CN115703761A

CN115703761A - Compound as WWP1 inhibitor and application thereof

Info

Publication number: CN115703761A
Application number: CN202210972383.3A
Authority: CN
Inventors: 张明亮; 曹鑫涛; 高如新; 孙永亮; 路畅; 孙颖慧; 刘希杰; 陈曦
Original assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Current assignee: Capital Pharmaceutical Holdings Beijing Co ltd
Priority date: 2021-08-13
Filing date: 2022-08-12
Publication date: 2023-02-17

Abstract

The application relates to a compound as a WWP1 inhibitor and application thereof, wherein the compound as the WWP1 inhibitor has a structure shown in a formula (III). In particular, the invention relates to a compound shown in a formula (III), a preparation method thereof, a pharmaceutical composition thereof, and application of the compound and the pharmaceutical composition thereof in treating diseases mediated by WWP1 protein or NEDD4 protein, such as cancer.

Description

Compound as WWP1 inhibitor and application thereof

Technical Field

The invention belongs to the technical field of medicines, and relates to a compound, pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound, a preparation method of the compound, application of the compound as a therapeutic agent, in particular as WWP1 or NEDD4 inhibitor and the like, and application of the compound in medicines for treating and/or preventing hyperproliferative diseases such as cancers, and/or virus-induced infectious diseases, and/or cardiovascular diseases and/or diseases caused by fungi.

Background

PTEN (phosphatase and tensin homolog) is an important cancer suppressor gene, encodes a tumor suppressor phosphatase, dimerizes in the inner membrane of cytoplasm, dephosphorylates the second messenger PIP3, plays a reverse function with PI3K kinase, inhibits the PI3K-Akt signal pathway, regulates the physiological functions of cell proliferation, energy metabolism, migration and survival, and also plays an important role in maintaining genome stability, participating in physiological processes such as DNA damage repair and cell cycle regulation. Furthermore, loss of functional portions of PTEN was shown in human and mouse studies to be sufficient to promote the development of some cancers, with PTEN levels falling below 50% further promoting cancer progression (Yu-Ru et al, nature Reviews Molecular Cell Biology,2018, alimontia et al, nature Genetics, 2010. The important function of PTEN in cancer inhibition provides a basis for treating tumors by a strategy of stabilizing PTEN.

PTEN is influenced by various mechanisms such as transcription level and posttranslational modification, and regulates the cellular localization, enzyme activity and protein stability of PTEN, wherein ubiquitination modification is the main mode for regulating the stability of PTEN, polyubiquitinated PTEN is degraded by proteasome, and the down-regulation of PTEN level mediated by intracellular ubiquitination modification is the main mechanism of function loss of PTEN. E3 ubiquitin ligases of PTEN include Nedd4-1, WWP1 (WW Domain organizing ubiquitin E3 ligand 1), WWP2, XIAP (X-linked inhibitor of apoptosis protein) and CHIP (C-terminal of HSC70-interacting protein) (Deng L et al, signal Transduction and Targeted Therapy, 2020.). Wherein the C-terminal of the Nedd4-1, WWP1 and WWP2 proteins all contain an HECT structural domain and belong to an HECT type E3.

Nedd4-1 promotes monoubiquitination and polyubiquitination modification of K13 and K289 of PTEN, which is generally stable in the nucleus and is not modified by polyubiquitination, and transport of monophasically modified PTEN from the nucleus to the cytoplasm and subsequent polyubiquitination for recognition and degradation by proteasomes. In 80% of non-small Cell lung cancers, nedd4-1 is highly expressed and can promote PTEN ubiquitin dependent degradation (Wang X et al, cell,2007, 128 (1)); high expression of Nedd4-1 has also been reported to be associated with modulation of PTEN levels in bladder, gastric and colorectal cancers, but loss or gene interference of Nedd4-1 in mice, PTEN stability is not significantly enhanced, and thus other E3's play a stronger role in modulating PTEN stability (F folladkou et al, PNAS, 2008).

WWP1 can mediate K27 polyubiquitination of PTEN, inhibit dimerization of PTEN, cytoplasmic membrane recruitment and tumor suppressor function (Yu-Ru Lee et al, science, 2019). WWP1 gene is located on chromosome 8q21, a region that is amplified in a variety of tumors, with WWP1 gene amplified in 31% -51% of prostate and breast cancers. There are also mutations in the WWP1 gene in tumors, especially in prostate cancer (Chen C et al Oncogene, 2007). WWP1 expression is positively associated with ER α and IGF-1R and with poor prognosis in breast cancer (Huu N et al, journal of Pathology, 2010.) WWP1 is downstream of Myc and can be transcriptionally activated by Myc proto-oncogene, deletion of WWP1 gene has been shown to reactivate PTEN function in Myc-induced mouse prostate cancer models and in vitro tumor cells, inhibition of Myc-induced tumorigenesis of PI3K-Akt pathway, suggesting that interference with WWP1 can reactivate PTEN tumor-suppressor function, and inhibition of WWP1 can provide the basis for a strategy for tumor therapy (Yu-Ru Lee et al, science, 2019).

At present, the research on WWP1 inhibition is still in the initial stage, only indole-3-carbinol (I3C) is a compound in cruciferae plants, is an inhibitor of natural Nedd4-1 and WWP1, inhibits the activity of WWP1 by combining with the HECT structure domain of WWP1, and re-activates PTEN by inhibiting ubiquitination of PTEN by WWP1 in a dose-dependent manner to achieve the function of inhibiting tumors, but the inhibition effect of WWP1 and tumor cells can be achieved by high-concentration I3C, so that the improvement space is large. Although the compound still has the defects of weak cell activity and poor druggability, the research preliminarily proves the possibility of finding the WWP1 inhibitor.

In conclusion, WWP1 plays an important role in the occurrence and development of tumors and becomes a new target for tumor treatment; at present, the research on WWP1 inhibitors is still in the initial stage, and the research and development of high-activity and high-selectivity inhibitors have important significance; however, no WWP1 inhibitor enters the clinic at present, and a compound with a novel structure and better drug effect still needs to be developed; the invention designs and synthesizes the compound with the structure shown in the general formula (III), and finds that the compound with the structure shows better WWP1 inhibitory activity and has good tumor cell antiproliferative activity.

Disclosure of Invention

In view of the above problems, the present invention provides a novel compound, or a pharmaceutically acceptable salt, solvate, polymorph, deuteride or tautomer thereof, which can be used to inhibit proteins such as WWP1 and NEDD4, can reduce or inhibit proteins such as WWP1 and NEDD4 in cells, and is used in a medicament for treating and/or preventing diseases mediated by WWP1 protein or NEDD4 protein, particularly hyperproliferative diseases or induced infectious diseases and/or cardiovascular diseases and/or diseases caused by fungi.

In one aspect, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof:

wherein R is ^x Selected from the group consisting of 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, which may beOptionally substituted by R ⁵ The substitution is carried out by the following steps,

ry is selected from 4-8 membered heterocycloalkyl and 5-12 membered heteroaryl, the heteroatom of which is selected from N or/and O or/and S, ry may optionally be (= O) or R ⁶ The substitution is carried out by the following steps,

rz is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said cycloalkyl and heterocycloalkyl being optionally substituted by R7 or (= O), said aryl and heteroaryl being optionally substituted by R ⁷ The substitution is carried out by the following steps,

z is selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) -NH-CH ₂ -、-O-CH ₂ -、-S-CH ₂ -, -C.ident.C-, - (CO) -NH-, -CH = CH- (CO) -NH-, or- (SO) ₂ ) -NH-, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

L ¹ 、L ² and L ³ Each independently selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) - (NH-CH) ₂ ) _1-4 -、-(NH-CH ₂ -CH ₂ ) _1-4 -、-(O-CH ₂ ) _1-4 -、-(O-CH ₂ -CH ₂ ) _1-4 -、-(S-CH ₂ ) _1-4 -、-(S-CH ₂ -CH ₂ ) _1-4 -、-C≡C-、-(CO)-、-(CO)-NH-、-CH＝CH-(CO)-NH-、-(SO ₂ )-、-(SO ₂ ) -NH-, 3-10 membered carbocycle, 3-10 membered heterocycle, arylene, or heteroarylene, said-NH-, CH ₂ Carbocycle, heterocycle, arylene and heteroarylene optionally substituted with halogen, C _1-6 Alkyl, NH ₂ Or an OH substitution, or a substituted OH,

R ⁵ 、R ⁶ and R ⁷ Each independently selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -H, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-SR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by halogen, (= O), (= CN, -OH, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -H, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-SR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Is substituted and

two adjacent R ⁵ Or two adjacent R ⁷ Or R ⁵ And R ⁶ May be optionally linked together to form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, the carbocyclic or heterocyclic ring formed being optionally substituted by halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ The substitution is carried out by the following steps,

R ⁴ is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl being optionally substituted with halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CH) ₂ ) _1-4 -OR ¹ 、-(CH ₂ ) _1-4 -NR ¹ R ² 、-OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ¹ and R ² Each independently selected from H and C _1-6 Alkyl and 3-to 8-membered cycloalkyl,

n is 0, 1,2, 3 or 4.

In another aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof:

wherein R is ^x Selected from the group consisting of 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with R ⁵ The substitution is carried out by the following steps,

ry is selected from 4-8 membered heterocycloalkyl and 5-12 membered heteroaryl, the heteroatoms of which are selected from N or/and O or/and S, R ^y May optionally be (= O) or R ⁶ The substitution is carried out by the following steps,

R ^z selected from the group consisting of 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said cycloalkyl and heterocycloalkyl being optionally substituted by R7 or (= O), said aryl and heteroaryl being optionally substituted by R ⁷ The substitution is carried out by the following steps,

e and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-,) -O-, -S-) -NH-CH ₂ -、-O-CH ₂ -、-S-CH ₂ -, -C.ident.C-, - (CO) -NH-, -CH = CH- (CO) -NH-, or- (SO) ₂ ) -NH-, said C _1-6 Alkylene groups optionally being halogenatedElements, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ⁵ 、R ⁶ and R ⁷ Each independently selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -H, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-SR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl being optionally substituted by halogen, (= O), (= CN, -OH, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -H, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-SR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Is substituted and

two adjacent R ⁵ Or two adjacent R ⁷ Or R ⁵ And R ⁶ May be optionally linked together to form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, the carbocyclic or heterocyclic ring formed being optionally substituted by halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkanesA group, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ The substitution is carried out by the following steps,

R ⁴ is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ¹ and R ² Each independently selected from H, C _1-6 Alkyl and 3-8 membered cycloalkyl.

In some embodiments, E and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) -NH-CH ₂ -、-O-CH ₂ -, or-S-CH ₂ -, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ⁵ 、R ⁶ and R ⁷ Each independently selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by halogen, (= O), (= CN, -OH, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Is substituted and

R ¹ 、R ² and R ⁴ As defined above.

In some embodiments, E and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-or-O-, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ⁵ 、R ⁶ and R ⁷ Each independently selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by halogen, (= O), (= CN, -OH, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Is substituted and

two adjacent R ⁵ Or two adjacent R ⁷ May be optionally linked together to form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, the carbocyclic or heterocyclic ring formed being optionally substituted by halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ The substitution is carried out by the following steps,

R ⁴ is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl, said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl being optionally substituted by halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ¹ and R ² As defined above.

In another aspect, the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, polymorph, deuteron or tautomer thereof:

R ^y selected from 4-8 membered heterocycloalkyl and 5-12 membered heteroaryl, the heteroatoms of which are selected from N or/and O or/and S, R ^y May optionally be (= O) or R ⁶ The substitution is carried out by the following steps,

R ^z selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said cycloalkyl and heterocycloalkyl optionally substituted with R ⁷ Or (= O), the aryl and heteroaryl groups may be optionally substituted with R ⁷ The substitution is carried out by the following steps,

L ¹ 、L ² and L ³ Each independently selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) - (NH-CH) ₂ ) _1-4 -、-(NH-CH ₂ -CH ₂ ) _1-4 -、-(O-CH ₂ ) _1-4 -、-(O-CH ₂ -CH ₂ ) _1-4 -、-(S-CH ₂ ) _1-4 -、-(S-CH ₂ -CH ₂ ) _1-4 -、-C≡C-、-(CO)-、-(CO)-NH-、-CH＝CH-(CO)-NH-、-(SO ₂ )-、-(SO ₂ ) -NH-, 3-10 membered carbocycle, 3-10 membered heterocycle, arylene, or heteroarylene, said-NH-, CH ₂ Carbocycle, heterocycle, arylene and heteroarylene optionally substituted with halogen, C _1-6 Alkyl, NH ₂ Or an OH substituent, or a salt thereof,

R ⁴ is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CH) ₂ ) _1-4 -OR ¹ 、-(CH ₂ ) _1-4 -NR ¹ R ² 、-OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

n is 0, 1,2, 3 or 4.

In some embodiments, L ¹ 、L ² And L ³ Is a bond.

In some embodiments, R ^y Is selected from

R ^y Optionally substituted with R ⁶ Substituted, R ⁶ As defined above.

In some embodiments, R ^y Is selected from

R ^y Optionally substituted by R ⁶ The substitution is carried out by the following steps,

two adjacent R ⁵ Or two adjacent R ⁷ Or R ⁵ And R ⁶ May be optionally linked together to form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, the carbocyclic or heterocyclic ring formed may optionally beHalogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ The substitution is carried out by the following steps,

R ⁴ 、R ¹ 、R ² and n is as defined above.

In some embodiments, R ⁴ Is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl optionally substituted with halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² Substitution;

in some embodiments, R ^y Is composed of

R ^y Optionally substituted with R ⁶ Substituted, R ⁶ As defined above;

in some embodiments, R ^x Selected from phenyl and 5-6 membered heteroaryl, optionally substituted with R ⁵ Substituted, R ⁵ As defined above;

in some embodiments, R ⁵ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² Said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups being optionally substituted by halogen, (iii)＝O)、-CN、CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Substituted, R ¹ 、R ² And R ⁴ As defined above;

in some embodiments, R ⁵ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² ，R ¹ And R ² As defined above;

in some embodiments, R ⁶ Selected from halogen, C _1-6 Alkyl and 3-12 membered cycloalkyl, preferably halogen or C _1-6 Alkyl, said alkyl and cycloalkyl being optionally substituted by halogen;

in some embodiments, R ⁷ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² Said alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl being optionally substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Substituted, R ¹ 、R ² And R ⁴ As defined above;

in some embodiments, R ⁷ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² ，R ¹ And R ² As defined above;

in some embodiments, the present invention provides the following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, deuterons, or tautomers thereof:

the compounds of the present invention may be used in the treatment of diseases mediated by the WWP1 protein or the NEDD4 protein.

Yet another aspect of the present invention is directed to a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron or tautomer thereof, and a pharmaceutically acceptable carrier;

in another aspect, the present invention provides a method of treating a disease mediated by a WWP1 protein or a NEDD4 protein, the method comprising administering to a subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, polymorph, deuteron or tautomer thereof, or a composition thereof.

In some embodiments of the invention, the subject to which the invention relates is a mammal including a human;

in another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron or tautomer thereof, in the manufacture of a medicament for the treatment of a disease mediated by the WWP1 protein or the NEDD4 protein.

In some embodiments, the disease mediated by the WWP1 protein or the NEDD4 protein is a hyperproliferative disease and/or an induced infectious disease and/or a cardiovascular disease and/or a disease caused by fungi, preferably lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, kidney cancer, a tumor of the nervous system, lymphoma or leukemia, more preferably acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, burkitt's lymphoma, follicular lymphoma, breast cancer, non-small cell lung cancer, melanoma, kidney cancer, ovarian cancer, prostate cancer, colon cancer, or a tumor of the central nervous system.

Detailed Description

The features and advantages of the present invention may be better understood by referring to the following detailed description of the invention.

It should be understood that the scope of the various aspects of the invention is defined by the claims and that methods and structures within the scope of these claims and their equivalents are intended to be covered thereby.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

It is to be understood that both the foregoing general description and the following detailed description are exemplary, explanatory and are not restrictive of any inventive subject matter. The use of the singular forms also includes the plural unless specifically stated otherwise. The use of "or", "or" means "and/or" unless stated otherwise. Furthermore, the terms "include," "including," and other forms, such as "includes," "including," and "containing," are not limiting.

Certain chemical terms

The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" means "unsubstituted alkyl" or "substituted alkyl". And, optionally substituted groups may be unsubstituted (e.g.: CH) ₂ CH ₃ ) Fully substituted (e.g.: -CF ₂ CF ₃ ) Monosubstituted (for example: -CH ₂ CH ₂ F) Or any level between mono-and fully substituted (e.g.: -CH ₂ CHF ₂ 、-CF ₂ CH ₃ 、-CFHCHF ₂ One skilled in the art will appreciate that any substitution or substitution pattern for any group containing one or more substituents that is not sterically impossible and/or cannot be synthesized is not introduced.

Unless otherwise indicated, conventional methods within the skill of the art are employed, such as mass spectrometry, nuclear magnetism, high performance liquid chromatography, infrared and ultraviolet/visible spectroscopy, and pharmacological methods. Unless a specific definition is set forth, the nomenclature used herein in connection with analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry, and the laboratory procedures and techniques, are those known in the art. The above techniques and methods can be generally performed according to conventional methods well known in the art, based on the general description of various and more specific documents cited and discussed in the present specification. In the present specification, groups and substituents thereof may be selected by one skilled in the art to provide stable moieties and compounds.

When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

As used herein, the terms "group," "chemical group," and "chemical group" refer to a particular moiety or functional group of a molecule.

Some of the chemical groups named herein may be referred to by a shorthand notation for the total number of carbon atoms. E.g. C ₁ -C ₆ Alkyl describes an alkyl group, as defined below, having a total of 1 to 6 carbon atoms. The total number of carbon atoms indicated by shorthand notation does not include carbon atoms on possible substituents.

The terms "halogen", "halo" or "halide" refer to bromine, chlorine, fluorine or iodine.

The terms "aromatic", "aromatic ring", "aromatic-cyclic" refer to a planar ring portion of one or more rings having a delocalized electron-conjugated system of 4n +2 electrons, where n is an integer. The aromatic compound may be optionally substituted and may be monocyclic or fused-ring polycyclic. The term aromatic compound includes all carbocyclic rings (e.g., benzene rings) and rings containing one or more heteroatoms (e.g., pyridine).

The heteroatoms are independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different from each other.

The term "fused" or "fused ring" refers to a ring structure in which two or more rings share one or more bonds.

The term "spiro" or "spirocyclic" refers to a cyclic structure in which two or more rings share one or more atoms.

The term "alkyl" refers to an optionally substituted straight chain or optionally substituted branched chain monovalent saturated hydrocarbon having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, 2-methylhexyl, 3 methylhexyl, n-octyl, n-nonyl, n-decyl, and the like.

The term "alkylene" refers to a straight or branched chain divalent hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms.

The term "alkenyl" refers to an optionally substituted straight or optionally substituted branched chain monovalent hydrocarbon radical having one or more C = C double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The double bond in these groups may be in either the cis or trans conformation and should be understood to encompass both isomers. Examples include, but are not limited to, vinyl (CH = CH) ₂ ) 1-propenyl (CH) ₂ CH＝CH ₂ ) Isopropenyl (C (CH) ₃ )＝CH ₂ ) Butenyl, 1, 3-butadienyl and the like, when an alkenyl group as defined herein appears in a numerical range, e.g. "C ₂ -C ₆ Alkenyl "or" C _2-6 By alkenyl is meant a group which may be substituted by 2 carbon atoms, 3 carbon atoms, 4 carbon atoms,An alkenyl group of 5 carbon atoms or 6 carbon atoms, and the alkenyl group herein also covers the case where no numerical range is specified.

The term "alkynyl" refers to an optionally substituted, straight or branched chain, monovalent hydrocarbon radical having one or more C.ident.C triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, and 1, 3-butynyl and the like ₂ -C ₆ Alkynyl "or" C _2-6 Alkynyl "refers to an alkynyl group that can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, and alkynyl groups herein also encompass instances where no numerical range is specified.

The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated pi-electron system, having 6 to 14 carbon atoms, preferably 6 to 12 carbon atoms, most preferably 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents, examples of which include, but are not limited to, alkyl, alkyloxy, aryl, aralkyl, amino, halo, hydroxy, sulfonyl, sulfinyl, phosphoryl, and heteroalicyclic.

The term "arylene" refers to a divalent group derived from a monovalent aromatic radical as defined above.

The term "heteroaryl" refers to a monocyclic or fused ring of 5 to 12 ring atoms, having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, containing 1,2, 3 or 4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a completely conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazinyl.

The term "heteroarylene" refers to a divalent radical derived from a monovalent heteroaryl group as defined above.

The term "cycloalkyl" refers to a stable monovalent non-aromatic monocyclic or polycyclic hydrocarbon group containing only carbon and hydrogen atoms, possibly including fused, spiro or bridged ring systems, containing 3 to 15 ring-forming carbon atoms, preferably 3 to 10 ring-forming carbon atoms, more preferably 3 to 8 ring-forming carbon atoms, which may or may not be saturated, attached to the rest of the molecule by a single bond. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "carbocycle" refers to a stable monovalent non-aromatic ring comprising 3 to 12 carbon atoms unless otherwise specified, the carbocycle may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may contain fused, spiro, or bridged ring systems, and the carbocycle may be partially or fully saturated.

The terms "heterocyclyl", "heterocycloalkyl", "heterocycle" and "refers to a stable 3-to 18-membered monovalent non-aromatic ring containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur unless otherwise specified, heterocyclyl groups may be monocyclic, bicyclic, tricyclic or tetracyclic systems, which may contain fused, spiro or bridged ring systems, the nitrogen, carbon or sulfur of the heterocyclyl may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and the heterocyclyl may be partially or fully saturated. Heterocyclic groups containing fused rings may contain one or more aromatic or heteroaromatic rings, provided that the atom on the non-aromatic ring is attached to the remainder of the molecule. For purposes of this application, a heterocyclyl group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl and the like.

The term "polymorph" or "polymorph" refers to a compound of the invention having multiple lattice morphologies some compounds of the invention may have more than one crystal form, and the invention encompasses all polymorphs or mixtures thereof.

