Protein tyrosine phosphatase degradation agent and application thereof

Abstract

Provided herein are useful for degrading protein tyrosine phosphatase, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1), and useful for treating related diseases, disorders and conditions that contribute to the treatment of PTPN1 or PTPN2 degrading agents, degradation agent compounds, compositions, and methods for treating cancer, such as cancer or metabolic diseases.

Description

Cross-references

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 517,192, filed August 2, 2023, which is incorporated herein by reference in its entirety. Background of the Invention

[0002] Cancer immunotherapy regimens targeting immune evasion mechanisms, including checkpoint blockade (e.g., PD-1 / PD-L1 and CTLA-4 blocking antibodies), have been shown to be effective in treating a variety of cancers and significantly improve outcomes in some populations that are difficult to treat with conventional therapies. However, incomplete clinical responses and the development of intrinsic or acquired resistance continue to limit the patient populations that may benefit from checkpoint blockade.

[0003] Protein tyrosine phosphatase type 2 (PTPN2), also known as T-cell protein tyrosine phosphatase (TC-PTP), is a member of the intracellular subfamily 1 of phosphorylated tyrosine-specific phosphatases. Phosphorylated tyrosine-specific phosphatases control a variety of cellular regulatory processes by removing phosphate ester groups from the tyrosine matrix. PTPN2 is widely expressed, but its expression is highest in hematopoietic cells and placental cells. In humans, PTPN2 expression is posttranscribed and exists in two splice variants: a 45 kDa form with a nuclear localization signal upstream of the C-terminus of the splice junction; and a 48 kDa canonical form with a C-terminal ER retention motif. The 45 kDa isoform can be passively infused into the cytosol under certain cellular stress conditions. Both isoforms share the N-terminal phosphorylated tyrosine phosphatase catalytic domain. PTPN2 negatively regulates signal transduction of non-receptor tyrosine kinases (e.g., JAK1, JAK3), receptor tyrosine kinases (e.g., INSR, EGFR, CSF1R, PDGFR), transcription factors (e.g., STAT1, STAT3, STAT5a / b), and Src family kinases (e.g., Fyn, Lck). As a key negative regulator of the JAK-STAT pathway, PTPN2 directly regulates signal transduction via intercytokine receptors (including IFNγ). The PTPN2 catalytic domain shares 74% sequence homology with PTPN1 (also known as PTP1B) and shares similar enzymatic kinetics. Data from in vivo gene loss-of-function screening in a mouse B16F10 transplantable tumor model using CRISPR / Cas9 genome editing showed that deletion of the Ptpn2 gene in tumor cells improved the response to an immunotherapy regimen combining a GM-CSF secretory vaccine (GVAX) with PD-1 checkpoint blockade. PTPN2 deficiency sensitizes tumors to immunotherapy by enhancing IFNγ-mediated antigen presentation and growth inhibition. The same screening also revealed that under selective pressure from immunotherapy, genes known to be involved in immune evasion (including PD-L1 and CD47) were depleted, while genes involved in the IFNγ signaling pathway (including IFNGR, JAK1, and STAT1) were enriched. These observations suggest that therapeutic strategies that enhance IFNγ sensing and signaling may help improve the efficacy of cancer immunotherapy regimens.

[0004] Protein tyrosine phosphatase non-receptor type 1 (PTPN1), also known as protein tyrosine phosphatase-1B (PTP1B), has been shown to play a crucial role in insulin and leptin signaling and is a major mechanism for downregulating insulin and leptin receptor signaling pathways. Animals lacking PTP1B exhibit improved glucose regulation and lipid profiles and are resistant to weight gain when fed a high-fat diet. Therefore, PTP1B inhibitors are expected to be used to treat type 2 diabetes, obesity, and metabolic syndrome.

[0005] One approach to externally influencing protein activity is to reduce the levels of specific proteins through targeted protein degradation. Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). UPP is important for the regulation of almost all cellular processes, including antigen processing; apoptosis; organelle biogenesis; cell circulation; DNA transcription and repair; differentiation and development; immune responses and inflammation; neural and muscular degeneration; morphogenesis of neural networks; regulation of cell surface receptors, ion channels, and secretory pathways; responses to stress and extracellular regulators; ribosome biogenesis; and viral infection. Proteasome degradation of proteins is marked by the covalently linking of multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligases, in which the protein is digested into small peptides and ultimately into its constituent amino acids, which serve as building blocks for new proteins. There are over 600 E3 ubiquitin ligases that promote the ubiquitination of various proteins in the body, which can be divided into four families: HECT domain E3, U-box E3, monomeric RING E3, and multi-subunit E3. The first E3 ligase successfully targeted by a small molecule was SCF. βTrCPThis involves using a hybrid formed by linking a small MetAP2 inhibitor to an IκBα phosphopeptide epitope known to bind to ubiquitin E3 ligase (Sakamoto et al., PNAS 2001, 98 (15) 8554). Schneekloth et al. described a degrader (PROTAC3) targeting the FK506-binding protein (FKBP12) and used green fluorescent protein (GFP) imaging to show that both PROTAC2 and PROTAC3 hit their respective targets. Schneekloth et al. (Chem Bio Chem 2005, 6, 40-46). In an unrelated parallel study, scientists investigated thalidomide toxicity and found that cereblon is a thalidomide-binding protein. Ito et al. (Science 2010, 327, 1345-1350). Cereblon forms part of an E3 ubiquitin ligase protein complex that interacts with damaged DNA-binding protein 1, forming an E3 ubiquitin ligase complex with Cullin 4 and the E2-binding protein ROC1 (also known as RBX1). This E3 ubiquitin ligase complex acts as a matrix acceptor to select proteins for ubiquitination. This study reveals that thalidomide-cereblon binding in vivo may be the cause of thalidomide teratogenicity. Following the discovery of thalidomide binding to the cereblon E3 ubiquitin ligase, researchers began exploring the incorporation of thalidomide and certain derivatives into compounds for targeted protein destruction. See G. Lu et al. (Science, 343, 305-309 (2014)); and J. Kronke et al. (Science, 343, 301-305 (2014)).

[0006] Although progress has been made in the field of UPP regulation of protein degradation in vivo, additional compounds and methods are needed to make fuller use of UPP for therapeutic treatment, such as developing targeted PTPN1 or PTPN2 degraders for the treatment of cancer, type 2 diabetes, obesity and metabolic syndrome. Invention Overview

[0007] This document discloses compounds, compositions, and methods for inducing the degradation of protein tyrosine phosphatases, such as protein tyrosine phosphatase non-receptor type 2 (PTPN2) and / or protein tyrosine phosphatase non-receptor type 1 (PTPN1) (also known as protein tyrosine phosphatase-1B (PTP1B)), via the ubiquitin-proteasome pathway (UPP). In some embodiments, the compounds described herein comprise a “targeting ligand” bound to the protein tyrosine phosphatase, a “degradation determinant” bound (e.g., non-covalently) to an E3 ligase (e.g., a cereblon component), and a linker covalently linking the targeting ligand to the degradation determinant.

