Amide-indolizine compound, preparation method therefor, and use thereof

Abstract

The present invention provides an amide-indolizine compound, a preparation method therefor, and a use thereof. The structure of the amide-indolizine compound is as shown in formula I. The amide-indolizine compound provided by the present invention can effectively degrade a CBP and / or p300 protein, and has an excellent anti-cancer effect.

Description

An amide indolizine compound and a preparation method and application thereof

[0001] Cross-reference to Related Applications

[0002] This application claims the benefit of Chinese application number 2024106584895, filed May 24, 2024. The application number 2024106584895 is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to an amide indolizine compound and a preparation method and application thereof, and particularly relates to an amide indolizine compound and a preparation method and application thereof. BACKGROUND

[0004] Epigenetic modifications are crucial for the development of diseases such as inflammation and tumors. The basic epigenetic modifications mediated by regulation include DNA methylation and histone post-translational modification (PTM). Among them, post-translational modification includes acetylation, methylation, phosphorylation and ubiquitination, etc. The level of histone acetylation is a highly dynamic process, which is controlled by acetyltransferase "writer", deacetylase "eraser" and bromodomain "reader". Among them, acetyltransferase and deacetylase have opposite enzyme activities. The bromodomain family protein is an important epigenetic reader, which can specifically recognize histone lysine and recruit transcription factors, thereby affecting gene expression.

[0005] Bromodomain proteins are named because they were first discovered in Drosophila genes. Bromodomain proteins have also been found in many nuclear proteins, such as histone acetyltransferases (HATs), ATP-dependent chromatin remodeling complexes, methyltransferases and transcription coactivators. Human encodes 61 bromodomain proteins, which are divided into 8 families. Among them, the cyclic AMP response element binding protein (CREB) binding protein (CBP) and its highly homologous 300kDa adenovirus E1A binding protein (p300) belong to the third family member.

[0006] CBP / p300 proteins are multifunctional domains, both of which contain a bromodomain (BRD) and an acetyltransferase (HAT) domain, involved in post-translational modification and recruitment of histones and non-histone proteins. CBP / p300 bromodomain is composed of four alpha-helical bundles (including alpha Z, alpha A, alpha B and alpha C) and two flexible loop regions (ZA and BC loop) connected by a linker. CBP / p300 proteins are involved in cell growth, proliferation differentiation, apoptosis and necrosis, etc. Many studies have shown that CBP / p300 as a transcriptional coactivator is closely related to the occurrence and development of inflammation, various cancers and tumor immune escape in vivo. Therefore, inhibiting the function of CBP / p300 can inhibit the development of related cancers, thereby achieving a therapeutic effect.

[0007] At present, there are many small molecule inhibitors targeting CBP / p300 bromodomain, such as SGC-CBP30, GN7-781, GNE-049, CCS1477, Y08284, etc. Among them, only CCS1477 enters the clinical phase 2 study for the treatment of solid tumors and hematological malignancies. CBP / p300 acetyltransferase small molecule inhibitors mainly include C646, A485, B026, etc., which are used for the treatment of breast cancer, prostate cancer, leukemia and other diseases.

[0008] In recent years, the proteolysis-targeting chimera (PROTAC) technology is developing rapidly. Studies have shown that targeted protein degradation agents not only can inhibit the activity of target proteins, but also can use the ubiquitin-proteasome system (UPS) in vivo to eliminate target proteins, thereby achieving a therapeutic purpose. At present, seven CBP and / or p300 degradation agents have been reported, which are dCBP-1, JQAD-1, JET-209, CBPD-268, CBP-409, QC-182 and XYD190.

[0009] These degradation agents have good preclinical antitumor activity in vivo or in vitro. However, there is no degradation agent targeting CBP and / or p300 entering the clinic. Therefore, it is of great significance to develop new compounds that can effectively induce the degradation of CBP and / or p300. SUMMARY

[0010] In view of the deficiencies of the prior art, the purpose of the present application is to provide an amide indolizine compound and a preparation method and application thereof, in particular to provide an amide indolizine compound and a preparation method and application thereof. The amide indolizine compound provided by the present application can effectively degrade CBP and / or p300 protein and has excellent anticancer effect.

[0011] To achieve the purpose of the present application, the following technical solutions are adopted:

[0012] In a first aspect, the present application provides an amide indolizine-based isoxazole compound, the structure of which is shown in Formula I:

[0013] wherein R 1 is selected from any one of hydrogen, a halogen atom, a hydroxyl group, an aldehyde group, a carboxyl group, a hydroxymethyl group, a methyl ester group, a trifluoromethyl group, an amide group, a 2-methoxytetrahydropyranyl group, an alkoxycarbonyl group, or a 2,2-dimethylpropionic acid ethyl ester group.

[0014] R 2 is selected from any one of hydrogen, a halogen atom, a C1-C10 alkyl group, or a C1-C10 cycloalkyl group.

[0015] R 3 is selected from any one of hydrogen, a halogen atom, a C1-C10 alkyl group, an amino group, or a Boc-protected amino group.

[0016] R 4 is selected from any one of hydrogen, a C1-C10 alkyl group, a C1-C10 cycloalkyl group, an amino group, a Boc-protected amino group, or a methylamino group.

[0017] R 5 is selected from any one of hydrogen, a C1-C10 alkyl group, a C1-C10 cycloalkyl group, a substituted C1-C10 cycloalkyl group, a C1-C10 cycloalkenyl group, a pyridyl group, a substituted pyridyl group, a pyrazinyl group, a substituted pyrazinyl group, a pyrimidinyl group, a morpholinyl group, a substituted morpholinyl group, a substituted pyrimidinyl group, a pyridazinyl group, a substituted pyridazinyl group, a piperidyl group, a substituted piperidyl group, a furanyl group, a substituted furanyl group, a thienyl group, a substituted thienyl group, a pyrrolyl group, a substituted pyrrolyl group, an imidazolyl group, a substituted imidazolyl group, a pyrazolyl group, a substituted pyrazolyl group, a quinolinyl group, an isoquinolinyl group, or a benzenesulfonic acid group.

[0018] Y 1 is selected from any one of a single bond, -R a O-, -R a S-, -R a NR’-, -R a OC(O)-, -R a OC(O)O-, -R a OCONR’-, -R a C(O)-, -R a C(O)O-, -R a CONR’-, -R a S(O)-, -R a S(O)2-, -R a SO2NR’-, -R a NR’C(O)O-, -R a NR’C(O)-, -Ra NR'C(O)NR"-, -R a NR'S(O)-, -R a NR'S(O)2-, -R a NR'S(O)2NR"-, substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13spiro cycloalkyl, substituted or unsubstituted C5-C13spiro heterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, any of said substituted groups being selected from the group consisting of halogen, hydroxyl, R b , R b is selected from the group consisting of C1-C6alkyl.

[0019] R a is selected from the group consisting of a single bond, substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13spiro cycloalkyl, substituted or unsubstituted C5-C13spiro heterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, any of said substituted groups being selected from the group consisting of halogen, hydroxyl, R c , R c is selected from the group consisting of C1-C6alkyl.

[0020] R', R" are independently selected from the group consisting of substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C2-C8alkenyl, substituted or unsubstituted C2-C8alkynyl, substituted or unsubstituted C1-C8alkoxy, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, or R', R" and the atom to which they are attached form a C3-C20cycloalkyl or C4-C20heterocyclyl, any of said substituted groups being selected from the group consisting of halogen, hydroxyl, R d , R d is selected from the group consisting of C1-C6alkyl.

[0021] Y2 is selected from any one of -0-, -NH-, -CH2-, -C(O)-, or a single bond.

[0022] L is selected from any one of a single bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkenylene, substituted or unsubstituted C2-C8 alkynylene, ether, thioether, ester, amine, amide, carbamate, urea, sulfone, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, carbonyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, wherein the substituted groups are selected from halogen, hydroxyl, R e , R e is selected from C1-C6 alkyl.

[0023] E has a structure according to any one of Formulae II-1 to II-4, wherein denotes the position of the group attachment:

[0024] wherein Y 3 is selected from any one of -0-, -S-, -CHR f -, -C(O)-, -S02-, -NR g -.

[0025] R f , R g are independently selected from any one of H, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 heterocyclyl, wherein the substituted groups are selected from halogen, hydroxyl, R h , R h is selected from C1-C5 alkyl.

[0026] Y 4 , Y 5 , Y 6 , Y 7 are independently selected from -CR i = or -N=.

[0027] R i is selected from any one of H, halogen, cyano, nitro, C1-C5 alkyl;

[0028] Y 8 is selected from CH or N.

[0029] T 1 , T 2 , T 3 are independently selected from O or S.

[0030] R 6, R 7 is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 heterocyclyl, the substituted groups being selected from any one of halogen, hydroxyl, R j is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C1-C10 heterocyclyl, the substituted groups being selected from any one of halogen, hydroxyl, R j is selected from C1-C5 alkyl.

[0031] R 8 is selected from any one of H, halogen, cyano, C1-C5 alkyl, C1-C5 alkoxy or C1-C5 haloalkane.

[0032] Q is selected from any one of -CH2-, -O-, -S-, -NR k -, -C(O)NR l -.

[0033] R k , R l is independently selected from any one of H, C1-C10 alkyl, halogen.

[0034] The compounds of the specific structure described above can effectively degrade CBP and p300 proteins, and have excellent anti-cancer effect.

[0035] Preferably, Y 4 , Y 5 , Y 6 , Y 7 is selected from -CH=.

[0036] Preferably, Y 4 , Y 5 , Y 6 , Y 7 is -CH=.

[0037] Preferably, L is selected from any one of the following groups, denotes the position of the group connection:

[0038] wherein n, p, q are independently selected from an integer from 1 to 10; m is selected from an integer from 0 to 10, m being 0 means that the group does not exist here; A, D, E, G, J, L, M and Z are independently selected from -CH= or -N=.

[0039] Preferably, Y 3 is selected from -CH2- or -C(O)-, preferably -C(O)-.

[0040] Preferably, T 1 , T 2, T 3 selected from O.

[0041] Preferably, the amide indolizine compound has a structure as shown in Formula III:

[0042] wherein R 2 , R 3 , R 4 , E, Y 1 , Y 2 , L have the same defined range as R 9 is any one of C2-C6 alkyl or C3-C6 cycloalkyl.

[0043] Preferably, the amide indolizine compound has a structure as shown in Formula IV-IX:

[0044] wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , E, Y 1 , Y 2 , L have the same defined range as described above;

[0045] Preferably, the R 2 is selected from a fluorine atom;

[0046] Preferably, the R 3 is H;

[0047] Preferably, the R 4 is methyl or ethyl;

[0048] Preferably, the R 6 , R 7 are independently selected from H or C1-C10 alkyl;

[0049] Preferably, the R 9 is methyl or cyclopropyl;

[0050] Preferably, the Y 1 is selected from any one of substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl;

[0051] Preferably, the Y 2 is selected from any one of -NH-, -C(O)- or a single bond;

[0052] Preferably, said L is selected from any one of the following groups, denotes the position of attachment of the group:

[0053] wherein n, p, q are independently selected from an integer from 1 to 10; m is selected from an integer from 0 to 10, m being 0 means that the group is not present.

[0054] Preferably, said amide indolizine compound is selected from any one of the following structures:

[0055] 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0056] 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)- 2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0057] 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0058] 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)- 4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0059] 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0060] 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0061] 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino]-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0062] 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0063] 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0064] 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0065] 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0066] 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0067] 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl- 1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0068] 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)hexyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl- 1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0069] 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino]-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl- 1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0070] 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4- yl)amino)butyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl- 1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0071] 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3- (1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0072] 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5- (hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0073] 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5- (hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide)

[0074] 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0075] 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0076] 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0077] 3-acetyl-7-(1-(1-(2-(2,6-dioxoisoindolin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxapentadecan-15-hydroxy)piperidin-4-yl)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0078] 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide

[0079] 3-acetyl-7-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide

[0080] 3-acetyl-7-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide

[0081] 3-acetyl-7-((6-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-6-oxohexyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl) phenyl)indolizine-1-carboxamide

[0082] 3-acetyl-7-((7-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-7-oxoheptyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl) phenyl)indolizine-1-carboxamide

[0083] 3-acetyl-7-((8-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-8-oxooctyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl) phenyl)indolizine-1-carboxamide

[0084] 3-acetyl-7-(2-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0085] 3-acetyl-7-(4-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0086] 3-acetyl-7-((5-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-5- oxapentyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0087] 3-acetyl-7-((6-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-6- oxohexyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0088] 3-acetyl-7-((7-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-7- oxooctyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0089] 3-acetyl-7-((8-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-8-oxooctyl)oxy)- N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0090] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0091] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0092] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0093] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0094] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1- yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0095] In a second aspect, the present application provides a method for preparing the amide indolizine compounds as described above, which is shown in Scheme 1:

[0096] R 2 , R 3 , R 4 , R 9 , R 10 , Y 1 , L, Y 2 , E has the same defined range as described above;

[0097] wherein, R 10 and R 11 are independently selected from any one of substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkenylene, substituted or unsubstituted C2-C8 alkynylene, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, substituted or unsubstituted C4-C13 fused cycloalkyl, substituted or unsubstituted C4-C13 fused heterocyclyl, substituted or unsubstituted C5-C13 bridged cycloalkyl, substituted or unsubstituted C5-C13 bridged heterocyclyl, substituted or unsubstituted C5-C13 spirocycloalkyl, substituted or unsubstituted C5-C13 spiroheterocyclyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, the substituted group is selected from any one of halogen, R m , hydroxyl, -OR m , the R m is selected from C1-C6 alkyl;

[0098] The reaction steps are as follows: the substrate 1-a is obtained by substitution reaction to obtain 2-a, the substrate 2-a is salted to obtain 3-a, the substrate 3-a is cyclized to obtain 4-a, the substrate 4-a is de-methyl ester to obtain 5-a, the substrate 6-a is brominated to obtain 7-a, the substrate 7-a is reduced to obtain 8-a, the substrate 8-a is substituted to obtain 9-a, the substrate 9-a is reduced by iron powder to obtain 10-a, the substrate 10-a is coupled by Suzuki to obtain 11-a, the substrate 11-a is condensed with 5-a to obtain 12-a, the substrate 12-a is reduced to obtain 13-a, the substrate 13-a is subjected to affinity substitution to obtain 14-a, the substrate 14-a is deprotected under acidic conditions to obtain 15-a, and the substrate 15-a is condensed to obtain the compound shown in formula II.