Intermediate compounds of the present invention and polymorphs thereof are also within the scope of the present invention.

Unless otherwise specified, the compounds of the present invention contain olefinic double bonds including E and Z isomers.

It will be appreciated that the compounds of the invention may contain asymmetric centers which may independently be in the R or S configuration. It is to be understood that the compounds of the present invention include their individual geometric and stereoisomers as well as mixtures thereof, including racemic mixtures. These isomers can be separated from their mixtures by carrying out or modifying known methods such as chromatography techniques and recrystallization techniques, or they can be prepared separately from the appropriate isomers of their intermediates.

The term "pharmaceutically acceptable salt" as used herein includes both acid and base addition salts.

"pharmaceutically acceptable acid addition salts" refers to those salts formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, capric acid, caproic acid, carbonic acid, cinnamic acid, citric acid, and the like, which retain the biological potency and properties of the free base of the compound, which are not biologically or otherwise undesirable. "pharmaceutically acceptable salt with base" refers to those salts that retain the biological potency and properties of the free acid of the compound and are not biologically or otherwise undesirable.

Salt-forming organic bases include, but are not limited to, primary, secondary, tertiary, cyclic amines, and the like, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and the like.

The term "solvate" as used herein refers to a combination of one or more molecules of a compound of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also retain water or a mixture of water and some other solvent only by chance. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized in a solvent solvates of the compounds of the present invention are also included within the scope of the present invention.

The term "pharmaceutical composition" as used herein refers to a formulation mixed with a compound of the present invention and a vehicle generally accepted in the art for delivering biologically active compounds to a mammal, such as a human.

As used herein, the term "acceptable" in reference to a formulation, composition or ingredient means that there is no lasting deleterious effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a substance (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological response or interacting in an adverse manner with any of the components contained in the composition.

"pharmaceutically acceptable carriers" include, but are not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by the relevant governmental authorities for use in humans and domestic animals.

The terms "subject," "patient," "subject" or "individual" as used herein refer to an individual having a disease, disorder or condition, and the like, including mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; in one embodiment of the methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease or condition associated with a mammal, particularly a human, and includes

(i) Preventing the development of a disease or condition in a mammal, particularly a mammal that has previously been exposed to the disease or condition but has not been diagnosed as having the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its development;

(iii) Relieving the disease or condition, i.e., causing regression of the disease or condition;

(iv) Relieving symptoms caused by the disease or disorder.

The terms "disease" and "condition" as used herein may be used interchangeably and may have different meanings, as certain specific diseases or conditions have no known causative agent (and therefore the cause of the disease is not yet clear) and therefore are not considered as a disease but can be considered as an unwanted condition or syndrome, with more or less specific symptoms being confirmed by clinical researchers.

The terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein, refer to an amount of at least one agent or compound sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent upon administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a condition.

The terms "administering," "administration," "administering," and the like, as used herein, refer to a method of delivering a compound or composition to a desired site for a biological effect. These methods include, but are not limited to, oral routes, via the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention;

the structure of the compound of the invention is hydrogen spectrum by nuclear magnetic resonance ( ¹ H-NMR) and Mass Spectrometry (MS) to confirm that the purity of the compound is determined by High Performance Liquid Chromatography (HPLC), ¹ H-NMR was measured by a nuclear magnetic resonance spectrometer using deuterated dimethyl sulfoxide (DMSO-d) as a solvent ₆ ) And deuterated chloroform (CDCl) ₃ ) Internal standard is Tetramethylsilane (TMS);

measuring Mass spectrum MS by using an Advion Mass expression CMS Mass spectrometer, and measuring HPLC by using an Agilent 1260 Inlimit liquid chromatography system;

thin Layer Chromatography (TLC) adopts a thin layer chromatography silica gel plate, a self-made silica gel thin layer plate adopts GF254 silica gel, and silica gel column chromatography generally adopts 300-400 mesh silica gel;

the starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art;

in the absence of specific indication, all reactions of the present invention are carried out under continuous magnetic stirring, the solvent is dry solvent, and the reaction temperature is given in degrees centigrade.

Example 1: 3-phenyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Step 1: synthesis of example 1

3-Phenylfuran-2, 5-dione (200 mg) and (tetrahydro-2H-pyran-4-yl) methylamine (157 mg) were added to dioxane (5 mL) and acetic acid (1 mL), and the mixture was heated to 110 ℃ and stirred for 12 hours; spin-drying the solvent, extracting with ethyl acetate, and extracting with H ₂ Washing with saturated saline solution for 3 times, drying over anhydrous sodium sulfate, filtering, distilling the filtrate under reduced pressure to remove the solvent, and separating by silica gel column chromatography to obtain a white solid (180 mg). ¹ H NMR(400MHz，DMSO)，7.97-8.00(m，2H)，7.46-7.50(m，3H)，7.27(s，1H)，3.76-3.82(m，2H)，3.33(d，J＝7.2Hz，2H)，3.20(td，J＝11.2Hz，1.6Hz，2H)，1.78-1.88(m，1H)，1.46-1.52(m，2H)，1.10-1.20(m，2H)。

Example 2: 1-phenyl-3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.93(m，2H)，7.37-7.47(m，5H)，7.25-7.34(m，3H)，6.74(s，1H)，4.74(s，2H).

Example 3: 1-phenyl-4-phenylpyridin-2 (1H) -ones

Step 1: synthesis of Compound II

4-Chloropyridin-2 (1H) -one (I) (500 mg), phenylboronic acid (567 mg), potassium carbonate (1.61 g) and Pd (dppf) Cl ₂ (142 mg) 5mL of dioxane and 5mL of water were added, and the mixture was heated to 100 ℃ and stirred for 4 hours under nitrogen protection; after cooling to room temperature, the solvent was dried by rotation, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give white solid (II) (418 mg).

Step 2: synthesis of example 3

Compound II (200 mg), 4- (bromomethyl) tetrahydro-2H-pyran (312 mg) and potassium carbonate (484 mg) were added to DMF (6 mL), heated to 60 ℃ and stirred for 4 hours; appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give white solid (II) (205 mg). ¹ H NMR(400MHz，DMSO)，7.85(d，J＝7.2Hz，1H)，7.66-7.72(m，2H)，7.41-7.48(m，3H)，7.24-7.37(m，5H)，6.69(d，J＝2.0Hz，1H)，6.59(dd，J＝7.2Hz，2.0Hz，1H)，5.11(s，2H).

Example 4: 1-phenyl-6-phenylpyrimidin-4 (3H) -ones

The synthesis method is referred to example 3. ¹ H NMR(400MHz，DMSO)，8.75(s，1H)，8.02-8.06(m，2H)，7.44-7.49(m，3H)，7.26-7.36(m，5H)，6.98(s，1H)，5.12(s，2H).

Example 5: 3-phenyl-1- (piperidin-4-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride

Step 1: synthesis of Compound II

Synthesis of compound II reference was made to example 1.

And 2, step: synthesis of example 5

Compound II (100 mg) was added to 4M dioxane hydrochloride solution (6 mL) and stirred at 25 ℃ for 4 hours; an appropriate amount of isopropyl ether was added to precipitate a white solid, which was filtered to give a white solid (example 5) (38 mg). ¹ H NMR(400MHz，DMSO)，8.53-8.84(br，1H)，8.16-8.52(br，1H)，7.96-8.02(m，2H)，7.46-7.51(m，3H)，7.31(s，1H)，3.35(d，J＝6.8Hz，2H)，3.18-3.27(m，2H)，2.72-2.85(m，2H)，1.83-1.96(m，1H)，1.70-1.78(m，2H)，1.23-1.37(m，2H)。

Example 6: 3-phenyl-1-phenylimidazolidine-2, 4-dione

Step 1: synthesis of Compound II

Aniline (500 mg) and cyanogen bromide (621 mg) were added to dioxane (20 mL), and stirred at room temperature for 12 hours; the solvent was dried, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a yellow solid (II) (482 mg).

And 2, step: synthesis of Compound III

Compound II (400 mg) and NaH (244 mg) were added to anhydrous tetrahydrofuran (20 mL), and stirred at room temperature for 1 hour; methyl bromoacetate (773 mg) was then added and stirred at room temperature for 4 hours; the solvent was dried, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL × 3), the extract was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give compound III (528 mg) as a yellow solid.

And step 3: synthesis of Compound IV

Compound III (500 mg, N) was added to 50% H ₂ SO ₄ (5 mL) and THF (5 mL) at 50 ℃ for 12h; the solvent was dried, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a yellow solid (IV) (287 mg).

And 4, step 4: synthesis of example 6

Compound IV (200 mg), benzyl bromide (231 mg) and K ₂ CO ₃ (472 mg) was added to anhydrous DMF (20 mL) and stirred at room temperature for 1 hour; appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give white solid (TM-4) (249 mg). ¹ H NMR(400MHz，DMSO)，7.61(d，J＝8.0Hz，2H)，7.34-7.39(m，2H)，7.24-7.34(m，5H)，7.11(t，J＝7.6Hz，1H)，4.63(s，2H)，4.56(s，2H)。

Example 7: 3-phenyl-1- (tetrahydro-2H-pyran-4-yl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.87-7.91(m，2H)，7.42-7.49(m，3H)，6.68(s，1H)，4.21(tt，J＝12.0Hz，4.4Hz，1H)，4.07(dd，J＝12.0Hz，4.4Hz，2H)，3.45(td，J＝12.0Hz，1.6Hz，2H)，2.50(qd，J＝12.0Hz，4.4Hz，2H)，1.58-1.64(m，2H).

Example 8: 3-phenyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) pyrrolidine-2, 5-dione

Step 1: synthesis of example 8

Example 1 (200 mg) and Pd/C (20 mg) were added to methanol (10 mL), and the mixture was stirred at room temperature for 12 hours with hydrogen gas introduced; pd/C was filtered off, the solvent was dried by evaporation, and the product was isolated by column chromatography as a white solid, example 8 (153 mg). ¹ H NMR(400MHz，CDCl ₃ )，7.33-7.39(m，2H)，7.27-7.33(m，1H)，7.17-7.21(m，2H)，4.01(dd，J＝9.6Hz，4.8Hz，1H)，3.90-3.97(m，2H)，3.47(d，J＝7.2Hz，2H)，3.32(tt，J＝11.6Hz，2.4Hz，2H)，3.20(dd，J＝20.4Hz，9.6Hz，1H)，2.83(dd，J＝20.4Hz，4.8Hz，1H)，1.92-2.04(m，1H)，1.46-1.56(m，2H)，1.29-1.41(m，2H)。

Example 9: 1-phenyl-3- ((tetrahydro-2H-pyran-4-yl) methyl) imidazolidine-2, 4-dione

The synthesis method is referred to example 6. ¹ H NMR(400MHz，CDCl ₃ )，7.55(d，J＝8.0Hz，2H)，7.36-7.41(m，2H)，7.13-7.18(m，1H)，4.30(s，2H)，3.93-3.98(m，2H)，3.50(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.96-2.08(m，1H)，1.56-1.62(m，2H)，1.34-1.45(m，2H)。

Example 10:1- ((1-methylpiperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，7.96-8.01(m，2H)，7.46-7.50(m，3H)，7.26(s，1H)，3.32(d，J＝6.0Hz，2H)，2.67-2.74(m，2H)，2.10(s，3H)，1.72-1.82(m，2H)，1.48-1.58(m，3H)，1.08-1.19(m，2H).

Example 11:1- (Oxetan-3-yl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.92(m，2H)，7.44-7.51(m，3H)，6.74(s，1H)，5.22-5.27(m，3H)，4.83-4.90(m，2H).

Example 12: 5-benzyl-3-phenyl-1, 2, 4-oxadiazoles

Step 1: synthesis of Compound II

Benzonitrile (I) (500 mg), hydroxylamine hydrochloride (402 mg) and TEA (1.47 g) were added to ethanol (20 mL), heated to 90 ℃ and stirred for 12 hours; after cooling to room temperature, the solvent was dried by evaporation, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (II) (501 mg).

Step 2: synthesis of example 12

Compound II (150 mg), CDI (232 mg) and phenylacetic acid (1.47 g) were added to DMF (20 mL) and stirred at 75 ℃ for 4 hours; appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give example 12 (162 mg) as a white solid. ¹ H NMR(400MHz，CDCl ₃ )，8.03-8.09(m，2H)，7.41-7.51(m，3H)，7.26-7.40(m，5H)，4.28(s，2H).

Example 13: 4-phenyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) pyridin-2 (1H) -one

The synthesis method is referred to example 3. ¹ H NMR(400MHz，CDCl ₃ )，7.51-7.55(m，2H)，7.37-7.44(m，3H)，7.22(d，J＝6.8Hz，1H)，6.76(d，J＝2.0Hz，1H)，6.38(dd，J＝6.8Hz，2.0Hz，1H)，3.91-3.96(m，2H)，3.80(d，J＝7.6Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，2.12-2.23(m，1H)，1.54-1.61(m，2H)，1.31-1.41(m，2H).

Example 14: 6-phenyl-3- ((tetrahydro-2H-pyran-4-yl) methyl) pyrimidin-4 (3H) -one

The synthesis method is referred to example 3. ¹ H NMR(400MHz，DMSO)，8.52(s，1H)，8.02-8.05(m，2H)，7.44-7.48(m，3H)，6.95(s，1H)，3.78-3.84(m，4H)，3.21(td，J＝11.6Hz，1.6Hz，2H)，1.95-2.08(m，1H)，1.40-1.46(m，2H)，1.20-1.30(m，2H).

Example 15: 3-phenyl-1- (pyridin-4-ylmethyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，DMSO)，8.48-8.50(m，2H)，7.98-8.04(m，2H)，7.47-7.51(m，3H)，7.38(s，1H)，7.26-7.28(m，2H)，4.68(s，2H).

Example 16: 4-benzyl-5- (hydroxymethyl) -2-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Step 1: synthesis of Compound III

Compound I (369 mg), compound II (500 mg) and NaOH (1.12 g) were added to water (10 mL), heated to 100 ℃ and stirred for 12 hours; after cooling to room temperature, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (III) (516 mg).

And 2, step: synthesis of Compound IV

Compound III (500 mg), bromobenzene (397 mg), cuI (64 mg) and potassium phosphate (716 mg) were added to dioxane (10 mL), heated to 110 ℃ and stirred for 12 hours; after cooling to room temperature, the solvent was dried by spinning, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give white solid (IV) (263 mg).

And step 3: synthesis of example 16

Adding the compound IV (200 mg) and Pd/C into methanol (10 mL), introducing hydrogen, heating to 50 ℃, and stirring for 12 hours; pd/C was filtered off and spin-dried to give example 16 (109 mg) as a white solid. ¹ H NMR(400MHz，DMSO)，7.88(d，J＝8.4Hz，2H)，7.42-7.46(m，2H)，7.26-7.36(m，5H)，7.21(t，J＝7.6Hz，1H)，5.77(t，J＝6.0Hz，1H)，4.96(s，2H)，4.39(d，J＝6.0Hz，2H).

Example 17:5- (hydroxymethyl) -2-phenyl-4- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The synthesis method is referred to example 16. ¹ H NMR(400MHz，DMSO)，7.86-7.90(m，2H)，7.40-7.46(m，2H)，7.17-7.22(m，1H)，5.73(s，1H)，4.46(s，2H)，3.78-3.85(m，2H)，3.62(d，J＝7.2Hz，2H)，3.22(td，J＝11.6Hz，2.0Hz，2H)，2.04-2.16(m，1H)，1.46-1.53(m，2H)，1.19-1.30(m，2H)。

Example 18:1- (4-Aminocyclohexyl) -3-phenyl-1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，7.88-8.08(m，5H)，7.45-7.50(m，3H)，7.23(s，1H)，3.76-3.86(m，1H)，2.96-3.08(m，1H)，1.96-2.12(m，4H)，1.70-1.78(m，2H)，1.36-1.50(m，2H).

Example 19:3- (2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) piperidine-2, 6-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，11.07(s，1H)，7.97-8.01(m，2H)，7.47-7.53(m，3H)，7.38(s，1H)，5.01(dd，J＝12.8Hz，4.8Hz，1H)，2.80-2.89(m，1H)，2.40-2.60(m，2H)，1.96-2.04(m，1H).

Example 20: 3-phenyl-5- ((tetrahydro-2H-pyran-4-yl) methyl) -1,2, 4-oxadiazole

Synthetic methods refer to example 12. ¹ H NMR(400MHz，CDCl ₃ )，8.04-8.07(m，2H)，7.43-7.51(m，3H)，3.93-3.99(m，2H)，3.40(td，J＝12.0Hz，4.0Hz，2H)，2.88(d，J＝6.8Hz，2H)，2.11-2.23(m，1H)，1.65-1.72(m，2H)，1.40-1.51(m，2H)。

Example 21:1- (4-hydroxycyclohexyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.87-7.90(m，2H)，7.43-7.47(m，3H)，6.67(s，1H)，3.96-4.05(m，1H)，3.69-3.77(m，1H)，2.19-2.30(m，2H)，2.04-2.12(m，2H)，1.70-1.77(m，2H)，1.35-1.46(m，2H)。

Example 22: 3-phenyl-1- (pyrrolidin-3-yl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，8.94-9.54(br，2H)，7.95-8.01(m，2H)，7.47-7.52(m，3H)，7.31(s，1H)，4.73-4.80(m，1H)，3.36-3.46(m，3H)，3.19-3.30(m，1H)，2.18-2.26(m，2H).

Example 23:1- (3-hydroxycyclohexyl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.87-7.90(m，2H)，7.42-7.46(m，3H)，6.66(s，1H)，4.45-4.52(m，1H)，4.28-4.32(m，1H)，2.40(td，J＝12.8Hz，2.8Hz，1H)，2.05-2.16(m，1H)，1.71-1.90(m，4H)，1.62-1.70(m，1H)，1.49-1.56(m，1H)。

Example 24: (z) -3-benzylidene-1- ((tetrahydro-2H-pyran-4-yl) methyl) pyrrolidine-2, 5-dione

Step 1: synthesis of Compound II

Furan-2, 5-dione (I) (500 mg) and (tetrahydro-2H-pyran-4-yl) methylamine (587 mg) were added to acetic acid (20 mL), heated to 100 ℃ and stirred for 12 hours; it was cooled to room temperature, the solvent was dried by evaporation, and column chromatography gave (II) as a white solid (667 mg).

Step 2: synthesis of example 24

Compound II (500 mg), benzaldehyde (272 mg) and PPh ₃ (671 mg) was added to ethanol (40 mL), and stirred at room temperature for 12 hours; filtration and washing of the filter cake with ethanol gave example 24 (415 mg) as a white solid. ¹ H NMR(400MHz，DMSO)，7.60-7.64(m，2H)，7.39-7.48(m，4H)，3.77-3.82(m，2H)，3.70(d，J＝2.4Hz，2H)，3.37(d，J＝7.6Hz，2H)，3.20(td，J＝12.0Hz，1.6Hz，2H)，1.81-1.91(m，1H)，1.45-1.52(m，2H)，1.11-1.21(m，2H)。

Example 25: 3-benzyl-1-phenylpyrimidine-2, 4 (1H, 3H) -dione

Step 1: synthesis of Compound II

Pyrimidine-2,4 (1H, 3H) -dione (I) (800 mg), cuI (271 mg), potassium phosphate (3.10 g), and bromobenzene (2.22 g) were added to dioxane (15 mL), heated to 120 ℃ and stirred for 12 hours; cooling to room temperature, ethyl acetate was added, filtration was carried out, the filtrate was concentrated under reduced pressure, and the residue was isolated by column chromatography to give white solid (II) (497 mg).

Step 2: synthesis of example 25

Compound II (200 mg), benzyl bromide (218 mg) and potassium carbonate (439 mg) were added to DMF (40 mL), and the mixture was heated to 60 ℃ and stirred for 4 hours; after cooling to room temperature, ethyl acetate extraction (50 mL. Times.3) was performed, the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (V) (200 mg). ¹ H NMR(400MHz，CDCl ₃ )，7.51-7.55(m，2H)，7.38-7.49(m，3H)，7.23-7.33(m，6H)，5.86(d，J＝7.6Hz，1H)，5.16(s，2H).

Example 26:2, 4-dibenzyl-5- (hydroxymethyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The synthesis of example 26 is according to example 16. ¹ H NMR(400MHz，DMSO)，7.21-7.35(m，10H)，5.61(s，1H)，4.88(s，2H)，4.87(s，2H)，4.23(s，2H).

Example 27:1- (4-Morpholinobenzyl) -3-phenyl-1H-pyrrole-2, 5-dione

Step 1: synthesis of Compound II

4-fluorobenzonitrile (I) (800 mg), morpholine (1.15 g) and potassium carbonate (2.76 g) were added to DMF (20 mL) and the mixture was heated to 100 ℃ and stirred for 12 hours; after cooling to room temperature, ethyl acetate extraction (50 mL. Times.3) was performed, the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (II) (807 mg).

Step 2: synthesis of Compound III

Compound II (800 mg) was added to THF (20 mL), and LiAlH was slowly added at room temperature ₄ (315 mg), heated to 80 ℃ and stirred for 12 hours; cooled to room temperature, quenched with water, extracted with ethyl acetate, the extract was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (III) (490 mg).

And 3, step 3: synthesis of example 27

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，7.97-8.00(m，2H)，7.46-7.50(m，3H)，7.30(s，1H)，7.11-7.16(m，2H)，6.85-6.89(m，2H)，4.53(s，2H)，3.67-3.70(m，4H)，3.01-3.05(m，4H)。

Example 28: 3-benzyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) pyrrolidine-2, 5-dione

The synthesis method is referred to example 8. ¹ H NMR(400MHz，DMSO)，7.24-7.29(m，2H)，7.16-7.21(m，3H)，3.69-3.79(m，2H)，3.09-3.21(m，5H)，3.01(dd，J＝13.6，4.4Hz，1H)，2.84(dd，J＝13.6Hz，8.8Hz，1H)，2.66(dd，J＝18.0Hz，8.8Hz，1H)，2.39(dd，J＝18.0Hz，4.4Hz，1H)，1.64-1.75(m，1H)，1.33-1.40(m，1H)，0.95-1.19(m，3H).

