A protein-targeted degradation compound and its use

Abstract

The present invention relates to a protein-targeted degradation compound and its use. The protein-targeted degradation compound is composed of three parts: M, L, and ULM. M is covalently linked to L, and ULM is covalently linked to L. M represents a MLKL protein inhibitor or an analog thereof with the same function; ULM represents a small molecule ligand of VHL or CRBN protease with ubiquitination function. The present invention selects an inhibitor targeting MLKL protein as an anchoring element, combines the E3 ligase ligand and the MLKL protein inhibitor via a linker, and develops a degrader targeting MLKL protein. Ls specifically recognizes the target protein, while the E3 ligase specifically ubiquitinates the MLKL protein, thereby achieving degradation and clearance.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular, relates to a protein-targeted degradation compound and also to uses thereof. Background Art

[0002] The earliest descriptions of the morphology of cell death date back to the mid-19th century, but the concept of "programmed cell death" was not coined until 1964. In 1973, Schweichael et al. first attempted to categorize cell death. These authors analyzed the response of rat embryos to toxic substances and proposed that cells can undergo type I cell death (apoptosis), type II cell death (autophagy), and type III cell death (necrosis), which is not digested. In 1988, Laster et al. reported that tumor necrosis factor (TNF) induces not only apoptosis but also necrosis, suggesting that necrosis may also be regulated by genetically encoded mechanisms. Since then, increasing evidence has emerged to support the concept of programmed necrosis. In 2005, Yuan Junying's laboratory discovered necrostain-1, a small molecule inhibitor that inhibits TNF-induced regulated necrosis, which they termed necroptosis. In 2008, the molecular target of necrostain-1 was identified as RIPK1. In the same year, a large-scale systems biology study on necrosis reported the discovery of 432 necrosis regulators. In 2009, three different research groups deciphered the necroptosis mechanism of the RIPK1-related kinase RIPK3, a landmark event in the field of necroptosis research.

[0003] In 2012, Wang Xiaodong's laboratory discovered a compound through high-throughput screening that could specifically block the downstream activity of the RIPK3 protein, thereby inhibiting necroptosis. By combining chemical biology and biochemistry, they discovered that the compound targets MLKL, which has been confirmed to be a key substrate in the RIPK3-induced necroptosis process. During necroptosis, after RIPK3 phosphorylates threonine 357 and serine 358 of MLKL, the MLKL monomer becomes unstable and tends to oligomerize. Once MLKL oligomerizes, it can bind to phosphatidylinositol phosphate lipids (PIPs) and cardiolipin, causing MLKL to translocate from the cytoplasm to the cell membrane, triggering an influx of calcium or sodium ions, increasing osmotic pressure, leading to cell membrane collapse, and thus necroptosis. Therefore, MLKL plays the role of "executioner" in necroptosis. Necrosis plays a vital role in the pathogenesis of various diseases, such as ischemia-reperfusion injury, neurodegenerative diseases, infectious diseases (such as viral infection, bacterial infection), liver and kidney damage and tumor metastasis. Therefore, the discovery of necrosis pathway inhibitors is of great significance for necrosis-related diseases. A variety of small molecule inhibitors of MLKL have been reported, but they have not been further developed due to their weak efficacy, unclear structure-activity relationship, high toxicity and unknown efficacy in animals.

[0004] Based on the molecular mechanisms of necrosis, degradation of necrosis-related targets through the ubiquitin-proteasome system is a reasonable strategy to inhibit necrosome formation. Ubiquitin-mediated protein degradation is the most important negative regulatory mechanism for intracellular proteins. This process is carried out through the coordinated action of the ubiquitin-activating enzyme E1, the ubiquitin-conjugating enzyme E2, and the ubiquitin ligase E3. After substrate proteins are ubiquitinated, they are degraded in the proteasome. The specific recognition ability of the ubiquitin ligase E3 for substrate proteins determines the specificity of ubiquitin-mediated protein degradation. PROTAC is an emerging protein targeted degradation technology composed of three parts: a ligand for the target protein, an E3 ubiquitin ligase ligand, and a linker. One end of the PROTAC molecule binds to the target protein, and the other end binds to the E3 ubiquitin ligase. After forming a ternary complex, the E3 ubiquitin ligase adds a ubiquitinated protein tag to the target protein, and the target protein is specifically degraded through the ubiquitin-proteasome pathway. The ubiquitin-proteasome system ubiquitinates and selectively degrades the target protein. Compared with traditional targeted inhibitors, PROTAC has the advantages of catalytic mechanism, stronger efficacy, higher selectivity and less prone to drug resistance.

[0005] To date, there have been no reports of using PROTAC technology to degrade MLKL protein. This disclosure discloses the first designed and synthesized MLKL-PROTAC series of compounds that can effectively degrade MLKL protein by recruiting VHL and CRBN E3 ligases. Summary of the Invention

[0006] One of the objects of the present invention is to provide a group of protein-targeted degradation compounds, their pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotope-labeled compounds, metabolites or prodrugs.

[0007] Another object of the present invention is to provide a method for synthesizing the protein-targeted degradation compound.

[0008] Another object of the present invention is to provide a composition containing the protein targeted degradation compound, or a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug thereof.

[0009] Another object of the present invention is to provide a pharmaceutical composition or pharmaceutical preparation comprising the protein targeted degradation compound, its pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotope-labeled compounds, metabolites or prodrugs as active ingredients, as well as the use of the pharmaceutical composition in treating or preventing tumor-related diseases.

[0010] Definition of terms

[0011] The terminology used in this description of the present invention is intended only to describe specific embodiments and is not intended to limit the invention. The nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and biology described herein are well known and commonly used in the art. Unless otherwise noted, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art.

[0012] As used in the description of the embodiments of the present invention and the appended claims, the singular forms "a," "an," "the," and "its" are intended to refer to both the singular and the plural, unless the context clearly dictates otherwise. For example, a compound includes one or more than one compound.

[0013] As used herein, "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items.

[0014] As used herein, the term "disease" or "disorder" refers to any change in the state of the body or some organ that interrupts or interferes with the performance of its functions and / or causes symptoms.

[0015] As used herein, the term "tumor" refers to a localized mass formed by abnormal cell proliferation in the body due to various pathogenic factors, including benign tumors, malignant tumors, and borderline tumors. Examples include, but are not limited to, breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumors, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic myeloid leukocytosis, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.

[0016] As used herein, the term "treatment" is intended to alleviate or eliminate the disease state or condition being treated. If a subject receives a therapeutic amount of a compound or a pharmaceutically acceptable salt, isomer, polymorph, solvate, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition thereof according to the methods described herein, and the subject exhibits an observable and / or detectable reduction or improvement in one or more signs and symptoms, the subject is successfully "treated." It should also be understood that treatment of the disease state or condition includes not only complete treatment, but also achieving some biologically or medically relevant results while not achieving complete treatment.

[0017] As used herein, the term "subject" may refer to a patient or other animal that receives the composition of the present invention to treat, prevent, alleviate and / or alleviate the disease or condition described in the present invention, and in the present invention, particularly refers to humans and mammals.

[0018] Technical Topic 1

[0019] The present invention provides a compound having a structure as shown in Formula I, and a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug thereof:

[0020]

[0021] Among them, M is covalently connected to L, and ULM is covalently connected to L;

[0022] M represents an MLKL protein inhibitor or an analog thereof with the same function;

[0023] ULM stands for small molecule ligand of VHL or CRBN protease with ubiquitination function;

[0024] L is a linking group representing a substituted or unsubstituted straight or branched alkylene chain, a substituted or unsubstituted spirocyclylene group, a substituted or unsubstituted 1,4-piperazinylene group or a substituted or unsubstituted 1,3-diynylene group, wherein the straight or branched alkylene chain is optionally substituted at the carbon chain end or / and interrupted one or more times by one or more -O-, -CONH-, -NHCO-, -NHCONH-, -NH-, -S-, sulfinyl, sulfonyl, -aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, 1,4-piperazinylene, triazolyl or any combination thereof.

[0025] In some preferred embodiments of the present invention, M represents any compound represented by the following general structural formula:

[0026]

[0027] Among them, R1 represents

[0028] R2 represents H or cyano.

[0029] In some preferred embodiments of the present invention, the ULM represents a compound having a structure as shown in Formula II:

[0030]

[0031] wherein X represents -CH2- or -CO-, Y represents -CH2-, -NH-, or -O-, and Z represents a carbonyl group or is absent.

[0032] In some preferred embodiments of the present invention, the ULM represents a compound having a structure as shown in Formula III:

[0033]

[0034] wherein Q represents a carbonyl group or is absent.

[0035] In some preferred embodiments of the present invention, said L represents:

[0036] ① Substituted or unsubstituted linear or branched C1-C20 alkylene chain;

[0037] ② The linear or branched C1-C20 alkylene chain in ① is interrupted one or more times by one or more -O-, -CONH-, -NHCO-, -NHCONH-, -NH-, -S-, sulfinyl, sulfonyl, -aminosulfonylamino, alkynylene, alkenylene, cycloalkylene, arylene, heterocyclylene, heteroarylene, or any combination thereof;

[0038] ③ One or both ends of the carbon chain of ① or ② are substituted by one or more piperazine groups, arylene groups, cycloalkylene groups, heterocyclylene groups, heteroarylene groups, -CONH-, triazolyl groups, alkynylene groups, alkenylene groups or any combination thereof;

[0039] In some preferred embodiments of the present invention, the substitution is one or more substitutions with one or more substituents selected from hydroxyl, amino, mercapto, halogen or Cm-n alkyl.

[0040] In some preferred embodiments of the present invention, L represents a straight or branched C1-C20 alkylene chain substituted by one or more substituents selected from hydroxyl, amino, mercapto, halogen, Cm-n alkyl or a combination thereof, and the substituents can be selected from any integer from 1 to 10.

[0041] In some preferred embodiments of the present invention, said L represents:

[0042] -(CH2)n1-, -(CH2)n1O(CH2)n2O(CH2)n3-, -(CH2)n1-(O(CH2)n2)m1-, -(CH2)n1-(O(CH2)n2)m1-O-(CH2)n3-, -(CR3R4)n1-(O(CR3R4)n2)m1-O-(CR3R4)n3-, -(CH2)n1-(CONH-(CH2)n2)m1-, -(CH2)n1-CONH-(CH2)n2-, -(CH2)n1-(CONH-(CH2)n2)m1-(CH2)n3-, -(CH2)n1-(O(CH2)n2)m1-O-(CH2)n3-CONH-(CH2)n4-(O(CH2)n5)m2-O-(CH2)n6-, (CR3R4)n1-(O(CR3R4)n2)m1-O-(CR3R4)n3-CONH-(CR3R4)n4-(O(CR3R4)n5)m2-O-(CR3R4)n6-, -(CH2)n1-NHCO-(CH2)n2-, -(CH2)n1-NHCO-(O(CR3R4)n2)m1, -(CH2)n1-NHCO-(CH2)n2-(O(CH2)n3)m!-O-(CH2)n4-, -(CH2)n1-(O(CH2)n2)m1-O-(CH2)n3-NHCO-(CH2)n4-(O(CH2)n5)m2-O-(CH2)n6-, (CR3R4)n1-(O(CR3R4)n2)m1-O-(CR3R4)n3-NHCO-(CR3R4)n4-(O(CR3R4)n5)m2-O-(CR3R4)n!6-, -(CH2)n1-CONH-(O(CR3R4)n2)m1, -(CH2)n1-triazolyl-(CH2)n2-, -(CH2)n1-(O(CH2)n2)m1-O-(CH2)n3-triazolyl-(CH2)n4-(O(CH2)n5)m2-O-(CH2)n6-, -(CH2)n1-triazolyl-(CH2)n2-(O(CH2)n3)m1-O-(CH2)n4-, -(CH2)n1-(O(CH2)n2)m1-O-(CH2)n3-triazolyl-(CH2)n4-, -(CH2)n1-NHCONH-(CH2)n2-, --(CH2)n1-S-(CH2)n2-, -(CH2)n1-SO-(CH2)n2-, -(CH2)n1-SO2-(CH2)n2-, -(CH2)n1-CH=CH-(CH2)n2-,-(CH2)n1-C≡C-(CH2)n2-, -(CH2)n1-piperazinylene-(CH2)n2-, -(CH2)n1-phenylene-(CH2)n2- or -(CH2)n1-piperazinylene-(CH2)n2-phenylene-(CH2)n2-CONH(CH2)n3-;

[0043] R3 and R4 independently represent H, a linear or branched C1-C10 alkyl group or a cycloalkyl group;

[0044] n1, n2, n3, n4, n5, n6, m1, and m2 independently represent an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0045] In some preferred embodiments of the present invention, said L represents:

[0046] -(CH2)2O(CH2)2OCH2-, -CH2O(CH2)2OCH2-, -(CH2)3O(CH2)2OCH2-, -(CH2)3O(CH2)2O(CH2)2-, -(CH2)2OCH2-, -(CH2)2O(CH2)2-, -( CH2)3O(CH2)3-, -(CH2)3O(CH2)2-, -(CH2)2O(CH2)2O(CH2)2-, -(CH2)2O(CH2)2O(CH2)2O(CH2)2-, -(CH2)2O(CH2)2O(CH2)2O(CH2)2O (CH2)2-, -(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2-, -(CH2)3O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2-, -(CH2)3O(CH2)2O( CH2)2O(CH2)2O(CH2)2O(CH2)3-, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2) 10 -、-(CH2) 11 -、-(CH2) 12 -、-(CH2) 13 -、-(CH2) 14 -、-(CH2) 15-、-CH2-NHCO-CH2-、-CH2-NHCO-(CH2)2-、-CH2-NHCO-(CH2)3-、-CH2-NHCO-(CH2)4-、-CH2-NHCO-(CH2)5-、-CH2-NHCO-(CH2)6-、-(CH2)2-NHCO-CH2 -、-(CH2)2-NHCO-(CH2)2-、-(CH2)2-NHCO-(CH2)3-、-(CH2)2-NHCO-(CH2)4-、-(CH2)2-NHCO-(CH2)5-、-(CH2)2-NHCO-(CH2)6-、-(CH2)3-NHCO-CH2 -、-(CH2)3-NHCO-(CH2)2-、-(CH2)3-NHCO-(CH2)3-、-(CH2)3-NHCO-(CH2)4-、-(CH2)3-NHCO-(CH2)5-、-(CH2)3-NHCO-(CH2)6-、-(CH2)4-NHCO-CH2 -、-(CH2)4-NHCO-(CH2)2-、-(CH2)4-NHCO-(CH2)3-、-(CH2)4-NHCO-(CH2)4-、-(CH2)4-NHCO-(CH2)5-、-(CH2)4-NHCO-(CH2)6-、-(CH2)5-NHCO-CH2 -、-(CH2)5-NHCO-(CH2)2-、-(CH2)5-NHCO-(CH2)3-、-(CH2)5-NHCO-(CH2)4-、-(CH2)5-NHCO-(CH2)5-、-(CH2)5-NHCO-(CH2)6-、-CH2-NHCO-CH2-O- (CH2)2-、-(CH2)2-NHCO-CH2-O-(CH2)2-、-(CH2)3-NHCO-CH2-O-(CH2)2-、-CH2-NHCO-CH2-O-(CH2)2-O-(CH2)2-、-(CH2)2-NHCO-CH2-O-(CH2)2-O- (CH2)2-、-(CH2)3-NHCO-CH2-O-(CH2)2-O-(CH2)2-、-(CH2)2-NHCONH-(CH2)2-、-(CH2)3-NHCONH-(CH2)3-、-(CH2)2-NHCONH-(CH2)4-、-(CH2)4-NHCONH-(CH2)5-、-(CH2)3-NHCONH-(CH2)5-、-CH2-CONH-CH2-、-CH2-CONH-(CH2)2-、-CH2-CONH-(CH2)3-、-CH2-CONH-(CH2)4-、-CH2-CONH-(CH2)5-、-CH2-CONH-(CH2)6-, -(CH2)2-CONH-CH2-, -(CH2)2-CONH-(CH2)2-, -(CH2)2-CONH-(CH2)3-, -(CH2)2-CONH-(CH2)4-, -(CH2)2-CONH-(CH2)5-, -(CH2)2-CONH-(CH2)6-, -(CH2)3-CONH-CH2-, -(CH2)3-CONH-(CH2)2-, -(CH2)3-CONH-(CH2)3-, -(CH2)3-CONH-(CH2)4-, -(CH2)3-CONH-(CH2)5-, -(CH2)3-CONH-(CH2)6-, -(CH2)4-CONH-CH2-, -(CH2)4-CONH-(CH2)2-, -(CH2)4-CONH-(CH2)3-, -(CH2)4-CONH-(CH2)4-, -(CH2)4-CONH-(CH2)5-, -(CH2)4-CONH-(CH2)6-, -(CH2)5-CONH-CH2-, -(CH2)5-CONH-(CH2)2-, -(CH2)5-CONH-(CH2)3-, -(CH2)5-CONH-(CH2)4-, -(CH2)5-CONH-(CH2)5-, -(CH2)5-CONH-(CH2)6-, -(CH2)2-S-(CH2)2-, -(CH2)3-S-(CH2)3-, -(CH2)2-S-(CH2)4-, -(CH2)4-S-(CH2)5-, -(CH2)3-S-(CH2)5, -(CH2)2-SO-(CH2)2-, -(CH2)3-SO-(CH2)3-, -(CH2)2-SO-(CH2)4-, -(CH2)4-SO-(CH2)5-, -(CH2)3-SO-(CH2)5-, -(CH2)2-SO2-(CH2)2-, -(CH2)3-SO2-(CH2)3-, -(CH2)2-SO2-(CH2)4-, -(CH2)4-SO2-(CH2)5-, -(CH2)3-SO2-(CH2)5-, -(CH2)2-CH=CH-(CH2)2-, -(CH2)3-CH=CH-(CH2)3-, -(CH2)2-C≡C-(CH2)2-, -(CH2)3-C≡C-(CH2)3-, -NHCO-(CH2)3-, -NHCO-(CH2)-(CH2)4-piperazinylene-(CH2)5-, -(CH2)3-piperazinylene-(CH2)5-, -(CH2)2-phenylene-(CH2)2-, -(CH2)3-phenylene-(CH2)3-, -(CH2)2-phenylene-(CH2)4-, -(CH2)4-phenylene-(CH2)5-, -(CH2)3-phenylene-(CH2)5-, -(CH2)3-NHCO-arylene-piperazinylene-,

[0047]

[0048] 4-diynylidene, Spiro[3,3]heptanylidene, spiro[4,5]decanylidene, spiro[5,5]undecaneylidene, 4-methylspiro[2,4]heptanylidene.