[0099] In a third aspect, the present application provides a pharmaceutically acceptable salt of the amide indolizine compound as described above.

[0100] In a fourth aspect, the present application provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable excipient.

[0101] The active ingredient comprises at least one amide indolizine compound as described above and / or at least one pharmaceutically acceptable salt as described above.

[0102] In a fifth aspect, the present application provides use of an amide indolizine compound as described above, a pharmaceutically acceptable salt as described above or a pharmaceutical composition as described above in the manufacture of a CBP protein and / or p300 protein degrader.

[0103] The CBP protein and / or p300 protein degrader described above can be used for non-therapeutic purposes as a reagent for scientific research for the study of protein properties and related mechanisms.

[0104] In a sixth aspect, the present application further provides use of an amide indolizine compound as described above, a pharmaceutically acceptable salt as described above or a pharmaceutical composition as described above in the manufacture of a medicament for preventing or treating cancer, a cell proliferative disorder, inflammation, an autoimmune disease or sepsis.

[0105] The cancer comprises any one of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, glioma, lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer or breast cancer.

[0106] The inflammation is selected from any one of pharyngolaryngeal inflammation, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, pelvic inflammatory disease, urethritis, pneumonia, conjunctivitis, otitis media, meningitis, myocarditis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease, thyroiditis or allergic dermatitis.

[0107] The autoimmune disease is selected from any one of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating disease, primary adrenocortical atrophy, chronic thyroiditis, juvenile diabetes, hyperthyroidism, chronic nonspecific ulcerative colitis, chronic active hepatitis, pernicious anemia, atrophic gastritis, autoimmune glomerulonephritis, Goodpasture's syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura or idiopathic leukopenia.

[0108] In the present application, the cell proliferative disorder disease includes benign soft tissue tumor, brain and spinal cord tumor, eyelid and orbital tumor, granuloma, lipoma, meningioma, multiple endocrine tumor, nasal polyp, pituitary tumor, prolactinoma, sebaceous keratotic, gastric polyp, thyroid nodule, liver hemangioma, vocal cord nodule, polyp, cyst, pilar cyst or pyogenic granuloma.

[0109] In the present application, the inflammation disease includes inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergy, Crohn's disease, intestinal syndrome, ulcerative colitis, tissue graft rejection, organ graft rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease, autoimmune disease, autoimmune alopecia, anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenia, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, Hashimoto's thyroiditis, allergic dermatitis, degenerative joint disease, Guillain-Barre syndrome, mycosis fungoides or acute inflammatory reaction.

[0110] Further aspects and features of the present application are described below.

[0111] Various terms and phrases used in the present application have the ordinary meaning as is commonly understood by one of ordinary skill in the art, even though the present application desires to set forth herein more detailed explanations and interpretations of these terms and phrases, if they are inconsistent with the ordinary meanings. The following are definitions of various terms used in the present application, which are applicable to the terms as used throughout the specification and claims unless otherwise indicated. The following provides definitions of various groups of the compounds of the present application, which are uniformly used throughout the specification and claims unless otherwise defined.

[0112] As used herein, the terms "halo", "halogen", "halogen atom" and the like mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0113] As used herein, the term "alkyl" means an alkyl group having the indicated number of carbon atoms, which can be a straight chain alkyl or a branched alkyl, for example, the "C1-C6 alkyl" means a straight chain alkyl or a branched alkyl having 1 to 6 carbon atoms, and specific groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl and the like, as well as similar groups.

[0114] As referred to herein, the term "cycloalkyl" refers to cyclic alkyl groups having the indicated number of ring carbon atoms, e.g., as referred to by "C3-C10 cycloalkyl," which means cyclic alkyl having from 3 to 10 carbon atoms, specific groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as similar groups.

[0115] As referred to herein, the term "alkenyl" refers to alkenyl groups (hydrocarbyl groups having one or more C=C double bonds) having the indicated number of carbon atoms, which can be straight chain or branched, e.g., as referred to by "C2-C20 alkenyl," which means straight chain or branched alkenyl having from 2 to 20 carbon atoms, specific groups include ethenyl, propenyl, allyl, 1-butenyl, 2-butenyl, 1,3- butadienyl, 1-pentenyl, 2-pentenyl, 1,3-pentadienyl, 1-hexenyl, 2-hexenyl, and the like, as well as similar groups.

[0116] As referred to herein, the term "cycloalkenyl" refers to cyclic alkenyl groups (hydrocarbyl groups having one or more C=C double bonds) having the indicated number of carbon atoms, e.g., as referred to by "C3-C10 cycloalkenyl," which means cyclic alkenyl having from 3 to 10 carbon atoms, specific groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like, as well as similar groups.

[0117] As referred to herein, the term "alkynyl" refers to alkynyl groups (hydrocarbyl groups having one or more C≡C triple bonds) having the indicated number of carbon atoms, which can be straight chain or branched, e.g., as referred to by "C2-C20 alkynyl," which means straight chain or branched alkynyl having from 2 to 20 carbon atoms, specific groups include ethynyl, propynyl, 1-butenyl, 2-butenyl, 1-pentynyl, 2-hexynyl, and the like, as well as similar groups.

[0118] As referred to herein, the term "heterocyclyl" refers to non-aromatic heterocyclic rings in which one or more of the ring-forming atoms is a heteroatom such as O, N, or S. Heterocyclyl groups can include monocyclic or polycyclic (e.g., with 2, 3, or 4 fused rings) ring systems as well as spirocyclic rings. Examples of preferred "heterocyclyl" groups include, but are not limited to: aziridinyl, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, and the like. Also included within the definition of heterocyclyl are moieties having one or more aromatic rings fused to the non-aromatic heterocyclyl ring (e.g., with a shared bond), such as 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, benzo-l,4-dioxanyl, phthalimidyl, naphthalimidyl, and the like. Heterocyclyl groups having one or more fused aromatic rings can be attached through either the aromatic or non-aromatic portion.

[0119] As referred to herein, the term "aryl" refers to aromatic hydrocarbons, such as phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like, which are monocyclic or polycyclic (e.g., with 2, 3, or 4 fused rings).

[0120] As referred to herein, the term "heteroaryl" refers to aromatic heterocyclic rings having at least one ring member which is a heteroatom such as O, N, or S. Heteroaryl groups include monocyclic or polycyclic (e.g., with 2, 3, or 4 fused rings) ring systems. Any N atom which forms a ring in a heteroaryl group can also be oxidized to form an N-oxide. Examples of preferred "heteroaryl" groups include, but are not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, thienyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and the like.

[0121] As referred to herein, the term "single bond" refers to the direct attachment of two groups to the position; for example, when Y 1 is a single bond, L is directly attached to the phenyl ring, and the structure represented by Formula I can be represented as: when Y 2 is a single bond, the group Y 1 is directly attached to E, and the structure represented by Formula I can be represented as:

[0122] As referred to herein, the term "compound", as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, isotopes.

[0123] The compounds of the present application can be asymmetric, for example, having one or more stereocenters. Unless otherwise stated, all stereoisomers, both enantiomeric and diastereomeric, are intended. Compounds of the present application containing an asymmetrically substituted carbon atom can be isolated in optically pure or racemic form. The optically pure form can be obtained by resolution of racemic mixtures using standard techniques, or by using chiral synths or chiral reagents in a synthesis step.

[0124] The compounds of the present application can also include tautomeric forms. Tautomeric forms arise from the interchange of a single bond and an adjacent bond together with the migration of a proton.

[0125] The compounds of the present application can also include all isotopic variations of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include deuterium and tritium.

[0126] As referred to herein, the term "pharmaceutical composition", which can also be referred to as "composition", is meant to be a composition useful for achieving a therapeutic and / or prophylactic effect of the diseases or conditions described herein in a subject, in particular a mammal.

[0127] As referred to herein, the term "disease and / or condition" is meant to refer to a physical state of the subject which is associated with the diseases and / or conditions described herein. For example, the diseases and / or conditions described herein can refer to both a physical state and a disease state. No distinction is made herein between a physical state and a disease state, or both can be referred to interchangeably.

[0128] As referred to herein, the term "pharmaceutically acceptable salt" means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic material which is pharmaceutically useful, for example, a salt formed as an intermediate in a chiral resolution, although such intermediate salt cannot be directly administered to the subject, the salt can play a role in obtaining the final product of the present application.

[0129] The pharmaceutically acceptable salts of the compounds of Formula I can be formed in two forms: one is a salt formed with an acid; the other is a salt formed with a base or alkali metal. The acids with which the compounds of Formula I form pharmaceutically acceptable salts include inorganic acids and organic acids. Suitable inorganic acids include hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids include aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic acids, examples of which include but are not limited to formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkyl sulfonic acid, aromatic sulfonic acid, and the like. The alkali metals with which the compounds of Formula I form pharmaceutically acceptable salts include lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, and the like; the bases with which the compounds of Formula I form pharmaceutically acceptable salts include choline, diethanolamine, morpholine, and the like.

[0130] As mentioned in the present application, the term "prodrug" is a derivative of some compounds of Formula I which is converted (for example: hydrolyzed, reduced or oxidized) into a compound of Formula I in vivo by means of metabolism in vivo, and such derivatives are referred to as prodrugs. For example, a compound of Formula I containing a hydroxyl group can be reacted with an acid to prepare a corresponding ester, which is a prodrug, and the prepared ester can hydrolyze the parent drug in vivo. Suitable acids for preparing "prodrugs" include but are not limited to acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene-bis-beta-hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0131] Compared with the prior art, the present application has the following beneficial effects:

[0132] The present application provides an amide indolizine compound, by selecting specific groups, the compound can effectively degrade CBP and p300 proteins, and has excellent anticancer effect. BRIEF DESCRIPTION OF DRAWINGS

[0133] Figure 1 is a graph showing the down-regulation of CBP and p300 protein levels in MOLM-16 cells by Example 16 at different concentrations;

[0134] Figure 2 is a graph showing the down-regulation of CBP and p300 protein levels in MOLM-16 cells by Example 16 at different concentrations;

[0135] Figure 3 is a graph showing the change in tumor volume in mice during the administration of Example 16;

[0136] Figure 4 is a graph showing the change in body weight of mice during the administration of Example 16. DETAILED DESCRIPTION

[0137] The technical solutions of the present application are further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations on the present application.

[0138] The synthesis routes of amide indolizine compound intermediates 1-14 and 1-15a-1-15f are as follows:

[0139] Step 1, synthesis of 3-bromo-4-fluoro-5-nitrobenzaldehyde (1-2)

[0140] At 0°C, 4-fluoro-3-nitrobenzaldehyde (50 g, 29 mmol) was dissolved in 300 mL of concentrated sulfuric acid, and NBS (70 g, 354 mmol) was added in three portions within 15 min. The reaction was carried out at room temperature for 16 h. After the reaction was completed, it was cooled to room temperature, and the reaction solution was slowly added to ice water, extracted with ethyl acetate three times, and the organic phases were combined. After drying over anhydrous sodium sulfate, it was concentrated. After separation by silica gel column chromatography, 62 g of yellow solid was obtained with a yield of 85%. 1H NMR (500 MHz, CDCl3) δ 9.99 (s, 1H), 8.51 (dd, J = 6.3, 2.0 Hz, 1H), 8.39 (dd, J = 5.5, 2.0 Hz, 1H).

[0141] Step 2, synthesis of (3-bromo-4-fluoro-5-nitrophenyl)methanol (1-3)

[0142] 3-bromo-4-fluoro-5-nitrobenzaldehyde (62 g, 250 mmol) was dissolved in 300 mL of methanol, and sodium borohydride (14.2 g, 375 mmol) was slowly added to the reaction system at 0°C. After the reaction was stable, it was transferred to room temperature and reacted for 2 h. After the reaction was completed, the solvent was rotary evaporated, extracted and separated with ethyl acetate and water, the organic phases were combined, dried over anhydrous Na2SO4, and the solvent was rotary evaporated to obtain 62 g of yellow solid with a yield of 100%. 1H NMR (500 MHz, DMSO-d6) δ 8.05 (dd, J = 22.9, 5.7 Hz, 2H), 5.63 (s, 1H), 4.56 (d, J = 5.5 Hz, 2H).

[0143] Step 3, synthesis of 2-((3-bromo-4-fluoro-5-nitrobenzyl)oxy)tetrahydro-2H-pyran (1-4)

[0144] (3-bromo-4-fluoro-5-nitrophenyl)methanol (62 g, 250 mmol), dihydropyran (25 g, 297 mmol), PPTS (6 g, 24 mmol) were dissolved in 1,2-dichloroethane and heated to 50 °C for 5 h. After the reaction was completed, it was extracted with dichloromethane / water, and the organic phase was collected. After washing with brine, drying over anhydrous sodium sulfate, and rotary evaporation of the solvent, 68.8 g of a light yellow liquid was obtained with a yield of 81.4%.1H NMR (500 MHz, DMSO-d6) δ 8.20 - 8.05 (m, 2H), 4.78 - 4.68 (m, 2H), 4.54 (d, J = 13.0 Hz, 1H), 3.76 (ddd, J = 11.2, 8.2, 3.0 Hz, 1H), 3.48 (dd, J = 10.9, 5.4 Hz, 1H), 1.78 - 1.71 (m, 1H), 1.71 - 1.65 (m, 1H), 1.59 - 1.44 (m, 4H).

[0145] Step 4, synthesis of 3-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline (1-5)

[0146] Iron powder (29 g, 515 mmol), AcOH (13.7 g, 227 mmol) and NH4Cl (0.55 g, 10 mmol) were added to a small amount of water, activated at 80 °C for 10 min, and then 2-((3-bromo-4-fluoro-5-nitrobenzyl)oxy)tetrahydro-2H-pyran (34.4 g, 203 mmol) dissolved in EtOH was added to the reaction system. After 30 min of reaction, the reaction solution was suction filtered, the filtrate was rotary evaporated, extracted with EA / H2O, and the organic phase was collected. After washing with brine, drying over anhydrous sodium sulfate, 24 g of brown oil was obtained with a yield of 76.4%.1HNMR (500 MHz, DMSO-d6) δ 6.71 (dd, J = 17.9, 6.7 Hz, 2H), 5.48 (s, 2H), 4.62 (s, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.27 (d, J = 12.1 Hz, 1H), 3.75 (dd, J = 13.8, 5.4 Hz, 1H), 3.57 - 3.40 (m, 1H), 1.80 - 1.69 (m, 1H), 1.64 (t, J = 9.1 Hz, 1H), 1.49 (dd, J = 12.3, 8.7 Hz, 4H).