Example 29: 3-phenyl-1- (2- (tetrahydro-2H-pyran-4-yl) ethyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.90-7.94(m，2H)，7.42-7.48(m，3H)，6.72(s，1H)，3.92-3.97(m，2H)，3.62(t，J＝7.2Hz，2H)，3.36(td，J＝12.0Hz，1.6Hz，2H)，1.65-1.72(m，2H)，1.56-1.61(m，2H)，1.43-1.53(m，1H)，1.26-1.37(m，2H)。

Example 30:1- (4-Morpholinophenyl) -3-phenyl-1H-pyrrole-2, 5-dione

Step 1: synthesis of Compound II

4- (4-Nitrophenyl) morpholine (I) (600 mg) and Pd/C (20 mg) were added to MeOH (20 mL), hydrogen was bubbled through and stirred at room temperature for 12h; filtration and concentration of the filtrate under reduced pressure removed the solvent to give white solid (II) (441 mg).

Step 2: synthesis of example 30

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.95-7.98(m，2H)，7.45-7.50(m，3H)，7.24-7.28(m，2H)，6.96-7.00(m，2H)，6.85(s，1H)，3.85-3.88(m，4H)，3.18-3.20(m，4H)。

Example 31: 4-benzyl-5- (hydroxymethyl) -2- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Synthetic methods refer to example 16. ¹ H NMR(400MHz，DMSO)，7.21-7.34(m，5H)，5.60(s，1H)，4.85(s，2H)，4.23(s，2H)，3.77-3.83(m，2H)，3.55(d，J＝6.8Hz，2H)，3.18-3.26(m，2H)，1.87-1.99(m，1H)，1.40-1.47(m，2H)，1.14-1.24(m，2H).

Example 32: 1-phenyl-3- ((tetrahydro-2H-pyran-4-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione

The synthesis method is referred to example 25. ¹ H NMR(400MHz，DMSO)，7.73(d，J＝7.6Hz，1H)，7.38-7.51(m，5H)，5.77(d，J＝8.4Hz，1H)，3.76-3.83(m，2H)，3.72(d，J＝7.2Hz，2H)，3.20(td，J＝11.6Hz，1.6Hz，2H)，1.86-1.98(m，1H)，1.44-1.51(m，2H)，1.16-1.26(m，2H).

Example 33: 1-Ethyl-5-phenyl-3- ((tetrahydro-2H-pyran-4-yl) methyl) pyrimidine-2, 4 (1H, 3H) -dione

Step 1: synthesis of Compound II

3-benzoyl-5-bromopyrimidine-2, 4 (1H, 3H) -dione (I) (800 mg), iodoethane (508 mg), and potassium carbonate (1.12 g) were added to DMF (15 mL), and stirred at room temperature for 12 hours; extraction with ethyl acetate (50 mL. Times.3), washing of the extract with saturated brine (30 mL. Times.3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by column chromatography gave white solid (II) (280 mg).

Step 2: synthesis of Compound III

Compound II (250 mg), phenylboronic acid (114 mg), pb (PPh) ₃ ) ₄ (44.8 mg) and potassium carbonate (535 mg) were added to dioxane (10 mL) and water (3 mL), heated to 100 ℃ and stirred for 4 hours; after cooling to room temperature, ethyl acetate extraction (50 mL. Times.3) was performed, the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (III) (114 mg).

And step 3: synthesis of example 33

Compound III (100 mg), 4- (bromomethyl) tetrahydro-2H-pyran (124 mg) and potassium carbonate (1)93 mg) was added to DMF (5 mL) and stirred at room temperature for 4 hours; extraction with ethyl acetate (50 mL. Times.3), washing of the extract with saturated brine (30 mL. Times.3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and separation of the residue by column chromatography gave example 33 (121 mg) as a white solid. ¹ H NMR(400MHz，CDCl ₃ )，7.46-7.50(m，2H)，7.34-7.40(m，2H)，7.28-7.33(m，2H)，3.90-3.96(m，4H)，3.86(q，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，2.01-2.13(m，1H)，1.53-1.59(m，2H)，1.40-1.50(m，2H)，1.35(t，J＝7.2Hz，3H).

Example 34: 4-benzyl-2-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Step 1: synthesis of Compound II

Phenylhydrazine hydrochloride (I) (600 mg) was added to water (15 mL), 50% glyoxylic acid (612 mg) was added thereto at 0 ℃ and the mixture was stirred at room temperature for 2 hours; filtering, washing a filter cake with water to obtain a yellow intermediate, then adding the intermediate into toluene (13 mL), slowly adding triethylamine (500 mg) and DPPA (1.08 g), stirring at room temperature for 2 hours, heating to 100 ℃, and stirring for 1 hour; after cooling to room temperature, 2N NaOH (20 mL) was added, the pH was adjusted to 1 with concentrated hydrochloric acid, ethyl acetate was extracted (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a yellow solid (II) (322 mg).

Step 2: synthesis of example 34

Compound II (100 mg), benzyl bromide (127 mg) and potassium carbonate (259 mg) were added to DMF (5 mL), and the mixture was heated to 60 ℃ and stirred for 4 hours; after cooling to room temperature, ethyl acetate extraction (50 mL. Times.3) was performed, the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (TM-11) (123 mg). ¹ H NMR(400MHz，DMSO)，8.34(s，1H)，7.88(d，J＝8.0Hz，2H)，7.40-7.46(m，2H)，7.27-7.40(m，5H)，7.18-7.24(m，1H)，4.86(s，2H).

Example 35: 4-phenyl-2- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Step 1: synthesis of Compound II

Aniline (I) (500 mg), methyl carbazate (532 mg) and trimethyl orthoformate (875 mg) were added to ethanol (10 mL), heated to 80 ℃ and stirred for 12 hours; cooling to room temperature, adding sodium ethoxide (1.10 g), heating to 80 deg.C, and stirring for 4 hr; cooled to room temperature, the solvent was spun off, 25mL of water was added, the pH was adjusted to 1 with concentrated HCl, and filtration gave (II) as a white solid (511 mg).

And 2, step: synthesis of example 35

Compound II (100 mg), 4- (bromomethyl) tetrahydro-2H-pyran (133 mg) and potassium carbonate (259 mg) were added to DMF (5 mL), heated to 60 ℃ and stirred for 4 hours; after cooling to room temperature, ethyl acetate extraction (50 mL. Times.3) was performed, the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give example 35 (99.7 mg) as a white solid. ¹ H NMR(400MHz，DMSO)，8.45(s，1H)，7.65-7.69(m，2H)，7.46-7.51(m，2H)，7.32-7.37(m，1H)，3.78-3.84(m，2H)，3.62(d，J＝6.8Hz，2H)，3.24(td，J＝12.0Hz，2.0Hz，2H)，1.92-2.04(m，1H)，1.47-1.54(m，2H)，1.18-1.28(m，2H).

Example 36:1- ((1-Acrylopiperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione

Step 1: synthesis of example 36

3-phenyl-1- (piperidin-4-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride (I) (150 mg) and TEA (149 mg) were added to DCM (10 mL), and acryloyl chloride (66.1 mg) was slowly added dropwise at 0 ℃ with stirring at 0 ℃ for 2 hours; spin-drying of solvent, column layerExample 36 (113 mg) was isolated as a white solid. ¹ H NMR(400MHz，CDCl ₃ )，7.90-7.93(m，2H)，7.43-7.48(m，3H)，6.74(s，1H)，6.54(dd，J＝16.8Hz，10.4Hz，1H)，6.24(dd，J＝16.8Hz，1.6Hz，1H)，5.65(dd，J＝10.4Hz，1.6Hz，1H)，4.61-4.69(m，1H)，3.94-4.03(m，1H)，3.49(d，J＝7.6Hz，2H)，2.96-3.06(m，1H)，2.58-2.66(m，1H)，1.94-2.06(m，1H)，1.68-1.76(m，2H)，1.18-1.34(m，2H).

Example 37: 3-phenyl-1- (pyridin-3-ylmethyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，8.53(d，J＝1.6Hz，1H)，8.46(dd，J＝4.8Hz，1.6Hz，1H)，7.97-8.02(m，2H)，7.66-7.70(m，1H)，7.46-7.51(m，3H)，7.32-7.36(m，2H)，4.68(s，2H)。

Example 38: (S) -3-phenyl-1- (piperidin-3-yl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，8.86-9.28(br，2H)，7.94-8.00(m，2H)，7.46-7.52(m，3H)，7.30(s，1H)，4.22-4.34(m，1H)，3.18-3.38(m，3H)，2.75-2.88(m，1H)，2.04-2.14(m，1H)，1.65-1.92(m，3H).

Example 39: (R) -3-phenyl-1- (piperidin-3-yl) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，9.18-9.30(br，1H)，8.96-9.13(br，1H)，7.94-8.00(m，2H)，7.46-7.52(m，3H)，7.29(s，1H)，4.23-4.33(m，1H)，3.20-3.38(m，3H)，2.75-2.88(m，1H)，2.04-2.14(m，1H)，1.66-1.92(m，3H).

Example 40:1- (3-aminocyclohexyl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，DMSO)，7.98-8.02(m，2H)，7.39-7.47(m，4H)，4.21-4.25(m，1H)，4.04-4.09(m，1H)，1.82-1.88(m，1H)，1.50-1.80(m，6H)，1.40-1.48(m，1H)。

Example 41:4- (2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) benzonitrile

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.95-7.98(m，2H)，7.78(d，J＝8.4Hz，2H)，7.65(d，J＝8.4Hz，2H)，7.48-7.55(m，3H)，6.92(s，1H)。

Example 42:4- ((2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) methyl) piperidine-1-carbonitrile

Step 1: synthesis of example 42

3-phenyl-1- (piperidin-4-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride (I) (150 mg), brCN (51.4 mg) and potassium carbonate (203 mg) were added to ACN (10 mL), and stirred at room temperature for 12 hours; the solvent was dried by spinning, extracted with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give example 42 (73.7 mg) as a white solid. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.93(m，2H)，7.43-7.49(m，3H)，6.74(s，1H)，3.49(d，J＝6.8Hz，2H)，3.40-3.46(m，2H)，2.97(td，J＝12.4Hz，2.8Hz，2H)，1.78-1.90(m，1H)，1.65-1.72(m，2H)，1.36-1.47(m，2H).

Example 43:1- ((4-Fluoropiperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，9.20-9.51(br，2H)，7.96-8.02(m，2H)，7.47-7.52(m，3H)，7.36(s，1H)，3.68(d，J＝20.0Hz，2H)，3.14-3.24(m，2H)，2.83-2.94(m，2H)，1.87-2.09(m，4H)。

Example 44: (R) -3-phenyl-1- (pyrrolidin-3-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，9.52-9.82(br，2H)，7.96-8.02(m，2H)，7.44-7.50(m，3H)，7.30(s，1H)，3.46-3.56(m，2H)，3.12-3.28(m，2H)，2.97-3.08(m，1H)，2.75-2.84(m，1H)，2.46-2.55(m，1H)，1.91-2.01(m，1H)，1.52-1.63(m，1H).

Example 45:4- ((2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) methyl) benzonitrile

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，7.97-8.03(m，2H)，7.76-7.81(m，2H)，1.45-7.52(m，5H)，7.36(s，1H).

Example 46: 2-phenyl-4- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 4-dihydro-3H-1, 2, 4-triazol-3-one

Synthetic methods refer to example 34. ¹ H NMR(400MHz，CDCl ₃ )，7.93-7.97(m，2H)，7.49(s，1H)，7.39-7.45(m，2H)，7.19-7.24(m，1H)，3.95-4.01(m，2H)，3.59(d，J＝6.8Hz，2H)，3.36(td，J＝12.0Hz，1.6Hz，2H)，2.00-2.10(m，1H)，1.58-1.65(m，2H)，1.33-1.43(m，2H)。

Example 47:1- (4-aminophenyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，7.98-8.04(m，2H)，7.46-7.53(m，3H)，7.35(s，1H)，6.93(d，J＝8.8Hz，2H)，6.59(d，J＝8.8Hz，2H)，5.28(s，2H)。

Example 48: 2-benzyl-4-phenyl-2, 4-dihydro-3H-1, 2, 4-triazol-3-one

The synthesis was as in example 35. ¹ H NMR(400MHz，DMSO)，8.48(s，1H)，7.67-7.71(m，2H)，7.47-7.52(m，2H)，7.25-7.38(m，6H)，4.94(s，2H).

Example 49:1- ((4-Hydroxypiperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，8.89-9.00(br，1H)，8.53-8.68(br，1H)，7.97-8.03(m，2H)，7.47-7.52(m，3H)，7.33(s，1H)，4.98(s，1H)，3.43(s，2H)，3.04-3.11(m，2H)，2.87-2.99(m，2H)，1.68-1.77(m，2H)，1.53-1.61(m，2H).

Example 50: (S) -3-phenyl-1- (pyrrolidin-3-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，9.06-9.24(br，2H)，7.97-8.03(m，2H)，7.46-7.52(m，3H)，7.31(s，1H)，3.48-3.58(m，2H)，3.15-3.32(m，2H)，3.00-3.11(m，1H)，2.78-2.88(m，1H)，2.49-2.57(m，1H)，1.94-2.02(m，1H)，1.54-1.64(m，1H)。

Example 51:1- (cyclohexylmethyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CD ₃ OD)，7.90-7.94(m，2H)，7.42-7.48(m，3H)，6.71(s，1H)，3.41(d，J＝7.6Hz，2H)，1.60-1.76(m，6H)，1.11-1.26(m，3H)，0.91-1.02(m，2H)。

Example 52:1- (4-aminobenzyl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.86-7.92(m，2H)，7.39-7.42(m，3H)，7.21(d，J＝8.4Hz，2H)，6.70(s，1H)，6.61(d，J＝8.4Hz，2H)，4.62(s，2H)。

Example 53:1- (3-aminophenyl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic method referenceExample 1. ¹ H NMR(400MHz，DMSO)，7.99-8.04(m，2H)，7.48-7.53(m，3H)，7.38(s，1H)，7.08(t，J＝8.0Hz，1H)，6.4-6.58(m，1H)，6.50(t，J＝2.0Hz，1H)，6.43-6.66(m，1H)，5.27(s，2H).

Example 54:1- (4- (morpholine-4-carbonyl) phenyl) -3-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 1. ¹ H NMR(400MHz，DMSO)，8.02-8.06(m，2H)，7.50-7.55(m，5H)，7.45-7.49(m，3H)，3.32-3.71(m，8H)。

Example 55:1- ((1-acetylpiperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 36. ¹ H NMR(400MHz，CDCl ₃ )，7.88-7.94(m，2H)，7.42-7.49(m，3H)，6.73(s，1H)，4.56-4.63(m，1H)，3.76-3.83(m，1H)，3.44-3.53(m，2H)，2.95-3.02(m，1H)，2.48-2.55(m，1H)，2.06(s，3H)，1.90-2.03(m，1H)，1.60-1.73(m，2H)，1.13-1.28(m，2H).

Example 56:1- (4- (morpholinomethyl) benzyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.92(m，2H)，7.41-7.47(m，3H)，7.33(d，J＝8.4Hz，2H)，7.27(d，J＝8.4Hz，2H)，6.73(s，1H)，4.72(s，2H)，3.66-3.69(m，4H)，3.45(s，2H)，2.39-2.42(m，4H)。

Example 57:1- (4- (morpholinomethyl) phenyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis method is referred to example 1. ¹ H NMR(400MHz，DMSO)，8.00-8.06(m，2H)，7.48-7.54(m，3H)，7.38-7.44(m，3H)，7.30-7.34(m，2H)，3.54-3.58(m，4H)，3.49(s，2H)，2.31-2.39(m，4H).

Example 58:3- (naphthalen-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Step 1: synthesis of Compound II

3-Bromofuran-2, 5-dione (I) (5 g) and (tetrahydro-2H-pyran-4-yl) methylamine (4.87 g) were added to AcOH (5 mL) and dioxane (20 mL) and reacted at 110 ℃ for 12H; after the reaction was completed, the solvent was dried by rotation, and column chromatography was performed to obtain yellow solid (II) (5.23 g) in a yield of 68.2%.

Step 2: synthesis of example 58

Compound II (150 mg), naphthalen-1-ylboronic acid (188 mg), sodium carbonate (289 mg) and Pb (dppf) Cl2 (20 mg) were added to dioxane (6 mL) and water (3 mL) and reacted at 70 ℃ for 4h; after completion of the reaction, ethyl acetate extraction (50 mL. Times.3), washing with saturated NaCl (30 mL. Times.3), drying of the organic phase over anhydrous sodium sulfate, and column chromatography gave example 58 (79 mg) as a yellow solid in a yield of 45.2%. ¹ H NMR(400MHz，CDCl ₃ )，7.97-8.01(m，1H)，7.88-7.95(m，2H)，7.69(d，J＝7.2Hz，1H)，7.51-7.57(m，3H)，6.83(s，1H)，3.94-4.01(m，2H)，3.54(d，J＝6.8Hz，2H)，3.32-3.39(m，2H)，1.96-2.08(m，1H)，1.57-1.64(m，2H)，1.35-1.45(m，2H).

Example 59:3- (4-fluorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.05-809(m，2H)，7.32-7.36(m，2H)，7.27(s，1H)，3.76-3.82(m，2H)，3.32(d，J＝7.6Hz，2H)，3.17-3.23(m，2H)，1.77-1.89(m，1H)，1.45-1.52(m，2H)，1.09-1.20(m，2H).

Example 60:3- (naphthalen-2-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.70(s，1H)，7.92-7.96(m，1H)，7.88(d，J＝8.4Hz，1H)，7.83-7.86(m，1H)，7.79(dd，J＝8.8Hz，2.0Hz，1H)，7.51-7.59(m，2H)，6.83(s，1H)，3.94-4.00(m，2H)，3.52(d，J＝7.6Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.94-2.06(m，1H)，1.56-1.63(m，2H)，1.35-1.45(m，2H)。

Example 61:3- (4-chlorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.00-8.04(m，2H)，7.55-7.59(m，2H)，7.32(s，1H)，3.76-3.82(m，2H)，3.32(d，J＝7.2Hz，2H)，3.20(td，J＝12.0Hz，2.0Hz，2H)，1.76-1.88(m，1H)，1.46-1.52(m，2H)，1.09-1.20(m，2H)。

Example 62:3- (4-methoxyphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.91-7.95(m，2H)，6.94-6.98(m，2H)，6.58(s，1H)，3.92-3.98(m，2H)，3.86(s，3H)，3.46(d，J＝7.6Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H).

Example 63:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (4- (trifluoromethyl) phenyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.03(d，J＝8.0Hz，2H)，7.71(d，J＝8.0Hz，2H)，6.83(s，1H)，3.93-3.98(m，2H)，3.49(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.92-2.02(m，1H)，1.53-1.60(m，2H)，1.32-1.42(m，2H)。

Example 64:1- (4- (morpholine-4-carbonyl) benzyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.93(m，2H)，7.41-7.48(m，5H)，7.34-7.38(m，2H)，6.75(s，1H)，4.75(s，2H)，3.22-3.92(m，8H).

Example 65:1- ((1- (methylsulfonyl) piperidin-4-yl) methyl) -3-phenyl-1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.89-7.93(m，2H)，7.43-7.48(m，3H)，6.74(s，1H)，3.75-3.82(m，2H)，3.51(d，J＝7.2Hz，2H)，2.75(s，3H)，2.63(td，J＝12.0Hz，2.4Hz，2H)，1.73-1.91(m，3H)，1.35-1.45(m，2H).

Example 66:3- (3-fluorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.66-7.70(m，2H)，7.40-7.46(m，1H)，7.14-7.19(m，1H)，6.75(s，1H)，3.93-3.98(m，2H)，3.48(d，J＝6.8Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.52-1.59(m，2H)，1.31-1.42(m，2H)。

Example 67:3- (2-chlorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.66-7.68(m，1H)，7.48-7.50(m，1H)，7.33-7.39(m，2H)，6.99(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝6.8Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.53-1.59(m，2H)，1.31-1.41(m，2H).

Example 68: 3-chloro-4-phenyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.91-7.94(m，2H)，7.47-7.51(m，3H)，3.93-3.98(m，2H)，3.53(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.92-2.03(m，1H)，1.54-1.60(m，2H)，1.32-1.42(m，2H).

Example 69:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (o-tolyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.48(d，J＝7.6Hz，1H)，7.32-7.36(m，1H)，7.25-7.30(m，2H)，6.58(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.34(d，J＝12.0Hz，2.0Hz，2H)，2.37(s，3H)，1.92-2.03(m，1H)，1.52-1.59(m，2H)，1.31-1.42(m，2H)。

Example 70:3- (benzo [ b ] thiophen-7-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.30(d，J＝7.2Hz，1H)，7.94(d，J＝8.0Hz，1H)，7.48-7.54(m，2H)，7.44(d，J＝5.6Hz，1H)，7.16(s，1H)，3.94-4.00(m，2H)，3.53(d，J＝7.2Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.95-2.06(m，1H)，1.56-1.62(m，2H)，1.34-1.44(m，2H).

Example 71:3- (2-fluorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.04(td，J＝7.6Hz，2.0Hz，1H)，7.51-7.57(m，1H)，7.31-7.39(m，2H)，7.08(d，J＝2.4Hz，1H)，3.76-3.82(m，2H)，3.34(d，J＝6.8Hz，2H)，3.20(td，J＝11.6Hz，2.0Hz，2H)，1.76-1.89(m，1H)，1.46-1.52(m，2H)，1.10-1.20(m，2H)。

Example 72:4- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) benzonitrile

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.01-8.05(m，2H)，7.72-7.76(m，2H)，6.86(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.51-1.58(m，2H)，1.30-1.41(m，2H).