[0008] This article discloses a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0009] This article discloses a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0010] This article also discloses a pharmaceutical composition comprising the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0011] This article also discloses a method for treating cancer in a subject in need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0012] A method for treating cancer in a subject in need, the method comprising administering to the subject the pharmaceutical composition disclosed herein.

[0013] This article also discloses a method for treating type 2 diabetes in a subject in need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0014] This article also discloses a method for treating type 2 diabetes in a subject in need, the method comprising administering the pharmaceutical composition disclosed herein to the subject.

[0015] This article also discloses a method for treating and / or controlling obesity in a subject in need, the method comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0016] This article also discloses a method for treating and / or controlling obesity in a subject in need, the method comprising administering the pharmaceutical composition disclosed herein to the subject.

[0017] This article also discloses a method for treating metabolic diseases in a subject in need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0018] This article also discloses a method for treating metabolic diseases in subjects in need, the method comprising administering the pharmaceutical composition disclosed herein to the subject.

[0019] In some implementations, the method further includes administering an additional therapeutic agent.

[0020] In some implementations, the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0021] In some implementations, the additional therapeutic agent is CAR-T cell therapy. In some implementations, the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene autoleucel, cilta-cabtagene autoleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisagenlecleucel.

[0022] This document also discloses a method for producing leukocytes with enhanced ability to kill target cells, the method comprising contacting leukocytes with the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof under conditions that enable a degrading agent to deactivate PTPN2 in the leukocytes, thereby producing leukocytes with enhanced ability to kill target cells.

[0023] In some implementations, leukocytes are exposed to the compound in the absence of helper T cells.

[0024] In some implementations, white blood cells are derived from subjects with cancer.

[0025] In some implementations, the white blood cells are neutrophils, eosinophils, basophils, monocytes, or lymphocytes.

[0026] In some implementations, the lymphocytes are tumor-infiltrating lymphocytes.

[0027] In some implementations, white blood cells are regulated or engineered to have specificity for cancer antigens.

[0028] In some implementations, the engineered specificity is provided by a recombinant chimeric receptor or T-cell receptor that specifically binds to the cancer antigen.

[0029] In some implementations, the target cells are cancer cells.

[0030] This article also discloses a method for treating cancer, comprising the following steps: in the presence of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, culturing leukocytes from a cancer subject to be treated or a tissue-compatible donor of a cancer subject to be treated in vitro under conditions that enable a degrading agent to inactivate PTPN2 in leukocytes, thereby forming a cell composition having an enhanced ability to kill target cancer cells; administering the cell composition to the subject, thereby treating cancer.

[0031] In some implementations, the white blood cells are neutrophils, eosinophils, basophils, monocytes, or lymphocytes.

[0032] In some implementations, the lymphocytes are tumor-infiltrating lymphocytes or peripheral blood lymphocytes.

[0033] In some implementations, white blood cells are regulated or engineered to be specific to the cancer being treated.

[0034] In some implementations, the engineered specificity is provided by a recombinant chimeric receptor or T-cell receptor that specifically binds to the cancer antigen. By incorporating via reference

[0035] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent and patent application were specifically and individually indicated to be incorporated by reference. Invention Details

[0036] definition In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout this specification and the appended claims, the word “comprise” and its variations (such as “comprises” and “comprising”) should be interpreted in an open, inclusive sense, that is, as “including but not limited to”. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0037] Throughout this specification, the phrases “some embodiments” or “implementation” refer to the inclusion of a specific feature, structure, or characteristic described in connection with an embodiment in at least one embodiment. Therefore, the phrases “in one embodiment” or “in an embodiment” appearing in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in one or more embodiments in any suitable manner. Additionally, as used in this specification and the appended claims, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include plural indicators. It should also be noted that unless the context clearly specifies otherwise, the term “or” is generally used to mean “and / or”.

[0038] Unless otherwise indicated, the terms used herein have the following meanings: "Oxytochemical" refers to the compound oxygen (O).

[0039] "Amine" refers to -NH2.

[0040] "Hydroxy group" refers to -OH.

[0041] The "carboxyl group" refers to -COOH.

[0042] "alkyl" means a straight-chain or branched monovalent hydrocarbon group having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and similar groups. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" mean that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkyl" without a specified numerical range. In some embodiments, the alkyl group is C1-C6. 10 Alkyl group. In some embodiments, the alkyl group is C1-C6 alkyl. In some embodiments, the alkyl group is C1-C5 alkyl. In some embodiments, the alkyl group is C1-C4 alkyl. In some embodiments, the alkyl group is C1-C3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, or heteroaryl and similar groups. In some embodiments, the alkyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted with a halogen.

[0043] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in a cis or trans or Z or E conformation around the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and similar groups. Whenever appearing herein, numerical ranges such as "C2-C6 alkenyl" mean that the alkenyl group may consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, or heteroaryl groups and similar groups. In some embodiments, the alkenyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkenyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0044] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and similar groups. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkynyl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl, and similar groups. In some embodiments, the alkynyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkynyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe groups. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0045] "alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specified in this specification, the alkylene group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the alkylene group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the alkylene group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkylene group is optionally substituted with a halogen.

[0046] "Alkoxy" refers to a group of the formula -O alkyl, wherein the alkyl group is as defined above. Unless otherwise specifically stated in this specification, the alkoxy group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the alkoxy group is optionally substituted with one or more halogens, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with a halogen.

[0047] "Aryl" refers to a group derived from a hydrocarbon ring system, comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cyclic or heterocyclic hydrocarbon ring, the aryl group is bonded through aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, anthraquinone, naphthyl, phenanthrenyl, azulel, phenyl, chrysenyl, fluoranthenyl, fluorenyl, asymmetric indoxcyclopentadiene (as-indacenyl), symmetric indoxcyclopentadiene (s-indacenyl), indanyl, indyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrene, and triphenyl. Unless otherwise specifically stated in this specification, the aryl group may optionally be substituted with, for example, one or more halogens, amino groups, nitriles, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid esters, aryl groups, cyclic hydrocarbon groups, heterocyclic hydrocarbon groups, or heteroaryl groups and similar groups. In some embodiments, the aryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, -COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted with one or more halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group is optionally substituted with a halogen.