[0049] In some preferred embodiments of the present invention, the compound of formula I is selected from the following:

[0050] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)acetylamino)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0051] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)propionamide)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0052] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)butanamide

[0053] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide

[0054] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)pentanamide

[0055] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0056] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)pentanamide

[0057] (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)hexanamide

[0058] (E)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)heptylamide

[0059] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0060] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0061] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 6 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)adipamide

[0062] (E)-N 1 -(2-((2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 7 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pimelamide

[0063] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)benzamide

[0064] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)benzamide (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide

[0065] (E)-N-(4-(N-(5-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0066] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0067] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0068] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0069] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propionamide)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0070] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)butanamide

[0071] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide

[0072] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0073] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0074] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0075] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0076] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamide)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0077] (E)-2-Cyano-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0078] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)benzamide

[0079] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)benzamide

[0080] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0081] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0082] (E)-2-Cyano-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0083] (E)-2-Cyano-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0084] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0085] (E)-2-Cyano-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0086] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0087] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0088] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0089] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0090] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0091] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)acetamide)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0092] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0093] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0094] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5-(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0095] N 1 -(3-(5-((4-((E)-2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-N 5 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide

[0096] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0097] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0098] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)adipamide

[0099] (2S,4R)-4-Hydroxy-1-((S)-2-(4-(1-(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophene)-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)-1H-1,2,3-triazol-4-yl)butanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0100] (2S,4R)-1-((S)-2-(4-(1-(3-(5-((4-((E)-2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-1H-1,2,3-triazol-4-yl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0101] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0102] 5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide

[0103] 4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanamide

[0104] 6-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hexanamide

[0105] 7-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptylamide

[0106] 2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0107] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0108] 2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0109] 2-(1-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)pentyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0110] (2S,4R)-1-((S)-2-(4-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0111] (2S,4R)-1-((S)-2-(2-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0112] (2S,4R)-1-((S)-2-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0113] (2S,4R)-1-((S)-2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0114] (2S,4R)-1-((S)-2-(2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)acetylamino)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0115] (2S,4R)-1-((S)-2-(4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0116] (2S,4R)-1-((S)-3,3-dimethyl-2-(5-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)pentanoylamino)butanoyl)-4-hydroxy-N-(4-(4)-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0117] (2S,4R)-1-((S)-3,3-dimethyl-2-(7-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)heptanoylamino)butanoyl)-4-hydroxy-N-(4-(4)-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0118] (2S,4R)-1-((S)-3,3-dimethyl-2-(9-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino))pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)nonanoylamino)butanoyl)-4-hydroxy-N-(4-(4)-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0119] 3-((4-((4-(3-(3-(1-(8-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)octyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0120] 3-((4-((4-(3-(3-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0121] 3-((4-((4-(3-(3-(1-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0122] (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)hexanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0123] (2S,4R)-1-((S)-3,3-dimethyl-2-(8-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)octanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0124] 3-((4-((4-(3-(3-(1-(5-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0125] 3-((4-((4-(3-(3-(1-(7-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)heptyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0126] (2S,4R)-1-((2S)-2-(3-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)propionamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0127] (2S,4R)-1-((2S)-2-(5-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0128] (2S,4R)-1-((2S)-2-(7-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)heptylamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0129] (2S,4R)-1-((2S)-2-(9-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0130] (2S,4R)-1-((2S)-2-(4-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0131] (2S,4R)-1-((2S)-2-(6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0132] (2S,4R)-1-((2S)-2-(8-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0133] 6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide

[0134] 4-((6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0135] 4-((5-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0136] 4-((9-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0137] 4-((7-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione.

[0138] As used herein, "halo" or "halogen" may be fluorine, chlorine, bromine or iodine, and is preferably F, Cl, Br.

[0139] As used herein, the term "alkyl," used alone or in combination, refers to a straight or branched chain alkyl group. The term "Cm-n alkyl" (m and n are each integers) refers to a straight or branched chain alkyl group containing x to y carbon atoms. The term "C1-10 alkyl," used alone or in combination in the present invention, refers to a straight or branched chain alkyl group containing 1 to 10 carbon atoms. The C1-10 alkyl group of the present invention is preferably a C1-9 alkyl group, more preferably a C1-8 alkyl group, still more preferably a C2-8 alkyl group, more preferably a C1-7 alkyl group, even more preferably a C1-6 alkyl group, a C1-5 alkyl group, or a C1-4 alkyl group. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. The term "C1-3 alkyl" of the present invention refers to an alkyl group containing 1 to 3 carbon atoms, representative examples of which include methyl, ethyl, n-propyl and isopropyl.

[0140] As used herein, the "alkyl" group is optionally substituted, and the substituents are preferably one or more substituents selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, heterocyclyl, or a combination thereof.

[0141] As used herein, the term "alkylene" (which is used interchangeably with "alkylene chain"), used alone or in combination, refers to a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms. The term alkylene chain refers to a straight or branched alkylene group containing a plurality of carbon atoms. The alkylene chain of the present invention is preferably C1-C30 alkylene, C1-C29 alkylene, C1-C28 alkylene, C1-C27 alkylene, C1-C26 alkylene, C1-C25 alkylene, C1-24 alkylene, C1-C23 alkylene, C1-C22 alkylene, C1-C21 alkylene, C1-C20 alkylene, C1-C19 alkylene, C1-C18 alkylene, C1-C17 Alkylene, C1-C16 alkylene, C1-C15 alkylene, C1-C14 alkylene, C1-C13 alkylene, C1-C12 alkylene, C1-C11 alkylene, C1-C10 alkylene, C1-C9 alkylene, C1-C8 alkylene, C1-C7 alkylene, C1-C6 alkylene, C1-C5 alkylene, C1-C4 alkylene, C1-C3 alkylene, or C1-C2 alkylene. Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene, neopentylene, tert-pentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tetradecylene, pentadecylene, hexadecylene, heptadecylene, octadecylene, nonadecylene, eicosylene, heneicosylene, docosylene, tricosylene, tetracosylene, pentacosylene, hexacosylene, heptacosylene, octacosylene, nonacosylene, and triacontylene.

[0142] As used herein, the term "aryl" used alone or in combination refers to an aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenyl, naphthyl, or fluorenyl. In the present invention, the "aryl" is an optionally substituted aryl. Substituted aryl refers to an aryl group substituted 1-3 times with a substituent selected from C1-3 alkyl, C1-3 alkoxy, halogen, amino, or hydroxy.

[0143] As used herein, the term "arylene" used alone or in combination refers to a divalent aromatic hydrocarbon group containing 5 to 14 carbon atoms and optionally containing one or more fused rings, such as phenylene, naphthylene, or phthalene. In the present invention, the "arylene" is an optionally substituted arylene. Substituted arylene refers to an arylene substituted 1-3 times with a substituent selected from C1-3 alkyl, C1-3 alkoxy, halogen, amino, or hydroxyl.

[0144] As used herein, the term "C1-3 alkoxy," alone or in combination, refers to a straight or branched chain alkoxy group containing 1 to 3 carbon atoms. Representative examples of C1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy. Preferred are methoxy and ethoxy.

[0145] As used herein, the term "cycloalkyl," alone or in combination, refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic hydrocarbon ring having 3 to 12 carbon atoms. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, decahydronaphthalene, octahydropentalene, octahydro-1H-indene, and spirocyclyl.

[0146] As used herein, the term "cycloalkylene," alone or in combination, refers to a saturated or partially unsaturated (i.e., having one or more double bonds, but not fully conjugated) monocyclic or bicyclic hydrocarbon divalent radical having 3 to 12 carbon atoms. Representative examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclopentenylene, cyclohexylene, cyclohexenylene, cycloheptylene, cyclooctylene, decahydronaphthylene, octahydropentalenylene, octahydro-1H-indenylene, and spirocyclylene.

[0147] As used herein, the term "heteroaryl," alone or in combination, refers to a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Representative examples of such heteroaryl groups include, but are not limited to, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzo[2,1,3]oxadi ... ,1,3]thiadiazolyl, benzo[1,2,3]thiadiazolyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-a]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 4H -fluoro[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl and imidazo[2,1-b]thiazolyl. According to the specific definition, heteroaryl groups can be unsubstituted or substituted. Substituted heteroaryl refers to heteroaryl groups that are substituted 1 to 3 times by substituents, wherein the substituents are preferably selected from C1-3 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino or hydroxyl.

[0148] As used herein, the term "heteroarylene," alone or in combination, refers to a 5- to 10-membered monocyclic or bicyclic divalent aromatic ring group containing 1 or more (e.g., 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3) heteroatoms independently selected from oxygen, nitrogen, and sulfur. Representative examples of such heteroarylene groups include, but are not limited to, furanylene, oxazolylene, isoxazolylene, oxadiazolylene, thienylene, thiazolylene, isothiazolylene, thiadiazolylene, pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene, pyrimidylene, pyridazinylene, pyrazinylene, indolylene, isoindolylene, benzofuranylene, isobenzofuranylene, benzothienylene, indazolylene, benzimidazolylene, benzoxazolylene, benzisoxazolylene, benzothiazolylene, benzisothiazolylene, benzotriazolylene, benzo[2,1,3]um The heteroaryl groups may be unsubstituted or substituted. Substituted heteroarylene refers to a heteroarylene group substituted 1 to 3 times by a substituent, wherein the substituent is preferably selected from C1-3 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino or hydroxyl.

[0149] As used herein, the term "heterocyclyl" used alone or in combination refers to a 4- to 6-membered saturated monocyclic monovalent hydrocarbon radical containing one or more heteroatoms independently selected from sulfur, oxygen, and nitrogen. Examples of such heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, triazolyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl, and dioxanyl. The heterocyclyl may be unsubstituted or substituted as specifically defined. Substituted heterocyclyl refers to a heterocyclyl substituted 1-3 times with a substituent, wherein the substituent may preferably be selected from C1-3 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino, or hydroxy.

[0150] In the present invention, the term "heterocyclylene" used alone or in combination refers to a 4- to 6-membered saturated monocyclic bivalent hydrocarbon radical containing one or more heteroatoms independently selected from sulfur, oxygen and nitrogen. Examples of the heterocyclylene include, but are not limited to, azetidinylene, oxetanylene, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, triazolylene, tetrahydrofuranylene, tetrahydrothiophenylene, tetrahydrothiopyranylene, oxazolidinylene, thiazolidinylene, piperidinylene, piperazinylene, morpholinylene, thiomorpholinylene, piperidinylene and dioxanylene. The heterocyclylene may be unsubstituted or substituted as clearly defined. Substituted heterocyclylene refers to a heterocyclylene substituted 1-3 times by a substituent, wherein the substituent may preferably be selected from C1-3 alkyl, C1-3 alkoxy, cyano, trifluoromethyl, heterocyclyl, halogen, amino or hydroxyl.

[0151] As used herein, the term "spirocyclylene" alone or in combination refers to a divalent group derived from the free valence carbon atom of an alicyclic hydrocarbon group in which two carbon rings share a carbon atom. Representative examples include, but are not limited to, spiro[3,3]heptanylene (e.g. ), spiro[4,5]decanediyl, spiro[5,5]undecandiyl, 4-methylspiro[2,4]heptanediyl, etc.

[0152] As used herein, the term "alkynyl," alone or in combination, refers to a straight or branched hydrocarbon group containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon triple bonds. Preferred examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, and 1,3-diynyl.

[0153] As used herein, the term "alkynylene," alone or in combination, refers to a straight or branched divalent hydrocarbon radical containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms and having one or more carbon-carbon triple bonds. Preferred examples of alkynylene include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-diynylene.

[0154] As used herein, the term "alkenyl," alone or in combination, refers to a straight or branched hydrocarbon group containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon double bonds. Preferred examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, and 1-butenyl.

[0155] As used herein, the term "alkenylene," alone or in combination, refers to a straight or branched divalent hydrocarbon group containing 2 to 10 (preferably 2 to 6, more preferably 2 to 4) carbon atoms having one or more carbon-carbon double bonds. Preferred examples of alkenyl groups include, but are not limited to, vinylene (e.g., -CH=CH-), 1-propenylene, and 1-butenylene.

[0156] As used herein, "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the target compound and exhibit minimal undesirable toxicological effects. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of the compound of the present invention with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable bases include salts prepared from inorganic bases and organic bases, and the salts of the inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, and the like. Salts of the organic non-toxic bases include salts of primary, secondary, and tertiary amines, including substituted amines and cyclic amines. For example: N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, guaiac, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid or nitric acid; organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, aminosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, and the like, including salts formed with sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0157] As used herein, "pharmaceutically acceptable ester" refers to an ester formed between the -OH group present in the compounds provided herein and a suitable acid (e.g., a carboxylic acid or an oxygen-containing inorganic acid). Suitable ester groups include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, ethylsuccinates, stearates, or palmitates.

[0158] As used herein, "isomers" refers to the ability of compounds of the present invention to exist as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, single diastereomers, geometric isomers, and the like, when the compounds of Formula I contain one or more asymmetric centers and / or double bonds. These compounds may be represented by the symbols "R" or "S," depending on the configuration of substituents around the stereogenic carbon atom, or by the symbols "Z" or "E," depending on the arrangement of substituents around the carbon-carbon double bond, or the substituents around the carbon-carbon double bond may be referred to as "cis" or "trans." The compounds disclosed herein may exist as tautomers, and both tautomeric forms are intended to be included within the scope of the present invention, even if only one tautomeric structure is depicted, such as keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like.

[0159] As used herein, "polymorphism" means that the compound of Formula I may also exist in various crystalline forms, and different single crystalline forms and polymorphic mixtures thereof can be obtained by recrystallizing the compound or a pharmaceutically acceptable salt thereof in a solvent.

[0160] As used herein, "solvate" means that the compound of formula I may exist in the form of a solvate (e.g., a hydrate) in which the compound of the invention contains a polar solvent, such as water, methanol, or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio.

[0161] As used herein, "isotopes" refer to compounds of Formula I and are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, but with deuterium (2H) or tritium (3H) replacing hydrogen, or with 13C- or 14C-carbon atoms replacing carbon, are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

[0162] As used herein, "prodrug" means that the compound of formula I can also be in the form of a prodrug or can release the active ingredient after metabolic changes in the body. The selection and preparation of appropriate prodrug derivatives are well known to those skilled in the art.

[0163] Technical Topic 2

[0164] The present invention also provides a method for synthesizing the compound represented by Formula I. Although the compound of the present invention can be prepared by the following method, the conditions of the method, such as the reactants, solvents, acids, bases, amounts of the compounds used, reaction temperature, reaction time, etc., are not limited to the following description. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known to those skilled in the art. Such combinations can be readily performed by those skilled in the art to which the present invention relates.

[0165] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 1. Route 1

[0166]

[0167] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 2. Route 2

[0168]

[0169] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 3. Route 3

[0170]

[0171] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 4. Route 4

[0172]

[0173] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 5. Route 5

[0174]

[0175] When M is Formula 1a, when R1 is When R2 is cyano, the M part adopts the method shown in Scheme 6. Scheme 6

[0176]

[0177] When M is Formula 1a, when R1 is When R2 is cyano, the M part adopts the method shown in route 7,

[0178] Route 7

[0179]

[0180] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 8. Route 8

[0181]

[0182] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in Route 9. Route 9

[0183]

[0184] When M is Formula 1a, when R1 is When R2 is H, the M part adopts the method shown in route 10. Route 10

[0185]

[0186] When M is Formula 1b, the M portion adopts the method shown in Scheme 11,

[0187] Route 11

[0188]

[0189] When M is Formula 1c, the M portion adopts the method shown in Scheme 12,

[0190] Route 12

[0191]

[0192] When M is Formula Id, the M portion adopts the method shown in Scheme 13. Scheme 13

[0193]

[0194] When M is Formula 1e, the M portion adopts the method shown in Scheme 14. Scheme 14

[0195]

[0196] Preparation method of intermediate ULM (lenalidomide alkyl carbon chain L):

[0197] Preparation method of intermediate ULM (lenalidomide carbonyl alkyl carbon chain L):

[0198]

[0199] Preparation method of intermediate LM (pomalidomide alkyl carbon chain L):

[0200] Preparation method of intermediate ULM (VHL-1 alkyl carbon chain L):

[0201]

[0202] Preparation method of special intermediate ULM (VHL-1 azide carbon chain L):

[0203]

[0204] General synthetic method of the compound of the present invention:

[0205]

[0206] Technical Theme 3

[0207] The present invention provides a pharmaceutical composition comprising a compound having a substituted benzoheterocyclic structure as shown in Formula I, a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.

[0208] As used herein, a "pharmaceutical composition" comprises a therapeutically effective amount of the polysubstituted benzoheterocyclic compound of Formula I, or a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, elixirs, decoctions, lozenges, mixtures, suppositories, injections, inhalants, or sprays. The pharmaceutical composition preferably contains 0.1% to 99.5% by weight of the polysubstituted benzoheterocyclic compound of the present invention, or a pharmaceutically acceptable salt thereof, as the active ingredient, and more preferably contains 0.5% to 99.5% by weight of the active ingredient.

