Chimeric derivative for targeted degradation of N-phenylpyrrole formamide protein and application of chimeric derivative

Abstract

The invention discloses a chimera derivative for targeted degradation of N-phenylpyrrole formamide protein and application of the chimera derivative. The compound has a compound represented by general formula (I) # imgabs0 #, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The series of compounds can specifically recognize bromodomains of BET family proteins and collect E3 ubiquitin ligase to form a ternary complex, and target proteins are induced to generate ubiquitination degradation. More importantly, the series of compounds can act on BRD2 / 3 / 4 and BRDT subtypes at the same time through a protein degradation mechanism, and the defect that a traditional inhibitor is insufficient in selectivity is overcome. Therefore, the compound has an important application value in preparation of drugs for treating BET abnormal activation related diseases (including hematological malignant tumors and solid tumors), and particularly provides an innovative solution for overcoming the problem of drug resistance of tumors.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to chimeric derivatives of N-phenylpyrrolecarboxamide proteins for targeted degradation and applications thereof. Background Art

[0002] Cancer is one of the leading causes of death worldwide, yet its five-year survival rate remains low, and early detection and treatment remain challenging. Despite significant progress in kinase-based anti-cancer drugs over the past few decades, existing treatments have encountered bottlenecks in clinical application due to target limitations, drug resistance, and safety concerns associated with multiple targets. Therefore, the development of novel therapeutic approaches, particularly for the prevention, treatment, and overcoming of tumor drug resistance, holds significant clinical and research value.

[0003] Bromodomains (BRDs) are a class of conserved protein domains that specifically recognize acetylated lysine residues in histones. In mammals, 61 bromodomains have been identified, distributed across 46 bromodomain proteins. The BET (Bromodomain and Extra-Terminal) protein family is the most intensively studied, comprising four members: BRD2, BRD3, BRD4, and BRDT. As coregulators of gene transcription, BET proteins play key roles in a variety of physiological and pathological processes. For example, BRD3 regulates the expression of erythroid-specific genes by interacting with the transcription factor GATA1; while BRD4 promotes the dissociation of HEXIM1, activating P-TEFb and subsequently phosphorylating RNA Pol II to regulate gene transcription. Furthermore, BET proteins drive the development and progression of various tumors by regulating the expression of the proto-oncogene MYC. BRDTs play a crucial role in chromatin remodeling during spermatogenesis, maintaining the chromatin structure of the sperm head.

[0004] BET proteins not only play an important role in cancer, but are also involved in the pathological processes of various diseases such as inflammation, HIV infection and cardiovascular disease. Currently, research on BET protein inhibitors is mainly focused on the field of cancer, and nearly 20 compounds have entered clinical trials. However, the structural types of existing small molecule inhibitors are relatively simple, mainly triazoles, quinolinones and pyridone-pyrroles. These inhibitors generally have problems such as poor selectivity for the BET Bromodomain, poor pharmacokinetic (PK) properties and insufficient in vitro activity. In addition, in clinical trials, non-selective pan-BET inhibitors have poor patient tolerance at high doses, and often require dose reduction to reduce side effects, which seriously limits their efficacy. Therefore, the development of BET inhibitors with high selectivity and good pharmacokinetic properties has become the focus of current research.

[0005] In recent years, the introduction of proteolysis-targeting chimeras (PROTACs) has brought new opportunities for the development of BET protein drugs. PROTACs offer a novel therapeutic strategy by inducing ubiquitination and degradation of target proteins. As the first PROTAC drug to enter clinical trials, ARV-110 has significantly advanced the development of BET protein degraders. Summary of the Invention

[0006] By studying the crystal structure model of BET proteins and summarizing the structure-activity relationship of BET, this paper designed and synthesized chimeric derivatives of N-phenylpyrrolecarboxamides for targeted protein degradation, as well as their preparation methods and applications. Pharmacological test results demonstrate that the BET-inhibiting compounds of the present invention possess excellent BET protein inhibitory activity. Furthermore, these bifunctional protein degraders can efficiently induce cell apoptosis, demonstrating promising application prospects, particularly as BET protein-targeted chimeras for medical applications.

[0007] In order to solve the problems of the prior art, the technical solution adopted by the present invention is:

[0008] The compound represented by formula (I), or its stereoisomer, or its pharmaceutically acceptable salt, wherein the formula (I) is

[0009]

[0010] Among them, BI is a phenylacetylpyrrole-like ligand group recognized / bound by BET proteins;

[0011] D is the E3 ubiquitin ligase ligand group, which serves as a degradation tag;

[0012] L is a covalent bond connecting group between BI and D;

[0013] n is the number of degradation tags connected to the BET protein ligand, and n is selected from 1, 2 or 3.

[0014] As an improvement, BI is a compound of the general formula (BI-1) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the general formula (BI-1) is

[0015] in,

[0016] A represents a single bond, -C≡CR 1a -、-R 1a -、-R 1a CO-, -NH-, -NR 1a -、-NR 1a CO-、-O-、-OR 1a -、-OR 1aCO-, and R 1a Selected from -C 1-8 Alkyl-, -C 2-8 Alkenyl-, -PEG 1-10 -; preferably -OR 1a -、-OR 1a CO-;

[0017] The CyA ring is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-8 membered aryl, or 5-8 membered heteroaryl;

[0018] R 1 For hydrogen, -CN, -NO2, -OR 1b , halogen, -OR 1b 、-SR 1b 、-NR 1b 、-N(R 1b )2, or independently selected from unsubstituted or substituted by halogen, hydroxyl, -C 1-8 -C substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein, R 1b Indicates C 1-8 Alkyl; t represents 1-4;

[0019] R 2 Selected from hydrogen, halogen, oxo, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-C(=NR 2a )NR 2b R 2c 、-SO2N(R 2a R 2b )、-SO2N(R 2a COR 2b ), -SO2NR 2a CONR 2b R 2c )、-SO2N(R 2a CO2R 2b )、-SO2N(R 2a SONR 2b R 2c )、-SO2N(R 2a SO2NR 2b R 2c )、-SO2N(R 2aSO2R 2b ), or independently selected from unsubstituted or substituted by halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl-substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0020] R 2a 、R 2b and R 2c are each independently hydrogen, unsubstituted or substituted with at least one substituent R 2d Replaced by -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 2a and R 2b )、(R 2b and R 2c ), or (R 2c and R 2a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 2e replace;

[0021] R 2e are independently hydrogen, unsubstituted or substituted with at least one substituent, wherein the substituent is -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0022] As an improvement,

[0023] A is selected from a single bond, -O(CH2) 1-8 CO-, -O(PEG) 1-8 CO-;

[0024] The CyA ring is selected from the group consisting of naphthalene, quinoline, isoquinoline, benzene, benzodioxolane, benzodioxane, pyridine, pyrimidine, pyridazine, triazine, pyrazole, thiazole, thiophene, oxazole, isoxazole, piperidine, cycloheptane, cyclohexane, and cyclopentane;

[0025] R 1 are independently selected from hydrogen, halogen, -CN, and haloalkyl, and t represents 1-4;

[0026] R 2 Independently selected

[0027] As an improvement, the D is an E3 ubiquitination ligase ligand group, and the E3 ligase is selected from vonHippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HE RC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMU RF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAI P3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GR AIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, M indBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3; preferably VHL, Cereblon, MDM2, or cIAP;

[0028] The L is (Linker) u Each Linker independently forms a chemical bond directly, or is selected from C 1-8 Alkylene, C 2-8 Alkyne, -CO-, -O-, -NH-, -CONH-, -NHCO-, -CH(CH3)-, -CHF-, -CF2-, -CH(OCH3)-, or optionally substituted by one or more halogen or C 1-8Alkyl-substituted cycloalkyl, heterocycloalkyl, heteroaromatic ring or aromatic ring, wherein the cycloalkyl is selected from Wherein the heterocycloalkyl group is selected from:

[0029]

[0030] and wherein the aromatic ring is selected from a benzene ring;

[0031] u is an integer selected from 1-20.

[0032] As an improvement, the D has the general formula shown below:

[0033]

[0034] Where: Each G is independently selected from CR C2 R C3 NR C2 , CO, or SO2; Y is selected from a single bond, or NH;

[0035] p is selected from 0, 1 or 2;

[0036] Each of W1, W2, W3, W4 and W5 is independently selected from N or CR C4 ;

[0037] Each X5 is independently selected from O or S;

[0038] Each V1 is independently a direct chemical bond, or is selected from -NH-, -O-, -S-, -SO-, -SO 2- 、-SO2NR C2- 、-CO-、-CO 2- 、-C(O)NR C2 -、-C(S)NR C2 -、-NR C2 CO-、-NR C2 CONR C3 -, unsubstituted or optionally substituted by R C4 Substituted -C 1-8 Alkylene-, -C 2-8 Alkenyl-, -C 2-8 Alkyne-, cycloalkyl, heterocyclyl, aryl, or heteroaryl, preferably directly forming a chemical bond, -O-, -CH2-, -CH=CH-, or -NH-;

[0039] Each V2 is independently selected from CR C2 R C3 NR C2 , O or S;

[0040] Each Z is independently selected from hydrogen, halogen, hydroxy, amino, unsubstituted or replaced by RC5 Substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0041] R C1 、R C2 、R C3 、R C4 and R C5 Selected from hydrogen, carboxyl, cyano, nitro, halogen atoms, -OR C6 、-SO2R C6 、-SO2NR C6 R C7 、-COR C6 、-CO2R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO2R C7 、-NR C6 SO2NR C7 R C8 、-NR C6 SO2R C7 , unsubstituted or replaced by at least one R C9 Substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

[0042] R C6 、R C7 、R C8 and R C9 Selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0043] Preferably, D is selected from:

[0044]

[0045] And V1 directly forms a chemical bond, or is selected from -O-, -CH2-, -N-, -NH- or -CH=CH-.

[0046] A further improvement is that D is selected from:

[0047]

[0048] Furthermore, V1 is a direct chemical bond, or is selected from -O-, -CH2-, and -NH-.

[0049] As an improvement, the L is selected from:

[0050]

[0051] Preferred

[0052]

[0053] As an improvement,

[0054] The CyA ring is preferably a quinoline ring, a benzene ring, a benzodioxolane ring, a benzodioxane ring, or a pyridine ring, and more preferably a benzene ring or a pyridine ring; R 1 is selected from hydrogen, -Cl, -F, -CF3, -SMe, -ethyl, -N(Me)2, methyl, preferably hydrogen, F; t is preferably 1 and 2; A is selected from a single bond, -O(CH2) 1-4 CO-, -O(PEG) 1-2 CO-;

[0055] R 2 Preferably selected from

[0056] L preferred

[0057] D preferred

[0058] , more preferably And V1 directly forms a chemical bond, or is selected from CO.

[0059] As an improvement, the compound is specifically:

[0060] 4-Acetyl-N-(2-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-1a)

[0061] 4-Acetyl-N-(2-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-2a)

[0062] 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-3a)

[0063] 4-Acetyl-N-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-4a)

[0064] 4-Acetyl-N-(2-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-5a)

[0065] 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-6a)

[0066] 4-Acetyl-N-(2-(4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-7a)

[0067] 4-Acetyl-N-(2-(4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-8a)

[0068] 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-13-oxo-3,6,9-trioxa-12-azahexadec-16-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-9a)

[0069] 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa-15-azanonadecan-19-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-10a)

[0070] 4-Acetyl-N-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-11a)

[0071] 4-Acetyl-N-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-12a)

[0072] 4-Acetyl-N-(2-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-13a)

[0073] 4-Acetyl-N-(2-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-14a)

[0074] 4-Acetyl-N-(2-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-15a)

[0075] 4-Acetyl-N-(2-(4-((3aR,6aS)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-16a)

[0076] 4-Acetyl-N-(2-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-17a)

[0077] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18a)

[0078] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18b)

[0079] 4-Acetyl-N-(2-(4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18c)

[0080] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18d)

[0081] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (I-18e)

[0082] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide (I-18f)

[0083] 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19a)

[0084] 4-Acetyl-N-(2-(4-(4-((4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19b)

[0085] 4-Acetyl-N-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-20a)

[0086] 4-Acetyl-N-(2-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-21a)

[0087] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-22a)

[0088] 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-23a)

[0089] 4-Acetyl-N-(2-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1a)

[0090] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1b)

[0091] 4-Acetyl-N-(2-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1c)

[0092] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1d)

[0093] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1e)

[0094] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1f)

[0095] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-dimethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1g)

[0096] 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1a)

[0097] 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1a)

[0098] 4-Acetyl-N-(2-((1-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1c)

[0099] 4-Acetyl-N-(2-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1d).

[0100] The specific structure is shown in the table:

[0101]

[0102]

[0103]

[0104] A pharmaceutical composition comprising the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0105] Use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or pharmaceutical composition in the preparation of a medicament for treating and / or preventing BET-mediated diseases and related diseases, wherein the BET-mediated diseases and related diseases are selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor, sarcoma or myelodysplastic syndrome.

[0106] Beneficial effects:

[0107] Compared with the prior art, the present invention relates to a new class of compounds with significant anti-tumor activity and their medical uses. Systematic in vitro anti-proliferation experiments have confirmed that the compounds of the present invention exhibit excellent proliferation inhibition effects on a variety of hematological malignant tumor cell lines (including MV4-11 acute myeloid leukemia cells) and solid tumor cell lines (MDA-MB-231 breast cancer cells), with a half inhibitory concentration (IC 50) are generally lower than 50nM, and the optimal compound shows a super strong activity level of 1-5nM in some cell lines. More importantly, the compound of the present invention exhibits a proteasome ubiquitination mechanism: on the one hand, it destroys the transcriptional regulation of oncogenes by efficiently degrading BRD4 protein (Western blot analysis showed that the BRD4 protein level decreased by >90% at a concentration of 1μM after 48 hours of treatment). On the other hand, it still maintains potent activity in the SHP099 resistant MV4-11 cell model. This feature is significantly better than existing BET inhibitors and provides a new solution to the problem of clinical drug resistance. In-depth mechanism studies have shown that the compound has a typical concentration-effect positive correlation and exhibits a linear dose-effect relationship in the concentration range of 10-100nM. Flow cytometric analysis confirmed that after 48 hours of treatment with the drug concentration, it can induce tumor cell apoptosis and enable the drug to arrest the cell cycle in the G1 phase. This dual mechanism of action effectively blocks the proliferation pathway of tumor cells. Based on the above excellent in vitro activity and clear mechanism of action, the compounds of the present invention can be developed into new anticancer drugs, which are particularly suitable for the treatment of BRD4-dependent malignant tumors (including but not limited to acute leukemia, triple-negative breast cancer, etc.), and have important application value in different clinical scenarios such as tumor prevention (for high-risk populations), adjuvant therapy (postoperative recurrence prevention) and late palliative treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0108] Figure 1 Western blot analysis of BRD4 protein and c-Myc, immunoblotting of BRD4, c-Myc and GAPDH in MV4-11 cells treated with DMSO and different concentrations of compounds I-3a (A), I-5a (B), I-9a (C), I-10a (D), I-18a (E) and I-19a (F) for 48 h.

