selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is 1,2 or 3;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl ";

R³independently is halogen or C₁-C₇An alkyl group;

R^1-7and R^2-7Independently halogen or hydroxy.

In a preferred embodiment, the compound of formula I is

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

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

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

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

In a preferred embodiment, when said ring A is C₆-C₁₀When aryl, said C₆-C₁₀Aryl is phenyl or naphthyl, preferably phenyl.

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

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

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

In a preferred embodiment, when ring a is a 5-to 10-membered heteroaryl group, the 5-to 10-membered heteroaryl group is a 5-or 6-membered heteroaryl group, and the heteroatoms are sulfur and/or nitrogen, in number of 1 or 2.

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

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

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

Wherein the right end is linked to the methylene group and the left end is linked to ring B.

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

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

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

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

Preference is given to

Left end connected to ring A and right end connected to R¹Are connected.

In a preferred embodiment, when said ring B is C₆-C₁₀When aryl, said C₆-C₁₀Aryl is phenyl or naphthyl, preferably phenyl.

In a preferred embodiment, when said ring B is C₆-C₁₀Aryl is said to C₆-C₁₀Aryl is

Wherein the left end is connected with ring A and the right end is connected with R¹Are connected.

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

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

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

In a preferred embodiment, when ring B is a 5-10 membered heteroaryl, the heteroatom in the 5-10 membered heteroaryl is ortho to the site of attachment to ring A.

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

In a preferred embodiment, when said ring B is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is a pyridyl, further preferablyIs composed of

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

In a preferred embodiment, when R¹Independently halogen, the halogen is F, Br, Cl or I, preferably F.

In a preferred embodiment, when R¹Independently is "R^1-7Substituted C₁-C₇When it is alkyl ", said R^1-7The number of (a) is 4,5, 6 or 7.

In a preferred embodiment, when R¹Independently is "R^1-7Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃The alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl) is more preferably an isopropyl group.

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

In a preferred embodiment, when R¹Independently is "R^1-7Substituted C₁-C₇When alkyl is mentioned, "R" is^1-7Substituted C₁-C₇Alkyl is

In a preferred embodiment, when R²Independently halogen, the halogen is F, Br, Cl or I, preferably F.

In a preferred embodiment, when R²Independently is "R^2-7Substituted C₁-C₇When it is alkyl ", said R^2-7The number of (2) is 3.

In a preferred embodiment, when R²Independently is "R^2-7Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.

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

In a preferred embodiment, when R²Independently is "R^2-7Substituted C₁-C₇When alkyl is mentioned, "R" is^2-7Substituted C₁-C₇Alkyl "is trifluoromethyl.

In a preferred embodiment, when R³Independently halogen, the halogen is F, Br, Cl or I, preferably F or Cl.

In a preferred embodiment, when R³Independently is C₁-C₇When alkyl, said C₁-C₇Alkyl is C₁-C₃The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.

In a preferred embodiment, when R⁴Independently halogen, the halogen is F, Br, Cl or I, preferably Cl.

In a preferred embodiment, when R⁴When independently halogen, the halogen is preferably F or Cl.

In a preferred embodiment, when R⁴Independently is C₁-C₇When alkyl, said C₁-C₇Alkyl is C₁-C₃The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.

In a preferred embodiment, when R⁴Independently is "R^4-4Substituted C₁-C₇When it is alkyl ", said R^4-4The number of (2) is 3.

In a preferred embodiment, when R⁴Independently is "R^4-4Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃The alkyl group (for example, methyl, ethyl, n-propyl, or isopropyl) is more preferably a methyl group.

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

In a preferred embodiment, when R⁴Independently is "R^4-4Substituted C₁-C₇When alkyl is mentioned, "R" is^4-4Substituted C₁-C₇Alkyl "is trifluoromethyl.

In a preferred embodiment, when any two non-adjacent R's are⁵And together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group, said 4-10 membered cycloalkyl group is a 7 membered cycloalkyl group.

In a preferred embodiment, when ring B is 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, said R is¹Is located para to the ring a linkage.

In a preferred embodiment, ring B is substituted at a position on ring A with

Are not adjacent.

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

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

In a preferred embodiment, u is 0 or 1.

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

In a preferred embodiment, p is 1 or 2.

In a preferred embodiment, s is 1 or 2.

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

In a preferred embodiment, W is CH.

In a preferred embodiment, Z is CH.

In a preferred embodiment, ring A is 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, preferably C₆-C₁₀Aryl or 5-10 membered heteroaryl.

In a preferred embodiment, ring B is 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, preferably C₆-C₁₀And (4) an aryl group.

In a preferred embodiment, R¹Independently is halogen or "R^1-7Substituted C₁-C₇Alkyl groups ".

In a preferred embodiment, R²Independently halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo, preferably halogen or" R^2-7Substituted C₁-C₇Alkyl groups ".

In a preferred embodiment, R³Independently of one another, halogen, C₁-C₇Alkyl or oxo, preferably halogen or "R^3-7Substituted C₁-C₇Alkyl groups ".

In a preferred embodiment, R⁴Independently halogen, -CN, -OR^4-1、C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo, R^4-1Is H.

In a preferred embodiment, R⁴Independently of one another, halogen, C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo.

In a preferred embodiment, R^1-7、R^2-7、R^3-7And R^4-4Independently halogen or hydroxy.

In a certain preferred embodiment of the process according to the invention,

in a certain preferred embodiment of the process according to the invention,

and is connected with the ring B through a right broken bond; preference is given to

In a certain preferred embodiment of the process according to the invention,

preference is given to

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

the invention also provides a compound I-a:

wherein m, n, p, s, t, Y, Z, W, Q, R⁴And R⁵Are as defined above, and said compound I-a 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 a retention time of 2.705min

(i.e. Compound (I))

The chiral preparation conditions are as follows: and (3) chromatographic column: a chiral column CHIRALPAK IH-3; a mobile phase A: a solution of 0.1% ethylenediamine in n-hexane; and (3) mobile phase B: isopropyl alcohol; flow rate: 1 ml/min; elution conditions: eluting with 60% mobile phase A and 40% mobile phase B for 14 min; flow rate: 1.0 ml/min; detector wavelength: 220 nm; temperature: at room temperature, "%" is volume percent.

The invention also provides a preparation method of the spiroheterocyclic compound shown in the formula I, pharmaceutically acceptable salts, solvates of the pharmaceutically acceptable salts, metabolites or prodrugs of the metabolites, wherein the preparation method is any one of the following methods:

the method comprises the following steps:

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

wherein m, n, p, s, u, v, t, Y, Z, W, Q, R¹、R²、R³、R⁴、R⁵Ring A and ring B are as defined above;

the second method comprises the following steps:

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

wherein R is⁶Is composed of

m、n、p、s、u、v、t、Y、Z、W、Q、R¹、R²、R³、R⁴、R⁵Ring A and ring B are as defined above.

In process one, the conditions and procedures for reductive amination described may be those conventional in the art for such reactions, with the following conditions and procedures being particularly preferred in the present invention:

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

In process one, 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 from 5:1 to 2:1, for example 3: 1.

In process one, the molar ratio of said compound I-b to said compound I-a is preferably from 0.9:1 to 3:1, for example 1: 1.

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

In method one, the progress of the reductive amination reaction can be monitored by methods conventional in the art (e.g., TLC or HPLC), generally with the end point of the reaction being the absence or disappearance of the compound I-a. The time of the reductive amination reaction is preferably 12 to 36 hours.

In the first method, the post-treatment step after the reductive amination reaction is finished is preferably as follows: concentrating and performing column chromatography (e.g. eluent is methanol and dichloromethane with volume content of 0-1: 10).

In the second method, the conditions and operation of the Suzuki can be the conditions and operation conventional in such reactions in the field, and the following conditions and operation are particularly preferred in the present invention:

in the second method, the Pd catalyst is preferably [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf) Cl₂) And/or [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex.

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

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

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

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

In method two, the temperature of the Suzuki reaction is preferably 80 to 110 ℃, for example 100 ℃.

In method one, the progress of the Suzuki reaction can be monitored by methods conventional in the art (e.g., TLC or HPLC), and the end point of the reaction is generally determined as the absence or disappearance of the compounds I-d. The time of the Suzuki reaction is preferably 8 to 24 hours, for example 16 hours.

In the second method, the post-treatment step after the completion of the Suzuki reaction is preferably as follows: concentrating and performing column chromatography (e.g. eluent is methanol and dichloromethane with volume content of 0-1: 10).

The invention also provides a pharmaceutical composition, which comprises the spiroheterocyclic compound shown in the formula I, pharmaceutically acceptable salts thereof, solvates of the pharmaceutically acceptable salts thereof, metabolites thereof or prodrugs thereof, and a pharmaceutically acceptable carrier.

The invention also provides the application of the substance X in preparing ROR gamma t protein receptor modulators; the substance X is the spiro-heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition.

The invention also provides the application of the substance X in preparing the medicament; the substance X is the spiro-heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition.

The invention also provides the application of the substance X in preparing the medicament; the medicine is used for preventing or treating diseases related to ROR gamma t protein receptor; the substance X is the spiro-heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition.

The disease related to the ROR gamma t protein receptor is preferably autoimmune disease.

The autoimmune disease is preferably one or more of Psoriasis (Psoriasisis), Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), Inflammatory Bowel Disease (IBD), ankylosing spondylitis, systemic lupus erythematosus, Behcet's disease and chronic obstructive pulmonary disease.

The invention also provides the application of the substance X in preparing the medicament; the substance X is the spiroheterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition; the medicine is used for preventing or treating one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory enteritis, ankylosing spondylitis, systemic lupus erythematosus, white-padded last-name disease and chronic obstructive pulmonary disease.

The present invention also provides a method for preventing and/or treating a disease, which comprises administering an effective amount of substance X; wherein the disease is related to a ROR gamma t protein receptor, and the substance X is the spiro heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition.

In the method, the diseases related to the ROR gamma t protein receptor are the same as the above.

The present invention also provides a method for preventing and/or treating a disease, which comprises administering an effective amount of substance X; wherein the disease is one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory enteritis, ankylosing spondylitis, systemic lupus erythematosus, white-padded last-name disease and chronic obstructive pulmonary disease; the substance X is the spiro-heterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition.

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

The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts 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. The pharmaceutically acceptable acids include inorganic acids including, but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. The pharmaceutically acceptable acids include organic acids including, but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular 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 Camile 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. The solvent molecules in the solvate may be present in an ordered or unordered arrangement. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.

The terms "pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" as defined above refer to a substance formed by combining compound 1 of the present invention, prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, and 2, with a stoichiometric or non-stoichiometric amount of a solvent. The "solvate of a pharmaceutically acceptable salt" includes, but is not limited to, the hydrochloride monohydrate of the compound of the present invention.

The terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can exist in crystalline or amorphous form. The term "crystal form" refers to a form in which ions or molecules are arranged strictly periodically in a three-dimensional space in a defined manner and have a periodic recurring pattern at a distance; due to the above described periodic arrangement, various crystal forms, i.e. polymorphism, may exist. The term "amorphous" refers to a state in which ions or molecules are distributed in a disordered manner, i.e., the ions and molecules do not have a periodic arrangement.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" if stereoisomers are present, may be present as a single stereoisomer or as a mixture thereof (e.g. as a racemate). The term "stereoisomer" refers to either a cis-trans isomer or an optical isomer. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like. The term "single stereoisomer" means that the mass content of one stereoisomer of the compound according to the invention is not less than 95% relative to all stereoisomers of the compound.

The terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" if present as a tautomer, may exist as a single tautomer or as a mixture thereof, preferably as a more stable tautomer.

The atoms in the terms "compound", "pharmaceutically acceptable salt", "solvate" and "solvate of a pharmaceutically acceptable salt" may be present in their natural or unnatural abundance. In the case of hydrogen atoms, in its natural abundance, it is understood that about 99.985% is protium and about 0.015% is deuterium; in a non-naturally abundant form such as wherein about 95% is deuterium. That is, one or more atoms in the terms "compound," "pharmaceutically acceptable salt," "solvate," and "solvate of a pharmaceutically acceptable salt" can be an atom that is present in a non-natural abundance.

When any variable (e.g. R)^1-1-1) In the definition of the compoundsWhen the variable is represented by (A) and (B), the definition of the occurrence of each position of the variable is irrelevant to the definition of the occurrence of the other positions, and the meanings of the variable are independent and independent from each other. Thus, if a group is substituted by 1,2 or 3R^1-1-1Substituted by radicals, i.e. the radical may be substituted by up to 3R^1-1-1Substituted in the position R^1-1-1Is defined by the definition of (1) and the remaining positions R^1-1-1Are defined independently of each other. In addition, 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 chain monovalent hydrocarbon radical having from one to twelve carbon atoms (e.g., C)₁-C₆Alkyl radicals, also e.g. C₁-C₄Alkyl). Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-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-2-pentyl, 2-methyl-1-butyl, 2-pentyl, 2-methyl-2-pentyl, and the like, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl and 1-octyl.

The term "alkenyl" refers to a group having at least one site of unsaturation, i.e., a carbon-carbon sp²A straight or branched monovalent hydrocarbon radical of two to twelve carbon atoms of the double bond (e.g. C)₂-C₆Alkenyl radicals, further e.g. C₂-C₄Alkenyl) 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 having three to twenty carbon atoms (e.g., C)₃-C₆Cycloalkyl) including monocyclic cycloalkyl and polycyclic cycloalkyl. 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.

Polycyclic cycloalkyl groups are polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, including spiro, fused, and bridged cycloalkyl groups. Wherein spirocyclic cycloalkyl "refers to a 5 to 20 membered polycyclic group sharing one carbon atom (called spiro) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, according to the number of spiro atoms shared between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Examples of spirocycloalkyl groups 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 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Examples of fused ring alkyl groups include, but are not limited to:

"bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Can be divided into bicyclic, tricyclic and tetracyclic rings according to the number of constituent ringsA cyclic or polycyclic bridged cycloalkyl group, 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 from 3 to 20 ring atoms in which at least one ring atom is a heteroatom independently selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, the remaining ring atoms being C. The group may be a carbon group or a heteroatom group (i.e. it may be C-linked or N-linked, 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, thioxanyl, and piperazinyl. Fused ring moieties, spiro moieties and bridged ring moieties are also included within this definition. For example, the group derived from tetrahydropyrrole may be tetrahydropyrrole-1-yl (N-linked) or tetrahydropyrrole-3-yl (C-linked). For example, a 3-7 membered ring 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 are optionally substituted by one or more oxygen atoms to give a ring system like NO, BOH, PO₂A group of SeO; n may be optionally quaternized; s atoms optionally substituted by one or more oxygen or nitrogen atoms to give compounds like SO, SO₂、S(＝O)(＝NR^a),S(＝NR^b) Or S (═ NR)^c)₂Of (a) and at the same time, R^a、R^bAnd R^cIndependently of the other is cyano, C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, 1-4C₁～C₇Heteroaryl ", C₆～C₁₀Aryl or C₁～C₇An alkoxy group; at the same time, -CH₂The-group may optionally be substituted by-C (═ O) -, -C (═ S) -, or-C(＝NR^d) -substitution, R^dIndependently of the other is cyano, C₁～C₇Alkyl radical, C₃～C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl with 1-4 heteroatoms selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, 1-4C₁～C₇Heteroaryl ", C₆～C₁₀Aryl or C₁～C₇An alkoxy group; when the ring is a three-membered ring, in which there is only one heteroatom), or, a bicyclic ring of 7-10 atoms (4-9 carbon atoms and 1-3 heteroatoms selected from N, O, P, B, Si, S, where N, S, B or P is optionally substituted with one or more oxygen atoms to give a ring like NO, BOH, SO₂，PO，PO₂The group of SeO, simultaneously with-CH₂The group may optionally be replaced by-C (═ O) -. Depending on the structure, the heterocyclic group may be a monovalent group or a divalent group, i.e., a heterocyclylene group.

The term "heterocycloalkenyl" refers to a non-aromatic cyclic hydrocarbon radical (e.g., C) having three to twenty carbon atoms with a single ring moiety of unsaturation (containing 1 or 2 double bonds)₃-C₆Cycloalkenyl groups).

The term "aryl" refers to any stable monocyclic or bicyclic carbocyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic. Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl). It will be understood that where the aryl substituent is a bicyclic substituent and one of the rings is non-aromatic, the attachment is through an aromatic ring.

The term "heteroaryl" refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Heteroaryl groups within the scope of this definition include, but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothiopheneA group selected from the group consisting of a benzofuranyl group, a quinolinyl group, an isoquinolinyl group, an oxazolyl group, an isoxazolyl group, an indolyl group, a pyrazinyl group, a pyridazinyl group, a pyridyl group, a pyrimidinyl group, a pyrrolyl group, and a tetrahydroquinoline group. "heteroaryl" is also to be understood as including any N-oxide derivative of a nitrogen-containing heteroaryl group. 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 via the aromatic ring, respectively. The heteroaromatic ring, bicyclic heteroaromatic ring system may form a ring in a fused form. Wherein N, S, B, P or Se are optionally substituted by one or more oxygen atoms to give compounds like NO, SO₂、BOH、PO、PO₂The group of SeO, the N atom may be quaternized. The heteroaryl radical may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. Depending on the structure, heteroaryl groups can be monovalent or divalent, i.e., heteroarylene.

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

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

The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See pharmacopoeia of the people's republic of China (2015), or Handbook of Pharmaceutical Excipients (Raymond C Rowe,2009Sixth Edition).

The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or 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 a disease or condition described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as desired by one of skill in the art.

The term "patient" refers to any animal, preferably a mammal, most preferably a human, who is about to, or has received administration of the compound or composition according to the 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, and the like, with humans being most preferred.

The term "active ingredient" refers to the active ingredients in the pharmaceutical composition or combination kit of the present invention, i.e., compound I, its pharmaceutically acceptable salt, its solvate of pharmaceutically acceptable salt, its metabolite or its prodrug, an anticancer drug, or a combination thereof.

In the present invention, "room temperature" means 15 to 35 ℃ and "overnight" means 10 to 18 hours.

The above preferred conditions may be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the general knowledge in the art.