[0048] "Arylene" refers to the divalent aryl group as defined above. Unless otherwise specified in this specification, the arylene group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the arylene group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the arylene group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the arylene group is optionally substituted with a halogen.

[0049] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused ring systems (bonded by non-aromatic atoms when fused with an aryl or heteroaryl ring), spirocyclic systems, and / or bridging ring systems. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, those having three to fifteen carbon atoms (e.g., C3-C5). 15Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), three to ten carbon atoms (e.g., C3-C) 10 Fully saturated cycloalkyl or C3-C 10 Cycloalkyl groups comprising three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl group is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl and spiro[5.3]nonyl. Partially saturated cyclic hydrocarbon groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, the cyclic hydrocarbon group is optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the cyclic hydrocarbon group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cyclic hydrocarbon group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cyclic hydrocarbon group is optionally substituted with a halogen.

[0050] "Cycloalkyl group" refers to the divalent cyclic alkyl group as defined above. Unless otherwise specifically stated in this specification, the cyclic alkyl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic alkyl, heterocyclic alkyl, or heteroaryl groups and similar groups. In some embodiments, the cyclic alkyl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the cyclic alkyl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the cyclic alkyl group is optionally substituted with a halogen.

[0051] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0052] "Halogenated alkyl" means an alkyl group defined above that has been halogenated by one or more of the alkyl groups defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and similar groups.

[0053] "Haloalkoxy" refers to -O-haloalkyl, where the haloalkyl is as defined above.

[0054] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0055] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0056] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuterium groups. In some embodiments, the alkyl group is substituted with one deuterium group. In some embodiments, the alkyl group is substituted with one, two, or three deuterium groups. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium groups. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0057] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof). The heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises one to six carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof), and the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. In another aspect, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group comprises one to six carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur, and the heteroalkyl group is attached to the remainder of the molecule at a carbon atom. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in this specification, the heteroalkyl group is optionally substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocyclic, or heteroaryl groups and similar groups. In some embodiments, the heteroalkyl group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the heteroalkyl group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe groups. In some implementations, heteroalkyl groups are optionally replaced by halogens.

[0058] "Heterocyclic hydrocarbon group" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic hydrocarbon group is fully saturated. In some embodiments, the heterocyclic hydrocarbon group is C-linked. In some embodiments, the heterocyclic hydrocarbon group is N-linked. In some embodiments, the heterocyclic hydrocarbon group comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic hydrocarbon group comprises 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic hydrocarbon group comprises 1 to 3 nitrogen atoms. In some embodiments, the heterocyclic hydrocarbon group comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic hydrocarbon group comprises 1 nitrogen atom. In some embodiments, the heterocyclic hydrocarbon group comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise specified in this specification, the heterocyclic hydrocarbon group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocyclic hydrocarbon group is bonded by non-aromatic ring atoms), helical, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic hydrocarbon group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic hydrocarbon groups include, but are not limited to, those having two to fifteen carbon atoms (e.g., C2-C). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, two to ten carbon atoms (e.g., C2-C) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkenyl groups, having two to eight carbon atoms (e.g., C2-C8 fully saturated heterocyclic alkyl or C2-C8 heterocyclic alkenyl), two to seven carbon atoms (e.g., C2-C7 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to six carbon atoms (e.g., C2-C6 fully saturated heterocyclic alkyl or C2-C7 heterocyclic alkenyl), two to five carbon atoms (e.g., C2-C5 fully saturated heterocyclic alkyl or C2-C5 heterocyclic alkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocyclic alkyl or C2-C4 heterocyclic alkenyl). Examples of such heterocyclic hydrocarbon groups include, but are not limited to, azirropropyl, azirrobutyl, oxacyclobutyl, 1,3-dioxacyclopentyl, thieno[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, and pyrazolidine. The term heterocyclic hydrocarbon group includes quinine, thiazolyl, tetrahydrofuranyl, trithiazolyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholine, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxacyclopentan-4-yl, and 2-oxo-1,3-dioxacyclopentan-4-yl. The term heterocyclic hydrocarbon group also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic hydrocarbon group has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic hydrocarbon group, the number of carbon atoms in the heterocyclic hydrocarbon group is not the same as the total number of atoms constituting the heterocyclic hydrocarbon group (i.e., the skeleton atoms of the heterocyclic hydrocarbon group ring), including heteroatoms. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 8-membered heterocyclic hydrocarbon group. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 7-membered heterocyclic hydrocarbon group. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 6-membered heterocyclic hydrocarbon group. In some embodiments, the heterocyclic hydrocarbon group is a 4- to 6-membered heterocyclic hydrocarbon group. In some embodiments, the heterocyclic hydrocarbon group is a 5- to 6-membered heterocyclic hydrocarbon group. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic hydrocarbon group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic hydrocarbon group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic hydrocarbon group is a 5- to 6-membered heterocyclic alkenyl group. Unless otherwise specified in this specification, heterocyclic hydrocarbon groups may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, heteroaryl and similar groups.In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe groups. In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with a halogen.

[0059] "Heterocyclic hydrocarbon group" refers to the divalent heterocyclic hydrocarbon group as defined above. Unless otherwise specifically stated in this specification, the heterocyclic hydrocarbon group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon or heteroaryl and similar groups. In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2 groups. In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with one or more halogens, -CN, -OH or -OMe. In some embodiments, the heterocyclic hydrocarbon group is optionally substituted with a halogen.

[0060] "Heteroaryl" refers to a 5- to 14-membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl group comprises one to three nitrogen atoms. In some embodiments, the heteroaryl group comprises one or two nitrogen atoms. In some embodiments, the heteroaryl group comprises one nitrogen atom. In some embodiments, the heteroaryl group is C-linked. In some embodiments, the heteroaryl group is N-linked. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused (when fused with a cyclic or heterocyclic hydrocarbon ring, the heteroaryl group is bonded through aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atom can optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered ring comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur.Examples include, but are not limited to, azepinyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzdioxolyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranone, benzofuranyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2] -a] Pyridyl, carbazolyl, cenolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazole, indoleyl, isoindoleyl, indolelinyl, isoindolelinyl, isoquinolinyl, indoleazinyl, isoxazolyl, naphridyl, oxadiazolyl, 2-oxoazonicyclic heptenyl, oxazolyl, 1-oxopyridinyl, 1-oxopyridinyl, 1-oxopyridinyl, 1-oxopyridyl The heteroaryl group may be substituted with, for example, one or more halogen, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purine, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, the heteroaryl group may optionally be substituted with, for example, one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0061] "Heteroaryl" refers to the divalent heteroaryl group defined above. Unless otherwise specifically stated in this specification, the heteroaryl group may optionally be substituted with, for example, one or more oxo, halogen, amino, nitrile, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cyclic hydrocarbon, heterocyclic hydrocarbon, or heteroaryl and similar groups. In some embodiments, the heteroaryl group is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted with one or more halogens, -CN, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with a halogen.