Example 73:3- (benzo [ b ] thiophen-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，DMSO)，8.14(d，J＝8.0Hz，1H)，7.90(d，J＝5.6Hz，1H)，7.68(dd，J＝7.2Hz，0.8Hz，1H)，7.63(dd，J＝6.0Hz，0.8Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.21(s，1H)，3.78-3.84(m，2H)，3.38(d，J＝6.8Hz，2H)，3.21(td，J＝12.0Hz，2.0Hz，2H)，1.81-1.92(m，1H)，1.50-1.56(m，2H)，1.12-1.23(m，2H)。

Example 74:3- (1H-indol-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.58-8.71(br，1H)，7.89(d，J＝8.0Hz，1H)，7.51(d，J＝8.0Hz，1H)，7.33-7.35(m，1H)，7.27(t，J＝8.0Hz，1H)，6.91(s，1H)，6.70-6.72(m，1H)，3.94-4.00(m，2H)，3.52(d，J＝6.8Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.95-2.07(m，1H)，1.56-1.63(m，2H)，1.34-1.45(m，2H)。

Example 75:3- (2, 6-dichlorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.38-7.41(m，2H)，7.29-7.33(m，1H)，6.71(s，1H)，3.92-3.98(m，2H)，3.50(d，J＝7.6Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.94-2.04(m，1H)，1.52-1.58(m，2H)，1.30-1.41(m，2H).

Example 76:3- (2, 3-Dihydrobenzo [ b ] [1,4] Dioxin-6-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.50(d，J＝2.0Hz，1H)，7.47(dd，J＝8.8Hz，2.0Hz，1H)，6.90(d，J＝8.8Hz，1H)，6.56(s，1H)，4.25-4.32(m，4H)，3.91-3.97(m，2H)，3.44(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.40(m，2H)。

Example 77:3- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) benzonitrile

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.26(t，J＝1.6Hz，1H)，8.11-8.13(m，1H)，7.73-7.76(m，1H)，7.59(t，J＝7.6Hz，1H)，6.83(s，1H)，3.93-3.98(m，2H)，3.49(d，J＝6.8Hz，2H)，3.33(td，J＝12.0Hz，2.4Hz，2H)，1.90-2.03(m，1H)，1.52-1.61(m，2H)，1.31-1.42(m，2H).

Example 78:3- (2, 3-dichlorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.55(dd，J＝8.4Hz，1.6Hz，1H)，7.50(d，J＝8.4Hz，1.6Hz，1H)，7.30(t，J＝8.4Hz，1H)，6.95(s，1H)，3.92-3.98(m，2H)，3.49(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H).

Example 79:3- (benzo [ b ] thiophen-3-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.65(s，1H)，7.98(d，J＝7.6Hz，1H)，7.94(d，J＝8.0Hz，1H)，7.51(td，J＝7.6Hz，1.2Hz，1H)，7.45(td，J＝8.0Hz，1.2Hz，1H)，6.87(s，1H)，3.94-3.99(m，2H)，3.52(d，J＝7.2Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.95-2.06(m，1H)，1.55-1.62(m，2H)，1.34-1.44(m，2H).

Example 80:3- (1H-indol-6-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.43-8.53(br，1H)，8.34(s，1H)，7.67(d，J＝8.8Hz，1H)，7.52(dd，J＝8.8Hz，1.6Hz，1H)，7.33-7.35(m，1H)，6.69(s，1H)，6.57-6.59(m，1H)，3.93-3.99(m，2H)，3.49(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.92-2.03(m，1H)，1.44-1.61(m，2H)，1.33-1.44(m，2H)。

Example 81:3- (2-methoxyphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.24(dd，J＝8.0Hz，2.0Hz，1H)，7.39-7.43(m，1H)，7.09(s，1H)，7.02-7.06(m，1H)，6.97(dd，J＝8.8Hz，1.2Hz，1H)，3.92-3.97(m，2H)，3.90(s，3H)，3.46(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.4Hz，2H)，1.91-2.01(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H).

Example 82:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (2- (trifluoromethyl) phenyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.77(d，J＝7.6Hz，1H)，7.63(t，J＝7.6Hz，1H)，7.57(t，J＝7.2Hz，1H)，7.41(d，J＝7.2Hz，1H)，6.68(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.03(m，1H)，1.50-1.57(m，2H)，1.29-1.40(m，2H)。

Example 83:3- (2, 3-dimethylphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.21-7.24(m，1H)，7.13-7.19(m，2H)，6.52(s，1H)，3.92-3.98(m，2H)，3.47(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.31(s，3H)，2.21(s，3H)，1.91-2.02(m，1H)，1.52-1.58(m，2H)，1.30-1.41(m，2H)。

Example 84: 3-methylene-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，6.92(s，2H)，6.50(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，2.29(s，3H)，2.13(s，6H)，1.93-2.04(m，1H)，1.50-1.57(m，2H)，1.30-1.41(m，2H).

Example 85:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (3- (trifluoromethoxy) phenyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.82-7.85(m，2H)，7.49(t，J＝8.4Hz，1H)，7.32(d，J＝8.4Hz，1H)，6.78(s，1H)，3.93-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.03(m，1H)，1.52-1.59(m，2H)，1.31-1.42(m，2H).

Example 86:3- (2-methylnaphthalen-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.82-7.86(m，2H)，7.53-7.58(m，1H)，7.43-7.48(m，2H)，7.39(d，J＝8.8Hz，1H)，6.71(s，1H)，3.96-4.02(m，2H)，3.55(d，J＝6.8Hz，2H)，3.78(td，J＝12.0Hz，2.0Hz，2H)，2.37(s，3H)，1.99-2.10(m，1H)，1.56-1.64(m，2H)，1.34-1.46(m，2H)。

Example 87: 3-methyl-4-phenyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.53-7.57(m，2H)，7.37-7.46(m，3H)，3.89-3.94(m，2H)，3.44(d，J＝7.2Hz，2H)，3.30(td，J＝12.0Hz，2.0Hz，2H)，2.17(s，3H)，1.88-1.99(m，1H)，1.50-1.57(m，2H)，1.28-1.38(m，2H).

Example 88:3- (2, 6-dimethylphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.20(t，J＝7.6Hz，1H)，7.09(d，J＝7.6Hz，2H)，6.52(s，1H)，3.92-3.98(m，2H)，3.49(d，J＝6.8Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，2.17(s，6H)，1.93-2.04(m，1H)，1.50-1.57(m，2H)，1.30-1.41(m，2H).

Example 89:3- (furan-3-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.31(s，1H)，7.49-7.50(m，1H)，6.64(d，J＝1.6Hz，1H)，6.43(s，1H)，3.92-3.97(m，2H)，3.44(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.88-2.00(m，1H)，1.50-1.57(m，2H)，1.29-1.40(m，2H)。

Example 90:3- (3-isopropylphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.77(s，1H)，7.70(dt，J＝7.6Hz，2.0Hz，1H)，7.31-7.38(m，2H)，6.71(s，1H)，3.92-3.97(m，2H)，3.46(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，2.89-3.00(m，1H)，1.90-2.02(m，1H)，1.52-1.58(m，2H)，1.30-1.41(m，2H)，1.26(d，J＝7.2Hz，6H).

Example 91:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (thiophen-3-yl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.35-8.37(m，1H)，7.38-7.43(m，2H)，6.52(s，1H)，3.90-3.96(m，2H)，3.44(d，J＝7.6Hz，2H)，3.31(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.00(m，1H)，1.50-1.57(m，2H0，1.29-1.39(m，2H).

Example 92:2- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) benzonitrile

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.94(dd，J＝8.0Hz，0.8Hz，1H)，7.80(dd，J＝8-7.2Hz，1.6Hz，1H)，7.71(td，J＝8.0Hz，1.6Hz，1H)，7.56(td，J＝7.2Hz，1.6Hz，1H)，7.18(s，1H)，3.92-3.98(m，2H)，3.50(d，J＝6.8Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.53-1.60(m，2H)，1.31-1.41(m，2H)。

Example 93:3- (2-isopropylphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.39-7.42(m，2H)，7.21-7.26(m，2H)，6.53(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝6.8Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，2.89-2.99(m，1H)，1.91-2.03(m，1H)，1.51-1.58(m，2H)，1.30-1.41(m，2H)，1.22(d，J＝6.8Hz，6H).

Example 94:3- (2, 3-difluorophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.98-8.03(m，1H)，7.23-7.30(m，1H)，7.16-7.21(m，1H)，6.99(d，J＝2.8Hz，1H)，3.91-3.97(m，2H)，3.48(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.51-1.58(m，2H)，1.30-1.40(m，2H)。

Example 95:3- (dibenzo [ b, d ] furan-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.53(dd，J＝8.0Hz，1.2Hz，1H)，7.99(dd，J＝7.6Hz，1.2Hz，1H)，7.93(d，J＝8.0Hz，1H)，7.59(d，J＝8.4Hz，1H)，7.53(s，1H)，7.46-7.51(m，1H)，7.35-7.42(m，2H)，3.93-3.99(m，2H)，3.51(d，J＝7.6Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.94-2.06(m，1H)，1.55-1.63(m，2H)，1.34-1.44(m，2H).

Example 96:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (3- (trifluoromethyl) phenyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.18(s，1H)，8.08(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，1H)，7.58(t，J＝8.0Hz，1H)，6.82(s，1H)，3.91-3.97(m，2H)，3.47(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.51-1.58(m，2H)，1.30-1.40(m，2H).

Example 97:3- (benzofuran-7-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.42(d，J＝7.6Hz，1H)，7.69-7.73(m，2H)，7.42(s，1H)，7.34(t，J＝7.6Hz，1H)，6.86(d，J＝2.4Hz，1H)，3.93-3.98(m，2H)，3.51(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.95-2.04(m，1H)，1.54-1.61(m，2H)，1.33-1.44(m，2H).

Example 98:3- (2-ethylphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.31-7.41(m，3H)，7.23-7.28(m，1H)，6.56(s，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.6Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，2.65(q，J＝7.6Hz，2H)，1.92-2.03(m，1H)，1.52-1.58(m，2H)，1.31-1.41(m，2H)，1.21(t，J＝7.6Hz，3H)。

Example 99:3- (3, 5-Dimethylisoxazol-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，6.48(s，1H)，3.88-3.94(m，2H)，3.42(d，J＝6.8Hz，2H)，3.29(td，J＝12.0Hz，2.0Hz，2H)，2.52(s，3H)，2.29(s，3H)，1.85-1.96(m，1H)，1.47-1.54(m，2H)，1.26-1.36(m，2H).

Example 100:3- (phenylamino) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthesis of example 100

Add Compound I (150 mg), aniline (188 mg), and TEA (289 mg) to DCM (6 mL) and stir at 25 ℃ for 4h; extraction with ethyl acetate (50 mL. Times.3), washing of the extract with saturated NaCl (30 mL. Times.3), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and purification of the residue by column chromatography gave the objective product (133 mg). ¹ H NMR(400MHz，CDCl ₃ )，7.37-7.42(m，2H)，7.22-7.26(br，1H)，7.11-7.17(m，3H)，5.49(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.52-1.60(m，2H)，1.30-1.40(m，2H)。

Example 101:3- (8-chloronaphthalen-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.15(dd，J＝8.0Hz，1.2Hz，1H)，8.03(d，J＝8.0Hz，1H)，7.61-7.70(m，2H)，7.51-7.56(m，2H)，6.98(s，1H)，3.78-3.84(m，2H)，3.36(d，J＝6.4Hz，2H)，3.22(t，J＝11.2Hz，2H)，1.81-1.92(m，1H)，1.42-1.58(m，2H)，1.12-1.22(m，2H)。

Example 102:3- (2-aminophenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.50(dd，J＝7.6Hz，1.6Hz，1H)，7.20-7.24(m，1H)，6.79-6.83(m，1H)，6.75(dd，J＝8.4Hz，1.2Hz，1H)，6.73(s，1H)，4.20-4.42(br，2H)，3.92-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H)。

Example 103:3- (1-methyl-1H-indol-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.91(dd，J＝7.6Hz，0.8Hz，1H)，7.45(dt，J＝8.0Hz，0.8Hz，1H)，7.30(t，J＝8.0Hz，1H)，7.19(d，J＝3.2Hz，1H)，6.90(s，1H)，6.63(dd，J＝3.2Hz，0.8Hz，1H)，3.94-3.99(m，2H)，3.84(s，3H)，3.51(d，J＝7.6Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.94-2.06(m，1H)，1.56-1.64(m，2H)，1.34-1.44(m，2H).

Example 104:3- (benzofuran-3-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Reference to synthetic methodsExample 58. ¹ H NMR(400MHz，CDCl ₃ )，8.68(s，1H)，7.72(dd，J＝7.2Hz，2.0Hz，1H)，7.59(dd，J＝7.6Hz，1.6Hz，1H)，7.36-7.44(m，2H)，6.82(s，1H)，3.93-3.99(m，2H)，3.49(d，J＝6.8Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.92-2.04(m，1H)，1.54-1.62(m，2H)，1.32-1.43(m，2H)。

Example 105:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (2- (trifluoromethoxy) phenyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.02(dd，J＝8.0Hz，2.0Hz，1H)，7.48(td，J＝8.0Hz，1.6Hz，1H)，7.34-7.41(m，2H)，6.91(s，1H)，3.91-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.03(m，1H)，1.51-1.58(m，2H)，1.30-1.41(m，2H).

Example 106:3- (quinolin-8-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.93(dd，J＝8.0Hz，2.0Hz，1H)，8.51(dd，J＝7.2Hz，1.6Hz，1H)，8.18(dd，J＝8.4Hz，1.6Hz，1H)，7.88(dd，J＝8.0Hz，1.2Hz，1H)，7.77(s，1H)，7.61(t，J＝8.0Hz，1H)，7.46(dd，J＝8.0Hz，4.0Hz，1H)，3.91-3.97(m，2H)，3.51(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.93-2.05(m，1H)，1.55-1.62(m，2H)，1.33-1.43(m，2H).

Example 107:3- (quinolin-5-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.95(dd，J＝4.4Hz，1.6Hz，1H)，8.29(d，J＝8.8Hz，1H)，8.21(dd，J＝8.0Hz，1.6Hz，1H)，7.74-7.80(m，2H)，7.46(dd，J＝8.4Hz，4.4Hz，1H)，6.79(s，1H)，3.93-3.99(m，2H)，3.54(d，J＝6.8Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.95-2.06(m，1H)，1.55-1.62(m，2H)，1.33-1.44(m，2H)。

Example 108:3- (benzylamino) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method refers to example 100. ¹ H NMR(400MHz，CDCl ₃ )，7.33-7.39(m，3H)，7.26-7.30(m，2H)，5.65(s，1H)，4.84(s，1H)，4.33(d，J＝5.6Hz，2H)，3.90-3.96(m，2H)，3.28-3.36(m，4H)，1.84-1.96(m，1H)，1.49-1.56(m，2H)，1.26-1.37(m，2H)。

Example 109: 3-phenyl-1- (1- (pyridin-4-yl) ethyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.57(d，J＝5.2Hz，2H)，7.86-7.89(m，2H)，7.40-7.46(m，3H)，7.33(d，J＝6.0Hz，2H)，6.71(s，1H)，5.38(q，J＝7.6Hz，1H)，1.84(d，J＝7.6Hz，3H)。

Example 110: 3-phenoxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthesis of example 110

Compound I (150 mg), phenol (188 mg) and t-BuOK (289 mg) were added to THF (6 mL), stirred at 25 ℃ for 1h; the reaction was quenched with water, extracted with ethyl acetate (50 mL. Times.3), the extract was washed with saturated NaCl (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to give the objective product (81.9 mg). ¹ H NMR(400MHz，CDCl ₃ )，7.41-7.46(m，2H)，7.28-7.33(m，1H)，7.15-7.20(m，2H)，5.26(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.60(m，2H)，1.29-1.40(m，2H)。

Example 111:3- (2, 3-Dimethoxyphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.61(dd，J＝8.0Hz，1.6Hz，1H)，7.12(t，J＝8.0Hz，1H)，7.07(s，1H)，7.01(dd，J＝8.4Hz，1.2Hz，1H)，3.92-3.98(m，2H)，3.89(s，3H)，3.83(s，3H)，3.47(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.03(m，1H)，1.52-1.60(m，2H)，1.31-1.42(m，2H).

Example 112:3- (1-methyl-1H-indazol-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.11(s，1H)，7.94(d，J＝7.2Hz，1H)，7.53(d，J＝8.4Hz，1H)，7.45-7.49(m，1H)，6.95(s，1H)，4.12(s，3H)，3.93-3.99(m，2H)，3.52(d，J＝7.2Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.94-2.05(m，1H)，1.56-1.63(m，2H)，1.34-1.44(m，2H)。

Example 113:3- (3-Isopropoxyphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.47(t，J＝2.0Hz，1H)，7.43(d，J＝8.0Hz，1H)，7.32(t，J＝8.0Hz，1H)，6.98(dd，J＝8.0Hz，2.4Hz，1H)，6.69(s，1H)，4.54-4.63(m，1H)，3.91-3.97(m，2H)，3.46(d，J＝6.8Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.02(m，1H)，1.51-1.58(m，2H)，1.30-1.40(m，8H)。

Example 114: 3-cyclopropyl-1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，5.94(s，1H)，3.88-3.94(m，2H)，3.34(d，J＝6.8Hz，2H)，3.29(td，J＝11.6Hz，2.4Hz，2H)，1.80-1.93(m，2H)，1.45-1.52(m，2H)，1.24-1.34(m，2H)，1.12-1.17(m，2H)，0.93-0.97(m，2H).

Example 115:3- (cyclohex-1-en-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.35(t，J＝4.4Hz，1H)，6.14(s，1H)，3.88-3.95(m，2H)，3.37(d，J＝7.6Hz，2H)，3.30(td，J＝12.0Hz，2.0Hz，2H)，2.23-2.30(m，2H)，2.14-2.20(m，2H)，1.84-1.96(m，1H)，1.68-1.76(m，2H)，1.58-1.65(m，2H)，1.47-1.54(m，2H)，1.26-1.36(m，2H)。

Example 116:3- (3, 6-dihydro-2H-pyran-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.33(s，1H)，6.21(s，1H)，4.33-4.36(m，2H)，3.91-3.96(m，2H)，3.88(t，J＝5.6Hz，2H)，3.39(d，J＝7.6Hz，2H)，3.31(td，J＝12.0Hz，2.0Hz，2H)，2.28-2.34(m，2H)，1.84-1.98(m，1H)，1.48-1.55(m，2H)，1.25-1.38(m，2H).

Example 117:3- (3-fluoro-2- (trifluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.56-7.62(m，1H)，7.32(t，J＝9.2Hz，1H)，7.10(d，J＝8.0Hz，1H)，6.61(s，1H)，3.92-3.98(m，2H)，3.47(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，1.6Hz，2H)，1.91-2.02(m，1H)，1.49-1.56(m，2H)，1.28-1.39(m，2H).

Example 118:3- (1-methyl-1H-indol-7-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MH[z，CDCl ₃ )，7.70-7.75(m，1H)，7.12-7.16(m，2H)，7.03(d，J＝2.8Hz，1H)，6.57(s，1H)，6.56(d，J＝2.8Hz，1H)，3.94-4.00(m，2H)，3.67(s，3H)，3.53(d，J＝7.2Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.96-2.07(m，1H)，1.53-1.60(m，2H)，1.33-1.44(m，2H)。

Example 119:3- (3-fluoro-2- (trifluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.63(d，J＝8.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.18(d，J＝7.6Hz，1H)，6.56(s，1H)，3.92-3.98(m，2H)，3.47(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.49-1.56(m，2H)，1.28-1.39(m，2H).

Example 120:3- (Phenylthio) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to example 100. ¹ H NMR(400MHz，CDCl ₃ )，7.53-7.56(m，2H)，7.44-7.49(m，3H)，5.63(s，1H)，3.91-3.97(m，2H)，3.40(d，J＝7.2Hz，2H)，3.32(td，J＝12.0Hz，2.4Hz，2H)，1.86-1.97(m，1H)，1.49-1.56(m，2H)，1.27-1.38(m，2H).

Example 121:1- (3-chloro-4-methylphenyl) -3- (3- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) phenethyl) urea

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.70(s，1H)，7.68(d，J＝8.4Hz，1H)，7.34(t，J＝7.6Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.22(s，1H)，7.15(s，1H)，7.01-7.06(m，2H)，6.65(s，1H)，5.30(t，J＝2.0Hz，1H)，3.89-3.96(m，2H)，3.40-3.46(m，4H)，3.30(td，J＝12.0Hz，2.0Hz，2H)，2.80(t，J＝6.8Hz，2H)，2.24(s，3H)，1.86-1.97(m，1H)，1.49-1.56(m，2H)，1.27-1.38(m，2H).

Example 122:1- (3-chloro-4-methylphenyl) -3- (3- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) phenyl) urea

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.90(s，1H)，8.75(s，1H)，8.07(s，1H)，7.67(d，J＝2.0Hz，1H)，7.58(d，J＝8.0Hz，1H)，7.54(d，J＝7.6Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.14-7.23(m，3H)，3.76-3.82(m，2H)，3.33(d，J＝7.2Hz，2H)，3.21(t，J＝11.6Hz，2H)，2.23(s，3H)，1.77-1.89(m，1H)，1.46-1.52(m，2H)，1.10-1.21(m，2H)。

Example 123:3- (2- (difluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.71-7.74(m，1H)，7.53-7.60(m，2H)，7.49-7.52(m，1H)，6.78(t，J＝55.2Hz，1H)，6.68(s，1H)，3.91-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.51-1.58(m，2H)，1.30-1.40(m，2H).

Example 124:3- (2- (difluoromethoxy) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.04(dd，J＝8.0Hz，2.0Hz，1H)，7.46(td，J＝8.0Hz，2.0Hz，1H)，7.30(td，J＝8.0Hz，1.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，6.97(s，1H)，6.56(t，J＝73.6Hz，1H)，3.92-3.98(m，2H)，3.48(d，J＝7.6Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H)。

Example 125:3- (2, 2-Difluorobenzo [ d ] [1,3] Dioxolan-4-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.13(dd，J＝7.6Hz，2.0Hz，1H)，7.15-7.21(m，2H)，7.07(s，1H)，3.93-3.98(m，2H)，3.49(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.91-2.03(m，1H)，1.51-1.60(m，2H)，1.31-1.42(m，2H).