[0209] As used herein, "pharmaceutically acceptable carriers or excipients" include: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art will understand that certain pharmaceutically acceptable excipients can be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example, when used for oral administration, oral preparations such as tablets, capsules, granules and pills can be prepared, containing fillers (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (e.g., gelatin, polyvinyl pyrrolidone and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants and spices, etc.). When used parenterally, the drug can be prepared as an injection, including sterile powder for injection and solvent for injection. The carrier or excipient used includes sterile water, Ringer's solution, and isotonic sodium chloride solution. Suitable additives such as antioxidants, buffers, and antibacterial agents may also be added depending on the properties of the drug. When used for rectal administration, the drug can be prepared as a suppository, etc. When used for pulmonary administration, the drug can be prepared as an inhaler or spray, etc. There are many resources available to those skilled in the art that describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books such as "Remington's Pharmaceutical Compendium," "Chinese Pharmaceutical Annals," and "Pharmaceutics."

[0210] The present invention can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ocularly, nasally, inhaled, subcutaneously, intramuscularly, buccally, sublingually, orally, orally, or by rectal administration. The compound as described above can be administered in any amount of 1 μg to 2000 mg / kg of subject body weight, for example, 1 μg to 1000 mg / kg body weight / day, 50 μg to 1000 mg / kg body weight / day, 100 μg to 1000 mg / kg body weight / day, 1 to 500 mg / kg body weight / day, 2 to 200 mg / kg body weight / day, or 5 to 100 mg / kg body weight / day. In some embodiments of the present invention, the compound as described above can be administered 4 times a day, 3 times a day, 2 times a day, once a day, once every two days, once a week, or at other intervals, and the dosing regimen as described above can be repeated weekly or monthly as appropriate. In the present invention, the dosage of the compound can be adjusted according to factors such as the severity of the patient's or subject's condition, age, weight, gender, administration method, and treatment course.

[0211] The compounds of the present invention can be used alone or in combination with one or more other active ingredients for the treatment, prevention, suppression or improvement of a disease or condition, wherein the combined use of the drugs is safer or more effective than the use of any one drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention in the manner and amount commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing the other drugs and the compounds of the present invention in a unit dosage form is preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combination therapy can also include administering the compounds of the present invention and one or more other drugs on different overlapping schedules. It can also be expected that, when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used alone. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention also include those compositions containing one or more other active ingredients.

[0212] Technical Theme 4

[0213] The present invention also provides the use of a PROTAC compound of Formula I, its pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotope-labeled compounds, metabolites or prodrugs in the preparation of drugs for anti-tumor, inflammation, anti-fibrosis, liver injury, ischemia-reperfusion injury, infectious diseases and neurodegenerative diseases.

[0214] In some embodiments of the present invention, the compound of formula I, its pharmaceutically acceptable salts or esters, solvates, isomers, polymorphs, isotope-labeled compounds, metabolites or prodrugs are used in therapeutic treatment. In some embodiments of the present invention, the therapeutic treatment is used to treat related diseases such as tumors, inflammation, fibrosis, liver damage, ischemia-reperfusion injury, infectious diseases and neurodegenerative diseases.

[0215] In some embodiments, the disease of interest is atherosclerosis, abdominal aortic aneurysm (AAA) disease, acute disseminated encephalomyelitis, Moyamoya disease, Takayasu disease, acute coronary syndrome, transplant heart and vascular disease, pneumonia, acute respiratory distress syndrome, pulmonary fibrosis, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, bullous pemphigoid, Chagas disease, chronic obstructive pulmonary disease, celiac disease, dermatomyositis, type 1 diabetes, type 2 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, disease), idiopathic thrombocytopenic purpura, interstitial cystitis, systemic lupus erythematosus (SLE), metabolic syndrome, multiple sclerosis, myasthenia gravis, myocarditis, narcolepsy, obesity, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, rheumatoid arthritis, schizophrenia, scleroderma, Sjögren's syndrome, vasculitis, vitiligo, Wegener's granulomatosis, allergic rhinitis, prostate cancer, non-small cell lung cancer, ovarian cancer, breast cancer, melanoma, gastric cancer, colorectal cancer, brain cancer, metastatic bone disease, pancreatic cancer, type A lymphoma, nasal polyps, gastrointestinal cancer, ulcerative colitis, Crohn's disease disorder), collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Bethesda syndrome, infectious colitis, indeterminate colitis, inflammatory liver disease, endotoxic shock, septic shock, rheumatoid spondylitis, ankylosing spondylitis, gouty arthritis, polymyalgia rheumatica, Alzheimer's disease, Parkinson's disease disorder), epilepsy, AIDS dementia, asthma, adult respiratory distress syndrome, bronchitis, fibrosis, leukocyte-mediated acute lung injury, distal proctitis, Wegener's granulomatosis, fibromyalgia, bronchitis, uveitis, conjunctivitis, psoriasis, eczema, dermatitis, smooth muscle proliferative disease, meningitis, herpes zoster, encephalitis, nephritis, tuberculosis, retinitis, atopic dermatitis, pancreatitis, periodontitis, coagulative necrosis, liquefactive necrosis, fibrinoid necrosis, neointimal hyperplasia, myocardial infarction, stroke, organ transplant rejection, influenza, or a combination thereof.

[0216] In some embodiments of the present invention, the present invention relates to a method for binding to MLKL protein in vivo or in vitro, comprising the step of administering to a subject or mammalian cell an effective amount of any one of the compounds of Formula I of the present invention, or a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug thereof.

[0217] In some embodiments of the present invention, the present invention relates to a method for inhibiting MLKL kinase activity in vivo or in vitro, comprising the step of administering to a subject or mammalian cell an effective amount of any one of the compounds of Formula I of the present invention, or a pharmaceutically acceptable salt or ester, solvate, isomer, polymorph, isotope-labeled compound, metabolite or prodrug thereof.

[0218] Advantageous Effects of the Invention

[0219] The compound developed by the present invention is a degrader targeting a specific protein. It consists of three parts: a target protein anchoring element, a protein degradation system (such as an E3 ligase) recruitment element, and a linker. The present invention selects an inhibitor targeting the MLKL protein as the anchoring element, and combines the E3 ligase ligand and the MLKL protein inhibitor via the linker to develop a degrader targeting the MLKL protein. Through the specific recognition of the target protein by the Ls, the E3 ligase specifically ubiquitinates the MLKL protein, thereby achieving degradation and clearance. BRIEF DESCRIPTION OF THE DRAWINGS

[0220] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for describing the specific embodiments.

[0221] Figure 1 The results are the in vitro degradation activity of the representative compounds of the present invention on the target protein MLKL.

[0222] Figure 2 The inhibitory activity of the representative compounds of the present invention on cell anti-necrosis: A is a bar graph of cell survival rate; B is an electron micrograph of cell survival. DETAILED DESCRIPTION

[0223] The present invention is described below in conjunction with specific examples. These examples are not intended to limit the scope of the present invention, but rather to provide guidance for those skilled in the art to prepare and use the compounds, compositions, and methods of the present invention. Where specific conditions are not specified in the examples, conventional conditions or manufacturer's recommended conditions were used. Reagents or instruments used, for which the manufacturer is not specified, are commercially available conventional products.

[0224] The chemical names of the compounds described in this application follow the principles of IUPAC nomenclature.

[0225] Example 1

[0226]

[0227] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0228] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)acetylamino)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0229] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=7.5Hz,1H),8.15(s,1H),7.92–7.78(m,4H),7.77–7.69(m,2H),7.65(d,J=2 .1Hz,1H),7.13–6.97(m,2H),6.89(d,J=15.1Hz,1H),6.74(dd,J=7.4,2.1Hz,1H),5.74(s,1H),5.46(d,J=19. 3Hz,1H),4.67(t,J=7.0Hz,1H),4.25–4.14(m,2H),3.89(d,J=11.9Hz,4H),3.13–2.94(m,2H),2.88(dddd,J=1 2.4,11.1,9.0,5.7Hz,2H),2.76–2.53(m,2H),1.98(dq,J=13.2,7.0Hz,1H),0.90(tdd,J=9.5,7.2,5.2Hz,2H).

[0230] Example 2

[0231]

[0232] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)propanamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0233] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)propionamide)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0234] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=7.5Hz,1H),8.03(s,1H),7.90–7.69(m,7H),7.36(dd,J=7.5,2.0Hz,1H),7. 17(t,J=7.5Hz,1H),6.93–6.81(m,2H),6.72(dd,J=7.5,2.1Hz,1H),5.59(d,J=19.3Hz,1H),4.62(t,J=6.9Hz,1 H),4.00(d,J=19.3Hz,1H),3.91(s,3H),3.67(td,J=12.3,1.6Hz,1H),3.55–3.45(m,1H),3.14–2.84(m,4H),2 .73–2.64(m,2H),2.68–2.52(m,2H),2.23–2.11(m,1H),1.92–1.73(m,3H),1.58(qdd,J=12.5,2.8,1.7Hz,1H).

[0235] Example 3

[0236]

[0237] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)butanamide

[0238] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)butanamide

[0239] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.77(s,1H),10.65(s,1H),8.15(d, J=4.3Hz,1H),7.95(d,J=8.8Hz,2H),7.85(s,1H),7.83(dd,J=4.2,2.2Hz,2 H),7.79(s,1H),7.62(s,1H),7.58(d,J=4.5Hz,1H),7.25(t,J=7.7Hz,1H), 6.93–6.85(m,2H),6.73(d,J=8.1Hz,1H),5.63(t,J=5.5Hz,1H),5.11(dd,J= 13.2,5.1Hz,1H),4.25–4.08(m,2H),3.87(s,3H),3.13–3.08(m,2H),3.05( q,J=6.6,5.9Hz,2H),2.97–2.87(ddd,J=17.5,13.7,5.5Hz,1H),2.61(d,J=1 6.3Hz,1H),2.57–2.52(m,2H),2.31–2.25(m,1H),2.16(t,J=7.0Hz,2H),2. 03–1.99(m,1H),1.79(dt,J=12.3,6.2Hz,2H),1.72(dt,J=14.0,6.3Hz,2H).

[0240] Example 4

[0241]

[0242] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)pentanamide

[0243] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide

[0244] 1 H NMR (600MHz, DMSO-d6) δ10.98(s,1H),10.74(s,1H),10.63(s,1H),8.13(d,J=4.4Hz,1H),7.95(dd,J=8.9,2.5Hz,2H),7.84(dd,J=9.0,2.3Hz,2H),7.8 2–7.78(m,2H),7.63–7.59(m,1H),7.57(t,J=4.0Hz,1H),7.24(t,J=7.7Hz, 1H),6.92–6.86(m,2H),6.72(d,J=8.0Hz,1H),5.55(t,J=5.4Hz,1H),5.10(d d,J=13.3,5.1Hz,1H),4.24–4.10(m,2H),3.88(s,3H),3.11(dt,J=12.5,7. 1Hz,2H),3.04(q,J=6.7Hz,2H),2.95–2.90(m,1H),2.62(d,J=13.7Hz,1H),2 .54(t,J=7.5Hz,2H),2.29(qd,J=13.3,4.5Hz,1H),2.08(t,J=7.1Hz,2H),2 .03(dtd,J=12.7,5.3,2.5Hz,1H),1.72(p,J=7.2Hz,2H),1.61–1.51(m,4H).

[0245] 13 C NMR(151MHz,DMSO-d6)δ173.34,172.37,171.68,169.35,163.23,163.21,161.30, 151.14,151.12,146.93,144.17,143.05,143.04,132.91,132.50,131.25,130.84, 130.81,129.61,129.19,126.93,126.05,119.19,112.18,110.38,66.57,53.93,51.98,49.06,46.21,42.93,38.38,35.62,31.71,31.18,29.04,28.57,23.43,23.29.

[0246] Example 5

[0247]

[0248] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide

[0249] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)pentanamide

[0250] 1 H NMR (600MHz, DMSO-d6) δ10.97(s,1H),10.85(s,1H),10.69(s,1H),8.55(s,1H),8.26–8.23(m,1H),7.97(d,J=8.8Hz,2H),7.91(d,J=4.4Hz,1H),7. 83(d,J=8.6Hz,2H),7.73–7.64(m,1H),7.60(s,1H),7.26–7.21(m,1H),6. 90(d,J=7.4Hz,1H),6.71(d,J=8.0Hz,1H),5.07(dd,J=13.2,5.1Hz,1H),4 .23–4.08(m,2H),3.87(s,3H),3.10(t,J=6.6Hz,2H),3.03(q,J=6.7Hz,2 H),2.89(ddd,J=18.0,13.7,5.4Hz,1H),2.61(d,J=15.8Hz,1H),2.53(t,J =7.4Hz,2H),2.30(qd,J=13.2,4.3Hz,1H),2.07(t,J=6.8Hz,2H),1.96(q, J=6.6Hz,1H),1.71(p,J=7.1Hz,2H),1.55(ddt,J=19.7,14.0,6.9Hz,4H).

[0251] Example 6

[0252]

[0253] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0254] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0255] 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.32(d,J=7.5Hz,1H),8.05(s,1H),7.87–7.75(m,2H),7 .77–7.65(m,4H),7.25–7.11(m,2H),6.93–6.81(m,3H),4.74–4.60(m,2H),4.10–3.97(m,2H), 3.93(s,3H),3.62(td,J=12.3,2.9Hz,1H),3.52–3.39(m,2H),2.97(dt,J=15.2,7.1Hz,1H),2 .80–2.57(m,2H),2.49–2.25(m,2H),2.24–2.04(m,2H),1.82–1.60(m,2H),1.58–1.43(m,1H).

[0256] Example 7

[0257]

[0258] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyraz in-2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide

[0259] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)pentanamide

[0260] 1 H NMR(400MHz, DMSO-d6)δ8.70(s,1H),8.45–8.36(m,2H),8.26(s,1H),7.94(d,J=7.5Hz,1H),7.84–7.78(m,2H),7.76–7.69(m,2H),7.23(dd ,J=7.5,2.1Hz,1H),7.14(t,J=7.5Hz,1H),6.86–6.77(m,2H),4.93(d,J=19.3Hz,1H),4.63(t,J=7.0Hz,1H),4.18(d,J=19.3Hz,1H),3.91( d,J=12.5Hz,1H),3.91(s,3H),3.51(d,J=12.5Hz,1H),3.26(dtd,J=41.8,12.4,3.1Hz,2H),2.92(dt,J=15.1,7.0Hz,1H),2.64(dt,J=15.1 ,7.0Hz,1H),2.58–2.44(m,1H),2.39–2.19(m,2H),2.04–1.87(m,2H),1.81–1.65(m,1H),1.43–1.27(m,1H),1.17(qt,J=12.4,2.6Hz,1H).

[0261] Example 8

[0262]

[0263] (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)hexanamide

[0264] (E)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)hexanamide

[0265] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),10.92(s,1H),10.64(s,1H),8.89(s,1 H),8.14(d,J=4.3Hz,1H),7.95(d,J=8.9Hz,2H),7.86(d,J=9.0Hz,2H),7.83 –7.77(m,2H),7.62(s,1H),7.57(d,J=4.5Hz,1H),7.25(t,J=7.7Hz,1H),6.9 8–6.89(m,2H),6.71(d,J=7.9Hz,1H),5.10(dd,J=13.3,5.1Hz,1H),4.24–4.0 9(m,2H),3.88(s,3H),3.09(dd,J=7.6,5.8Hz,2H),3.03(q,J=6.7Hz,2H),2. 92(ddd,J=17.5,13.6,5.4Hz,1H),2.61(d,J=16.8Hz,1H),2.55–2.51(m,2H) ,2.28(qd,J=13.2,4.5Hz,1H),2.04(t,J=7.4Hz,2H),2.01–1.95(m,1H),1.7 1(p,J=7.2Hz,2H), 1.53(dh,J=23.3,7.7Hz,4H), 1.34(dd,J=6.1,3.7Hz,2H).

[0266] 13C NMR (101MHz, DMSO) δ172.89,171.91,171.25,168.87,162.78,150.64,146.53,143.72,142.6 6,132.38,132.02,130.81,130.35,129.18,128.70,126.45,125.67,118.69,111.68,109.88 ,54.92,53.48,53.42,51.48,45.74,42.61,41.69,40.15,39.94,39.73,39.52,39.31,39.10,38.89,37.86,35.39,31.24,30.71,28.56,28.29,26.30,25.15,22.84,18.01,16.71,12.30.

[0267] Example 9

[0268]

[0269] (E)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)heptanamide

[0270] (E)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)heptylamide

[0271] 11H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 11.00 (s, 1H), 10.64 (s, 1H), 9.13 (s, 1H), 8.13 (d, J = 4.3 Hz, 1H), 7.97–7.86 (m, 4H), 7.79 (d, J = 15.2 Hz, 2H), 7.62 (s, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 7.00 (d, J = 15.6 Hz, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.25–4.10 (m, 2H), 3.87 (s, 3H), 3.60 (dd, J = 6.6, 2.7 Hz, 2H), 3.09–3.06 (m, 2H), 3.03 (q, J = 6.8 Hz, 2H), 2.97–2.87 (m, 1H), 2.61 (d, J = 17.2 Hz, 1H), 2.56–2.51 (m, 2H), 2.29 (qd, J = 13.3, 4.4 Hz, 1H), 2.03 (t, J = 7.2 Hz, 3H), 1.71 (p, J = 7.2 Hz, 2H), 1.59–1.52 (m, 2H), 1.48 (dt, J = 15.0, 7.5 Hz, 2H), 1.39–1.31 (m, 2H).

[0272] 13 13C NMR (101 MHz, DMSO) δ 172.92, 172.00, 171.26, 168.90, 162.83, 150.64, 146.59, 143.74, 142.73, 132.32, 132.03, 130.82, 130.31, 129.19, 128.69, 126.49, 125.77, 118.69, 111.70, 109.91, 54.93, 53.49, 53.38, 51.51, 45.79, 42.74, 41.65, 40.15, 39.94, 39.73, 39.52, 39.31, 39.10, 38.89, 37.88, 35.40, 31.26, 30.72, 28.57, 28.42, 26.43, 25.30, 22.85, 17.99, 16.71, 12.25.