[0147] Step 5, synthesis of 2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)aniline

[0148] To a solution of 3-bromo-2-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline (24 g, 78.9 mmol), PdCl2(dppf) (644 mg, 7.89 mmol), Ba(OH)2·8H2O (86 g, 236.7 mmol) and 1-methyl-4-pyrazole boronic acid pinacol ester (19.2 g, 94.7 mmol) in DMSO was heated to 90 °C overnight under N2protection. After the reaction was completed, the reaction was cooled to room temperature and filtered by Celite pad. To the filtrate was added 300 mL of water and extracted with EA for three times. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 3:1) to give 21 g of brown oil in 87.3% yield.1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.79 (s, 1H), 6.69 (dd, J = 61.3, 6.6 Hz, 2H), 5.16 (s, 2H), 4.65 (s, 1H), 4.52 (d, J = 11.7 Hz, 1H), 4.29 (d, J = 11.7 Hz, 1H), 3.88 (s, 3H), 3.80 (dd, J = 13.9, 5.6 Hz, 1H), 3.51 - 3.39 (m, 1H), 1.78 - 1.70 (m, 1H), 1.65 (t, J = 9.3 Hz, 1H), 1.58 - 1.37 (m, 4H).

[0149] Step 6, synthesis of 4-benzyloxy pyridine (1-8)

[0150] NaH (27 g, 693 mmol, 60% dispersion in mineral oil) was slowly added to 200 mL of DMF under ice bath condition, then benzyl alcohol (37.5 g, 347 mmol) was added dropwise and stirred for 10 min. 4-chloropyridine hydrochloride (40 g, 267 mmol) was added to the reaction in three portions and stirred for 10 min, then heated to 60 °C for 2 h. The reaction was cooled to room temperature, quenched with water, extracted with ethyl acetate, and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 49 g of yellow liquid was obtained in 99% yield.1H NMR (500 MHz, CDCl3) δ 8.43 (d, J = 4.7 Hz, 2H), 7.40 (d, J = 3.1 Hz, 4H), 7.37 - 7.32 (m, 1H), 6.87 (d, J = 4.7 Hz, 2H), 5.10 (s, 2H).

[0151] Step 7, synthesis of 4-(benzyloxy)-1-(2-oxopropyl)pyridine-1-chloride (1-9)

[0152] To a solution of 4-benzyloxy-pyridine (49 g, 265 mmol) and 1-chloropropan-2-one (29 g, 317 mmol) in acetone, was added triethylamine (18.8 g, 184 mmol) dropwise, followed by methyl propiolate (12.4 g, 147 mmol) slowly at room temperature. The reaction was stirred at 60 °C for 16 h. White solid was precipitated, which was filtered off and washed with EA to give 34 g of white solid in 46% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 7.5 Hz, 2H), 7.53 (d, J = 6.8 Hz, 2H), 7.48 - 7.40 (m, 3H), 5.69 (s, 2H), 5.50 (s, 2H), 2.28 (s, 3H).

[0153] Step 8, Synthesis of methyl 3-acetyl-7-(benzyloxy)indolizine-1-carboxylate (1-10)

[0154] To a solution of 4-(benzyloxy)-1-(2-oxopropyl)pyridine-1 -chloride (34 g, 123 mmol) in DCM was added triethylamine (18.8 g, 184 mmol) dropwise, followed by methyl propiolate (12.4 g, 147 mmol) slowly at room temperature. The reaction was stirred at room temperature for 10 h. After the reaction was completed, the organic solvent was evaporated, and the product was purified by column chromatography (PE:DCM = 2:1) to give 30 g of yellow solid in 76% yield. 1H NMR (400 MHz, CDCl3) 9.75 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.51 - 7.36 (m, 5H), 6.77 (dd, J = 7.6, 2.8 Hz, 1H), 5.19 (s, 2H), 3.91 (s, 3H), 2.54 (s, 3H).

[0155] Step 9, Synthesis of 3-acetyl-7-(benzyloxy)indolizine-1-carboxylic acid (1-11)

[0156] To a solution of 3-acetyl-7-(benzyloxy)-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)indolizine-l -carboxamide (1-12) (0.1 g, 0.16 mmol) in 2 mL of THF was added 2 mL of 1 M LiOH solution. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified with 1 M HCl solution to pH = 3. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), dried over Na2S04, filtered and concentrated. The residue was purified by preparative HPLC to give 3-acetyl-7-(benzyloxy)-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)indolizine-l -carboxamide (1-13) (0.05 g, 0.09 mmol, 55% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 9.66 (d, J = 7.8 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.51 (d, J = 7.1 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 5.26 (s, 2H), 2.50 (s, 3H).

[0157] Step 10, synthesis of 3-acetyl-7-(benzyloxy)-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)indolizine-l -carboxamide (1-12)

[0158] To a solution of 2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2- yl)oxy)methyl)aniline (16 g, 52.5 mmol), 3-acetyl-7-(benzyloxy)indolizine-l-carboxylic acid (17.8 g, 57.7 mmol), CMPI (20.1 g, 78.7 mmol) and DIPEA (20.3 g, 157.4 mmol) in THF (300 mL) was added at 70 °C and stirred overnight. The organic solvent was removed by rotary evaporation, and 300 mL of water was added. The mixture was extracted with EA (3x300 mL), and the organic phase was combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (DCM:MeOH = 80: 1) to give 15 g of yellow solid in 48% yield. 1H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 8.56 (s, 1H), 8.17 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J = 7.0 Hz, 4H), 7.41 (t, J = 7.5 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.00 (dd, J = 7.7, 2.7 Hz, 1H), 5.24 (s, 2H), 4.70 (dd, J = 15.8, 7.7 Hz, 2H), 4.46 (d, J = 11.9 Hz, 1H), 3.91 (s, 3H), 3.86 - 3.80 (m, 1H), 3.51 (dd, J = 10.8, 5.4 Hz, 1H), 2.53 (s, 3H), 1.79 - 1.73 (m, 1H), 1.68 (t, J = 11.0 Hz, 1H), 1.58 - 1.47 (m, 4H).

[0159] Step 11, 3-acetyl-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2- yl)oxy)methyl)phenyl)-7-hydroxyindolizine-l-carboxamide (1-13)

[0160] To a solution of 3-acetyl-7-(benzyloxy)-N-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)indolizine-1-carboxamide QP204 (10 g, 16.8 mmol) and 5% palladium on carbon (7 g) in 300 mL of methanol, under H2condition, at room temperature for 16 h. The reaction mixture was filtered through a Buchner funnel and the organic solvent was evaporated and purified by column chromatography (DCM:MeOH = 50:1). 5 g of yellow solid was obtained with a yield of 59%.1H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.66 (d, J = 7.2 Hz, 2H), 8.51 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 7.2 Hz, 2H), 6.82 (dd, J = 7.6, 2.6 Hz, 1H), 4.70 (dd, J = 19.0, 7.8 Hz, 2H), 4.46 (d, J = 11.9 Hz, 1H), 3.91 (s, 3H), 3.87 - 3.80 (m, 1H), 3.51 (dd, J = 10.8, 5.4 Hz, 1H), 2.50 (s, 3H), 1.81 - 1.73 (m, 1H), 1.68 (t, J = 11.0 Hz, 1H), 1.54 (ddd, J = 17.5, 9.9, 6.3 Hz, 4H).

[0161] Step 12, synthesis of tert-butyl 2-((3-acetyl-1-((2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7- yl)oxy)acetate (1-15a)

[0162] To a solution of 3-acetyl-N-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)-7-hydroxyindolizine-1-carboxamide QP206 (2.0 g, 3.95 mmol), tert-butyl bromoacetate (925 mg, 4.74 mmol) and Cs2CO3(2.6 g, 7.91 mmol) in DMF, at 80 °C for 4 h. After the reaction was completed, the solvent was evaporated and purified by column chromatography to give 1.5 g of white solid with a yield of 61%.

[0163] tert-Butyl 2-((3-acetyl-l-((2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)azaindan-7-yl)oxy)acetate (1.5 g, 4.51 mmol) and 3 mL of TFA were added to 3 mL of DCM and reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated, and column chromatography was performed (DCM:MeOH = 50:1) to isolate the product. This resulted in 0.8 g of a white solid, with a yield of 69%.1H NMR (500 MHz, DMSO) δ 9.72 (s, 1H), 9.68 (d, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.47 (dd, J = 25.3, 5.9 Hz, 2H), 6.98 (d, J = 5.9 Hz, 1H), 5.28 (s, 1H), 4.83 (s, 2H), 4.52 (s, 2H), 3.91 (s, 3H), 2.53 (s, 3H).

[0164] The synthesis method of 1-14, 1-15b to 1-55f was performed with reference to 1-15a.

[0165] Example 1

[0166] Synthesis of 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4-yl)phenyl)azaindan-l-formamide

[0167] Step 1. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-l,3-dione

[0168] A 500 mL flask was charged with 4-fluorophthalic anhydride (5.6 g, 33.71 mmol, 1.0 eq), 3-amino-2,6-piperidine dione hydrochloride (6.10 g, 37.08 mmol, 1.1 eq), and sodium acetate (7.7 g, 94.39 mmol, 2.8 eq), and 100 mL of acetic acid was added. The mixture was reacted at 120°C overnight. After the reaction was completed, most of the acetic acid was removed by evaporation, and 400 mL of water was added to the residue. A large amount of solid was precipitated, and after standing for 10 minutes, the solid was filtered, washed with water, and dried to obtain 7.6 g of a gray solid, 2-1, with a yield of 82%. 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.00 (dd, J = 8.4, 4.4 Hz, 1H), 7.84 (dd, J = 2.4, 7.2 Hz, 1H), 7.75 - 7.68 (m, 1H), 5.16 (dd, J = 12.8, 5.2 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.66 - 2.52 (m, 2H), 2.14 - 2.02 (m, 1H).

[0169] Step 2, synthesis of 5-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

[0170] 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (6 g, 21.74 mmol), N-tert- butoxycarbonyl-1,2-ethanediamine (3.8 g, 23.91 mmol) and DIPEA (5.6 g, 43.48 mmol) were added into DMF and reacted at 80 °C overnight. The solvent was rotary evaporated and purified by column chromatography (PE:EA = 1:1) to give 700 mg of compound 1 as green solid with a yield of 7%. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.13 (t, J = 5.9 Hz, 1H), 6.97 (s, 1H), 6.91 (t, J = 5.6 Hz, 1H), 6.86 (dd, J = 8.5, 2.2 Hz, 1H), 5.03 (dd, J = 12.7, 5.4 Hz, 1H), 3.23 (q, J = 6.4 Hz, 2H), 3.10 (q, J = 6.5 Hz, 2H), 2.87 (ddd, J = 16.5, 13.7, 5.4 Hz, 1H), 2.61 - 2.52 (m, 2H), 2.01 - 1.96 (m, 1H), 1.37 (s, 9H).

[0171] Step 3, synthesis of 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0172] To a solution of 2-((3-acetyl-l-((2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)carbamoyl)indolizin-7-yl)oxy)acetic acid (62 mg, 0.13 mmol), 5- ((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (43 mg, 0.14 mmol), HATU (49 mg 0.13 mmol) and DIPEA (33 mg, 0.26 mmol) in DMF was added and stirred at room temperature for 4 h. After completion of the reaction, the solvent was evaporated and purified by column chromatography to get 51 mg of green solid in 49% yield. MS (ESI), m / z for C 39 H 35 FN8O9([M+H] + ) calcd, 778.25; found, 801.5. HPLC analysis: MeOH-H20 (80:20), 4.50 min, 95.34% purity. NMR missing

[0173] Example 2

[0174] Synthesis of 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)propyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l-formamide

[0175] The synthesis was carried out by following the procedure of Example 1.

[0176] Step 1, Synthesis of 5-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

[0177] Green solid in 5% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 7.77 (s, 2H), 7.59 (d, J = 8.3 Hz, 1H), 7.17 (s, 1H), 6.98 (s, 1H), 6.88 (dd, J = 8.4, 1.6 Hz, 1H), 5.03 (dd, J = 12.7, 5.4 Hz, 1H), 3.27 (dd, J = 12.7, 6.6 Hz, 2H), 2.90 (d, J = 6.6 Hz, 3H), 2.65 - 2.54 (m, 2H), 2.05 - 1.96 (m, 1H), 1.90 - 1.78 (m, 2H).

[0178] Step 2, synthesis of 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)propyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4- yl)phenyl)indolizine-1-carboxamide

[0179] Green solid, yield 60%. 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.83 - 9.63 (m, 2H), 8.56 (s, 1H), 8.35 (t, J = 5.4 Hz, 1H), 8.15 (s, 1H), 7.94 - 7.80 (m, 2H), 7.57 - 7.41 (m, 3H), 7.09 - 6.92 (m, 2H), 6.87 (s, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.30 (s, 1H), 5.02 (dd, J = 12.7, 5.3 Hz, 1H), 4.66 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H), 3.25 (d, J = 5.9 Hz, 2H), 3.13 (d, J = 5.4 Hz, 2H), 2.96 - 2.81 (m, 1H), 2.64 - 2.53 (m, 2H), 2.51 (s, 3H), 2.08 - 1.94 (m, 1H), 1.80 - 1.67 (m, 2H).

[0180] Example 3

[0181] Synthesis of 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)- 4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0182] The synthesis method refers to the synthesis of Example 1.

[0183] Step 1, synthesis of 4-((3-acetyl-1-((2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4- yl)phenyl)carbamoyl)indolizin-7-yl)oxy)butanoic acid

[0184] Step 1, Synthesis of 3-acetyl-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)-7-hydroxyindolizine-l-carboxamide QP206 To a solution of 3-acetyl-N-(2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)-7-hydroxyindolizine-l-carboxamide QP206 (4.3 g, 8.5 mmol), 4-bromobutanoic acid tert-butyl ester (2.27 g, 10.2 mmol) and Cs2CO3(5.52 g, 17.0 mmol) in DMF was added and reacted at 80 °C for 4 h. After completion of the reaction, the solvent was evaporated and purified by column chromatography to give 3.8 g of yellow solid in 69% yield. To a solution of 4-((3-acetyl-l-((2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7-yl)oxy)butanoic acid tert-butyl ester (3.8 g, 5.86 mmol) and 3 mL of TFA was added to 3 mL of DCM and reacted at room temperature overnight. After completion of the reaction, the solvent was evaporated and purified by column chromatography (DCM:MeOH = 50:1) to give 2.0 g of yellow solid in 67% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 9.65 (d, J = 7.7 Hz, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.67 (t, J = 6.8 Hz, 2H), 6.93 (dd, J = 7.7, 2.8 Hz, 1H), 5.44 (s, 2H), 4.11 (t, J = 6.4 Hz, 2H), 3.92 (s, 3H), 2.53 (s, 3H), 2.42 (t, J = 7.3 Hz, 2H), 2.07 - 1.93 (m, 2H).