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

The positive progress effects of the invention are as follows: the compound has inhibitory activity on ROR gamma t, and can effectively inhibit a ROR gamma t protein receptor, thereby regulating and controlling the differentiation of Th17 cells, inhibiting the generation of IL-17, and further treating ROR gamma t mediated related autoimmune diseases.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

The structures of all compounds of the invention can be determined by nuclear magnetic resonance¹HNMR) and/or mass spectrometric detection (MS) identification.

¹H NMR chemical shifts (. delta.) in PPM (10)^-6) And (6) recording. NMR was performed on a Bruker AVANCE-400 spectrometer.

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

HPLC was determined by Agilent 1260 high performance liquid chromatography. Specific conditions of HPLC: mobile phase A is water (0.1% formic acid), and mobile phase B is acetonitrile; column time: 15 min; column type: waters Xselect, 5 μm, 4.6X 250 mm.

The thin-layer silica gel plate is a silicon source HSGF254 or Qingdao GF254 silica gel plate. The column chromatography generally uses 200-mesh and 300-mesh silica gel of the yellow sea of the tobacco Taiwan as a carrier.

Preparation example 1 (preparation of Key intermediate)

The first step is as follows:

to compound 1-a (20g,85.822mmol,1.00equiv) and Trifluoromethyltrimethylsilane (TMSCF) at 0 deg.C₃61.02g,429.111mmol,5.00 equiv) in tetrahydrofuran (200mL) was added tetrabutylammonium fluoride (54.15g,171.644mmol,2.00equiv) and stirred at room temperature overnight. After the reaction was monitored by LCMS to completion, it was quenched by addition of 1N HCl at 0 ℃. The reaction solution was extracted with ethyl acetate and anhydrous Na₂SO₄(sodium sulfate) drying. The reaction solution was concentrated and separated by column chromatography (EA/PE, 15% -30%) to give the compound 1-b as a pale yellow oil (11.80g,34.602mmol, 40.32% yield). LCMS (ESI, M/z) [ M-1 ]]^-＝338.75。¹H NMR (300MHz, chloroform-d) δ 7.66(dd, J ═ 8.6,7.0Hz,1H),7.52(dd, J ═ 9.6,2.2Hz,1H), 7.45-7.33 (m,1H),3.56(s, 1H).

The second step is that:

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

Preparation example 2 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 2-a (1g,3.86mmol,1equiv) in N, N-Dimethylformamide (DMF) (10mL) at 0 ℃ was added dropwise 2mL of sodium nitrite (NaNO)₂) (293mg,4.24mmol,1.1equiv) followed by additional HCl (6M,2mL,11.58mmol,3.0equiv) dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for a further 1 hour. KI (673mg,4.05mmol,1.05eq) was added at 0 ℃ and then stirred at room temperature overnight. The reaction was monitored by LCMS for completion, and water (30mL) was added to dilute the reaction and extracted with ethyl acetate (3X 15 mL). The organic phases were combined, washed with saturated brine and concentrated to dryness, and the residue was isolated by column chromatography (EA/PE, 10% -50%) to give compound 2-b (912mg,2.46mmol, 63.87% yield) as a yellow oily liquid. LCMS (ESI, M/z) [ M-1 ]]^-＝368.9。

The second step is that:

to a solution of Compound 2-b (23.00g,62.16mmol,1equiv) in 1, 4-dioxane (300mL) was added pinacol diboron (20.52g,80.80mmol,1.30equiv), potassium acetate (18.30g,186.47mmol,3equiv) and Pd (dppf) Cl₂(2.27g,3.11mmol,0.05 equiv). The reaction mixture was stirred at 95 ℃ overnight under nitrogen. LCMS monitors the reaction is complete, the solvent is removed in vacuum, and the residue is purified by column chromatography (EA/PE, 10% -40%) to obtain compound 2(28g crude product, 69% purity: (¹H NMR)), a white solid, LCMS (ESI, M/z) [ M-1 ]]^-＝369.05.¹H-NMR:¹H NMR(400MHz,DMSO-d₆)δ8.79(s,1H),7.85–7.76(m,2H),7.75–7.67(m,2H),1.30(s,12H)。¹⁹F NMR(377MHz,DMSO-d₆)δ-73.85。

Preparation example 3 (preparation of Key intermediate)

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,3.00 eqiv). The reaction mixture was stirred at 80 ℃ overnight under nitrogen. LCMS monitoring reaction completion, solvent was removed in vacuo, the residue was isolated by column chromatography (EA/PE, 0% -40%) to give crude product, which was purified by n-hexane pulping to give compound 3(2.491g,7.153mmol, 52.94% yield) as a yellow solid. LCMS (ESI, M/z) [ M-1 ]]^-＝347.00.¹H NMR(400MHz,DMSO-d₆)δ10.07(s,1H),8.84(s,1H),8.02(d,J＝8.3Hz,2H),7.99–7.88(m,4H),7.82(d,J＝8.3Hz,2H).¹⁹F NMR(377MHz,DMSO-d₆)δ-73.89。

Preparation example 4 (preparation of Key intermediate)

The synthesis of key intermediate 4 is described in patent WO2012077655a 1.

Preparation example 5 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 5-a (6.96g,74.74mmol,1.00equiv) in methyl t-butyl ether (75mL) and water (100mL) was added sodium dithionite (Na)₂S₂O₄)(15.61g,89.65mmol,1.20equiv), sodium bicarbonate (NaHCO)₃) (7.53g,89.65mmol,1.20equiv) and nBu₄N.HSO₄(3.00g,8.84mmol,0.12 equiv). To the above system was added heptafluoro-2-iodopropane (26.53g,89.65mmol,1.20 equiv). The reaction mixture was stirred at room temperature for 2 hours. Completion of the reaction was monitored by dot plate (TLC). The organic phase was washed with 0.75N HCl (65ml) and then with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified by column chromatography (EA/PE, 0% -20%) to give compound 5-b (11.70g,44.80mmol, 59.95% yield) as a brown oil.¹H NMR (300MHz, chloroform-d) delta 7.43-7.34 (m,2H), 6.79-6.70 (m,2H),3.94(s, 2H).

The second step is that:

iodine (I) was added to a solution of Compound 5-b (11.70g,44.80mmol,1.00equiv) in acetonitrile (200mL)₂) (11.37g,44.80mmol,1.00equiv), copper iodide (CuI) (9.39g,49.28mmol,1.10equiv) and tert-butyl nitrite (6.93g,67.20mmol,1.50 equiv). The reaction mixture was stirred at 80 ℃ for 1.5 hours. Monitoring reaction completion by dot plate (TLC), removing solvent under reduced pressure, adding water to the residue, extracting with ethyl acetate, filtering off insoluble substance, and adding 10% Na to organic phase₂S₂O₃And washed with water, dried over anhydrous sodium sulfate, the solvent removed in vacuo, and the residue isolated by column chromatography (EA/PE, 0% to 10%) to give compound 5-c (11.10g,29.84mmol, 66.60% yield) as a yellow oil.¹H NMR (400MHz, chloroform d) delta 7.89-7.83 (m,2H), 7.37-7.30 (m,2H).¹⁹F NMR (377MHz, chloroform-d) δ -75.69(d, J ═ 7.1Hz), -182.83(p, J ═ 7.4 Hz).

The third step:

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

Preparation example 6 (preparation of Key intermediate)

To a solution of the 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,1.20equiv), K₂CO₃(2.79g,20.16mmol,3.00equiv) and Pd (PPh)₃)₄(776.55mg,0.67mmol,0.10 equiv). The reaction mixture was stirred at 80 ℃ for 16 hours. TLC monitored the reaction was complete, the solvent was removed under reduced pressure and the residue was isolated by column chromatography (EA/PE, 0% to 20%) to give compound 6(1.45g,4.14mmol, 61.61% yield) as a white solid.¹H NMR(400MHz,DMSO-d₆)δ10.11(s,1H),8.05(t,J＝8.3Hz,4H),8.00(d,J＝8.1Hz,2H),7.82(d,J＝8.2Hz,2H).¹⁹FNMR(377MHz,DMSO-d₆)δ-75.21(t,J＝7.7Hz),-181.90(p,J＝7.2Hz)。

Preparation example 7 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 4-a (8.0g,46.5mmol,1.00equiv) in 100mL tetrahydrofuran at-60 deg.C was added NaHMDS (2M,25.58mL,51.16mmol,1.1 equiv). The reaction mixture was stirred at-15 ℃ for 1 hour. Then adding BF again at-60 deg.C₃.Et₂O (14.52mL,102.31mmol,2.20equiv) and a solution of 1-t-butoxycarbonyl-3-pyrrolidone (7-a) (10.34g,55.81mmol,1.2equiv) in THF (50 mL). The reaction mixture was stirred at-60 ℃ for 3h, then at room temperature for 3h, and LCMS monitored for completion. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 300 mL). The organic phases were combined, the solvent was removed under reduced pressure and the residue was isolated by column chromatography (MeOH/DCM, 0% -10%) to give compound 7-b (6.3g,46.5mmol, 37.9% yield) as a yellow solid. LCMS (ESI, M/z): [ M +1]⁺＝358.25。

The second step is that:

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

The third step:

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

Compound 7 was fractionated 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: elution with 60% mobile phase A and 40% mobile phase B for 14 minutes; flow rate: 1.0 ml/min; temperature: room temperature, "%" as a volume percentage) to give 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 intermediate)

The first step is as follows:

LDA (2M,14.53mL,29.06mmol,1.2equiv) was added to 50mL THF of Compound 8-a (5g,24.22mmol,1.00equiv) at-78 deg.C. After the reaction was stirred at-78 ℃ for an additional 30 minutes, a solution of N-tert-butoxycarbonyl-4-piperidone (5.79g,29.08mmol,1.2equiv) in THF (20mL) was added at-78 ℃. The reaction mixture was stirred at-78 ℃ for 3h, LCMS monitored reaction completion, saturated NaHCO₃The reaction was quenched with aqueous solution and extracted with ethyl acetate (3X 300 mL). The organic phases were combined, removed under reduced pressure and the residue was isolated by column chromatography (methanol/dichloromethane, 0% to 10%) to give compound 8-b (7.8g,19.23mmol, 80% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝405.05。

The second step is that:

to 1, 4-dioxane (100mL) of compound 8-b (7.8g,19.23mmol,1equiv) was added CuI (366.15mg,1.92mmol,0.10 equiv), Cs₂CO₃(12.53g,38.45mmol,2.00equiv) and 1,2-cyclohexanediamine (219.54mg,1.92mmol,0.1 equiv). The reaction was stirred at 100 ℃ overnight. LCMS showed reaction completion, saturated NaHCO₃The aqueous solution was quenched, extracted with ethyl acetate (3X 30mL), and the combined organic phases were freed from solvent under reduced pressure. The residue was subjected to column chromatography (methanol/dichloromethane, 0% to 10%) to give compound 8-c (2.1g,6.47mmol, 33% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝325.81。

The 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 (PPh)₃)₄(747.1mg,7.76mmol,0.10eqiv) and K₂CO₃(1.79g,12.93mmol,2.00 eqiv). The reaction mixture was stirred under nitrogen at 100 ℃ overnight. Reaction completion was monitored by LCMS, solvent was removed under reduced pressure, and the residue was subjected to column chromatography (ethyl acetate/petroleum ether, 0% -40%) to give compound 8-d (490mg,1.61mmol, 25% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝305.28。

The fourth step:

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

Preparation example 9 (preparation of Key intermediate)

The first step is as follows:

at room temperature, 4-bromobenzoic acid (1g,4.97mmol,1.00equiv) and oxalyl chloride (883.94mg,6.96mmol,1.4equiv) were added to a solution of DMF (18.18mg,0.248mmol,0.05equiv) in dichloromethane (10mL) and stirred vigorously at room temperature for 1 hour, the solvent was removed in vacuo, the residue was dissolved in acetonitrile (10mL), compound 9-a (30.3mg,14.92mmol,3equiv), Ph, was added₃P (808mg,12.44mmol,2.5 equiv). After the reaction mixture was stirred at room temperature for 5 hours, it was cooled to room temperature, water (20mL) and pyridine were added, and it was stirred vigorously at 80 ℃ for 1.5 hours, and then cooled to room temperature. Water (50mL) was added to the reaction system, and extraction was performed with methyl tert-butyl ether (3X 50 mL). The organic phases were combined and anhydrous Na₂SO₄Drying, solvent removal in vacuo, and silica gel column chromatography (ethyl acetate/petroleum ether, 10% -30%) of the residue afforded compound 9-b (500mg,1.74mmol, 35% yield) as a brown solid. LCMS (ESI, M/z) [ M-1 ]]^-＝284.9。

The second step is that:

to a solution of compound 9-b (500mg,1.74mmol,1equiv) in 1.4-dioxane (8mL) and water (2mL) was added 4-formylphenylboronic acid (313.4mg,20.2mmol,1.2equiv), K₂CO₃(772.19mg,5.23mmol,3equiv) and Pd (dppf)₂Cl₂(142.25mg,0.174mmol,0.1 equiv). The reaction mixture was stirred at 100 ℃ overnight under nitrogen. LCMS showed the reaction was complete, the solvent was removed under reduced pressure and the residue was isolated by silica gel column chromatography (EA/PE, 10% -30%) to give compound 9(230mg,0.73mmol, 42% yield) as a brown solid. LCMS (ESI, M/z) [ M-1 ]]^-＝311.05；¹H-NMR:¹H NMR (300MHz, chloroform-d) δ 10.07(s,1H),7.98(d, J ═ 8.0Hz,2H),7.76(d, J ═ 8.1Hz,2H),7.71(s,4H),6.14(t, J ═ 54.4Hz,2H).¹⁹F NMR (282MHz, chloroform-d) delta-130.11- -132.87 (m).

Preparation example 10 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 10-a (25.00g,262.88mmol,1.00equiv) in DMF (350ml) at 0 ℃ was added NaH (60%, 10.51g,262.88mmol,1.00 equiv). The reaction mixture was stirred at 0 ℃ for 30 minutes, then at this temperature, MOMCl (21.16g,262.88mmol,1.00equiv) was added. The reaction was allowed to warm to room temperature and continued stirring for 16 h LCMS indicated completion of the reaction, saturated NH₄Aqueous Cl solution and water (700ml) were quenched and extracted with ethyl acetate (3X 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 (22.70g,163.13mmol, 62.05% yield) as a yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝140.15.¹H NMR (400MHz, chloroform-d) δ 8.41(dd, J ═ 2.9,0.7Hz,1H),8.27(dd, J ═ 4.7,1.4Hz,1H),7.37(m,1H),7.22(m,1H),5.20(s,2H),3.49(s, 3H).

The second step is that:

to a solution of compound 10-b (15.00g,107.79mmol,1.00equiv) in THF (300ml) at-70 deg.C was added s-BuLi (1.3M,124.38ml,161.69mmol,1.50 equiv). The reaction mixture was stirred at-70 ℃ for 1 hour, then at this temperature, acetaldehyde (12.35g,280.27mmol,2.60equiv) was added and stirred while maintaining the temperature for 3 hours. LCMS shows reaction completion, transThe mixture is saturated with NH₄Aqueous Cl solution and water (300ml) were quenched, extracted with ethyl acetate (3X 300ml), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was isolated by silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to give compound 10-c (17.00g,92.79mmol, 86.08% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝184.10。¹H 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 ═ 6.5Hz,1H),3.51(s,3H),1.49(d, J ═ 6.5Hz, 3H).

The third step:

to a solution of compound 10-c (13.00g,70.96mmol,1.00equiv) in DCM (100ml) was added NaHCO at room temperature₃(17.88g,212.87mmol,3.00equiv) and DMP (51.16g,120.63mmol,1.70 equiv.) the reaction mixture was stirred at room temperature for 1 hour. LCMS showed reaction completion, reaction saturated Na₂S₂O₃The aqueous solution was quenched with water (300ml) and extracted with ethyl acetate (3X 300 ml). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was isolated by silica gel column chromatography (ethyl acetate/petroleum ether, 50% to 80%) to give compound 10-d (8.80g,48.57mmol, 68.45% yield) as a red oil. LCMS (ESI, M/z) [ M +1]]⁺＝182.10。¹H NMR (400MHz, chloroform-d) δ 8.64(s,1H),8.38(d, J ═ 4.9Hz,1H),7.46(dd, J ═ 4.8,0.6Hz,1H),5.33(s,2H),3.54(s,3H),2.64(s, 3H).

The fourth step:

to a solution of compound 10-d (10.55g,58.23mmol) in MeOH (100ml) at room temperature was added HCl (50ml) and the reaction mixture was stirred at 80 ℃ for 3 h. LCMS showed the reaction was complete and the reaction mixture was basified to pH 9 with NaOH (2M aq) and stripped under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to isolate compound 10-e (5.95g,43.39mmol, 74.51% yield) as a yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝138.20。¹H 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:

to a solution of compound 10-e (5.95g,43.39mmol,1.00equiv) in acetonitrile (90ml) at room temperatureTo this was added pyrrolidine (pyrrolidine, 9.26g,130.16mmol,3.00equiv), acetic acid (7.82g,130.16mmol,3.00equiv) and tert-butyl 3-oxoazetidine-1-carboxylate (tert-butyl 3-oxoazetidine-1-carboxylate) (11.14g,65.08mmol,1.50 equiv). The reaction mixture was stirred at 65 ℃ 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 (10mM NH)₄HCO₃) 40% to 60%) to give compound 10-f (5.68g,19.56mmol, 45.09% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝291.10。¹H NMR (400MHz, chloroform-d) δ 8.61(s,1H),8.40(d, J ═ 5.0Hz,1H),7.62(d, J ═ 4.9Hz,1H),4.12(d, J ═ 9.5Hz,2H),3.98(d, J ═ 9.6Hz,2H),3.12(s,2H),1.45(s, 9H).