[0273] Example 10

[0274]

[0275] (E)-N 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)glutaramide

[0276] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0277] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.90(s,1H),10.65(s,1H),9.82(s,1H),8.88(s,1H),8.15(d,J=4.3Hz,1H),7.96(d,J=8.9Hz ,2H),7.87(d,J=9.0Hz,2H),7.84–7.78(m,2H),7.64(s,1H),7.58(d,J=4.5Hz,1H),7.52–7.45(m,2H),6.94(d,J=15.6Hz,1H),5.14(d d,J=13.3,5.1Hz,1H),4.43–4.31(m,2H),3.89(s,3H),3.06(q,J=6.7Hz,2H),2.92(ddd,J=17.4,13.6,5.4Hz,1H),2.60(d,J=18.2Hz, 1H),2.55(t,J=7.6Hz,2H),2.40–2.29(m,3H),2.13(t,J=7.3Hz,2H),2.04–1.99(m,1H),1.82(p,J=7.4Hz,2H),1.73(p,J=7.5Hz,2H).

[0278] Example 11

[0279]

[0280] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0281] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 5 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0282] 1 H NMR (400MHz, DMSO-d6) δ9.53(s,1H),8.52(s,1H),8.35(d,J=7.6Hz,1H),8.27(s,1H),7.88–7.75(m,4H),7.77–7.62(m,3H),7. 46(dd,J=7.6,2.1Hz,1H),7.37(t,J=7.5Hz,1H),6.89(d,J=15.1Hz,1H),5.78(d,J=19.3Hz,1H),4.60(t,J=7.0Hz,1H),4.34(d, J=19.3Hz,1H),3.98(d,J=12.5Hz,1H),3.92(s,3H),3.54(d,J=12.3Hz,1H),3.07–2.86(m,2H),2.71–2.55(m,2H),2.59–2.48(m ,2H),2.48–2.30(m,2H),2.28(dddd,J=16.1,12.1,4.3,1.9Hz,2H),2.03(td,J=12.5,2.7Hz,1H),1.88(dq,J=13.2,7.0Hz,1H).

[0283] Example 12

[0284]

[0285] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 6-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)adipamide

[0286] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 6 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)adipamide

[0287] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.89(d,J=12.7Hz,1H),10.65(s,1H),9.83(s,1H),8.79(s,1H),8.14(d,J=4.2Hz,1H),7.96 (d,J=8.7Hz,2H),7.87(d,J=8.7Hz,2H),7.85–7.78(m,3H),7.58(d,J=4.2Hz,1H),7.51–7.44(m,2H),6.95(dd,J=15.6,6.2Hz,1H), 5.14(dd,J=13.2,4.8Hz,1H),4.44–4.29(m,2H),3.88(s,3H),3.05(q,J=6.3Hz,2H),2.92(ddd,J=17.8,13.8,4.9Hz,1H),2.65–2.5 7(m,1H),2.56(d,J=7.7Hz,2H),2.41–2.32(m,3H),2.10(dt,J=13.0,6.7Hz,2H),2.02(dd,J=10.5,5.2Hz,1H),1.71(dq,J=14.8,7.0 Hz,2H),1.56(s,4H).

[0288] 13C NMR(101MHz,DMSO)δ172.85,171.80,171.24,171.05,167.83,162.79,150.65,149.44,146.54, 142.67,135.26,133.79,133.76,132.65,132.40,131.37,130.82,130.35,128.73,128.57,125. 67,125.25,118.96,118.70,53.44,51.52,46.50,41.71,40.15,39.94,39.73,39.52,39.31,39.10,38.89,37.90,35.62,35.19,31.21,30.71,28.59,24.96,24.86,22.62,18.01,16.71,12.32.

[0289] Example 13

[0290]

[0291] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 7 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)heptanediamide

[0292] (E)-N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-N 7 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pimelamide

[0293] 11H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 10.95 (s, 1H), 9.82 (s, 1H), 9.25 (s, 1H), 8.13 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.83–7.76 (m, 3H), 7.59 (s, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.50–7.43 (m, 2H), 6.97 (d, J = 15.6 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.42–4.30 (m, 2H), 3.87 (s, 3H), 3.02 (q, J = 6.7 Hz, 2H), 2.96–2.86 (m, 1H), 2.60 (d, J = 16.9 Hz, 1H), 2.53 (s, 2H), 2.34 (p, J = 5.3 Hz, 3H), 2.03 (q, J = 7.6 Hz, 3H), 1.70 (dt, J = 13.9, 7.0 Hz, 2H), 1.59 (p, J = 7.7 Hz, 2H), 1.51 (dt, J = 15.1, 7.5 Hz, 2H), 1.36–1.29 (m, 2H).

[0294] 13 13C NMR (101 MHz, DMSO) δ 173.31, 172.35, 171.80, 171.52, 168.28, 163.22, 151.07, 147.03, 142.97, 134.27, 134.13, 133.10, 132.77, 131.28, 130.79, 129.08, 129.01, 126.20, 125.65, 119.37, 119.10, 53.88, 53.71, 52.00, 46.99, 42.02, 40.61, 40.40, 40.19, 39.98, 39.77, 39.56, 39.35, 38.33, 36.12, 35.74, 31.67, 31.15, 29.05, 28.76, 25.52, 25.33, 23.09, 14.43, 12.82.<000^814>

[0295] Example 14

[0296]

[0297] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-<000^821>

[0298] ((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)benzamide

[0299] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)benzamide

[0300] 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.32(d,J=7.5Hz,1H),7.92(d,J=1.0Hz,1H),7.87–7.78(m,2H),7.80–7.69(m,4H),7.62–7.55(m,2 H),7.33(dd,J=7.5,2.1Hz,1H),7.14(t,J=7.5Hz,1H),7.01(dd,J=7.5,2.1Hz,1H),6.93–6.85(m,3H),4.82–4.65(m,2H),4.50(d,J=19. 3Hz,1H),3.89(s,3H),3.75–3.49(m,4H),3.33(td,J=12.5,2.4Hz,1H),3.25–3.11(m,2H),3.16–2.98(m,4H),3.01–2.87(m,2H),2.80(t d,J=12.8,2.4Hz,1H),2.55–2.42(m,1H),2.02(dq,J=13.2,7.0Hz,1H),1.82(qt,J=12.2,2.5Hz,1H),1.39(qdd,J=12.6,3.7,2.4Hz,1H).

[0301] Example 15

[0302]

[0303] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyraz in-2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)benzamide

[0304] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperazin-1-yl)benzamide

[0305] 1 H NMR(400MHz, DMSO-d6)δ8.45(s,1H),8.32–8.25(m,2H),7.86–7.75(m,2H),7.77–7.67(m,4H),7. 62–7.55(m,2H),7.33(dd,J=7.5,2.1Hz,1H),7.05(dd,J=7.5,2.1Hz,1H),7.00–6.92(m,2H),4.82 –4.67(m,2H),4.38(d,J=19.5Hz,1H),3.89(s,3H),3.75–3.49(m,4H),3.37–3.12(m,5H),2.94(d t,J=14.4,7.1Hz,1H),2.69(ddt,J=33.3,14.5,7.4Hz,2H),2.59–2.34(m,3H),2.08–1.81(m,2H).

[0306] Example 16

[0307]

[0308] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0309] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0310] 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.76(s,1H),10.64(s,1H),8.46(s,1H),8.15(d,J=4.3Hz,1H),7.95(d,J=8.9Hz,2H),7.86–7.76(m,4H) ,7.60(s,1H),7.58(d,J=4.5Hz,1H),7.26(t,J=7.7Hz,1H),6.93(d,J=7.0Hz,1H),6.88(d,J=15.6Hz,1H),6.82(d,J=8.0Hz,1H),5.10(dd,J=13 .3,5.1Hz,1H),4.27–4.10(m,2H),3.87(s,3H),3.86(s,2H),3.61(t,J= 5.3Hz,2H),3.36(q,J=5.7Hz,2H),3.11–3.06(m,2H),2.90(ddd,J=17.5 ,13.7,5.5Hz,1H),2.58(d,J=16.9Hz,1H),2.52(d,J=1.7Hz,2H),2.27(qd,J=13.3,12.4,3.6Hz,1H),2.04–1.97(m,1H),1.70(p,J=7.3Hz,2H).

[0311] 13 C NMR (101MHz, DMSO) δ172.87,171.21,169.07,168.81,162.78,150.64,149.41,146.74,146.5 2,143.50,142.65,135.56,135.27,132.41,132.13,131.35,130.83,130.39,129.20,128.74 ,126.65,125.65,118.70,112.09,110.41,69.86,69.40,59.77,54.93,53.48,51.51,45.75,42.30,40.15,39.94,39.73,39.52,39.31,39.11,38.90,37.61,31.23,30.67,28.55,22.80.

[0312] Example 17

[0313]

[0314] (E)-N-(4-(N-(5-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl))-1-oxoisoindolin-4-yl)amino)ethoxy)etho xy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0315] (E)-N-(4-(N-(5-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0316] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.32(d,J=7.5Hz,1H),8.15(s,1H),7.90–7.74(m,3H),7.78–7.69(m,3H),7.20(dd,J=7.5, 2.1Hz,1H),7.11(t,J=7.5Hz,1H),6.89(d,J=15.1Hz,1H),6.77(dd,J=7.5,2.0Hz,1H),5.31(d,J=19.3Hz,1H),4.58(t,J=6.9Hz,

[0317] 1H),4.15(d,J=12.5Hz,1H),4.09–3.92(m,2H),3.85(s,3H),3.51–3.29(m,3H),3.33–3.23(m,2H),3.26–3.06(m,3H),3.09– 2.99(m,2H),2.98–2.78(m,2H),2.78–2.47(m,3H),1.92–1.79(m,1H),1.76–1.61(m,1H),1.34(qdd,J=12.6,3.6,2.5Hz,1H).

[0318] Example 18

[0319]

[0320] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)-1H-1,2 ,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0321] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0322] 1 H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.37(d,J=7.5Hz,1H),8.20(s,1H),7.90–7.78(m,4H),7.76–7.69(m,2H),7.26(dd,J=7.5,2 .1Hz,1H),7.17(t,J=7.5Hz,1H),6.93–6.79(m,3H),5.34(d,J=19.3Hz,1H),4.59(t,J=7.0Hz,1H),4.42(td,J=12.1,3.2Hz,1H), 4.22(td,J=12.4,2.8Hz,1H),4.06(d,J=19.3Hz,1H),3.94(s,3H),3.47(td,J=12.5,2.7Hz,1H),3.30(td,J=12.2,3.4Hz,1H),2. 98–2.86(m,1H),2.71–2.48(m,2H),1.86(dq,J=13.0,6.9Hz,1H),1.72(dddd,J=15.4,12.8,10.2,3.6Hz,1H),1.58–1.10(m,6H).

[0323] Example 19

[0324]

[0325] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl))-1-oxoisoindolin-4-yl)amino)methoxy)methoxy)ethy l)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0326] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0327] 1 H NMR(400MHz, DMSO-d6)δ8.50(s,1H),8.37(d,J=7.5Hz,1H),8.25(s,1H),8.00–7.86(m,3H),7.86–7.69(m,3H),7.3 4–7.19(m,2H),6.93–6.83(m,2H),6.33(s,1H),5.62(d,J=12.5Hz,1H),4.94(d,J=12.5Hz,1H),4.65(t,J=6.9Hz,1 H),4.55(d,J=19.3Hz,1H),4.49–4.35(m,2H),4.31–4.18(m,3H),3.94(s,3H),3.80(ddd,J=12.3,8.5,1.1Hz,1H), 3.40(ddd,J=12.5,3.9,1.2Hz,1H),2.89(dt,J=14.2,7.0Hz,1H),2.63–2.41(m,2H),2.00(dq,J=13.0,7.0Hz,1H).

[0328] Example 20

[0329]

[0330] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0331] (E)-N-(4-(N-(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0332] 1 H NMR(500MHz,DMSO-d6)δ11.12(s,1H),10.74(s,1H),10.69(s,1H),8.17–8.12(m,2H),7.97–7.82(m,4H),7.81–7 .78(m,1H),7.61(s,1H),7.60–7.55(m,2H),7.06(d,J=7.1Hz,1H),6.94(t,J=5.6Hz,1H),6.88–6.82(m,2H),5.0 7(dd,J=12.7,5.4Hz,1H),3.92(dd,J=15.8,5.6Hz,2H),3.88(s,3H),3.17(q,J=6.6Hz,1H),3.11(q,J=6.6Hz,2H ),2.89(ddd,J=16.6,13.8,5.2Hz,1H),2.60(s,1H),2.56–2.52(m,2H),2.05–1.99(m,1H),1.74(p,J=7.2Hz,2H).

[0333] 13C NMR(151MHz,DMSO-d6)δ172.75,169.99,168.66,168.35,167.28,162.72,150 .65,149.44,146.78,146.43,145.81,142.55,136.15,135.31,132.46,132.03 ,131.33,130.79,130.36,128.73,126.81,125.53,118.93,118.70,117.41,110.93,109.86,53.45,48.55,45.20,40.06,38.07,30.96,30.59,28.40,22.15.

[0334] Example 21

[0335]

[0336] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propanamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0337] (E)-N-(4-(N-(5-(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propionamide)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0338] 1H NMR(600MHz,DMSO-d6)δ11.06(s,1H),10.75(d,J=17.3Hz,1H),10.61(s,1H ),8.13(t,J=4.0Hz,1H),7.97(t,J=5.6Hz,1H),7.95(d,J=8.8Hz,1H),7.86– 7.83(m,2H),7.82–7.77(m,2H),7.60(s,1H),7.57(d,J=4.6Hz,1H),7.27(s ,1H),7.12(d,J=8.6Hz,1H),7.01(d,J=7.0Hz,1H),6.89(dd,J=15.6,10.6Hz ,1H),6.68(t,J=6.0Hz,1H),5.02(dd,J=12.9,5.5Hz,1H),3.87(s,3H),3.5 0(q,J=6.3Hz,2H),3.06(q,J=6.7Hz,2H),2.86(ddd,J=17.2,13.7,5.2Hz,1H ),2.57(d,J=13.9Hz,1H),2.53(d,J=7.3Hz,2H),2.46(dd,J=13.1,4.5Hz,1H ), 2.39 (t, J = 6.5 Hz, 2H), 1.97 (dq, J = 7.3, 2.8 Hz, 1H), 1.71 (p, J = 7.2 Hz, 2H).

[0339] Example 22

[0340]

[0341] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)butanamide

[0342] (E)-4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)butanamide

[0343] 1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.37(d,J=7.5Hz,1H),8.04(s,1H),7.90–7.77(m,5H),7 .73(d,J=7.6Hz,2H),7.42(t,J=7.5Hz,1H),7.04–6.94(m,2H),6.89(d,J=15.1Hz,1H),5.22– 5.11(m,1H),3.87(s,3H),3.49(td,J=12.3,2.3Hz,1H),3.37–3.11(m,3H),2.97–2.75(m,2H) ,2.74–2.44(m,4H),2.22–2.02(m,2H),1.88–1.62(m,3H),1.55(tdt,J=12.3,3.7,2.5Hz,1H).

[0344] Example 23

[0345]

[0346] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)pentanamide

[0347] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide

[0348] 11H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.74 (s, 1H), 10.69 (s, 1H), 8.15 (d, J = 4.3 Hz, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.86–7.78 (m, 4H), 7.61 (s, 1H), 7.59 (d, J = 4.5 Hz, 1H), 7.55–7.50 (m, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 6.85 (d, J = 15.6 Hz, 1H), 6.56 (t, J = 5.9 Hz, 1H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 3.87 (s, 3H), 3.31–3.25 (m, 2H), 3.03 (q, J = 6.6 Hz, 2H), 2.92–2.83 (m, 1H), 2.57 (d, J = 17.9 Hz, 1H), 2.55–2.51 (m, 3H), 2.07 (t, J = 6.7 Hz, 2H), 2.04–1.98 (m, 1H), 1.70 (p, J = 7.2 Hz, 2H), 1.58–1.49 (m, 4H).

[0349] 13 13C NMR (126 MHz, DMSO-d6) δ 172.90, 171.82, 170.18, 168.94, 167.33, 162.78, 149.43, 146.84, 146.51, 146.37, 142.63, 136.25, 135.59, 135.31, 132.57, 132.23, 131.40, 130.91, 130.55, 128.81, 125.55, 118.74, 117.20, 110.38, 109.01, 54.98, 53.53, 48.55, 41.53, 37.92, 35.06, 31.01, 30.74, 28.64, 28.33, 22.69, 22.18.

[0350] Example 24

[0351]

[0352] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0353] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0354] 1 H NMR (600MHz, DMSO-d6) δ11.07(s,1H),10.82(s,1H),10.67(s,1H),8.57(s,1H),8.25(d,J=4.4Hz,1H),7.99–7.92(m,3H),7.84 (d,J=8.8Hz,2H),7.80(t,J=5.6Hz,1H),7.61(s,1H),7.55–7.51(m,1H),7.06(d,J=8.6Hz,1H),6.99(d,J=7.0Hz,1H),6.53(t,J =5.5Hz,1H),5.03(dd,J=12.9,5.4Hz,1H),3.88(s,3H),3.30–3.27(m,2H),3.04(q,J=6.6Hz,2H),2.87(ddd,J=17.0,13.9,5.4H z,1H),2.58(d,J=17.9Hz,1H),2.56–2.51(m,3H),2.08(t,J=6.6Hz,2H),2.04–2.00(m,1H),1.72(q,J=7.2Hz,2H),1.54(s,4H).

[0355] Example 25

[0356]

[0357] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0358] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0359] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.44(s,1H),8.35(d,J=7.5Hz,1H),8.27(s,1H),7.88–7.81(m,2H),7.83 –7.69(m,5H),7.40(t,J=7.5Hz,1H),6.99(td,J=7.7,2.0Hz,2H),6.89(d,J=15.1Hz,1H),5.22–5.10(m,1H),3. 90(d,J=12.5Hz,1H),3.86(s,3H),3.56–3.37(m,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.42(td,J=12.5, 1.6Hz,1H),2.25(ddd,J=12.7,5.1,1.8Hz,1H),2.14–2.00(m,1H),1.93(qt,J=12.6,2.0Hz,1H),1.78(tddd,J=

[0360] 12.3, 4.7, 2.9, 1.4Hz, 1H), 1.35 (ddt, J=15.4, 10.8, 2.3Hz, 1H), 0.98 (dddd, J=17.1, 12.7, 5.6, 3.0Hz, 1H).