[0062] The terms “optional” or “optionally” mean that the event or situation subsequently described may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Additionally, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or any degree of substitution between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). With respect to any group containing one or more substituents, those skilled in the art will understand that such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which are defined as including optionally substituted alkyl groups, possibly infinitely). Therefore, any substituents described should generally be understood to have a maximum molecular weight of about 1,000 Daltons and more typically up to about 500 Daltons.

[0063] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three, or four or more substituents. In some embodiments, the subject group is optionally substituted by one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted by one, two, or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0064] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses that effectively produces the desired therapeutic effect.

[0065] "Treatment" of an individual (e.g., a mammal, such as a human) or cell refers to any type of intervention intended to alter the natural course of disease in an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after triggering a pathological event or exposure to a pathogen, and includes stabilizing symptoms (e.g., preventing symptoms from worsening) or alleviating symptoms.

[0066] "Synergization" or "synergistic effect" refers to the combined effect of a combination that is greater than the sum of the effects of the individual components at the same dose.

[0067] As used herein, the term "PTPN2-mediated condition or disease" or alternatively "PTPN2-related condition or disease" means any disease or other harmful symptom in which PTPN2 or its mutants are known to play a role. Therefore, in some embodiments, the method relates to treating one or more diseases in which PTPN2 or its mutants are known to play a role, or to reducing their severity.

[0068] As used herein, the term "PTPN1-mediated condition or disease" or alternatively "PTPN1-related condition or disease" means any disease or other harmful symptom in which PTPN1 or its mutants are known to play a role. Therefore, in some embodiments, the method relates to treating one or more diseases in which PTPN1 or its mutants are known to play a role, or to reducing their severity.

[0069] compound This article describes compounds or their pharmaceutically acceptable salts, solvates or stereoisomers that can act as PTPN1 / PTPN2 degraders.

[0070] This article discloses a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0071] in: Ring A is a heterocyclic hydrocarbon group or a heteroaryl group; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1They combine to form oxygen; Or two Rs on the same carbon 1 They combine to form cyclic or heterocyclic hydrocarbon groups; each is optionally substituted by one or more R groups; Or two R on different atoms 1 They combine to form cyclic hydrocarbon groups, heterocyclic hydrocarbon groups, aryl groups, or heteroaryl groups; each may optionally be substituted by one or more R groups. n can be 0, 1, 2, 3, or 4; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase target; L 2 for -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -、-[C(R 3 )2] m -、-O[C(R 3 )2] m -、-NR 2 [C(R 3 )2] m -、-[C(R 3 )2] m O- or -[C(R) 3 )2]m NR 2 -; R 2 For hydrogen, -C(=O)R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R 3 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocyclic alkyl; wherein each alkyl, cycloalkyl and heterocyclic alkyl group is independently and optionally substituted by one or more R; Or two Rs 3 They combine to form cyclic or heterocyclic hydrocarbon groups; each is optionally substituted by one or more R groups; m can be 1, 2, 3, or 4; Each R 4 Independently deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocyclic alkyl; p is 0, 1, or 2; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0072] In some embodiments of the compound of formula (I), ring A is a 4- to 6-membered heterocyclic hydrocarbon group containing one or two heteroatoms selected from O, S and N.

[0073] In some embodiments of the compound of formula (I), ring A is a 4-membered heterocyclic hydrocarbon group containing one heteroatom selected from O, S and N.

[0074] In some embodiments of the compound of formula (I), ring A is a 5-membered heterocyclic hydrocarbon group containing one heteroatom selected from O, S and N.

[0075] In some embodiments of the compound of formula (I), ring A is a 5-membered heterocyclic hydrocarbon group containing one heteroatom selected from O and N.

[0076] In some embodiments of the compound of formula (I), ring A is a 5-membered heterocyclic hydrocarbon group containing one N heteroatom.

[0077] In some embodiments of the compound of formula (I), ring A is a 6-membered heterocyclic hydrocarbon group containing one or two heteroatoms selected from O, S and N.

[0078] In some embodiments of the compound of formula (I), ring A is a 6-membered heterocyclic hydrocarbon group containing one or two heteroatoms selected from O and N.

[0079] In some embodiments of the compound of formula (I), ring A is a 6-membered heterocyclic hydrocarbon group containing one or two N heteroatoms.

[0080] In some embodiments of the compound of formula (I), n is 0. In some embodiments of the compound of formula (I), n is 1.

[0081] In some embodiments of the compound of formula (I), L 2 For -[C(R) 3 )2] m -

[0082] In some embodiments of the compound of formula (I), each R 3 It is hydrogen.

[0083] In some embodiments of the compound of formula (I), m is 1. In some embodiments of the compound of formula (I), m is 2. In some embodiments of the compound of formula (I), m is 3.

[0084] In some embodiments of the compound of formula (I), p is 0. In some embodiments of the compound of formula (I), p is 1.

[0085] In some embodiments of the compound of formula (I), W is N.

[0086] Also disclosed is a compound of formula (II) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0087] in: Ring A is a 7- to 15-membered cyclic hydrocarbon group or a 7- to 15-membered heterocyclic hydrocarbon group containing 1 to 4 heteroatoms selected from O, S and N; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1 They combine to form oxygen; n can be 0, 1, 2, 3, or 4; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 It can be hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocyclicalkyl; s is 1-20; M is an E3 ligase target; X is CR X Or N; RX For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Y is CR Y Or N; R Y For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Z is CR Z Or N; R Z For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or Rc and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0088] In some embodiments of the compound of formula (II), ring A is a 7-membered alkyl group. In some embodiments of the compound of formula (II), ring A is an 8-membered alkyl group.

[0089] In some embodiments of the compound of formula (II), ring A is a 7-membered heterocyclic hydrocarbon group containing one heteroatom selected from O, S, and N. In some embodiments of the compound of formula (II), ring A is a 7-membered heterocyclic hydrocarbon group containing one heteroatom selected from O and N. In some embodiments of the compound of formula (II), ring A is a 7-membered heterocyclic hydrocarbon group containing one heteroatom of N.

[0090] In some embodiments of the compound of formula (II), ring A is an 8-membered heterocyclic hydrocarbon group containing one heteroatom selected from O, S, and N. In some embodiments of the compound of formula (II), ring A is an 8-membered heterocyclic hydrocarbon group containing one heteroatom selected from O and N. In some embodiments of the compound of formula (II), ring A is an 8-membered heterocyclic hydrocarbon group containing one heteroatom of N.