And a sixth step:

NaBH was added to a solution of compound 10-f (3.00g,10.33mmol,1.00equiv) in methanol (30ml) at 0 deg.C₄(781.87mg,20.67mmol,2.00 equiv). The reaction mixture was stirred at 50 ℃ for 1 h. LCMS showed reaction completion. The residue was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) 35% to 55%) to give compound 10-g (2.60g,8.89mmol, 86.07% yield) as a light yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝293.10。¹H 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 ═ 5.9Hz,1H),4.21(dd, J ═ 9.6,1.0Hz,1H), 4.11-4.04 (m,2H),3.96(dd, J ═ 9.4,1.1Hz,1H),2.48(s,1H), 2.44-2.28 (m,2H),1.45(s, 9H).

The seventh step:

et was added to a solution of 10-g (1.30g,4.45mmol,1.00equiv) of the compound in dichloromethane (25mL) at 0 deg.C₃N (1.35g,13.34mmol,3.00 equiv). The mixture was stirred at 0 ℃ for 30 minutes, and MsCl (764.05mg,6.67mmol,1.50equiv) was added to the above reaction system. The reaction mixture was stirred at room temperature for 16 h, diluted with water (50ml) and extracted with dichloromethane (3X 20 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo. The residue was stirred at 100 ℃ for 4 hours after addition of DBU (13ml) and LCMS indicated completion of the reaction. The reaction mixture was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) 40% to 60%) was isolated as 10-h (700.00mg,2.55 mmo)l, 57.38% yield), yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝275.10。¹H 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 ═ 9.8Hz,1H),6.15(d, J ═ 9.9Hz,1H),4.29 to 4.22(m,2H),4.01(m,2H),1.45(s, 9H).

Eighth step:

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

The ninth step:

to a solution of compound 10-i (695.00mg,2.52mmol) in dichloromethane (10ml) was added HCl (4M ethyl acetate solution, 10 ml). The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was basified in methanol (10ml) with NaOH (2M aqueous solution) to pH 11 and stirred at room temperature for 1 hour. LCMS showed the reaction was complete and the reaction mixture was chromatographed on reverse phase column (C18 silica gel; acetonitrile/water (0.1% NH)₃.H₂O), 25% to 45%) to give compound 10(290.00mg,1.65mmol, 65.43% yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝177.10。¹H NMR(400MHz,DMSO-d₆)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 intermediate)

The first step is as follows:

LDA (2M n-hexane solution, 29.06ml,58.12mmol,1.20equiv) was added to a solution of compound 11-a (10.00g,48.43mmol,1.00equiv) in tetrahydrofuran (80ml) at-70 ℃. The reaction mixture was stirred at-70 ℃ for 30 minutes, and then tert-butyl 4-oxopiperidine-1-carboxylate (tert-butyl 4-oxo) was added to the above solution at this temperaturepiperidine-1-carboxylate, 11.58g,58.12mmol,1.20equiv) in THF (20 ml). The reaction mixture was stirred at-70 ℃ for an additional 3 hours. LCMS showed reaction completion. The reaction mixture was saturated NaHCO₃The aqueous solution was quenched with water (100ml) and extracted with ethyl acetate (3X 100ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to isolate compound 11-b (13.82g,34.06mmol, 70.33% yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝405.00.¹H NMR (400MHz, chloroform-d) δ 8.20(d, J ═ 4.9Hz,1H),7.22(d, J ═ 4.9Hz,1H),3.90(m,2H), 3.11-3.01 (m,4H), 1.76-1.64 (m,4H),1.44(s, 9H).

The second step is that:

to a solution of compound 11-b (13.82g,34.06mmol,1.00equiv) in 1, 4-dioxane (130ml) was added CuI (648.73mg,3.41mmol,0.10equiv), Cs at room temperature₂CO₃(22.20g,68.13mmol,2.00equiv) and 1,2-cyclohexanediamine (1,2-diaminocyclohexane, 388.97mg,3.41mmol,0.10 equiv). The reaction mixture was stirred at 100 ℃ for 5 hours. LCMS showed reaction completion. The reaction mixture was saturated NaHCO₃The aqueous solution was quenched with water (200ml) and extracted with ethyl acetate (3X 200 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to obtain a crude product (7.30 g). The crude product (1.00g) was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) 45% to 65%) to give compound 11(0.55g,1.69mmol) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝325.05。¹H 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 intermediate)

To a solution of compound 2(10.1g,27.29mmol,1equiv) in 1, 4-dioxane (80mL) and water (20mL) was added 4-bromo-3, 5-difluorobenzoic acidAldehyde (7.24g,32.75mmol,1.2equiv), K₂CO₃(11.31g,81.87mmol,3equiv) and Pd (PPh)₃)₄(3.15g,2.73mmol,0.1 equiv). The reaction mixture was stirred at 100 ℃ overnight under nitrogen. 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 (0.1% FA (trifluoroacetic acid)), 45% to 75%) to isolate compound 12(3.7g,9.63mmol, 35.3% yield) as a white solid. LCMS (ESI, M/z): [ M-1 ]]^-＝382.85。¹H NMR (300MHz, chloroform-d) δ 10.01(s,1H),7.88(d, J ═ 8.3Hz,2H),7.64(d, J ═ 8.6Hz,2H),7.57(d, J ═ 7.3Hz,2H),3.49(s, 1H).

Preparation example 13 (preparation of Key intermediate)

To a solution of compound 13-a (1.00g,2.58mmol,1equiv) in 1, 4-dioxane (8mL) and water (2mL) was added 5-bromo-2-pyridinecarbaldehyde (5-bromopyrrolidinaldehyde, 576.6mg,3.10mmol,1.2equiv), K₂CO₃(1.07g,7.74mmol,3equiv) and Pd (PPh)₃)₄(268.3mg,0.26mmol,0.1 equiv). The reaction mixture was stirred at 100 ℃ overnight under nitrogen. LCMS showed reaction completion. The solvent was removed under reduced pressure. The residue was subjected to high performance liquid chromatography (column model: Gemini-NX C18 AXAI Packed, 21.2X 150mm 5 um; mobile phase A: water (10MMOL/L NH)₄HCO₃) The mobile phase B is acetonitrile; the flow rate is 25 mL/min; gradient, 10B to 10B in 2min,10B to 41B in 2.5min,41B to 65B in 10.5min,220 nm; retention time 9.67min) to give compound 13(213.2mg,0.58mmol, 23% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝368.00。¹H 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).¹⁹F NMR (377MHz, chloroform-d) delta-75.45, -115.15.

Preparation 14 (preparation of Key intermediate)

To a solution of compound 2(1.00g,2.7mmol,1equiv) in 1, 4-dioxane (8mL) and water (2mL) was added compound 14-a (660.96mg,3.24mmol,1.2equiv), K₂CO₃(1.11g,8.1mmol,3equiv) and Pd (PPh)₃)₄(311.58mg,0.27mmol,0.1 equiv). The reaction mixture was stirred at 100 ℃ overnight under nitrogen. LCMS shows completion of the reaction, solvent was removed under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (column model: Gemini-NX C18 AXAI pad, 21.2X 150mm 5 um; mobile phase A: water (10MMOL/L NH)₄HCO₃) The mobile phase B is acetonitrile; the flow rate is 25 mL/min; gradient, 10B to 10B in 2min,10B to 41B in 2.5min,41B to 65B in 10.5min,220 nm; retention time 9.67min) to give compound 14(202.2mg,0.55mmol, 20% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝368.00。¹H 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).¹⁹F NMR(377MHz,CDCl₃)δ-75.416,-123.758。

Preparation example 15 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 15-a (5g,29.07mmol,1.00equiv) in 50mL tetrahydrofuran at-78 deg.C was added LDA (2M,17.44mL,34.88mmol,1.2 equiv). The reaction mixture was stirred at this temperature for 30 minutes. While maintaining the temperature, a solution of compound 15-b (7.86g,34.88mmol,1.2equiv) in tetrahydrofuran (20mL) was added to the above reaction system, and the reaction mixture was stirred at-78 ℃ for 3 h. LCMS shows the reaction is complete and the reaction system is saturated NaHCO₃The aqueous solution was quenched and extracted with ethyl acetate (3X 300 mL). The organic phases were combined and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% -10%) to give compound 15-c (3.2g,8.05mmol, 28% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝398.31。

The second step is that:

to a solution of compound 15-c (1.0g,2.51mmol,1equiv) in 1, 4-dioxane (10mL) was added CuI (47.69mg,0.251mmol,0.10 equiv), Cs₂CO₃(1.64g,5.02mmol,2.00equiv) and 1,2-cyclohexanediamine (1,2-cyclohexanediamine, 28.61mg,0.251mmol,0.1 equiv). The reaction mixture was stirred at 100 ℃ overnight. LCMS showed reaction completion, saturated NaHCO₃The aqueous solution was quenched and extracted with ethyl acetate (3X 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 15-d (520mg) which was used directly in the next step. LCMS (ESI, M/z) [ M +1]]⁺＝317.31。

The third step:

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

Preparation example 16 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 16-a (5.00g,36.46mmol,1.00equiv) in acetonitrile (75ml) was added pyrrolidine (7.78 g,109.38mmol,3.00equiv), AcOH (6.57g,109.38mmol,3.00equiv) and compound 16-b (11.24g,65.63mmol,1.80equiv) at room temperature. The reaction mixture was stirred at 65 ℃ for 5 hours. LCMS showed reaction completion and solvent was removed under reduced pressure. The residue was subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) From 40% to 60%) Compound 16-c was isolated (1.60g,5.51mmol, 15.12% yield) as a pale yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝291.10。

The second step is that:

NaBH was added to a solution of compound 16-c (2.80g,9.64mmol,1.00equiv) in methanol (30ml) at 0 deg.C₄(729.74mg,19.29mmol,2.00 equiv). The reaction mixture was stirred at 50 ℃ for 1.5h and LCMS indicated completion of the reaction. The residue was subjected to reverse phase column chromatography (C18 silica gel acetonitrile/water (10mM NH)₄HCO₃) 40% to 60%) was isolated to give compound 16-d (2.30g,7.87mmol, 81.58% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝293.10。¹H 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 ═ 4.7Hz,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 ═ 14.1,5.0Hz,1H),2.28(dd, J ═ 14.1,4.4Hz,1H),1.45(s, 9H).

The third step:

et was added to a solution of Compound 16-d (1.50g,5.13mmol,1.00equiv) in dichloromethane (30mL) at 0 deg.C₃N (1.56g,15.39mmol,3.00 equiv). After the reaction mixture was stirred at 0 ℃ for 30 minutes, MsCl (881.60mg,5.13mmol,1.50equiv) was added, and stirred at room temperature for 16 hours. The reaction was diluted with water (50ml) and extracted with dichloromethane (3X 20 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. DBU (15ml) was added to the residue and stirred at 100 ℃ for 4 hours. LCMS showed reaction complete. The reaction system is subjected to reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) 40% to 60%) was isolated to give compound 16-e (900.00mg,3.28mmol, 63.94% yield) as a pale yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝275.15。¹H 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 ═ 9.9Hz,1H),4.24(dd, J ═ 9.6,1.1Hz,2H),4.03(dd, J ═ 9.6,1.0Hz,2H),1.46(s, 9H).

The fourth step:

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

The fifth step:

a mixture of compound 16-f (500.00mg,1.81mmol) and HCl (4M in ethyl acetate, 5.00ml) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was basified in methanol (5ml) with NaOH (2M aq) to pH 11 and stirred at room temperature for 1.5 h. LCMS showed complete reaction and the reaction mixture was chromatographed on reverse phase column (C18 silica; acetonitrile/water (10mM NH)₄HCO₃) 15% to 35%) was isolated to give compound 16(215.00mg,1.22mmol, 67.43% yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝177.10。¹H NMR(400MHz,DMSO-d₆)δ8.21(s,1H),8.16(d,J＝5.5Hz,1H),6.79(d,J＝5.6Hz,1H),3.60–3.54(m,2H),3.39–3.34(m,2H),2.75(m,2H),2.10(m,2H)。

Preparation example 17 (preparation of Key intermediate)

Compound 8-c (400mg,1.23mmol,1equiv) and HCl (4M in 1, 4-dioxane, 4.62mL,18.47mmol,15equiv) were stirred at room temperature for 1.5 h. LCMS showed reaction completion, solvent was removed under reduced pressure, residue was diluted with water, basified to pH 8 with NaOH (2M aq) and reverse phase column chromatography (C18 silica gel; acetonitrile/water (3% NH)₃.H₂O), 15% to 25%) was isolated to give compound 17(80mg,0.36mmol, 29% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝225.69。¹H 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 18 (preparation of Key intermediate)

The first step is as follows:

to a solution of compound 18-a (20.00g,114.94mmol,1.00equiv) in 400mL of DMF at 0 deg.C was added NaH (60%, 9.19g,229.89mmol,2.00 equiv). After the reaction mixture was stirred at 0 ℃ for 30 minutes, MOMCl (11.11g,137.93mmol,1.20equiv) was added at this temperature, followed by stirring at room temperature for 2 hours. LCMS showed reaction completion, quenched with water (1000ml), extracted with ethyl acetate (3 × 300 ml). The organic phase was washed with saturated brine (2X 200ml), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% -10%) to give compound 18-b (9.20g,42.19mmol, 36.71% yield) as a pale yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝217.95。¹H NMR(400MHz,DMSO-d₆)δ8.61(s,1H),8.40(d,J＝5.6Hz,1H),7.22(d,J＝5.6Hz,1H),5.42(s,2H),3.41(s,3H)。

The second step is that:

to a solution of compound 18-b (10.40g,47.70mmol,1.00equiv) in toluene (100mL) under nitrogen was added tributyl (1-ethoxyvinyl) tin (tributyl (1-ethoxyvinyl) stannane, 25.84g,71.54mmol,1.50equiv) and Pd (PPh)₃)₄(5.51g,4.77mmol,0.10 equiv). The reaction mixture was stirred at 110 ℃ for 4 hours. LCMS showed the reaction was complete and the solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (methanol/dichloromethane, 0% -10%) to give compound 18-c (4.70g, crude) as a yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝210.10。

The third step:

to a solution of compound 18-c (4.70g, crude) in methanol (20ml) was added HCl (12N,50ml,27.00equiv), followed by stirring at 70 ℃ for 16 hours. LCMS indicated completion of the reaction, concentrated under reduced pressure, and the residue neutralized to pH 8 and isolated by silica gel column chromatography (methanol/dichloromethane, 0% to 10%) to give compound 18-d (2.20g,16.04mmol, 33.63% 2 step total yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝138.15。¹H NMR(400MHz,DMSO-d₆)δ11.83(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:

to a solution of compound 18-d (2.20g,16.04mmol,1.00equiv) in methanol (40ml) was addedPyrrolidine (2.28 g,32.08mmol,2.00equiv) and tert-butyl 4-oxopiperidine-1-carboxylate (tert-butyl-4-oxopiperidine-1-carboxylate, 3.20g,16.04mmol,1.00equiv) were added. The reaction mixture was stirred at 80 ℃ for 4 hours. LCMS shows reaction completion followed by reverse phase column chromatography (C18 silica; acetonitrile/water (10mM NH)₄HCO₃) 40% to 60%) to give compound 18-e (2.10g,6.60mmol, 41.12% yield) as a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝319.10。¹H NMR (300MHz, chloroform-d) δ 9.01(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 (3.90g,12.25mmol,1.00equiv) in methanol (40ml) at 0 deg.C was added NaBH₄(926.88mg,24.50mmol,2.00 equiv). The reaction mixture was stirred at 50 ℃ for 1.5 hours. LCMS showed the reaction was complete and the reaction was purified by reverse phase column chromatography (C18 silica gel; acetonitrile/water (10mM NH)₄HCO₃) 40% to 60%) was isolated to give compound 18-f (3.50g,10.92mmol, 89.18% yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝321.15。¹H NMR(400MHz,DMSO-d₆)δ8.48(s,1H),8.21(d,J＝5.6Hz,1H),6.78(d,J＝5.6Hz,1H),5.56(d,J＝6.0Hz,1H),4.78(d,J＝8.6Hz,1H),3.67(s,2H),3.24(s,1H),3.09(s,1H),2.14(dd,J＝13.7,5.9Hz,1H),1.85–1.75(m,2H),1.73–1.63(m,2H),1.63–1.53(m,1H),1.40(s,9H)。

And a sixth step:

et was added to a solution of Compound 18-f (2.70g,8.43mmol,1.00equiv) in dichloromethane (50mL) at 0 deg.C₃N (2.56g,25.28mmol,3.00 equiv). After the reaction mixture was stirred at 0 ℃ for 30 minutes, MsCl (1.45g,12.64mmol,1.50equiv) was added, and the mixture was stirred at room temperature for 16 hours. Water (100ml) was added for dilution, dichloromethane (3X 50ml) was extracted, the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was stirred at 100 ℃ for 4 hours after addition of DBU (28 ml). LCMS shows reaction completion followed by reverse phase column chromatography (C18 silica; acetonitrile/water (10mM NH)₄HCO₃) 45% to 65%) to yield compound 18-g (1.80g,5.95mmol, 70.64% yield) as a pale yellow solidAnd (3) a body. LCMS (ESI, M/z) [ M +1]]⁺＝303.10。¹H NMR (400MHz, chloroform-d) δ 8.25(d, J ═ 5.6Hz,1H),8.15(s,1H),6.72(d, J ═ 5.5Hz,1H),6.41(dd, J ═ 10.0,0.8Hz,1H),5.59(d, J ═ 9.9Hz,1H),3.86(s,2H),3.28(s,2H),1.98(d, J ═ 13.7Hz,2H),1.64(ddd, J ═ 13.9,11.6,4.9Hz,2H),1.47(s, 9H).