Example 126:3- (4-chloro-2- (trifluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.77(d，J＝1.6Hz，1H)，7.61(dd，J＝8.4Hz，2.0Hz，1H)，7.39(d，J＝8.4Hz，1H)，6.70(s，1H)，3.93-3.98(m，2H)，3.49(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，.2H)，1.91-2.03(m，1H)，1.50-1.56(m，2H)，1.30-1.40(m，2H)。

Example 127:2- ((tetrahydro-2H-pyran-4-yl) methyl) isochromyl [3,4-c ] pyrrole-1, 3 (2H, 5H) -dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.30-7.41(m，3H)，7.06(d，J＝7.6Hz 1H)，5.42(d，J＝12.4Hz，1H)，5.22(d，J＝12.4Hz，1H)，3.89-3.98(m，2H)，3.43-3.52(m，2H)，3.29-3.39(m，2H)，1.94-2.04(m，1H)，1.46-1.58(m，2H)，1.29-1.42(m，2H).

Example 128:3- (4-fluoro-2- (trifluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.43-7.50(m，2H)，7.33(td，J＝8.0Hz，2.8Hz，1H)，6.68(s，1H)，3.91-3.97(m，2H)，3.47(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.48-1.56(m，2H)，1.28-1.39(m，2H).

Example 129:3- (2-methoxypyridin-3-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.69(dd，J＝8.0Hz，2.0Hz，1H)，8.19(dd，J＝4.8Hz，2.0Hz，1H)，7.16(s，1H)，6.98(dd，J＝8.0Hz，4.8Hz，1H)，4.04(s，3H)，3.90-3.96(m，2H)，3.45(d，J＝7.2Hz，2H)，3.31(td，J＝12.0Hz，1.6Hz，2H)，1.88-2.00(m，1H)，1.50-1.57(m，2H)，1.28-1.39(m，2H).

Example 130:3- (2, 4-bis (trifluoromethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.02(s，1H)，7.90(d，J＝8.0Hz，1H)，7.58(d，J＝8.0Hz，1H)，6.75(s，1H)，3.92-3.98(m，2H)，3.49(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.91-2.04(m，1H)，1.50-1.56(m，2H)，1.29-1.40(m，2H)。

Example 131:1- (3-chloro-4-methylphenyl) -3- (3- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrole) -3-yl) benzyl) urea

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，DMSO)，8.67(s，1H)，7.93(s，1H)，7.84(d，J＝7.6Hz，1H)，7.63(d，J＝2.4Hz，1H)，7.38-7.46(m，2H)，7.23(s，1H)，7.14(d，J＝8.4Hz，1H)，7.08(dd，J＝8.4Hz，2.0Hz，1H)，6.71(t，J＝6.0Hz，1H)，4.30(d，J＝6.0Hz，2H)，3.76-3.81(m，2H)，3.32(d，J＝7.2Hz，2H)，3.19(td，J＝12.0Hz，2.0Hz，2H)，2.20(s，3H)，1.76-1.88(m，1H)，1.44-1.51(m，2H)，1.09-1.19(m，2H).

Example 132:3- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) benzoic acid methyl ester

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.52(t，J＝2.0Hz，1H)，8.10-8.15(m，2H)，7.53(t，J＝8.0Hz，1H)，6.81(s，1H)，3.91-3.97(m，5H)，3.47(d，J＝7.6Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.51-1.58(m，2H)，1.30-1.41(m，2H).

Example 133:3- (4-hydroxyphenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.89(d，J＝8.8Hz，2H)，6.89(d，J＝8.8Hz，2H)，6.58(s，1H)，5.33(s，1H)，3.93-3.98(m，2H)，3.46(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.02(m，1H)，1.52-1.58(m，2H)，1.31-1.41(m，2H)。

Example 134:3- (3- (dimethylamino) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.27-7.31(m，2H)，7.19(d，J＝7.6Hz，1H)，6.82(dd，J＝8.4Hz，2.8Hz，1H)，6.69(s，1H)，3.92-3.98(m，2H)，3.46(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.99(s，6H)，1.91-2.02(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H)。

Example 135:3- (2- (dimethylamino) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.85(dd，J＝7.6Hz，1.6Hz，1H)，7.34-7.38(m，1H)，7.11(d，J＝8.0Hz，1H)，7.09(s，1H)，7.05(td，J＝8.0Hz，1.2Hz，1H)，3.93-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，2.68(s，6H)，1.92-2.04(m，1H)，1.52-1.59(m，2H)，1.32-1.42(m，2H).

Example 136:3- (3- (hydroxymethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.91(s，1H)，7.83(d，J＝7.2Hz，1H)，7.42-7.49(m，2H)，6.74(s，1H)，4.74(d，J＝3.2Hz，2H)，3.92-3.98(m，2H)，3.47(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.02(m，2H)，1.52-1.59(m，2H)，1.30-1.41(m，2H).

Example 137:3- (isoquinolin-8-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，9.38(s，1H)，9.61(d，J＝6.0Hz，1H)，7.90-7.96(m，1H)，7.75-7.78(m，2H)，7.72(d，J＝6.0Hz，1H)，6.90(s，1H)，3.95-4.01(m，2H)，3.56(d，J＝7.6Hz，2H)，3.36(td，J＝12.0Hz，2.0Hz，2H)，1.97-2.09(m，1H)，1.57-1.64(m，2H)，1.35-1.46(m，2H).

Example 138: n- (4- ((2, 5-dioxo-3-phenyl-2, 5-dihydro-1H-pyrrol-1-yl) methyl) phenyl) acrylamide

The synthesis method is referred to example 36. ¹ H NMR(400MHz，CDCl ₃ )，7.88-7.92(m，2H)，7.52(d，J＝8.8Hz，2H)，7.41-7.47(m，3H)，7.36(d，J＝8.8Hz，2H)，7.21-7.27(br，1H)，6.72(s，1H)，6.41(d，J＝16.8Hz，1H)，6.21(dd，J＝16.8Hz，10.0Hz，1H)，5.75(d，J＝10.0Hz，1H)，4.69(s，2H)。

Example 139:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (2- (trifluoromethoxy) phenoxy) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.34-7.42(m，3H)，7.27-7.30(m，1H)，5.23(s，1H)，3.92-3.97(m，2H)，3.42(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.50-1.57(m，2H)，1.28-1.38(m，2H).

Example 140:4- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) -N, N-dimethylbenzamide

The synthesis was performed as described in example 58. ¹ H MR(400MHz，CDCl ₃ )，7.95(d，J＝8.4Hz，2H)，7.48(d，J＝8.4Hz，2H)，6.76(s，1H)，3.91-3.97(m，2H)，3.47(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，3.10(s，3H)，2.96(s，3H)，1.89-2.01(m，1H)，1.51-1.58(m，2H)，1.30-1.40(m，2H)。

Example 141:3- (naphthalen-1-yloxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.30(d，J＝8.0Hz，1.6Hz，1H)，8.01(d，J＝8.0Hz，1.2Hz，1H)，7.65(d，J＝8.0Hz，1H)，7.49-7.58(m，2H)，7.26(s，1H)，6.84(d，J＝8.0Hz，1H)，6.75(s，1H)，3.99-4.05(m，2H)，3.55(d，J＝7.6Hz，2H)，3.40(td，J＝11.6Hz，2.0Hz，2H)，1.97-2.09(m，1H)，1.59-1.66(m，2H)，1.38-1.48(m，2H).

Example 142:3- (3- (morpholinomethyl) phenyl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.86(s，1H)，7.80(d，J＝7.2Hz，1H)，7.38-7.46(m，2H)，6.73(s，1H)，3.92-3.98(m，2H)，3.68-3.71(m，4H)，3.53(s，2H)，3.47(d，J＝7.6Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，2.43-2.45(m，4H)，1.90-2.01(m，1H)，1.52-1.59(m，2H)，1.31-1.41(m，2H).

Example 143:2- (2, 5-dioxo-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) -N, N-dimethylbenzamide

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.56-7.60(m，1H)，7.44-7.49(m，2H)，7.34-7.38(m，1H)，6.63(s，1H)，3.91-3.97(m，2H)，3.42(d，J＝7.6Hz，2H)，3.32(td，J＝12.0Hz，2.0Hz，2H)，3.01(s，3H)，2.99(s，3H)，1.86-1.99(m，1H)，1.52-1.60(m，2H)，1.26-1.37(m，2H).

Example 144:3- (2-Methylquinolin-8-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，8.56(d，J＝7.6Hz，1H)，8.08(d，J＝8.0Hz，1H)，7.92(s，1H)，7.84(dd，J＝8.0Hz，1.2Hz，1H)，7.55(t，J＝8.0Hz，1H)，7.35(d，J＝8.4Hz，1H)，3.84-4.00(m，2H)，3.52(d，J＝7.2Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，2.75(s，3H)，1.95-2.06(m，1H)，1.58-1.66(m，2H)，1.35-1.46(m，2H).

Example 145:3- (isoquinolin-5-yl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，9.31(s，1H)，8.60(d，J＝6.4Hz，1H)，8.08(d，J＝8.0Hz，1H)，7.96(d，J＝6.8Hz，1H)，7.78(d，J＝6.4Hz，1H)，7.70(t，J＝8.0Hz，1H)，6.87(s，1H)，3.94-4.00(m，2H)，3.55(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，1.6Hz，2H)，1.95-2.06(m，1H)，1.56-1.63(m，2H)，1.35-1.45(m，2H)。

Example 146:3- (isoquinolin-4-yl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 58. ¹ H NMR(400MHz，CDCl ₃ )，9.32(s，1H)，8.70(s，1H)，8.07(d，J＝8.4Hz，1H)，7.94(d，J＝8.8Hz，1H)，7.77-7.81(m，1H)，7.67-7.72(m，1H)，6.92(s，1H)，3.95-4.01(m，2H)，3.56(d，J＝7.6Hz，2H)，3.37(td，J＝11.6Hz，2.4Hz，2H)，1.97-2.09(m，1H)，1.57-1.64(m，2H)，1.36-1.46(m，2H)。

Example 147:3- (2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) -N, N-dimethylbenzamide

The synthesis was performed as described in example 58. ¹ H NMR(400MHz，CDCl ₃ )，7.93-7.98(m，2H)，7.47-7.53(m，2H)，6.76(s，1H)，3.92-3.98(m，2H)，3.47(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，3.12(s，3H)，3.00(s，3H)，1.90-2.01(m，1H)，1.52-1.58(m，2H)，1.30-1.41(m，2H)。

Example 148:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (m-methoxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.30(t，J＝7.6Hz，1H)，7.10(d，J＝7.2Hz，1H)，6.94-6.99(m，2H)，5.26(s，1H)，3.93-3.97(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，1.6Hz，2H)，2.37(s，3H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.40(m，2H)。

Example 149:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (p-tolyloxy) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.21(d，J＝8.8Hz，2H)，7.04(d，J＝8.8Hz，2H)，5.24(s，1H)，3.92-3.98(m，2H)，3.42(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.35(s，3H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.28-1.39(m，2H).

Example 150:3- (1H-pyrrolo [2,3-b ] pyridin-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.56(d，J＝4.0Hz，1H)，8.41(dd，J＝4.8Hz，1.6Hz，1H)，7.93(dd，J＝8.0Hz，1.6Hz，1H)，7.59(s，1H)，7.22(dd，J＝7.6Hz，5.2Hz，1H)，6.68(d，J＝7.6Hz，1H)，3.94-3.98(m，2H)，3.49(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，1.6Hz，2H)，1.93-2.04(m，1H)，1.54-1.61(m，2H)，1.32-1.43(m，2H)。

Example 151:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (2- (trifluoromethyl) phenoxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.75(d，J＝8.4Hz，1H)，7.64(td，J＝8.0Hz，1.2Hz，1H)，7.44(t，J＝8.0Hz，1H)，7.28(d，J＝8.4Hz，1H)，5.25(s，1H)，3.93-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.50-1.57(m，2H)，1.29-1.39(m，2H)。

Example 152:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (3, 4, 5-trimethoxyphenoxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，6.40(s，2H)，5.35(s，1H)，3.92-3.98(m，2H)，3.83(s，3H)，3.82(s，6H)，3.43(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.00(m，1H)，1.52-1.58(m，2H)，1.29-1.39(m，2H)。

Example 153:3- (3, 5-Dimethoxyphenoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，6.36(t，J＝2.0Hz，1H)，6.31(d，J＝2.0Hz，2H)，5.37(s，1H)，3.91-3.98(m，2H)，3.77(s，6H)，3.42(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.51-1.58(m，2H)，1.28-1.39(m，2H).

Example 154: 3-chloro-5- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.61(t，J＝2.0Hz，1H)，7.47(t，J＝2.0Hz，1H)，7.41(t，J＝2.0Hz，1H)，5.45(s，1H)，3.93-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.88-2.01(m，1H)，1.51-1.58(m，2H)，1.29-1.40(m，2H)。

Example 155:3- (4-chlorophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.41(d，J＝8.8Hz，2H)，7.13(d，J＝8.8Hz，2H)，5.29(s，1H)，3.93-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，1.6Hz，2H)，1.89-2.01(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H).

Example 156:3- (1H-benzo [ d ] imidazol-1-yl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，9.09(s，1H)，7.88-7.90(m，1H)，7.57-7.60(m，1H)，7.41-7.49(m，2H)，6.57(s，1H)，3.95-4.00(m，2H)，3.54(d，J＝6.8Hz，2H)，3.35(td，J＝12.0Hz，2.0Hz，2H)，1.94-2.04(m，1H)，1.53-1.62(m，2H)，1.34-1.44(m，2H).

Example 157:3- (benzyloxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.36-7.40(m，5H)，5.40(s，1H)，5.09(s，2H)，3.90-3.95(m，2H)，3.37(d，J＝7.2Hz，2H)，3.30(td，J＝11.6Hz，2.0Hz，2H)，1.84-1.95(m，1H)，1.47-1.54(m，2H)，1.25-1.35(m，2H)。

Example 158:3- (2-Oxopyridin-1 (2H) -yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，7.88(dd，J＝7.2Hz，2.4Hz，1H)，7.48-7.52(m，1H)，7.21(s，1H)，6.49-6.52(m，1H)，6.35-6.39(m，1H)，3.76-3.82(m，2H)，3.33(d，J＝7.2Hz，2H)，3.20(td，J＝11.6Hz，1.6Hz，2H)，1.75-1.86(m，1H)，1.47-1.54(m，2H)，1.09-1.20(m，2H).

Example 159:3- ((5-Chloropyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.55(d，J＝1.6Hz，1H)，8.45(d，J＝2.4Hz，1H)，7.58(t，J＝2.0Hz，1H)，5.41(s，1H)，3.91-3.97(m，2H)，3.43(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.98(m，1H)，1.50-1.57(m，2H)，1.27-1.38(m，2H)。

Example 160:3- (naphthalen-2-yloxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.92(d，J＝8.8Hz，1H)，7.86-7.89(m，1H)，7.79-7.83(m，1H)，7.62(d，J＝2.4Hz，1H)，7.49-7.57(m，2H)，7.30(dd，J＝8.8Hz，2.4Hz，1H)，5.32(s，1H)，3.93-3.99(m，2H)，3.45(d，J＝6.8Hz，2H)，3.34(td，J＝12.0Hz，1.6Hz，2H)，1.90-2.03(m，1H)，1.53-1.60(m，2H)，1.31-1.41(m，2H)。

Example 161:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (o-methoxy) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.16-7.27(m，3H)，7.06(dd，J＝8.4Hz，1.6Hz，1H)，5.08(s，1H)，3.90-3.96(m，2H)，3.41(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.4Hz，2H)，2.21(s，3H)，1.87-1.97(m，1H)，1.50-1.57(m，2H)，1.27-1.38(m，2H)。

Example 162:3- (quinolin-8-oxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.91(dd，J＝4.4Hz，1.6Hz，1H)，8.22(dd，J＝8.4Hz，1.6Hz，1H)，7.77-7.82(m，1H)，7.55-7.58(m，2H)，7.48(dd，J＝8.4Hz，4.4Hz，1H)，5.01(s，1H)，3.93-3.97(m，2H)，3.43(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，1.6Hz，2H)，1.90-2.02(m，1H)，1.54-1.61(m，2H)，1.29-1.40(m，2H)。

Example 163 is as follows: 3- (1H-indol-1-yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.30(d，J＝3.6Hz，1H)，7.65(d，J＝6.8Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.36(td，J＝8.0Hz，1.6Hz，1H)，7.29(td，J＝7.6Hz，1.2Hz，1H)，6.74(d，J＝3.6Hz，1H)，6.42(s，1H)，3.84-3.99(m，2H)，3.51(d，J＝7.6Hz，2H)，3.35(dd，J＝11.6Hz，1.6Hz，2H)，1.94-2.06(m，1H)，1.54-1.62(m，2H)，1.33-1.44(m，2H)。

Example 164:3- (indol-1-yl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.19-7.28(m，3H)，7.05(td，J＝7.6Hz，1.2Hz，1H)，5.69(s，1H)，4.50(t，J＝8.4Hz，2H)，3.92-3.98(m，2H)，3.42(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，1.6Hz，2H)，3.20(t，J＝8.4Hz，2H)，1.90-2.01(m，1H)，1.52-1.59(m，2H)，1.30-1.41(m，2H).

Example 165:3- (3, 4-dihydroquinolin-1 (2H) -yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthesis methodReference is made to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.23-7.26(m，1H)，7.11-7.16(m，2H)，7.04-7.08(m，1H)，5.53(s，1H)，4.04-4.07(m，2H)，3.92-3.98(m，2H)，3.39(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.80(t，J＝6.4Hz，2H)，1.88-2.02(m，3H)，1.52-1.60(m，2H)，1.29-1.40(m，2H)。

Example 166:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.77(d，J＝8.4Hz，2H)，7.32(d，J＝8.4Hz，2H)，5.42(s，1H)，3.92-3.98(m，2H)，3.44(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H).

Example 167:3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzaldehyde

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，10.00(s，1H)，7.82(d，J＝7.6Hz，1H)，7.70(t，J＝2.0Hz，1H)，7.63(t，J＝8.0Hz，1H)，7.43-7.47(m，1H)，5.31(s，1H)，3.90-3.96(m，2H)，3.42(d，J＝6.8Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.99(m，1H)，1.50-1.57(m，2H)，1.27-1.38(m，2H).

Example 168:3- (3, 5-Dichlorophenoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.32(t，J＝2.0Hz，1H)，7.12(t，J＝2.0Hz，2H)，5.41(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.50-1.57(m，2H)，1.28-1.39(m，2H)。

Example 169:3- ((6-Chloropyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.35(d，J＝3.2Hz，1H)，7.52(dd，J＝8.8Hz，3.2Hz，1H)，7.43(d，J＝8.8Hz，1H)，5.37(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.50-1.58(m，2H)，1.28-1.39(m，2H)。

Example 170:3- ((2-Methylquinolin-8-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.08(d，J＝8.4Hz，1H)，7.72(td，J＝8.0Hz，1.6Hz，1H)，7.45-7.53(m，2H)，7.33(d，J＝8.4Hz，1H)，5.03(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝6.8Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，2.67(s，3H)，1.92-2.02(m，1H)，1.53-1.61(m，2H)，1.31-1.41(m，2H).

Example 171:3- (4- (morpholine-4-carbonyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.50(d，J＝8.8Hz，2H)，7.24(d，J＝8.8Hz，2H)，5.33(s，1H)，3.92-3.98(m，2H)，3.28-3.88(m，12H)，1.88-1.99(m，1H)，1.50-1.58(m，2H)，1.28-1.39(m，2H)。

Example 172:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (3- (trifluoromethyl) phenoxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.58-7.62(m，2H)，7.47(s，1H)，7.38-7.42(m，1H)，5.32(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H)。

Example 173:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) -N, N-dimethylbenzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.52(d，J＝8.4Hz，2H)，7.22(d，J＝8.4Hz，2H)，5.33(s，1H)，3.93-3.98(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，1.6Hz，2H)，3.11(s，3H)，2.99(s，3H)，1.89-2.01(m，1H)，1.52-1.59(m，2H)，1.29-1.40(m，2H).

Example 174: 9-hydroxy-2- ((tetrahydro-2H-pyran-4-yl) methyl) chromene [2,3-c ] pyrrole-1, 3 (2H, 9H) -dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.61-7.64(m，1H)，7.39-7.44(m，1H)，7.30-7.34(m，2H)，5.81(s，1H)，3.91-3.97(m，2H)，3.46(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，3.08-3.18(brs，1H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.29-1.40(m，2H)。

Example 175:3- (2- (morpholine-4-carbonyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.44-7.51(m，2H)，7.38(td，J＝7.6Hz，1.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，5.33(s，1H)，3.92-3.98(m，2H)，3.52-3.90(m，6H)，3.20-3.43(m，6H)，1.86-1.97(m，1H)，1.50-1.58(m，2H)，1.28-1.38(m，2H)。

Example 176:3- (2, 6-dimethylphenoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.05-7.14(m，3H)，4.98(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝6.8Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，2.18(s，6H)，1.90-2.01(m，1H)，1.50-1.57(m，2H)，1.29-1.40(m，2H).

Example 177:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzoic acid methyl ester

Synthesis method referring to examples110. ¹ H NMR(400MHz，CDCl ₃ )，8.13(d，J＝8.8Hz，2H)，7.25(d，J＝8.8Hz，2H)，5.36(s，1H)，3.92-3.98(m，5H)，3.44(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.29-1.40(m，2H).

Example 178:3- (2-chlorophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.48(dd，J＝8.0Hz，1.6Hz，1H)，7.33(td，J＝8.0Hz，1.6Hz，1H)，7.21-7.28(m，2H)，5.14(s，1H)，3.91-3.97(m，2H)，3.42(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.50-1.57(m，2H)，1.28-1.38(m，2H)。

Example 179: methyl 3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzoate

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.96(d，J＝7.6Hz，1H)，7.83(t，J＝2.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.36(dd，J＝8.4Hz，2.4Hz，1H)，5.28(s，1H)，3.89-3.96(m，5H)，3.41(d，J＝6.8Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.98(m，1H)，1.50-1.56(m，2H)，1.27-1.37(m，2H)。

Example 180:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzaldehyde

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，10.02(s，1H)，7.99(d，J＝8.4Hz，2H)，7.36(d，J＝8.8Hz，2H)，5.41(s，1H)，3.93-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，1.6Hz，2H)，1.88-2.01(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H).

Example 181:3- (4- (morpholinomethyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.40(d，J＝8.4Hz，2H)，7.12(d，J＝8.8Hz，2H)，5.26(s，1H)，3.91-3.97(m，2H)，3.69-3.72(m，4H)，3.52(s，2H)，3.42(d，J＝7.6Hz，2H)，3.32(td，J＝11.6Hz，1.6Hz，2H)，2.42-2.50(m，4H)，1.87-2.00(m，1H)，1.50-1.58(m，2H)，1.28-1.38(m，2H).