[0091] In some embodiments of the compound of formula (II), n is 0. In some embodiments of the compound of formula (II), n is 1.

[0092] In some embodiments of the compound of formula (II), X is CR X .

[0093] In some embodiments of the compound of formula (II), R X It is a halogen.

[0094] In some embodiments of the compound of formula (II), Y is CR Y .

[0095] In some embodiments of the compound of formula (II), R Y It is -OH.

[0096] In some embodiments of the compound of formula (II), Z is CR Z .

[0097] In some embodiments of the compound of formula (II), R Z It is hydrogen.

[0098] In some embodiments of the compound of formula (II), W is N.

[0099] This article also discloses a compound of formula (III) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0100] in: Ring A is a 6- to 15-membered bicyclic cyclic hydrocarbon group or a 6- to 15-membered bicyclic heterocyclic hydrocarbon group containing 1 to 4 heteroatoms selected from O, S and N; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1 They combine to form oxygen; n can be 0, 1, 2, 3, or 4; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5-、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase target; X is CR X Or N; R X For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Y is CR Y Or N; R Y For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c Rd C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Z is CR Z Or N; R Z For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each Rb Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0101] In some embodiments of compounds of formula (III), ring A is a 6- to 15-membered bicyclic cyclic hydrocarbon group. In some embodiments of compounds of formula (III), ring A is a 6- to 10-membered bicyclic cyclic hydrocarbon group.

[0102] In some embodiments of the compound of formula (III), ring A is a 6- to 15-membered bicyclic heterocyclic hydrocarbon group comprising one to four heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (III), ring A is a 6- to 15-membered bicyclic heterocyclic hydrocarbon group comprising one or two heteroatoms selected from O and N. In some embodiments of the compound of formula (III), ring A is a 6- to 10-membered bicyclic heterocyclic hydrocarbon group comprising one or two heteroatoms selected from O and N.

[0103] In some embodiments of the compound of formula (III), n is 0. In some embodiments of the compound of formula (III), n is 1.

[0104] In some embodiments of the compound of formula (III), X is CR X .

[0105] In some embodiments of the compound of formula (III), R X It is a halogen.

[0106] In some embodiments of the compound of formula (III), Y is CR Y .

[0107] In some embodiments of the compound of formula (III), R Y It is -OH.

[0108] In some embodiments of the compound of formula (III), Z is CR Z .

[0109] In some embodiments of the compound of formula (III), R Z It is hydrogen.

[0110] In some embodiments of the compound of formula (III), W is N.

[0111] This article also discloses a compound of formula (IV) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0112] Formula (IV), in: Ring A is a 3- to 15-membered cyclic hydrocarbon group or a 3- to 15-membered heterocyclic hydrocarbon group containing 1 to 4 heteroatoms selected from O, S and N; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1 They combine to form oxygen; n can be 0, 1, 2, 3, or 4; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase target; X is CR X Or N; R X For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)ORb -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Y is CR Y Or N; R Y For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0113] In some embodiments of the compound of formula (IV), ring A is a 3- to 15-membered cyclic hydrocarbon group. In some embodiments of the compound of formula (IV), ring A is a 3- to 10-membered cyclic hydrocarbon group. In some embodiments of the compound of formula (IV), ring A is a 3- to 6-membered cyclic hydrocarbon group.

[0114] In some embodiments of the compound of formula (IV), ring A is a 3- to 15-membered heterocyclic hydrocarbon group comprising 1 to 4 heteroatoms selected from O, S, and N. In some embodiments of the compound of formula (IV), ring A is a 3- to 15-membered heterocyclic hydrocarbon group comprising 1 to 4 heteroatoms selected from O and N. In some embodiments of the compound of formula (IV), ring A is a 3- to 10-membered heterocyclic hydrocarbon group comprising 1 to 4 heteroatoms selected from O and N. In some embodiments of the compound of formula (IV), ring A is a 3- to 6-membered heterocyclic hydrocarbon group comprising 1 to 4 heteroatoms selected from O and N.

[0115] In some embodiments of the compound of formula (IV), n is 0. In some embodiments of the compound of formula (IV), n is 1.

[0116] In some embodiments of the compound of formula (IV), X is CR X .

[0117] In some embodiments of the compound of formula (IV), R X It is a halogen.

[0118] In some embodiments of the compound of formula (IV), Y is CR Y .

[0119] In some embodiments of the compound of formula (IV), R Y It is -OH.

[0120] In some embodiments of the compound of formula (IV), W is N.

[0121] This article also discloses a compound of formula (V) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0122] Equation (V), in: Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R dC1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1 They combine to form oxygen; m can be 0, 1, 2, 3, or 4; p is 1, 2, or 3; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase target; X is CR X Or N; R X For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)Ra -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Y is CR Y Or N; R Y For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R aIndependently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0123] In some embodiments of the compound of formula (V), m is 0. In some embodiments of the compound of formula (V), m is 1.

[0124] In some embodiments of the compound of formula (V), p is 0. In some embodiments of the compound of formula (V), p is 1.

[0125] In some embodiments of the compound of formula (V), X is CR X .

[0126] In some embodiments of the compound of formula (V), R X It is a halogen.

[0127] In some embodiments of the compound of formula (V), Y is CR Y .

[0128] In some embodiments of the compound of formula (V), R Y It is -OH.

[0129] In some embodiments of the compound of formula (V), Z is CR Z .

[0130] In some embodiments of the compound of formula (V), R Z It is hydrogen.

[0131] In some embodiments of the compound of formula (V), W is N.

[0132] This article also discloses a compound of formula (VI) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

[0133] Formula (VI), in: Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 1 They combine to form oxygen; m can be 0, 1, 2, 3, or 4; R 3 For hydrogen, -S(=O)R a-S(=O)2R a -S(=O)2NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, C1-C6 alkyl (cycloalkyl), C1-C6 alkyl (heterocyclic alkyl), C1-C6 alkyl (aryl), or C1-C6 alkyl (heteroaryl); wherein each alkyl, cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl group is independently and optionally marked by one or more R 3a replace; Each R 3a Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -OC(=O)R a -OC(=O)OR b -OC(=O)NR c R d -SH, -SR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -NR b C(=O)NR c R d -NR b C(=O)R a -NR b C(=O)OR b -NR b S(=O)2R a -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; Or two R atoms on the same atom 3a They combine to form oxygen; p is 1-3; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase target; X is CR X Or N; R X For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Y is CR Y Or N; RY For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; W is CR W Or N; R W For hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a -S(=O)R a -S(=O)2R a -S(=O)2NR c R d -NR c R d -C(=O)R a -C(=O)OR b -C(=O)NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclic alkyl, aryl or heteroaryl; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R bIndependently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; Or R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more Rs; L is absent or is a C1-C3 alkylene group that is independently and optionally substituted with one or more Rs; and Each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1 -C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl or C1-C3 heteroalkyl; Or two R atoms on the same atom can combine to form an oxo atom.