The seventh step:

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

Eighth step:

a mixture of 18-h (890.00mg,2.92mmol) and HCl (4M in ethyl acetate, 10.00ml) was stirred at room temperature for 1 hour and then the solvent was removed under reduced pressure, the methanol (5ml) solution of the residue was basified to pH 11 with NaOH (2N in water) and stirred at room temperature for 1.5 hours, LCMS indicated complete reaction, reverse phase column chromatography (C18 silica; acetonitrile/water (0.1% NH)_3.H₂O), 25% to 50%) was isolated to give compound 18(509.00mg,2.49mmol, 85.22% yield) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝205.10。¹H NMR(400MHz,DMSO-d₆)δ8.20(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

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (50mg,0.263mmol) and 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (3) (91mg,0.263mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50. mu.L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (167mg, 0.788mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution is concentratedThe crude product was purified by flash column chromatography (methanol: dichloromethane 0-10%) to give the objective compound (I-1)29mg as a yellow solid in 21% yield.¹H NMR(400MHz,CDCl₃)δ8.10(s,2H),7.85(d,J＝8.3Hz,2H),7.69(d,J＝8.7Hz,2H),7.62(d,J＝8.0Hz,2H),7.50(d,J＝3.3Hz,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

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (50mg,0.263mmol) and 2' -fluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (1) (96mg,0.263mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50. mu.L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (167mg, 0.788mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-2)74mg as a yellow solid in 52% yield.¹H NMR(400MHz,CDCl₃)δ8.10(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

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (50mg,0.263mmol) and 4'- (perfluoropropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (6) (92mg,0.263mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50 μ L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (167mg, 0.788mmol) was added, and stirring was again performed at room temperature for 18 hours. Concentrating the reaction solution, separating and purifying the obtained crude product by flash column chromatography (methanol: dichloromethane ═ 0-10%) to obtain the target productCompound 14mg, yellow solid, yield 10%. 1H NMR (400MHz, CDCl3) δ 8.17(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

The first step is as follows:

anhydrous THF (20mL) was added to a three-necked flask under Ar, cooled to-78 ℃. A solution of phenyllithium (2.0M/L,5mL) was added slowly, followed by diisopropylamine (17mg, 0.17mmol), and stirring was continued at this temperature for 10 min. 2, 4-dichloropyridine (I-4-a) (1.48g, 10mmol) was added dropwise to the reaction system, followed by warming to-40 ℃ and stirring for 1 hour. Cooling to-78 deg.C, and adding N-Boc-1-oxa-6-azaspiro [ 2.5%]Octane (1.065g, 5mmol) in THF (5mL) and reacted at-60 ℃ for 2 hours. After TLC monitoring reaction is finished, the reaction system is saturated NH₄Aqueous Cl (10mL) quench. Water (30mL) and ethyl acetate (30mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate: petroleum ether ═ 1:2) to give 4- ((2, 4-dichloropyridin-3-yl) methyl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I-4-b) (740mg) as a pale yellow oil. LC-MS M/z (M-55)⁺＝305.0。

The second step is that:

tert-butyl 4- ((2, 4-dichloropyridin-3-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-4-b) (388mg,1.07mmol) was dissolved in dry DMF (10mL) under Ar, cooled to 0 ℃ on an ice bath, NaH (60%, 107mg, 2.68mmol) was added, warmed slowly to room temperature and stirred for 16 h. After completion of the TLC monitoring, the reaction was cooled to 0 ℃ and saturated NH was used₄Aqueous Cl (10mL) quench. Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined and washed with saturated sodium chloride solution (20mL)Washed and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying by column chromatography (ethyl acetate: petroleum ether: 1:2) to obtain 4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (I-4-c) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-4-d) -1' -carboxylate (272mg) as a pale yellow oil. LC-MS M/z (M + H)⁺＝324.8。

The third step:

reacting 4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (I-4-c) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines]The mixture of tert-butyl (I-4-d) -1' -carboxylate (150mg, 0.46mmol) was added to dioxane hydrochloride solution (4M/L,8 mL). Stirred at room temperature for 4 hours. After the LC-MS monitoring reaction is finished, evaporating the reaction system to dryness to obtain 4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines](I-4-e) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines](I-4-f) (176mg), a white solid, crude was used directly in the next reaction. LC-MS M/z (M + H)⁺＝224.6。

The fourth step:

the last step of the reaction is 4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines](I-4-e) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines](I-4-f) crude mixture (44mg), 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl-]-4-Formaldehyde (52mg, 0.15mmol) was dissolved in DMF (8mL), and triethylamine (46mg, 0.45mmol) and acetic acid (14mg, 0.225mmol) were added in this order, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (96mg, 0.45mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 2- (4' - ((4-chloro-3H-spiro [ furo [3, 2-c))]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropyl-2-ol (I-4) (25mg) as a white solid. LC-MS M/z (M + H)⁺＝557.0。1H NMR(400MHz,CDCl3)δ8.07(d,J＝5.5Hz,1H),7.80(d,J＝8.2Hz,2H),7.67(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,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

The first step is as follows:

4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (I-4-c) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-4-d) -1' -carboxylate mixture (125mg,0.385mmol) was dissolved in methanol (10 mL). 10% Pd/C (30mg) was added and the system was placed in H₂The mixture was stirred at room temperature for 16 hours under an atmosphere. After completion of the TLC monitoring reaction, Pd/C was removed by filtration and the filtrate was evaporated to dryness. To obtain 3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (I-5-a) and 3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines]Crude mixture (130mg) of tert-butyl (I-5-b) -1' -carboxylate, yellow oil. LC-MS M/z (M + H)⁺＝290.8。

The second step is that:

reacting 4-chloro-3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (I-5-a) and 4-chloro-3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines]The crude mixture of tert-butyl (I-5-b) -1' -carboxylate (130mg) was added to dioxane hydrochloride solution (4M/L,8 mL). Stirred at room temperature for 4 hours. After the LC-MS monitoring reaction is finished, evaporating a reaction system to dryness to obtain the 3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines](I-5-c) and 3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines](I-5-d) mixture (146mg), white solid, crude product was used directly in the next reaction. LC-MS M/z (M + H)⁺＝190.7。

The third step:

the 3H-spiro [ furo [3,2-c ] in the last step]Pyridine-2, 4' -piperidines](I-5-c) and 3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines](I-5-d) mixture (146mg), 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl ]]-4-Formaldehyde (134mg, 0.39mmol) was dissolved in N, N-dimethylformamide (8mL), and triethylamine (117mg, 1.16mmol) and acetic acid (35mg, 0.58mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Adding triethyl phosphateSodium acyloxyborohydride (245mg, 0.39mmol) was stirred at room temperature for 16 h. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 2- (4' - ((3H-spiro [ furo [2, 3-b)]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) -hexafluoropropyl-2-ol (I-5) (53mg) as a white solid. LC-MS M/z (M + H)⁺＝523.0。¹H 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)。

Examples 6 and 11

Reacting 3H-spiro [ furo [3,2-c ]]Pyridine-2, 4' -piperidines](I-5-c) and 3H-spiro [ furo [2,3-b ]]Pyridine-2, 4' -piperidines](I-5-d) mixture (80mg), 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (74mg, 0.20mmol) was dissolved in N, N-dimethylformamide (8mL), and triethylamine (61mg, 0.60mmol) and acetic acid (18mg, 0.30mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (127mg, 0.60mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. Concentrating organic phase, purifying with high performance liquid chromatography to obtain 2- (4' - ((3H-spiro [ furo [3, 2-c))]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) -2-fluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropyl-2-ol (I-11) (34mg) and 2- (4' - ((3H-spiro [ furo [2,3-b ]))]Pyridine-2, 4' -piperidines]-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 to 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 to 1.83(m, 2H). HPLC (Methods HCOOH 5 ~ 95.M), Retention Time (RT): 7.381 minutes. Compound I-6: a 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

The first step is as follows:

2-bromo-5-formylpyridine (I-7-a) (100mg, 0.538mmol), 1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) propyl-2-ol (398mg, 1.075mmol) was placed in N, N-dimethylformamide (20 mL). Adding Pd (PPh)₃)₂Cl₂(74mg，0.105mmol)，K₃PO₄(456mg, 2.15 mmol). And an Ar gas protection system is heated to 90 ℃ for reaction for 16 hours. After completion of the reaction, water (20mL) and ethyl acetate (20mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (20 mL. times.2), washed with water (20mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate 10:1) to give 6- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) phenyl) nicotinaldehyde (I-7-b) (140mg) as a white solid. LC-MS M/z (M + H)⁺＝350.0。

The second step is that:

the last step, 6- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) phenyl) nicotinaldehyde (I-7-b) (140mg, 0.40mmol), 3H-spiro [ furo [2,3-c ] was added]Pyridine-2, 4' -piperidines](4) (76mg, 0.40mmol) was dissolved in N, N-dimethylformamide (8mL), and triethylamine (122mg, 1.20mmol) and acetic acid (36mg, 0.60mmol) were added in this order, followed by stirring at room temperature for 30 minutes. Adding triacetoxyborohydrideSodium (254mg, 1.20mmol), stirred at room temperature for 16 h. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying by column chromatography (dichloromethane: methanol ═ 20:1) to obtain 2- (4- (5- ((3H-spiro [ furo [2, 3-c)]Pyridine-2, 4' -piperidines]-1' -yl) methyl) pyridin-2-yl) phenyl) -1,1,1,3,3, 3-hexafluoropropyl-2-ol (I-7) (96mg) as a white solid. LC-MS M/z (M + H)⁺＝524.0。¹H 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

The first step is as follows:

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

The second step is that:

1' - (4-bromo-3-fluorobenzyl) -3H-spiro [ furan [2, 3-c)]Pyridine-2, 4' -piperidines](I-9-b) (200mg,0.53mmol) was dissolved in 1, 4-dioxane (15mL), and 1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (2) (294mg, 0.80mmol), potassium carbonate (223mg, 1.59mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] were added to the reaction solution]Palladium dichloride (78mg, 0.11mmol) was added and the reaction was heated to 100 ℃ under nitrogen and stirred for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography (dichloromethane/methanol 0-10%) to obtain a target compound 2- (4' - ((3H-spiro [ furan [2,3-c ])]Pyridine-2, 4' -piperazinesPyridine (I)]-1' -yl]Methyl) -2 '-fluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-9) (121mg, 42.22%). LC-MS: 541.0[ M +1]]⁺。1H NMR(400MHz,CDCl3)δ8.14–8.05(m,2H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝7.6Hz,2H),7.44(t,J＝8.0Hz,1H),7.27–7.21(m,1H),7.17(d,J＝4.6Hz,0H),2.82(d,J＝39.8Hz,2H),2.02(d,J＝5.1Hz,2H),0.89(ddd,J＝11.7,8.1,4.3Hz,1H)。

Example 10

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 3' -pyrrolidines](52mg,0.295mmol) (7),2' -fluoro-4 ' - ((1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (140mg,0.38mmol) (1) was added to 20ml of dichloromethane, followed by addition of sodium borohydride acetate (130mg,0.62mmol), and stirred at room temperature overnight. The reaction mixture was concentrated, 10ml of saturated sodium carbonate solution was added, dichloromethane was extracted twice (2 × 25ml), the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated on a column {7M aminomethanol (dichloromethane: ethyl acetate: 12:2) } 0-15%, whereby 75mg of a white solid (I-10) was obtained with a yield of 48%. LC-MS M/z (M + H)⁺＝526。1H NMR(400MHz,CDCl3)δ8.11–7.94(m,2H),7.72–7.62(m,2H),7.59–7.49(m,3H),7.45(d,2H),7.17(d,1H),3.85–3.71(m,2H),3.29(q,2H),3.06(d,1H),2.98(m,1H),2.85–2.71(m,2H),2.43(m,1H),2.19–2.04(m,1H)。

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

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

Example 14

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (52mg,0.273mmol) and 4- (5- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) pyridin-2-yl) benzaldehyde (I-14-a) (95mg,0.273mmol) were dissolved in dichloromethane (10ml), followed by addition of trifluoroacetic acid (50. mu.L). After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (174mg, 0.821mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-14)21mg as a yellow solid in a yield of 15%.¹H 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:

the first step is as follows:

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

The second step is that:

reacting 1' - (((2-chloropyrimidin-5-yl) methyl) -3H-spiro [ furan [2, 3-c)]Pyridine-2, 4' -piperidines](16mg,0.05mmol) (I-15-b),1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (22mg,0.06mmol) (2), potassium carbonate (20mg,0.14mmol), water (0.1mL) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (6mg, 0.0074mmol) was added to 5ml of 1, 4-dioxane and stirred overnight at 100 ℃ under nitrogen. The reaction solution was concentrated by filtration and separated on a thin layer chromatography plate (methanol (dichloromethane: ethyl acetate: 10: 2) ═ 1: 10}. The obtained objective product was dissolved in methylene chloride, 0.1ml of 4M dioxane hydrochloride was added thereto, and the solvent was distilled off to obtain 3mg of a white solid (I-15) in a yield of 10%. LC-MS M/z (M + H)⁺＝525。1H NMR(400MHz,MeOD)δ9.15(s,2H),8.61(d,J＝8.9Hz,2H),8.43(s,2H),7.97(d,J＝5.4Hz,1H),7.92(d,J＝8.5Hz,2H),4.61(s,2H),3.61(m,6H),2.40(m,4H)。

Example 16

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (63mg,0.331mmol) and 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (12) (127mg,0.331mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50 μ L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (210mg, 0.991mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-16)40mg as a yellow solid in 22% yield.¹H NMR(400MHz,DMSO)δ8.86(s,1H),8.16-8.02(m,2H),7.81(d,J＝8.3Hz,2H),7.64(d,J＝8.4Hz,2H),7.26(dd,J＝21.7,6.5Hz,3H),3.62(s,2H),3.08(s,2H),2.57(s,2H),1.87(dd,J＝18.9,14.3Hz,4H).LC-MS:m/z:(M+H)⁺＝559.1。

Example 17

The first step is as follows:

dissolving 1, 4-dibromobenzene (I-17-a) (5.72g, 24.2mmol) in anhydrous tetrahydrofuran (20mL), cooling the reaction solution to-78 ℃, dropwise adding N-butyl lithium N-hexane solution (25.5mL, 1N) into the reaction solution, stirring the reaction solution at-78 ℃ for 0.5 hour after dropwise adding, adding ethyl 2, 2-difluoroacetate (6.62g, 53.3mmol) into the reaction solution, stirring the reaction solution at-78 ℃ for 1 hour after adding, adding saturated ammonium chloride aqueous solution into the reaction solution to quench the reaction, heating the reaction solution to room temperature, extracting ethyl acetate, washing an organic phase with saline water, drying anhydrous sodium sulfate, filtering, concentrating, and performing silica gel column chromatography (petroleum ether/ethyl acetate is 0-10%) to obtain a target compound 1- (4-bromophenyl) -2, 2-Difluoroethan-1-one (I-17-b) (4.0g, 70%).

The second step is that:

dissolving 1- (4-bromophenyl) -2, 2-difluoroethane-1-one (I-17-b) (4.0g, 17mmol) in tetrahydrofuran (20mL), cooling the reaction solution to 0 ℃, adding trimethyl (trifluoromethyl) silane (4.8g, 34mmol) into the reaction solution, slowly dropwise adding a tetrahydrofuran solution (34mL, 1N) of tetrabutylammonium fluoride, controlling the temperature to be lower than 5 ℃ when dropwise adding is finished, stirring at the temperature of the reaction solution chamber for 16 hours after dropwise adding is finished, adding an aqueous solution into the reaction solution to quench the reaction, extracting ethyl acetate, washing an organic phase with saline water, drying with anhydrous sodium sulfate, filtering, concentrating, performing silica gel column chromatography (petroleum ether/ethyl acetate is 0-10%) to obtain a target compound 2- (4-bromophenyl) -1,1,1,3, 3-Pentafluoropropan-2-ol (I-17-c) (4.2g, 81%).

The third step:

dissolving 2- (4-bromophenyl) -1,1,1,3, 3-pentafluoropropane-2-ol (I-17-c) (500mg, 1.64mmol) in 1, 4-dioxane (20mL), and adding 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (I-23-c) (295mg, 1.97mmol), potassium carbonate (690mg, 4.92mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] to the reaction mixture under nitrogen]Palladium dichloride (240mg, 0.33mmol) was added and the reaction was heated to 100 ℃ and stirred for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography (petroleum ether/ethyl acetate is 0-10%) to obtain a target compound 4'- (1,1,1,3, 3-pentafluoro-2-hydroxypropane-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (I-17-d) (170mg, 31.41%). LC-MS: 331[ M +1]]⁺。

The fourth step:

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

Example 18

The first step is as follows:

dissolving 2-bromothiazole-5-carbaldehyde (I-28-a) (100mg,0.52 mmol) in N, N-dimethylformamide (10mL), adding 1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenyl) propan-2-ol (2) (386, mg, 1.04mmol), potassium phosphate (442mg, 2.08mmol) and bis (triphenylphosphine) palladium (73mg, 0.1mmol) to the reaction solution under nitrogen protection, heating the reaction solution to 100 ℃, stirring for 16 hours, concentrating the reaction solution, and performing silica gel column chromatography (petroleum ether/ethyl acetate ═ 0-10%) to obtain the target compound 2- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) thiazole-5-yl Formaldehyde (I-18-b) (76mg, 41.08%).