[0109] Figure 2 Western blot analysis of BRD4 protein and c-Myc. Immunoblotting of BRD4, c-Myc and GAPDH in MDB-MA-231 cells after treatment with culture medium and different concentrations of compounds I-18a (A) and I-19a (B) for 48 h.

[0110] Figure 3 Cell cycle analysis and statistical results of MV4-11 treated with compound I-18a for 24 hours.

[0111] Figure 4 This is the flow cytometric analysis and statistical results of the apoptosis-promoting effect of compound I-18a on MV4-11 at 48 hours. DETAILED DESCRIPTION

[0112] The synthetic route of the compound of the present invention is as follows (all conventional synthetic routes in the prior art):

[0113]

[0114] a Reagents and conditions: (a) HNO3, H2SO4, 0℃ to rt.4h; (b) R 2a H,N,N-diisopropyl ethylamine(DIPEA),DCM,0℃ to rt.,4h; (c)NaOH(50%w / w),DMSO,0℃ to80℃,6h;(d)BrA1Boc or BrA1Ot-Bu,K2CO3,DMF,70℃,4hrs;(e)Fe,NH4Cl,EtOH / H2O,80℃,4hrs;(f)i:NaNO2,AcOH / H2O,0℃ to rt,12h;ii:Znpowder,pentane-2,4-dione,AcOH / H2O,0℃ to80℃,over night; (g) LiOH·H2O, THF / H2O, rt, 4h; (h) triethylamine (TEA), HATU, DMF, 100℃, 6hrs; (i) trifluoroacetic acid(TFA),DCM,rt.,4hrs; (j)DLH or DLBr,DIPEA,HATU,DMF,rt.,6hrs;

[0115] The melting point was determined using a micro melting point tester WRX-4 from Shanghai Yice Instrument Co., Ltd. 1 HNMR was performed using a JEOL FX90Q Fourier transform nuclear magnetic resonance instrument and a BRUKERAM-600 nuclear magnetic resonance instrument (TMS as internal standard); MS was determined using a Nicolet 2000 Fourier transform mass spectrometer and a MAT-212 mass spectrometer.

[0116] Example 1

[0117] 4-Acetyl-N-(2-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-1a)

[0118]

[0119] To a stirred solution of ethyl 3-oxo-3-phenylpropanoate (5.00 g, 26.01 mmol, 1.0 equiv) in acetic acid (20 mL) at 0°C was added dropwise an aqueous solution of sodium nitrite (2.69 g, 39.02 mmol, 1.5 equiv) (5 mL). After the addition was complete, the reaction solution was stirred at room temperature for 12 hours. Subsequently, zinc powder (3.40 g, 52.03 mmol, 2.0 equiv) and 2,4-pentanedione (2.60 g, 26.01 mmol, 1.0 equiv) were added sequentially at 0°C, and the reaction system was heated to 80°C overnight. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate gradient elution) to obtain the target compound (s1a-1, 3.90 g, 14.37 mmol) in a yield of 55% as an off-white solid. 1 H NMR(600MHz,Chloroform-d)δ10.11(brs,1H),7.39–7.33(m,3H),7.31–7.26( m,2H),4.07(q,J=7.1Hz,2H),2.57(s,3H),1.81(s,3H),0.98(t,J=7.1Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ196.89,161.70,138.97,135.70,132.70,130.05 (2C),127.82(2C),127.54,123.61,118.04,77.16,60.47,30.84,14.51,13.84.

[0120] To a solution of compound s1a-1 (4.80 g, 17.69 mmol, 1.0 equivalent) in tetrahydrofuran (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (2.22 g, 53.07 mmol, 3.0 equivalent) and stirred at room temperature for about 4 hours. Subsequently, the solution was concentrated under reduced pressure, diluted with water (100 mL), and extracted with ethyl acetate (50 mL×3), and then the aqueous layer was acidified to a pH of about 1 with hydrochloric acid. The aqueous layer was then extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target compound (s1a-2) (3.76 g, 15.46 mmol, 87% yield) as an off-white solid. 1HNMR(400MHz,DMSO-d6)δ12.19(brs,1H),12.13(brs,1H),7.38–7.31(m,3H),7.27–7.23(m,2H),2.42(s,3H),1.66(s,3H). 13 C NMR (101MHz, DMSO-d6) δ194.81,161.70,137.99,135.92,131.19,130.06(2C),127.50(2C),126.95,122.79,118.06,39.52,30.28,13.66.

[0121] Nitric acid (1.63 mL, 36.3 mmol, 1.5 equiv) was added dropwise to a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24.2 mmol, 1.0 equiv) in sulfuric acid (16 mL) at 0°C. The mixture was stirred at 0°C for 4 hours, then poured into ice and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate, and then evaporated to give the target compound (s1a-3) (4.68 g, 18.6 mmol, 76% yield) as a light yellow solid. 1 HNMR(600MHz,Chloroform-d)δ8.51(d,J=2.4Hz,1H),8.21(dd,J=9.0,2.4Hz,1H),7.31(d,J=9.0Hz,1H),4.11(s,3H). 13 C NMR (101MHz, Chloroform-d) δ157.74,139.27,135.87,132.92,125.53,114.57,57.66.

[0122] To a solution of compound s1a-3 (700 mg, 2.78 mmol, 1.0 equivalent) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (1.45 mL, 8.35 mmol, 3.0 equivalent) at 0°C, and morpholine (292 μL, 3.34 mmol, 1.2 equivalent) was added dropwise, followed by stirring at room temperature for about 4 hours. The solution was concentrated under reduced pressure, diluted with 30 mL of water, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the target compound (s1a-4) (450 mg, 1.49 mmol, 53% yield) as a light yellow solid. 1H NMR (600MHz, Chloroform-d) δ8.24(d,J=2.3Hz,1H),7.94(dd,J=8.8,2.3Hz,1H),4.08(s,3H),3.86–3.67(m,4H),3.05(t,J=4.7Hz,4H). 13 C NMR (101MHz, Chloroform-d) δ156.16,139.50,133.53,127.62,125.76,114.13,66.12(2C),57.27,46.08(2C).

[0123] Aqueous sodium hydroxide (10 mL, 50% by mass) was added dropwise to a solution of compound s1a-4 (8.40 g, 27.8 mmol, 1.0 equivalent) in dimethyl sulfoxide (25 mL) at 0°C. The reaction mixture was then heated to 80°C for 6 hours. The reaction mixture was cooled to 0°C and acidified with hydrochloric acid to a pH of approximately 1. The precipitate was filtered to obtain the title compound (s1a-5) (5.30 g, 18.39 mmol, 66% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.28(brs,1H),8.15(d,J=2.3Hz,1H),7.85(dd,J=8.8,2.3Hz,1H),7.34(d,J=8.8Hz,1H),3.66–3.59(m,4H),2.94–2.84(m,4H). 13 C NMR (101MHz, DMSO-d6) δ155.66,136.95,133.58,125.61,124.60,120.07,65.25(2C),45.83(2C).

[0124] To a solution of compound s1a-5 (5.30 g, 18.4 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) were added potassium carbonate (7.62 g, 55.1 mmol, 3.0 equiv) and tert-butyl 4-bromobutyrate (4.92 g, 22.0 mmol, 1.2 equiv). The reaction mixture was heated to 70°C and stirred for 4 hours. Water (300 mL) was added to the mixture for dilution, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (s1a-6) (5.22 g, 12.1 mmol, 66% yield) as an off-white solid. 1H NMR(600MHz,Chloroform-d)δ8.21(d,J=2.2Hz,1H),7.89(dd,J=8.8,2.3Hz,1H),7.24(d,J=8.9Hz,1H),4.27(t ,J=6.2Hz,2H),3.78–3.73(m,4H),3.08–2.98(m,4H),2.48(t,J=7.0Hz,2H),2.14(p,J=6.6Hz,2H),1.45(s,9H). 13 C NMR(101MHz,Chloroform-d)δ172.27,155.51,139.49,133.46,127.39,125. 71,114.90,80.90,69.33,66.09(2C),46.06(2C),31.22,28.21(3C),24.21.

[0125] Ammonium chloride (1.95 g, 36.4 mmol, 3.0 equiv) and iron powder (3.39 g, 60.6 mmol, 5.0 equiv) were added to a solution of compound s1a-6 (5.22 g, 12.1 mmol, 1.0 equiv) in ethanol (30 mL) and water (10 mL). The reaction mixture was heated to 80°C and stirred for 4 hours. The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. The organic phases were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the target compound (s1a-7) (4.53 g, 11.3 mmol, 93% yield) as an off-white solid. 1 HNMR(400MHz,Chloroform-d)δ7.08(dd,J=8.4,2.3Hz,1H),7.03(d,J=2.2Hz,1H),6.83(d,J=8.4Hz,1H),4.13–4 .03(m,4H),3.73–3.69(m,4H),2.99–2.94(m,4H),2.43(t,J=7.2Hz,2H),2.12(p,J=7.2,6.7Hz,2H),1.44(s,9H). 13 C NMR(101MHz,Chloroform-d)δ172.41,149.82,137.07,126.93,118.81,113.22, 110.62,80.79,77.16,67.79,66.24(2C),46.20(2C),32.11,28.23(3C),24.65.

[0126] Compound s1a-2 (500 mg, 2.06 mmol, 0.5 equiv) was added to 5 mL of N,N-dimethylformamide (DMF), followed by triethylamine (TEA, 1.43 mL, 10.3 mmol, 5.0 equiv) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.17 g, 3.08 mmol, 1.5 equiv). After stirring at room temperature for about 20 minutes, compound s1a-7 (823 mg, 2.06 mmol, 0.5 equiv) was added. After heating to 100°C and stirring for 3 hours, a DMF (5 mL) solution consisting of compound s1a-2 (500 mg, 2.06 mmol, 0.5 equiv), triethylamine (1.43 mL, 10.3 mmol, 5.0 equiv), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.17 g, 3.08 mmol, 1.5 equiv) was added and stirred at 100°C for 3 hours. After completion of the reaction, the reaction mixture was diluted with 100 mL of water and then extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the target compound (s1a-8) (1.15 g, 1.84 mmol, 44% yield) as a light yellow solid. 1 HNMR(600MHz,Chloroform-d)δ10.18(s,1H),8.68(d,J=2.3Hz,1H),7.64(s,1H),7 .54(dt,J=11.0,6.9Hz,3H),7.46(dd,J=7.7,1.6Hz,2H),7.43–7.31(m,3H),6.87( d,J=8.7Hz,1H),3.89(t,J=7.0Hz,2H),3.73(t,J=4.6Hz,4H),3.02(t,J=4.6Hz,4H ),2.55(s,3H),2.23(t,J=7.2Hz,2H),1.83–1.81(m,2H),1.74(s,3H),1.47(s,9H). 13CNMR(151MHz,Chloroform-d)δ196.04,172.02,159.47,150.71,138.95,134.61,130.59,130.07,129.65,129.03,128.11,127.71,127.6 6,127.08,124.46,123.83,120.64,120.47,110.71,81.10,77.16,67 .91,66.30(2C),46.19(2C),31.48,30.50,28.26(3C),23.69,14.65.

[0127] Compound (s1a-8) (1.20 g, 1.92 mmol) was added to dichloromethane (10 mL) and stirred to dissolve. Trifluoroacetic acid (3 mL) was then added dropwise, followed by stirring at room temperature for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the title compound (s1a-9) (1.18 g, 2.07 mmol, 108% yield) as a brown solid. 1 HNMR (600MHz, DMSO-d6) δ12.39(brs,1H),8.67(s,1H),7.65(s,1H),7.57(t,J=3.2Hz,3H),7.47(dd,J=6.9,2.8Hz,2H),7.35–7.24(m,2H),7.17(d,J =8.7Hz,1H),3.96(t,J=7.0Hz,2H),3.61(t,J=4.5Hz,4H),2.84(t,J=4.5H z,4H),2.48(s,3H),2.27(t,J=7.2Hz,2H),1.74–1.69(m,2H),1.67(s,3H). 13 C NMR(151MHz,DMSO-d6)δ194.29,173.96,158.79,149.87,138.65,134.33,130.27(2C),129.34(2C),129.09,127.96,127.21 ,125.65,123.77,122.68,120.70,118.63,111.54,67.52,65.31(2C),45.87(2C),39.52,30.12,29.56,22.97,13.88,13.77.

[0128] A solution of compound s1a-9 (0.21 mmol, 1 equiv) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equiv) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equiv). The mixture was stirred at room temperature for 0.5 hour. Compound s1a-9 (1.1 equiv) was then added, and the mixture was stirred at room temperature for 2 hours. When thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to afford the target compound I-1a (130 mg, 0.15 mmol, yield 71%) as a yellow solid powder. mp 128-133°C. 1 H NMR(600MHz,Chloroform-d)δ10.65(s,1H),9.41(s,1H),8.66(d,J=2.3Hz,1H),7.65(s,1H),7.53–7.47(m,3 H),7.43–7.39(m,3H),7.31–7.29(m,1H),7.03(d,J=7.1Hz,1H),6.88(dd,J=15.9,8.7Hz,2H),6.71(d,J=6.0 Hz,1H),6.38(t,J=5.8Hz,1H),4.94–4.88(m,1H),3.87(t,J=6.9Hz,2H),3.66–3.62(m,4H),3.47–3.36(m,4H ),2.94–2.89(m,4H),2.79–2.68(m,3H),2.51(s,3H),2.15(t,J=7.0Hz,2H),1.87–1.82(m,2H),1.69(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.24,172.80,172.22,169.57,169.37,167.66,159.46,150.72,146. 76,139.12,136.34,134.54,132.55,130.53,129.60,129.57,128.99,128.24,127.81,126.59,124.41 ,123.72,120.73,120.06,116.81,115.37,111.93,110.94,110.36,67.97,66.20,66.15,49.07,46.16 ,42.22,39.08,38.72,36.62,31.84,31.50,30.48,29.78,29.75,27.01,23.83,22.78,14.48.HRMS-EI m / z[M+Na] + calcdfor C 43 H 45 N7NaO 11 S + :890.2790,found:890.2790.