[0134] In some embodiments of the compound of formula (VI), m is 0. In some embodiments of the compound of formula (VI), m is 1.

[0135] In some embodiments of the compound of formula (VI), p is 0. In some embodiments of the compound of formula (VI), p is 1.

[0136] In some embodiments of the compound of formula (VI), R3 It is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (VI), R... 3 For hydrogen. In some embodiments of compounds of formula (VI), R... 3 It is a C1-C6 alkyl group.

[0137] In some embodiments of the compound of formula (VI), X is CR X .

[0138] In some embodiments of the compound of formula (VI), R X It is a halogen.

[0139] In some embodiments of the compound of formula (VI), Y is CR Y .

[0140] In some embodiments of the compound of formula (VI), R Y It is -OH.

[0141] In some embodiments of the compound of formula (VI), Z is CR Z .

[0142] In some embodiments of the compound of formula (VI), R Z It is hydrogen.

[0143] In some embodiments of the compound of formula (VI), W is N.

[0144] In some embodiments of compounds of formulas (I)-(VI), each L 1 Independently -O-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneylene, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R.

[0145] In some embodiments of compounds of formulas (I)-(VI), each L 1 Independently -O-, -NR 5 -、-C(=O)NR 5 -、-NR 5 C(=O)-、C1-C 10Alkylene, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, cycloalkylene, heteroalkylene, arylene, and heteroarylene is optionally substituted by one or more R independently.

[0146] In some embodiments of compounds of formulas (I)-(VI), each L 1 Independently for -NR 5 -、-C(=O)NR 5 -、-NR 5 C(=O)-、C1-C 10 Alkylene, arylene, or heteroarylene; wherein each alkylene, arylene, and heteroarylene is optionally substituted by one or more R.

[0147] In some embodiments of compounds of formulas (I)-(VI), each L 1 Independently for -NR 5 -、-C(=O)NR 5 -、-NR 5 C(=O)-、C1-C 10 Alkylene or arylene; wherein each alkylene and arylene is optionally substituted by one or more R.

[0148] In some embodiments of compounds of formulas (I)-(VI), each L 1 Independently for -NR 5 -、-C(=O)NR 5 -、-NR 5 C(=O)-、C1-C 10 Alkylenes; wherein each alkylene is optionally substituted independently by one or more R.

[0149] In some embodiments of compounds of formulas (I)-(VI), each R 5 It is independently hydrogen or C1-C6 alkyl.

[0150] In some embodiments of compounds of formula (I)-(VI), s is 1-15. In some embodiments of compounds of formula (I)-(VI), s is 1-10. In some embodiments of compounds of formula (I)-(VI), s is 1-5. In some embodiments of compounds of formula (I)-(VI), s is 5-10. In some embodiments of compounds of formula (I)-(VI), s is 5-15. In some embodiments of compounds of formula (I)-(VI), s is 5-20. In some embodiments of compounds of formula (I)-(VI), s is 2. In some embodiments of compounds of formula (I)-(VI), s is 3. In some embodiments of compounds of formula (I)-(VI), s is 4. In some embodiments of compounds of formula (I)-(VI), s is 5. In some embodiments of compounds of formula (I)-(VI), s is 6. In some embodiments of compounds of formula (I)-(VI), s is 7. In some embodiments of compounds of formula (I)-(VI), s is 8. In some embodiments of compounds (I)-(VI), s is 9. In some embodiments of compounds (I)-(VI), s is 10. In some embodiments of compounds (I)-(VI), s is 11. In some embodiments of compounds (I)-(VI), s is 12. In some embodiments of compounds (I)-(VI), s is 13. In some embodiments of compounds (I)-(VI), s is 14. In some embodiments of compounds (I)-(VI), s is 15. In some embodiments of compounds (I)-(VI), s is 16. In some embodiments of compounds (I)-(VI), s is 17. In some embodiments of compounds (I)-(VI), s is 18. In some embodiments of compounds (I)-(VI), s is 19. In some embodiments of compounds (I)-(VI), s is 20.

[0151] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0152] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C4-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0153] In some embodiments of compounds of formula (I)-(VI), -(L1 ) s - is a C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0154] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 Alkylene-NR 5 C(=O)-C1 alkylene-.

[0155] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C4-C 10 Alkylene-NR 5 C(=O)-C1 alkylene-.

[0156] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is a C1-C5 alkylene-NR 5 C(=O)-C1 alkylene-.

[0157] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0158] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0159] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0160] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Alkylene-NR5 C(=O)-C1 alkylene-.

[0161] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Alkylene-NR 5 C(=O)-C1 alkylene-.

[0162] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-NR 5 C(=O)-C1 alkylene-.

[0163] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Alkylene-.

[0164] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-.

[0165] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Alkylene-.

[0166] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 C(=O)-C1-C 10 Alkylene-.

[0167] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 C(=O)-C1-C5 alkylene-.

[0168] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 C(=O)-C4-C10 Alkylene-.

[0169] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 Alkylene-.

[0170] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is a -C1-C5 alkylene-.

[0171] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C4-C 10 Alkylene-.

[0172] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 alkylene-cyclic hydrocarbon-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0173] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C5 alkylene-cycloene-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0174] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C3 alkylene-cyclic hydrocarbon-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0175] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 alkylene-heterocyclic hydrocarbon-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0176] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s- is -C1-C5 alkylene-heterocyclic-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0177] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C3 alkylene-heterocyclic hydrocarbon-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0178] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 alkylene-arylene-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0179] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C5 alkylene-arylene-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0180] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C3 alkylene-arylene-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0181] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 alkylene-heteroaryl-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0182] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C5 alkylene-heteroaryl-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0183] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s- is -C1-C3 alkylene-heteroaryl-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0184] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 alkylene-cyclic hydrocarbon-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0185] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-cycloene-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0186] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C3 alkylene-cycloene-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0187] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 alkylene-heterocyclic hydrocarbon-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0188] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-heterocyclic-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0189] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C3 alkylene-heterocyclic-C1-C3 alkylene-NR 5C(=O)-C1-C3 alkylene-.

[0190] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 alkylene-arylene-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0191] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-arylene-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0192] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C3 alkylene-arylene-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0193] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 alkylene-heteroaryl-C1-C 10 Alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0194] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 alkylene-heteroaryl-C1-C5 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0195] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C3 alkylene-heteroaryl-C1-C3 alkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0196] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-O-C1-C 10 Heteroalkylene-.