Example 182:3- (pyridin-3-yloxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.59(dd，J＝4.8Hz，1.2Hz，1H)，8.57(d，J＝2.8Hz，1H)，7.53-7.56(m，1H)，7.42(dd，J＝8.0Hz，4.8Hz，1H)，5.32(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.33(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.29-1.40(m，2H).

Example 183:3- (1-Oxoisoquinolin-2 (1H) -yl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.40(d，J＝8.0Hz，1H)，8.01(d，J＝7.6Hz，1H)，7.70(td，J＝7.6Hz，1.2Hz，1H)，7.50-7.54(m，2H)，7.33(s，1H)，6.58(d，J＝8.0Hz，1H)，3.93-3.98(m，2H)，3.48(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.53-1.60(m，2H)，1.31-1.41(m，2H)。

Example 184:3- (3, 4-Dichlorophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.52(d，J＝8.8Hz，1H)，7.33(d，J＝2.8Hz，1H)，7.06(dd，J＝8.4Hz，2.8Hz，1H)，5.36(s，1H)，3.92-3.97(m，2H)，3.42(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.99(m，1H)，1.50-1.57(m，2H)，1.28-1.38(m，2H).

Example 185:3- ((2, 6-dichlorophenyl) thio) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.50(d，J＝7.6Hz，2H)，7.37-7.41(m，1H)，5.54(s，1H)，3.92-3.97(m，2H)，3.41(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.99(m，1H)，1.50-1.56(m，2H)，1.27-1.38(m，2H)。

Example 186:3- (2, 6-Dichlorophenoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.41(d，J＝8.0Hz，2H)，7.23(t，J＝7.6Hz，1H)，5.18(s，1H)，3.93-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.51-1.58(m，2H)，1.29-1.40(m，2H).

Example 187:3- (4-bromophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.57(d，J＝8.8Hz，2H)，7.08(d，J＝8.8Hz，2H)，5.30(s，1H)，3.93-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.02(m，1H)，1.52-1.59(m，2H)，1.29-1.40(m，2H)。

Example 188:3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.57-7.64(m，2H)，7.49-7.50(m，1H)，7.44-7.47(m，1H)，5.35(s，1H)，3.92-3.97(m，2H)，3.43(d，J＝7.6Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.99(m，1H)，1.50-1.57(m，2H)，1.29-1.39(m，2H).

Example 189:2- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.75(dd，J＝8.0Hz，1.6Hz，1H)，7.70(td，J＝8.0Hz，1.6Hz，1H)，7.44(t，J＝8.0Hz，1H)，7.32(d，J＝8.0Hz，1H)，5.35(s，1H)，3.92-3.97(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.89-1.99(m，1H)，1.51-1.58(m，2H)，1.28-1.38(m，2H).

Example 190:3- (4- (methylsulfonyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.06(d，J＝9.2Hz，2H)，7.39(d，J＝9.2Hz，2H)，5.44(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，3.09(s，3H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.30-1.40(m，2H)。

Example 191:3- (4- (methylthio) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.28(d，J＝9.2Hz，2H)，7.09(d，J＝9.2HZ，2H)，5.27(s，1H)，3.91-3.97(m，2H)，3.42(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，2.48(s，3H)，1.88-1.99(m，1H)，1.51-1.57(m，2H)，1.28-1.38(m，2H).

Example 192:3- ((1H pyrrolo [2,3-b ] pyridin-5-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.93(s，1H)，8.23(d，J＝2.4Hz，1H)，7.76(d，J＝2.8Hz，1H)，7.42-7.44(m，1H)，6.54-6.56(m，1H)，5.24(s，1H)，3.944.00(m，2H)，3.45(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.91-2.02(m，1H)，1.54-1.60(m，2H)，1.31-1.41(m，2H)。

Example 193:3- ((5- (morpholine-4-carbonyl) pyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.58-8.64(m，2H)，7.63(t，J＝2.0Hz，1H)，5.43(s，1H)，3.92-3.98(m，2H)，3.38-3.86(m，10H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.00(m，1H)，1.50-1.58(m，2H)，1.29-1.39(m，2H)。

Example 194:3- ((2-bromopyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.37(dd，J＝4.8Hz，1.2Hz，1H)，7.56(dd，J＝8.0Hz，1.6Hz，1H)，7.38(dd，J＝8.0Hz，4.8Hz，1H)，5.23(s，1H)，3.91-3.96(m，2H)，3.42(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.50-1.56(m，2H)，1.27-1.37(m，2H)。

Example 195:3- ((6-methylpyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.42(d，J＝2.8Hz，1H)，7.41(dd，J＝8.4Hz，2.8Hz，1H)，7.24(d，J＝8.4Hz，1H)，5.29(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.58(s，3H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H)。

Example 196:3- ((5-bromopyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.65(d，J＝2.0Hz，1H)，8.50(d，J＝2.8Hz，1H)，7.73(t，J＝2.0Hz，1H)，5.41(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.50-1.57(m，2H)，1.28-1.39(m，2H)。

Example 197:3- ((1H-indazol-5-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.75-11.14(brs，1H)，8.51(s，1H)，8.05(d，J＝9.2Hz，1H)，7.75(s，1H)，7.59(d，J＝9.2Hz，1H)，5.33(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝6.8Hz，2H)，3.34(t，J＝11.2Hz，2H)，1.89-2.02(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H).

Example 198:3- (4-methyl-2-oxoquinolin-1 (2H) -yl) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400Mz，CDCl ₃ )，7.73(dd，J＝8.0Hz，1.2Hz，1H)，7.45-7.49(m，1H)，7.29(t，J＝7.6Hz，1H)，6.99(s，1H)，6.88(s，1H)，6.56(s，1H)，3.92-3.98(m，2H)，3.47-3.53(m，2H)，3.34(td，J＝11.6Hz，1.6Hz，2H)，2.50(s，3H)，1.92-2.03(m，1H)，1.54-1.62(m，2H)，1.30-1.40(m，2H)。

Example 199:3- ((2-Chloropyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.37(dd，J＝4.8Hz，1.6Hz，1H)，7.60(dd，J＝8.4Hz，1.6Hz，1H)，7.36(dd，J＝8.0Hz，4.8Hz，1H)，5.23(s，1H)，3.90-3.95(m，2H)，3.41(d，J＝6.8Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，1.86-1.98(m，1H)，1.48-1.55(m，2H)，1.26-1.36(m，2H)。

Example 200:3- ((1H-indazol-6-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，8.11(s，1H)，7.84(d，J＝8.8Hz，1H)，7.48(s，1H)，7.06(dd，J＝9.2Hz，2.0Hz，1H)，5.54(s，1H)，3.77-3.83(m，2H)，3.29(d，J＝7.2Hz，2H)，3.21(td，J＝11.6Hz，2.0HZ，2H)，1.74-1.86(m，1H)，1.46-1.53(m，2H)，1.08-1.18(m，2H)。

Example 201:3- (4-Aminophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，8.07-11.09(brs，3H)，7.28-7.40(m，4H)，5.58(s，1H)，3.76-3.82(m，2H)，3.28(d，J＝7.2Hz，2H)，3.20(td，J＝11.6Hz，1.6Hz，2H)，1.72-1.84(m，1H)，1.45-1.52(m，2H)，1.06-1.17(m，2H).

Example 202:3- (4-methoxyphenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.09(d，J＝8.8Hz，2H)，6.92(d，J＝8.8Hz，2H)，5.22(s，1H)，3.93-3.98(m，2H)，3.81(s，3H)，3.43(d，J＝6.8HZ，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.29-1.40(m，2H)。

Example 203:3- (isoquinoline-5-oxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，9.35(s，1H)，8.61(d，J＝6.0Hz，1H)，7.97(d，J＝8.0Hz，1H)，7.76(d，J＝5.6Hz，1H)，7.65(t，J＝8.0Hz，1H)，7.54(d，J＝7.6Hz，1H)，5.21(s，1H)，3.94-4.00(m，2H)，3.47(d，J＝7.6Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.92-2.03(m，1H)，1.54-1.62(m，2H)，1.32-1.42(m，2H).

Example 204:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- (4- (trifluoromethyl) phenoxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.73(d，J＝8.8Hz，2H)，7.32(d，J＝8.8Hz，2H)，5.36(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.52-1.58(m，2H)，1.30-1.40(m，2H).

Example 205:3- (2, 5-bis (trifluoromethyl) phenoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.91(d，J＝8.0Hz，1H)，7.71(d，J＝8.8Hz，1H)，7.56(s，1H)，5.37(s，1H)，3.94-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.51-1.58(m，2H)，1.29-1.40(m，2H)。

Example 206:3- (3-Aminophenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，7.23-7.30(m，1H)，6.72-6.82(m，3H)，5.54(s，1H)，3.76-3.82(m，2H)，3.27(d，J＝7.2Hz，2H)，3.20(td，J＝12.0Hz，1.6Hz，2H)，1.73-1.84(m，1H)，1.44-1.52(m，2H)，1.07-1.17(m，2H)。

Example 207:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- ((6- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.67(d，J＝2.4Hz，1H)，7.82(d，J＝8.8Hz，1H)，7.72(dd，J＝8.4Hz，2.8Hz，1H)，5.47(s，1H)，3.94-3.99(m，2H)，3.46(d，J＝6.8Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.58(m，2H)，1.30-1.40(m，2H)。

Example 208:5- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) nicotinonitrile

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.84(d，J＝2.0Hz，1H)，8.78(d，J＝2.4Hz，1H)，7.82-7.83(m，1H)，5.48(s，1H)，3.92-3.98(m，2H)，3.45(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H).

Example 209: n- (3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) phenyl) acetamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.68-7.74(m，2H)，7.33(t，J＝8.0Hz，1H)，7.19(dd，J＝8.0Hz，1.2Hz，1H)，6.88(dd，J＝8.0Hz，1.6Hz，1H)，5.32(s，1H)，3.92-3.98(m，2H)，3.42(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.16(s，3H)，1.87-1.99(m，1H)，1.52-1.58(m，2H)，1.28-1.38(m，2H).

Example 210: 2-chloro-4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.78(d，J＝8.4Hz，1H)，7.40(d，J＝2.4Hz，1H)，7.23(dd，J＝8.4Hz，2.0Hz，1H)，5.52(s，1H)，3.92-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.00(m，1H)，1.50-1.58(m，2H)，1.29-1.39(m，2H).

Example 211:3- (quinoline-5-oxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.99(dd，J＝4.4Hz，1.6Hz，1H)，8.32(d，J＝8.8Hz，1H)，8.09(d，J＝8.8Hz，1H)，7.74(t，J＝8.4Hz，1H)，7.48(dd，J＝8.4Hz，4.4Hz，1H)，7.39(d，J＝7.6Hz，1H)，5.25(s，1H)，3.94-4.00(m，2H)，3.47(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.92-2.02(m，1H)，1.54-1.61(m，2H)，1.32-1.42(m，2H)。

Example 212:3- ((1H-indol-4-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.80(s，1H)，7.32(d，J＝8.4Hz，1H)，7.20(t，J＝2.8Hz，1H)，7.15(t，J＝8.4Hz，1H)，6.90(d，J＝7.6Hz，1H)，6.42-6.44(m，1H)，5.17(s，1H)，3.94-4.00(m，2H)，3.45(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，1.6Hz，2H)，1.90-2.02(m，1H)，1.53-1.60(m，2H)，1.31-1.41(m，2H)。

Example 213: n- (4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) phenyl) acetamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.95(s，1H)，7.57(d，J＝8.8Hz，2H)，7.08(d，J＝8.4Hz，2H)，5.23(s，1H)，3.90-3.96(m，2H)，3.40(d，J＝7.2Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，2.15(s，3H)，1.86-1.98(m，1H)，1.50-1.57(m，2H)，1.26-1.36(m，2H)。

Example 214:3- (3-chloro-5- (trifluoromethyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.71(d，J＝2.4Hz，1H)，7.60(dd，J＝8.8Hz，2.4Hz，1H)，7.24(d，J＝8.8Hz，1H)，5.29(s，1H)，3.91-3.96(m，2H)，3.41(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，1.6Hz，2H)，1.86-1.99(m，1H)，1.48-1.55(m，2H)，1.27-1.37(m，2H).

Example 215:3- (5-fluoro-2- (trifluoromethyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.75(dd，J＝8.8Hz，6.0Hz，1H)，7.12-7.17(m，1H)，7.03(dd，J＝8.4Hz，2.4Hz，1H)，5.37(s，1H)，3.92-3.97(m，2H)，3.42(，d J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.99(m，1H)，1.49-1.56(m，2H)，1.27-1.38(m，2H).

Example 216:3- ([ 1,1' -biphenyl ] -2-oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.43-7.50(m，3H)，7.35-7.42(m，4H)，7.27-7.32(m，1H)，7.23-7.26(m，1H)，4.97(s，1H)，3.89-3.94(m，2H)，3.25-3.32(m，4H)，1.76-1.88(m，1H)，1.35-1.40(m，2H)，1.17-1.28(m，2H)。

Example 217:3- ((1H-indol-5-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.39(s，1H)，7.39-7.42(m，2H)，7.30(t，J＝2.4Hz，1H)，6.99(dd，J＝8.4Hz，2.4Hz，1H)，6.55-6.58(m，1H)，5.22(s，1H)，3.94-4.00(m，2H)，3.44(d，J＝7.6Hz，2H)，3.35(td，J＝11.6Hz，1.6Hz，2H)，1.90-2.01(m，1H)，1.53-1.61(m，2H)，1.31-1.41(m，2H).

Example 218:3- ((4-methylpyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.43(d，J＝4.4Hz，1H)，8.41(s，1H)，7.25(d，J＝4.4Hz，1H)，5.17(s，1H)，3.92-3.98(m，2H)，3.43(d，J＝7.6Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.28(s，3H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H).

Example 219:3- (phenylethynyl) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Step 1: synthesis of example 219

Compound I (200 mg), phenylacetylene (74 mg), pdCl2 (PPh 3) 2 (25 mg), cuI (14 mg) and triethylamine (221 mg) were added to THF (10 mL) under nitrogen protection, heated to 65 ℃ and stirred for 12 hours, cooled to room temperature, concentrated under reduced pressure, added with an appropriate amount of water, extracted with ethyl acetate (50 mL × 3), the extract was washed with saturated saline (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography to give a white solid (131 mg).

¹ H NMR(400MHz，CDCl ₃ )，7.56-7.59(m，2H)，7.36-7.46(m，3H)，6.68(s，1H)，3.92-3.98(m，2H)，3.46(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.89-2.00(m，1H)，1.50-1.57(m，2H)，1.29-1.40(m，2H).

Example 220:3- (4- (dimethylamino) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.02(d，J＝8.8Hz，2H)，6.69(d，J＝8.8Hz，2H)，5.23(s，1H)，3.92-3.98(m，2H)，3.42(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.95(s，6H)，1.88-2.00(m，1H)，1.52-1.58(m，2H)，1.29-1.39(m，2H).

Example 221:3- (3- (dimethylamino) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.22(t，J＝8.0Hz，1H)，6.58(dd，J＝8.0Hz，2.4Hz，1H)，6.43-6.48(m，2H)，5.32(s，1H)，3.92-3.98(m，2H)，3.42(d，J＝6.8Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.94(s，6H)，1.89-2.00(m，1H)，1.51-1.58(m，2H)，1.29-1.39(m，2H).

Example 222:3- ((6- (morpholine-4-carbonyl) pyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.50(d，J＝2.8Hz，1H)，7.87(d，J＝8.8Hz，1H)，7.66(dd，J＝8.4Hz，2.8Hz，1H)，5.42(s，1H)，3.93-3.99(m，2H)，3.82(s，4H)，3.71(s，4H)，3.45(d，J＝6.8Hz，2H)，3.34(td，J＝11.6Hz，1.6Hz，2H)，1.89-2.02(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H)。

Example 223:5- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) -N, N-dimethylpyridinamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.50(d，J＝2.8Hz，1H)，7.79(d，J＝8.8Hz，1H)，7.63(dd，J＝8.8Hz，2.8Hz，1H)，5.40(s，1H)，3.92-3.97(m，2H)，3.44(d，J＝7.6Hz，2H)，3.32(td，J＝7.6Hz，1.6Hz，2H)，3.13(s，3H)，3.10(s，3H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.28-1.39(m，2H)。

Example 224:3- (quinolin-4-yloxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.43(dd，8.0Hz，1.6Hz，1H)，7.89(d，J＝8.0Hz，1H)，7.64-7.68(m，1H)，7.53(d，J＝8.4Hz，1H)，7.46(t，J＝8.0Hz，1H)，6.69(s，1H)，6.38(d，J＝8.4Hz，1H)，3.96-4.01(m，2H)，3.55(d，J＝7.2Hz，2H)，3.36(td，J＝11.6Hz，2.0Hz，2H)，1.94-2.06(m，1H)，1.55-1.62(m，2H)，1.34-1.45(m，2H).

Example 225:3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) pyridine nitrile

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.69(d，J＝4.0Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.65(dd，J＝8.0Hz，4.0Hz，1H)，5.50(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，1.6Hz，2H)，1.89-2.01(m，1H)，1.52-1.59(m，2H)，1.29-1.39(m，2H).

Example 226:3- ([ 1,1' -biphenyl ] -4-oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.64(d，J＝8.8Hz，2H)，7.54-7.58(m，2H)，7.43-7.47(m，2H)，7.35-7.40(m，1H)，7.25(d，J＝8.8Hz，2H)，5.36(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.91-2.03(m，1H)，1.53-1.60(m，2H)，1.31-1.41(m，2H).

Example 227: 4-chloro-N- (4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) phenyl) benzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，10.44(s，1H)，7.96(d，J＝8.4Hz，2H)，7.86(d，J＝9.2Hz，2H)，7.60(d，J＝8.8Hz，2H)，7.32(d，J＝9.2Hz，2H)，5.55(s，1H)，3.77-3.83(m，2H)，3.28(d，J＝7.2Hz，2H)，3.21(td，J＝11.6Hz，2.0Hz，2H)，1.74-1.86(m，1H)，1.46-1.53(m，2H)，1.08-1.18(m，2H)。

Example 228:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- ((4- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.63-8.84(m，2H)，7.67(d，J＝4.8Hz，1H)，5.38(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，1.6Hz，2H)，1.89-2.00(m，1H)，1.50-1.57(m，2H)，1.29-1.39(m，2H).

Example 229:3- (quinoline-3-oxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.85(d，J＝2.8Hz，1H)，8.17(d，J＝8.8Hz，1H)，7.97(d，J＝2.8Hz，1H)，7.84(d，J＝8.0Hz，1H)，7.76-7.80(m，1H)，7.62-7.66(m，1H)，5.39(s，1H)，3.94-4.00(m，2H)，3.47(d，J＝7.2Hz，2H)，3.35(td，J＝11.6Hz，1.6Hz，2)，1.91-2.03(m，1H)，1.54-1.61(m，2H)，1.32-1.42(m，2H)。

Example 230:3- (pyridin-4-yloxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.07(d，J＝8.4Hz，2H)，6.42(d，J＝8.4Hz，2H)，6.29(s，1H)，3.90-3.96(m，2H)，3.45(d，J＝6.8Hz，2H)，3.30(td，J＝11.6Hz，2.0Hz，2H)，1.86-1.96(m，1H)，1.48-1.54(m，2H)，1.27-1.37(m，2H)。

Example 231:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) -N-benzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.98(d，J＝8.8Hz，2H)，7.79(s，1H)，7.62(d，J＝8.0Hz，2H)，7.36-7.40(m，2H)，7.32(d，J＝9.2Hz，2H)，7.15-7.20(m，1H)，5.37(s，1H)，3.94-3.99(m，2H)，3.45(d，J＝6.8Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.52-1.59(m，2H)，1.30-1.41(m，2H).