[0185] Step 2, Synthesis of 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l-carboxamide

[0186] Green solid, 62% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.74 (s, 1H), 9.63 (d, J = 7.7 Hz, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.44 (d, J = 5.5 Hz, 1H), 7.16 (s, 1H), 6.96 (s, 1H), 6.90 (dd, J = 7.7, 2.6 Hz, 1H), 6.84 (dd, J = 8.4, 1.6 Hz, 1H), 5.31 (s, 1H), 5.03 (dd, J = 12.7, 5.4 Hz, 1H), 4.51 (s, 2H), 4.09 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.63 - 3.55 (m, 2H), 3.11 (dd, J = 14.5, 7.2 Hz, 2H), 2.92 - 2.80 (m, 1H), 2.67 - 2.53 (m, 2H), 2.52 (s, 3H), 2.29 (t, J = 7.2 Hz, 2H), 2.06 - 1.98 (m, 3H).

[0187] Example 4

[0188] Synthesis of 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)propyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l-carboxamide

[0189] Synthesis method refers to Example 1, green solid, yield 64%. 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.70 (s, 1H), 9.63 (d, J = 7.3 Hz, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.86 (d, J = 18.7 Hz, 2H), 7.53 - 7.38 (m, 3H), 7.05 (s, 1H), 6.90 (s, 2H), 6.79 (d, J = 7.9 Hz, 1H), 5.28 (s, 1H), 5.01 (d, J = 8.5 Hz, 1H), 4.51 (s, 2H), 4.10 (s, 2H), 3.90 (s, 3H), 3.17 (s, 4H), 2.85 (d, J = 13.2 Hz, 1H), 2.67 - 2.55 (m, 2H), 2.52 (s, 3H), 2.29 (s, 2H), 2.01 (s, 3H), 1.70 (s, 2H).

[0190] Example 5

[0191] Synthesis of 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0192] The synthesis method refers to Example 1.

[0193] Step 1, Synthesis of 5-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

[0194] Green solid, yield 5%. 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.74 (s, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 5.3 Hz, 1H), 6.96 (d, J = 1.5 Hz, 1H), 6.86 (dd, J = 8.4, 1.9 Hz, 1H), 5.03 (dd, J = 12.8, 5.4 Hz, 1H), 3.20 (d, J = 5.4 Hz, 2H), 2.93 - 2.87 (m, 1H), 2.85 - 2.79 (m, 2H), 2.66 - 2.53 (m, 2H), 2.05 - 1.94 (m, 1H), 1.66 - 1.58 (m, 4H).

[0195] Step 2, synthesis of 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0196] Green solid, yield 58%. 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.77 (s, 1H), 9.61 (d, J = 7.7 Hz, 1H), 8.59 (s, 1H), 8.11 (s, 1H), 7.94 (t, J = 5.3 Hz, 1H), 7.89 - 7.75 (m, 2H), 7.55 - 7.35 (m, 3H), 7.13 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 7.2 Hz, 2H), 6.76 (d, J = 8.2 Hz, 1H), 5.32 (t, J = 5.7 Hz, 1H), 4.98 (dd, J = 12.7, 5.4 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.04 (t, J = 6.3 Hz, 2H), 3.86 (d, J = 8.2 Hz, 3H), 3.05 (dd, J = 13.4, 6.3 Hz, 4H), 2.89 - 2.77 (m, 1H), 2.61 - 2.52 (m, 2H), 2.51 (s, 3H), 2.23 (t, J = 7.2 Hz, 2H), 1.95 (dd, J = 13.5, 6.4 Hz, 3H), 1.64 - 1.33 (m, 4H).

[0197] Example 6

[0198] Synthesis of 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0199] Synthesis method refers to Example 1.

[0200] Step 1, synthesis of 5-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0201] Green solid, yield 6%. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.71 (s, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 4.9 Hz, 1H), 6.94 (s, 1H), 6.84 (dd, J = 8.4, 1.8 Hz, 1H), 5.02 (dd, J = 12.8, 5.4 Hz, 1H), 3.19 - 3.13 (m, 2H), 2.93 - 2.84 (m, 1H), 2.78 (dd, J = 13.5, 6.6 Hz, 2H), 2.66 - 2.55 (m, 2H), 2.04 - 1.95 (m, 1H), 1.61 - 1.51 (m, 4H), 1.41 - 1.32 (m, 4H).

[0202] Step 2, synthesis of 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)hexyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l -carboxamide

[0203] Green solid, yield 58%. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.74 (s, 1H), 9.64 (d, J = 7.7 Hz, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 20.2 Hz, 3H), 7.52 (t, J = 8.2 Hz, 2H), 7.44 (d, J = 5.5 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 2H), 6.79 (d, J = 8.1 Hz, 1H), 5.32 (s, 1H), 5.02 (dd, J = 12.5, 5.1 Hz, 1H), 4.51 (s, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.72 - 3.55 (m, 2H), 3.07 (ddd, J = 26.5, 14.4, 6.5 Hz, 6H), 2.97 - 2.79 (m, 1H), 2.61 (d, J = 25.2 Hz, 2H), 2.51 (s, 3H), 2.26 (t, J = 6.6 Hz, 2H), 1.99 (s, 3H), 1.49 (d, J = 6.7 Hz, 2H), 1.37 (d, J = 6.4 Hz, 2H).

[0204] Example 7

[0205] Synthesis of 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)octyl)amino]-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0206] The synthesis method is referred to Example 1.

[0207] Step 1, Synthesis of 5-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione

[0208] Green solid, yield 5%. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.68 (s, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.13 (d, J = 5.3 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.02 (dd, J = 12.8, 5.4 Hz, 1H), 3.20 - 3.08 (m, 2H), 2.94 - 2.85 (m, 1H), 2.81 - 2.70 (m, 2H), 2.67 - 2.54 (m, 2H), 2.04 - 1.94 (m, 1H), 1.58 - 1.48 (m, 4H), 1.41 - 1.21 (m, 8H).

[0209] Step 2, Synthesis of 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)octyl)amino]-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0210] Green solid, yield 47%. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.74 (s, 1H), 9.63 (s, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.86 (d, J = 22.7 Hz, 3H), 7.52 (s, 2H), 7.44 (d, J = 5.2 Hz, 1H), 7.08 (s, 1H), 6.90 (s, 2H), 6.79 (d, J = 7.6 Hz, 1H), 5.35 (s, 1H), 5.17 - 4.99 (m, 1H), 4.51 (s, 2H), 4.07 (s, 2H), 4.03 - 3.90 (m, 3H), 3.59 (d, J = 6.0 Hz, 4H), 3.21 - 3.05 (m, 6H), 3.01 (d, J = 5.4 Hz, 2H), 2.87 (t, J = 12.8 Hz, 1H), 2.68 - 2.53 (m, 2H), 2.51 (s, 3H), 2.25 (s, 2H), 1.98 (d, J = 5.0 Hz, 3H), 1.49 (s, 2H), 1.34 (s, 2H).

[0211] Example 8

[0212] Synthesis of 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)butyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l -carboxamide

[0213] The synthesis method is referenced to Example 1.

[0214] Green solid, yield 35%. 1H NMR (500 MHz, DMSO-de) δ 11.08 (s, 1H), 9.75 (s, 1H), 9.69 (d, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 11.7 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 5.7 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.90 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 5.03 (dd, J = 12.7, 5.2 Hz, 1H), 4.65 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H), 3.15 (d, J = 37.2 Hz, 4H), 2.88 (t, J = 12.7 Hz, 1H), 2.65 - 2.55 (m, 2H), 2.53 (s, 3H), 1.99 (s, 1H), 1.55 (s, 4H). MS (ESI), m / z for C 41 H 39 FN8O9([M+H] + ) calcd, 806.28; found, 829.3. HPLC analysis: MeOH-H20 (80:20), 4.46 min, 95.32% purity.

[0215] Example 9

[0216] Synthesis of 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l-formamide

[0217] Synthetic procedure refers to Example 1.

[0218] Step 1, Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione

[0219] Grey solid, yield = 87%. 1 H NMR (500 MHz, DMSO-de) δ 11.08 (s, 1H), 9.75 (s, 1H), 9.69 (d, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 11.7 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 7.44 (d, J = 5.7 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.90 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.33 (s, 1H), 5.03 (dd, J = 12.7, 5.2 Hz, 1H), 4.65 (s, 2H), 4.51 (s, 2H), 3.90 (s, 3H), 3.15 (d, J = 37.2 Hz, 4H), 2.88 (t, J = 12.7 Hz, 1H), 2.65 - 2.55 (m, 2H), 2.53 (s, 3H), 1.99 (s, 1H), 1.55 (s, 4H). MS (ESI), m / z for C

[0220] Step 2, synthesis of 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

[0221] Green solid, yield 30%. 1 HNMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.90 (s, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 7.0 Hz, 1H), 6.84 (t, J = 6.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 3.58 (d, J = 5.6 Hz, 2H), 2.99 (s, 2H), 2.95 - 2.86 (m, 1H), 2.66 - 2.55 (m, 2H), 2.02 (dd, J = 8.9, 3.8 Hz, 1H).

[0222] Step 3, synthesis of 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0223] Yellow solid, yield 12%. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.72 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 8.55 (s, 2H), 8.14 (s, 1H), 7.86 (d, J = 16.0 Hz, 2H), 7.61 - 7.37 (m, 3H), 7.13 (d, J = 8.6 Hz, 1H), 6.98 (t, J = 6.6 Hz, 2H), 6.71 (s, 1H), 5.32 (s, 1H), 5.03 - 4.93 (m, 1H), 4.64 (s, 2H), 4.50 (d, J = 4.4 Hz, 2H), 3.90 (s, 3H), 3.65 - 3.53 (m, 2H), 3.12 (d, J = 6.8 Hz, 2H), 2.86 (t, J = 13.0 Hz, 1H), 2.67 - 2.54 (m, 2H), 2.52 (s, 3H), 2.00 (d, J = 6.6 Hz, 1H).

[0224] Example 10

[0225] Synthesis of 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)propyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0226] The synthesis method is referred to Example 1.

[0227] Step 1, Synthesis of 4-((3-aminopropyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

[0228] Green solid, yield 32%. 1 HNMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.68 (s, 2H), 7.65 - 7.53 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.75 (t, J = 6.3 Hz, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 3.40 (d, J = 6.3 Hz, 2H), 2.95 - 2.84 (m, 3H), 2.65 - 2.56 (m, 2H), 2.07 - 2.00 (m, 1H), 1.89 - 1.78 (m, 2H).

[0229] Step 2, Synthesis of 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)propyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0230] Yellow solid, yield 47%. 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.86 - 9.63 (m, 2H), 8.56 (s, 1H), 8.40 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.63 - 7.34 (m, 3H), 7.12 - 6.90 (m, 3H), 6.62 (s, 1H), 5.32 (s, 1H), 5.09 - 4.95 (m, 1H), 4.66 (s, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 3.25 (dd, J = 24.0, 5.1 Hz, 4H), 2.85 (t, J = 12.9 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.52 (s, 3H), 1.99 (s, 1H), 1.71 (s, 2H).

[0231] Example 11

[0232] Synthesis of 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)ethyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l -carboxamide

[0233] The synthesis method is referred to Example 2.

[0234] Yellow solid, yield 35%. 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.86 - 9.63 (m, 2H), 8.56 (s, 1H), 8.40 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.63 - 7.34 (m, 3H), 7.12 - 6.90 (m, 3H), 6.62 (s, 1H), 5.32 (s, 1H), 5.09 - 4.95 (m, 1H), 4.66 (s, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 3.25 (dd, J = 24.0, 5.1 Hz, 4H), 2.85 (t, J = 12.9 Hz, 1H), 2.64 - 2.53 (m, 2H), 2.52 (s, 3H), 1.99 (s, 1H), 1.71 (s, 2H).

[0235] Example 12

[0236] Synthesis of 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)propyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0237] Synthetic Procedure Refer to Example 1.

[0238] Green solid, yield 52%.1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.75 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.90 (s, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 18.1, 5.9 Hz, 2H), 7.15 (s, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.31 (s, 1H), 5.04 (d, J = 13.0 Hz, 1H), 4.78 (s, 1H), 4.52 (d, J = 4.6 Hz, 2H), 3.92 (s, 3H), 3.78 - 3.58 (m, 6H), 3.47 (d, J = 5.0 Hz, 2H), 3.14 (s, 2H), 2.83 (d, J = 17.3 Hz, 1H), 2.71 - 2.57 (m, 2H), 2.56 - 2.51 (m, 5H), 2.00 (s, 3H), 1.63 (d, J = 43.5 Hz, 2H).

[0239] Example 13

[0240] Synthesis of 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0241] Synthetic Procedure Refer to Example 1.

[0242] Step 1, Synthesis of 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione

[0243] Green solid, yield 41%. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.74 (s, 2H), 7.65 - 7.51 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.62 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.36 (d, J = 6.3 Hz, 2H), 2.94 - 2.87 (m, 1H), 2.85 - 2.76 (m, 2H), 2.67 - 2.53 (m, 2H), 2.09 - 1.97 (m, 1H), 1.61 (s, 4H).

[0244] Step 2, synthesis of 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l -carboxamide

[0245] Green solid, yield 55%. 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.71 (s, 1H), 9.63 (d, J = 7.6 Hz, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 7.88 (t, J = 24.5 Hz, 3H), 7.51 (t, J = 7.6 Hz, 2H), 7.44 (d, J = 6.0 Hz, 1H), 6.99 (dd, J = 21.6, 7.8 Hz, 2H), 6.89 (d, J = 7.4 Hz, 1H), 6.45 (s, 1H), 5.32 (s, 1H), 5.03 (dd, J = 12.7, 5.3 Hz, 1H), 4.51 (s, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.23 (d, J = 6.2 Hz, 2H), 3.08 (d, J = 5.9 Hz, 2H), 2.91 - 2.81 (m, 1H), 2.59 (t, J = 17.5 Hz, 2H), 2.50 (s, 3H), 2.26 (t, J = 6.9 Hz, 2H), 2.08 - 1.96 (m, 3H), 1.52 (d, J = 6.9 Hz, 2H), 1.45 (d, J = 6.8 Hz, 2H).