[0197] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is an -O-C1-C5 heteroalkylene-.

[0198] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-O-C4-C 10 Heteroalkylene-.

[0199] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-O-C1-C 10 Heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0200] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is an O-C1-C5 heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0201] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-O-C4-C 10 Heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0202] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-O-C1-C 10 Heteroalkylene-NR 5 -C1-C3 alkylene-.

[0203] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is an O-C1-C5 heteroalkylene-NR 5 -C1-C3 alkylene-.

[0204] In some embodiments of compounds of formula (I)-(VI), -(L 1 )s -for-O-C4-C 10 Heteroalkylene-NR 5 -C1-C3 alkylene-.

[0205] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Heteroalkylene-.

[0206] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 heteroalkylene-.

[0207] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Heteroalkylene-.

[0208] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0209] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0210] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Heteroalkylene-NR 5 C(=O)-C1-C3 alkylene-.

[0211] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C 10 Heteroalkylene-NR 5 -C1-C3 alkylene-.

[0212] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C1-C5 heteroalkylene-NR 5 -C1-C3 alkylene-.

[0213] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-NR 5 -C4-C 10 Heteroalkylene-NR 5 -C1-C3 alkylene-.

[0214] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 Alkylene-NR 5 -C1-C 10 Alkylene-.

[0215] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is a C1-C5 alkylene-NR 5 -C1-C5 alkylene-.

[0216] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is a C1-C3 alkylene-NR 5 -C1-C3 alkylene-.

[0217] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for-C1-C 10 Alkylene-O-C1-C 10 Alkylene-.

[0218] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C5 alkylene-O-C1-C5 alkylene-.

[0219] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s - is -C1-C3 alkylene-O-C1-C3 alkylene-.

[0220] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0221] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0222] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0223] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0224] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0225] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0226] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0227] In some embodiments of compounds of formula (I)-(VI), -(L 1 ) s -for .

[0228] In some embodiments of compounds of formula (I)-(VI), -(L1 ) s -for .

[0229] In some embodiments of the compounds of formulas (I)-(VI), the E3 ligase target is cereblon E3 ligase, VHL E3 ligase, MDM2 ligase, TRIM24 ligase, TRIM21 ligase, KEAP1 ligase, or IAP ligase.

[0230] In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... .

[0231] In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... In some embodiments of compounds of formulas (I)-(VI), the E3 ligase target is... .

[0232] In some embodiments of the compounds disclosed herein, each R a Independently, each of the following groups is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl group is optionally substituted by one or more R groups. In some embodiments of the compounds disclosed herein, each R group... a Independently, each alkyl, cycloalkyl, or heteroalkyl group is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocyclic alkyl group; wherein each alkyl, cycloalkyl, and heterocyclic alkyl group is optionally substituted by one or more R groups. In some embodiments of the compounds disclosed herein, each R group... aIndependently, each alkyl group is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein each alkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R... a Independently, each R is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R a Independently, each alkyl group is a C1-C6 alkyl or C1-C6 haloalkyl group; wherein each alkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R a Independently, each R is a C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a It is independently a C1-C6 alkyl group.

[0233] In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl group is optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R... b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocyclicalkyl; wherein each alkyl, cycloalkyl, and heterocyclicalkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein each alkyl group is optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R... b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R... bIndependently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein each alkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R b Independently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R... b Independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R... b It is hydrogen. In some embodiments of the compounds disclosed herein, each R... b It is independently a C1-C6 alkyl group.

[0234] In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl group is optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R... c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, -L-cycloalkyl, or -L-heterocyclicalkyl; wherein each alkyl, cycloalkyl, and heterocyclicalkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; wherein each alkyl group is optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R... c and R d Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; wherein each alkyl group is optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R dIndependently, it is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R... c and R d Independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R... c and R d It is hydrogen. In some embodiments of the compounds disclosed herein, each R... c and R d It is independently a C1-C6 alkyl group.

[0235] In some embodiments of the compounds disclosed herein, R c and R d It combines with the atoms it is attached to to form a heterocyclic hydrocarbon group that is independently and optionally substituted by one or more R.

[0236] In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene group independently and optionally substituted with one or more R groups. In some embodiments of the compounds disclosed herein, L is a C1-C3 alkylene group. In some embodiments of the compounds disclosed herein, L is a C1-C2 alkylene group. In some embodiments of the compounds disclosed herein, L is a C1 alkylene group. In some embodiments of the compounds disclosed herein, L is a C2 alkylene group. In some embodiments of the compounds disclosed herein, L is a C3 alkylene group. In some embodiments of the compounds disclosed herein, L is absent.

[0237] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteralkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 heteroalkyl; or two Rs on the same atom are combined to form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 heteroalkyl; or two Rs on the same atom are combined to form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently a deuterium, halogen, -CN, -OH, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl; or two Rs on the same atom are combined to form an oxo group.

[0238] Any combination of groups described above for various variables is covered herein. Throughout this specification, those skilled in the art will select groups and their substituents to provide stable moieties and compounds.

[0239] In some embodiments, the compounds disclosed herein are selected from the compounds in Table 1 or their pharmaceutically acceptable salts, solvates or stereoisomers.

[0240] Table 1

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] In some embodiments, the compounds disclosed herein are compounds selected from the group consisting of: Or, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0248] Other forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist in geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, each center existing independently in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epiomers and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compounds with an optically active resolving agent to form diastereomeric compound pairs, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, the diastereomers are preferably dissociable complexes. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are subsequently recovered by any practical means that does not cause racemization.

[0249] Labeled compounds In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds listed herein, but in which one or more atoms are replaced by atoms whose atomic mass or mass number differs from that commonly found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively such as 2 H, 3 H, 13 C 14 C l5 N、 18 O、 17 O、 31P, 32 P, 35 S, 18 F and 36 Cl. Other isotopes described herein containing the aforementioned isotopes and / or other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotopically labeled compounds, for example, and having such... 3 H and 14 Compounds of radioactive isotopes of C can be used in drug and / or matrix tissue distribution assays. Tritium isotopes (i.e.,...) 3 H) and carbon-14 isotopes (i.e., ... 14 C) is particularly preferred due to its ease of preparation and detectability. Furthermore, the use of substances such as deuterium (i.e., 2 Heavy isotope substitution of H) produces certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0250] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0251] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0252] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting a purified compound in its free form with a suitable acid or base alone and isolating the resulting salt.