Example 232:3- ((2-methylpyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.48(d，J＝4.8Hz，1H)，7.44(d，J＝8.0Hz，1H)，7.24(dd，J＝8.0Hz，4.8Hz，1H)，5.15(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，2.50(s，3H)，1.90-2.02(m，1H)，1.52-1.58(m，2H)，1.30-1.40(m，2H)。

Example 233:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) -N-methylbenzamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.85(d，J＝8.8Hz，2H)，7.25(d，J＝8.8Hz，2H)，6.08-6.16(brs，1H)，5.33(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.6Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，3.03(d，J＝4.8Hz，3H)，1.90-2.00(m，1H)，1.52-1.60(m，2H)，1.30-1.40(m，2H)。

Example 234:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) -N-ethylbenzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.86(d，J＝8.8Hz，2H)，7.25(d，J＝8.8Hz，2H)，6.01-6.08(m，1H)，5.33(s，1H)，3.93-3.99(m，2H)，3.47-3.54(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H)，1.26(t，J＝7.2Hz，3H)。

Example 235:3- ([ 1,1' -biphenyl ] -3-propoxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.36-7.57(m，8H)，7.14-7.17(m，1H)，5.35(s，1H)，3.93-3.99(m，2H)，3.45(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.02(m，1H)，1.53-1.60(m，2H)，1.30-1.41(m，2H)。

Example 236:3- ((4-Chloropyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole- -2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.56(s，1H)，8.51(d，J＝4.8Hz，1H)，7.49(d，J＝4.8Hz，1H)，5.25(s，1H)，3.93-3.99(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，1.90-2.01(m，1H)，1.51-1.59(m，2H)，1.30-1.40(m，2H)。

Example 237:3- ((2, 6-Dimethylpyridin-3-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.29(d，J＝8.8Hz，1H)，7.04(d，J＝8.8Hz，1H)，5.11(s，1H)，3.91-3.96(m，2H)，3.41(d，J＝6.8Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，2.52(s，3H)，2.42(s，3H)，1.86-1.99(m，1H)，1.49-1.56(m，2H)，1.27-1.37(m，2H)。

Example 238:3- ((1H-indol-6-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.33(s，1H)，7.65(d，J＝8.4Hz，1H)，7.27-7.29(m，1H)，7.21(d，J＝2.0Hz，1H)，6.94(dd，J＝8.4Hz，2.0Hz，1H)，6.58-6.69(m，1H)，5.26(s，1H)，3.94-3.99(m，2H)，3.44(d，J＝6.8Hz，2H)，3.35(td，J＝11.6Hz，2.0Hz，2H)，1.91-2.01(m，1H)，1.54-1.60(m，2H)，1.31-1.41(m，2H)。

Example 239:3- ((5-Chloropyridin-3-yl) oxy) -1- ((4-fluoropiperidin-4-yl) methyl) -1H-pyrrole-2, 5-dione hydrochloride

The synthesis method is referred to example 5. ¹ H NMR(400MHz，DMSO)，9.01-9.27(brs，2H)，8.63(d，J＝2.0Hz，2H)，8.16(t，J＝2.0Hz，1H)，6.06(s，1H)，3.65(d，J＝21.2Hz，2H)，3.18-3.26(m，2H)，2.84-2.96(m，2H)，1.83-2.02(m，4H)。

Example 240:3- ((2, 6-dichloropyridin-4-yl) oxy) -1- ((tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.13(s，2H)，5.75(s，1H)，3.91-3.96(m，2H)，3.43(d，J＝7.6Hz，2H)，3.31(td，J＝11.6Hz，1.6Hz，2H)，1.86-1.97(m，1H)，1.48-1.55(m，2H)，1.27-1.37(m，2H)。

Example 241:3- ((5-Chloropyridin-3-yl) oxy) -1- (piperidin-4-ylmethyl) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，8.89-9.05(brs，1H)，8.58-8.80(m，3H)，8.14(t，J＝2.4Hz，1H)，6.01(s，1H)，3.31(d，J＝7.2Hz，2H)，3.16-3.25(m，2H)，2.72-2.84(m，2H)，1.79-1.91(m，1H)，1.68-1.78(m，2H)，1.26-1.38(m，2H)。

Example 242:1- (3-aminopropyl) -3- (5-chloropyridin-3-yl) oxy) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，8.61-8.62(m，2H)，8.13(t，J＝2.0Hz，1H)，7.87-8.06(brs，3H)，6.01(s，1H)，3.48(t，J＝6.8Hz，2H)，2.72-2.82(m，2H)，1.76-1.83(m，2H)。

Example 243:1- (3-aminopropyl) -3- (3, 5-dichlorophenoxy) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，DMSO)，7.76-7.90(brs，3H)，7.61(t，J＝2.0Hz，1H)，7.53(d，J＝2.0Hz，2H)，5.95(s，1H)，3.47(t，J＝6.8Hz，2H)，2.74-2.82(m，2H)，1.74-1.82(m，2H)。

Example 244:1- (3-chloro-4-methylphenyl) -3- (3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) phenyl) urea

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.59(s，1H)，7.41(t，J＝2.0Hz，1H)，7.36(s，1H)，7.23-7.28(m，2H)，7.06-7.11(m，3H)，6.80(dd，J＝7.6Hz，2.0Hz，1H)，5.31(s，1H)，3.93-3.99(m，2H)，3.42(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz.2.0Hz，2H)，2.25(s，3H)，1.87-1.99(m，1H)，1.52-1.59(m，2H)，1.28-1.39(m，2H)。

Example 245:1- ((tetrahydro-2H-pyran-4-yl) methyl) -3- ((5- (trifluoromethyl) pyridin-3-yl) oxy) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.86(s，1H)，8.76(d，J＝2.4Hz，1H)，7.79(t，J＝2.4Hz，1H)，5.43(s，1H)，3.92-3.98(m，2H)，3.44(d，J＝7.6Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-1.98(m，1H)，1.50-1.57(m，2H)，1.28-1.39(m，2H)。

Example 246:1- (3-chloro-4-methylphenyl) -3- (3- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzyl) urea

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.38(t，J＝8.0Hz，1H)，7.32(d，J＝2.0Hz，1H)，7.22(d，J＝7.6Hz，1H)，7.04-7.14(m，4H)，6.48(s，1H)，5.27(s，1H)，5.19(t，J＝6.0Hz，1H)，4.44(d，J＝6.0Hz，2H)，3.92-3.98(m，2H)，3.43(d，J＝7.2Hz，2H)，3.33(td，J＝11.6Hz，2.0Hz，2H)，2.30(s，3H)，1.88-2.02(m，1H)，1.52-1.60(m，2H)，1.29-1.39(m，2H)。

Example 247: n- (2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) benzamide

Step 1: synthesis of Compound II

Compound I (200 mg) was added to ethanol (6 mL) and ammonia methanol solution (6 mL), stirred at room temperature for 12 hours, concentrated under reduced pressure, added an appropriate amount of water, extracted with ethyl acetate (50 mL × 3), the extract was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by column chromatography to give yellow solid (II) (132 mg).

Step 2: synthesis of example 247

Compound II (100 mg), benzoic acid (70 mg), HATU (271 mg) and DIEA (184 mg) were added to anhydrous DMF (20 mL), heated to 60 ℃ and stirred for 12 hours, cooled to room temperature, an appropriate amount of water was added, extraction was performed with ethyl acetate (50 mL. Times.3), the extract was washed with saturated brine (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated by column chromatography to give example 247 (92.7 mg) as a white solid. ¹ H NMR(400MHz，CDCl ₃ )，8.55(s，1H)，7.88(d，J＝7.6Hz，2H)，7.63(t，J＝7.6Hz，1H)，7.52(t，J＝7.6Hz，2H)，6.67(s，1H)，3.91-3.96(m，2H)，3.43(d，J＝7.2Hz，2H)，3.31(td，J＝11.6Hz，2.0Hz，2H)，1.87-1.98(m，1H)，1.49-1.56(m，2H)，1.27-1.38(m，2H)。

Example 248: n- (2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) cinnamamide

Synthetic methods refer to example 247. ¹ H NMR(400MHz，CDCl ₃ )，8.09(s，1H)，7.81(d，J＝15.6Hz，1H)，7.52-7.59(m，2H)，7.38-7.44(m，3H)，6.63(s，1H)，6.60(d，J＝15.6Hz，1H)，3.92-3.98(m，2H)，3.42(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，1.6Hz，2H)，1.87-1.99(m，1H)，1.49-1.56(m，2H)，1.27-1.38(m，2H)。

Example 249:3- (3- (2-hydroxypropan-2-yl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.35-7.37(m，2H)，7.31-7.33(m，1H)，6.99-7.03(m，1H)，5.25(s，1H)，3.89-3.94(m，2H)，3.40(d，J＝7.2Hz，2H)，3.30(td，J＝11.6Hz，1.6Hz，2H)，2.28(s，1H)，1.85-1.96(m，1H)，1.49-1.56(m，8H)，1.25-1.37(m，2H)。

Example 250:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，8.02(s，1H)，7.97(d，J＝8.4Hz，2H)，7.38-7.44(m，3H)，5.69(s，1H)，3.78-3.83(m，2H)，3.29(d，J＝6.8Hz，2H)，3.21(dd，J＝11.6Hz，1.6Hz，2H)，1.74-1.85(m，1H)，1.46-1.53(m，2H)，1.08-1.18(m，2H)。

Example 251:3- (3-acetylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.84(d，J＝7.6Hz，1H)，7.73(t，J＝2.0Hz，1H)，7.52(t，J＝7.6Hz，1H)，7.34-7.37(m，1H)，5.26(s，1H)，3.86-3.92(m，2H)，3.38(d，J＝7.2Hz，2H)，3.28(td，J＝11.6Hz，2.0Hz，2H)，2.56(s，3H)，1.84-1.95(m，1H)，1.46-1.54(m，2H)，1.23-1.34(m，2H)。

Example 252:3- (4-Acetylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.06(d，J＝8.8Hz，2H)，7.28(d，J＝8.8Hz，2H)，5.37(s，1H)，3.93-3.98(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，2.0Hz，2H)，2.62(s，3H)，1.89-2.00(m，1H)，1.52-1.59(m，2H)，1.30-1.40(m，2H)。

Example 253:3- (4- (1-hydroxyethyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.44(d，J＝8.4Hz，2H)，7.14(d，J＝8.4Hz，2H)，5.26(s，1H)，4.82(q，J＝6.8Hz，1H)，3.91-3.97(m，2H)，3.42(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，2.06(s，1H)，1.88-2.00(m，1H)，1.51-1.58(m，2H)，1.49(d，J＝6.8Hz，3H)，1.28-1.38(m，2H)。

Example 254:3- (4- (2-hydroxypropan-2-yl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.54(d，J＝8.4Hz，2H)，7.11(d，J＝8.4Hz，2H)，5.27(s，1H)，3.90-3.96(m，2H)，3.41(d，J＝6.8Hz，2H)，3.32(td，J＝11.6Hz，2.0Hz，2H)，1.88-2.16(m，2H)，1.50-1.59(m，8H)，1.27-1.38(m，2H)。

Example 255:3- (4- (1-hydroxycyclobutyl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.56(d，J＝8.4Hz，2H)，7.16(d，J＝8.4Hz，2H)，5.28(s，1H)，3.91-3.96(m，2H)，3.42(d，J＝7.2Hz，2H)，3.32(td，J＝11.6Hz，1.6Hz，2H)，2.49-2.58(m，2H)，2.28-2.40(m，3H)，1.88-2.10(m，2H)，1.66-1.77(m，1H)，1.51-1.58(m，2H)，1.28-1.38(m，2H)。

Example 256:3- (4- (3-Hydroxyoxan-3-yl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.72(d，J＝8.4Hz，2H)，7.23(d，J＝8.4Hz，2H)，5.30(s，1H)，4.92(d，J＝7.2Hz，2H)，4.88(d，J＝7.2Hz，2H)，3.92-3.98(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝11.6Hz，1.6Hz，2H)，2.85(s，1H)，1.89-2.02(m，1H)，1.52-1.59(m，2H)，1.29-1.40(m，2H)。

Example 257: n- (4-hydroxy-2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) -4-toluenesulfonamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，DMSO)，7.94-8.18(brs，2H)，7.06(d，J＝8.8Hz，2H)，7.01(d，J＝8.4Hz，2H)，3.76-3.82(m，2H)，3.27(d，J＝6.8Hz，2H)，3.20(td，J＝11.6Hz，1.6Hz，2H)，2.20(s，3H)，1.74-1.86(m，1H)，1.40-1.48(m，2H)，1.06-1.16(m，2H)。

Example 258:1- (2- (2-Aminoethoxy) ethoxy) ethyl) -3- (3, 5-dichlorophenoxy) -1H-pyrrole-2, 5-dione hydrochloride

Synthetic methods refer to example 5. ¹ H NMR(400MHz，CD ₃ OD)，7.46(s，1H)，7.37(s，2H)，5.63(s，1H)，3.54-3.75(m，10H)，3.08-3.15(m，2H)。

Example 259:3- (4- (4-Hydroxytetrahydro-2H-pyran-4-yl) phenoxy) -1- (tetrahydro-2H-pyran-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.56(d，J＝8.8Hz，2H)，7.17(d，J＝8.8Hz，2H)，5.28(s，1H)，3.85-3.96(m，6H)，3.42(d，J＝6.8Hz，2H)，3.32(td，J＝11.6HZ，1.6Hz，2H)，2.11-2.19(m，2H)，1.88-1.99(m，2H)，1.64-1.70(m，2H)，1.51-1.58(m，2H)，1.28-1.38(m，2H)。

Example 260:5- (4- ((3- ((5-chloropyridin-3-yl) oxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) piperidine-1-carbonyl) -2- (2, 6-dioxopyridin-3-yl) isoindole-1, 3-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.57(d，J＝2.0Hz，1H)，8.48(d，J＝2.4Hz，1H)，8.07(s，1H)，7.93(d，J＝7.6Hz，1H)，7.86(s，1H)，7.77(dd，J＝7.6Hz，1.2Hz，1H)，7.59(t，J＝2.0Hz，1H)，5.44(s，1H)，5.00(dd，J＝12.4Hz，4.8Hz，1H)，4.66-4.77(m，1H)，3.57-3.68(m，1H)，3.49(d，J＝6.8Hz，2H)，2.70-3.10(m，5H)，2.14-2.19(m，1H)，1.96-2.08(m，1H)，1.77-1.88(m，1H)，1.48-1.72(m，3H)。

Example 261: n- (3, 5-dichlorophenoxy) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-1-yl) propyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisopropylene glycol-5-carboxamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.30(s，1H)，8.27(dd，J＝7.6Hz，1.2Hz，1H)，8.23(s，1H)，7.95(d，J＝8.0Hz，1H)，7.34(t，J＝1.6Hz，1H)，7.19(t，J＝6.0Hz，1H)，7.15(d，J＝1.6Hz，2H)，5.47(s，1H)，5.01(dd，J＝12.4Hz，5.6Hz，1H)，3.69(t，J＝6.0Hz，2H)，3.47(q，J＝6.0Hz，2H)，2.74-2.93(m，3H)，2.14-2.19(m，1H)，1.91-1.97(m，2H)。

Example 262:4- ((3- ((5-chloropyridin-3-yl) oxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisopropylin-5-yl) methyl) piperidine-1-carboxamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.57(d，J＝2.0Hz，1H)，8.48(d，J＝2.4Hz，1H)，8.16(s，1H)，7.79-7.82(m，2H)，7.69(d，J＝7.2Hz，1H)，7.59(t，J＝2.0Hz，1H)，5.43(s，1H)，5.05(t，J＝5.6Hz，1H)，4.96(dd，J＝12.0Hz，5.2Hz，1H)，4.53(d，J＝6.0Hz，2H)，3.94-4.00(m，2H)，3.46(d，J＝6.8Hz，2H)，2.69-2.92(m，5H)，2.11-2.17(m，1H)，1.84-1.96(m，1H)，1.64-1.71(m，2H)，1.18-1.28(m，2H)。

Example 263: n- (2- (2- (2- (3- (5-chloropyridin-3-yl) oxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) ethyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoquinoline-5-carboxamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，11.13(s，1H)，8.93(t，J＝5.6Hz，1H)，8.61(d，J＝2.4Hz，2H)，8.32(s，1H)，8.30(dd，J＝8.0Hz，1.2Hz，1H)，8.13(t，J＝2.4Hz，1H)，8.00(d，J＝7.6Hz，1H)，5.96(s，1H)，5.16(dd，J＝12.8Hz，5.6Hz，1H)，3.46-3.58(m，10H)，3.40-3.45(m，2H)，2.82-2.92(m，1H)，2.48-2.62(m，2H)，2.01-2.09(m，1H)。

Example 264: n- (4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) phenyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoquinoline-5-carboxamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CD ₃ OD)，8.33(s，1H)，8.30(dd，J＝8.0Hz，1.2Hz，1H)，7.92(d，J＝7.6Hz，1H)，7.63(d，J＝8.8Hz，2H)，7.32(d，J＝8.8Hz，2H)，7.28(t，J＝1.2Hz，1H)，7.10(d，J＝1.2Hz，2H)，5.41(s，1H)，4.95-5.00(m，1H)，4.63(s，2H)，2.71-2.84(m，3H)，2.11-2.14(m，1H)。

Example 265: n- (2- (2- (2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) ethyl) -2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisopropyldiazine-5-carboxamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.67(s，1H)，8.33(s，1H)，8.28(dd，J＝8.0Hz，1.2Hz，1H)，7.89(d，J＝7.6Hz，1H)，7.41-7.46(brs，1H)，7.30(t，J＝2.0Hz，1H)，7.11(d，J＝1.6Hz，2H)，5.40(s，1H)，4.99(dd，J＝12.0Hz，5.2Hz，1H)，3.72-3.74(m，2H)，3.59-3.69(m，10H)，2.70-2.91(m，3H)，2.12-2.16(m，1H)。

Example 266:4- ((1- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoquinolin-5-yl) methyl) -2, 5-dioxo-2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.03(s，1H)，7.92(d，J＝8.8Hz，2H)，7.85-7.87(m，2H)，7.76(d，J＝8.0Hz，1H)，7.28(d，J＝8.8Hz，2H)，5.50-6.18(brs，2H)，5.41(s，1H)，4.97(dd，J＝12.0Hz，5.6Hz，1H)，4.83(s，2H)，2.70-2.93(m，3H)，2.12-2.16(m，1H)。

Example 267:5- ((3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.20(s，1H)，7.83-7.85(m，2H)，7.74(dd，J＝8.0Hz，1.2Hz，1H)，7.33(t，J＝1.6Hz，1H)，7.13(d，J＝1.6Hz，2H)，5.47(s，1H)，4.95-4.99(m，1H)，4.82(s，2H)，2.70-2.92(m，3H)，2.11-2.15(m，1H)。

Example 268:4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N-methylbenzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，8.38-8.42(m，1H)，7.77(d，J＝8.0Hz，2H)，7.61(t，J＝2.0Hz，1H)，7.58(d，J＝2.0Hz，2H)，7.32(d，J＝8.4Hz，2H)，5.96(s，1H)，4.64(s，2H)，2.74(d，J＝4.4Hz，3H)。

Example 269:4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N-ethylbenzamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.72(d，J＝8.4Hz，2H)，7.42(d，J＝8.0Hz，2H)，7.32(t，J＝1.6Hz，1H)，7.12(d，J＝1.6Hz，2H)，6.02(s，1H)，5.43(s，1H)，4.72(s，2H)，3.45-3.52(m，2H)，1.24(t，J＝7.2Hz，3H)。

Example 270:4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N-phenylbenzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，10.20(s，1H)，7.99(d，J＝8.4Hz，2H)，7.73(d，J＝8.0Hz，2H)，7.61(t，J＝2.0Hz，1H)，7.59(d，J＝2.0Hz，2H)，7.41(d，J＝8.0Hz，2H)，7.32(t，J＝8.0Hz，2H)，7.07(t，J＝7.6Hz，1H)，5.98(s，1H)，4.69(s，2H)。

Example 271:3- (3, 5-Dichlorophenoxy) -1-phenyl-1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.45-7.49(m，2H)，7.35-7.39(m，4H)，7.20(d，J＝1.6Hz，2H)，5.57(s，1H)。

Example 272: n- (4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) phenyl) acrylamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.53(d，J＝7.6Hz，2H)，7.41(s，1H)，7.31-7.34(m，3H)，7.11(d，J＝1.2Hz，2H)，6.42(dd，J＝16.8，1.2Hz，1H)，6.23(dd，J＝16.8Hz，10.0Hz，1H)，5.76(dd，J＝10.0Hz，1.2Hz，1H)，5.41(s，1H)，4.64(s，2H)。

Example 273:2- (2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，7.99-8.02(m，2H)，7.93-7.96(m，2H)，6.99(s，1H)，3.78-3.82(m，2H)，3.35(d，J＝6.8Hz，2H)，3.19-3.25(m，2H)，1.76-1.88(m，1H)，1.44-1.51(m，2H)，1.10-1.23(m，2H)。

Example 274:4- ((2, 5-dioxy-1- (piperidin-4-ylmethyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzamide hydrochloride

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，DMSO)，8.88-8.98(brs，1H)，8.56-8.70(brs，1H)，8.06(s，1H)，7.98(d，J＝8.8Hz，2H)，7.45(s，1H)，7.39(d，J＝8.8Hz，2H)，5.73(s，1H)，3.30(d，J＝6.8Hz，2H)，3.17-3.24(m，2H)，2.72-2.84(m，2H)，1.79-1.92(m，1H)，1.70-1.78(m，2H)，1.25-1.36(m，2H)。

Example 275:4- ((1- ((1-acryloylpiperidin-4-yl) methyl) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzonitrile

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.78(d，J＝8.8Hz，2H)，7.33(d，J＝8.8Hz，2H)，6.54(dd，J＝16.8Hz，10.4Hz，1H)，6.23(dd，J＝16.8Hz，1.2Hz，1H)，5.65(dd，J＝10.8Hz，1.6Hz，1H)，5.42(s，1H)，4.65(d，J＝12.8Hz，1H)，3.99(d，J＝12.8Hz，1H)，3.45(d，J＝6.8Hz，2H)，3.01(t，J＝12.8Hz，1H)，2.60(t，J＝12.8Hz，1H)，1.90-2.02(m，1H)，1.70(d，J＝12.8Hz，2H)，1.15-1.25(m，2H)。

Example 276:4- (2- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.11(s，1H)，7.68(dd，J＝8.0Hz，7.2Hz，1H)，7.48(d，J＝7.2Hz，1H)，7.32(t，J＝2.0Hz，1H)，7.21(d，J＝8.4Hz，1H)，7.16(d，J＝1.6Hz，2H)，5.46(s，1H)，4.94(dd，J＝12.4Hz，5.2Hz，1H)，4.38(t，J＝5.6Hz，2H)，4.05(t，J＝5.6Hz，2H)，2.64-2.91(m，3H)，2.07-2.12(m，1H)。

Example 277: n-benzyl-4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) benzamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.75(d，J＝8.8Hz，2H)，7.41(d，J＝8.0Hz，2H)，7.26-7.35(m，6H)，7.11(d，J＝1.6Hz，2H)，6.38(t，J＝5.2Hz，1H)，5.42(s，1H)，4.71(s，2H)，4.63(d，J＝5.2Hz，2H)。

Example 278:4- ((3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N-phenylcyclohexane-1-carboxamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.50(d，J＝7.6Hz，2H)，7.33(t，J＝2.0Hz，1H)，7.30(t，J＝7.6Hz，2H)，7.13(s，1H)，7.14(d，J＝1.6Hz，2H)，7.08(t，J＝8.0Hz，1H)，5.42(s，1H)，3.41(d，J＝7.2Hz，2H)，2.12-2.21(m，1H)，1.96-2.04(m，2H)，1.69-1.86(m，3H)，1.51-1.62(m，2H)，1.00-1.11(m，2H)。

Example 279:4- ((3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N-methylcyclohexane-1-carboxamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.32(t，J＝1.6Hz，1H)，7.13(d，J＝1.6Hz，2H)，5.43-5.50(brs，1H)，5.40(s，1H)，3.37(d，J＝6.8Hz，2H)，2.78(d，J＝5.2Hz，3H)，1.96-2.04(m，1H)，1.86-1.93(m，2H)，1.65-1.80(m，3H)，1.38-1.49(m，2H)，0.94-1.05(m，2H)。

Example 280:4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N, N-dimethylbenzamide