[0246] Example 14

[0247] Synthesis of 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)hexyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0248] Synthetic procedure refers to Example 1, yellow solid, yield 48%. 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.72 (s, 1H), 9.64 (d, J = 7.7 Hz, 1H), 8.55 (s, 1H), 8.14 (s, 1H), 8.02 - 7.78 (m, 3H), 7.52 (dd, J = 16.4, 8.1 Hz, 2H), 7.44 (d, J = 5.5 Hz, 1H), 7.10 - 6.94 (m, 2H), 6.94 - 6.82 (m, 1H), 6.45 (s, 1H), 5.32 (s, 1H), 5.03 (dd, J = 12.8, 5.1 Hz, 1H), 4.51 (s, 2H), 4.07 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.63 - 3.57 (m, 2H), 3.20 (d, J = 6.3 Hz, 2H), 3.12 (d, J = 7.3 Hz, 2H), 3.02 (d, J = 6.0 Hz, 2H), 2.93 - 2.81 (m, 1H), 2.60 (t, J = 18.9 Hz, 2H), 2.50 (s, 3H), 2.25 (t, J = 7.1 Hz, 1H), 2.00 (dd, J = 13.0, 6.6 Hz, 3H), 1.55 - 1.45 (m, 2H), 1.41 - 1.32 (m, 2H).

[0249] Example 15

[0250] Synthesis of 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)octyl)amino]-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0251] Synthetic procedure refers to Example 2, yellow solid, yield 44%. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.73 (s, 1H), 9.65 (s, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.87 (d, J = 18.6 Hz, 3H), 7.53 (d, J = 18.2 Hz, 2H), 7.44 (s, 1H), 7.11 - 6.95 (m, 2H), 6.91 (s, 1H), 6.47 (s, 1H), 5.32 (s, 1H), 5.03 (d, J = 12.1 Hz, 1H), 4.51 (s, 2H), 4.07 (s, 2H), 3.90 (s, 3H), 3.60 (s, 6H), 3.23 (s, 2H), 3.12 (d, J = 5.8 Hz, 2H), 3.00 (s, 2H), 2.87 (s, 1H), 2.76 - 2.55 (m, 2H), 2.50 (s, 3H), 2.25 (s, 2H), 1.99 (s, 3H), 1.49 (s, 2H), 1.34 (s, 2H).

[0252] Example 16

[0253] Synthesis of 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)butyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH- pyrazol-4-yl)phenyl)indolizine-l-formamide

[0254] Synthesis method refers to Example 1, green solid, yield 65%. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.70 (s, 1H), 9.68 (d, J = 7.7 Hz, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.13 (s, 1H), 7.86 (d, J = 14.6 Hz, 2H), 7.50 (dd, J = 13.5, 6.4 Hz, 2H), 7.43 (d, J = 5.8 Hz, 1H), 7.00 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 7.0 Hz, 1H), 6.46 (s, 1H), 5.30 (s, 1H), 5.03 (dd, J = 12.7, 5.3 Hz, 1H), 4.64 (s, 2H), 4.50 (s, 2H), 3.90 (s, 3H), 3.23 (d, J = 5.7 Hz, 2H), 3.17 (d, J = 5.7 Hz, 2H), 2.93 - 2.82 (m, 1H), 2.60 (t, J = 18.8 Hz, 2H), 2.51 (s, 3H), 2.07 - 1.94 (m, 1H), 1.52 (s, 4H).

[0255] Example 17

[0256] Synthesis of 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0257] The synthesis method refers to Example 1.

[0258] Step 1, Synthesis of tert-butyl 4-((3-acetyl-1-((2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5- (((tetrahydro-2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7-yl)oxy)piperidine- 1-carboxylate

[0259] tert-Butyl 4-((3-acetyl-1-((2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro-2H- pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7-yl)oxy)piperidine-1-carboxylate (1.00 g, 1.62 mmol) was dissolved in THF (10 mL) and cooled to 0 °C. LiBH4 (0.1 mL, 2.43 mmol) was added dropwise and the reaction was stirred at 0 °C for 1 h. The reaction was quenched with water and the solvent was removed. The residue was purified by column chromatography to give 600 mg of white solid with a yield of 60%.

[0260] Step 2, synthesis of 3-acetyl-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)-7-(piperidin-4-yloxy)indolizine-1-carboxamide

[0261] tert-Butyl 4-((3-acetyl-1-((2-fluoro-3-(1-methyl-1H-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7-yl)oxy)piperidine-1- carboxylate (600 mg, 0.87 mmol) and 3 mL of TFA were added to 3 mL of DCM and reacted at room temperature overnight. After the reaction was completed, the solvent was evaporated and separated by column chromatography (DCM:MeOH = 50:1). 350 mg of white solid was obtained with a yield of 69%. 1 H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.69 (d, J = 7.7 Hz, 1H), 8.58 (s, 1H), 8.14 (s, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 7.46 (dd, J = 17.4, 6.6 Hz, 2H), 6.97 (dd, J = 7.7, 2.8 Hz, 1H), 5.30 (s, 1H), 4.98 - 4.79 (m, 1H), 4.51 (s, 2H), 3.91 (s, 3H), 3.27 (s, 2H), 3.17 (s, 2H), 2.53 (s, 3H), 2.20 - 2.14 (m, 2H), 1.97 - 1.85 (m, 2H).

[0262] Step 3, synthesis of 3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)propanoic acid

[0263] Yellow solid, yield 4%. 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 5.4 Hz, 1H), 7.00 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 3.64 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 5.3 Hz, 2H), 3.45 - 3.40 (m, 2H), 2.97 - 2.80 (m, 1H), 2.69 - 2.54 (m, 2H), 2.46 (t, J = 6.3 Hz, 2H), 2.07 - 1.94 (m, 1H).

[0264] Step 4, synthesis of 3-acetyl-7-((l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2- fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4-yl)phenyl)indolizine-l- carboxamide

[0265] Green solid, yield 52%. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.75 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.90 (s, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 18.1, 5.9 Hz, 2H), 7.15 (s, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.31 (s, 1H), 5.04 (d, J = 13.0 Hz, 1H), 4.78 (s, 1H), 4.52 (d, J = 4.6 Hz, 2H), 3.92 (s, 3H), 3.78 - 3.58 (m, 6H), 3.47 (d, J = 5.0 Hz, 2H), 3.14 (s, 2H), 2.83 (d, J = 17.3 Hz, 1H), 2.71 - 2.57 (m, 2H), 2.56 - 2.51 (m, 5H), 2.00 (s, 3H), 1.63 (d, J = 43.5 Hz, 2H).

[0266] Example 18

[0267] Synthesis of 3-acetyl-7-((l-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2- fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4-yl)phenyl)indolizine-l- carboxamide

[0268] Synthetic procedure is referenced to Example 1.

[0269] Step 1, synthesis of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoic acid

[0270] Yellow solid, yield 4%. 1HNMR (500 MHz, DMSO-d6) δ 12.17 (s, 1H), 11.04 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.12 (t, J = 5.5 Hz, 1H), 7.00 (s, 1H), 6.90 (dd, J = 8.4, 1.9 Hz, 1H), 5.02 (dd, J = 12.7, 5.4 Hz, 1H), 3.59 (dd, J = 8.0, 4.6 Hz, 4H), 3.55 - 3.48 (m, 4H), 3.45 - 3.40 (m, 2H), 2.93 - 2.81 (m, 1H), 2.67 - 2.53 (m, 2H), 2.46-2.38 (m, 2H), 2.05 - 1.95 (m, 1H).

[0271] Step 2, synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5- (hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0272] Green solid, yield 50%. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.75 (s, 1H), 9.66 (d, J = 7.7 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 3.3 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 19.3, 6.4 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 5.31 (t, J = 5.2 Hz, 1H), 5.05 (dd, J = 12.8, 5.3 Hz, 1H), 4.78 (s, 1H), 4.52 (d, J = 5.1 Hz, 2H), 3.93 (d, J = 13.2 Hz, 3H), 3.86 - 3.50 (m, 10H), 3.46 (d, J = 5.4 Hz, 2H), 3.13 (s, 2H), 2.87 (t, J = 12.6 Hz, 1H), 2.67 - 2.57 (m, 2H), 2.56 - 2.51 (m, 5H), 2.06 - 1.91 (m, 3H), 1.63 (dd, J = 52.0, 8.3 Hz, 2H).

[0273] Example 19

[0274] Synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0275] The synthesis method is referred to Example 1.

[0276] Step 1, 3-(2-(2-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy) methoxy)propanoic acid yellow solid, yield 5%. 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 5.5 Hz, 1H), 7.01 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.58 (m, 4H), 3.57 - 3.52 (m, 4H), 3.51 - 3.47 (m, 6H), 2.94 - 2.84 (m, 1H), 2.62 - 2.57 (m, 2H), 2.41 (t, J = 6.2 Hz, 2H), 2.05 - 1.94 (m, 1H).

[0277] Step 2, Synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0278] Green solid, yield 48%. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.75 (s, 1H), 9.67 (d, J = 7.8 Hz, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 7.91 (d, J = 6.3 Hz, 2H), 7.74 - 7.54 (m, 1H), 7.48 (d, J = 17.7 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.33 (s, 1H), 5.06 (d, J = 13.1 Hz, 1H), 4.79 (s, 1H), 4.52 (d, J = 4.6 Hz, 2H), 3.91 (s, 3H), 3.85 - 3.48 (m, 16H), 3.14 (s, 2H), 2.99 - 2.83 (m, 1H), 2.69 - 2.56 (m, 7H), 1.99 (d, J = 19.1 Hz, 3H), 1.63 (d, J = 55.0 Hz, 2H).

[0279] Example 20

[0280] Synthesis of 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0281] The synthesis method refers to Example 1.

[0282] Synthesis of 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0283] 50 mg of green solid, yield 77%. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.75 (s, 1H), 9.67 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 7.90 (s, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (dd, J = 18.1, 5.9 Hz, 2H), 7.15 (s, 1H), 7.02 (d, J = 6.7 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.31 (s, 1H), 5.04 (d, J = 13.0 Hz, 1H), 4.78 (s, 1H), 4.52 (d, J = 4.6 Hz, 2H), 3.92 (s, 3H), 3.78 - 3.58 (m, 6H), 3.47 (d, J = 5.0 Hz, 2H), 3.14 (s, 2H), 2.83 (d, J = 17.3 Hz, 1H), 2.71 - 2.57 (m, 2H), 2.56 - 2.51 (m, 5H), 2.00 (s, 3H), 1.63 (d, J = 43.5 Hz, 2H).

[0284] Example 21

[0285] Synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0286] The synthesis method refers to Example 1.

[0287] Step 1, synthesis of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoic acid.

[0288] The synthesis method refers to Example 1, yellow solid, yield 7%. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 7.58 (dd, J = 8.3, 7.3 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.2 Hz, 1H), 5.04 (dd, J = 12.7, 5.4 Hz, 1H), 3.60 (dd, J = 12.8, 6.1 Hz, 4H), 3.58 - 3.48 (m, 4H), 3.46 (dd, J = 10.7, 5.3 Hz, 2H), 2.95 - 2.84 (m, 1H), 2.66 - 2.55 (m, 2H), 2.42 (t, J = 6.3 Hz, 2H), 2.08 - 1.98 (m, 1H).

[0289] Step 2, synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5- (hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0290] Yellow solid, yield 38%.1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.75 (s, 1H), 9.66 (d, J = 7.7 Hz, 1H), 8.58 (s, 1H), 8.16 (s, 1H), 7.90 (d, J = 3.3 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.48 (dd, J = 19.3, 6.4 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 5.31 (t, J = 5.2 Hz, 1H), 5.05 (dd, J = 12.8, 5.3 Hz, 1H), 4.78 (s, 1H), 4.52 (d, J = 5.1 Hz, 2H), 3.93 (d, J = 13.2 Hz, 3H), 3.86 - 3.50 (m, 10H), 3.46 (d, J = 5.4 Hz, 2H), 3.13 (s, 2H), 2.87 (t, J = 12.6 Hz, 1H), 2.67 - 2.57 (m, 2H), 2.56 - 2.51 (m, 5H), 2.06 - 1.91 (m, 3H), 1.63 (dd, J = 52.0, 8.3 Hz, 2H).

[0291] Example 22

[0292] Synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0293] Synthetic procedure refers to Example 1.

[0294] Step 1, Synthesis of 3-(2-(2-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)ethoxy)propanoic acid

[0295] Yellow solid, yield 9%. 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.78 - 7.37 (m, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.63 - 3.57 (m, 4H), 3.57 - 3.51 (m, 4H), 3.50 - 3.45 (m, 6H), 2.93 - 2.81 (m, 1H), 2.66 - 2.56 (m, 2H), 2.41 (t, J = 6.3 Hz, 2H), 2.06 - 1.98 (m, 1H).

[0296] Example 23

[0297] Step 2, Synthesis of 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)ethoxy)propanoyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0298] 3-acetyl-7-(1-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- tetraoxypentadecan-15-yl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H- pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0299] Yellow solid, yield 50%. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.74 (s, 1H), 9.65 (d, J = 7.7 Hz, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.95 - 7.87 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 6.1 Hz, 1H), 7.45 (d, J = 5.8 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.57 (t, J = 5.4 Hz, 1H), 5.32 (s, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 4.78 (s, 1H), 4.51 (s, 2H), 3.90 (s, 3H), 3.86 - 3.41 (m, 20H), 3.12 (dd, J = 7.2, 4.2 Hz, 2H), 2.95 - 2.83 (m, 1H), 2.61 - 2.51 (m, 7H), 2.00 (dd, J = 24.2, 18.8 Hz, 3H), 1.63 (dd, J = 54.2, 8.1 Hz, 2H).