[0361] Example 26

[0362]

[0363] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin -2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0364] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophene-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide

[0365] 1 H NMR (400MHz, DMSO-d6) δ8.50–8.39(m,2H),8.33(d,J=16.1Hz,2H),7.81(d,J=7.5Hz,1H),7.73(s,4H),7.39( t,J=7.5Hz,1H),6.97(ddd,J=10.6,7.5,2.1Hz,2H),5.22–5.10(m,1H),3.88(d,J=12.5Hz,1H),3.85(s,3H),3 .46(td,J=12.5,2.7Hz,1H),3.30(d,J=12.5Hz,1H),3.13(td,J=12.4,3.2Hz,1H),2.97–2.81(m,2H),2.66–2. 52(m,2H),2.44(td,J=12.6,1.7Hz,1H),2.28–2.02(m,2H),1.66(qdd,J=12.7,3.1,1.9Hz,1H),1.29–1.13(m,

[0366] 1H),0.99(qt,J=12.7,3.2Hz,1H).

[0367] Example 27

[0368]

[0369] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0370] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0371] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.31(d,J=7.5Hz,1H),8.15(s,1H),7.95(d,J=1.4Hz,1H),7.87–7.77(m,2H),7.81–7.69(m,4H),7 .57(t,J=7.5Hz,1H),7.27(dd,J=7.5,2.1Hz,1H),6.98(dd,J=7.5,1.9Hz,1H),6.89(d,J=15.1Hz,1H),5.20–5.10(m,1H),4.45(ddd,J= 12.5,10.6,1.9Hz,1H),4.24(d,J=12.3Hz,1H),3.96(d,J=12.3Hz,1H),3.89(s,3H),3.53(ddd,J=12.5,2.3,1.4Hz,1H),3.33–3.15(m, 2H),3.20–3.10(m,1H),3.02–2.82(m,4H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.75(qdd,J=12.5,4.4,3.1Hz,1H),1.29–1.14(m,1H).

[0372] Example 28

[0373]

[0374] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acet amido)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0375] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamide)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0376] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.66(s,1H),8.35–8.26(m,2H),7.82(d,J=7.5Hz,1H),7.77–7.68(m,4H),7.3 6(t,J=7.5Hz,1H),7.20(d,J=15.1Hz,1H),7.00(ddd,J=13.2,7.5,2.1Hz,2H),6.89(d,J=15.1Hz,1H),5.16(t,J=6. 8Hz,1H),4.27–4.15(m,4H),3.89(s,3H),3.79(ddd,J=12.5,8.0,1.3Hz,1H),3.60(d,J=12.3Hz,1H),3.47(ddd,J= 12.3, 5.4, 1.2Hz, 1H), 3.20 (ddd, J=12.3, 8.1, 1.2Hz, 1H), 2.97–2.82 (m, 1H), 2.66–2.51 (m, 2H), 2.15–2.00 (m, 1H).

[0377] Example 29

[0378]

[0379] (E)-2-cyano-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)eth oxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0380] (E)-2-Cyano-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0381] 1 H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.69(s,1H),8.36(d,J=7.5Hz,1H),8.15(s,1H),7.95–7.87(m,2H),7.81– 7.69(m,4H),7.37(t,J=7.5Hz,1H),6.98(dd,J=7.5,0.9Hz,2H),5.22–5.10(m,1H),4.34(d,J=12.5Hz,1H),4.07 (d,J=12.5Hz,1H),3.83(s,3H),3.86–3.68(m,2H),3.35(td,J=12.3,3.8Hz,1H),3.28–3.03(m,3H),2.97–2.73 (m,3H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.62(qt,J=12.2,2.6Hz,1H),1.29(qdd,J=12.6,3.8,2.3Hz,1H).

[0382] Example 30

[0383]

[0384] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)benzamide

[0385] (E)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)benzamide

[0386] 1 H NMR (500MHz, DMSO-d6) δ11.12(s,1H),10.74(s,1H),10.69(s,1H),8.23(t,J=5.6Hz,1H),8.15(d,J=4.3Hz,1H),7.96(d, J=8.8Hz,2H),7.84(d,J=8.9Hz,2H),7.81(d,J=15.6Hz,1H),7.74(t,J=7.9Hz,3H),7.66(s,1H),7.59(d,J=4.5Hz,1H),7. 40(d,J=8.1Hz,2H),7.02(d,J=8.9Hz,2H),6.86(d,J=15.6Hz,1H),5.12(dd,J=12.7,5.5Hz,1H),3.89(s,3H),3.44(s,8H) ,3.24(q,J=6.6Hz,2H),2.88(ddd,J=16.8,14.0,5.4Hz,1H),2.64–2.51(m,4H),2.08–2.00(m,1H),1.84(p,J=7.3Hz,2H).

[0387] 13C NMR(126MHz,DMSO-d6)δ172.90,170.07,165.82,162.78,152.55,150.69,149 .51,146.97,146.52,142.63,136.02,135.58,133.69,132.57,131.45,130.91 ,130.55,128.82,128.48,125.56,124.20,123.83,118.76,116.85,115.23,113.83,54.98,53.57,50.22,48.85,47.31,38.58,30.99,30.90,28.76,22.10.

[0388] Example 31

[0389]

[0390] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin -2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)benzamide

[0391] (E)-N-(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-4-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperazin-1-yl)benzamide

[0392] 1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.43–8.33(m,2H),7.95–7.85(m,2H),7.82–7.69(m,4H),7.62–7.56( m,2H),7.38(t,J=7.5Hz,1H),7.27(dd,J=7.6,2.0Hz,1H),6.97–6.86(m,3H),5.22–5.10(m,1H),4.33(ddd, J=12.6,11.8,3.4Hz,1H),3.91(s,3H),3.70–3.46(m,4H),3.49–3.37(m,2H),3.35–3.12(m,3H),3.00–2.8 2(m,3H),2.74–2.52(m,3H),2.15–2.00(m,1H),1.85(qt,J=12.6,2.7Hz,1H),1.46(qt,J=12.6,2.8Hz,1H).

[0393] Example 32

[0394]

[0395] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1 ,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0396] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0397] 1H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.66(s,1H),8.38(d,J=7.5Hz,1H),8.20(s,1H),7.91–7.79(m,4H),7.76–7.69(m ,2H),7.43(t,J=7.5Hz,1H),7.00(ddd,J=19.2,7.5,2.0Hz,2H),6.89(d,J=15.1Hz,1H),5.47(td,J=12.2,3.7Hz,1H), 5.22–5.11(m,1H),4.10–3.97(m,1H),3.66(s,3H),3.54(dt,J=12.9,3.4Hz,1H),3.39(td,J=12.4,1.8Hz,1H),2.97–2 .82(m,1H),2.66–2.51(m,2H),2.15–2.00(m,1H),1.93–1.56(m,4H),1.60–1.48(m,1H),0.94(qd,J=12.4,3.0Hz,1H).

[0398] Example 33

[0399]

[0400] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)methoxy)methoxy)et hyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0401] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0402] 1H NMR(400MHz, DMSO-d6)δ8.61(s,1H),8.54(s,1H),8.38(d,J=7.5Hz,1H),8.21(s,1H),7.91–7.78(m,4H),7.76–7.69(m,2H) ,7.43(t,J=7.5Hz,1H),7.16(dd,J=7.5,1.9Hz,1H),6.98(dd,J=7.5,2.1Hz,1H),6.89(d,J=15.1Hz,1H),5.28–5.12(m,2H), 4.83(d,J=12.5Hz,1H),4.64–4.49(m,2H),4.33(ddd,J=12.5,11.4,4.7Hz,1H),4.18(d,J=12.3Hz,1H),3.95(s,3H),3.74(d dd,J=12.3,11.3,2.9Hz,1H),3.60(ddd,J=12.3,11.1,4.6Hz,1H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H).

[0403] Example 34

[0404]

[0405] (E)-2-cyano-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)- 1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0406] (E)-2-Cyano-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0407] 1H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.59(s,1H),8.53(s,1H),8.42(d,J=7.5Hz,1H),8.24(s,1H),7.98(d,J=7 .5Hz,1H),7.88–7.81(m,2H),7.76–7.69(m,2H),7.43(t,J=7.5Hz,1H),7.01(ddd,J=21.8,7.5,2.0Hz,2H),5.2 2–5.10(m,1H),4.45(td,J=12.2,3.3Hz,1H),4.28(td,J=12.3,3.3Hz,1H),3.94(s,3H),3.42–3.31(m,1H),3.2 3–3.12(m,1H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.75–1.49(m,1H),1.49–1.25(m,5H).

[0408] Example 35

[0409]

[0410] (E)-2-cyano-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methoxy)methox y)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0411] (E)-2-Cyano-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0412] 1H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.55(s,1H),8.45(d,J=7.5Hz,1H),8.17(s,1H),8.02(d,J=7.5Hz,1H),7.85–7. 79(m,2H),7.76–7.69(m,2H),7.54(t,J=7.5Hz,1H),7.21(dd,J=7.6,2.0Hz,1H),6.98(dd,J=7.5,2.0Hz,1H),5.58(d ,J=12.5Hz,1H),5.22–5.10(m,1H),5.04(s,1H),4.87(d,J=12.5Hz,1H),4.66–4.54(m,2H),4.39(dt,J=12.3,1.7Hz, 1H), 4.19 (d, J = 12.5Hz, 1H), 3.97 (s, 3H), 3.77–3.57 (m, 2H), 2.97–2.82 (m, 1H), 2.66–2.52 (m, 2H), 2.14–2.00 (m, 1H).

[0413] Example 36

[0414]

[0415] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2 ,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0416] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0417] 1H NMR(400MHz, DMSO-d6)δ8.58(s,1H),8.32(d,J=7.5Hz,1H),7.91–7.79(m,2H),7.73(s,4H),7.55–7.46(m,2H),7.38 (t,J=7.5Hz,1H),7.02–6.85(m,3H),5.22–5.10(m,1H),4.48–4.30(m,2H),3.88(s,3H),3.43(dt,J=12.4,3.1Hz,1H ),3.19(dtd,J=32.8,12.4,2.8Hz,2H),2.97–2.82(m,1H),2.70(dd,J=12.4,3.0Hz,2H),2.70–2.58(m,2H),2.62–2. 52(m,2H),2.15–2.00(m,1H),1.94–1.75(m,3H),1.64(qt,J=12.5,2.7Hz,1H),1.51–1.38(m,1H),1.35–1.19(m,1H).

[0418] Example 37

[0419]

[0420] (E)-2-cyano-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H -1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0421] (E)-2-Cyano-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0422] 1H NMR(400MHz, DMSO-d6)δ8.70(s,1H),8.61(s,1H),8.36(d,J=7.6Hz,1H),7.94–7.85(m,2H),7.81–7.69(m, 4H),7.37(t,J=7.5Hz,1H),6.97(td,J=7.6,2.0Hz,2H),5.22–5.10(m,1H),4.45–4.26(m,2H),3.84(s,3H), 3.58(dt,J=12.4,3.0Hz,1H),3.27(td,J=12.3,1.9Hz,1H),3.13(td,J=12.2,4.0Hz,1H),2.97–2.82(m,1H) ,2.74–2.40(m,5H),2.15–1.96(m,2H),1.95–1.75(m,2H),1.66(qt,J=12.8,2.7Hz,1H),1.36–1.10(m,2H).

[0423] Example 38

[0424]

[0425] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)ethoxy)methyl)-1 H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0426] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0427] 1H NMR(400MHz, DMSO-d6)δ9.03(s,1H),8.32(d,J=7.5Hz,1H),8.09(d,J=1.0Hz,1H),7.88–7.78(m,2H),7.7 9–7.69(m,4H),7.59(d,J=1.5Hz,1H),7.45(t,J=7.5Hz,1H),7.02–6.94(m,2H),6.89(d,J=15.1Hz,1H),5. 22–5.10(m,1H),4.41–4.23(m,3H),4.15(dd,J=12.4,1.4Hz,1H),3.93(s,3H),3.64–3.47(m,1H),3.49–3. 41(m,2H),3.30–3.11(m,2H),2.97–2.75(m,2H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.97–1.72(m,2H).

[0428] Example 39

[0429]

[0430] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butyl)-1H-1,2,3 -triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0431] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0432] 1H NMR(400MHz, DMSO-d6)δ8.34(d,J=7.5Hz,1H),7.91–7.81(m,2H),7.82–7.75(m,2H),7.77–7.6 9(m,2H),7.42–7.33(m,2H),7.13(t,J=7.5Hz,1H),6.93–6.77(m,3H),5.06(d,J=19.3Hz,1H), 4.49–4.30(m,3H),4.08(d,J=19.5Hz,1H),3.93(s,3H),3.27–3.09(m,3H),2.96–2.77(m,3H), 2.38–2.26(m,1H),2.29–2.10(m,2H),2.07–1.83(m,2H),1.83–1.53(m,2H),1.39–1.24(m,2H).

[0433] Example 40

[0434]

[0435] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)oxy)butyl)-1H-1,2, 3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0436] (E)-N-(4-(N-(5-(3-(4-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0437] 1H NMR(400MHz, DMSO-d6)δ8.32(d,J=7.5Hz,1H),7.88–7.80(m,3H),7.84–7.72(m,3H),7.76–7.62(m,3H),7.51(dd,J=7.5,2.1Hz, 1H),7.36(dd,J=7.5,2.0Hz,1H),6.89(d,J=15.1Hz,1H),5.22–5.10(m,1H),4.68–4.53(m,1H),4.54–4.44(m,1H),4.15(dtt,J=1 2.3,2.8,1.1Hz,1H),3.99(ddt,J=12.6,10.3,1.4Hz,1H),3.92(s,3H),3.53(dddt,J=13.6,4.1,2.8,1.2Hz,1H),3.09–2.83(m,2 H),2.78–2.67(m,1H),2.66–2.52(m,2H),2.35(tt,J=12.9,2.0Hz,1H),2.15–1.86(m,3H),1.90–1.80(m,2H),1.85–1.64(m,2H).

[0438] Example 41

[0439]

[0440] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)methyl)-1H -1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0441] (E)-N-(4-(N-(5-(3-(4-((2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0442] 1H NMR(400MHz, DMSO-d6)δ8.33(d,J=7.5Hz,1H),8.06–7.95(m,2H),7.90–7.79(m,2H),7.77–7.64(m,4H),7 .68–7.49(m,4H),6.89(d,J=15.1Hz,1H),5.22–5.11(m,1H),4.54(dd,J=12.5,0.8Hz,1H),4.47–4.35(m, 1H), 4.29 (dd, J=12.5, 2.4Hz, 1H), 3.98 (dt, J=12.3, 1.6Hz, 1H), 3.82 (s, 3H), 3.81–3.70 (m, 1H), 3.43–3. 32(m,1H),3.13–2.97(m,2H),2.97–2.82(m,1H),2.72–2.52(m,3H),2.15–2.00(m,1H),1.91–1.79(m,2H).

[0443] Example 42

[0444]

[0445] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0446] (E)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-N-(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide

[0447] 1H NMR(400MHz, DMSO-d6)δ8.35(s,1H),8.29(d,J=7.6Hz,1H),7.79–7.63(m,6H),7.61–7.47(m, 2H),7.38(dd,J=7.5,2.1Hz,1H),6.89(d,J=15.1Hz,1H),5.22–5.11(m,1H),4.21–4.10(m,1H) ,4.09–3.92(m,2H),3.84(s,3H),3.24(d,J=12.5Hz,1H),3.04(ddd,J=12.5,5.0,1.6Hz,1H),2 .97–2.82(m,1H),2.66–2.42(m,3H),2.15–2.00(m,1H),1.79–1.59(m,2H),1.63–1.49(m,1H).

[0448] Example 43

[0449]

[0450] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)aceta mido)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0451] (E)-N-(4-(N-(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)acetamide)prop-1-yn-1-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0452] 1H NMR(400MHz, DMSO-d6)δ8.88(s,1H),8.32(d,J=7.6Hz,1H),8.10(s,1H),7.87–7.61(m,8H),7.55( dd,J=7.3,2.2Hz,1H),6.89(d,J=15.1Hz,1H),5.20–5.11(m,1H),4.59(ddd,J=12.2,11.1,4.4Hz, 1H),3.98(s,3H),4.08–3.82(m,4H),3.76(d,J=12.5Hz,1H),3.38(d,J=12.5Hz,1H),3.28(ddd,J= 11.9,11.1,2.3Hz,1H),2.97–2.82(m,1H),2.66–2.51(m,2H),2.08(tdd,J=11.7,6.3,4.1Hz,1H).

[0453] Example 44

[0454]

[0455] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)-1H-1, 2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0456] (E)-N-(4-(N-(5-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)hexyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0457] 1H NMR (400MHz, DMSO-d6) δ8.37(d,J=7.5Hz,1H),8.27(d,J=3.8Hz,2H),7.91–7.69(m,6H),7.68– 7.57(m,3H),6.89(d,J=15.1Hz,1H),5.20–5.05(m,2H),4.89(td,J=12.2,2.7Hz,1H),4.18(ddt ,J=12.4,4.8,1.6Hz,1H),3.87(s,3H),3.80–3.68(m,1H),2.97–2.82(m,1H),2.66–2.51(m,2H ),2.08(tdd,J=11.7,6.3,4.1Hz,1H),1.83–1.65(m,2H),1.58–1.42(m,2H),1.41–1.13(m,2H).

[0458] Example 45

[0459]

[0460] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methoxy)methoxy)eth yl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0461] (E)-N-(4-(N-(5-(1-(2-((((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)methoxy)methoxy)ethyl)-1H-1,2,3-triazol-4-yl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide

[0462] 1H NMR(400MHz, DMSO-d6)δ8.79(s,1H),8.47(s,1H),8.37(d,J=7.5Hz,1H),7.90–7.75(m,3H),7.79–7.68 (m,5H),7.65(dd,J=7.5,2.1Hz,1H),7.52(dd,J=7.3,2.0Hz,1H),6.89(d,J=15.1Hz,1H),5.36(d,J=12 .3Hz,1H),5.20–5.10(m,1H),4.78(d,J=12.5Hz,1H),4.52–4.35(m,2H),4.31–4.16(m,2H),4.08(d,J= 12.4Hz,1H),3.72(s,3H),3.42–3.29(m,1H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H).