[0129] Example 2

[0130] 4-Acetyl-N-(2-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-2a)

[0131] Compound I-2a was prepared according to the synthetic procedure of I-1a using 0.14 mmol of s1a-9. Purification by column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-2a (87 mg, 0.098 mmol, 70% yield). A yellow solid powder with a mp of 123-126°C was obtained. 11H NMR (600 MHz, Chloroform-d) δ 10.68 (s, 1H), 9.37 (s, 1H), 8.66 (d, J = 2.3 Hz, 1H), 7.66 (s, 1H), 7.53–7.50 (m, 3H), 7.43–7.40 (m, 3H), 7.33–7.32 (m, 1H), 7.02 (d, J = 7.1 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.43 (t, J = 6.0 Hz, 1H), 6.39 (t, J = 5.9 Hz, 1H), 4.96–4.92 (m, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.66–3.63 (m, 4H), 3.37–3.31 (m, 2H), 3.30–3.24 (m, 2H), 2.94–2.90 (m, 4H), 2.80–2.70 (m, 4H), 2.53 (s, 3H), 2.18 (t, J = 7.0 Hz, 2H), 1.87–1.84 (m, 2H), 1.81–1.77 (m, 2H), 1.70 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.22, 172.51, 172.10, 1六十九点五七, 169.28, 167.71, 159.47, 150.77, 146.71, 139.13, 136.29, 134.55, 132.60, 130.52, 129.59, 128.99, 128.23, 127.78, 126.56, 124.47, 123.71, 120.71, 120.06, 116.67, 115.39, 111.61, 110.92, 110.17, 68.01, 66.19, 66.14, 49.03, 46.17, 43.45, 40.14, 38.72, 37.20, 31.85, 31.48, 30.47, 30.46, 29.77, 29.74, 29.22, 27.00, 23.87, 22.87, 14.50. HRMS-EI m / z + calcd for C 44 H 47 N7NaO 11 S + : 904.2946, found: 904.2946.

[0132] Example 3

[0133] 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-3a)

[0134] Compound I-3a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.17 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-3a (105 mg, 0.11 mmol, 66% yield). A yellow solid powder was obtained. mp 113-117°C. 1 H NMR(600MHz,Chloroform-d)δ10.58(s,1H),9.30(s,1H),8.68(d,J=2.3Hz,1H),7.66(s,1H),7.53–7.49( m,3H),7.45–7.41(m,3H),7.34–7.31(m,1H),7.05(d,J=7.0Hz,1H),6.85(dd,J=8.7,4.5Hz,2H),6.22–6.1 3(m,2H),4.96–4.90(m,1H),3.92–3.85(m,2H),3.67–3.63(m,4H),3.30–3.22(m,4H),2.97–2.93(m,4H), 2.79–2.69(m,3H),2.53(s,3H),2.16(t,J=7.1Hz,2H),1.89–1.85(m,2H),1.71(s,3H),1.66–1.55(m,4H). 13 CNMR(151MHz,Chloroform-d)δ196.20,171.99,171.97,169.76,169.17,167.69,159.44,150. 73,146.90,139.06,136.34,134.60,132.58,130.54,129.60,129.00,128.26,127.84,126.76, 124.39,123.75,120.74,120.18,116.79,115.33,111.69,110.82,110.09,68.04,66.19,49.07 ,46.19,42.24,39.26,38.73,32.03,31.53,30.50,27.12,26.64,23.97,22.93,14.53.HRMS-EI m / z[M+Na] + calcd for C45 H 49 N7NaO 11 S + :918.3103,found:918.3099.

[0135] Example 4

[0136] 4-Acetyl-N-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-4a)

[0137] Compound I-4a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.17 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-4a (107 mg, 0.12 mmol, 67% yield). A yellow solid powder was obtained. mp 123-127°C. 1 H NMR(600MHz,Chloroform-d)δ10.60(s,1H),9.21(s,1H),8.68(d,J=2.2Hz,1H),7.66(s,1H),7.55–7.48(m,3H),7.45–7.4 0(m,3H),7.33–7.30(m,2H),7.05(d,J=7.1Hz,1H),6.85(t,J=9.2Hz,2H),6.19(t,J=5.7Hz,1H),6.05(t,J=5.9Hz,1H),4. 95–4.89(m,1H),3.89(t,J=6.7Hz,2H),3.68–3.64(m,4H),3.27–3.18(m,4H),2.94(t,J=4.4Hz,4H),2.80–2.71(m,4H),2. 53(s,3H),2.16(t,J=7.1Hz,2H),1.90–1.84(m,3H),1.71(s,3H),1.66–1.59(m,2H),1.55–1.48(m,2H),1.41–1.39(m,2H). 13C NMR(151MHz,Chloroform-d)δ196.21,171.97,171.87,169.73,169.12,167.71,159.42,150.74,1 47.00,139.03,136.32,134.59,132.55,130.51,129.58,128.98,128.24,127.93,126.70,124.37, 123.75,120.72,120.14,116.82,115.34,111.58,110.80,109.98,68.09,66.18,49.04,46.18,42 .48,39.50,38.72,32.04,31.52,30.50,29.31,28.82,27.01,24.33,23.96,22.91,14.51.HRMS-EI m / z[M+Na] + calcd for C 46 H 51 N7NaO 11 S + :932.3259,found:932.3268.

[0138] Example 5

[0139] 4-Acetyl-N-(2-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-5a)

[0140] Compound I-5a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.14 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-5a (110 mg, 0.12 mmol, 85% yield). A yellow solid powder was obtained. mp 125-128°C. 11H NMR (600 MHz, Chloroform-d) δ 10.62 (s, 1H), 9.19 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 7.67 (s, 1H), 7.54–7.49 (m, 3H), 7.46–7.41 (m, 3H), 7.34–7.32 (m, 1H), 7.05 (d, J = 7.1 Hz, 1H), 6.88–6.82 (m, 2H), 6.19 (t, J = 5.7 Hz, 1H), 5.97 (t, J = 5.8 Hz, 1H), 4.95–4.91 (m, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.69–3.65 (m, 4H), 3.25–3.18 (m, 4H), 3.09 (s, 1H), 2.97–2.93 (m, 4H), 2.81–2.69 (m, 3H), 2.54 (s, 3H), 2.15 (t, J = 7.1 Hz, 2H), 1.89–1.84 (m, 2H), 1.71 (s, 3H), 1.64–1.57 (m, 2H), 1.51–1.44 (m, 2H), 1.42–1.39 (m, 3H), 1.34–1.30 (m, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.18, 171.84, 169.71, 169.11, 167.74, 159.41, 150.71, 147.04, 139.05, 136.26, 134.60, 132.56, 130.51, 129.58, 128.97, 128.23, 127.89, 127.80, 126.73, 124.36, 123.73, 120.72, 120.15, 116.80, 115.35, 111.50, 110.78, 109.95, 68.04, 66.18, 49.03, 46.18, 43.46, 42.55, 39.61, 32.03, 31.52, 30.48, 29.55, 29.09, 27.00, 26.68, 23.96, 22.91, 14.50. HRMS-EI m / z + calcd for C 47 H 53 N7NaO 11 S + : 946.3416, found: 946.3412.

[0141] Example 6

[0142] 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-6a)

[0143] Compound I-6a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-6a (45 mg, 0.05 mmol, 57% yield). A yellow solid powder was obtained. mp 144-148°C. 1 H NMR(600MHz,Chloroform-d)δ10.77(s,1H),9.41(s,1H),8.64(d,J=2.2Hz,1H),8.00(s,1H),7.66(s,1H),7.52–7. 47(m,3H),7.45–7.39(m,3H),7.33–7.29(m,1H),6.86(dd,J=8.7,2.9Hz,1H),6.80(s,1H),6.60(d,J=8.5Hz,1H),6. 37(s,1H),4.98–4.89(m,1H),3.89(t,J=6.9Hz,2H),3.68–3.65(m,4H),3.25–3.16(m,2H),3.09–3.02(m,2H),2.94– 2.90(m,4H),2.86–2.68(m,4H),2.51(s,3H),2.19–2.15(m,2H),1.90–1.84(m,3H),1.70(s,3H),1.57–1.45(m,4H). 13C NMR(151MHz,Chloroform-d)δ196.31,172.36,172.06,169.68,168.22,167.66,162.78,159.51, 154.00,150.89,139.18,134.62,134.56,130.70,130.52,129.61,129.00,128.08,127.82,126. 63,125.48,124.41,123.75,120.70,120.12,117.63,110.96,106.06,68.11,66.20,66.16,49.2 1,46.18,43.10,39.26,36.64,32.07,31.59,30.49,27.21,26.02,24.02,22.86,14.48.HRMS-EI m / z[M+Na] + calcd for C 45 H 49 N7NaO 11 S + :918.3103,found:918.3106.

[0144] Example 7

[0145] 4-Acetyl-N-(2-(4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-7a)

[0146] Compound I-7a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-7a (47 mg, 0.05 mmol, 57% yield). A yellow solid powder was obtained. mp 128-130°C.

[0147] 11H NMR (600 MHz, Chloroform-d) δ δ 10.42 (s, 1H), 9.41 (s, 1H), 8.60 (d, J = 2.2 Hz, 1H), 7.63 (s, 1H), 7.52–7.46 (m, 3H), 7.45–7.39 (m, 3H), 7.32 (dd, J = 8.6, 2.2 Hz, 1H), 7.10 (d, J = 7.0 Hz, 1H), 6.83 (t, J = 7.8 Hz, 2H), 6.51 (t, J = 5.4 Hz, 1H), 6.31 (t, J = 5.6 Hz, 1H), 4.92–4.86 (m, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.72–3.66 (m, 4H), 3.60–3.53 (m, 2H), 3.45–3.36 (m, 4H), 2.96–2.92 (m, 4H), 2.85–2.67 (m, 3H), 2.52 (s, 3H), 2.13 (t, J = 7.7 Hz, 2H), 1.98–1.91 (m, 3H), 1.88–1.80 (m, 2H), 1.73 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ δ 195.86, 172.39, 171.69, 169.35, 169.41, 167.26, 159.11, 150.57, 146.31, 138.62, 136.59, 134.27, 132.32, 130.21, 129.33, 129.23, 127.51, 127.40, 126.44, 124.18, 123.45, 120.43, 120.17, 116.57, 111.58, 110.57, 110.11, 70.38, 69.06, 67.71, 65.92, 48.74, 45.88, 42.03, 39.21, 31.66, 31.19, 30.21, 23.60, 22.7I, 14.23. HRMS-EI m / z + calcd for C 45 H 50 N7NaO 12 S + : 912.3233, found: 912.3228.

[0148] Example 8

[0149] 4-Acetyl-N-(2-(4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-8a)

[0150] Compound I-8a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-8a (42 mg, 0.044 mmol, 50% yield). A yellow solid powder was obtained. mp 121-124°C. 1 H NMR(600MHz,Chloroform-d)δ10.46(s,1H),9.38(s,1H),8.62(d,J=2.3Hz,1H),7.61(s,1H),7.54–7.48(m,3H),7.47–7.41 (m,3H),7.34(dd,J=8.7,2.3Hz,1H),7.08(d,J=7.1Hz,1H),6.85(t,J=7.9Hz,2H),6.49(t,J=5.5Hz,1H),6.33(t,J=5.5Hz,1 H),4.96–4.89(m,1H),3.88(t,J=6.6Hz,2H),3.70–3.68(m,4H),3.65–3.60(m,4H),3.58–3.55(m,2H),3.47–3.38(m,4H),2 .98–2.94(m,4H),2.87–2.69(m,3H),2.54(s,3H),2.15(t,J=7.6Hz,2H),2.00–1.93(m,3H),1.90–1.82(m,2H),1.71(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.16,172.09,171.89,169.65,169.21,167.66,159.41,150.8 7,146.81,138.92,136.29,134.57,132.62,130.51,129.63,129.03,127.81,127.70,126.74, 124.48,123.75,120.73,120.37,116.87,111.88,110.87,110.41,70.68,70.14,69.93,69.26 ,68.01,66.22,49.04,46.18,42.33,39.51,31.96,31.49,30.51,23.90,23.01,14.53.HRMS-EI m / z[M+Na] + calcd for C 47 H 53 N7NaO 13 S + :978.3314,found:978.3324.

[0151] Example 9

[0152] 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-13-oxo-3,6,9-trioxa-12-azahexadec-16-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-9a)

[0153] Compound I-9a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.096 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-9a (52 mg, 0.052 mmol, 54% yield). A yellow solid powder was obtained. mp 110-114°C. 11H NMR (600 MHz, Chloroform-d) δ 10.60 (s, 1H), 9.38 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.54–7.48 (m, 3H), 7.47–7.41 (m, 3H), 7.33 (dd, J = 8.6, 2.4 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 6.86 (dd, J = 8.7, 5.6 Hz, 2H), 6.51–6.44 (m, 2H), 4.97–4.91 (m, 1H), 3.88 (t, J = 6.7 Hz, 2H), 3.68–3.66 (m, 4H), 3.63–3.61 (m, 4H), 3.61–3.56 (m, 4H), 3.54–3.50 (m, 2H), 3.44–3.38 (m, 4H), 2.99–2.92 (m, 4H), 2.85–2.71 (m, 3H), 2.53 (s, 3H), 2.23 (s, 2H), 2.16 (t, J = 7.1 Hz, 2H), 2.13–2.07 (m, 1H), 1.90–1.81 (m, 2H), 1.71 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.14, 172.12, 171.98, 169.50, 169.27, 167.71, 159.41, 150.74, 146.80, 139.04, 136.22, 134.57, 132.59, 130.50, 129.60, 129.00, 127.84, 127.75, 126.68, 124.39, 123.71, 120.72, 120.20, 116.88, 111.77, 110.84, 110.35, 70.67, 70.55, 70.42, 70.20, 69.88, 69.41, 68.02, 66.18, 49.01, 46.17, 42.37, 39.37, 31.91, 31.50, 30.49, 23.85, 22.90, 14.47. HRMS-EI m / z + calcd for C 49 H 57 N7NaO 14 S + : 1022.3576, found: 1022.3579.