[0300] Example 24

[0301] 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0302] 4-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0303] Step 1, 3-Bromophthalic anhydride (5.6 g, 22.10 mmol), 3-amino-2,6-piperidinedione hydrochloride (4 g, 24.31 mmol,) and sodium acetate (5.4 g, 66.30 mmol,) were added to a flask, then 100 mL acetic acid was added, and the reaction was carried out at 120 °C overnight. After the reaction was completed, most of the acetic acid was removed by rotary evaporation, 400 mL water was added to the residue, and a large amount of solid was precipitated. After standing for 10 minutes, the filter cake was suction filtered and washed with water. After suction drying, the filter cake was collected and dried by rotary evaporation to obtain 7.5 g of gray solid with a yield of 100%. 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 5.17 (dd, J = 12.9, 5.4 Hz, 1H), 2.93 - 2.86 (m, 1H), 2.65 - 2.56 (m, 2H), 2.21 - 1.94 (m, 1H).

[0304] Step 2, 4-(3-Aminopropyl-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0305] 4-Bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, Pd(PPh3)2Cl2 (0.21 g, 0.30 mmol), and cuprous iodide (0.11 g, 0.60 mmol) were added to a flask. After vacuum pumping with an oil pump, 30 mL of DMF was added, followed by the addition of TEA (9.03 g, 89.29 mmol). The reaction was carried out at 80 °C overnight under N2 protection. After the reaction was completed, the solvent was dried by rotary evaporation, and column chromatography (PE:EA = 1:1) was used for separation and purification. 2.2 g of yellow solid was obtained with a yield of 90%.

[0306] The obtained yellow solid (2.2 g, 5.35 mmol) and 3 mL of TFA were added to 3 mL of DCM, and the reaction was carried out at room temperature overnight. After the reaction was completed, the solvent was dried by rotary evaporation, and column chromatography (DCM:MeOH = 20:1) was used for separation. 1.5 g of red solid was obtained with a yield of 90%. 1H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.44 (s, 2H), 8.00 (d, J = 6.5 Hz, 1H), 7.96 - 7.77 (m, 2H), 5.16 (dd, J = 12.8, 5.4 Hz, 1H), 4.22 (d, J = 62.2 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.69 - 2.54 (m, 2H), 2.13 - 2.00 (m, 1H).

[0307] Step 3, tert-butyl 2-((3-acetyl-l-((2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)azaindan-7-yl)oxy)acetate (60 (60 mg, 0.13 mmol), 4-(3-aminopropyl-l-yn-l-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (36 mg, 0.11 mmol), HATU (86 mg, 0.23 mmol) and DIPEA (59 mg, 0.45 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was spun down and purified by silica gel chromatography to obtain 40 mg of white solid with a yield of 45.51%. 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.72 (s, 1H), 9.64 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 16.7 Hz, 2H), 7.64 (q, J = 7.3 Hz, 2H), 7.55 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 6.3 Hz, 2H), 6.98 (d, J = 7.5 Hz, 1H), 5.45 (s, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 4.62 (s, 2H), 4.47 (s, 2H), 3.87 (s, 3H), 3.15 (d, J = 5.3 Hz, 2H), 3.01 - 2.90 (m, 2H), 2.88 - 2.77 (m, 1H), 2.59 (t, J = 19.7 Hz, 5H), 2.08 - 1.94 (m, 1H), 1.83 - 1.70 (m, 2H). Yellow solid, yield 48%.1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.75 (s, 1H), 9.70 (d, J = 7.7 Hz, 1H), 8.93 (t, J = 5.4 Hz, 1H), 8.59 (s, 2H), 8.15 (s, 1H), 7.90 - 7.82 (m, 2H), 7.78 (d, J = 5.1 Hz, 2H), 7.48 (d, J = 6.4 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.03 (dd, J = 7.6, 2.3 Hz, 1H), 5.33 (t, J = 5.1 Hz, 1H), 5.12 (dd, J = 12.8, 5.3 Hz, 1H), 4.73 (s, 2H), 4.50 (d, J = 4.5 Hz, 2H), 4.29 (d, J = 5.4 Hz, 2H), 3.90 (s, 3H), 2.93 - 2.81 (m, 1H), 2.67 - 2.56 (m, 2H), 2.53 (s, 3H), 2.08 - 2.01 (m, 1H).

[0308] Example 25

[0309] 3-acetyl-7-(4-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0310] Synthesis was similar to Example 24. Yellow solid, yield 27%. 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.73 (s, 1H), 9.61 (d, J = 7.7 Hz, 1H), 8.54 (s, 2H), 8.15 (s, 1H), 7.89 (s, 1H), 7.84 (dd, J = 10.1, 3.2 Hz, 2H), 7.77 (d, J = 3.5 Hz, 2H), 7.49 (d, J = 6.1 Hz, 1H), 7.44 (d, J = 5.8 Hz, 1H), 6.90 (dd, J = 7.7, 2.5 Hz, 1H), 5.33 (t, J = 5.6 Hz, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.51 (d, J = 5.2 Hz, 2H), 4.21 (d, J = 5.3 Hz, 2H), 4.10 (t, J = 6.1 Hz, 2H), 3.90 (s, 3H), 2.95 - 2.78 (m, 1H), 2.64 - 2.53 (m, 2H), 2.51 (s, 3H), 2.34 (t, J = 7.1 Hz, 2H), 2.08 - 2.00 (m, 3H).

[0311] Example 26

[0312] 3-acetyl-7-((5-((3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop-2-yn-l- yl)amino)-5-oxopentyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4-yl) phenyl)indolizine-l-carboxamide

[0313] Synthesis was similar to Example 24. Yellow solid, 38% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.74 (s, 1H), 9.64 (d, J = 7.7 Hz, 1H), 8.57 (s, 1H), 8.49 (t, J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.93 - 7.83 (m, 3H), 7.83 - 7.74 (m, 2H), 7.51 (d, J = 6.4 Hz, 1H), 7.45 (d, J = 5.5 Hz, 1H), 6.92 (dd, J = 7.7, 2.5 Hz, 1H), 5.32 (t, J = 5.7 Hz, 1H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 4.52 (d, J = 5.6 Hz, 2H), 4.21 (d, J = 5.4 Hz, 2H), 4.11 (t, J = 6.1 Hz, 2H), 3.91 (s, 3H), 2.92 - 2.80 (m, 1H), 2.72 - 2.56 (m, 2H), 2.53 (s, 3H), 2.23 (t, J = 7.1 Hz, 2H), 2.13 - 2.02 (m, 1H), 1.88 - 1.75 (m, 2H), 1.75 - 1.67 (m, 2H). MS (ESI), m / z for C43H38FN7O9 ([M+Na]+) calcd, 815.27; found, 838.26. HPLC analysis: MeOH-H2O (80:20), 7.18 min, 96.49% purity.

[0314] Example 27

[0315] 3-acetyl-7-((6-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)amino)-6- oxohexyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0316] Synthesis was similar to Example 24. Yellow solid, yield 38%. 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.74 (s, 1H), 9.61 (d, J = 7.7 Hz, 1H), 8.56 (s, 1H), 8.46 (dd, J = 10.1, 6.9 Hz, 2H), 8.15 (s, 1H), 7.89 (s, 1H), 7.84 - 7.78 (m, 3H), 7.54 - 7.47 (m, 1H), 7.45 (t, J = 5.7 Hz, 1H), 6.88 (dd, J = 7.7, 2.6 Hz, 1H), 5.33 (s, 1H), 5.12 (dd, J = 12.8, 5.3 Hz, 1H), 4.51 (s, 2H), 4.19 (d, J = 5.4 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 2.94 - 2.80 (m, 1H), 2.63 - 2.54 (m, 2H), 2.52 (s, 3H), 2.16 (t, J = 7.2 Hz, 2H), 2.07 - 2.00 (m, 1H), 1.82 - 1.72 (m, 2H), 1.63 - 1.57 (m, 2H), 1.46 - 1.40 (m, 2H).

[0317] Example 28

[0318] 3-acetyl-7-((7-(3-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)prop-2-yn-l- yl)amino)-7-oxoheptyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4- yl)phenyl)indolizine-l-carboxamide

[0319] Synthesis was similar to Example 24. Yellow solid, yield 38%. 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.72 (s, 1H), 9.62 (d, J = 7.7 Hz, 1H), 8.55 (s, 1H), 8.42 (t, J = 5.4 Hz, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.88 - 7.73 (m, 4H), 7.50 (d, J = 6.8 Hz, 1H), 7.44 (d, J = 5.6 Hz, 1H), 6.90 (dd, J = 7.7, 2.6 Hz, 1H), 5.32 (t, J = 5.7 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.19 (d, J = 5.4 Hz, 2H), 4.06 (t, J = 6.3 Hz, 2H), 3.90 (s, 3H), 2.94 - 2.79 (m, 1H), 2.65 - 2.54 (m, 2H), 2.52 (s, 3H), 2.13 (t, J = 7.3 Hz, 2H), 2.10 - 2.02 (m, 1H), 1.80 - 1.71 (m, 2H), 1.60 - 1.50 (m, 2H), 1.50 - 1.39 (m, 2H), 1.37 - 1.28 (m, 2H).

[0320] Example 29

[0321] 3-acetyl-7-((8-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)amino)-8- oxooctyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide

[0322] Synthesis was similar to Example 24. Yellow solid, 38% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.73 (s, 1H), 9.63 (d, J = 7.7 Hz, 1H), 8.56 (s, 1H), 8.40 (t, J = 5.4 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 9.8 Hz, 2H), 7.86 - 7.78 (m, 3H), 7.49 (d, J = 6.5 Hz, 1H), 7.44 (d, J = 5.5 Hz, 1H), 6.90 (dd, J = 7.6, 2.4 Hz, 1H), 5.31 (t, J = 5.7 Hz, 1H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.18 (d, J = 5.4 Hz, 2H), 4.06 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 2.92 - 2.82 (m, 1H), 2.65 - 2.56 (m, 2H), 2.52 (s, 3H), 2.12 (t, J = 7.3 Hz, 2H), 2.08 - 2.01 (m, 1H), 1.80 - 1.71 (m, 2H), 1.58 - 1.48 (m, 2H), 1.41 (dt, J = 14.4, 7.4 Hz, 2H), 1.36 - 1.26 (m, 4H). MS (ESI), m / z for C44H46FN7O9 ([M+Na]+) calcd, 857.32; found, 880.33. HPLC analysis: MeOH-H2O (80:20), 8.17 min, 95.62% purity.

[0323] Example 30

[0324] 3-acetyl-7-(2-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)- 2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0325] Step 1, 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0326] Dissolve 4-(3-aminopropyl-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione and 5% palladium on carbon (800 mg) in 30 mL of methanol. React at room temperature under H2condition for 24 h. After the reaction is completed, extract the reaction solution, collect the filtrate, spin dry the solvent, and separate by column chromatography (DCM:MeOH=20:1). Obtain 620 mg of red solid with a yield of 74%. 1HNMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.82 (q, J = 6.6 Hz, 4H), 7.73 (d, J = 8.0 Hz, 1H), 5.15 (dd, J = 12.8, 5.4 Hz, 1H), 3.09 (t, J = 7.6 Hz, 2H), 2.96 - 2.87 (m, 1H), 2.84 (s, 2H), 2.67 - 2.55 (m, 2H), 2.11 - 2.02 (m, 1H), 1.95 - 1.86 (m, 2H).

[0327] Step 2, tert-butyl 2-((3-acetyl-l-((2-fluoro-3-(l-methyl-lH-pyrazol-4-yl)-5-(((tetrahydro- 2H-pyrazol-2-yl)oxy)methyl)phenyl)carbamoyl)indolizin-7-yl)oxy)acetate (60 mg, 0.13 mmol), 4-(3-aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione (36 mg, 0.11 mmol), HATU (86 mg, 0.23 mmol) and DIPEA (59 mg, 0.45 mmol) were dissolved in DMF (2 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was evaporated and purified by silica gel chromatography to obtain 40 mg of white solid with a yield of 45.51%. 1 HNMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.72 (s, 1H), 9.64 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.83 (d, J = 16.7 Hz, 2H), 7.64 (q, J = 7.3 Hz, 2H), 7.55 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 6.3 Hz, 2H), 6.98 (d, J = 7.5 Hz, 1H), 5.45 (s, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 4.62 (s, 2H), 4.47 (s, 2H), 3.87 (s, 3H), 3.15 (d, J = 5.3 Hz, 2H), 3.01 - 2.90 (m, 2H), 2.88 - 2.77 (m, 1H), 2.59 (t, J = 19.7 Hz, 5H), 2.08 - 1.94 (m, 1H), 1.83 - 1.70 (m, 2H).

[0328] Example 31

[0329] 3-acetyl-7-(4-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)- 4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0330] Synthesis was similar to Example 30. White solid, 53% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.73 (s, 1H), 9.63 (d, J = 7.5 Hz, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.70 (s, 2H), 7.64 (s, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.44 (d, J = 4.9 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 5.31 (s, 1H), 5.10 (dd, J = 11.5, 3.5 Hz, 1H), 4.51 (s, 2H), 4.09 (s, 2H), 3.90 (s, 3H), 3.12 - 3.07 (m, 2H), 3.03 - 2.94 (m, 2H), 2.92 - 2.80 (m, 1H), 2.65 - 2.54 (m, 2H), 2.52 (s, 3H), 2.33 - 2.21 (m, 2H), 2.08 - 1.95 (m, 3H), 1.80 - 1.63 (m, 2H).

[0331] Example 32

[0332] 3-acetyl-7-((5-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)- 5-oxapentyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0333] Synthesis was similar to Example 30. White solid, 42% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.72 (s, 1H), 9.63 (d, J = 7.7 Hz, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.89 (s, 2H), 7.86 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 6.4 Hz, 2H), 7.67 (d, J = 6.2 Hz, 1H), 7.50 (d, J = 6.5 Hz, 1H), 7.44 (d, J = 5.7 Hz, 1H), 6.90 (dd, J = 7.6, 2.5 Hz, 1H), 5.30 (t, J = 5.7 Hz, 1H), 5.11 (dd, J = 12.7, 5.4 Hz, 1H), 4.51 (d, J = 5.6 Hz, 2H), 4.09 (t, J = 5.6 Hz, 2H), 3.90 (s, 3H), 3.07 (dd, J = 12.5, 6.4 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H), 2.95 - 2.82 (m, 1H), 2.69 - 2.55 (m, 2H), 2.52 (s, 3H), 2.14 (t, J = 7.1 Hz, 2H), 2.08 - 2.01 (m, 1H), 1.81 - 1.62 (m, 6H). MS (ESI), m / z for C43H42FN7O9 ([M+H]+) calcd, 819.30; found, 820.33. HPLC analysis: MeOH-H2O (80:20), 7.16 min, 98.97% purity.