The second step is that:

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

Example 20

The first step is as follows:

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

The second step is that:

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

The third step:

reacting 1' - ((5-bromopyrimidin-2-yl) methyl) -3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](I-20-c) (110mg,0.3mmol),1,1,1,3,3, 3-hexafluoro-2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) propan-2-ol (130mg,0.35mmol) (2), potassium carbonate (100mg,0.72mmol), water (1ml) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (25mg, 0.03mmol) was added to 8ml of 1, 4-dioxane and stirred overnight at 100 ℃ under nitrogen. The reaction mixture was concentrated by filtration and separated on a thin layer chromatography plate {7M methanolic ammonia (dichloromethane: ethyl acetate: 12:2) ═ 1: 14}. 60mg of (I-20) was obtained as a white solid in 37% yield. LC-MS M/z (M + H)⁺＝525。1H NMR(400MHz,CDCl3)δ8.95(s,2H),8.05(s,2H),7.97(d,J＝8.3Hz,2H),7.66(d,J＝8.6Hz,2H),7.16(d,J＝4.5Hz,1H),3.98(s,2H),3.04(s,2H),2.80(s,4H),2.12–1.92(m,4H)。

Example 21

The first step is as follows:

4-bromo-2, 3-difluorobenzaldehyde (I-21-a) (0.3g,1mmol),1,1,1,3,3, 3-hexafluoro-2- [4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl]Propan-2-ol (2) (0.6g,2mmol) and potassium carbonate (2M,1.5mL) were dissolved in 1, 4-dioxane, then [1, 1-bis (diphenylphosphino) ferrocene ] was added]Palladium (II) dichloride (0.1g,0.1mmol) was reacted at 90 ℃ for 16 hours under argon by replacing the air in the flask with argon. Thin layer chromatography silica gel plate (TLC) (petroleum ether: ethyl acetate 10:1) showed the reaction was complete. LCMS showed product formation. Cooling the reaction solution in air, concentrating, purifying the residue by column chromatography (0-20% of petroleum ether/ethyl acetate) to obtain a white solid product 2, 3-difluoro-4- [4- [2,2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl]Phenyl radical]Benzaldehyde (I-21-b) (0.4g,1 mmol). LC-MS M/z (M + H)⁺＝385.0。

The second step is that:

2, 3-difluoro-4- [4- [2,2, 2-trifluoro-1-hydroxy-1- (trifluoromethyl) ethyl]Phenyl radical]Benzaldehyde (I-21-b) (100mg,0.2603mmol), spiro [ 3H-furan [2, 3-c)]Pyridine-2, 4' -piperidines](4) (60mg,0.31539mmol) was dissolved in anhydrous N, N-dimethylformamide (5mL), N-diethylethylamine (10mg,0.098824mmol) and acetic acid (20mg,0.3331mmol) were added, and after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (165mg,0.77852mmol) was added, and stirring was continued for 16 hours. Thin layer chromatography silica gel plates (petroleum ether: ethyl acetate ═ 3:1 and 0:1) showed new dot formation. LCMS showed product. The reaction mixture was diluted with ethyl acetate (30mL) and washed three times with water (20 mL. times.3). The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Purifying the residue by column chromatography (0-100% of petroleum ether/ethyl acetate and 0-10% of dichloromethane/methanol) to obtain a white solid product 2- [4- [2, 3-difluoro-4- (spiro [ 3H-furan [2,3-c ]]Pyridine compound]-2,4' -piperidine]-1' -methyl) phenyl]Phenyl radical]-1,1,1,3,3, 3-hexafluoropropan-2-ol (I-21) (27mg,0.04834 mmol).¹H-NMR(CDCl₃):δ8.07(d,2H,J＝5.6Hz,2H),7.89(d,2H,J＝8.4Hz),7.72–7.62(m,2H),7.28–7.22(m,2H),7.19–7.13(m,1H),3.74(d,J＝1.6Hz,2H),3.03(d,J＝1.2Hz,2H),2.69(s,4H),2.02(d,J＝13.2Hz,2H),1.91–1.86(m,2H)。LC-MS:m/z(M+H)⁺＝559.2。

Example 22

Reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (26mg,0.136mmol) and 5- (2-fluoro-4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) pyridinecarboxaldehyde (13) (50mg,0.136mmol) were dissolved in dichloromethane (10ml), followed by the addition of trifluoroacetic acid (50. mu.L). After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (86mg, 0.406mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-22)8mg as a yellow solid in a yield of 11%.¹H NMR(400MHz,CDCl₃)δ8.69(s,1H),8.17-8.06(m,2H),7.92(d,J＝8.0Hz,1H),7.67(d,J＝8.2Hz,2H),7.62-7.48(m,2H),7.16(d,J＝4.7Hz,1H),3.84(s,2H),3.06(s,2H),2.76(s,4H),2.04(d,J＝13.4Hz,4H).LC-MS:m/z:(M+H)⁺＝542.1。

Example 23

The first step is as follows:

methyl 4-bromo-3- (trifluoromethyl) benzoate (I-23-a) (1.0g, 3.5mmol) and trimethyl (trifluoromethyl) silane (2.5g, 18mmol) were dissolved in tetrahydrofuran (10mL), the reaction was cooled to 0 ℃, a tetrahydrofuran solution of tetrabutylammonium fluoride (7.1mL, 1N) was slowly added to the reaction, and after completion of the addition, the temperature was raised to room temperature, and the reaction was stirred for 16 hours. The reaction was completed as indicated by dot plates, and the reaction mixture was concentrated and subjected to silica gel column chromatography (0 to 10% petroleum ether/ethyl acetate) to obtain the target compound 2- (4-bromo-3- (trifluoromethyl) phenyl) -1,1,1,3,3, 3-hexafluoropropane-2-ol (I-23-b) (820mg, 59%).

The second step is that:

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

The third step:

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

Example 24

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

Example 25

The first step is as follows:

5-bromo-4-methylpyrimidine (I-25-a) (476mg, 2.75mmol) was placed in a three-necked flask, Ar blanket, and anhydrous THF (20mL) was added to the three-necked flask and cooled to-78 ℃. Lithium Diisopropylamide (LDA) (2.0M/L, 1.65mL) was added slowly dropwise and stirred at this temperature for 30 min. N-Boc-4-piperidone (657mg, 3.3mmol) in anhydrous Tetrahydrofuran (THF) solution (5mL) was added dropwise to the reaction system, and the reaction was incubated for 3 hours after the addition. After TLC monitoring reaction is finished, the reaction system is saturated NH₄Aqueous Cl (8mL) was quenched. Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (30mL), and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (ethyl acetate: petroleum ether ═ 1:2) to give 4- ((5-bromopyrimidin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (I-25-b) (491mg) as a pale yellow oil. LC-MS M/z (M-55)⁺＝316.0,318.0。

The second step is that:

tert-butyl 4- ((5-bromopyrimidin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-25-b) (206mg, 0.554mmol) was dissolved in toluene (15mL), and cuprous iodide (48mg, 0.252mmol), 8-hydroxyquinoline (72mg, 0.50mmol), and cesium carbonate (391mg, 1.2mmol) were added in that order. The system is protected by argon, and the temperature is increased to 110 ℃ for reaction for 16 hours. After TLC monitoring reaction is finished, the reaction system is saturated NH₄Aqueous Cl (8mL) was quenched. Water (20mL) was added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying by column chromatography (ethyl acetate: petroleum ether: 1) to obtain 7H-spiro [ furo [3,2-d ]]Pyrimidine-6, 4' -piperidines]-1' -ATert-butyl ester (I-25-c) (105mg) as a pale yellow oil. LC-MS M/z (M + H)⁺＝292.1。

The third step:

reacting 7H-spiro [ furo [3,2-d ]]Pyrimidine-6, 4' -piperidines]Tert-butyl (I-25-c) -1' -carboxylate (105mg, 0.36mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (2mL) was added slowly, and the mixture was stirred at room temperature for 5 hours. After the LC-MS monitoring reaction is finished, the system is evaporated to dryness to obtain the 7H-spiro [ furo [3,2-d ]]Pyrimidine-6, 4' -piperidines]Crude (I-25-d) (125mg) as a yellow oil. LC-MS M/z (M + H)⁺＝192.0。

The fourth step:

mixing the above 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl group]-4-Formaldehyde (1) (131mg, 0.36mmol), 7H-spiro [ furo [3, 2-d)]Pyrimidine-6, 4' -piperidines](I-25-d) the crude product (125mg) was dissolved in N, N-dimethylformamide (8mL), and triethylamine (101mg, 1.0mmol) and acetic acid (29mg, 0.48mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (229mg, 1.08mmol) was added and stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 2- (4' - ((7H-spiro [ furo [3, 2-d)]Pyrimidine-6, 4' -piperidines]-1 '-yl) methyl) -2-fluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropyl-2-ol (I-25) (43mg) as a white solid. LC-MS M/z (M + H)⁺＝542.1。1H NMR(400MHz,CDCl3)δ8.69(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) pyridinecarboxaldehyde (14) (100mg, 0.27mmol) was dissolved in dichloromethane (15mL), and 3H-spiro [ furan [2,3-c ] was added to the reaction mixture]Pyridine-2, 4' -piperidines](4) (54mg, 0.29mmol) andsodium triacetoxyborohydride (115mg, 0.54mmol) was stirred at room temperature for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography (dichloromethane/methanol is 0-10%) to obtain the target compound 2- (4- (6- ((3H-spiro [ furan [2,3-c ])]Pyridine-2, 4' -piperidines]-1' -yl) methyl) -5-fluoropyridin-3-yl) phenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-27) (65mg, 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

The compound (7 peak A) (66mg,0.374mmol) and 4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl were added]-4-Formaldehyde (3) (130mg,0.374mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50. mu.L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (238mg, 1.12mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-28A) mg as a yellow solid in 18% yield.¹H NMR(400MHz,MeOD)δ8.05(d,J＝4.8Hz,1H),8.01(s,1H),7.82(d,J＝8.4Hz,2H),7.77–7.71(m,2H),7.68(d,J＝8.3Hz,2H),7.51(d,J＝8.2Hz,2H),7.31(dd,J＝4.8,0.8Hz,1H),3.85(q,J＝12.8Hz,2H),3.38(d,J＝4.8Hz,2H),3.14(d,J＝10.9Hz,1H),3.05(dt,J＝9.4,7.4Hz,1H),2.91–2.80(m,2H),2.44–2.33(m,1H),2.24–2.13(m,1H).LC-MS:m/z:(M+H)⁺＝509.1。

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

Example 29

4'- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropyl-2-yl) - [1,1' -biphenyl ] is added]-4-Formaldehyde (1) (118mg, 0.32mmol), 5-methyl-3H-spiro [ furo [2, 3-c)]Pyridine-2, 4' -piperidines](8) (66mg, 0.32mmol) was dissolved in N, N-dimethylformamide (10mL), and triethylamine (125mg, 1.24mmol) and acetic acid (50mg, 0.83mmol) were added in this order, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (265mg, 1.25mmol) was added and stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (5 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 1,1,1,3,3, 3-hexafluoro-2- (2-fluoro-4' - ((5-methyl-3H-spiro [ furo [2, 3-c))]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) propyl-2-ol (I-29) (45mg) as a white solid. LC-MS M/z (M + H)⁺＝555.2。¹H 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

The first step is as follows:

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

The second step is that:

1- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) -2-oxo-1, 2-dihydropyridine-4-carbaldehyde (I-30-b) (180mg, 0.49mmol) was dissolved in dichloromethane (15mL), and 3H-spiro [ furan [2,3-c ] was added to the reaction mixture]Pyridine-2, 4' -piperidines](4) (98mg, 0.52mmol) and sodium triacetoxyborohydride (209mg, 0.99mmol), and the reaction solution was stirred at room temperature for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography (dichloromethane/methanol is 0-10%) to obtain a target compound 4- ((3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]-1' -yl) methyl) -1- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) pyridin-2 (1H) -one (I-30) (67mg, 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

Reacting 5-chloro-3H-spiro [ furo [2,3-c ]]Pyridine-2, 4' -piperidines](17) (40mg, 0.19mmol) was dissolved in dichloromethane (15mL), and 2' -fluoro-4 ' - ((1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl was added to the reaction mixture]4-Formaldehyde (1) (68mg, 0.19mmol) and sodium triacetoxyborohydride (75mg, 0.36mmol), and the reaction mixture was stirred at room temperature for 16 hours. Concentrating the reaction solution, and performing silica gel column chromatography (dichloromethane/methanol is 0-10%) to obtain the target compound 2- (4' - ((5-chloro-3H-spiro [ furan [2,3-c ])]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) -2-fluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-31) (55mg, 53.74%). LC-MS: 575.1[ M +1]]⁺。1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.64–7.51(m,5H),7.45(d,J＝8.0Hz,2H),7.14(s,1H),3.66(s,2H),3.03(s,2H),2.67(s,4H),2.01(d,J＝12.9Hz,2H),1.91(dd,J＝16.4,10.1Hz,2H)。

Example 32

4' - (1,1,3, 3-tetrafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] -4-carbaldehyde (9) (100mg, 0.32mmol) was dissolved in dichloromethane (15mL), 3H-spiro [ furan [2,3-c ] pyridine-2, 4' -piperidine ] (4) (67mg, 0.35mmol) and sodium triacetoxyborohydride (136mg, 0.64mmol) were added to the reaction solution, and the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and subjected to silica gel column chromatography (dichloromethane/methanol ═ 0 to 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-tetrafluoropropane-2-ol (I-32) (58mg, 37.23%). LC-MS: 487.2[ M +1] +. 1H NMR (400MHz, DMSO) δ 8.19-8.01 (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

The first step is as follows:

(4-formylphenyl) boronic acid (I-23-c) (120mg,0.47mmol) and (S) -1- (4-bromophenyl) -2,2, 2-trifluoroethan-1-ol (I-33-a) (84mg,0.56mmol) were dissolved in dioxane (5ml) and water (5ml), followed by addition of tetratriphenylphosphine palladium (55mg,0.047mmol) and potassium carbonate (195mg,1.41 mmol). Stirring is carried out for 16 hours at 100 ℃ under the protection of nitrogen. The reaction mixture was concentrated, and the resulting crude product was separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 0 to 10%) to give the objective compound (I-33-b)62mg as a yellow solid in a yield of 47%.¹H NMR(400MHz,CDCl₃)δ10.09(s,1H),7.99(d,J＝8.2Hz,2H),7.78(d,J＝8.2Hz,2H),7.71(d,J＝8.3Hz,2H),7.63(d,J＝8.2Hz,2H),5.14(q,J＝6.6Hz,1H).LC-MS:m/z:(M+H)⁺＝281.1。

The second step is that:

reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](4) (84mg,0.3mmol) and (S) -4'- ((2,2, 2-trifluoro-1-hydroxyethyl) - [1,1' -biphenyl]-4-Formaldehyde (I-33-b) (57mg,0.3mmol) was dissolved in dichloromethane (10ml), followed by the addition of trifluoroacetic acid (50. mu.L). After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (191mg, 0.9mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-33)13mg as a yellow solid in a yield of 10%.¹H NMR(400MHz,DMSO)δ8.18–7.99(m,2H),7.70(dd,J＝16.7,7.3Hz,4H),7.58(d,J＝8.1Hz,2H),7.45(s,2H),7.28(d,J＝4.5Hz,1H),6.86(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

The first step is as follows:

(4-formylphenyl) boronic acid (I-23-c) (170mg,0.66mmol) and (R) -1- (4-bromophenyl) -2,2, 2-trifluoroethan-1-ol (I-34-a) (120mg,0.8mmol) were dissolved in dioxane (5ml) and water (5ml), followed by addition of tetratriphenylphosphine palladium (77mg,0.066mmol) and potassium carbonate (276mg,2.0 mmol). Stirring is carried out for 16 hours at 100 ℃ under the protection of nitrogen. The reaction solution was concentrated, and the resulting crude product was separated and purified by flash column chromatography (ethyl acetate: petroleum ether ═ 0 to 10%) to give the target compound (I-34-b)120mg as a yellow solid in a yield of 64%. LC-MS M/z (M + H)⁺＝281.1。

The second step is that:

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

Example 35

2' H, 4' H-spiro [ piperidine-4, 3' -pyran [3,2-c ]]Pyridine compound](18) (50mg,0.245mmol) and 5- (2-fluoro-4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) pyridinecarboxaldehyde (1) (89mg,0.243mmol) were dissolved in dichloromethane (10ml), followed by the addition of trifluoroacetic acid (50. mu.L). After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (155mg, 0.731mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0-10%) to give the objective compound (I-35)12mg as a yellow solid in a yield of 9%.¹H NMR(400MHz,DMSO)δ9.05(s,1H),8.21(s,1H),8.14(d,J＝5.6Hz,1H),7.73(t,J＝8.3Hz,1H),7.64–7.52(m,4H),7.46(d,J＝8.1Hz,2H),6.76(d,J＝5.6Hz,1H),3.58(s,2H),2.72(t,J＝6.5Hz,2H),2.61(d,J＝11.4Hz,2H),2.41(t,J＝9.4Hz,2H),1.83(t,J＝6.6Hz,2H),1.71(dt,J＝10.3,8.6Hz,4H).LC-MS:m/z:(M+H)+＝555.2。

EXAMPLE 41

The first step is as follows:

1- (tert-butoxycarbonyl) piperidine-4-carboxylic acid (I-41-a) (10).00g,43.62mmol) was dissolved in N, N-dimethylformamide (150ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI,12.54g,65.42mmol), 1-hydroxybenzotriazole (HOBt,8.84g,65.42mmol) and N, N-diisopropylethylamine (DIPEA,22.55g,174.46mmol) were added sequentially. After stirring at room temperature for 10 minutes, N, O-dimethylhydroxylamine hydrochloride (5.11g,52.34mmol) was added. The reaction was stirred at room temperature for 92 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (600ml), and the organic phase was washed with brine (2X 300ml) and anhydrous Na₂SO₄Drying and concentration gave tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate (I-41-b) (crude 13g) as a yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝273.15。

The second step is that:

tert-butyl 4- (methoxy (methyl) carbamoyl) piperidine-1-carboxylate (I-41-b) (6.00g,22.03mmol) was dissolved in methylene chloride (24ml), trifluoroacetic acid (12ml) was added at room temperature, and the reaction was stirred at this temperature for 1.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (10ml) and adjusted to pH 11 with aqueous ammonia. After stirring at room temperature for 1 hour, the reverse phase preparation (C18 silica; acetonitrile: water (0.1% NH)₃.H₂O), 15% to 35%) to give N-methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.10g,6.39mmol) as a light yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝173.20。

The third step:

N-methoxy-N-methylpiperidine-4-carboxamide (I-41-c) (1.00G,5.81mmol) was dissolved in 1, 4-dioxane (20ml), and tert-butyl ((1,1,1,3,3, 3-hexafluoro-2- (4-iodophenyl) propan-2-yl) oxy) dimethylsilane (3.37G,6.97mmol), RuPhos Pd G3(0.49G,0.58mmol), RuPhos (0.27G,0.58mmol) and cesium carbonate (3.78G,11.61mmol) were added. The protective system was replaced with nitrogen, and the temperature was raised to 90 ℃ to react for 18 hours. After the reaction was completed, the reaction mixture was concentrated by cooling, and subjected to column chromatography (ethyl acetate: petroleum ether ═ 1:1) to give 1- (4- (2- ((tert-butyldimethylsilyl) oxy) -1,1,1,3,3, 3-hexafluoroprop-2-yl) phenyl) -N-methoxy-N-methylpiperidine-4-carboxamide (I-41-d) (1.25g,2.36mmol) as a yellow oil. LCMS (ESI, M/z) [ M +1]]⁺＝529.35。

The fourth step:

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) (1.10g,2.08mmol) was dissolved in dry tetrahydrofuran (10ml) under nitrogen. Cooled to-70 ℃ and diisobutylaluminum hydride (1.5M in toluene, 2.08ml,3.12mmol) was added slowly dropwise, and the reaction was incubated at-70 ℃ for 1 hour. After the detection reaction is finished, saturated NH is used for the system₄Quenched with aqueous Cl, extracted with ethyl acetate (3X 50ml), the organic phases combined and taken over Na₂SO₄Drying and concentrating. The concentrated residue was dissolved in tetrahydrofuran (10ml), the system was purged with nitrogen, cooled to 0 ℃ and tetrabutylammonium fluoride (TBAF, 1.0M,4.16ml,4.16mmol) was added. After 30 minutes of reaction at 0 ℃, the reaction system was saturated with NH₄Aqueous Cl solution was quenched and extracted with ethyl acetate (3X 50 ml). The organic phases are combined and anhydrous Na₂SO₄Dried, concentrated under reduced pressure, and the residue was separated by column chromatography (dichloromethane: methanol ═ 10:1) to give 1- (4- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) phenyl) piperidine-4-carbaldehyde (I-41-e) (220mg,0.62mmol) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝356.05。¹H 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 ═ 13.4,3.9Hz,2H),1.77(m, 2H).