[0463] Example 46

[0464]

[0465] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)glutaramide

[0466] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0467] 1H NMR(400MHz, DMSO-d6)δ9.09(s,1H),8.35(d,J=7.5Hz,1H),8.23(s,1H),8.04(s,1H),7.86–7.78(m,3H),7.78–7.69(m, 6H),7.67–7.60(m,2H),6.89(d,J=15.1Hz,1H),4.75–4.62(m,2H),4.43(d,J=12.5Hz,1H),4.29(pd,J=7.0,5.0Hz,1H),3 .94(d,J=9.1Hz,4H),3.56(dd,J=9.5,7.0Hz,1H),3.29–3.20(m,2H),3.23–3.08(m,2H),3.07–2.95(m,2H),2.69–2.51( m,2H),2.43(s,3H),2.08–1.89(m,2H),1.94–1.81(m,2H),1.85–1.63(m,2H),1.55(dt,J=13.2,7.0Hz,1H),0.93(s,9H).

[0468] Example 47

[0469]

[0470] N 1 -(3-(5-((4-((E)-2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-N 5 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide

[0471] N 1 -(3-(5-((4-((E)-2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)prop-2-yn-1-yl)-N 5 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)glutaramide

[0472] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.62(s,1H),8.50(s,1H),8.39(d,J=7.5Hz,1H),8.23(s,1H),8.16(s,1H),7 .93(d,J=7.5Hz,1H),7.84–7.76(m,2H),7.77–7.65(m,6H),7.51(s,1H),4.95–4.83(m,2H),4.64(t,J=7.0Hz,1H), 4.49(s,1H),4.36–4.13(m,3H),3.91(s,3H),3.59(dd,J=9.5,7.0Hz,1H),3.41(d,J=12.5Hz,1H),3.26(dd,J=9.5, 7.0Hz,1H),2.52–2.35(m,2H),2.37(s,3H),2.37–2.26(m,2H),2.07–1.92(m,2H),1.89–1.66(m,2H),0.93(s,9H).

[0473] Example 48

[0474]

[0475] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)glutaramide

[0476] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)glutaramide

[0477] 1H NMR(400MHz, DMSO-d6)δ9.09(s,1H),8.35(d,J=7.5Hz,1H),8.23(s,1H),8.04(s,1H),7.86–7.78(m,3H),7.78–7.69(m, 6H),7.67–7.60(m,2H),6.89(d,J=15.1Hz,1H),4.75–4.62(m,2H),4.43(d,J=12.5Hz,1H),4.29(pd,J=7.0,5.0Hz,1H),3 .94(d,J=9.1Hz,4H),3.56(dd,J=9.5,7.0Hz,1H),3.29–3.20(m,2H),3.23–3.08(m,2H),3.07–2.95(m,2H),2.69–2.51( m,2H),2.43(s,3H),2.08–1.89(m,2H),1.94–1.81(m,2H),1.85–1.63(m,2H),1.55(dt,J=13.2,7.0Hz,1H),0.93(s,9H).

[0478] Example 49

[0479]

[0480] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0481] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 5 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide

[0482] 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.46(s,1H),8.35(d,J=7.6Hz,1H),8.24(d,J=9.7Hz,2H),7.88–7.75(m,4H ),7.77–7.66(m,4H),7.57–7.48(m,3H),6.89(d,J=15.1Hz,1H),4.85(d,J=5.0Hz,1H),4.78–4.64(m,2H),4.61( s,1H),4.34–4.20(m,2H),3.91(s,3H),3.98–3.84(m,2H),3.51(d,J=12.5Hz,1H),3.39(dd,J=9.5,7.0Hz,1H),2 .78–2.65(m,1H),2.41(s,3H),2.30–2.15(m,4H),2.00(dt,J=13.2,7.0Hz,1H),1.88–1.74(m,1H),0.93(s,9H).

[0483] Example 50

[0484]

[0485] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)adipamide

[0486] N 1 -((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)-N 6 -(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)adipamide

[0487] 1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.37(d,J=7.6Hz,1H),8.23(s,1H),8.04(s,1H),7.91–7.77(m,5H),7.8 2–7.67(m,6H),7.56(s,1H),6.89(d,J=15.1Hz,1H),4.87–4.73(m,3H),4.41(s,1H),4.29(pd,J=7.0,5.0Hz, 1H),4.04(dt,J=12.4,0.9Hz,1H),3.92(dd,J=9.5,7.0Hz,1H),3.89(s,3H),3.31–3.03(m,3H),2.91–2.71(m ,2H),2.76–2.67(m,2H),2.41(s,3H),2.49–2.21(m,4H),2.06–1.49(m,6H),1.41–1.26(m,1H),0.93(s,9H).

[0488] Example 51

[0489]

[0490] (2S,4R)-4-hydroxy-1-((S)-2-(4-(1-(3-(6-methoxy-5-((4-((E))-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl )propyl)-1H-1,2,3-triazol-4-yl)butanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0491] (2S,4R)-4-Hydroxy-1-((S)-2-(4-(1-(3-(6-methoxy-5-((4-((E)-3-(5-nitrothiophene)-2-yl)acrylamido)phenyl)sulfonamido)pyrazin-2-yl)propyl)-1H-1,2,3-triazol-4-yl)butanamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0492] 1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.37(d,J=7.5Hz,1H),8.23(s,1H),7.90–7.77(m,5 H),7.77–7.68(m,4H),7.61–7.53(m,4H),6.89(d,J=15.1Hz,1H),4.75–4.63(m,3H),4.57 (s,1H),4.43–4.22(m,4H),3.93–3.83(m,4H),3.32(dd,J=9.5,7.0Hz,1H),2.74–2.49(m ,4H),2.41(s,3H),2.34–2.23(m,1H),2.05–1.92(m,2H),1.93–1.74(m,3H),0.93(s,9H).

[0493] Example 52

[0494]

[0495] (2S,4R)-1-((S)-2-(4-(1-(3-(5-((4-((E))-2-cyano-3-(5-nitrothiophen-2-yl)acrylamido)phenyl)sulfonamido)-6-methoxypyrazin-2-yl)propy l)-1H-1,2,3-triazol-4-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0496] (2S,4R)-1-((S)-2-(4-(1-(3-(5-((4-((E)-2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-1H-1,2,3-triazol-4-yl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0497] 1H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.70(s,1H),8.42(d,J=7.5Hz,1H),8.23(s,1H),7.97(d,J=7.5Hz,1H) ,7.91–7.80(m,3H),7.77–7.68(m,4H),7.62–7.50(m,4H),4.82(d,J=5.0Hz,1H),4.74(t,J=7.0Hz,1H),4.69 –4.60(m,2H),4.47–4.29(m,2H),4.34–4.22(m,2H),3.91(s,3H),3.37(dd,J=9.5,7.0Hz,1H),3.27–3.13(m ,1H),2.74–2.54(m,2H),2.41(s,4H),2.47–2.17(m,3H),2.07–1.95(m,2H),1.95–1.82(m,2H),0.93(s,9H).

[0498] Example 53

[0499]

[0500] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop -1-yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0501] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0502] 11H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.68 (s, 1H), 7.70 (dd, J = 7.8, 0.9 Hz, 1H), 7.53 (dd, J = 7.5, 0.9 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.25–7.19 (m, 1H), 6.98–6.94 (m, 1H), 6.93–6.87 (m, 2H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 5.00 (s, 2H), 4.41–4.30 (m, 2H), 4.21 (s, 3H), 4.14 (s, 2H), 4.07 (dd, J = 5.3, 3.7 Hz, 2H), 3.75 (dd, J = 5.2, 3.7 Hz, 2H), 3.73–3.70 (m, 2H), 3.69–3.66 (m, 2H), 3.54 (s, 3H), 3.28 (s, 3H), 2.89 (td, J = 13.1, 12.6, 6.8 Hz, 1H), 2.58 (d, J = 16.5 Hz, 1H), 2.35 (qd, J = 13.2, 4.4 Hz, 1H), 2.03–1.96 (m, 1H).

[0503] 13 13C NMR (101 MHz, DMSO-d6) δ 172.84, 171.00, 168.41, 167.72, 158.23, 154.87, 150.01, 145.29, 144.43, 134.87, 132.84, 132.72, 129.81, 128.58, 126.34, 124.07, 122.61, 119.73, 116.61, 116.01, 109.66, 83.93, 82.63, 70.38, 69.94, 69.75, 68.87, 67.20, 53.55, 51.51, 43.24, 34.09, 28.02, 22.56, 18.08, 16.73.

[0504] Example 54

[0505]

[0506] 5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-`3`-yl)-1-oxoisoindolin-4-yl)pentanamide

[0507] 5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentanamide

[0508] 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.83(s,1H),7.81(dd,J=7.0,1.8Hz,1H),7.52–7.45(m,2H),7.2 8–7.22(m,1H),6.98–6.91(m,3H),5.14(dd,J=13.3,5.1Hz,1H),5.00(s,2H),4.42–4.30(m,2H),4.21(s ,3H),3.99(s,2H),3.54(s,3H),3.28(s,3H),2.91(ddd,J=17.5,13.6,5.4Hz,1H),2.60(d,J=16.8Hz,1H ),2.43(t,J=6.6Hz,2H),2.33(qd,J=13.3,4.4Hz,1H),2.02(ddd,J=10.5,5.1,3.3Hz,1H),1.75(s,4H).

[0509] 13 C NMR(101MHz,DMSO-d6)δ172.85,171.16,171.06,167.81,158.46,154.87 ,150.01,145.29,133.75,133.70,132.66,129.85,128.60,125.26,123. 89,122.63,118.99,116.70,116.02,109.65,83.90,82.66,67.26,51.52 ,46.51,43.24,35.34,34.09,33.18,31.21,28.13,28.03,22.64,21.71.

[0510] Example 55

[0511]

[0512] 4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanamide

[0513] 4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butanamide

[0514] 1 H NMR(400MHz, DMSO-d6)δ11.01(s,1H),9.86(s,1H),7.82(dd,J=6.8,2.2Hz,1H),7.52–7.45(m, 2H),7.25(t,J=8.0Hz,1H),6.99–6.93(m,3H),5.13(dd,J=13.3,5.1Hz,1H),5.00(s,2H),4.39– 4.26(m,2H),4.21(s,3H),4.02(t,J=6.2Hz,2H),3.54(s,3H),3.28(s,3H),2.97–2.86(m,1H), 2.60(d,J=16.1Hz,1H),2.56–2.51(m,2H),2.30(qd,J=13.2,4.3Hz,1H),2.02(p,J=6.9Hz,3H).

[0515] 13 C NMR(101MHz,DMSO-d6)δ172.85,171.02,170.80,167.81,158.40,154.87,150.01,145.28,144.42,133.71,132.64,129.88,128.60,125.28,1 23.98,122.64,119.00,116.85,115.94,109.66,83.94,82.61,67.03, 51.48,46.41,43.24,34.09,33.17,32.24,31.20,28.03,24.57,22.64.

[0516] Example 56

[0517]

[0518] 6-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hexanamide

[0519] 6-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hexanamide

[0520] 1 H NMR (400MHz, DMSO-d6) δ9.48(s,1H),7.73(dd,J=7.5,2.1Hz,1H),7.49(dd,J=7.5,2.1Hz,1H),7.39(t,J=7.5Hz,1H),7.30(t,J=2.0H z,1H),7.26–7.12(m,2H),7.03(dt,J=7.3,2.2Hz,1H),5.66(d,J=12.5Hz,1H),5.25(d,J=19.3Hz,1H),4.97(d,J=12.5Hz,1H),4.76( t,J=7.0Hz,1H),4.54(d,J=19.3Hz,1H),3.95(s,3H),3.86(td,J=12.0,3.5Hz,1H),3.20(s,3H),3.09(s,3H),2.87–2.72(m,1H),2.6 3–2.37(m,4H),2.23(dddd,J=12.9,9.8,4.1,1.7Hz,1H),1.96–1.81(m,1H),1.74–1.57(m,2H),1.60–1.38(m,2H),1.05–0.90(m,1H).

[0521] Example 57

[0522]

[0523] 7-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptanamide

[0524] 7-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptylamide

[0525] 1 H NMR(400MHz, DMSO-d6)δ8.29(dd,J=7.6,2.0Hz,1H),7.75(dd,J=7.6,2.0Hz,1H),7.45–7.36(m,2H),7.37–7.28(m,2H),7.03(dt,J=7.3,2.0H z,1H),5.89(d,J=12.5Hz,1H),4.97(d,J=19.5Hz,1H),4.79–4.70(m,2H),4.74–4.62(m,2H),4.46(ddd,J=12.4,10.4,5.3Hz,1H),3.80(tt,J =12.4,0.9Hz,1H),3.64(s,3H),3.36–3.24(m,1H),3.20(s,3H),3.10(s,3H),2.70(dt,J=16.3,7.0Hz,1H),2.33(dt,J=16.3,7.1Hz,2H),2.3 1–2.14(m,2H),2.18–2.04(m,2H),1.99–1.86(m,2H),1.90–1.69(m,1H ),1.60(tt,J=12.2,3.8Hz,1H),1.57–1.41(m,2H),1.46–1.29(m,2H).

[0526] Example 58

[0527]

[0528] 2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0529] 2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide

[0530] 1 H NMR (400MHz, DMSO-d6) δ8.20 (dd, J=7.5, 1.9Hz, 1H), 7.70 (dd, J=7.5, 2.1Hz,

[0531] 1H),7.40–7.17(m,4H),7.03(dt,J=7.3,2.1Hz,1H),5.65(d,J=12.3Hz,1H),5. 53(d,J=19.3Hz,1H),4.99(d,J=12.5Hz,1H),4.75(t,J=7.0Hz,1H),4.54(d,J= 19.3Hz,1H),4.18–3.94(m,4H),3.95(s,3H),3.52–3.43(m,2H),3.20(s,3H),3 .10(s,3H),2.85–2.73(m,1H),2.68–2.45(m,2H),1.82(dq,J=12.7,6.9Hz,1H).

[0532] Example 59

[0533]

[0534] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1 -yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0535] 2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0536] 1 H NMR (400MHz, DMSO-d6) δ7.86 (dd, J=7.5, 2.1Hz, 1H), 7.63 (t, J=7.5Hz, 1H), 7.40 (dd, J=7.6, 2.0Hz, 1H), 7.30–7.18(m,3H),7.03(ddd,J=6.3,3.1,2.0Hz,1H),5.64(d,J=12.5Hz,1H),5.22–5.10(m,1H),4.97(d ,J=12.5Hz,1H),4.32(d,J=12.5Hz,1H),4.14(d,J=12.5Hz,1H),3.94(s,4H),4.01–3.86(m,2H),3.34(t d,J=8.8,8.4,5.2Hz,2H),3.26–3.06(m,10H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H).

[0537] Example 60

[0538]

[0539] 2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)p henoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0540] 2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0541] 1 H NMR (400MHz, DMSO-d6) δ8.63(dd,J=7.5,2.0Hz,1H),7.68–7.57(m,2H),7.40(dd,J=7.5,2.0Hz,1H),7.28–7.18(m,3H),7.03(d dd,J=6.3,3.4,1.9Hz,1H),5.64(d,J=12.5Hz,1H),5.22–5.10(m,1H),4.97(d,J=12.3Hz,1H),4.45(ddd,J=12.3,11.3,4.6Hz,1 H),4.31(ddd,J=12.5,11.1,3.2Hz,1H),3.95(s,3H),3.99–3.90(m,2H),3.86(d,J=12.3Hz,1H),3.62(ddd,J=12.5,11.1,4.7Hz ,1H),3.56–3.44(m,2H),3.25–3.16(m,2H),3.20(s,3H),3.10(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H).

[0542] Example 61

[0543]

[0544] 2-(1-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl))-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl )phenoxy)pentyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0545] 2-(1-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)pentyl)-1H-1,2,3-triazol-4-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)acetamide

[0546] 1 H NMR(400MHz, DMSO-d6)δ8.63(dd,J=7.5,2.1Hz,1H),7.68–7.57(m,2H),7.40(dd,J=7.6,2.0Hz,1H),7.29–7.16(m, 3H),7.03(ddd,J=6.6,3.1,2.1Hz,1H),5.61(d,J=12.5Hz,1H),5.22–5.10(m,1H),4.99(d,J=12.3Hz,1H),4.39(td ,J=12.1,3.3Hz,1H),4.22(td,J=12.4,2.8Hz,1H),4.02–3.92(m,2H),3.94(s,3H),3.95–3.81(m,1H),3.50(d,J=1 2.5Hz,1H),3.20(s,3H),3.10(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.78–1.40(m,4H).

[0547] Example 62

[0548]

[0549] (2S,4R)-1-((S)-2-(4-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy) ethyl)-1H-1,2,3-triazol-4-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0550] (2S,4R)-1-((S)-2-(4-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0551] 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.23(s,1H),7.70–7.63(m,2H),7.56–7.46(m,4H),7.29–7.21(m,3H),7.03( ddd,J=6.3,5.0,2.9Hz,1H),5.64(d,J=12.5Hz,1H),4.99(d,J=12.3Hz,1H),4.87–4.78(m,2H),4.65–4.51(m,2H) ,4.51–4.22(m,6H),3.95(s,3H),3.78(dd,J=9.5,7.0Hz,1H),3.25(dd,J=9.5,7.0Hz,1H),3.20(s,3H),3.13–2.9 8(m,4H),2.70–2.56(m,2H),2.52–2.40(m,2H),2.41(s,3H),2.30–2.18(m,1H),2.10–1.92(m,2H),0.93(s,10H).