[0334] Example 33

[0335] 3-acetyl-7-((6-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)- 6-oxohexyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0336] Synthesis was similar to Example 30. White solid, yield 50%. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.73 (s, 1H), 9.73 - 9.36 (m, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.87 - 7.81 (m, 2H), 7.70 (ddd, J = 23.3, 16.0, 7.2 Hz, 3H), 7.50 (d, J = 6.5 Hz, 1H), 7.44 (d, J = 5.7 Hz, 1H), 6.87 (dd, J = 7.6, 2.5 Hz, 1H), 5.30 (t, J = 5.5 Hz, 1H), 5.11 (dd, J = 12.6, 5.5 Hz, 1H), 4.51 (d, J = 5.2 Hz, 2H), 4.07 (t, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.07 (dd, J = 12.5, 6.3 Hz, 2H), 2.99 (t, J = 7.4 Hz, 2H), 2.92 - 2.81 (m, 1H), 2.67 - 2.54 (m, 2H), 2.52 (s, 3H), 2.08 (dd, J = 16.1, 8.9 Hz, 3H), 1.82 - 1.74 (m, 2H), 1.71 - 1.66 (m, 2H), 1.58 - 1.52 (m, 2H), 1.44 - 1.39 (m, 2H). MS (ESI), m / z for C44H44FN7O9 ([M+H]+) calcd, 833.32; found, 834.31. HPLC analysis: MeOH-H2O (80:20), 7.46 min, 94.85% purity.

[0337] Example 34

[0338] 3-acetyl-7-((7-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-7- oxoheptyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0339] Synthesis was similar to Example 30. White solid, yield 43%. 1H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.71 (s, 1H), 9.62 (d, J = 7.6 Hz, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.83 (d, J = 10.2 Hz, 2H), 7.71 (t, J = 7.4 Hz, 2H), 7.66 (d, J = 6.9 Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H), 7.44 (d, J = 5.8 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 5.30 (t, J = 5.4 Hz, 1H), 5.11 (dd, J = 12.8, 4.9 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.07 (t, J = 5.8 Hz, 2H), 3.90 (s, 3H), 3.06 (d, J = 6.1 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.94 - 2.82 (m, 1H), 2.65 - 2.55 (m, 2H), 2.52 (s, 3H), 2.06 (t, J = 7.2 Hz, 3H), 1.82 - 1.64 (m, 4H), 1.57 - 1.48 (m, 2H), 1.46 - 1.39 (m, 2H).

[0340] Example 35

[0341] 3-acetyl-7-((8-((3-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)propyl)amino)-8- oxooctyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(l-methyl-lH-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0342] Synthesis was similar to Example 30. White solid, 56% yield 1HNMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.72 (s, 1H), 9.63 (d, J = 7.5 Hz, 1H), 8.56 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.78 - 7.72 (m, 2H), 7.68 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 6.6 Hz, 1H), 7.44 (d, J = 5.9 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 5.29 (t, J = 5.5 Hz, 1H), 5.12 (dd, J = 12.6, 4.9 Hz, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.12 - 4.08 (m, 2H), 3.91 (s, 3H), 3.06 (d, J = 6.1 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.94 - 2.84 (m, 1H), 2.63 - 2.56 (m, 2H), 2.52 (s, 3H), 2.05 (t, J = 7.1 Hz, 3H), 1.79 - 1.67 (m, 4H), 1.54 - 1.45 (m, 2H), 1.45 - 1.38 (m, 2H), 1.36 - 1.28 (m, 4H).

[0343] Example 36

[0344] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0345] Synthesis was similar to Example 1. Yellow solid, 57% yield. 1HNMR (500 MHz, DMSO) δ 11.10 (s, 1H), 9.85 (s, 1H), 9.67 (d, J = 5.7 Hz, 1H), 8.66 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.72 (d, J = 24.5 Hz, 2H), 7.46 (s, 1H), 7.36 (s, 1H), 7.27 (d, J = 7.4 Hz, 2H), 6.97 (s, 1H), 5.09 (s, 1H), 5.02 (d, J = 19.1 Hz, 1H), 4.29 (s, 2H), 3.89 (s, 3H), 3.80 (s, 1H), 3.03 (s, 1H), 2.89 (s, 1H), 2.59 (d, J = 15.5 Hz, 2H), 2.52 (s, 3H), 2.35 (s, 3H), 2.05 (s, 2H), 1.77 (s, 4H), 1.65 (s, 2H), 1.00 (s, 1H).

[0346] Example 37

[0347] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0348] Synthesis was similar to Example 1.

[0349] Step 1, orange solid, 44% yield. 1 HNMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.87 (s, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.44 (dd, J = 19.2, 7.8 Hz, 2H), 5.11 (dd, J = 12.6, 5.3 Hz, 1H), 3.48 (s, 4H), 3.30 (s, 4H), 2.94 - 2.81 (m, 1H), 2.67 - 2.52 (m, 2H), 2.08 - 1.98 (m, 1H).

[0350] Step 2, 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1,3-dione, yellow solid, yield 57%. 1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.76 (s, 1H), 9.68 (d, J = 6.1 Hz, 1H), 8.59 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.43 (s, 2H), 7.35 (s, 1H), 7.24 (d, J = 6.9 Hz, 1H), 7.00 (s, 1H), 5.11 (s, 3H), 4.48 (s, 2H), 3.89 (s, 3H), 3.68 (s, 4H), 3.60 (s, 3H), 2.86 (d, J = 13.5 Hz, 1H), 2.59 (d, J = 18.9 Hz, 1H), 2.53 (s, 3H), 2.04 (s, 1H).

[0351] Example 38

[0352] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0353] The synthesis was similar to Example 1.

[0354] Step 1, synthesis of 4-(4-aminopiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, orange solid, yield 81%. 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.96 (d, J = 30.0 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 5.09 (dd, J = 12.7, 5.3 Hz, 1H), 3.72 (d, J = 12.3 Hz, 2H), 3.24 (s, 1H), 2.96 (t, J = 12.0 Hz, 2H), 2.93 - 2.82 (m, 1H), 2.66 - 2.53 (m, 2H), 2.10 - 1.95 (m, 3H), 1.80 - 1.68 (m, 2H).

[0355] Step 2, synthesis of 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide, yellow solid, yield 45%. 1 H NMR (500 MHz, DMSO) δ 11.08 (s, 1H), 9.74 (s, 1H), 9.69 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.44 (d, J = 6.2 Hz, 1H), 7.31 (dd, J = 15.0, 7.9 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.28 (t, J = 5.4 Hz, 1H), 5.09 (dd, J = 12.5, 5.3 Hz, 1H), 4.66 (s, 1H), 4.50 (d, J = 5.1 Hz, 1H), 3.89 (s, 2H), 3.62 (s, 2H), 3.19 - 3.07 (m, 1H), 2.98 (t, J = 10.8 Hz, 1H), 2.87 (t, J = 12.7 Hz, 1H), 2.68 - 2.54 (m, 1H), 2.54 (s, 1H), 2.08 - 1.99 (m, 1H), 1.86 (d, J = 9.6 Hz, 1H), 1.71 (dd, J = 22.5, 11.6 Hz, 1H).

[0356] Example 39

[0357] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide

[0358] Synthesis method similar to Example 1, yellow solid, yield 47%. 1H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 9.90 - 9.51 (m, 2H), 8.58 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.86 (d, J = 10.8 Hz, 2H), 7.60 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 6.5 Hz, 1H), 7.40 (d, J = 6.1 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 5.28 (s, 1H), 5.07 (dd, J = 12.7, 4.7 Hz, 1H), 4.68 (s, 2H), 4.48 (d, J = 4.2 Hz, 2H), 3.89 (s, 3H), 3.58 (d, J = 10.7 Hz, 3H), 3.07 (s, 15H), 2.85 (d, J = 12.7 Hz, 1H), 2.72 (s, 2H), 2.57 (d, J = 19.5 Hz, 1H), 2.54 - 2.48 (m, 11H), 2.01 (s, 2H), 1.73 (d, J = 11.1 Hz, 2H), 1.63 (s, 2H).

[0359] Example 40

[0360] 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide

[0361] The synthesis was similar to Example 1.

[0362] Step 1, synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-ylamino)isoindoline-1,3-dione, orange yellow solid, yield 50%. 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.76 (s, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.31 (d, J = 8.2 Hz, 1H), 5.08 (dd, J = 12.7, 5.4 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.06 (q, J = 10.3, 9.0 Hz, 2H), 2.97 - 2.84 (m, 1H), 2.65 - 2.54 (m, 2H), 2.17 - 2.09 (m, 2H), 2.09 - 2.01 (m, 1H), 1.74 - 1.62 (m, 2H).

[0363] Step 2, synthesis of 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1- methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide, yellow solid, yield 49.4%.1H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 9.75 (s, 1H), 9.68 (d, J = 7.7 Hz, 1H), 8.59 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.45 (dd, J = 13.6, 5.7 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.26 (d, J = 7.7 Hz, 1H), 5.30 (s, 1H), 5.06 (s, 1H), 5.02 (d, J = 5.3 Hz, 1H), 4.49 (s, 1H), 4.23 (d, J = 12.3 Hz, 1H), 3.89 (s, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.18 - 3.06 (m, 2H), 3.01 - 2.84 (m, 1H), 2.61 (d, J = 21.2 Hz, 1H), 2.53 (s, 1H), 2.00 (d, J = 6.6 Hz, 1H).

[0364] Test Example 1

[0365] In vitro activity experiment: the AlphaScreen detection technology is used to verify the CBP / p300 protein inhibition ability of the compound of the present application.

[0366] 1. Experimental purpose: to determine the inhibitory activity of the compound of the present application on CBP / p300 protein.

[0367] 2. Experimental materials: target protein CBP; experimental buffer MOPS (50 mm), CHAPS (50 μM), NaF (50 mM), BSA (0.1 mg / mL), PH 7.4; reagent kit donor microbead 5 μg / mL, acceptor microbead 5 μg / mL; CBP ligand, polypeptide H4KAc4-botin (SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR{Lys(biotin)}) 50 nM; 150 μL reaction system: CBP: 15 μL, experimental buffer: 15 μL, deionized water: 60 μL, small molecule compound: 15 μL, donor microbead: 15 μL, acceptor microbead: 15 μL; polypeptide: 15 μL. Positive inhibitor: CCS1477.

[0368] 3. Experimental method: add protein and polypeptide to the reaction solution, incubate at 20°C for 1.5 hours, add donor and acceptor microbeads, and incubate in the dark for 1 hour. Transfer to a 384-well plate, transfer 40 μL of liquid to each well, and detect the reading by PE Envison2104 multifunctional enzyme label instrument, excitation wavelength: 680 nM, emission wavelength: 520-620 nM.

[0369] The experimental results are shown in Table 1.

[0370] Table 1

[0371] According to the test results in Table 1, all the compounds in Table 1 can better bind to CBP / p300 protein and inhibit protein activity at a concentration of 1 μM, and the inhibition rate is more than 90%. The inhibitory activity is comparable to that of the positive control CCS1477. The molecular level activity data in Table 1 show that these compounds can effectively bind to CBP / p300 protein.

[0372] Test Example 2

[0373] The present application uses Cell Titer-Glo reagent to determine the ability of the compound of the present application to inhibit the proliferation of cancer cells.

[0374] Experimental purpose: to test the inhibitory activity of the compound of the present application and the compound CCS1477 in the prior art on the proliferation of cancer cells.

[0375] Experimental method: The used acute leukemia cells MV4-11, MOLM-16, KG-1 were suspended in RPMI1640 medium containing 10% FBS, and cultured at 37℃ in a 5% CO2 incubator. 500-1500 cells per well / 20μl were inoculated in 384 or 96 well plates, and incubated in a constant temperature incubator overnight. The compound was diluted to the specified concentration with the culture medium corresponding to the cells (+10% FBS), and the diluted compound was added to the well plate at 10μl per well, and the incubation was continued for 72-120h. 25μL of CellTiter-Glo reagent was added to each well, and the fluorescence signal was measured using a multifunctional enzyme label instrument (PerkinElmer).

[0376] The experimental results are shown in Tables 2 and 3:

[0377] Table 2 Note: IC 50 <1μM, very strong activity; 1≤IC 50 <10μM, strong activity; 10≤IC 50 <30μM, moderate activity; IC 50 ≥30μM, no activity.

[0378] Table 3 Note: IC 50 <1μM, very strong activity; 1≤IC 50 <10μM, strong activity; 10≤IC 50 <30μM, moderate activity; IC 50 ≥30μM, no activity.

[0379] As can be seen from Tables 2 and 3, the compounds of the present application, examples 4, 8, 10-11, 16-17, 20, 22-23, 28-37, have strong anti-proliferation inhibitory activity on MV4-11 cells, and the compounds of the present application, examples 11, 16 and 33, have strong anti-proliferation inhibitory activity on MOLM-16 and KG-1 cells at the same time, and the activity is better than that of the positive drug CCS1477.

[0380] Test example 3

[0381] Western Blot technology can be used to detect, characterize and semi-quantify proteins.

[0382] Experimental purpose: Western Blot experiment is used to determine the effect of the compound on the target protein level.

[0383] Experimental method: total protein sample collection: collect the cells after drug treatment, and take the supernatant after fully lysing the cells for SDS-PAGE electrophoresis separation. Then transfer the protein on the SDS-PAGE gel to the membrane, and after the transfer is completed, put the membrane into 5% skim milk for blocking. After the blocking is completed, cut the membrane according to the size of the protein molecular weight. Dilute the corresponding primary antibody to an appropriate concentration with blocking solution, and incubate with the PVDF membrane at 4°C overnight. After the incubation of the primary antibody is completed, wash the membrane with 1xTBST for 3-6 times, and then incubate with the corresponding secondary antibody diluent at room temperature for 1-2h. After the incubation is completed, wash the membrane with 1xTBST for 3-6 times, each time for 10min. Finally, perform chemiluminescence and development.

[0384] The experimental results are shown in Figures 1-2 as follows:

[0385] As shown in Figure 1, the compound of the present application, Example 11, 16, down-regulates the CBP and p300 protein levels in cells in a concentration-dependent manner, and can significantly down-regulate the CBP and p300 protein levels in cells at a concentration of 333nM;

[0386] As shown in Figure 2, the compound of the present application, Example 16, can significantly down-regulate the CBP and p300 protein levels in cells at a concentration of 500nM for 12h.