The fifth step:

reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](39mg,0.20mmol), 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 methylene chloride (10mL), and triethylamine (66mg,0.65mmol) and acetic acid (30mg,0.50mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (130mg,0.61mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (10 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying by column chromatography (dichloromethane: methanol 15:1) to obtain 2- (4- (4- ((3H-spiro [ furan [2, 3-c))]Pyridine compound-2,4' -piperidine]-1' -yl) methyl) piperidin-1-yl) phenyl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-41) (69mg) as a white solid. LCMS (ESI, M/z): [ M +1]⁺＝530.3。1H NMR(400MHz,DMSO)δ8.34(s,1H),8.18–7.99(m,2H),7.44(d,J＝8.7Hz,2H),7.27(d,J＝4.4Hz,1H),7.00(d,J＝9.1Hz,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

Spiro 3', 4' -dihydrospiro [ azetidine-3, 2' -pyran [2,3-c ]]Pyridine compound]Preparation example 10 (100mg,0.57mmol) was dissolved in dichloromethane (10mL), and 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] was added to the reaction mixture at room temperature]-4-carbaldehyde (preparation 12) (262mg,0.68mmol) and sodium triacetoxyborohydride (241mg,1.13mmol), and the reaction mixture was stirred at room temperature for 16 hours. Filtering the reaction solution, concentrating, evaporating to dryness, and performing silica gel column chromatography (dichloromethane/methanol is 0/100-10/900) to obtain a target compound 2- (4'- ((3', 4 '-dihydrospiro [3,2' -pyran [2,3-c ])]Pyridine compound]-1-yl) methyl) -2', 6' -difluoro- [1,1' -biphenyl]-4-yl) -1,1,1,3, 3-hexafluoropropan-2-ol (I-50) (65mg, 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

The first step is as follows:

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

The second step:

reacting 7-chloro-3H-spiro [2,3-c ]]Pyridine-2, 4' -piperidines]2,2, 2-Trifluoroacetate (I-51-a) (172mg,0.51mmol) was dissolved in dichloromethane (20mL), and 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] was added to the reaction mixture at room temperature]-4-carbaldehyde (234mg,0.61mmol) and sodium triacetoxyborohydride (215mg,1.02mmol), and the reaction solution was stirred at room temperature for 16 hours. Filtering the reaction solution, concentrating, evaporating to dryness, and performing silica gel column chromatography (dichloromethane/methanol is 0/100-10/900) to obtain a target compound 2- (4' - ((7-chloro-3H-spiro [ fluoro [2,3-c ])]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) -2', 6 '-difluoro- [1,1' -biphenyl]-4-yl) -1,1,1,1,3,3, 3-hexafluoropropan-2-ol (I-51) (222mg, 73.73%). LC-MS: 557.1[ M +1]]⁺。1H NMR(400MHz,CDCl3)δ7.87(s,3H),7.60(s,2H),7.07(d,J＝8.5Hz,3H),3.62(s,1H),3.12(s,1H),2.69(s,2H),1.98(d,J＝62.4Hz,2H)。

Example 52

The first step is as follows:

7-chloro-3H-spiro [ furo [2,3-c ]]Pyridine-2, 4' -piperidines]Tert-butyl (11) -1' -carboxylate (2.00g,6.16mmol) was dissolved in 1, 4-dioxane/water (5:1,20ml) and methyl boronic acid (442.30mg,7.39mmol), K, were added sequentially₂CO₃(1.70g,12.32mmol) and Pd (PPh)₃)₄(711.56mg,0.62 mmol). After the system was purged with nitrogen, the temperature was raised to 100 ℃ 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 give a crude product (1.20g), which was further prepared by reverse phase reaction (C18 silica gel, acetonitrile: water (10mM NH₄HCO₃) 45% to 65%) to obtain 7-methyl-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]Tert-butyl-1' -carboxylate (I-52-a) (460mg,1.51mmol), product as a white solid. LC-MS M/z (M + H)⁺305.10. 1H NMR (400MHz, chloroform-d) delta8.01(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)。

The second step is that:

reacting 7-methyl-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-52-a) -1' -carboxylate (460mg,1.51mmol) was dissolved in dichloromethane (5ml) and HCl in ethyl acetate (4mol/L,5ml) was added. The reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated, and the residue was dissolved in methanol (5ml) and adjusted to pH 11 using 2N aqueous NaOH. After stirring at room temperature for 1 hour, the reverse phase preparation (C18 silica gel, acetonitrile: water (10mM NH)₄HCO₃) 45% to 65%) to give 7-methyl-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](I-52-b) (235mg,1.15mmol), the product was a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝205.10.H-NMR:1H NMR(400MHz,DMSO-d6)δ7.90(d,J＝4.7Hz,1H),7.08(d,J＝4.7Hz,1H),3.01(s,2H),2.94–2.84(m,2H),2.69–2.59(m,2H),2.29(s,3H),1.75–1.59(m,4H)。

The third step:

reacting 7-methyl-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines](I-52-b)62mg,0.30mmol), 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (115mg,0.30mmol) was dissolved in N, N-dimethylformamide (10mL), and triethylamine (89mg,0.88mmol) and acetic acid (28mg,0.47mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (290mg,1.37mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction is finished, adding saturated NH₄Aqueous Cl (10 mL). Water (20mL) and ethyl acetate (20mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 2- (2',6' -difluoro-4 ' - ((7-methyl-3H-spiro [ furan [2, 3-c)]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-52) (36mg) as a white solid. LCMS (ESI, M/z) [ M +1]]⁺＝573.8。1H NMR(400MHz,CDCl3)δ7.97(d,J＝4.8Hz,1H),7.82(d,J＝8.3Hz,2H),7.57(d,J＝8.5Hz,2H),7.05(d,J＝8.5Hz,2H),6.97(d,J＝4.8Hz,1H),3.58(s,2H),3.01(s,2H),2.64(d,J＝9.8Hz,4H),2.44(s,3H),2.05–1.94(m,2H),1.85(dd,J＝17.4,9.7Hz,2H)。

Example 53

The first step is as follows:

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

The second step is that:

3-bromo-5-fluoro-4-methylpyridine (I-53-b) (3g,7.71mmol) was dissolved in anhydrous tetrahydrofuran (40mL), the reaction was cooled to-70 ℃ and lithium diisopropylamide (13.40mL,26.84mmol) was added to the reaction under nitrogen, and the reaction was stirred at-70 ℃ for 0.5 hour. A tetrahydrofuran solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.35g,26.84mmol) was added to the reaction mixture, the reaction mixture was stirred at-70 ℃ for 3 hours, water (100mL) was added to the reaction mixture to quench the reaction, the reaction mixture was extracted with ethyl acetate (100mL × 3), the organic phases were combined, 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 to 50/50) to give the target compound tert-butyl 4- (3-bromo-5-fluoropyridin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-53-c) (6.57g, 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)。

The third step:

tert-butyl 4- (3-bromo-5-fluoropyridin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-53-c) (3.00g,7.71mmol) was dissolved in dioxane (30mL), and copper iodide (146.78mg,0.77mmol), cesium carbonate (5.02g,15.41mmol) and 1,2-diaminocyclohexane (88.01mg,0.77mmol) were added to the reaction solution under nitrogen, and the reaction solution was heated to 100 ℃ and stirred for 5 hours. Water (100mL) was added to the reaction mixture, and ethyl acetate (80mL × 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, concentrated, and subjected to silica gel column chromatography (methanol/dichloromethane ═ 0/100 to 10/90) to give the target compound, 4-fluoro-3H-spiro [ fluoro [2,3-c ] pyridine-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester (I-53-d) (2.26g, 95.10%). LC-MS: 309.10[ M +1] +. 1H NMR (400MHz, chloroform-d) Δ 8.04(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' -piperidines]Tert-butyl (I-53-d) -1' -carboxylate (700mg,2.27mmol) was dissolved in methylene chloride (10mL), and the reaction mixture was stirred with a solution of hydrochloric acid in ethyl acetate (10mL,4M) at room temperature for 1 hour. Evaporating the reaction solution under reduced pressure, dissolving in methanol (10mL), adding sodium hydroxide (2M aqueous solution) to adjust pH to 11, stirring for 1 hr, evaporating under reduced pressure, and performing reverse phase C18 silica gel column chromatography (acetonitrile/water (0.1% NH4OH) ═ 27/73-47/53)) to obtain target compound 4-fluoro-3H-spiro [ fluoro [2,3-C ] fluorine]Pyridine-2, 4' -piperidines](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' -piperidines](I-53-e) (120mg,0.58mmol) was dissolved in dichloromethane (10mL), and 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] was added to the reaction mixture at room temperature]-4-carbaldehyde (266mg,0.69mmol) and sodium triacetoxyborohydride (244mg,1.15mmol), and the reaction solution was stirred at room temperature for 16 hours. Will be reversedFiltering the reaction solution, concentrating, evaporating to dryness, and performing silica gel column chromatography (dichloromethane/methanol is 0/100-10/900) to obtain a target compound 2- (2',6' -difluoro-4 ' - ((4-fluoro-3H-spiro [ fluoro [2,3-c ]))]Pyridine-2, 4' -piperidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) -1,1,1,1,3,3, 3-hexafluoropropan-2-ol (I-53) (131.0mg, 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

The first step is as follows:

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

The second step is that:

tert-butyl 4- (5-bromo-2-chloropyridin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-54-b) (7.8g,19.23mmol) was dissolved in dioxane (100mL), and copper iodide (366.15mg,1.92mmol), cesium carbonate (12.53g,38.45mmol) and 1,2-diaminocyclohexane (219.54mg,1.92mmol) were added to the reaction mixture under nitrogen, and the reaction mixture was heated to 100 ℃ and stirred for 5 hours. Adding water (100mL), extracting with ethyl acetate (100 mL. times.3), combining organic phases, drying with anhydrous sodium sulfate, filtering, evaporating to dryness, concentratingSilica gel column chromatography (methanol/dichloromethane: 0/100-10/90) gave the target compound, tert-butyl 4- (5-bromo-2-chloropyridin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-54-c) (2.1g, 33%). LC-MS: 325.81[ M +1]]⁺。

The third step:

tert-butyl 4- (5-bromo-2-chloropyridin-4-yl) methyl) -4-hydroxypiperidine-1-carboxylate (I-54-c) (100mg,0.31mmol) was dissolved in N, N-dimethylformamide (20mL), and palladium tetratriphenylphosphine (71.16mg,0.06mmol) and zinc cyanide (72.32mg,0.62mmol) were added to the reaction mixture under nitrogen, and the reaction mixture was heated to 120 ℃ and stirred for 16 hours. TLC showed the reaction was complete, and the reaction mixture was evaporated to dryness, concentrated and chromatographed on silica gel column (methanol/dichloromethane: 0/100-10/90) to give the target compound 5-cyano-3H-spiro [ furan [2,3-c ] pyridine-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester (I-54-d) (52mg, 53.55%).

The fourth step:

reacting 5-cyano-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-54-d) -1' -carboxylate (32.00mg,0.10mmol) was dissolved in methylene chloride (10mL), and trifluoroacetic acid (10mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. Decompressing and evaporating the reaction liquid to dryness to obtain a crude target compound 3H-spiro [2,3-c]Pyridine-2, 4' -piperidines]-5-Carbonitrile-2, 2, 2-trifluoroacetic acid salt (I-54-e) (30.00mg, 89.79%). LC-MS: 216.2[ M +1]]⁺。

The fifth step:

reacting 3H-spiro [2,3-c ]]Pyridine-2, 4' -piperidines]-5-Carbonitrile-2, 2, 2-trifluoroacetic acid salt (I-54-e) (30.0mg,0.09mmol) dissolved in dichloromethane (10mL) was added 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl ] at room temperature to the reaction mixture]-4-carbaldehyde (42.00mg,0.11mmol) and sodium triacetoxyborohydride (38.62mg, 0.11mmol), and the reaction mixture was stirred at room temperature for 16 hours. Filtering the reaction solution, concentrating, evaporating to dryness, and performing silica gel column chromatography (dichloromethane/methanol is 0/100-10/900) to obtain a target compound 1' - (2, 6-difluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropane-2-yl) - (1,1' -biphenyl)]-4-yl) methyl) -3H-spiro [ furan [2,3-c]Pyridine-2, 4' -piperidines]-5-Carbonitrile (I-54) (35.00mg, 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

The first step is as follows:

7-chloro-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]-1' -Carboxylic acid tert-butyl ester (2.00g,6.16mmol) was dissolved in N, N-dimethylformamide (20ml), and Zn (CN) was added under nitrogen protection₂(4.34g,36.95mmol), Zn (402.58mg,6.16mmol), DPPF (682.74mg,1.23mmol) and Pd₂(dba)₃(567.75mg,0.62 mmol). The reaction was stirred at 100 ℃ for 4 hours. After completion of the reaction, the system was added with water (200ml), extracted 3 times with ethyl acetate (3X 100ml), and the organic phase was washed with saturated brine (2X 100ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography (methanol: dichloromethane 0-10%) and the crude product was further purified by reverse phase flash column chromatography (C18 silica gel; ACN: H)₂O (0.1% FA) ═ 40-60%) gave compound (I-55-a) (1.17g,3.71mmol) as an off-white solid in 60.25% yield. LC-MS M/z (M + H)⁺＝316.3。

The second step is that:

7-cyano-3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-55-a) -1' -carboxylate (580.00mg,1.84mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (10ml) was added slowly at room temperature. The reaction was stirred at room temperature for 1 hour. Then concentrated under reduced pressure, the residue was dissolved in methanol (10ml) and basified with ammonia to pH 9, and stirred at room temperature for 1 hour. The crude product was isolated and purified by reverse phase flash column chromatography (C18 silica gel; acetonitrile: water (0.1% NH)₃.H₂O) ═ 25-45%) to give compound (I-55-b) (210.00mg,0.98mmol) as an off-white solid in 53.05% yield.¹H 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 ═ 1.3Hz,2H),2.90(M,2H),1.97(M,2H),1.80(M,2H). LC-MS: M/z (M + H)⁺＝216.10。

The third step:

reacting 3H-spiro [ furan [2,3-c ]]Pyridine-2, 4' -piperidines]-7-carbonitrile (I-55-b) (50mg,0.23mmol) and 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (90mg,0.23mmol) was dissolved in dichloromethane (10ml) and trifluoroacetic acid (50. mu.L) was added. After stirring at room temperature for 18 hours, sodium triacetoxyborohydride (148mg,0.69mmol) was added, and stirring was again performed at room temperature for 18 hours. The reaction solution was concentrated, and the resulting crude product was purified by flash column chromatography (methanol: dichloromethane 0 to 10%) to give the objective compound (I-55)21mg as a yellow solid in 16% yield.¹H NMR(400MHz,CDCl₃)δ8.22(d,J＝4.5Hz,1H),7.83(d,J＝8.2Hz,2H),7.60(d,J＝8.4Hz,2H),7.34(d,J＝4.5Hz,1H),7.07(d,J＝8.3Hz,2H),3.64(s,2H),3.13(s,2H),2.72(s,4H),2.15–2.06(m,2H),2.01–1.86(m,2H).LC-MS:m/z:(M+H)⁺＝584.2。

Example 56

The first step is as follows:

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

The second step is that:

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

The third step:

reacting 6-bromo-3H-spiro [ furan [2,3-b ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-56-c) -1' -carboxylate (950mg,2.57mmol) was dissolved in a mixed solvent (15mL) of dimethyl sulfoxide (DMSO)/water/tert-butanol (t-BuOH) (1:1:1), and cuprous iodide (49mg,0.257mmol), 2- ((2, 6-dimethylphenyl) amino) -2-oxoacetic acid (248.53mg,1.29mmol) and potassium hydroxide (288.69mg,5.15mmol) were added. The reaction mixture was warmed to 120 ℃ and stirred overnight. After completion of the reaction monitored by LCMS, the reaction was allowed to cool 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 give 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 4' -piperidines]Tert-butyl-1' -carboxylate (I-56-d) (410mg,1.34mmol), the product was a yellow solid. LCMS (ESI, M/z) [ M +23 ]]⁺＝329.05。

The fourth step:

reacting 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 4' -piperidines]Tert-butyl (I-56-d) -1' -carboxylate (410mg,1.34mmol) was dissolved in HCl in 1, 4-dioxane (4M,5.02mL,20.1mmol) and stirred at room temperature for 1.5 h. After completion of the reaction was monitored by LCMS, the reaction mixture was concentrated under reduced pressure, water (5mL) was added to the residue, pH was adjusted to 8 with saturated aqueous sodium bicarbonate (NaHCO3), the reaction was concentrated under reduced pressure, and the residue was prepared in reverse phase (C18 silica gel; acetonitrile: water (3% NH 3)₃.H₂O), 5% to 25%) to obtain 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 4' -piperidines](I-56-e) (192mg,0.93mmol, yield 70%) the product was a yellow solid. LCMS: (ESI, M/z): M +1]⁺＝207.00。1H NMR(400MHz,DMSO-d6)δ6.90–6.70(m,1H),5.30(m,1H),2.82(m,2H),2.71–2.54(m,4H),1.71–1.47(m,4H)。