[0552] Example 63

[0553]

[0554] (2S,4R)-1-((S)-2-(2-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy) ethyl)-1H-1,2,3-triazol-4-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0555] (2S,4R)-1-((S)-2-(2-(1-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethyl)-1H-1,2,3-triazol-4-yl)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0556] 1 H NMR(400MHz, DMSO-d6)δ9.06(s,1H),8.23(s,1H),7.71–7.63(m,2H),7.60(d,J=3.0Hz,2H),7.53(dt,J=7.5,1.1Hz,2H), 7.29–7.14(m,3H),7.03(dt,J=7.2,2.3Hz,1H),5.73(d,J=12.5Hz,1H),4.96–4.86(m,2H),4.79(d,J=5.0Hz,1H),4.73–4 .57(m,2H),4.42(dt,J=12.5,1.1Hz,1H),4.36–4.21(m,5H),4.09(s,3H),3.98(dd,J=12.5,2.1Hz,1H),3.86(dd,J=9.5, 7.0Hz,1H),3.31–3.20(m,2H),3.20(s,3H),3.13(s,3H),2.39(s,3H),2.10–1.98(m,1H),1.53–1.42(m,1H),0.93(s,9H).

[0557] Example 64

[0558]

[0559] (2S,4R)-1-((S)-2-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl))-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1- yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0560] (2S,4R)-1-((S)-2-(5-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0561] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.23(s,1H),7.85–7.78(m,2H),7.76–7.63(m,4H),7.27–7.13(m,2H),7.03(dt,J =7.4,2.1Hz,1H),5.69(d,J=12.5Hz,1H),5.10(d,J=12.5Hz,1H),4.83–4.72(m,2H),4.41(dt,J=12.3,1.0Hz,1H),4.34 –4.24(m,2H),4.02(s,1H),3.96(s,3H),3.99–3.83(m,2H),3.72–3.60(m,1H),3.20(s,3H),3.09(s,3H),2.88(dd,J=9. 5,7.0Hz,1H),2.53(s,3H),2.25(dt,J=13.2,7.0Hz,1H),1.99(dt,J=13.2,7.0Hz,1H),1.62–1.45(m,3H),0.93(s,9H).

[0562] Example 65

[0563]

[0564] (2S,4R)-1-((S)-2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl))-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-y l)phenoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0565] (2S,4R)-1-((S)-2-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)acetamide)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0566] 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.23(s,1H),7.66–7.55(m,4H),7.38–7.25(m,3H),6.77(s,1H),5.72 (d,J=12.5Hz,1H),5.10–4.96(m,2H),4.78(d,J=5.0Hz,1H),4.67(t,J=7.0Hz,1H),4.42–4.08(m,5H),4.01 (d,J=12.5Hz,1H),3.91(s,3H),3.75–3.62(m,2H),3.28(dd,J=9.5,7.0Hz,1H),3.20(s,3H),3.17–3.04(m ,4H),2.96(ddd,J=12.5,11.1,3.8Hz,1H),2.36(s,3H),2.12–2.01(m,1H),1.82–1.70(m,1H),0.93(s,9H).

[0567] Example 66

[0568]

[0569] (2S,4R)-1-((S)-2-(2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl))-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl) prop-1-yn-1-yl)phenoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-m (2S,4R)-1-((S)-2-(2-(1-(2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)acetamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0570] 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.23(s,1H),7.70–7.58(m,3H),7.52–7.44(m,2H),7.30–7.20(m,3H),7.03(ddd,J=5. 9,3.8,2.2Hz,1H),6.52(d,J=5.0Hz,1H),5.64(d,J=12.3Hz,1H),4.99(d,J=12.5Hz,1H),4.60(ddd,J=12.5,11.1,3.2Hz,1 H),4.49(t,J=7.0Hz,1H),4.40–4.22(m,3H),4.23(s,1H),3.94(s,3H),4.06–3.79(m,3H),3.70–3.47(m,4H),3.39(d,J=12 .4Hz,1H),3.24–3.09(m,8H),3.02(dd,J=9.5,7.0Hz,1H),2.41(s,3H),2.38–2.27(m,1H),2.08–1.96(m,1H),0.93(s,9H).

[0571] Example 67

[0572]

[0573] (2S,4R)-1-((S)-2-(4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl))-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1- yl)phenoxy)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0574] (2S,4R)-1-((S)-2-(4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0575] 1 H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.23(s,1H),7.71–7.64(m,2H),7.56–7.45(m,3H),7.32–7.16(m,3H),7.03(ddd,J =6.6,3.1,2.1Hz,1H),5.60(d,J=12.5Hz,1H),4.98(d,J=12.5Hz,1H),4.83–4.67(m,3H),4.45(s,1H),4.29(td,J=7.0,5 .0Hz,1H),4.20(dt,J=12.4,1.0Hz,1H),4.06–3.86(m,2H),3.93(s,3H),3.65(dd,J=9.5,7.0Hz,1H),3.20(s,3H),3.10( s,3H),3.03–2.91(m,2H),2.54(td,J=12.7,1.9Hz,1H),2.41(s,3H),2.34–2.22(m,1H),2.01–1.73(m,3H),0.93(s,9H).

[0576] Example 68

[0577]

[0578] (2S,4R)-1-((S)-3,3-dimethyl-2-(5-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoro methoxy)phenyl)-1H-1,2,3-triazol-1-yl)pentanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0579] (2S,4R)-1-((S)-3,3-dimethyl-2-(5-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)pentanoylamino)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0580] 1 H NMR(400MHz, DMSO-d6)δ9.46(s,1H),9.02(s,1H),8.45(dd,J=7.5,2.0Hz,1H),8.43(s,1H),8.24(d,J=5.7Hz,3H),8.06(s,1H),7.95 (dt,J=7.5,2.0Hz,1H),7.71–7.59(m,4H),7.54(td,J=3.7,3.0,2.0Hz,4H),7.46(s,2H),7.50–7.35(m,3H),7.33–7.20(m,3H),6.03 (d,J=5.0Hz,1H),4.82(d,J=5.0Hz,1H),4.76–4.64(m,2H),4.64–4.52(m,1H),4.48(s,1H),4.36–4.20(m,3H),3.73(dd,J=9.5,7.0H z,1H),3.31(s,3H),3.06(dd,J=9.5,7.0Hz,1H),2.88–2.78(m,1H),2.41(s,3H),2.33–2.20(m,2H),1.91–1.68(m,3H),0.93(s,9H).

[0581] Example 69

[0582]

[0583] (2S,4R)-1-((S)-3,3-dimethyl-2-(7-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoro methoxy)phenyl)-1H-1,2,3-triazol-1-yl)heptanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0584] (2S,4R)-1-((S)-3,3-dimethyl-2-(7-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)heptanoylamino)butanoyl)-4-hydroxy-N-(4-(4)-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0585] 1 H NMR (400MHz, DMSO-d6) δ9.43(s,1H),9.03(s,1H),8.45–8.37(m,2H),8.24(d,J=5.0Hz,1H),8.23(s,2H),8.06(s,1H),7.95(dt,J=7.5, 2.0Hz,1H),7.70–7.62(m,4H),7.60–7.29(m,10H),7.27–7.21(m,2H),6.03(d,J=5.0Hz,1H),4.91(d,J=12.3Hz,1H),4.78(t,J=7.0Hz,1 H),4.73–4.58(m,2H),4.60(s,1H),4.51(d,J=5.0Hz,1H),4.34–4.21(m,2H),3.85(dd,J=9.5,7.0Hz,1H),3.31(s,3H),2.58–2.48(m,1 H),2.42(s,3H),2.30(td,J=12.6,1.6Hz,1H),2.19–2.07(m,1H),1.98–1.78(m,2H),1.70–1.56(m,2H),1.30–1.17(m,2H),0.93(s,9H).

[0586] Example 70

[0587]

[0588] (2S,4R)-1-((S)-3,3-dimethyl-2-(9-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluor omethoxy)phenyl)-1H-1,2,3-triazol-1-yl)nonanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0589] (2S,4R)-1-((S)-3,3-dimethyl-2-(9-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino))pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)nonanoylamino)butanoyl)-4-hydroxy-N-(4-(4)-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0590] 1 H NMR(400MHz, DMSO-d6)δ8.62(s,1H),8.34–8.26(m,3H),8.23(s,2H),7.95(dt,J=7.6,2.1Hz,1H),7.74–7.59(m,5H),7.58–7.39(m,8H),7. 28–7.17(m,3H),6.03(d,J=5.0Hz,1H),5.00(td,J=12.3,1.5Hz,1H),4.85(t,J=7.0Hz,1H),4.68(dt,J=12.5,1.1Hz,1H),4.59–4.39(m,2H ),4.34–4.22(m,2H),4.02(dd,J=9.5,6.7Hz,1H),3.61(dd,J=9.4,6.7Hz,1H),3.31(s,3H),2.56(td,J=12.4,3.5Hz,1H),2.46–2.29(m,5H ),2.31–2.19(m,2H),2.09(dt,J=13.7,6.9Hz,1H),1.77–1.50(m,3H),1.49–1.14(m,3H),0.93(s,9H),0.86(tdd,J=12.3,6.4,3.2Hz,2H).

[0591] Example 71

[0592]

[0593] 3-((4-((4-(3-(3-(1-(8-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)octyl)-1H-1,2,3-tria zol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0594] 3-((4-((4-(3-(3-(1-(8-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)octyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0595] 1 H NMR(400MHz, DMSO-d6)δ8.39–8.21(m,5H),8.06(s,1H),7.95(dt,J=7.5,2.0Hz,1H),7.63–7.45(m,5H),7.46(s,2H),7.45–7.36(m,2H),7.2 8–7.21(m,2H),7.16(d,J=7.5Hz,1H),7.01(ddd,J=25.9,7.6,2.1Hz,2H),6.03(d,J=5.0Hz,1H),5.20–5.11(m,1H),4.76–4.65(m,1H),4.16( ddd,J=12.4,9.4,7.1Hz,1H),3.98(td,J=12.6,2.0Hz,1H),3.51(dtd,J=12.5,3.0,1.2Hz,1H),3.31(s,3H),2.97–2.82(m,1H),2.66–2.51( m,2H),2.25(qt,J=12.7,2.1Hz,1H),2.08(tdd,J=11.6,6.3,4.0Hz,1H),1.82–1.70(m,1H),1.66–1.12(m,7H),1.02(qt,J=12.6,2.8Hz,1H).

[0596] Example 72

[0597]

[0598] 3-((4-((4-(3-(3-(1-(6-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-tria zol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0599] 3-((4-((4-(3-(3-(1-(6-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0600] 1 H NMR(400MHz, DMSO-d6)δ9.47(s,1H),8.50(dd,J=7.5,2.0Hz,1H),8.44(s,1H),8.27–8.17(m,3H),8.06(s,1H),7.95(d t,J=7.5,2.1Hz,1H),7.71–7.64(m,2H),7.58–7.50(m,3H),7.48–7.27(m,5H),7.27–7.21(m,2H),6.96(ddd,J=15.1,7. 5,2.1Hz,2H),6.03(d,J=5.0Hz,1H),5.20–5.10(m,1H),4.46(td,J=12.2,3.5Hz,1H),4.33(td,J=12.2,3.7Hz,1H),3. 50–3.34(m,2H),3.31(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.49–1.30(m,3H),1.39(s,2H).

[0601] Example 73

[0602]

[0603] 3-((4-((4-(3-(3-(1-(4-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-tria zol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0604] 3-((4-((4-(3-(3-(1-(4-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0605] 1 H NMR(400MHz, DMSO-d6)δ9.47(s,1H),8.47(dd,J=7.5,2.1Hz,1H),8.45(s,1H),8.36(s,1H),8.27–8.21(m,2H),8.06(s,1H),7.9 5(dt,J=7.5,2.0Hz,1H),7.70–7.63(m,2H),7.54(ddq,J=5.8,4.0,2.0Hz,3H),7.48–7.28(m,5H),7.27–7.21(m,2H),6.97(ddd,J =11.7,7.5,2.0Hz,2H),6.03(d,J=5.0Hz,1H),5.20–5.10(m,1H),4.71(td,J=12.4,1.8Hz,1H),3.71(ddd,J=12.3,4.3,1.9Hz,1H ),3.48(ddd,J=12.5,11.6,1.6Hz,1H),3.31(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15–2.00(m,1H),1.76–1.28(m,4H).

[0606] Example 74

[0607]

[0608] (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluor omethoxy)phenyl)-1H-1,2,3-triazol-1-yl)hexanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0609] (2S,4R)-1-((S)-3,3-dimethyl-2-(6-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)hexanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0610] 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),9.03(s,1H),8.46(dd,J=7.6,2.0Hz,1H),8.38(s,1H),8.24(d,J=5.6Hz,3H),8.06(s,1H),7.95(dt,J=7.5, 2.0Hz,1H),7.78(s,1H),7.71–7.59(m,6H),7.57–7.35(m,6H),7.28–7.2 0(m,3H),6.03(d,J=5.0Hz,1H),5.21(dt,J=12.5,1.0Hz,1H),4.88–4.78 (m,2H),4.41–4.22(m,3H),4.21(s,1H),3.91(ddd,J=12.4,9.3,7.3Hz,1H),3.73(dd,J=9.5,7.0Hz,1H),3.31(s,3H),3.21(dd,J=9.5,7.0Hz,1H ),2.82(td,J=12.5,3.1Hz,1H),2.43(s,3H),2.28(dt,J=13.2,7.0Hz,1H ),2.08–1.87(m,3H),1.82–1.66(m,1H),1.23–0.87(m,3H),0.93(s,9H).

[0611] Example 75

[0612]

[0613] (2S,4R)-1-((S)-3,3-dimethyl-2-(8-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluor omethoxy)phenyl)-1H-1,2,3-triazol-1-yl)octanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0614] (2S,4R)-1-((S)-3,3-dimethyl-2-(8-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)octanamido)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0615] 1 H NMR (400MHz, DMSO-d6) δ9.46(s,1H),9.02(s,1H),8.49(dd,J=7.5,2.1Hz,1H),8.42(s,1H),8.24(d,J=5.0Hz,1H),8.23(s,2H) ,8.06(s,1H),7.95(dt,J=7.5,2.0Hz,1H),7.71–7.59(m,4H),7.64–7.36(m,9H),7.33–7.20(m,3H),6.03(d,J=5.0Hz,1H),4.84 –4.75(m,2H),4.58(dt,J=12.4,1.1Hz,1H),4.49–4.36(m,3H),4.35–4.23(m,2H),3.81(dd,J=9.5,7.0Hz,1H),3.31(s,3H),2. 68(td,J=12.5,1.5Hz,1H),2.43–2.31(m,4H),2.23(dt,J=13.3,7.0Hz,1H),2.10–1.95(m,2H),1.85–1.18(m,8H),0.93(s,9H).

[0616] Example 76

[0617]

[0618] 3-((4-((4-(3-(3-(1-(5-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)pentyl)-1H-1,2,3-tria zol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0619] 3-((4-((4-(3-(3-(1-(5-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0620] 1 H NMR (400MHz, DMSO-d6) δ8.42(dd,J=7.5,2.1Hz,1H),8.40(s,1H),8.34–8.27(m,2H),8.23(s,1H),8.05(s,1H),7.95(dt,J=7.5,2.0Hz,1H),7.67–7 .59(m,2H),7.58–7.50(m,2H),7.48–7.35(m,5H),7.28–7.17(m,3H),6.9 8(dq,J=7.4,2.0Hz,2H),6.03(d,J=5.0Hz,1H),5.22–5.10(m,1H),4.74(t d,J=12.4,2.3Hz,1H),4.31(ddd,J=12.4,3.9,2.0Hz,1H),3.41(td,J=12 .3,1.9Hz,1H),3.31(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.08(t dd,J=11.5,6.3,4.0Hz,1H),1.88–1.72(m,1H),1.55(dtd,J=13.6,11.8, 11.3, 2.3Hz, 2H), 1.44 (ddq, J=14.5, 11.1, 1.8Hz, 2H), 1.37–1.16 (m, 2H).

[0621] Example 77

[0622]

[0623] 3-((4-((4-(3-(3-(1-(7-((2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindolin-4-yl)amino)heptyl)-1H-1,2,3-tria zol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0624] 3-((4-((4-(3-(3-(1-(7-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)heptyl)-1H-1,2,3-triazol-4-yl)-4-(trifluoromethoxy)phenyl)ureido)phenyl)(methyl)amino)pyrimidin-2-yl)amino)benzenesulfonamide

[0625] 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),8.39(dd,J=7.5,2.1Hz,1H),8.34(s,1H),8.24(dd,J=5.9,2.5Hz,3H),8.05(s,1H),7.95(dt,J=7.5,2.1H z,1H),7.71–7.64(m,2H),7.58–7.45(m,3H),7.46(s,2H),7.38(dt,J=18.5,7.5Hz,2H),7.28–7.15(m,3H),6.96(ddd,J=18.2,7.6,2.0Hz,2H) ,6.03(d,J=5.0Hz,1H),5.22–5.10(m,1H),4.68(dt,J=12.7,3.1Hz,1H),4.34(td,J=12.2,1.7Hz,1H),3.66(tdd,J=10.0,5.0,2.0Hz,1H),3.4 1–3.31(m,1H),3.31(s,3H),2.97–2.82(m,1H),2.66–2.52(m,2H),2.15 –2.00(m,1H),1.96–1.72(m,2H),1.68–1.29(m,3H),1.26–1.06(m,3H).

[0626] Example 78

[0627]

[0628] (2S,4R)-1-((2S)-2-(3-(4-(3-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)p ropyl)-1H-1,2,3-triazol-1-yl)propanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0629] (2S,4R)-1-((2S)-2-(3-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)propionamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0630] 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.23(s,1H),8.06(d,J=1.2Hz,1H),7.86(d,J=1.5Hz,1H),7.76–7.69(m,2H),7.65(d,J=1.3Hz ,1H),7.59–7.51(m,4H),7.47(dd,J=7.5,5.8Hz,1H),7.39(dd,J=8.9,7.5Hz,1H),7.08(d,J=1.5Hz,1H),5.49–5.35(m,3H),4.88–4 .56(m,6H),4.39–4.22(m,3H),3.91(dd,J=9.5,7.0Hz,1H),3.38(dd,J=9.5,7.0Hz,1H),3.10–2.97(m,1H),2.87(dt,J=12.4,7.1Hz ,1H),2.76–2.61(m,5H),2.41(s,3H),2.35–2.18(m,1H),2.09–1.83(m,5H),1.83–1.65(m,4H),1.60(d,J=6.7Hz,3H),0.93(s,9H).