[0154] Example 10

[0155] 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa-15-azanonadecan-19-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-10a)

[0156] Compound I-10a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-10a (35 mg, 0.034 mmol, 38% yield). It was a yellow solid powder. mp 79.3-81.6°C. 1 H NMR(600MHz,Chloroform-d)δ10.57(s,1H),9.33(s,1H),8.66(d,J=2.3Hz,1H),7.65(s,1H),7.54–7.48(m,3H),7.47–7.40( m,3H),7.34(dd,J=8.5,2.4Hz,1H),7.06(d,J=7.1Hz,1H),6.89–6.84(m,2H),6.81–6.77(m,1H),6.51–6.44(m,1H),4.96–4.8 8(m,1H),3.89(t,J=6.8Hz,2H),3.69–3.67(m,4H),3.63–3.61(m,4H),3.60–3.56(m,6H),3.55–3.51(m,2H),3.45–3.38(m,4 H),2.98–2.94(m,4H),2.84–2.69(m,6H),2.54(s,3H),2.38–2.28(m,2H),2.20–2.15(m,2H),1.90–1.82(m,2H),1.71(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.13,172.07,171.89,169.42,169.20,167.70,159.34,150.71,146. 82,138.96,136.19,134.58,132.60,130.50,129.58,128.97,127.80,126.72,124.34,123.71,120.7 3,120.15,116.86,111.75,110.80,110.37,70.84,70.59,70.49,70.43,70.39,70.21,69.96,69.38, 68.06,66.19,48.99,46.16,42.36,39.32,38.70,31.82,30.48,29.77,23.89,22.91,14.48.HRMS-EI m / z[M+Na] + calcd for C 51 H 61 N7NaO 15 S + :1066.3839,found:1066.3837.

[0157] Example 11

[0158] 4-Acetyl-N-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-11a)

[0159] Compound I-11a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.07 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-11a (49 mg, 0.054 mmol, 78% yield). The product was a yellow solid powder. mp 177-180°C. 11H NMR (600 MHz, Chloroform-d) δ 10.52 (s, 1H), 9.05 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 7.68 (s, 1H), 7.58–7.50 (m, 3H), 7.47–7.40 (m, 2H), 7.35 (dd, J = 8.5, 2.3 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.6, 2.4 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.98–4.94 (m, 1H), 3.95 (t, J = 6.9 Hz, 2H), 3.83–3.77 (m, 2H), 3.70–3.65 (m, 4H), 3.61–3.56 (m, 2H), 3.45–3.36 (m, 4H), 2.99–2.93 (m, 4H), 2.85–2.74 (m, 3H), 2.53 (s, 3H), 2.34 (t, J = 6.8 Hz, 2H), 2.15–2.08 (m, 2H), 1.94–1.86 (m, 2H), 1.71 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.11, 171.70, 170.52, 168.92, 167.89, 167.26, 159.37, 154.99, 150.57, 139.02, 134.60, 134.34, 130.54, 129.63, 129.02, 127.83, 127.58, 126.79, 125.53, 124.36, 123.76, 120.74, 120.38, 120.11, 118.33, 111.01, 108.84, 106.08, 68.02, 66.19, 49.34, 47.34, 47.28, 46.18, 44.64, 41.07, 40.57, 31.54, 30.48, 28.80, 23.38, 22.80, 14.51. HRMS-EI m / z + calcd for C 45 H 47 N7NaO 11 S + : 916.2946, found: 916.2954.

[0160] Example 12

[0161] 4-Acetyl-N-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-12a)

[0162] Compound I-12a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-12a (25 mg, 0.026 mmol, 30% yield). A yellow solid powder was obtained. mp 205-208°C. 1 H NMR(600MHz,Chloroform-d)δ10.31(s,1H),8.71(d,J=2.1Hz,1H),8.69(s,1H),7.70(s,1H),7.63(d,J=8.2Hz,1H),7.57–7. 50(m,3H),7.46–7.42(m,2H),7.37(dd,J=8.6,2.3Hz,1H),6.96(d,J=8.7Hz,1H),6.77(s,1H),6.54–6.46(m,1H),4.96–4.91( m,1H),3.95(t,J=6.8Hz,2H),3.79–3.76(m,4H),3.72–3.69(m,4H),3.64–3.57(m,2H),3.40–3.35(m,2H),3.00–2.96(m,4H), 2.85–2.73(m,3H),2.56(s,3H),2.30(t,J=6.8Hz,2H),2.14–2.08(m,2H),1.91–1.87(m,2H),1.82–1.79(m,4H),1.73(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.15,171.48,170.10,168.82,167.96,167.59,159.3 1,155.06,150.63,138.81,134.59,134.41,130.55,129.65,127.84,127.54,125.43,1 24.38,123.84,120.77,120.16,118.26,114.26,110.97,105.08,66.25,61.02,49.24, 46.21,42.65,39.14,35.13,31.57,30.51,28.81,27.03,23.56,22.88,14.59.HRMS-EI m / z[M+Na] + calcd for C 48 H 51 N7NaO 11 S + :956.3259,found:956.3267.

[0163] Example 13

[0164] 4-Acetyl-N-(2-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-13a)

[0165] Compound I-13a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-13a (37 mg, 0.39 mmol, 45% yield). It was a yellow solid powder. mp 192-194°C. 11H NMR (600 MHz, Chloroform-d) δ 10.58 (s, 1H), 8.97 (s, 1H), 8.71 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.58–7.48 (m, 3H), 7.46–7.42 (m, 2H), 7.36 (dd, J = 8.7, 2.3 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.05–7.03 (m, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.97–4.91 (m, 1H), 3.94 (t, J = 6.7 Hz, 2H), 3.76–3.73 (m, 4H), 3.71–3.67 (m, 4H), 3.37–3.31 (m, 4H), 3.00–2.95 (m, 4H), 2.84–2.72 (m, 3H), 2.54 (s, 3H), 2.11–2.07 (m, 2H), 1.91–1.86 (m, 2H), 1.83–1.76 (m, 4H), 1.72 (s, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.21, 172.28, 171.63, 168.90, 168.00, 167.29, 159.30, 155.12, 150.56, 138.92, 134.64, 134.43, 130.52, 129.56, 128.94, 127.92, 127.90, 126.90, 125.55, 124.33, 123.81, 120.70, 120.06, 119.52, 118.45, 110.87, 109.02, 68.01, 66.24, 66.20, 59.75, 57.52, 49.29, 46.19, 45.21, 34.58, 33.65, 31.55, 30.50, 27.05, 23.11, 22.83, 14.52. HRMS-EI m / z + calcd for C 48 H 52 N7O 11 S + : 934.3440, found: 934.3445.

[0166] Example 14

[0167] 4-Acetyl-N-(2-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-14a)

[0168] Compound I-14a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-14a (27 mg, 0.029 mmol, 34% yield). A yellow solid powder was obtained. mp 187-189°C. 1 H NMR(600MHz,Chloroform-d)δ10.49(s,1H),8.88(s,1H),8.71(d,J=2.2Hz,1H),7.71(s,1H),7.62(d,J=8.2Hz,1H),7.57 –7.48(m,3H),7.46–7.42(m,2H),7.35(dd,J=8.6,2.3Hz,1H),6.93(d,J=8.7Hz,1H),6.74(d,J=2.2Hz,1H),6.51(dd,J=8. 4,2.1Hz,1H),4.97–4.90(m,1H),4.19(d,J=12.3Hz,4H),4.14–4.06(m,4H),3.94(t,J=6.7Hz,2H),3.73–3.67(m,4H),2.9 9–2.94(m,4H),2.89–2.71(m,4H),2.55(s,3H),2.14–2.09(m,1H),2.07(t,J=6.7Hz,2H),1.88–1.84(m,5H),1.73(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.24,171.85,171.56,168.92,167.87,167.51,159.30,154. 56,150.54,138.87,134.64,134.29,130.54,129.59,128.96,127.93,127.88,127.57,126.9 0,125.41,124.29,123.85,120.72,120.03,119.00,114.87,110.88,105.46,67.90,66.22,6 1.65,60.30,58.20,49.28,46.20,33.33,31.56,30.53,27.10,22.99,22.86,14.56.HRMS-EI m / z[M+Na] + calcd for C 46 H 47 N7NaO 11 S + :928.2946,found:928.2950.

[0169] Example 15

[0170] 4-Acetyl-N-(2-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-15a)

[0171] Compound I-15a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-15a (21 mg, 0.023 mmol, 25% yield). It was a yellow solid powder. mp 169-171°C. 11H NMR (600 MHz, Chloroform-d) δ 10.17 (s, 1H), 8.73 (d, J = 2.4 Hz, 1H), 8.55 (s, 1H), 7.71 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.57–7.50 (m, 3H), 7.46–7.43 (m, 2H), 7.38 (dd, J = 8.7, 2.4 Hz, 1H), 7.06–7.01 (m, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.98–4.91 (m, 1H), 3.96 (t, J = 6.8 Hz, 2H), 3.73–3.68 (m, 4H), 3.64–3.59 (m, 2H), 3.45–3.40 (m, 4H), 3.38–3.35 (m, 2H), 3.02–2.96 (m, 4H), 2.87–2.71 (m, 4H), 2.56 (s, 3H), 2.29 (t, J = 6.8 Hz, 2H), 2.15–2.09 (m, 1H), 1.92–1.86 (m, 2H), 1.74 (s, 3H), 1.68–1.60 (m, 4H), 1.55–1.45 (m, 4H). 13 13C NMR (151 MHz, Chloroform-d) δ 196.13, 171.35, 170.05, 168.69, 168.13, 167.38, 162.71, 159.24, 155.34, 150.60, 138.67, 134.61, 134.49, 130.55, 129.64, 129.03, 127.90, 127.50, 127.46, 126.88, 125.56, 124.37, 123.86, 120.79, 120.13, 118.97, 117.72, 110.95, 108.47, 68.17, 66.26, 49.28, 46.21, 43.50, 41.31, 37.64, 36.10, 34.85, 34.66, 31.59, 30.53, 30.16, 28.83, 23.60, 22.88, 14.63. HRMS-EI m / z + calcd for C 50 H 56 N7O 11 S + : 962.3753, found: 962.3764.

[0172] Example 16

[0173] 4-Acetyl-N-(2-(4-((3aR,6aS)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-16a)

[0174] Compound I-16a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.1 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-16a (48 mg, 0.052 mmol, 49% yield). The product was a yellow solid powder. mp 192-193°C. 1 H NMR(600MHz,Chloroform-d)δ10.65(s,1H),9.20(d,J=5.3Hz,1H),8.69(d,J=2.2Hz,1H),7.69(s,1H),7.58(d,J=8.4Hz,1H),7 .55–7.48(m,3H),7.44–7.39(m,2H),7.31(dd,J=8.6,2.3Hz,1H),6.95(d,J=8.8Hz,1H),6.87–6.84(m,1H),6.63–6.59(m,1H),4 .97–4.91(m,1H),3.96–3.87(m,2H),3.81–3.74(m,1H),3.71–3.62(m,6H),3.52–3.46(m,1H),3.33–3.24(m,2H),3.18–3.02(m ,2H),2.95–2.89(m,4H),2.86–2.69(m,3H),2.53(s,3H),2.28–2.21(m,2H),2.16–2.08(m,3H),1.90–1.81(m,2H),1.70(s,3H). 13CNMR(151MHz,Chloroform-d)δ196.14,171.89,170.79,169.17,168.12,167.62,159.35,151. 86,150.55,139.04,134.58,134.41,130.51,129.57,128.96,127.82,127.65,126.61,125.46, 124.28,123.70,120.74,119.88,117.52,115.71,111.02,106.44,68.05,66.15,52.19,52.00 ,50.54,49.98,49.20,46.15,42.39,40.55,30.46,30.22,26.98,23.12,22.83,14.48.HRMS-EI m / z[M+Na] + calcd for C 47 H 49 N7NaO 11 S + :942.3103,found:942.3104.

[0175] Example 17

[0176] 4-Acetyl-N-(2-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-17a)

[0177] Compound I-17a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.1 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-17a (19 mg, 0.02 mmol, 20% yield). It was a yellow solid powder. mp 182-184°C. 11H NMR (600 MHz, DMSO-d6) δ 12.41 (s, 1H), 11.09 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 7.69 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.58–7.55 (m, 3H), 7.47–7.44 (m, 2H), 7.35–7.32 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 6.92 (d, J = 2.2 Hz, 1H), 6.80 (dd, J = 8.6, 2.2 Hz, 1H), 5.10–5.01 (m, 1H), 3.98–3.94 (m, 2H), 3.73–3.63 (m, 2H), 3.63–3.58 (m, 6H), 3.34–3.29 (m, 2H), 3.16–2.99 (m, 2H), 2.92–2.83 (m, 3H), 2.83–2.78 (m, 4H), 2.62–2.52 (m, 2H), 2.47 (s, 3H), 2.31–2.22 (m, 2H), 2.03–1.99 (m, 1H), 1.75–1.68 (m, 2H), 1.64 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 194.29, 172.84, 170.15, 170.07, 167.68, 167.25, 158.76, 157.97, 157.76, 151.91, 149.93, 138.68, 134.34, 133.94, 130.26, 129.36, 129.28, 128.79, 127.57, 127.26, 125.55, 124.94, 123.77, 122.68, 120.69, 118.54, 118.27, 116.28, 116.07, 115.67, 111.59, 105.88, 67.86, 65.32, 54.93, 51.94, 51.75, 49.86, 49.50, 48.73, 45.89, 41.79, 40.06, 40.02, 31.01, 30.12, 29.39, 22.66, 22.26, 13.89. HRMS-EI m / z + calcd for C 47 H 49 N7NaO 11 S + : 942.3103, found: 942.3104.

[0178] Example 18

[0179] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18a)

[0180] Compound I-18a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.702 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-18a (340 mg, 0.343 mmol, 49% yield). It was a yellow solid powder. mp 187-188°C. 1 H NMR(600MHz,Chloroform-d)δ10.29(s,1H),8.85(s,1H),8.73(d,J=2.3Hz,1H),7.70(s,1H),7.65(d,J=8.5Hz,1H),7.57–7.50(m,3H),7.47–7. 41(m,2H),7.38(dd,J=8.7,2.3Hz,1H),7.03(dd,J=8.6,2.4Hz,1H),6.96(d,J=8.6Hz,1H),4.97–4.92(m,1H),3.99–3.89(m,4H),3.73–3.68(m, 4H),3.67–3.60(m,2H),3.43–3.37(m,2H),3.00–2.97(m,4H),2.97–2.9 1(m,2H),2.89–2.70(m,3H),2.56(s,3H),2.45–2.38(m,2H),2.38–2.33 (m,2H),2.28(t,J=6.7Hz,2H),2.21(d,J=7.1Hz,2H),2.14–2.10(m,1H) ,1.90–1.88(m,4H),1.87–1.85(m,2H),1.73(s,3H),1.30–1.21(m,2H). 13C NMR(151MHz,Chloroform-d)δ196.12,171.53,170.07,168.85,168.21,167.42,159.30,155.4 9,150.58,138.77,134.61,134.52,130.55,129.62,129.02,127.90,127.53,126.88,125.55, 124.36,123.82,120.79,120.11,118.67,117.91,110.95,108.69,68.14,66.25,64.14,53.82 ,53.26,49.26,48.09,46.20,33.28,31.59,30.50,30.07,28.76,23.51,22.88,14.59.HRMS-EI m / z[M+Na] + calcd for C 51 H 58 N8NaO 11 S + :1013.3838,found:1013.3843.