The fifth step:

reacting 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 4' -piperidines](I-56-e) (57mg,0.28mmol), 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (117mg,0.31mmol) was dissolved in N, N-dimethylformamide (10mL), and triethylamine (84mg,0.83mmol) and acetic acid (25mg,0.42mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (177mg,0.84mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (10mL) was added. Water (20mL) and ethyl acetate (30mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. times.3), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying 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 ] group]-4-yl) methyl) -3H-spiro [ furo [2,3-b]Pyridine-2, 4' -piperidines]-6-ol (I-56) (22mg), light yellow solid. LCMS: (ESI, M/z): M +1]⁺＝574.8。1H NMR(400MHz,MeOD)δ7.83(d,J＝8.3Hz,2H),7.56(d,J＝8.2Hz,2H),7.41(d,J＝8.0Hz,1H),7.13(d,J＝8.3Hz,2H),6.09(d,J＝8.0Hz,1H),3.66(s,2H),2.94(s,2H),2.68(s,4H),2.10–1.95(m,2H),1.95–1.77(m,2H)。

Example 57

The first step is as follows:

3-Methyleneazetidine-1-carboxylic acid tert-butyl ester (I-57-a) (20.00g,118.19mmol) was added to 100ml of dimethyl sulfoxide, followed by slow addition of N-bromosuccinimide (NBS, 42.07g,236.37mmol) and water (4.26g,236.37mmol) while cooling on ice. The reaction mixture was stirred at room temperature overnight. 600ml of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (methanol: dichloromethane 0-10%)24g of (I-57-b) was obtained as a colorless oil in a yield of 76%. LC-MS M/z (M + H)⁺＝266。

The second step:

tert-butyl 3- (bromomethyl) -3-hydroxyazetidine-1-carboxylate (I-57-b) (12.00g,45.09mmol) was added to 360ml of tetrahydrofuran followed by slow addition of sodium hydride (60%, 1.98g,49.60mmol) under ice bath and nitrogen protection. After stirring at room temperature for 5 hours, 400ml of a saturated aqueous ammonium chloride solution was added, followed by extraction with ethyl acetate (3X 200 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated, and then subjected to column chromatography (ethyl acetate: petroleum ether ═ 15 to 45%) to obtain 4.92g of a pale yellow oil (I-57-c) in 59% yield. LC-MS M/z (M + H)⁺＝186.20。

The third step:

3-bromo-2, 6-difluoropyridine (2.40g,12.36mmol) was added to 20ml of tetrahydrofuran, and n-butyllithium (5.44ml,13.60mmol) was added under nitrogen at-75 ℃. After stirring for 0.5 hour, 1-oxa-5-azaspiro [2.3 ] was added]Hexane-5-carboxylic acid tert-butyl ester (I-57-c) (2.29g,12.36mmol) and boron trifluoride in ethyl ether (1.93g,13.60 mmol). After stirring for 2h, the reaction was quenched with water and extracted with ethyl acetate (3X 60 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated, and then subjected to column chromatography (ethyl acetate: petroleum ether: 35-55%) to obtain (I-57-d) as a pale yellow solid 638mg, yield 17%. LC-MS M/z (M + H)⁺＝301.15。

The fourth step:

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

The fifth step:

mixing 6' -fluoro-3 ' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]Tert-butyl (I-57-e) 1-carboxylate (300.00mg,1.07mmol) was added to 6ml of dichloromethane followed by 3ml of trifluoroacetic acidAfter the mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated and added to 6ml of methanol, and the pH was adjusted to about 10 with a 2mol/L aqueous solution of sodium hydroxide. Stirred at room temperature for 1 hour, and the reaction mixture was subjected to reverse phase column chromatography (C18; acetonitrile: water (0.1% (NH))₃.H₂O ammonia water)) ═ 15% to 35%) to give 48mg of a white solid (I-57-f) in a yield of 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 ═ 7.9Hz,1H),4.06(d, J ═ 10.7Hz,2H),3.77(d, J ═ 10.2Hz,2H),3.52(s, 2H).

And a sixth step:

mixing 6' -fluoro-3 ' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound](I-57-f) (20mg,0.11mmol), 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (40mg,0.10mmol) was added to 10ml of dichloroethane, followed by addition of sodium borohydride acetate (430mg,2.03mmol), and stirring was carried out overnight at room temperature. The reaction mixture was concentrated, 10ml of saturated sodium carbonate solution was added thereto, the mixture was extracted with dichloromethane three times (2 × 20ml), and the organic phase was dried over anhydrous sodium sulfate and concentrated on a column { methanol (dichloromethane: ethyl acetate ═ 2:1) } 0 to 15% }, whereby 30mg of a white solid (I-57) was obtained with a yield of 49%. LC-MS M/z (M + H)⁺＝549。1H NMR(400MHz,MeOD)δ7.85(d,J＝8.4Hz,2H),7.71(t,J＝7.8Hz,1H),7.57(d,J＝8.7Hz,2H),7.18–7.09(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

The first step is as follows:

trimethyl sulfoxide iodide (I-58-a) (66.27g,301.13mmol) was dissolved in dry dimethyl sulfoxide (250mL), potassium tert-butoxide (33.79g,301.13mmol) was added at room temperature, and stirring was carried out at this temperature for 30 minutes. The system was cooled to 0 ℃ and a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (50g,250.94mmol) in ethylene glycol dimethyl ether (DME) (250mL) was added dropwise. After dropping, the mixture was slowly warmed to room temperature and stirred for 6 hours. After completion of the reaction, as monitored by LCMS, the reaction was quenched with water (50mL), extracted with ethyl acetate (3X 300mL) withThe organic phases are combined and concentrated under reduced pressure, and the residue is purified and separated by column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain 1-oxa-5-azaspiro [2.4 ]]Tert-butyl heptane-5-carboxylate (I-58-b) (4.1g) the product was a yellow oil.¹H 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).

The second step is that:

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

The third step:

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

The fourth step:

reacting 6-fluoro-3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Tert-butyl (I-58-d) (500mg,1.7mmol) of (E) -1' -carboxylate and benzyl alcohol (BnOH) (270.5mg,2.04mmol) were dissolved in dry tetrahydrofuran (10mL), sodium hydride (NaH) (60%, 135.9mg,3.4mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, LCMS monitors the reaction and water is added to quench (20 mL). The system was extracted with ethyl acetate (3X 100mL), the organic phases were combined and concentrated under reduced pressure, and the concentrated residue was purified by reverse phase preparative (C18 silica gel; acetonitrile: water (3% NH)₃.H₂O), 35% to 55%) to obtain 6- (benzyloxy) -3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Tert-butyl (I-58-e) 1' -carboxylate (550mg,1.44mmol), the product being a yellow solid. LCMS (ESI, M/z) [ M +1]]⁺＝383.1。

The fifth step:

6- (benzyloxy) -3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Tert-butyl (I-58-e) -1' -carboxylate (550mg,1.44mmol) was dissolved in methanol (10mL) and 10% Pd/C (55mg) was added at room temperature. Replacement of reaction System by H₂The atmosphere was maintained, and stirring was carried out at this temperature for 16 hours. After the reaction is monitored by LCMS, insoluble substances are filtered off, a filter cake is washed by methanol, filtrates are combined and concentrated to obtain the 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Crude tert-butyl (I-58-f) -1' -carboxylate (370mg) was used directly in the next reaction. LCMS (ESI, M/z) [ M +1-15 ]]⁺＝278.00。

And a sixth step:

reacting 6-hydroxy-3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Crude tert-butyl (I-58-f) -1' -carboxylate (370mg) was dissolved in methylene chloride (6mL), and trifluoroacetic acid (2mL) was added to conduct a reaction at room temperature for 2 hours. After completion of the reaction monitored by LCMS, the reaction was concentrated and the residue was purified using reverse phase preparative (C18 silica gel; acetonitrile: water (3% NH)₃.H₂O), 5% to 15%) to give 3H-spiro [ furan [2,3-b ] as a yellow solid]Pyridine-2, 3' -pyrrolidines]-6-ol (I-58-g) (186mg,0.967 mmol). LCMS (ESI, M/z) [ M +1]]⁺＝193.1。¹H NMR (300MHz, methanol-d₄)δ7.40(m,1H),6.10(d,J＝8.0Hz,1H),3.26(dd,J＝6.2,2.5Hz,2H),3.21(m,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)。

The seventh step:

reacting 3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]-6-ol (I-58-g) (58mg,0.30mmol), 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (127mg,0.33mmol) was dissolved in N, N-dimethylformamide (10mL), and triethylamine (91mg,0.90mmol) and acetic acid (27mg,0.45mmol) were added in this order, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (177mg,0.84mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (10mL) was added. Water (20mL) and ethyl acetate (30mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. times.3), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying 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 ] e]-4-yl) methyl) -3H-spiro [ furan [2,3-b]Pyridine-2, 3' -pyrrolidines]-6-ol (I-58) (25mg), white solid. LCMS: (ESI, M/z): M +1]⁺＝560.8。1H NMR(400MHz,MeOD)δ7.83(d,J＝8.3Hz,2H),7.55(d,J＝8.5Hz,2H),7.41(d,J＝8.1Hz,1H),7.14(d,J＝8.5Hz,2H),6.11(d,J＝8.0Hz,1H),3.77(q,J＝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

The first step is as follows:

reacting 6-fluoro-3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines]Tert-butyl (I-58-d) -1' -carboxylate (400mg,1.36mmol) was dissolved in methylene chloride (6mL), and trifluoroacetic acid (2mL) was added to react at room temperature for 2 hours. After completion of the reaction monitored by LCMS, the reaction was concentrated and the residue was purified using reverse phase preparative (C18 silica gel; acetonitrile: water (3% NH)₃.H₂O), 5% to 15%) to give 6-fluoro-3H-spiro [ furan [2,3-b ] as a yellow solid]Pyridine-2, 3' -pyrrolidines](I-59-a)(240mg,1.24mmol)。LCMS:(ESI,m/z):[M+1]⁺＝195.1。¹H 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)。

The second step is that:

reacting 6-fluoro-3H-spiro [ furan [2,3-b ]]Pyridine-2, 3' -pyrrolidines](I-59-a) (52mg,0.27mmol), 2, 6-difluoro-4 '- (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (124mg,0.32mmol) was dissolved in N, N-dimethylformamide (15mL), and triethylamine (82mg,0.81mmol) and acetic acid (24mg,0.40mmol) were sequentially added thereto, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (210mg,0.99mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (10mL) was added. Water (20mL) and ethyl acetate (30mL) were added to separate the organic phase, the aqueous phase was extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution (30 mL. times.3), and dried over anhydrous sodium sulfate. The organic phase is concentrated and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give 2- (2',6' -difluoro-4 ' - ((6-fluoro-3H-spiro [ furan [2,3-b ])]Pyridine-2, 3' -pyrrolidines]-1 '-yl) methyl) - [1,1' -biphenyl]-4-yl) -1,1,1,3,3, 3-hexafluoropropan-2-ol (I-59) (32mg) as a white solid. LCMS: (ESI, M/z): M +1]⁺＝562.8。1H NMR(400MHz,MeOD)δ7.82(d,J＝8.2Hz,2H),7.66(t,J＝7.7Hz,1H),7.55(d,J＝8.6Hz,2H),7.14(d,J＝8.5Hz,2H),6.48(d,J＝7.8Hz,1H),3.77(d,J＝3.9Hz,2H),3.35(d,J＝16.3Hz,2H),3.09(d,J＝10.7Hz,1H),2.97(dd,J＝15.4,6.8Hz,1H),2.87–2.74(m,2H),2.47–2.34(m,1H),2.23–2.09(m,1H)。

Example 60

The first step is as follows:

under the protection of nitrogen, 6' -fluoro-3 ' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]Tert-butyl (I-57-e) -1-carboxylate (1.00g,3.57mmol) was dissolved in dry tetrahydrofuran (20ml), cooled to 0 ℃ and added portionwise at room temperature sodium hydride (60%, 285.38mg,7.14mmol) and benzyl alcohol (424.38mg,3.92 mmol). The reaction system is heated to 60 ℃ for reaction for 2 hours. After completion of the reaction, LCMS monitored, cooled to room temperature and quenched by addition of water (20 mL). Acetic acid B for systemThe ester was extracted (3 × 50mL), the organic phases were combined and concentrated under reduced pressure, and the concentrated residue was separated by column chromatography (dichloromethane: methanol ═ 20:1) to give 6' - (benzyloxy) -3' H-spiro [ azetidine-3, 2' -furo [2,3-b ] furan]Pyridine compound]Tert-butyl 1-carboxylate (I-60-a) (1.23g,3.34mmol) as a bright yellow liquid. LCMS (ESI, M/z) [ M +1]]⁺＝369.20。

The second step:

6' - (benzyloxy) -3' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]Tert-butyl (I-60-a) (1.23g,3.34mmol) of (E) -1-carboxylate was dissolved in methanol (15mL), and 10% Pd/C (200mg) 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 is monitored by LCMS, insoluble substances are filtered off, a filter cake is washed by methanol, filtrates are combined and concentrated to obtain 6' -hydroxy-3 ' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]Crude tert-butyl (I-60-b) -1-carboxylate (701mg), which was used directly in the next reaction. LCMS (ESI, M/z) [ M +1]]⁺＝279.10。

The third step:

reacting 6' -hydroxy-3 ' H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]Crude tert-butyl (I-60-b) -1-carboxylate (180mg) was dissolved in methylene chloride (6mL), and trifluoroacetic acid (2mL) was added to react at room temperature for 2 hours. After the reaction is monitored by LCMS, the reaction solution is concentrated to obtain a crude product of 3 'H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]-6' -Alcoholtrifluoroacetate salt (I-60-c) (190mg), which was used directly in the next reaction. LCMS (ESI, M/z) [ M +1]]⁺179.20. 1H NMR (400MHz, methanol-d 4) δ 7.47(d, J ═ 8.0Hz,1H),6.24(d, J ═ 8.0Hz,1H),4.40(q, J ═ 11.9Hz,4H),3.49(s, 2H).

The fourth step:

reacting 3 'H-spiro [ azetidine-3, 2' -furan [2,3-b ]]Pyridine compound]-6' -Alcoholtrifluoroacetate salt (I-60-c) (50mg), 2, 6-difluoro-4 ' - (1,1,1,3,3, 3-hexafluoro-2-hydroxypropan-2-yl) - [1,1' -biphenyl]-4-Formaldehyde (92mg,0.24mmol) was dissolved in N, N-dimethylformamide (10mL), and triethylamine (73mg,0.72mmol) and acetic acid (27mg,0.45mmol) were added in this order, followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (227mg,1.08mmol) was added, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (10mL) was added. Water (20mL) and ethyl acetate (30) were addedmL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (30mL × 3), and dried over anhydrous sodium sulfate. Concentrating the organic phase, and purifying 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]Pyridine compound]-6' -ol (19mg), white solid. LCMS (ESI, M/z) [ M +1]]⁺＝547.1。1H NMR(400MHz,MeOD)δ7.83(d,J＝8.2Hz,2H),7.54(d,J＝8.1Hz,2H),7.43(d,J＝8.0Hz,1H),7.10(d,J＝8.2Hz,2H),6.15(d,J＝8.0Hz,1H),3.80(s,2H),3.61(q,J＝8.5Hz,4H),3.40(s,2H)。

With reference to the above examples, the compounds shown in table 1 were prepared and their structural characterization is as follows:

TABLE 1 list of compounds

Effect example 1

First, the inhibitory Activity of Compounds on ROR γ t

1. The test method comprises the following steps:

the compounds of the invention employ Fluorescence Resonance Energy Transfer (FRET) assays to determine the inhibitory activity of the compounds on ROR γ t.

2. Materials and reagents:

3. the experimental steps are as follows:

1) a 4x series of dilutions of the compound was prepared in 1x buffer.

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

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

4) To 384 assay plates (prepared in step b) was added 5ul 4x RORgt-LBD (prepared in step c).

5) Assay plates were incubated at room temperature for 15 minutes, protected from light.

6) A2 XSRC, anti-GST Eu and streptavidin-d 2 mixture was prepared in 1 Xfreezing buffer.

7) Add 10ul of 2x mixture (prepared in step f) to 384 assay plates (prepared in step d).

8) 384 test plates were centrifuged at 1000g for 1 min.

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

10) Plates at 665nm and 615nm wavelengths were read on an Envision 2104 plate reader.

4. And (3) data analysis:

relative Ratio (RR) the relative ratio of each well (665nm response/615 nm response-blank background response) was calculated.

Percent inhibition:

inhibition ratio [% 1- (compound fluorescence detection value-positive compound fluorescence detection average value)/(negative control fluorescence detection average value-positive compound fluorescence detection average value) ] x100

And calculating the IC50 and dose-effect curve of the compound, wherein the IC50 and the dose-effect curve of the compound are obtained by calculating the inhibition rate of the compound and the log value of the concentration of the compound and utilizing Graphpad 8.0.

And II, testing result data.

Table 2 determination of ROR γ inhibitory Activity of the Compounds of the examples

Remarking: "+" indicates that 1uM ≦ IC₅₀Less than or equal to 10uM, "+ +" indicates an IC of less than or equal to 100nM₅₀1uM ≦, "+ + +" indicates that 1nM ≦ IC₅₀≤100nM,

And (4) conclusion: as can be seen from Table 2, the compounds of the present invention have significant inhibitory effects on ROR γ t.