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.34-7.39(m，4H)，7.30(t，J＝1.6Hz，1H)，7.11(d，J＝1.6Hz，2H)，5.42(s，1H)，4.68(s，2H)，3.07(s，3H)，2.94(s，3H)。

Example 281:4- (2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxybenzoic acid tert-butyl ester

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.08(d，J＝8.0Hz，2H)，7.22(d，J＝8.4Hz，2H)，5.33(s，1H)，3.94-3.98(m，2H)，3.44(d，J＝7.2Hz，2H)，3.34(td，J＝12.0Hz，2.0Hz，2H)，1.89-2.01(m，1H)，1.52-1.60(m，11H)，1.30-1.40(m，2H)。

Example 282:4- ((2, 5-dioxy-1- ((tetrahydro-2H-pyran-4-yl) methyl) -2, 5-dihydro-1H-pyrrol-3-yl) oxy) benzoic acid

Synthetic methods refer to example 110. ¹ H NMR(400MHz，DMSO)，13.09(s，1H)，8.02(d，J＝8.8Hz，2H)，7.45(d，J＝8.8Hz，2H)，5.75(s，1H)，3.78-3.82(m，2H)，3.29(d，J＝7.2Hz，2H)，3.21(td，J＝11.6Hz，1.6Hz，2H)，1.74-1.85(m，1H)，1.50(d，J＝11.6Hz，2H)，1.08-1.18(m，2H)。

Example 283:4- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methylbenzoic acid methyl ester

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.99(d，J＝8.0Hz，2H)，7.41(d，J＝8.0Hz，2H)，7.32(t，J＝1.6Hz，1H)，7.12(d，J＝1.6Hz，2H)，5.44(s，1H)，4.73(s，2H)，3.90(s，3H)。

Example 284:5- (2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.10(s，1H)，7.77(d，J＝8.0Hz，1H)，7.33(t，J＝2.0Hz，1H)，7.32(d，J＝2.4Hz，1H)，7.17(dd，J＝8.4Hz，2.4Hz，1H)，7.14(d，J＝2.0Hz，2H)，5.47(s，1H)，4.95(dd，J＝12.4Hz，5.2Hz，1H)，4.27(t，J＝5.6Hz，2H)，4.01(t，J＝5.6Hz，2H)，2.68-2.92(m，3H)，2.11-2.15(m，1H)。

Example 285: (E) -3- (3, 5-dichlorophenoxy) -1- ((1- (4-methoxy-2-enoyl) piperidin-4-yl) methyl) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.31(t，J＝2.0Hz，1H)，7.12(d，J＝2.0Hz，2H)，6.80(dt，J＝15.2Hz，4.0Hz，1H)，6.47(dt，J＝15.2Hz，1.6Hz，1H)，5.40(s，1H)，4.63(d，J＝12.8Hz，1H)，3.99-4.06(m，3H)，3.42(d，J＝6.4Hz，2H)，3.37(s，3H)，2.98(t，J＝12.8Hz，1H)，2.58(t，J＝12.0Hz，1H)，1.87-1.99(m，1H)，1.64-1.71(m，2H)，1.12-1.22(m，2H)。

Example 286: 1-benzyl-3- (3, 5-dichlorophenoxy) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.28-7.38(m，6H)，7.11(d，J＝1.6Hz，2H)，5.41(s，1H)，4.69(s，2H)。

Example 287 to be used: 3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) piperidine-2, 6-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，DMSO)，11.09(s，1H)，7.63(t，J＝1.6Hz，1H)，7.61(d，J＝1.6Hz，2H)，6.00(s，1H)，4.99(dd，J＝13.2Hz，5.2Hz，1H)，2.78-2.87(m，1H)，2.50-2.59(m，1H)，2.34-2.46(m，1H)，1.92-2.00(m，1H)。

Example 288:1- ((1-Acrylopiperidin-4-yl) methyl) -3- ((5-chloropyridin-3-yl) oxy) -1H-pyrrole-2, 5-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.56(d，J＝2.0Hz，1H)，8.47(d，J＝2.0Hz，1H)，7.59(t，J＝2.0Hz，1H)，6.54(dd，J＝16.8Hz，10.4Hz，1H)，6.24(dd，J＝16.8Hz，2.0Hz，1H)，5.65(dd，J＝10.4Hz，2.0Hz，1H)，5.42(s，1H)，4.65(d，J＝12.8Hz，1H)，3.99(d，J＝13.6Hz，1H)，3.45(d，J＝6.8Hz，2H)，3.01(t，J＝12.4Hz，1H)，2.61(t，J＝12.4Hz，1H)，1.91-2.02(m，1H)，1.67-1.72(m，2H)，1.15-1.26(m，2H)。

Example 289: (E) -3- (3, 5-Dichlorophenoxy) -1- ((1- (4- (dimethylamino) -2-enoyl) piperidin-4-yl) methyl) -1H-pyrrole-2, 5-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.32(t，J＝1.6Hz，1H)，7.14(d，J＝1.6Hz，2H)，6.77(s，2H)，5.41(s，1H)，4.62(d，J＝12.4Hz，1H)，4.09(d，J＝13.6Hz，1H)，3.49(s，2H)，3.44(d，J＝7.2Hz，2H)，3.02(t，J＝12.4Hz，1H)，2.52-2.64(m，7H)，1.91-2.04(m，1H)，1.68-1.76(m，2H)，1.16-1.26(m，2H)。

Example 290:5- ((3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) propyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.55(s，1H)，7.49(d，J＝8.8Hz，1H)，7.32(t，J＝2.0Hz，1H)，7.13(d，J＝2.0Hz，2H)，6.86(d，J＝2.0Hz，1H)，6.69(dd，J＝8.4Hz，2.0Hz，1H)，5.45(s，1H)，5.17(t，J＝5.6Hz，1H)，4.93(dd，J＝12.0Hz，5.2Hz，1H)，3.64(t，J＝6.0Hz，2H)，3.19(q，J＝6.0Hz，2H)，2.66-2.88(m，3H)，2.07-2.13(m，1H)，1.86-1.92(m，2H)。

Example 291:5- (2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethoxy) -2- (1-methyl-2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.77(d，J＝8.0Hz，1H)，7.33(t，J＝2.0Hz，1H)，7.31(d，J＝2.4Hz，1H)，7.17(dd，J＝8.0Hz，2.4Hz，1H)，7.14(d，J＝2.0Hz，2H)，5.47(s，1H)，4.94(dd，J＝12.8Hz，5.6Hz，1H)，4.27(t，J＝5.6Hz，2H)，4.01(t，J＝5.6Hz，2H)，3.19(s，3H)，2.92-3.01(m，1H)，2.70-2.84(m，2H)，2.07-2.11(m，1H)。

Example 292:5- ((2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.61(s，1H)，7.53(d，J＝8.0Hz，1H)，7.30(t，J＝2.0Hz，1H)，7.10(d，J＝2.0Hz，2H)，6.89(d，J＝2.4Hz，1H)，6.71(dd，J＝8.0Hz，2.0Hz，1H)，5.45(s，1H)，5.14(t，J＝5.2Hz，1H)，4.93(dd，J＝12.0Hz，5.2Hz，1H)，3.81(t，J＝5.6Hz，2H)，3.40(q，J＝5.6Hz，2H)，2.72-2.87(m，3H)，2.06-2.12(m，1H)。

Example 293:5- (2- (4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) piperidin-1-yl) -2-oxoethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.21(s，0.3H)，8.19(s，0.7H)，7.78-7.81(m，1H)，7.39-7.41(m，0.3H)，7.26-7.34(m，2.7H)，7.13(d，J＝2.0Hz，2H)，5.43(s，0.7H)，5.42(s，0.3H)，4.92-4.97(m，1H)，4.82-4.85(m，2H)，4.55(d，J＝12.8Hz，1H)，3.84(d，J＝12.8Hz，0.7H)，3.59(d，J＝12.8Hz，0.3H)，3.45(d，J＝6.4Hz，2H)，2.51-3.09(m，5H)，2.10-2.15(m，1H)，1.90-2.03(m，1H)，1.67-1.79(m，2H)，1.14-1.30(m，2H)。

Example 294:4- ((3- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) -N, N-dimethylcyclohexane-1-carboxamide

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.29(t，J＝2.0Hz，1H)，7.11(d，J＝2.0Hz，2H)，5.39(s，1H)，3.36(d，J＝6.8Hz，2H)，2.99(s，3H)，2.89(s，3H)，2.37-2.46(m，1H)，1.66-1.78(m，5H)，1.43-1.53(m，2H)，0.95-1.04(m，2H)。

Example 295:4- ((2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) amino) -2- (2, 6-dioxopyridin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.55(s，1H)，7.48-7.52(m，1H)，7.30(t，J＝2.0Hz，1H)，7.09-7.11(m，3H)，6.95(d，J＝8.4Hz，1H)，6.41(t，J＝6.0Hz，1H)，5.44(s，1H)，4.91(dd，J＝12.0Hz，5.2Hz，1H)，3.80(t，J＝6.4Hz，2H)，3.50(q，J＝6.4Hz，2H)，2.67-2.85(m，3H)，2.06-2.10(m，1H)。

Example 296:4- ((2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) thio) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.04(s，1H)，7.70-7.76(m，2H)，7.66(dd，J＝6.8Hz，1.2Hz，1H)，7.34(t，J＝2.0Hz，1H)，7.14(d，J＝2.0Hz，2H)，5.44(s，1H)，4.97(dd，J＝12.0Hz，5.2Hz，1H)，3.82-3.86(m，2H)，3.29-3.33(m，2H)，2.69-2.92(m，3H)，2.12-2.17(m，1H)。

Example 297:4- (2- (4- ((3- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) methyl) piperidin-1-yl) -2-oxoethoxy) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Synthetic methods refer to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.56(s，0.5H)，8.49(s，0.5H)，7.65(t，J＝7.6Hz，1H)，7.47(d，J＝7.6Hz，1H)，7.25-7.32(m，2H)，7.12(s，2H)，5.40(s，1H)，4.83-5.11(m，3H)，4.45-4.55(m，1H)，3.95-4.04(m，1H)，3.41(d，J＝7.2Hz，2H)，3.02(t，J＝12.4Hz，1H)，2.68-2.87(m，3H)，2.52-2.63(m，1H)，2.08-2.16(m，1H)，1.87-2.00(m，1H)，1.61-1.74(m，2H)，1.04-1.30(m，2H)。

Example 298:5- ((2- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) amino) -2- (1-methyl-2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.60(d，J＝8.4Hz，1H)，7.33(t，J＝1.6Hz，1H)，7.12(d，J＝1.6Hz，2H)，6.94(d，J＝2.0Hz，1H)，6.76(dd，J＝8.4Hz，2.0Hz，1H)，5.45(s，1H)，4.98(t，J＝4.8Hz，1H)，4.92(dd，J＝12.4Hz，5.2Hz，1H)，3.86(t，J＝6.0Hz，2H)，3.44(q，J＝6.0Hz，2H)，3.19(s，3H)，2.94-2.97(m，1H)，2.69-2.83(m，2H)，2.05-2.10(m，1H)。

Example 299:5- ((2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) (methyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

Synthesis method reference is made to example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.05(s，1H)，7.68(d，J＝8.8Hz，1H)，7.31(t，J＝2.0Hz，1H)，7.10(d，J＝2.4Hz，1H)，7.05(d，J＝2.0Hz，2H)，6.90(dd，J＝8.8Hz，2.0Hz，1H)，5.38(s，1H)，4.93(dd，J＝12.0Hz，5.2Hz，1H)，3.78(t，J＝6.0Hz，2H)，3.70(t，J＝6.0Hz，2H)，3.11(s，3H)，2.67-2.93(m，3H)，2.08-2.15(m，1H)。

Example 300:5- ((2- (3, 5-Dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) (methyl) amino) -2- (1-methyl-2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，7.66(d，J＝8.4Hz，1H)，7.30(t，J＝2.0Hz，1H)，7.09(d，J＝2.4Hz，1H)，7.05(d，J＝2.0Hz，2H)，6.89(dd，J＝8.8Hz，2.4Hz，1H)，5.37(s，1H)，4.91(dd，J＝12.4Hz，5.2Hz，1H)，3.77(t，J＝6.0Hz，2H)，3.70(t，J＝6.0Hz，2H)，3.17(s，3H)，3.07(s，3H)，2.92-2.97(m，1H)，2.68-2.83(m，2H)，2.04-2.09(m，1H)。

Example 301:5- ((2- (3, 5-dichlorophenoxy) -2, 5-dioxy-2, 5-dihydro-1H-pyrrol-1-yl) ethyl) thio) -2- (2, 6-dioxopiperidin-3-yl) isoindole-1, 3-dione

The synthesis method is referred to in example 110. ¹ H NMR(400MHz，CDCl ₃ )，8.45(s，1H)，7.76-7.78(m，2H)，7.63(dd，J＝8.4Hz，1.6Hz，1H)，7.31(t，J＝2.0Hz，1H)，7.12(d，J＝2.0Hz，2H)，5.44(s，1H)，4.97(dd，J＝12.4Hz，5.2Hz，1H)，3.82(t，J＝6.8Hz，2H)，3.28(t，J＝6.8Hz，2H)，2.71-2.90(m，3H)，2.09-2.15(m，1H)。

Biological assay

Some pharmacological experiments and results are as follows:

tumor cell anti-tumor proliferation activity experiment:

to evaluate the antiproliferative effect, the breast cancer cell line MDA-MB-468 (Crownbio) was used, using a Promega corporation

The detection reagent establishes a screening method for WWP1 inhibitor to inhibit cell proliferation. MDA-MB468 was cultured in cell culture incubator (37 ℃ C., 5% CO2) using RPIM-1640 medium containing 10% Fetal Bovine Serum (FBS) (Biological Industries) and 100units/mL penicillin and 0.1mg/mL streptomycin (Gibco).

In the assay of compound activity, MDA-MB-468 was counted and plated in 96-well plates (Corning) at 2000 cells/well in sequence, and cultured at 37 ℃ overnight in 195. Mu.L of medium per well. The following day compounds were diluted in DMSO in 2-fold gradients (10 concentrations) from 250mM, and 4 μ L of each concentration was added to 46 μ L of medium and mixed by shaking. mu.L of the suspended compound was pipetted into MDA-MB-468 cells. After 3 days of compound action, the medium is removed and 25. Mu.L of the compound is added

Reagents, left for 10 min at room temperature, fluorescence signal read on EnVision Reader (PerkinElmer) and IC of compound on inhibition of cell proliferation calculated using GraphPad Prism 6.0 ₅₀ The value is obtained.

The results of pharmacological experiments with some preferred compounds are as follows:

experimental data for the Activity of the compounds of Table 1 on the breast cancer cell line MDA-MB-468:

the in vitro enzyme activity determination method comprises the following steps:

the full-length UBA1, ubiquitin and WWP1-HECT (aa 546-922) are expressed by Escherichia coli Rosetta, purified and quantified by a nickel column, and frozen at-80 ℃. FluorSH and UbFluor were synthesized and purified by David T.Krist et al (David T.Krist et al, curr Protoc Chem Biol, 2018). The UbFluor is modified by ubiquitin protein C-terminal fluorescent group FluorSH, when the UbFluor and WWP1 are subjected to thioreaction, the Ubquitin is connected to the cysteine at the position of WWP1890, and simultaneously the FluorSH group is free, the molecular weight of the free FluorSH group is reduced, the vibration frequency of a reaction system is accelerated, and the signal reduction can be detected by a Fluorescence Polarization (FP) method. The strength of the fluorescence signal directly reflects the strength of the enzymatic activity, and after the compound is added, the inhibition capability of the compound on WWP1 self-ubiquitination activity can be calculated according to the strength of the fluorescence signal.

This study measured the effective half inhibitory concentration of compounds on WWP1 autoubiquitination activity, i.e., IC ₅₀ The value is obtained. Compounds were diluted 5-fold in 100% DMSO (5 concentrations) starting at 250mM, 2. Mu.L each was added to 48. Mu.L of reaction buffer (50mM HEPES, pH7.4, 150mM NaCl,0.01% Tween-20,0.5mM TCEP), 5. Mu.L was added to a 384 well plate (OptiPlate-384 from PerkinElmer), 10. Mu.L WWP1 was added, 5. Mu.L UbFluor (final concentrations of 100nM and 2nM, respectively) was added, the mixture was centrifuged, and after incubation for 4 hours in a 23 ℃ incubator, the fluorescence signal was read on Envision (from PerkinElmer). IC of the resulting compound was calculated using GraphPad Prism 6.0 software ₅₀ The value is obtained.

table 2 experimental data on WWP1 protein activity of compounds:

the biological activity test result shows that the compound provided by the invention has the effect of inhibiting breast cancer cells; the compounds of the invention are useful for the treatment of various parenchymal organ cancers, including but not limited to various hematological malignancies, such as acute myelocytic leukemia, chronic myelocytic leukemia, lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, burkitt's lymphoma, follicular lymphoma, and solid tumors such as breast cancer, non-small cell lung cancer, melanoma, renal cancer, ovarian cancer, prostate cancer, colon cancer, and central nervous system tumors, among others. Accordingly, the present invention provides that the compounds of the present invention are useful in the preparation of anti-cancer drugs, and that the compounds of the present invention may also have therapeutic utility in other disease indications, including cardiac, viral, inflammatory and fungal diseases.

Finally, it should be understood that the embodiments described herein are merely illustrative of the principles of embodiments of the present invention; other variations are also possible within the scope of the invention; thus, by way of example, and not limitation, alternative configurations of embodiments of the invention may be considered consistent with the teachings of the invention; accordingly, the embodiments of the invention are not limited to the embodiments explicitly described and depicted.

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof:

R ^y selected from 4-8 membered heterocycloalkyl and 5-12 membered heteroaryl, the heteroatoms of which are selected from N or/and O or/and S, R ^y Can optionally be (= O) or R ⁶ The substitution is carried out by the following steps,

R ^z selected from the group consisting of 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, said cycloalkyl and heterocycloalkyl may beOptionally substituted by R ⁷ Or (= O), the aryl and heteroaryl groups may be optionally substituted with R ⁷ The substitution is carried out by the following steps,

n is 0, 1,2, 3 or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, having the structure of formula (I)

e and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) -NH-CH ₂ -、-O-CH ₂ -、-S-CH ₂ -, -C.ident.C-, - (CO) -NH-, -CH = CH- (CO) -NH-, or- (SO) ₂ ) -NH-, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ¹ and R ² Each independently selected from H and C _1-6 Alkyl and 3-8 membered cycloalkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein

E and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-; -O-, -S-) -NH-CH ₂ -、-O-CH ₂ -, or-S-CH ₂ -, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ⁵ 、R ⁶ and R ⁷ Each independently selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ and-NR ¹ -(SO ₂ )-R ⁴ Said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl being optionally substituted by halogen, (= O), (= CN, -OH, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CO) -R ⁴ 、-(CO)-OR ¹ 、-(CO)-NR ¹ R ² 、-(SO ₂ )-R ⁴ 、-(SO ₂ )-NR ¹ R ² 、-OR ¹ 、-NR ¹ R ² 、-O-(CO)-R ⁴ 、-NR ¹ -(CO)-R ⁴ 、-NR ¹ -(CO)-NR ¹ -R ⁴ 、-O-(SO ₂ )-R ⁴ or-NR ¹ -(SO ₂ )-R ⁴ Is substituted and

R ¹ 、R ² and R ⁴ As defined in claim 2.

4. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein

E and Z are each independently selected from C _1-6 Alkylene, a bond, -NH-or-O-, said C _1-6 Alkylene may optionally be substituted by halogen, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ⁴ is selected from C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, or 3-8 membered heterocycloalkyl, which alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may optionally be substituted with halo, (= O), -CN, CF ₃ 、C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, -OR ¹ or-NR ¹ R ² The substitution is carried out by the following steps,

R ¹ and R ² As defined in claim 2.

5. A compound of formula (IV) or a pharmaceutically acceptable salt, solvate, polymorph, deuteron or tautomer thereof:

wherein R is ^x 、R ^y 、R ^z 、L ₁ 、L ₂ 、L ₃ And n is as defined in claim 1.

6. The compound of claim 5, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein L ₁ 、L ₂ And L ₃ Is a bond.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein R ^y Is selected from

Wherein R is ^y Optionally substituted by R ⁶ Substituted, R ⁶ As defined in claim 1.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein R ^x Selected from phenyl and 5-6 membered heteroaryl, said phenyl and heteroaryl optionally substituted with R ⁵ Substituted, R ⁵ As defined in claim 1.

9. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein R ⁵ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² ，R ¹ And R ² As defined in claim 1.

10. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein R ⁶ Selected from halogen, C _1-6 Alkyl and 3-12 membered cycloalkyl, said alkyl and cycloalkyl being optionally substituted by halogen.

11. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, wherein R ⁷ Selected from halogen, -CN, CF ₃ 、C _1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, -OR ¹ and-NR ¹ R ² ，R ¹ And R ² As defined in claim 1.

12. The following compounds, or pharmaceutically acceptable salts, solvates, polymorphs, deuterons or tautomers thereof:

13. a pharmaceutical composition comprising a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, polymorph, deuteron, or tautomer thereof, and a pharmaceutically acceptable carrier.

14. Use of a compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, polymorph, deuteride, or tautomer thereof, or a pharmaceutical composition according to claim 13, in the manufacture of a medicament for the treatment of a disease mediated by WWP1 protein or NEDD4 protein; preferably, the disease mediated by the WWP1 protein or the NEDD4 protein is a hyperproliferative disease and/or an induced infectious disease and/or a cardiovascular disease and/or a disease due to fungi; more preferably, the disease mediated by WWP1 protein or NEDD4 protein is lung cancer, prostate cancer, cervical cancer, colorectal cancer, melanoma, ovarian cancer, breast cancer, renal cancer, nervous system tumor, lymphoma, or leukemia; most preferably, the disease mediated by the WWP1 protein or the NEDD4 protein is acute myelocytic leukemia, chronic myelocytic leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, burkitt's lymphoma, follicular lymphoma, breast cancer, non-small cell lung cancer, melanoma, renal cancer, ovarian cancer, prostate cancer, colon cancer, or central nervous system tumor.