[0181] Example 19

[0182] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18b)

[0183] Compound I-18b was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Purification by column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-18b (21 mg, 0.023 mmol, 25% yield). A yellow solid powder with a mp of 187-188°C was obtained. 11H NMR (600 MHz, Chloroform-d) δ 11.29 (s, 1H), 10.85 (s, 1H), 8.74 (d, J = 2.3 Hz, 1H), 7.81 (s, 1H), 7.65 - 7.60 (m, 1H), 7.54–7.41 (m, 5H), 7.35 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.6 Hz, 1H), 3.98–3.85 (m, 4H), 3.76–3.69 (m, 4H), 3.68–3.59 (m, 2H), 3.45–3.36 (m, 2H), 2.99–2.96 (m, 4H), 2.94–2.90 (m, 2H), 2.78–2.69 (m, 3H), 2.55 (s, 3H), 2.40–2.34 (m, 2H), 2.31–2.28 (m, 2H), 2.25 (t, J = 6.8 Hz, 2H), 2.20 (d, J = 7.3 Hz, 2H), 2.15–2.09 (m, 1H), 1.91–1.87 (m, 4H), 1.76–1.69 (m, 2H), 1.53 (s, 3H), 1.40–1.31 (m, 2H). 13 13C NMR (151 MHz, Chloroform-d) δ 187.32, 172.53, 171.12, 166.45, 160.30, 153.50, 149.32, 139.56, 135.54, 133.52, 129.45, 128.62, 128.02, 127.90, 127.53, 126.58, 125.53, 124.37, 123.56, 120.78, 120.31, 118.45, 115.79, 110.88, 108.74, 68.34, 66.65, 64.14, 53.82, 53.56, 49.56, 48.16, 46.22, 33.23, 31.49, 30.46, 30.67, 28.52, 23.62, 21.86, 15.63. HRMS-EI m / z + calcd for C 49 H 58 ClN8O 10 S + : 985.3680, found: 985.3689.

[0184] Example 20

[0185] 4-Acetyl-N-(2-(4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18c)

[0186] Compound I-18c was prepared according to the synthetic procedure of I-1a using s1a-9 (0.1 mmol). Purification by column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-18c (19 mg, 0.02 mmol, 20% yield). It was a yellow solid powder with a mp of 187-188°C. 1 H NMR(600MHz,Chloroform-d)δ11.08(s,1H),10.63(s,1H),8.62(d,J=2.2Hz,1H),7.89(s,1H),7.64–7.60(m,1H),7.54–7.40(m,5H), 7.35(d,J=8.5Hz,1H),7.13(d,J=8.5Hz,1H),6.96(d,J=8.5Hz,1H),3.96–3.83(m,4H),3.81(s,3H),3.74–3.67(m,4H),3.66–3.57(m, 2H),3.43–3.34(m,2H),2.97–2.93(m,4H),2.92–2.88(m,2H),2.76–2.67(m,3H),2.53(s,3H),2.38–2.32(m,2H),2.29–2.26(m,2H),2 .23(t,J=6.7Hz,2H),2.18(d,J=7.2Hz,2H),2.13–2.07(m,1H),1.89–1.85(m,4H),1.74–1.67(m,2H),1.51(s,3H),1.38–1.29(m,2H). 13C NMR(151MHz,Chloroform-d)δ186.50,171.80,170.50,165.70,159.60,152.80,148.60,138 .80,134.80,132.80,128.70,127.90,127.30,127.20,126.80,125.90,124.80,123.70,122 .90,120.10,119.70,117.80,115.10,110.20,108.10,67.70,66.00,63.50,54.80,53.20,5 2.90,48.90,47.50,45.60,32.60,30.80,29.90,30.00,27.90,23.00,21.20,15.00.HRMS-EI m / z[M+H] + calcd for C 50 H 61 N8O 11 S + :981.4175,found:981.4181.

[0187] Example 21

[0188] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18d)

[0189] 4-(2-(4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxamido)-4-(N,N-diethylaminosulfonyl)phenoxy)butanoic acid (0.089 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to obtain the target compound I-18d (33 mg, 0.033 mmol, yield 37%) as a yellow solid powder. mp 125-128°C. 1 H NMR(600MHz,Chloroform-d)δ11.32(s,1H),10.88(s,1H),8.76(d,J=2.4Hz,1H),7.83(s,1H),7.67-7.62(m,1H),7.56–7.43(m,5H) ,7.37(d,J=8.7Hz,1H),7.15(d,J=8.7Hz,1H),6.99(d,J=8.7Hz,1H),3.99–3.87(m,4H),3.70–3.61(m,2H),3.47–3.38(m,2H),3.18( q,J=8.1Hz,4H),2.96–2.92(m,2H),2.80–2.71(m,3H),2.57(s,3H),2.42–2.36(m,2H),2.33–2.30(m,2H),2.27(t,J=6.9Hz,2H),2. 22(d,J=7.4Hz,2H),2.17–2.11(m,1H),1.93–1.89(m,4H),1.78–1.71(m,2H),1.55(s,3H),1.42–1.33(m,2H),1.05(t,J=8.1Hz,6H). 13C NMR(151MHz,Chloroform-d)δ187.35,172.56,171.15,166.48,160.33,153.53,149.35,1 39.59,135.57,133.55,129.48,128.65,128.05,127.93,127.56,126.61,125.56,124.40, 123.59,120.81,120.34,118.48,115.82,110.91,108.77,68.37,64.17,53.85,53.59,49. 59,46.25,38.19,33.26,31.52,30.49,30.70,28.55,23.65,21.89,15.66,11.68.HRMS-EI m / z[M+H] + calcd for C 49 H 60 ClN8O9S + :971.3887,found:971.3893.

[0190] Example 22

[0191] 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (I-18e)

[0192] 4-(2-(4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamido)-4-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)butanoic acid (0.083 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. After thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to afford the target compound I-18e (37 mg, 0.036 mmol, 43% yield) as a yellow solid powder. mp 135-139°C. 1 H NMR(600MHz,Chloroform-d)δ11.12(s,1H),10.67(s,1H),8.65(d,J=2.3Hz,1H),7.92(s,1H),7.66–7.62(m,1H),7.56–7.42(m,5H),7.3 8(d,J=8.6Hz,1H),7.16(d,J=8.6Hz,1H),6.99(d,J=8.6Hz,1H),3.98–3.85(m,4H),3.83(s,3H),3.76–3.69(m,4H),3.68–3.59(m,2H),3. 45–3.36(m,2H),2.99–2.95(m,4H),2.94–2.90(m,2H),2.78–2.69(m,3H),2.55(s,3H),2.40–2.34(m,2H),2.31–2.28(m,2H),2.25(t,J= 6.8Hz,2H),2.27(s,3H),2.20(d,J=7.3Hz,2H),2.15–2.09(m,1H),1.91–1.87(m,4H),1.76–1.69(m,2H),1.53(s,3H),1.40–1.31(m,2H). 13C NMR(151MHz,Chloroform-d)δ186.70,172.00,170.70,165.90,162.90,159.80,153.00,148. 80,139.00,135.00,133.00,128.10,127.00,126.10,125.00,123.90,123.10,120.30,119.90 ,118.50,118.40,118.00,115.30,110.40,108.30,67.90,66.20,63.70,55.00,54.41,53.40, 53.10,49.10,47.70,45.80,32.80,31.00,30.10,30.20,28.10,23.20,21.40,15.20.HRMS-EI m / z[M+H] + calcd for C 50 H 60 F3ClFN9O9S + :1016.3902,found:1016.3898.

[0193] Example 23

[0194] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide (I-18f)

[0195] 4-(2-(4-acetyl-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamido)-4-(morpholinosulfonyl)phenoxy)butanoic acid (0.078 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. After thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to afford the target compound I-18f (36 mg, 0.034 mmol, 43% yield) as a yellow solid powder. mp 132-135°C. 1 H NMR(600MHz,Chloroform-d)δ10.35(s,1H),8.81(s,1H),8.70(d,J=2.2Hz,1H),7.73(s,1H),7.62(d,J=8.4Hz,1H),7.55–7.48(m,3H),7 .44–7.39(m,2H),7.00(dd,J=8.5,2.3Hz,1H),6.93(d,J=8.5Hz,1H),4.94–4.90(m,1H),3.96–3.86(m,4H),3.70–3.65(m,4H),3.64–3.5 7(m,2H),3.40–3.34(m,2H),2.97–2.94(m,4H),2.94–2.88(m,2H),2.86–2.67(m,3H),2.53(s,3H),2.42–2.35(m,2H),2.35–2.30(m,2H) ,2.25(t,J=6.6Hz,2H),2.18(d,J=7.0Hz,2H),2.11–2.07(m,1H),1.87–1.85(m,4H),1.84–1.82(m,2H),1.70(s,3H),1.27–1.18(m,2H). 13C NMR(151MHz,Chloroform-d)δ196.52,171.93,170.47,169.25,168.61,167.82,159.70,155.89, 150.98,139.17,134.91,134.82,130.85,129.92,129.32,128.20,127.83,127.18,126.29,125. 85,124.66,124.12,121.09,120.41,118.97,118.21,111.25,108.99,68.44,66.55,64.44,54.1 2,53.56,49.56,48.39,46.50,33.58,31.89,30.80,30.37,29.06,23.81,23.18,14.89.HRMS-EI m / z[M+Na] + calcd for C 52 H 57 F3N8NaO 11 S + :1081.3712,found:1081.3721.

[0196] Example 24

[0197] 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19a)

[0198] Compound I-19a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.105 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-19a (76 mg, 0.076 mmol, 73% yield). It was a yellow solid powder. mp 174-178°C. 11H NMR (600 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.10 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 7.69 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59–7.55 (m, 3H), 7.48–7.44 (m, 2H), 7.35–7.33 (m, 1H), 7.26–7.21 (m, 2H), 5.11–5.05 (m, 1H), 4.44–4.36 (m, 1H), 4.00–3.92 (m, 2H), 3.83–3.74 (m, 1H), 3.64–3.57 (m, 4H), 3.48–3.40 (m, 4H), 2.99–2.85 (m, 3H), 2.84–2.78 (m, 4H), 2.62–2.51 (m, 4H), 2.48 (s, 3H), 2.33 (t, J = 7.2 Hz, 2H), 2.19–2.11 (m, 1H), 2.04–1.99 (m, 1H), 1.84–1.76 (m, 1H), 1.75–1.68 (m, 4H), 1.65 (s, 3H), 1.00–0.86 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 194.28, 172.83, 170.10, 169.51, 167.58, 167.00, 158.76, 155.20, 149.98, 138.69, 134.35, 133.86, 130.25, 129.36, 128.78, 127.57, 127.23, 125.54, 124.91, 123.79, <122.67, 120.71, 118.61, 118.40, 117.79, 111.61, 107.9 <2, 67.88, 65.33, 52.62, 48.80, 46.81, 45.90, 44.76, 41.10, 40.06, 31.01, 30.14, 28.09, 23.15, 22.21, 13.91. HRMS-EI m / z + calcd for C 51 H 58 N8NaO 11 S + : 1013.3838, found: 1013.3848.

[0199] Example 25

[0200] 5-Acetyl-N-(2-(4-(4-((4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19b)

[0201] Compound I-19b was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Purification by column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-19b (35 mg, 0.035 mmol, 40% yield). It was a yellow solid powder with a mp of 176-180°C. 1 H NMR (600MHz, DMSO-d6) δ12.45(s,1H),11.07(s,1H),8.70(d,J=2.4Hz,1H),7.72(s,1H),7.64(d,J=8.5Hz,1H),7.57–7.5 3(m,3H),7.46–7.42(m,2H),7.32–7.30(m,1H),7.23–7.19(m,2H),5.08–5.02(m,1H),3.97–3.89(m,2H),3.80–3.71(m,1H ),3.61–3.54(m,4H),3.45–3.37(m,4H),2.96–2.82(m,3H),2.81–2.75(m,4H),2.59–2.48(m,4H),2.45(s,3H),2.30(t,J =7.3Hz,2H),2.16–2.08(m,1H),2.01–1.96(m,1H),1.81–1.73(m,1H),1.72–1.65(m,4H),1.62(s,3H),0.97–0.83(m,2H). 13C NMR(151MHz,DMSO-d6)δ194.32,172.87,170.14,169.55,160.31,158.79,155.23,150.0 1,138.72,134.38,133.89,130.28,129.39,128.81,127.60,127.26,125.57,124.94,123 .82,122.70,120.74,118.64,118.43,117.82,111.64,107.95,67.91,55.23,52.65,48.8 3,46.84,45.93,44.79,41.13,40.09,31.04,30.17,28.12,23.18,22.24,13.94.HRMS-EI m / z[M+H] + calcd for C 49 H 58 ClN8O 10 S + :985.3680,found:985.3677.

[0202] Example 26

[0203] 4-Acetyl-N-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-20a)

[0204] Compound I-20a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-20a (33 mg, 0.034 mmol, 38% yield). A yellow solid powder was obtained. mp 182-186°C. 11H NMR (600 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.10 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.56 (p, J = 3.8 Hz, 3H), 7.49–7.44 (m, 2H), 7.36–7.30 (m, 2H), 7.25–7.20 (m, 2H), 5.13–5.01 (m, 1H), 4.05 (d, J = 12.7 Hz, 2H), 3.96 (t, J = 7.0 Hz, 2H), 3.67–3.57 (m, 4H), 3.46–3.42 (m, 2H), 3.37–3.3X (m, 4H), 2.97–2.91 (m, 2H), 2.86–2.79 (m, 4H), 2.61–2.52 (m, 2H), 2.48 (s, 3H), 2.45–2.37 (m, 4H), 2.32 (t, J = 7.0 Hz, 2H), 2.05–1.96 (m, 1H), 1.82–1.76 (m, 2H), 1.75–1.68 (m, 2H), 1.65 (s, 3H), 1.48–1.38 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 194.28, 172.82, 170.12, 169.70, 167.61, 166.97, 158.75, 154.74, 149.95, 138.67, 134.34, 134.03, 130.25, 129.34, 128.76, 127.56, 127.23, 125.57, 125.00, 123.78, 122.66, 120.71, 118.60, 117.68, 111.59, 107.82, 67.XX, 65.31, 60.54, 48.84, 48.76, 48.50, 46.60, 45.88, 45.10, 41.43, 40.05, 31.00, 30.12, 27.95, 27.06, 26.35, 23.05, 22.21, 13.89. HRMS-EI m / z [M+H] + calcd for C 50 H 57 N8O 11 S + : 977.3862, found: 977.3861.