[0631] Example 79

[0632]

[0633] (2S,4R)-1-((2S)-2-(5-(4-(3-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)pro pyl)-1H-1,2,3-triazol-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0634] (2S,4R)-1-((2S)-2-(5-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)pentanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0635] 1 H NMR(400MHz, DMSO-d6)δ9.11(s,1H),8.23(s,1H),7.86(dd,J=8.4,1.4Hz,2H),7.76–7.68(m,2H),7.59–7.50(m,5H),7.51–7.34(m, 2H),7.08(d,J=1.5Hz,1H),5.47(s,2H),5.38(q,J=6.8Hz,1H),4.84(d,J=5.0Hz,1H),4.73–4.58(m,3H),4.40–4.14(m,5H),3.80(dd ,J=9.5,7.0Hz,1H),3.32(dd,J=9.5,7.0Hz,1H),3.09–2.97(m,1H),2.87(dt,J=12.5,7.1Hz,1H),2.72(t,J=7.6Hz,2H),2.65(t,J=5 .7Hz,2H),2.41(s,3H),2.33–2.19(m,2H),2.08–1.71(m,8H),1.75–1.65(m,2H),1.69–1.42(m,6H),1.41–1.25(m,1H),0.93(s,9H).

[0636] Example 80

[0637]

[0638] (2S,4R)-1-((2S)-2-(7-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)cyclohexyl)pro pyl)-1H-1,2,3-triazol-1-yl)heptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0639] (2S,4R)-1-((2S)-2-(7-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)heptylamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0640] 1 H NMR (400MHz, DMSO-d6) δ8.23(s,1H),8.16(d,J=1.3Hz,1H),7.89(d,J=1.5Hz,1H),7.83–7.67(m,4H),7.71–7.64(m ,2H),7.53–7.34(m,3H),7.15–7.07(m,2H),5.51(q,J=6.8Hz,1H),5.47(s,2H),4.70–4.52(m,3H),4.43–4.24(m,2H ),4.19–4.07(m,2H),3.80(dd,J=9.5,6.9Hz,1H),3.57(dd,J=9.5,7.0Hz,1H),2.88–2.52(m,7H),2.40(s,3H),2.27 (dt,J=13.2,7.0Hz,1H),2.20–1.69(m,10H),1.73–1.62(m,2H),1.67–1.56(m,4H),1.40–1.29(m,2H),0.93(s,9H).

[0641] Example 81

[0642]

[0643] (2S,4R)-1-((2S)-2-(9-(4-(3-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl) propyl)-1H-1,2,3-triazol-1-yl)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0644] (2S,4R)-1-((2S)-2-(9-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0645] 11H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.23 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.81 (s, 1H), 7.77 (s, 3H), 7.56 (d, J = 1.3 Hz, 1H), 7.48 (s, 1H), 7.51–7.34 (m, 2H), 7.12 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 5.0 Hz, 1H), 5.49–5.36 (m, 3H), 5.10 (d, J = 12.4 Hz, 1H), 4.75 (t, J = 7.0 Hz, 1H), 4.64 (s, 1H), 4.49 (p, J = 6.9 Hz, 1H), 4.36–4.19 (m, 3H), 3.87 (dd, J = 9.5, 6.9 Hz, 1H), 3.47 (dd, J = 9.5, 7.0 Hz, 1H), 2.93–2.68 (m, 5H), 2.65 (t, J = 5.6 Hz, 2H), 2.46–2.04 (m, 8H), 1.97–1.82 (m, 2H), 1.83–1.74 (m, 2H), 1.78–1.66 (m, 2H), 1.70–1.55 (m, 6H), 1.56–1.35 (m, 5H), 1.33–1.19 (m, 3H), 1.18–1.03 (m, 1H), 0.93 (s, 9H).

[0646] Example 82

[0647]

[0648] (2S,4R)-1-((2S)-2-(4-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0649] (2S,4R)-1-((2S)-2-(4-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)butanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0650] 1 H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.23 ​​(s, 1H), 7.97 (d, J = 1.2Hz, 1H), 7.91 ( d,J=1.5Hz,1H),7.80–7.72(m,2H),7.74–7.66(m,2H),7.61–7.51(m,3H),7.51 –7.29(m,3H),7.12(d,J=1.5Hz,1H),5.88(d,J=12.5Hz,1H),5.47(s,2H),5.38 (q,J=6.7Hz,1H),4.91(t,J=7.0Hz,1H),4.65–4.52(m,2H),4.34–4.19(m,2H),4 .10(dt,J=12.4,3.1Hz,1H),4.06(s,1H),3.64(dd,J=9.5,7.0Hz,1H),3.18(dd ,J=9.5,7.0Hz,1H),3.04(dt,J=12.5,7.1Hz,1H),2.95–2.72(m,2H),2.72(t,J= 7.6Hz,2H),2.65(t,J=5.8Hz,2H),2.47(s,3H),2.28(ddt,J=12.5,11.6,7.1Hz ,2H),2.15–1.71(m,9H),1.62(d,J=6.7Hz,3H),1.35–1.10(m,2H),0.93(s,9H).

[0651] Example 83

[0652]

[0653] (2S,4R)-1-((2S)-2-(6-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl) propyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0654] (2S,4R)-1-((2S)-2-(6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)hexanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0655] 1 H NMR(400MHz, DMSO-d6)δ9.11(s,1H),8.23(s,1H),7.87(dd,J=5.6,1.4Hz,2H),7.75–7.68(m,2H),7.59–7.34(m,7H) ,7.06(d,J=1.5Hz,1H),6.14(d,J=5.1Hz,1H),5.47(s,2H),5.38(q,J=6.7Hz,1H),4.79(t,J=7.0Hz,1H),4.58–4.45( m,2H),4.39–4.18(m,5H),3.67(dd,J=9.5,7.0Hz,1H),3.32(dd,J=9.5,7.0Hz,1H),3.05–2.82(m,3H),2.72(t,J=7. 6Hz,2H),2.65(t,J=5.6Hz,2H),2.41(s,3H),2.37–2.24(m,2H),2.17–1.55(m,13H),1.59–1.47(m,2H),0.93(s,9H).

[0656] Example 84

[0657]

[0658] (2S,4R)-1-((2S)-2-(8-(4-(3-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl) propyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0659] (2S,4R)-1-((2S)-2-(8-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)octanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

[0660] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.23(s,1H),8.16(d,J=1.2Hz,1H),7.88(d,J=1.5Hz,1H),7.72–7.57(m,5H),7.56–7.34(m, 3H),7.12(d,J=1.5Hz,1H),6.18(d,J=5.0Hz,1H),5.51(q,J=6.9Hz,1H),5.47(s,2H),4.66–4.47(m,2H),4.51(s,1H),4.47–4.22 (m,3H),4.14–4.00(m,2H),3.79(dd,J=9.5,7.0Hz,1H),3.29(dd,J=9.5,7.0Hz,1H),3.02(dt,J=12.0,6.9Hz,1H),2.90(dt,J=12 .4,7.1Hz,1H),2.76–2.54(m,5H),2.44(dt,J=13.2,7.0Hz,1H),2.39(s,3H),2.16–1.63(m,11H),1.68–1.43(m,5H),0.93(s,9H).

[0661] Example 85

[0662]

[0663] 6-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperid in-1-yl)propyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide

[0664] 6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)hexanamide

[0665] 1 H NMR(400MHz,DMSO-d6)δ8.32(d,J=1.3Hz,1H),8.01(dd,J=7.5,2.1Hz,1H),7.86– 7.72(m,2H),7.56(s,1H),7.51–7.40(m,2H),7.44–7.34(m,2H),7.14(d,J=1.6Hz,

[0666] 1H),5.49–5.35(m,3H),4.36–4.21(m,3H),3.00(dt,J=12.0,6.9Hz,1H),2.97 –2.71(m,4H),2.71(d,J=7.6Hz,2H),2.66(d,J=7.9Hz,2H),2.66–2.55(m,2H) ,2.60–2.43(m,2H),2.19–1.72(m,9H),1.76–1.64(m,5H),1.62(dddd,J=17.3 ,12.8,4.3,2.4Hz,1H),1.39–1.25(m,1H),1.05(qdd,J=13.1,2.1,1.1Hz,1H).

[0667] Example 86

[0668]

[0669] 4-((6-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pi peridin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0670] 4-((6-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0671] 1 H NMR (400MHz, DMSO-d6) δ8.59(s,1H),8.05(d,J=1.3Hz,1H),7.85(d,J=1.6Hz,1H),7.65(d,J=1.2Hz,1H),7.54(s,1H),7. 51–7.34(m,3H),7.09(d,J=1.6Hz,1H),6.99(ddd,J=9.4,7.5,2.0Hz,2H),5.49–5.35(m,3H),5.20–5.10(m,1H),4.33(p, J=7.0Hz,1H),4.29–4.21(m,2H),3.57–3.44(m,1H),3.42–3.28(m,1H),3.08–2.96(m,1H),2.97–2.83(m,2H),2.76–2.52 (m,6H),2.14–1.84(m,5H),1.83–1.65(m,4H),1.65–1.49(m,3H),1.45(ddd,J=10.0,7.8,4.5Hz,2H),1.37–1.19(m,3H).

[0672] Example 87

[0673]

[0674] 4-((5-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pi peridin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0675] 4-((5-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl))-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)pentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0676] 1 H NMR(400MHz, DMSO-d6)δ8.60(s,1H),7.87(dd,J=16.7,1.5Hz,2H),7.57–7.34(m,5H),7.08(d,J=1.5H z,1H),7.00(ddd,J=12.7,7.5,2.0Hz,2H),5.47(s,2H),5.38(q,J=6.8Hz,1H),5.20–5.10(m,1H),4.38 –4.21(m,3H),3.58–3.47(m,1H),3.44–3.31(m,1H),3.07–2.94(m,1H),2.97–2.83(m,2H),2.76–2.52( m,6H),2.15–1.83(m,5H),1.83–1.65(m,4H),1.65–1.48(m,4H),1.52–1.34(m,2H),1.35–1.20(m,2H).

[0677] Example 88

[0678]

[0679] 4-((9-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pi peridin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0680] 4-((9-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0681] 1 H NMR(400MHz, DMSO-d6)δ8.77(s,1H),7.87(dd,J=4.0,1.4Hz,2H),7.56–7.34(m,4H),7.30(s,1H),7.12–6.94(m ,3H),5.47(s,2H),5.37(q,J=6.9Hz,1H),5.20–5.10(m,1H),4.25(td,J=7.4,3.1Hz,3H),3.69–3.59(m,1H),3.5 8–3.44(m,1H),3.29(dt,J=12.5,7.1Hz,1H),2.97–2.83(m,2H),2.76–2.43(m,7H),2.42–2.18(m,2H),2.15–1.9 6(m,3H),1.81(dtt,J=32.5,8.0,5.5Hz,4H),1.63(dd,J=8.4,6.9Hz,5H),1.59–1.40(m,4H),1.39–1.12(m,7H).

[0682] Example 89

[0683]

[0684] 4-((7-(4-(3-(3-(4-(6-amino-5-((R))-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pi peridin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0685] 4-((7-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)heptyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione

[0686] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.03(d,J=1.3Hz,1H),7.83(d,J=1.5Hz,1H),7.59–7.34(m,5H),7.07( d,J=1.6Hz,1H),6.99(ddd,J=8.5,7.5,1.9Hz,2H),5.48(q,J=6.7Hz,1H),5.47(s,2H),5.20–5.10(m,1H),4. 38–4.21(m,3H),3.64–3.55(m,1H),3.28–3.16(m,1H),3.13–2.99(m,1H),2.95–2.84(m,2H),2.72(t,J=5.4 Hz,2H),2.69–2.52(m,4H),2.15–1.63(m,11H),1.62(d,J=6.8Hz,4H),1.45–1.18(m,2H),1.21–1.03(m,4H).

[0687] Example 90 Degradation Activity Test

[0688] The half degradation concentration (DC 50 ) determination

[0689] Western-blot assay

[0690] Cell plate: The compounds of the present embodiment were treated with 6 concentration gradients of 0 μM, 2.5 μM, 5 μM, 10 μM, 20 μM, and 40 μM, respectively. DMSO and the parent inhibitor group were set as negative and positive controls. After drug treatment for 24 hours, A549 cells were collected in a 1.5 mL EP tube and centrifuged at 3000 rpm for 3 minutes. After collecting the cell pellet, 30 μL of PBS was added to suspend the cells, and then 30 μL of 2× SDS lysis buffer was added. The tube was heated in a metal bath at 100°C for 5 minutes, then placed on ice for 5 minutes, and centrifuged at 10,000 rpm for 5 minutes. The supernatant was aspirated to extract the total cell protein. Protein concentration was determined using the Bradford method. After each sample was equal in concentration, bromophenol blue was added as a loading indicator. After 16 hours of drug treatment, cells were collected in 1.5 mL EP tubes and centrifuged at 3000 rpm for 3 minutes. After collecting the cell pellet, 30 μL of PBS was added to suspend the cells, followed by 30 μL of 2× SDS lysis buffer. The cells were heated in a metal bath at 100°C for 5 minutes, then placed on ice for 5 minutes and centrifuged at 10,000 rpm for 5 minutes. The supernatant was aspirated as the extracted total cell protein. Protein concentration was determined using the Bradford method. After each sample was equal in concentration, bromophenol blue was added as a loading indicator.

[0691] Electrophoresis: In a Bio Rad electrophoresis apparatus, the voltage was initially 80 V. After the dye entered the separation gel, the voltage was adjusted to 120 V.

[0692] Transfer: Cut filter paper and nitrocellulose membrane (NC membrane) to appropriate sizes; soak both filter paper and nitrocellulose membrane in transfer buffer. Arrange the membranes in the order of "filter paper-gel-NC membrane-filter paper" and place them in the electrophoresis tank. Maintain a constant voltage of 100V for 1.5 hours. Follow with antibody incubation and development according to the Cell Signaling Technology antibody datasheet.

[0693] The results are shown in Table 1: Western-blot was used to detect the expression of MLKL protein in A549 cells 24 hours after treatment with the compounds disclosed in this patent. The immunoblotting experiment showed that: (1) The PROTAC series compounds disclosed in this patent (i.e., the degraders) can induce the degradation of MLKL protein, and this degradation effect is dose-dependent. The commercial parent inhibitor only inhibits the activity of MLKL, and unlike the degraders disclosed in this patent, it can degrade the target protein. Some of the original blotting results are shown in Figure 1 .

[0694] Table 1 Degradation results of MLKL protein by PROTAC compounds of the disclosed embodiments

[0695]

[0696]

[0697] Example 91 In vitro necroptosis induction experiment

[0698] MLE12 cells were seeded in 12-well plates and allowed to adhere overnight. After treatment with Z-VAD-FMK (10 μM) for 30 minutes, necroptosis was induced by TNFα (10 ng / mL) and CHX (10 μg / mL) for 6 hours. Different PROTACs (1 μM) were added to the experimental groups and incubated overnight. Dead cells were washed with PBS, and the adherent cells were counted and statistically analyzed. Some original results are shown in [ 17 ]. Figure 2 The results showed that some compounds had good anti-necroptosis effects.

[0699] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following: ( E )-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxidoisoindolin-4-yl)amino)- N -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide; ( E )- N 1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)- N 7 -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pimelamide; ( E )- N -(4-( N -(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide; ( E )- N -(4-( N -(5-(3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide; ( E )- N -(4-( N -(5-(3-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide; ( E )-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)- N -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)pentanamide; ( E )- N -(3-(5-((4-(2-cyano-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)-6-methoxypyrazin-2-yl)propyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)pentanamide; ( E )-2-cyano- N -(4-( N -(5-(3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)acetamido)propyl)-3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophen-2-yl)acrylamide; ( E )-5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)- N -(3-(6-methoxy-5-((4-(3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)pentanamide; N 1 -(( S )-1-((2 S ,4 R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)- N 5 -(3-(6-methoxy-5-((4-(( E )-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)prop-2-yn-1-yl)glutaramide; N 1 -(( S )-1-((2 S ,4 R )-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)- N 6 -(3-(6-methoxy-5-((4-(( E )-3-(5-nitrothiophen-2-yl)acrylamide)phenyl)sulfonamide)pyrazin-2-yl)propyl)adipamide; 4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3 H -purin-3-yl)prop-1-yn-1-yl)phenoxy)- N -(2-(2,6-dioxapiperidin-3-yl)-1-oxoisoindolin-4-yl)butanamide; 2-(2-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3 H -purin-3-yl)prop-1-yn-1-yl)phenoxy)ethoxy)- N -(2-(2,6-dioxapiperidin-3-yl)-1-oxoisoindolin-4-yl)acetamide; (2S,4R)-1-((S)-2-(4-(3-(3-(1,7-dimethyl-8-(methylsulfonyl)-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl)prop-1-yn-1-yl)phenoxy)butyrylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; (2S,4R)-1-((S)-3,3-dimethyl-2-(5-(4-(5-(3-(4-(methyl(2-((3-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)phenyl)ureido)-2-(trifluoromethoxy)phenyl)-1H-1,2,3-triazol-1-yl)pentanoylamino)butanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide; 4-((9-(4-(3-(3-(4-(6-amino-5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)piperidin-1-yl)propyl)-1H-1,2,3-triazol-1-yl)nonyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolinone-1,3-dione.

2. A pharmaceutical composition comprising any one of the compounds according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients.

3. Use of any one of the compounds according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of drugs for treating tumors, inflammation, fibrosis, liver injury, ischemia-reperfusion injury, infectious diseases and neurodegenerative diseases.

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