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims

1. A spiroheterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof, or a prodrug thereof:

wherein 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;

R²independently halogen, -OR^2-1、-SR^2-2、-CN、-NR^2-3R^2-4、-C(＝O)R^2-5、-S(＝O)₂R^2-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-10 membered heteroaryl, C₁-C₇Alkyl group, "R^2-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R³independently halogen, -OR^3-1、-SR^3-2、-CN、-NR^3-3R^3-4、-C(＝O)R^3-5、-S(＝O)₂R^3-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4; or, any two non-adjacent R³Together with the carbon atoms to which they are attached form a 4-6 membered heterocycloalkyl group, in which the heteroatoms are O and/or N, the number being 1 or 2;

R^1-1、R^2-1、R^3-1and R^4-1Independently hydrogen, "halogen substitutionC of (A)₁-C₇Alkyl radical ", C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

said R^1-3-1And R^1-3-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

said R^3-3-1And R^3-3-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^4-2And R^4-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^4-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^4-2-2Substituted 3-14 membered heterocycloalkenyl "; said 3-to 14-membered heterocycloalkyl group, R^4-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycleAlkenyl and "R^4-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4;

said R^4-2-1And R^4-2-2Independently is hydroxy, -CN, -C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-6independently hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14-membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

R^2-6independently hydrogen, -OR^2-6-1、NR^2-6-2R^2-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

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^3-6-2and R^3-6-3Independently of one another is hydrogen、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is independently 1,2, 3 or 4;

or, R^2-5-2And R^2-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^2-5-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^2-5-2-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl, said "R^2-5-2-1Substituted 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkenyl and said "R^2-5-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4; said R^2-5-2-1And R^2-5-2-2Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-5-2And R^3-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl group^3-5-2-1Substituted 3-14 membered heterocycloalkyl, 3-14 membered heterocycloalkenyl or "R^3-5-2-2Substituted 3-14 membered heterocycloalkenyl; said 3-to 14-membered heterocycloalkyl, said "R^3-5-2-1Substituted 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkenyl and said "R^3-5-2-2The heteroatoms in the substituted 3-14 membered heterocycloalkenyl "are independently selected from one or more of boron, silicon, oxygen, sulphur, selenium, nitrogen and phosphorus, the number of heteroatoms being independently 1,2, 3 or 4; said R^3-5-2-1And R^3-5-2-2Independently is hydroxy, -CN, -C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R⁵independently is C₁-C₇An alkyl group; or, any two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group;

said R^1-7R is as described^2-7R is as described^3-7R is as described^4-4R is as described^1-3-1R is as described^1-3-2R is as described² ^-3-1Said R^2-3-2R is as described^3-3-1R is as described^3-3-2R is as described^1-5-2-1R is as described^1-5-2-2R is as described^2-5-2-1R is as described^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2Independently by number 1,2, 3, 4,5, 6 or 7; when said R is^1-7R is as described^2-7Said R^3-7R is as described^4-4R is as described^1-3-1Said R^1-3-2R is as described^2-3-1R is as described^2-3-2R is as described^3-3-1R is as described^3-3-2R is as described^1-5-2-1R is as described^1-5-2-2Said R^2-5-2-1R is as described^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2When the number of (A) is more than one, R is^1-7R is as described^2-7R is as described^3-7R is as described^4-4R is as described^1-3-1R is as described^1-3-2R is as described^2-3-1R is as described^2-3-2Said R^3-3-1R is as described^3-3-2R is as described¹ ^-5-2-1R is as described^1-5-2-2Said R^2-5-2-1Said R^2-5-2-2R is as described^3-5-2-1And said R^3-5-2-2Independently the same or different.

2. The spiroheterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof according to claim 1, wherein the compound of formula I is any one of the following schemes:

scheme 1:

in the compound shown in the formula I:

n is 0 or 1;

R^3-5independently of one another is hydrogen, -OR^3-5-1、NR^3-5-2R^3-5-3Or C₁-C₇An alkyl group;

R^1-6independently hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the hetero atoms in the 3-14 membered heterocyclic alkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of the hetero atoms is independently 1 or 2Or 3;

scheme 2:

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 C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-10 membered heteroaryl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogenA plurality, independently the number of heteroatoms is 1,2 or 3;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R³independently of one another, halogen, C₁-C₇Alkyl group, "R^3-7Substituted C₁-C₇Alkyl "or oxo; or, any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R^1-7、R^2-7、R^3-7and R^4-4Independently halogen or hydroxy;

scheme 3:

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;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R³independently of one another, halogen, C₁-C₇Alkyl or oxo, or, any two non-adjacent R³Is connected with itTogether form a 4-6 membered heterocycloalkyl group;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is hydrogen;

any two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-10 membered cycloalkyl group;

scheme 4:

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;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently of one another, halogen, C₁-C₇Alkyl or oxo;

R⁴independently halogen, -CN, -OR^4-1、C₁-C₇Alkyl or oxo;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is hydrogen;

scheme 5:

in the compound shown in the formula I:

R¹is "R^1-7Substituted C₁-C₇Alkyl ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently of one another, halogen, C₁-C₇Alkyl or oxo, or any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R⁴independently of one another, halogen, C₁-C₇Alkyl or oxo;

R^1-7and R^2-7Independently halogen or hydroxy;

scheme 6:

the compound of the formula I is shown as a 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;

R¹is R^1-7Substituted C₁-C₇An alkyl group;

R²independently halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo;

R^1-7、R^2-7and R^4-4Independently halogen or hydroxy;

R^4-1is hydrogen;

any two non-adjacent R⁵Together with the carbon atom to which they are attached form a 4-to 10-membered cycloalkyl group

Scheme 7:

the compound of the formula I is shown as a 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;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently is halogen or C₁-C₇Alkyl, or any two non-adjacent R³Together with the carbon atom to which they are attached form a 4-6 membered heterocycloalkyl group;

R⁴independently is C₁-C₇An alkyl group;

R^1-7and R^2-7Independently halogen or hydroxy;

scheme 8:

the compound of the formula I is a compound shown as a formula III:

R¹independently hydrogen, halogen, -OR^1-1、-CN、-NR^1-3R^1-4、-C(＝O)R^1-5、-S(＝O)₂R^1-6、C₁-C₇Alkyl or "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently halogen, -OR^2-1、-CN、-NR^2-3R^2-4、-C(＝O)R^2-5、-S(＝O)₂R^2-6、C₃-C₁₄Cycloalkyl, 3-14 membered heterocycloalkyl, C₁-C₇Alkyl group, "R^2-7Substituted C₁-C₇Alkyl "or oxo; the heteroatoms in the 3-14 membered heterocycloalkyl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R^1-3、R^1-4、R^2-3、R^2-4、R^3-3and R^3-4Independently of one another is hydrogen, C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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;

or, R^1-3And R^1-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^1-3-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and "R^1-3-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R^1-3-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-3And R^2-4Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^2-3-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and "R^2-3-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R^2-3-1Independent of each otherIs hydroxy, -CN, -C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-5independently of one another is hydrogen, -OR^1-5-1、NR^1-5-2R^1-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl 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^3-5independently of one another is hydrogen, -OR^3-5-1、NR^3-5-2R^3-5-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-14 membered heterocycloalkyl and the 5-10 membered heteroaryl are independently selected from one or more of oxygen, sulfur and nitrogen, and the number of heteroatoms is independently 1,2 or 3;

R^1-6independently hydrogen, -OR^1-6-1、NR^1-6-2R^1-6-3、C₁-C₇Alkyl radical, C₃-C₁₄Cycloalkyl or 3-14 membered heterocycloalkyl; the heteroatoms in the 3-to 14-membered heterocycloalkyl group are independently selected from oxygenOne or more of sulfur and nitrogen, the number of heteroatoms being independently 1,2 or 3;

or, R^1-5-2And R^1-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^1-5-2-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and said "R^1-5-2-1In substituted 3-to 14-membered heterocycloalkylIs independently selected from one or more of oxygen, sulphur and nitrogen, the number of heteroatoms being independently 1,2 or 3; said R^1-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^2-5-2And R^2-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^2-5-2-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and said "R^2-5-2-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R^2-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

or, R^3-5-2And R^3-5-3Together with the nitrogen atom to which they are attached form a 3-14 membered heterocycloalkyl or "R^3-5-2-1Substituted 3-14 membered heterocycloalkyl "; said 3-to 14-membered heterocycloalkyl group and said "R^3-5-2-1The heteroatoms in the substituted 3-14 membered heterocycloalkyl "are independently selected from one or more of oxygen, sulfur and nitrogen, the number of heteroatoms is independently 1,2 or 3; said R^3-5-2-1Independently is hydroxy, -oxo, -CN, C₁-C₇Alkyl or C₁-C₇An alkoxy group;

R^1-7、R^2-7and R^3-7Independently halogen, hydroxy, amino, mercapto, cyano, C₁-C₇Alkoxy radical, C₃-C₁₄Cycloalkyl 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;

scheme 9:

the compound of the formula I is a compound shown as a formula IV:

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

ring A is C₆-C₁₀An aryl group;

R¹is "R^1-7Substituted C₁-C₇Alkyl groups ";

R²independently is halogen or "R^2-7Substituted C₁-C₇Alkyl groups ";

R³independently is halogen or C₁-C₇An alkyl group;

R^1-7and R^2-7Independently halogen or hydroxy;

scheme 10:

the compound shown in the formula I:

and/or

3. The spiroheterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof according to claim 1 or 2, wherein when ring a is 3-14 membered heterocycloalkyl, the heteroatom in said 3-14 membered heterocycloalkyl is not substituted by oxygen;

and/or, when said ring a is 3-14 membered heterocycloalkyl, said heterocycloalkyl of said 3-14 membered heterocycloalkyl is heteromonocycloalkyl or heterobridged cycloalkyl;

and/or, when said ring a is 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkyl is attached to ring B through a heteroatom;

and/or, when ring a is 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkyl is 5-, 6-or 7-membered heterocycloalkyl, the heteroatoms are oxygen and/or nitrogen, the number is 1 or 2;

and/or, when said ring A is C₆-C₁₀Aryl is said to C₆-C₁₀Aryl is phenyl;

and/or, when said ring a is a 5-10 membered heteroaryl, said heteroaryl is monocyclic;

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

and/or, when said ring a is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is attached to ring B through a carbon atom;

and/or, when said ring a is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is a 5 or 6 membered heteroaryl, the heteroatoms are sulfur and/or nitrogen, the number is 1 or 2, preferably 5 or 6 membered heteroaryl, the heteroatoms are nitrogen, the number is 1 or 2;

and/or, when said ring B is a 3-14 membered heterocycloalkyl, the heteroatom in said 3-14 membered heterocycloalkyl is not substituted by oxygen;

and/or, when said ring B is a 3-14 membered heterocycloalkyl, the heterocycle in said 3-14 membered heterocycloalkyl is a heteromonocyclic ring;

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

and/or, when said ring B is C₆-C₁₀When aryl, said C₆-C₁₀Aryl is phenyl, preferably

Wherein the left end is connected with ring A and the right end is connected with R¹Connecting;

and/or, when ring B is a 5-10 membered heteroaryl, said heteroaryl is a monocyclic heteroaryl;

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

and/or, when said ring B is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is attached to ring a through a carbon atom;

and/or, when ring B is a 5-10 membered heteroaryl, the heteroatom in the 5-10 membered heteroaryl is ortho to the site of attachment to ring A;

and/or, when said ring B is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is a 5 or 6 membered heteroaryl, the heteroatom is nitrogen, the number is 1 or 2;

and/or when R¹When independently halogen, said halogen is F;

and/or when R¹Independently is "R^1-7Substituted C₁-C₇When it is alkyl ", said R^1-7The number of (a) is 4,5, 6 or 7;

and/or when R¹Independently is "R^1-7Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃An alkyl group, more preferably an isopropyl group;

and/or when R^1-7When the halogen is F, the halogen is F;

and/or when R²When independently halogen, said halogen is F;

and/or when R²Independently is "R^2-7Substituted C₁-C₇When it is alkyl ", said R^2-7The number of the (B) is 3;

and/or when R²Independently is "R^2-7Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃Alkyl, more preferably methyl;

and/or when R^2-7When the halogen is F, the halogen is F;

and/or when R³When independently halogen, said halogen is F or Cl;

and/or when R³Independently is C₁-C₇When alkyl, said C₁-C₇Alkyl is C₁-C₃Alkyl, more preferably methyl;

and/or when R⁴Independently halogen, said halogen is preferably F or Cl, such as Cl;

and/or when R⁴Independently is C₁-C₇When alkyl, said C₁-C₇Alkyl is C₁-C₃Alkyl, more preferably methyl;

and/or when R⁴Independently is "R^4-4Substituted C₁-C₇When it is alkyl ", said R^4-4The number of the (B) is 3;

and/or when R⁴Independently is "R^4-4Substituted C₁-C₇When alkyl is mentioned, said C₁-C₇Alkyl is C₁-C₃Alkyl, more preferably methyl;

and/or when R^4-4When the halogen is F, the halogen is F;

and/or, when any two non-adjacent R are⁵When the alkyl group and the carbon atom connected with the alkyl group form 4-10 membered cycloalkyl, the 4-10 membered cycloalkyl is 7 membered cycloalkyl;

and/or, ring B is substituted at a position on ring A with

Are not adjacent.

4. Spiroheterocycle based compound of formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof according to claim 3, wherein when ring A is a 3-14 membered heterocycloalkyl, said 3-14 membered heterocycloalkyl is piperidinyl or piperazinyl, more preferably said 3-14 membered heterocycloalkyl is piperazinyl

And/or, when ring a is a 5-10 membered heteroaryl group in which the heteroatom is nitrogen, the heteroatom is not quaternized;

and/or, when said ring A is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is a pyridyl, pyrimidinyl or thiazolyl group, more preferably

Preferably, it is

Wherein the right end is linked to methylene and the left end is linked to ring B;

and/or, when said ring B is a 3-14 membered heterocycloalkyl group, said 3-14 membered heterocycloalkyl group is a piperidinyl group or a piperazinyl group, more preferably

The left end is connected with ring A, the right end is connected with R¹Connecting;

and/or, when said ring B is a 5-10 membered heteroaryl group, where the heteroatom in said heteroaryl group is nitrogen, said heteroatom is not quaternized;

and/or, when said ring B is a 5-10 membered heteroaryl, said 5-10 membered heteroaryl is a pyridyl group, more preferably

and/or when R¹Independently is "R^1-7Substituted C₁-C₇When alkyl is mentioned, "R" is^1-7Substituted C₁-C₇Alkyl is

And/or when R²Independently is "R^2-7Substituted C₁-C₇When alkyl is mentioned, "R" is^2-7Substituted C₁-C₇Alkyl "is trifluoromethyl;

and/or when R⁴Independently is "R^4-4Substituted C₁-C₇When alkyl is mentioned, "R" is^4-4Substituted C₁-C₇Alkyl "is trifluoromethyl;

and/or, when ring B is 6-membered heterocycloalkyl, phenyl or 6-membered heteroaryl, said R¹Is located para to the ring a linkage.

5. Spiroheterocyclic compound according to formula I, its pharmaceutically acceptable salts, its solvates of pharmaceutically acceptable salts, its metabolites or its prodrugs according to claim 1 or 2, 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 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, preferably C₆-C₁₀Aryl or 5-10 membered heteroaryl;

and/or ring B is 3-14 membered heterocycloalkyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, preferably C₆-C₁₀An aryl group;

and/or, R¹Independently is halogen or "R^1-7Substituted C₁-C₇Alkyl groups ";

and/or, R²Independently is halogen, "R^2-7Substituted C₁-C₇Alkyl "or oxo, preferably halogen or" R^2-7Substituted C₁-C₇Alkyl groups ";

and/or, R³Independently of one another, halogen, C₁-C₇Alkyl or oxo, preferably halogen or "R^3-7Substituted C₁-C₇Alkyl groups ";

and/or, R⁴Independently of one another is halogen, C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo;

and/or, R^1-7、R^2-7、R^3-7And R^4-4Independently halogen or hydroxy.

6. Spiro-heterocyclic compounds of formula I, pharmaceutically acceptable salts thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof or prodrugs thereof according to claim 1 or 2, wherein R is R⁴Independently halogen, -CN, -OR^4-1、C₁-C₇Alkyl group, "R^4-4Substituted C₁-C₇Alkyl "or oxo, R^4-1Is H.

7. Spiro-heterocyclic compounds of formula I, pharmaceutically acceptable salts thereof, solvates of pharmaceutically acceptable salts thereof, metabolites thereof or prodrugs thereof according to claim 1 or 2,

is composed of

Preference is given to

And/or the presence of a gas in the gas,

is composed of

And/or the presence of a gas in the gas,

is composed of

Preference is given to

8. The spiroheterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof according to claim 1, wherein the compound of formula I is optionally any one of the following compounds:

9. a compound such as compound I-a:

wherein m, n, p, s, t, Y, Z, W, Q, R⁴And R⁵Are as defined in any of claims 1 to 7, and said compound I-a is not

10. The compound I-a according to claim 9, which is any one of the following compounds:

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

Or a retention time of 2.705min

The chiral preparation conditions are as follows: a chromatographic column: chiral column: CHIRALPAK IH-3; mobile phase A: a solution of 0.1% ethylenediamine in n-hexane; mobile phase B: isopropyl alcohol; flow rate: 1 ml/min; elution conditions: eluting with 60% mobile phase A and 40% mobile phase B for 14 min; flow rate: 1.0 ml/min; detector wavelength: 220 nm; temperature: and (4) room temperature.

11. A pharmaceutical composition comprising a spiroheterocyclic compound of formula I, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, a metabolite thereof or a prodrug thereof according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

12. The application of a substance X in the preparation of ROR gamma t protein receptor modulators or medicaments;

the substance X is the spiroheterocyclic compound shown in the formula I, pharmaceutically acceptable salt thereof, solvate of pharmaceutically acceptable salt thereof, metabolite thereof, prodrug thereof or the pharmaceutical composition of claim 11, which is shown in any one of claims 1 to 8;

the medicine is used for preventing or treating diseases related to ROR gamma t protein receptor;

the disease related to the ROR gamma t protein receptor is preferably autoimmune disease;

the autoimmune disease is preferably one or more of psoriasis, multiple sclerosis, rheumatoid arthritis, inflammatory enteritis, ankylosing spondylitis, systemic lupus erythematosus, white-padded last-name disease and chronic obstructive pulmonary disease.