[0205] Example 27

[0206] Note: In the 1H NMR data, "3.37–3.3X (m, 4H)" should be "3.37–3.33 (m, 4H)" in the original text. I have corrected it in the translation. Also, in the 13C NMR data, "67.XX" should be "67.83" in the original text. I have also corrected it in the translation.4-Acetyl-N-(2-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-21a)

[0207] Compound I-21a was prepared according to the synthetic procedure for I-1a using s1a-9 (0.052 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-21a (14 mg, 0.014 mmol, 28% yield). The product was a yellow solid powder. mp 178-179°C. 1 H NMR(600MHz,Chloroform-d)δ10.34(s,1H),8.74(d,J=2.4Hz,1H),8.73–8.69(m,1H),7.73(s,1H),7.69(d,J=8.5Hz,1H),7.57–7.50(m ,3H),7.46–7.43(m,2H),7.38(dd,J=8.6,2.3Hz,1H),7.27(d,J=2.3Hz,1H),7.06(dd,J=8.6,2.4Hz,1H),6.94(d,J=8.7Hz,1H),4.98–4 .92(m,1H),4.06(t,J=8.1Hz,2H),3.96–3.92(m,2H),3.74–3.68(m,4H),3.48–3.35(m,3H),3.23–3.16(m,1H),3.00–2.97(m,4H),2.92 –2.70(m,3H),2.56(s,3H),2.54–2.43(m,3H),2.17–2.10(m,1H),2.12–2.03(m,2H),1.92–1.86(m,2H),1.84–1.75(m,4H),1.73(s,3H). 13C NMR(151MHz,Chloroform-d)δ196.21,172.03,171.40,168.69,167.97,167.31,159. 25,155.40,150.49,138.70,134.67,134.35,130.55,129.59,128.97,128.00,127.90 ,126.99,125.53,124.31,123.90,120.72,120.07,118.43,110.90,108.99,68.03,6 6.25,53.62,49.33,49.25,47.26,46.20,31.58,30.54,23.06,22.86,14.62.HRMS-EI m / z[M+H] + calcd for C 48 H 53 N8O 11 S + :949.3549,found:949.3546.

[0208] Example 28

[0209] 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-22a)

[0210] Compound I-22a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-22a (59 mg, 0.059 mmol, 66% yield). A yellow solid powder was obtained. mp 173-175°C. 11H NMR (600 MHz, DMSO-d6) δ 12.42 (s, 1H), 11.13 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.60–7.55 (m, 3H), 7.49–7.45 (m, 2H), 7.43 (d, J = 7.3 Hz, 1H), 7.34 (dd, J = 8.6, 2.3 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 5.14–5.07 (m, 1H), 3.97 (t, J = 7.1 Hz, 2H), 3.64–3.56 (m, 6H), 3.51–3.42 (m, 2H), 2.92–2.85 (m, 3H), 2.85–2.79 (m, 4H), 2.62–2.52 (m, 2H), 2.48 (s, 3H), 2.37–2.25 (m, 4H), 2.23–2.09 (m, 2H), 2.06–2.00 (m, 1H), 1.86–1.78 (m, 2H), 1.75–1.69 (m, 2H), 1.66 (s, 3H), 1.28–1.22 (m, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 194.25, 172.77, 169.93, 166.72, 166.22, 162.31, 158.75, 158.10, 156.42, 149.94, 138.66, 134.36, 130.26, 129.34, 128.80, 128.75, 127.56, 127.21, 125.58, 123.77, 122.67, 120.70, 118.61, 113.69, 111.97, 111.81, 111.59, 67.81, 65.31, 54.91, 49.85, 49.06, 45.88, 40.06, 35.79, 30.97, 30.12, 27.95, 26.35, 23.02, 22.10, 13.88. 19 19F NMR (565 MHz, DMSO-d6) δ -112.09. HRMS-EI m / z [M + H] + calcd for C 51 H 58 FN8O 11 S + : 1009.3924, found: 1009.3923.

[0211] Example 29

[0212] 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-23a)

[0213] Compound I-23a was prepared according to the synthetic procedure of I-1a using s1a-9 (0.087 mmol). Column chromatography (DCM / MeOH: 100% to 90%) afforded the title compound I-23a (54 mg, 0.053 mmol, 61% yield). A yellow solid powder was obtained. mp 163-167°C. 1 H NMR (600MHz, DMSO-d6) δ12.42(s,1H),11.14(s,1H),8.68(d,J=2.2Hz,1H),7.77–7.71(m,1H),7.69(s,1H),7.62–7.53(m, 3H),7.50–7.45(m,2H),7.37–7.33(m,1H),7.23(d,J=8.8Hz,1H),5.16–5.08(m,1H),4.41(d,J=12.5Hz,1H),4.04–3.91(m, 2H),3.86–3.76(m,1H),3.63–3.59(m,4H),3.31–3.11(m,4H),3.01–2.89(m,2H),2.86–2.80(m,4H),2.63–2.51(m,4H),2. 48(s,3H),2.33(t,J=7.3Hz,2H),2.20–2.02(m,2H),1.77–1.68(m,4H),1.66(s,3H),1.28–1.22(m,4H),1.06–0.85(m,2H). 13 C NMR(151MHz,DMSO-d6)δ194.27,172.76,169.90,169.54,166.64,166.17,158.75, 158.20,156.52,149.95,138.67,134.35,130.25,129.35,128.77,127.57,127.21 ,125.56,123.77,122.67,120.70,118.58,111.58,67.87,65.31,53.62,49.11,45.88,41.86,40.06,30.77,30.12,28.07,23.14,22.08,18.09,16.73,13.88,12.49.19 F NMR(565MHz,DMSO-d6)δ-111.85.HRMS-EI m / z[M+H] + calcd for C 51 H 58 FN8O 11 S + :1009.3924,found:1009.3927.

[0214] Example 30

[0215] 4-Acetyl-N-(2-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1a)

[0216] 2-(2-(4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxamido)-4-(morpholinosulfonyl)phenoxy)acetic acid (0.092 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 2-(2,6-dioxopiperidin-3-yl)-5-(4-(piperazin-1-ylmethyl)piperidin-1-yl)isoindoline-1,3-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound II-1a (40 mg, 0.041 mmol, yield 45%) as a yellow solid powder. mp 165-169°C. 1HNMR(600MHz, DMSO-d6) δ 12.40 (s, 1H), 11.07 (s, 1H), 8.66 (d, J = 2.2 Hz, 1H), 7.67 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.57–7.53 (m, 3H), 7.46–7.42 (m, 2H), 7.33–7.31 (m, 1H), 7.24–7.19 (m, 2H), 5.09–5.03 (m, 1H), 4.79 (s, 2H), 4.42–4.34 (m, 1H), 3.81–3.72 (m, 1H), 3.62–3.55 (m, 4H), 3.46–3.38 (m, 4H), 2.97–2.83 (m, 3H), 2.82–2.76 (m, 4H), 2.60–2.49 (m, 4H), 2.46 (s, 3H), 2.17–2.09 (m, 1H), 2.02–1.97 (m, 1H), 1.82–1.74 (m, 1H), 1.73–1.66 (m, 2H), 1.63 (s, 3H), 0.98–0.84 (m, 2H). 13 C NMR(151MHz, DMSO-d6) δ 194.08, 172.63, 169.90, 169.31, 167.38, 166.80, 158.56, 155.00, 149.78, 138.49, 134.15, 133.66, 130.05, 129.16, 128.58, 127.37, 127.03, 125.34, 124.71, 123.59, 122.47, 120.51, 118.41, 118.20, 117.59, 111.41, 107.72, 67.32, 65.13, 52.42, 48.60, 46.61, 45.70, 44.56, 40.90, 39.86, 30.81, 27.89, 22.01, 13.71. HRMS-EI m / z + calcd for C 49 H 54 N8NaO 11 S + : 985.3525, found: 985.3532.

[0217] Example 31

[0218] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1b)

[0219] 2-(2-(4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxamido)-4-(morpholinosulfonyl)phenoxy)acetic acid (0.092 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound II-1b (37 mg, 0.038 mmol, yield 42%) as a yellow solid powder. mp 185-189°C. 1 HNMR(600MHz,DMSO-d6)δ12.45(s,1H),11.12(s,1H),8.70(d,J=2.2Hz,1H),7.70(s,1H),7.68(d,J=8.3Hz,1H),7 .59–7.56(m,3H),7.48–7.44(m,2H),7.35–7.33(m,1H),7.26–7.21(m,2H),5.12–5.06(m,1H),4.82(s,2H),3.84–3 .75(m,1H),3.65–3.58(m,4H),3.49–3.41(m,4H),3.00–2.86(m,3H),2.85–2.79(m,4H),2.63–2.52(m,4H),2.49(s ,3H),2.20–2.12(m,1H),2.05–2.00(m,1H),1.85–1.77(m,1H),1.76–1.69(m,2H),1.66(s,3H),1.01–0.87(m,2H). 13C NMR(151MHz,DMSO-d6)δ194.38,172.93,170.20,169.61,158.86,155.30,150.08 ,138.79,134.45,133.96,130.35,129.46,128.88,127.67,127.33,125.64,125.0 1,123.89,122.77,120.81,118.71,118.50,117.89,111.71,108.02,67.62,52.7 2,48.90,46.91,46.00,44.86,41.20,40.16,31.11,28.19,22.31,14.01.HRMS-EI m / z[M+Na] + calcdfor C 47 H 54 N8ClO 10 S + :957.3367,found:957.3371.

[0220] Example 32

[0221] 4-Acetyl-N-(2-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1c)

[0222] 2-(2-(4-acetyl-5-methyl-3-phenyl-1H-pyrrole-2-carboxamido)-4-(morpholinosulfonyl)phenoxy)acetic acid (0.092 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-methoxy-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound II-1c (38 mg, 0.039 mmol, yield 43%) as a yellow solid powder. mp 163-167°C. 1 HNMR(600MHz,DMSO-d6)δ12.32(s,1H),11.01(s,1H),8.63(d,J=2.1Hz,1H),7.62(s,1H),7.60(d,J=8.1Hz,1H),7.52 –7.50(m,3H),7.41–7.38(m,2H),7.30–7.28(m,1H),7.20–7.16(m,2H),5.07–5.02(m,1H),4.77(s,2H),3.79(s,3H),3 .80–3.71(m,1H),3.60–3.54(m,4H),3.45–3.37(m,4H),2.95–2.82(m,3H),2.81–2.75(m,4H),2.59–2.48(m,4H),2.4 5(s,3H),2.16–2.08(m,1H),2.01–1.96(m,1H),1.81–1.73(m,1H),1.72–1.65(m,2H),1.62(s,3H),0.97–0.83(m,2H). 13C NMR(151MHz,DMSO-d6)δ193.45,172.11,169.38,168.82,158.01,154.54,149.28,1 38.02,133.72,133.28,129.72,128.73,128.14,126.98,126.65,124.92,124.31,1 23.16,122.09,120.13,118.03,117.82,117.21,111.05,107.38,67.01,55.26,52. 11,48.31,46.27,45.39,44.27,40.61,39.58,30.56,27.67,21.78,13.48.HRMS-EI m / z[M+H] + calcd for C 49 H 58 N7O 11 S + :952.3910,found:952.3915.

[0223] Example 33

[0224] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1d)

[0225] 2-(2-(4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamido)-4-(morpholinosulfonyl)phenoxy)acetic acid (0.089 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound II-1d (40 mg, 0.041 mmol, yield 45%) as a yellow solid powder. mp 182-186°C. 1 H NMR (600MHz, DMSO-d6) δ12.42(s,1H),11.15(s,1H),8.67(d,J=2.2Hz,1H),7.72(s,1H),7.65(d,J=8.3Hz,1H),7. 57–7.53(m,2H),7.46–7.42(m,2H),7.32–7.30(m,1H),7.23–7.20(m,2H),5.10–5.04(m,1H),4.80(s,2H),3.82–3. 73(m,1H),3.63–3.56(m,4H),3.47–3.39(m,4H),2.98–2.84(m,3H),2.83–2.77(m,4H),2.61–2.50(m,4H),2.47(s ,3H),2.18–2.10(m,1H),2.03–1.98(m,1H),1.83–1.75(m,1H),1.74–1.67(m,2H),1.64(s,3H),0.99–0.85(m,2H). 13C NMR(151MHz,DMSO-d6)δ194.18,172.73,170.00,169.41,162.14,158.66,155.10 ,149.88,138.59,134.25,133.76,130.15,129.26,128.68,127.47,127.13,125.4 4,124.81,123.69,122.57,117.69,116.51,116.30,111.51,107.82,67.42,52.5 2,48.70,46.71,45.80,44.66,41.00,39.96,30.91,27.99,22.11,13.81.HRMS-EI m / z[M+Na] + calcd for C 47 H 52 ClFN8NaO 10 S + :997.3092,found:997.3099.

[0226] Example 34

[0227] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1e)

[0228] 2-(2-(4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamido)-4-((4-methylpiperazin-1-yl)sulfonyl)phenoxy)acetic acid (0.087 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. After thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to yield the target compound II-1e (38 mg, 0.038 mmol, 44% yield) as a yellow solid powder. mp 177-181°C. 1 H NMR (600MHz, DMSO-d6) δ12.35(s,1H),11.20(s,1H),8.70(d,J=2.1Hz,1H),7.75(s,1H),7.68(d,J=8.2Hz,1H),7.59– 7.55(m,2H),7.48–7.44(m,2H),7.34–7.32(m,1H),7.25–7.22(m,2H),5.13–5.07(m,1H),4.83(s,2H),3.85–3.76(m, 1H),3.66–3.59(m,4H),3.50–3.42(m,4H),3.01–2.87(m,3H),2.86–2.80(m,4H),2.64–2.53(m,4H),2.50(s,3H),2.2 3(s,3H),2.21–2.13(m,1H),2.06–2.01(m,1H),1.86–1.78(m,1H),1.77–1.70(m,2H),1.67(s,3H),1.02–0.88(m,2H). 13C NMR(151MHz,DMSO-d6)δ194.50,172.40,170.30,169.70,162.40,158.90,155.40,1 50.10,138.80,134.50,134.00,130.40,129.50,128.90,127.70,127.40,125.70,1 25.10,123.90,122.80,117.90,116.80,116.60,111.80,108.10,67.70,52.80,49. 00,47.90,47.00,46.10,44.90,41.30,40.20,31.20,28.20,22.40,14.10.HRMS-EI m / z[M+H] + calcd for C 48 H 56 ClFN9O9S + :988.3589,found:988.3593.