[0387] Test Example 4

[0388] MOLM-16 xenotransplantation model mouse in vivo efficacy study

[0389] Experimental purpose: xenotransplantation mouse experiment, the experiment is used to verify the inhibitory effect of the compound of the present application on tumors in vivo.

[0390] Experimental method: three-week-old male mice (strain: NOD / MrkBomTac-Prkdc scid) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. and used for xenotransplantation tumor establishment. MOLM-16 tumor cells were inoculated subcutaneously on one side of the lower abdomen of each mouse, and each mouse was injected with 3x10 6 cells, and the cells were suspended in 100μL of PBS and Matrigel (ratio 1:1). When the tumor volume reached about 100mm 3 around, the mice were randomly divided into groups (n=7 per group), and then the mice were administered by intraperitoneal injection, Example 16 was dissolved in 15% polyoxyethylene glycol castor oil (Cremophor EL), Calbiochem, 82.5% PBS and 2.5% dimethyl sulfoxide (DMSO) drug solvent, and administered continuously for 2 weeks, 7 days a week. The length (L) and width (W) of the tumor mass were monitored by caliper, and the volume was expressed in mm 3 , calculated by the following formula:

[0391] V = π / 6 x (L x W 2 Tumor growth inhibition (TGI) was calculated using the following formula: TGI = [1-(T-T0) / (C-C0)] x 100%, where T is the average tumor volume on a particular experimental day, T0 is the average tumor volume at the beginning of treatment; and C and C0 are the average tumor volumes of the control group on a particular experimental day and at the beginning of treatment, respectively.

[0392] Test Example 5

[0393] Using the mouse xenograft model test, MOLM-16 cell xenograft mouse model was selected, and Example 16 was administered orally (dose: 30 mg / kg), administered seven times a week, administered for 2 weeks, and the change in tumor volume in the mouse was observed. The data is expressed as the average tumor volume of animals in each treatment group ± standard deviation (n=7 per group).

[0394] The results of the tumor inhibition effect of Example 16 on the MOLM-16 mouse xenograft model are shown in Figure 3. Figure 3 shows that Example 16 at a dose of 30 mg / kg can significantly inhibit the growth of tumors in mice (TGI=60%). In addition, Figure 4 shows that at the dose, the mice have no significant change in body weight and behave normally. These results show that Example 16 has a significant effect on inhibiting the growth of tumors in the MOLM-16 mouse xenograft model, and has no obvious toxic effect.

[0395] The applicant states that the amide indolizine compounds of the present application and the use thereof are illustrated by the above examples, but the present application is not limited to the above examples, i.e. it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific methods, etc. fall within the scope of protection and disclosure of the present application.

Claims

1. An amide indolizine compound, characterized by, The amide indolizine compound has a structure as shown in formula I: Among them, R 1 It is selected from any one of hydrogen, halogen atom, hydroxyl group, aldehyde group, carboxyl group, hydroxymethyl group, methyl ester group, trifluoromethyl group, amide group, 2-methoxytetrahydropyranyl group, alkoxycarbonyl group or ethyl 2,2-dimethylpropionate group; R 2 any one selected from the group consisting of hydrogen, a halogen atom, a C1-C10 alkyl group or a C3-C10 cycloalkyl group; R 3 any one selected from the group consisting of hydrogen, a halogen atom, a C1-C10 alkyl group, an amino group, or a Boc-protected amino group; R 4 any one selected from the group consisting of hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, amino, Boc-protected amino, or methylamino; R 5 any one of hydrogen, C1-C10alkyl, C3-C10cycloalkyl, substituted C3-C10cycloalkyl, C3-C10cycloalkenyl, pyridyl, substituted pyridyl, pyrazinyl, substituted pyrazinyl, pyrimidinyl, morpholinyl, substituted morpholinyl, substituted pyrimidinyl, pyridazinyl, substituted pyridazinyl, piperidinyl, substituted piperidinyl, furanyl, substituted furanyl, thienyl, substituted thienyl, pyrrolyl, substituted pyrrolyl, imidazolyl, substituted imidazolyl, pyrazolyl, substituted pyrazolyl, quinolinyl, isoquinolinyl, or benzenesulfonic acidyl; Y 1 selected from a single bond, -R a O-, -R a S-, -R a NR'-, -R a OC(O)-, -R a OC(O)O-, -R a OCONR'-, -R a C(O)-, -R a C(O)O-, -R a CONR'-, -R a S(O)-, -R a S(O)2-, -R a SO2NR'-, -R a NR'C(O)O-, -R a NR'C(O)-, -R a NR'C(O)NR"-, -R a NR'S(O)-, -R a NR'S(O)2-, -R a NR'S(O)2NR"-, substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13spiro cycloalkyl, substituted or unsubstituted C5-C13spiro heterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, any of which is substituted with any one of halogen, hydroxyl, R b b C1-C6alkyl;​ R a any one of a single bond, substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13bridged cycloalkyl, substituted or unsubstituted C5-C13bridged heterocyclyl, substituted or unsubstituted C5-C13spirocycloalkyl, substituted or unsubstituted C5-C13spiroheterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, said substituted groups being selected from any one of halogen, hydroxyl, R c any one of a single bond, substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13bridged cycloalkyl, substituted or unsubstituted C5-C13bridged heterocyclyl, substituted or unsubstituted C5-C13spirocycloalkyl, substituted or unsubstituted C5-C13spiroheterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, said substituted groups being selected from any one of halogen, hydroxyl, R c C1-C6alkyl; R', R" are independently selected from any of substituted or unsubstituted C1-C8alkyl, substituted or unsubstituted C2-C8alkenyl, substituted or unsubstituted C2-C8alkynyl, substituted or unsubstituted C1-C8alkoxy, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, or R', R" together with the atom to which they are attached form a C3-C20cycloalkyl or C4-C20heterocycloaryl, said substituted groups being selected from any of halogen, hydroxyl, R d d R is selected from C1-C6alkyl;​ Y 2 is selected from any one of -0-, -NH-, -CH2-, -C(O)- or a single bond; L is selected from any one of a single bond, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted C2-C8 alkenylene, substituted or unsubstituted C2-C8 alkynylene, ether, thioether, ester, amine, amide, carbamate, urea, sulfone, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C6-C12 heteroaryl, carbonyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 heterocyclyl, said substituted groups being selected from any one of halogen, hydroxyl, R e e R is selected from C1-C6 alkyl;​ E has the structure of any one of Formulae II-1 to II-4, wherein indicates the position of the group attachment: wherein Y 3 is selected from -O-, -S-, -CHR f -, -C(O)-, -SO2-, -NR g -; R f , R g is independently selected from any one of H, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C3-C8heterocyclyl, the substituted groups being selected from any one of halogen, hydroxyl, R h , R h is selected from C1-C5alkyl; Y 4 , Y 5 , Y 6 , Y 7 are independently selected from -CR i = or -N=; R i selected from H, halogen, cyano, nitro, C1-C5alkyl; Y 8 is selected from CH or N; T 1 , T 2 , T 3 is independently selected from O or S; R 6 , R 7 is independently selected from any one of H, hydroxyl, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C1-C10heterocyclyl, the substituted groups being selected from any one of halogen, hydroxyl, R j , R j is selected from C1-C5alkyl; R 8 is selected from any one of H, halogen, cyano, C1-C5alkyl, C1-C5alkoxy or C1-C5halogenated hydrocarbon; Q is selected from -CH2-, -0-, -S-, -NR k -, -C(O)NR l - any one of the foregoing; R k , R l is independently selected from any one of H, C1-C10 alkyl, halogen.

2. The amide indolizine compound according to claim 1, characterized by said Y 4 , Y 5 , Y 6 , Y 7 is selected from -CH=; Preferably, Y 4 , Y 5 , Y 6 , Y 7 is -CH=; Preferably, said L is selected from any one of the following groups, indicates the position of the group attachment: wherein n, p, q are independently selected from an integer from 1 to 10; m is selected from an integer from 0 to 10, m being 0 means that the group is not present here. Preferably, said Y is selected from -CH2- or -C(O)-, preferably -C(O)-. 3 Preferably, said Y is selected from -CH2- or -C(O)-, preferably -C(O)-. Preferably, said T 1 , T 2 , T 3 is selected from O.

3. The amide indolizine compound according to claim 1 or 2, characterized by The amide indolizine compound has a structure as shown in formula III: wherein R 2 , R 3 , R 4 , E, Y 1 , Y 2 , L have the same defined range R 9 is any one of C2-C6 alkyl or C3-C6 cycloalkyl.

4. The amide indolizine compound according to any one of claims 1 to 3, wherein The amide indolizine compounds have structures as shown in formula IV-IX: wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , E, Y 1 , Y 2 , L have the same defined ranges as in claims 1-3; Preferably, said R 2 selected from a fluorine atom; Preferably, said R 3 is H; Preferably, said R 4 is methyl or ethyl; Preferably, said R 6 , R 7 are independently selected from H or C1-C10 alkyl; Preferably, said R 9 is methyl or cyclopropyl; Preferably, said Y 1 is selected from any one of substituted or unsubstituted Ci-C8alkylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl; Preferably, said Y is selected from -NH-, -C(O)- or a single bond. 2 is selected from -NH-, -C(O)- or a single bond; Preferably, said L is selected from any one of the following groups, indicates the position of the group attachment: wherein n, p, q are independently selected from an integer from 1 to 10; m is selected from an integer from 0 to 10, m being 0 means that the group is not present here.

5. The amide indolizine compound according to any one of claims 1 to 4, characterized in that, The amide indolizine compound is selected from any one of the structures shown in the following compounds: 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)propyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)hexyl)amino)-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)octyl)amino]-4-oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(2-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-2- oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(4-((8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)amino]-4- oxobutoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1- carboxamide 3-acetyl-7-(2-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxypropionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxypropionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-((1-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)propionyl)piperidin-4-yl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine-1-carboxamide 3-acetyl-7-(1-(1-(2-(2,6-dioxoisoindolin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxapentadecan-15-hydroxy)piperidin-4-yl)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indole-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1- yl)amino)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl) indolizine-1-carboxamide 3-acetyl-7-((6-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-6- oxohexyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-((7-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-7- oxoheptyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-((8-((3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)amino)-8- oxooctyl)oxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide 3-acetyl-7-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)methyl)piperidin- 1-yl)-2-oxoethoxy)-N-(2-fluoro-5-(hydroxymethyl)-3-(1-methyl-1H-pyrazol-4-yl)phenyl)indolizine- 1-carboxamide.

6. A process for the preparation of the amide indolizine compounds according to any one of claims 1 to 5, characterized in that, The preparation method is shown in Scheme 1: R 2 , R 3 , R 4 , R 9 , R 10 , Y 1 , L, Y 2 , E has the same defined range as in any of claims 1-5; wherein R 10 and R 11 are independently selected from any of substituted or unsubstituted C1-C8alkylene, substituted or unsubstituted C2-C8alkenylene, substituted or unsubstituted C2-C8alkynylene, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C4-C10heterocyclyl, substituted or unsubstituted C4-C13fused cycloalkyl, substituted or unsubstituted C4-C13fused heterocyclyl, substituted or unsubstituted C5-C13bridged cycloalkyl, substituted or unsubstituted C5-C13bridged heterocyclyl, substituted or unsubstituted C5-C13spirocycloalkyl, substituted or unsubstituted C5-C13spiroheterocyclyl, substituted or unsubstituted C6-C12aryl, substituted or unsubstituted C6-C12heteroaryl, said substituted groups being selected from any of halogen, R m , hydroxyl, -OR m , R m being selected from C1-C6alkyl; The reaction steps are as follows: the substrate 1-a is obtained by substitution reaction to obtain 2-a, the substrate 2-a is salified to obtain 3-a, the substrate 3-a is cyclized to obtain 4-a, the substrate 4-a is de-methyl ester to obtain 5-a, the substrate 6-a is brominated to obtain 7-a, the substrate 7-a is reduced to obtain 8-a, the substrate 8-a is substituted to obtain 9-a, the substrate 9-a is reduced by iron powder to obtain 10-a, the substrate 10-a is coupled by Suzuki to obtain 11-a, the substrate 11-a is condensed with 5-a to obtain 12-a, the substrate 12-a is reduced to obtain 13-a, the substrate 13-a is substituted by affinity to obtain 14-a, the substrate 14-a is de-protected under acidic conditions to obtain 15-a, and the substrate 15-a is condensed to obtain the compound shown in formula II.

7. A pharmaceutically acceptable salt of the amide indolizine compound of any one of claims 1-5.

8. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises an active ingredient and a pharmaceutically acceptable excipient; The active ingredient comprises the amide indolizine compound of any one of claims 1-5 and / or the pharmaceutically acceptable salt of claim 7.

9. Use of the amide indolizine compound of any one of claims 1-5, the pharmaceutically acceptable salt of claim 7, or the pharmaceutical composition of claim 8 in the preparation of a CBP and / or p300 protein inhibitor.

10. Use of the amide indolizine compound of any one of claims 1-5, the pharmaceutically acceptable salt of claim 7, or the pharmaceutical composition of claim 8 in the preparation of a medicament for preventing or treating cancer, a cell proliferative disorder, inflammation, an autoimmune disease, or sepsis, wherein: the cancer is any one of acute monocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia mixed lineage leukemia, NUT midline carcinoma, multiple myeloma, glioma, lung cancer, neuroblastoma, Burkitt's lymphoma, cervical cancer, esophageal cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, colorectal cancer, prostate cancer, or breast cancer; the inflammation is any one of pharyngolaryngeal inflammation, prostatitis, vaginitis, cervicitis, periarthritis of shoulder, pelvic inflammatory disease, urethritis, pneumonia, conjunctivitis, otitis media, meningitis, myocarditis, ulcerative colitis, asthma, allergic rhinitis, chronic obstructive pulmonary disease, thyroiditis, or allergic dermatitis; and the autoimmune disease is any one of rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, scleroderma, multiple sclerosis, myasthenia gravis, demyelinating disease, primary adrenocortical atrophy, chronic thyroiditis, and juvenile diabetes, hyperthyroidism, chronic nonspecific ulcerative colitis, chronic active hepatitis, pernicious anemia, atrophic gastritis, autoimmune glomerulonephritis, Goodpasture's syndrome, autoimmune hemolysis, idiopathic thrombocytopenic purpura, or idiopathic leukopenia. ​ ​ ​

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