[0229] Example 35

[0230] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1f)

[0231] 2-(2-(4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamido)-4-(N,N-diethylaminosulfonyl)phenoxy)acetic acid (0.091 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to yield the target compound II-1f (41 mg, 0.042 mmol, 46% yield) as a yellow solid powder. mp 175-179°C. 1 H NMR (600MHz, DMSO-d6) δ12.38(s,1H),11.23(s,1H),8.72(d,J=2.2Hz,1H),7.77(s,1H),7.70(d,J=8.3Hz,1H),7.61–7.57(m, 2H),7.50–7.46(m,2H),7.36–7.34(m,1H),7.27–7.24(m,2H),5.15–5.09(m,1H),4.85(s,2H),3.87–3.78(m,1H),3.68–3.61( m,4H),3.52–3.44(m,4H),3.25(d,J=8.5Hz,2H),3.03–2.89(m,3H),2.88–2.82(m,4H),2.66–2.55(m,2H),2.52(s,3H),2.23– 2.15(m,1H),2.08–2.03(m,1H),1.88–1.80(m,1H),1.79–1.72(m,2H),1.69(s,3H),1.04–0.90(m,2H),1.07(t,J=8.2Hz,6H). 13C NMR(151MHz,DMSO-d6)δ194.70,172.60,170.50,169.90,162.60,159.10,155.60 ,150.30,139.00,134.70,134.20,130.60,129.70,129.10,127.90,127.60,125.9 0,125.30,124.10,123.00,118.10,117.00,116.80,112.00,108.30,67.90,53.0 0,49.20,48.10,47.20,45.10,41.50,40.40,31.40,28.40,22.60,14.30.HRMS-EI m / z[M+H] + calcd for C 47 H 55 ClFN8O9S + :961.3480,found:961.3483.

[0232] Example 36

[0233] 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-dimethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1g)

[0234] 2-(2-(4-acetyl-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamido)-4-(N,N-dimethylaminosulfonyl)phenoxy)acetic acid (0.096 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 1-(2-chloro-5-(4-(piperazin-1-ylmethyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to yield the target compound II-1g (45 mg, 0.048 mmol, 50% yield) as a yellow solid powder. mp 165-169°C. 1 H NMR (600MHz, DMSO-d6) δ12.35(s,1H),11.26(s,1H),8.70(d,J=2.3Hz,1H),7.74(s,1H),7.68(d,J=8.4Hz,1H),7.59– 7.54(m,2H),7.48–7.43(m,2H),7.34–7.31(m,1H),7.25–7.21(m,2H),5.12–5.06(m,1H),4.82(s,2H),3.84–3.75(m, 1H),3.65–3.58(m,4H),3.49–3.41(m,4H),3.00–2.86(m,3H),2.85–2.79(m,4H),2.73(s,6H),2.63–2.52(m,2H),2.4 9(s,3H),2.20–2.12(m,1H),2.05–2.00(m,1H),1.85–1.77(m,1H),1.76–1.69(m,2H),1.66(s,3H),1.01–0.87(m,2H). 13C NMR(151MHz,DMSO-d6)δδ194.40,172.30,170.20,169.60,162.30,158.80,155.3 0,150.00,138.70,134.40,133.90,130.30,129.40,128.80,127.60,127.30,125. 60,125.00,123.80,122.70,117.80,116.70,116.50,111.70,108.00,67.60,52.7 0,48.90,47.80,46.90,44.80,41.20,40.10,38.11,31.10,28.10,22.30.HRMS-EI m / z[M+H] + calcd for C 45 H 50 ClFN8NaO9S + :955.2986,found:955.2993.

[0235] Example 37

[0236] 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1a)

[0237] To a solution of 4-acetyl-5-methyl-N-(5-(morpholinosulfonyl)-2-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)phenyl)-3-phenyl-1H-pyrrole-2-carboxamide (0.073 mmol, 1.0 equiv) in N,N-dimethylformamide were added N,N-diisopropylethylamine (DIPEA, 3 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.2 equiv). The mixture was heated to 90°C and stirred for 10 hours. When thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to obtain the target compound III-1a (30 mg, 0.032 mmol, yield 43%) as a yellow solid powder with a mp of 173-177°C. 1HNMR (600 MHz, Chloroform-d) δ 10.31 (s, 1H), 8.87 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.59–7.52 (m, 3H), 7.49–7.43 (m, 2H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 7.05 (dd, J = 8.7, 2.5 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 4.99–4.94 (m, 1H), 4.01–3.91 (m, 4H), 3.84 (d, J = 7.3 Hz, 2H), 3.75–3.70 (m, 4H), 3.69–3.62 (m, 2H), 3.45–3.39 (m, 2H), 3.02–2.99 (m, 4H), 2.99–2.93 (m, 2H), 2.91–2.72 (m, 3H), 2.58 (s, 3H), 2.40–2.35 (m, 2H), 2.26–2.18 (m, 1H), 2.12–2.04 (m, 1H), 1.92–1.90 (m, 4H), 1.89–1.87 (m, 2H), 1.75 (s, 3H), 1.32–1.23 (m, 2H). 13 CNMR (151 MHz, Chloroform-d) δ 196.30, 171.70, 169.00, 168.40, 167.60, 159.50, 155.60, 150.70, 138.90, 134.80, 134.70, 130.70, 129.80, 129.20, 128.10, 127.70, 127.00, 125.70, 124.50, 124.00, 120.90, 120.30, 118.80, 118.10, 111.10, 108.80, 76.40, 68.30, 64.30, 54.00, 53.40, 49.40, 48.20, 46.40, 33.40, 31.90, 31.70, 30.20, 28.90, 23.00, 14.70. HRMS-EI m / z + calcd for C 49 H 55 N7NaO 10 S + : 956.3623, found: 956.3617.

[0238] Example 38

[0239] 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1b)

[0240] To a solution of 4-acetyl-5-methyl-N-(5-(morpholinosulfonyl)-2-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)phenyl)-3-phenyl-1H-pyrrole-2-carboxamide (0.073 mmol, 1.0 equiv) in N,N-dimethylformamide were added N,N-diisopropylethylamine (DIPEA, 3 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione (1.2 equiv). The reaction mixture was heated to 90°C and stirred for 10 hours. When thin layer chromatography (TLC) analysis showed complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to obtain the target compound III-1b (26 mg, 0.027 mmol, yield 37%) as a yellow solid powder. mp 186-189°C. 1 HNMR(600MHz,Chloroform-d)δ10.33(s,1H),8.89(s,1H),8.77(d,J=2.5Hz,1H),7.74(s,1H),7.69(d,J=8.7Hz,1H),7.61–7.54(m,3H),7 .51–7.45(m,1H),7.42(dd,J=8.9,2.5Hz,1H),7.07(dd,J=8.8,2.6Hz,1H),7.00(d,J=8.8Hz,1H),5.01–4.96(m,1H),4.03–3.93(m,4H),3. 86(d,J=7.4Hz,2H),3.77–3.72(m,4H),3.71–3.64(m,2H),3.47–3.41(m,2H),3.04–3.01(m,4H),3.01–2.95(m,2H),2.93–2.74(m,3H),2. 60(s,3H),2.42–2.37(m,2H),2.28–2.20(m,1H),2.14–2.06(m,1H),1 .94–1.92(m,4H),1.91–1.89(m,2H),1.77(s,3H),1.34–1.25(m,2H). 13C NMR(151MHz,Chloroform-d)δδ196.50,171.90,169.20,168.60,167.80,159.70,157.80,1 54.90,139.10,135.00,134.90,130.90,130.00,129.40,128.30,127.90,127.20,125.90, 124.70,124.20,121.10,120.50,119.00,118.30,111.30,109.00,76.60,68.50,64.50,54 .20,53.60,49.60,48.40,46.60,33.60,32.10,31.90,30.40,29.10,23.20,14.90.HRMS-EI m / z[M+Na] + calcd for C 49 H 54 FN7NaO 10 S + :974.3529,found:974.3523.

[0241] Example 39

[0242] 4-Acetyl-N-(2-((1-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1c)

[0243] 4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (0.186 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). The reaction mixture was stirred at room temperature for 0.5 hours. Then, 4-acetyl-5-methyl-N-(5-(morpholinosulfonyl)-2-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)phenyl)-3-phenyl-1H-pyrrole-2-carboxamide (1.1 equivalents) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. After thin-layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound III-1c (50 mg, 0.053 mmol, yield 28%) as a yellow solid powder. mp 193-197°C. 1 H NMR(600MHz,Chloroform-d)δ10.33(s,1H),8.89(s,1H),8.77(d,J=2.3Hz,1H),7.74(s,1H),7.69(d,J=8.5Hz,1H),7.57–7.50(m,3H ),7.47–7.41(m,2H),7.42(dd,J=8.9,2.3Hz,1H),7.07(dd,J=8.8,2.4Hz,1H),7.00(d,J=8.8Hz,1H),4.03–3.93(m,4H),3.86(d,J=7 .2Hz,2H),3.77–3.72(m,4H),3.71–3.64(m,2H),3.47–3.41(m,2H),3.04–3.01(m,4H),3.01–2.95(m,2H),2.93–2.74(m,3H),2.60(s ,3H),2.42–2.37(m,2H),2.28–2.20(m,1H),2.14–2.06(m,1H),1.94–1.92(m,4H),1.91–1.89(m,2H),1.77(s,3H),1.34–1.25(m,2H). 13C NMR(151MHz,Chloroform-d)δ196.50,171.90,167.80,159.70,155.80,150.90,139. 10,135.00,134.90,130.90,130.00,129.40,128.30,127.90,127.20,125.90,124.7 0,124.20,121.10,120.50,119.00,118.30,111.30,109.00,76.60,68.50,54.20,53 .60,49.60,48.40,46.60,33.60,32.10,31.90,30.40,29.10,23.20,14.90.HRMS-EI m / z[M+H] + calcd for C 47 H 55 N7ClO9S + :928.3465,found:928.3470.

[0244] Example 40

[0245] 4-Acetyl-N-(2-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1d)

[0246] 3-(2,4-Dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoic acid (0.198 mmol, 1 equivalent) was added to anhydrous N,N-dimethylformamide (DMF), followed by N,N-diisopropylethylamine (DIPEA, 3 equivalents) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 1.5 equivalents). After stirring at room temperature for 0.5 hour, 4-acetyl-5-methyl-N-(5-(morpholinosulfonyl)-2-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methoxy)phenyl)-3-phenyl-1H-pyrrole-2-carboxamide (1.1 equivalents) was added, and the mixture was stirred at room temperature for 2 hours. When thin layer chromatography (TLC) analysis indicated complete conversion of the starting material, the mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH: 100% to 90%) to give the target compound III-1d (54 mg, 0.059 mmol, yield 29%) as a yellow solid powder. mp 156-159°C.1 HNMR(600MHz,Chloroform-d)δ10.35(s,1H),8.91(s,1H),8.79(d,J=2.4Hz,1H),7.76(s,1H),7.71(d,J=8.6Hz,1H),7.59–7.52(m,3 H),7.49–7.43(m,2H),7.44(dd,J=9.0,2.4Hz,1H),7.09(dd,J=8.9,2.5Hz,1H),7.02(d,J=8.9Hz,1H),4.05–3.95(m,4H),3.88(d,J=7 .3Hz,2H),3.79–3.74(m,4H),3.73–3.66(m,2H),3.49–3.43(m,2H),3.06–3.03(m,4H),3.03–2.97(m,2H),2.95–2.76(m,3H),2.62(s ,3H),2.44–2.39(m,2H),2.30–2.22(m,1H),2.16–2.08(m,1H),1.96–1.94(m,4H),1.93–1.91(m,2H),1.79(s,3H),1.36–1.27(m,2H). 13 CNMR(151MHz,Chloroform-d)δ1196.70,172.10,168.00,159.90,156.00,151.10,13 9.30,135.20,135.10,131.10,130.20,129.60,128.50,128.10,127.40,126.10,124. 90,124.40,121.30,120.70,119.20,118.50,111.50,109.20,76.80,68.70,54.40,5 3.80,49.80,48.60,46.80,33.80,32.30,32.10,30.60,29.30,23.40,15.10.HRMS-EI m / z[M+H] + calcdfor C 47 H 55 FN7O9S + :912.3761,found:912.3755.

[0247] Antitumor biological activity of the compound of Example 41

[0248] 1. Cell proliferation assay

[0249] Human acute leukemia MV4-11 cells (source: ATCC; CRL-9591DSMZ; ACC-102) and human triple-negative breast cancer MDA-MB-231 cells (source: Kunming Cell Bank, Chinese Academy of Sciences) in logarithmic growth phase were seeded in 96-well cell culture plates at a density of 4000 cells / well and 2000 cells / well, respectively (195 μL for MV4-11 plate and 100 μL for MDA-MB-231 plate), and the cells were treated with the indicated concentrations of compounds for 72 h. TM The luminescent cell viability detection reagent (Biyuntian, C0065M) and the test plate were equilibrated to room temperature, and an equal volume of luminescent detection reagent was added to each well of the MV4-11 cell plate. After incubation in the dark for 30 minutes, a multifunctional microplate reader (Thermo) was used for detection. 10 μl of CCK-8 reagent (Abbkine, BMU106-CN) was added to each well of the MDA-MB-231 cell plate and incubated for 2 hours. The absorbance was measured at 450 nm using a small microplate reader (BioTeK). Graphpad Prism was used to analyze the data and plot the graphs. The results are shown in Table 3: Table 1 Anti-proliferative activity of some representative target compounds on cancer cells

[0250]

[0251] Note a: All data were independently repeated at least twice, IC50 was diluted three times starting from 10 μM, and 10 concentration points were tested; b : Wild-type leukemia cell line; c : SHP099-resistant MV4-11 cell line; d : Inhibition rate at 200nM concentration, e : Not tested.

[0252] 2. Western blot analysis

[0253] Human acute leukemia MV4-11 cells (source: ATCC; CRL-9591DSMZ; ACC-102) and human triple-negative breast cancer MDA-MB-231 cells (source: Kunming Cell Bank, Chinese Academy of Sciences) in logarithmic growth phase were cultured at 2*10 6The cells were seeded in small dishes at a density of 100 μg / mL and treated with the compounds at the indicated concentrations for 48 hours. MV4-11 cells were collected and washed with PBS and placed on a shaker for 30 min with cell lysis buffer (RIPA: PMSF: PIC = 99: 1: 1). The lysates were centrifuged at 12,000 rpm for 20 min at 4°C, and the supernatants were collected and tested for protein concentration by BCA (Solarbio, PC0020) assay. Supernatants containing equal total protein were separated on 10% SDS-PAGE gels at 90 V and then blotted onto polyvinylidene fluoride (PVDF) membranes at 300 mA for 90 min. The membrane was blocked in 2% BCS in PBS at room temperature for 90 minutes. After blocking, it was washed three times with 1*TBST, and then incubated with the designated primary antibody at room temperature for one hour, incubated at 4°C overnight, and warmed up on a shaker for 30 minutes the next day. The primary antibody was recovered and washed three times with 1*TBST. It was incubated with the secondary antibody (peoteintech, goat anti-rabbit IgG-HRP, SA00001-2) at room temperature for 90 minutes. After the incubation, the secondary antibody was recovered and washed three times with 1*TBST. The membrane was visualized using an ultrasensitive ECL chemiluminescence kit (NCM, P10100). Finally, the level of the target protein was determined using an exposure instrument (BIORAD). BRD4 (peoteintech, 28486-1-AP), c-MYC (peoteintech, 10828-1-AP) and GAPDH (peoteintech, 10494-1-AP) antibodies were used in all experiments. The results are shown in Figure 2. Figure 1 and Figure 2 shown.

[0254] 3. Cell cycle analysis

[0255] Human acute leukemia MV4-11 cells in the logarithmic growth phase (source: ATCC; CRL-9591DSMZ; ACC-102) and human triple-negative breast cancer MDA-MB-231 cells (source: Kunming Cell Bank, Chinese Academy of Sciences) were seeded into 6-well plates at 100 ul / well and 50 ul / well respectively and incubated overnight. After 24 hours of treatment with the indicated doses of compounds, MV4-11 cells were harvested and washed twice with PBS. MDA-MB-231 cells were harvested with 0.25% EDTA-free trypsin and washed twice with PBS. They were fixed overnight with 75% ethanol in PBS and centrifuged at 2000 rpm for 5 minutes the next day. 500 μl / well of the dye (RNase A:PI = 1:9) in the cell cycle staining kit (Keygen Biosciences, KGA9101-50) was used to stain in the dark for 35 minutes. The percentage of cells in the G1 / G0, S, and G2 / M phases of the cell cycle was analyzed using flow cytometry (ACEA). Statistical analysis was performed using Graphpad Prism software. The results are shown in Figure 3. Figure 3 shown.

[0256] 4. Cell Apoptosis Analysis

[0257] Human acute leukemia MV4-11 cells in the logarithmic growth phase (source: ATCC; CRL-9591DSMZ; ACC-102) and human triple-negative breast cancer MDA-MB-231 cells (source: Kunming Cell Bank, Chinese Academy of Sciences) were seeded in 6-well plates at 100ul / well and 50ul / well and incubated overnight. After the cells were treated with the indicated doses of compounds for 48 hours, the MV4-11 cells were collected and washed twice with PBS, and the MDA-MB-231 cells were collected with 0.25% EDTA-free trypsin and washed twice with PBS. The cells were resuspended in the Binding Buffer in the apoptosis staining kit (Keygen Bio, KGA1102-20), the dye was added and mixed, and the cells were incubated in the dark for 15 minutes. The cell apoptosis experiment was analyzed by flow cytometry (ACEA) to separate the percentages in the Q2-2 and Q2-4 quadrants of the cell cycle. Statistical analysis was performed using GraphpadPrism software, and the results are shown in Figure 2. Figure 4 shown.

[0258] The present invention relates to a novel compound with significant anti-tumor activity and its medical use. Systematic in vitro anti-proliferation experiments have confirmed that the compound of the present invention exhibits excellent proliferation inhibition effects on a variety of hematological malignant tumor cell lines (including MV4-11 acute myeloid leukemia cells) and solid tumor cell lines (MDA-MB-231 breast cancer cells), with a half inhibitory concentration (IC 50) are generally below 50nM, with the optimal compound exhibiting exceptionally strong activity levels of 1-5nM in some cell lines. Notably, the compounds of this invention exhibit a proteasome ubiquitination mechanism: on the one hand, they efficiently degrade BRD4 protein (Western blot analysis showed a >90% decrease in BRD4 protein levels at 1μM after 48 hours of treatment), disrupting oncogene transcriptional regulation. On the other hand, they maintain potent activity in the SHP099-resistant MV4-11 cell model, a property that significantly outperforms existing BET inhibitors and provides a new solution to the problem of clinical drug resistance.

[0259] In-depth mechanism studies have shown that the compound has a typical concentration-effect positive correlation and exhibits a linear dose-effect relationship in the concentration range of 10-100nM. Flow cytometric analysis confirmed that after 48 hours of treatment with the drug concentration, it can induce tumor cell apoptosis and simultaneously enable the drug to block the cell cycle in the G1 phase. This dual mechanism of action effectively blocks the proliferation pathway of tumor cells. Based on the above excellent in vitro activity and clear mechanism of action, the compound of the present invention can be developed as a new type of anticancer drug, which is particularly suitable for the treatment of BRD4-dependent malignant tumors (including but not limited to acute leukemia, triple-negative breast cancer, etc.), and has important application value in different clinical scenarios such as tumor prevention (for high-risk populations), adjuvant therapy (postoperative recurrence prevention) and late palliative treatment.

Claims

1. A compound represented by formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The formula (I) is Among them, BI is a phenylacetylpyrrole-like ligand group recognized / bound by BET proteins; D is the E3 ubiquitin ligase ligand group, which serves as a degradation tag; L is a covalent bond connecting group between BI and D; n is the number of degradation tags connected to the BET protein ligand, and n is selected from 1, 2 or 3.

2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that Said BI is a compound of the general formula (BI-1) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein the general formula (BI-1) is in, A represents a single bond, -C≡CR 1a -、-R 1a -、-R 1a CO-, -NH-, -NR 1a -、-NR 1a CO-、-O-、-OR 1a -、-OR 1a CO-, and R 1a Selected from -C 1-8 Alkyl-, -C 2-8 Alkenyl-, -PEG 1-10 -; The CyA ring is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-8 membered aryl, or 5-8 membered heteroaryl; R 1 For hydrogen, -CN, -NO2, -OR 1b , halogen, -OR 1b 、-SR 1b 、-NR 1b 、-N(R 1b ) 2, independently selected from unsubstituted or substituted halogen, hydroxyl, -C 1-8 -C substituted by alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein R 1b Indicates C 1-8 Alkyl; t represents 1-4; R 2 Selected from hydrogen, halogen, oxo, -CN, -NO2, -OR 2a 、-SO2R 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-C(=NR 2a )NR 2b R 2c 、-SO2N(R 2a R 2b )、-SO2N(R 2a COR 2b ), -SO2NR 2a CONR 2b R 2c )、-SO2N(R 2a CO2R 2b )、-SO2N(R 2a SONR 2b R 2c )、-SO2N(R 2a SO2NR 2b R 2c )、-SO2N(R 2a SO2R 2b ), or independently selected from unsubstituted or substituted by halogen, hydroxy, -C 1-8 Alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl-substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R 2a 、R 2b and R 2c are each independently hydrogen, unsubstituted or substituted with at least one substituent R 2d Replaced by -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or (R 2a and R 2b )、(R 2b and R 2c ), or (R 2c and R 2a ) together with the atom or atoms to which they are attached form a 3- to 9-membered ring, and said ring contains 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being optionally substituted with at least one substituent R 2e replace; R 2e is selected from hydrogen, -C1-8 alkyl, -C2-8 alkenyl, -C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

3. The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that A is selected from a single bond, -O(CH2) 1-8 CO-, -O(PEG) 1-8 CO-; The CyA ring is preferably a naphthalene ring, a quinoline ring, an isoquinoline ring, a benzene ring, a benzodioxolane ring, a benzodioxane ring, a pyridine, a pyrimidine, a pyridazine, a triazole ring, a pyrazole, a thiazole, a thiophene, an oxazole ring, an isoxazole ring, a piperidine, a cycloheptane, a cyclohexane, or a cyclopentane ring; R 1 are independently selected from hydrogen, halogen, -CN, and haloalkyl, and t represents 1-4; R 2 Independently selected 4. The compound according to any one of claims 1 to 3, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The D is an E3 ubiquitination ligase ligand group, and the E3 ligase is selected from vonHippel-Lindau (VHL), Cereblon, XIAP, E3A, MDM2, anaphase promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC 2. HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMU RF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TN FAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cd c4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP(pan), ITCH / AIP4, KAP1, MARCH8, MindBomb 1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5 or ZNRF3; the L is (Linker) u , Each linker independently forms a chemical bond directly, or is selected from C 1-8 Alkylene, C 2-8 Alkyne, -CO-, -O-, -NH-, -CONH-, -NHCO-, -CH(CH3)-, -CHF-, -CF2-, -CH(OCH3)-, or optionally substituted by one or more halogen or C 1-8 Alkyl-substituted cycloalkyl, heterocycloalkyl, heteroaromatic ring or aromatic ring, wherein the cycloalkyl is selected from Wherein the heterocycloalkyl group is selected from: and wherein the aromatic ring is selected from a benzene ring; u is an integer selected from 1-20.

5. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The D has the general formula shown below: Where: Each G is independently selected from CR C2 R C3 NR C2 , CO, or SO2; Y is selected from a single bond, or NH; p is selected from 0, 1 or 2; Each of W1, W2, W3, W4 and W5 is independently selected from N or CR C4 ; Each X5 is independently selected from O or S; Each V1 is independently a direct chemical bond, or is selected from -NH-, -O-, -S-, -SO-, -SO 2- 、-SO2NR C2- 、-CO-、-CO 2- 、-C(O)NR C2 -、-C(S)NR C2 -、-NR C2 CO-、-NR C2 CONR C3 -, unsubstituted or optionally substituted by R C4 Substituted -C 1-8 Alkylene-, -C 2-8 Alkenyl-, -C 2-8 alkynylene-, cycloalkyl, heterocyclyl, aryl, or heteroaryl; Each V2 is independently selected from CR C2 R C3 NR C2 , O or S; Each Z is independently selected from hydrogen, halogen, hydroxy, amino, unsubstituted or replaced by R C5 Substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R C1 、R C2 、R C3 、R C4 and R C5 Selected from hydrogen, carboxyl, cyano, nitro, halogen atoms, -OR C6 、-SO2R C6 、-SO2NR C6 R C7 、-COR C6 、-CO2R C6 、-CONR C6 R C7 、-POR C6 R C7 、-NR C6 R C7 、-NR C6 COR C7 、-NR C6 CONR C7 R C8 、-NR C6 CO2R C7 、-NR C6 SO2NR C7 R C8 、-NR C6 SO2R C7 , unsubstituted or replaced by at least one R C9 Substituted -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; R C6 、R C7 、R C8 and R C9 Selected from hydrogen, halogen, hydroxy, amino, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

6. The compound according to claim 4, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The D is selected from: and V1 directly forms a chemical bond, or is selected from -O-, -CH2-, -N-, -NH-, -CH=CH-; The L is selected from:

7. The compound according to claim 1-6, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The CyA ring is selected from a quinoline ring, a benzene ring, a benzodioxolane ring, a benzodioxane ring, and a pyridine ring; R 1 is selected from hydrogen, -Cl, -F, -CF3, -SMe, -ethyl, -N(Me)2, methyl, t is selected from 1 or 2; A is selected from a single bond, -O(CH2) 1-4 CO-, -O(PEG) 1-2 CO-; R 2 Selected from L is selected from D is selected from 8. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that 4-Acetyl-N-(2-(4-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-1a) 4-Acetyl-N-(2-(4-((3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-2a) 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-3a) 4-Acetyl-N-(2-(4-((5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-4a) 4-Acetyl-N-(2-(4-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-5a) 4-Acetyl-N-(2-(4-((4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)butyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-6a) 4-Acetyl-N-(2-(4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-7a) 4-Acetyl-N-(2-(4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-8a) 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-13-oxo-3,6,9-trioxa-12-azahexadec-16-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-9a) 4-Acetyl-N-(2-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-16-oxo-3,6,9,12-tetraoxa-15-azanonadecan-19-yl)oxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-10a) 4-Acetyl-N-(2-(4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-11a) 4-Acetyl-N-(2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-7-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-12a) 4-Acetyl-N-(2-(4-(7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-13a) 4-Acetyl-N-(2-(4-(6-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,6-diazaspiro[3.3]heptane-2-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-14a) 4-Acetyl-N-(2-(4-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undec-3-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-15a) 4-Acetyl-N-(2-(4-((3aR,6aS)-5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-16a) 4-Acetyl-N-(2-(4-(5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-17a) 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18a) 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18b) 4-Acetyl-N-(2-(4-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18c) 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-18d) 4-Acetyl-N-(2-(4-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (I-18e) 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2-carboxamide (I-18f) 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19a) 4-Acetyl-N-(2-(4-(4-((4-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-19b) 4-Acetyl-N-(2-(4-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-20a) 4-Acetyl-N-(2-(4-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)azetidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-21a) 4-Acetyl-N-(2-(4-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-22a) 4-Acetyl-N-(2-(4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)-4-oxobutoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (I-23a) 4-Acetyl-N-(2-(2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1a) 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1b) 4-Acetyl-N-(2-(2-(4-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (II-1c) 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(morpholinylsulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1d) 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1e) 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-diethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1f) 4-Acetyl-N-(2-(2-(4-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperazin-1-yl)-2-oxoethoxy)-5-(N,N-dimethylaminosulfonyl)phenyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrrole-2-carboxamide (II-1g) 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1a) 4-Acetyl-N-(2-((1-((1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinylsulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1a) 4-Acetyl-N-(2-((1-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1c) 4-Acetyl-N-(2-((1-((1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoyl)piperidin-4-yl)methyl)piperidin-4-yl)methoxy)-5-(morpholinosulfonyl)phenyl)-5-methyl-3-phenyl-1H-pyrrole-2-carboxamide (III-1d). 9 . A pharmaceutical composition comprising the compound according to claim 1 , or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

10. Use of the compound according to any one of claims 1 to 8, or its stereoisomer, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating and / or preventing BET-mediated diseases and related diseases, characterized in that: The BET-mediated diseases and related diseases are selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, mammary duct cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-Hodgkin's lymphoma, colorectal villous adenoma, melanoma, cell tumor, sarcoma or myelodysplastic syndrome.

Images