[0253] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases. These salts include, but are not limited to, acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionate, decanoates, disglucuronates, glucuronates, dihydrogen phosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucohepate, glycerophosphates, glycolates, hemisulfates, heptasulfates, heptahydrates, hexyn-1,6-dicitates, and hydroxybenzoates. γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0254] Furthermore, the compounds described herein can be prepared into pharmaceutically acceptable salts by reacting their free base form with pharmaceutically acceptable inorganic or organic acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and their analogues; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, etc. Citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although pharmaceutically unacceptable on their own, are used to prepare salts that can serve as intermediates for obtaining the compounds, solvates, or stereoisomers thereof disclosed herein and their pharmaceutically acceptable acid addition salts.

[0255] In some embodiments, the compounds described herein containing free acid groups react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), with ammonia, or with pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum and similar salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C1-C4 alkyl)4 hydroxides and similar compounds.

[0256] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing group they contain. In some embodiments, such quaternization yields water-soluble, oil-soluble, or dispersible products.

[0257] solvates In some embodiments, the compounds described herein are present in the form of solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0258] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed using pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholic compound is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures using organic solvents including, but not limited to, dialkylene, tetrahydrofuran, or methanol. Additionally, the compounds provided herein can exist in both non-solventized and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solventized form.

[0259] tautomer In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, which is accompanied by the conversion of a single bond to one or more adjacent double bonds. A chemical equilibrium of tautomers will exist in the bond arrangements in which tautomerization is possible. All tautomer forms of the compounds disclosed herein are covered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0260] Treatment This article discloses a method for treating diseases in which inhibition of PTPN1 / PTPN2 is beneficial, the method comprising administering the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0261] This document discloses a method for treating diseases in which inhibition of PTPN1 is beneficial, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN1 is beneficial is cancer or a metabolic disease.

[0262] This document discloses a method for treating diseases in which inhibition of PTPN2 is beneficial, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease in which inhibition of PTPN2 is beneficial is cancer.

[0263] cancer In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are used to treat cancer.

[0264] As used in this article, "cancer" refers to human cancers and carcinomas, sarcomas, adenocarcinomas (such as papillary adenocarcinoma), lymphomas, leukemias, melanomas, etc., including solid tumors and lymphomas.

[0265] The term “leukemia” broadly refers to a progressive, malignant disease of the hematopoietic organs, typically characterized by abnormal proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemia is usually clinically classified based on the following: (1) duration and characteristics of the disease – acute or chronic; (2) cell type involved; bone marrow (myeloblastic), lymphoid (lymphogenic), or monocytic; and (3) increase or absence of abnormal cell numbers in the blood – leukocytosis or non-leukocytosis (subleukocytosis). Exemplary leukemias that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, chronic leukemia, acute non-lymphocytic leukemia, acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukocytic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, acute myeloblastic leukemia, chronic myeloblastic leukemia, cutaneous leukemia, embryonic leukemia, eosinophilic leukemia, erythroleukemia, and Gross' disease. Leukemia, hairy cell leukemia, hematopoietic leukemia, hematopoietic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloid leukemia, myeloid granulocytic leukemia, myeloid monocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, polycythemia vera, promyelocytic leukemia, Rieder cell leukemia. Leukemia, Schilling's leukemia, stem cell leukemia, subleukocytosis, or undifferentiated cell leukemia.

[0266] The term "sarcoma" generally refers to a tumor composed of material similar to embryonic connective tissue and typically consisting of tightly packed cells embedded in fibrous or homogeneous material. Sarcomas that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include chondrosarcoma, fibrosarcoma, leiomyosarcoma, lymphosarcoma, lymphangiosarcoma, lymphoendothelial sarcoma, melanoma, myxosarcoma, osteosarcoma, Abemethyst's sarcoma, liposarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, endothelial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, and Hodgkin's sarcoma. Sarcoma), idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukocytosis sarcoma, malignant mesenchymal sarcoma, osteosarcoma, extraperiosteal sarcoma, reticulum cell sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, or capillary dilatational sarcoma.

[0267] The term "cancer" refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and cause metastasis. Exemplary cancers that can be treated with the compounds, pharmaceutical compositions, or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinar cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basoid cell carcinoma, basoid carcinoma, basal squamous cell carcinoma, bile duct carcinoma, bladder cancer, breast cancer, and Brenner's carcinoma. Carcinoma, bronchioloalveolar carcinoma, bronchial carcinoma, brain cancer, cervical cancer, cholangiocarcinoma, chordoma, choriocarcinoma, clear cell carcinoma, colloid carcinoma, colon cancer, comedo carcinoma, uterine corpus cancer, cribriform carcinoma, armored carcinoma, dermoid carcinoma, columnar carcinoma, columnar cell carcinoma, cystadenocarcinoma, ductal carcinoma, mammary duct carcinoma, sclerosing carcinoma, embryonal carcinoma, medullary carcinoma, endometrioid carcinoma, epidermoid carcinoma, epithelial carcinoma, adenocarcinoma, exophytic carcinoma, ulcerative carcinoma, fibrocarcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulocytic carcinoma, pilosula carcinoma, hemangiocarcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, colloid carcinoma Carcinoma, adrenal carcinoma, embryonic carcinoma, carcinoma in situ, intraepithelial carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipoma-like carcinoma, lobular carcinoma, lung cancer, lymphoepithelial carcinoma, medullary carcinoma Medullare, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucinous cell carcinoma, mucinous epidermoid carcinoma, mucosal carcinoma, mucinous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, non-papillary renal cell carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, ovarian cancer, pancreatic duct carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, acanthoma, brain-like carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneider's carcinoma. (carcinoma), scleroderma of the breast, scrotal cancer, sebaceous gland cancer, seminoma, serous carcinoma, ring cell carcinoma, simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous carcinoma, squamous cell carcinoma, cord carcinoma, sweat gland carcinoma, capillary carcinoma, angiodilation tumor, transitional cell carcinoma, mass carcinoma, tubular carcinoma, nodular carcinoma, undifferentiated tumor, verrucous carcinoma, or villous carcinoma.

[0268] In some implementation schemes, cancers include acoustic neuroma, adrenocortical carcinoma, adrenal carcinoma, astrocytoma, benign monoclonal gamma globulinosis, biliary tract cancer, bladder cancer, bone cancer, brain tumor, breast cancer, bronchial cancer, hematologic histological cancer, hepatic stellate carcinoma, oral or pharyngeal cancer, pancreatic stellate carcinoma, cancer, central nervous system cancer, cervical cancer, colon cancer, colorectal cancer, craniopharyngioma, mammary duct cancer, endocrine system cancer, endometrial cancer, ependymoma, epithelial ovarian cancer, esophageal cancer, gastric cancer, urogenital tract cancer, glioblastoma multiforme, and glioma. Gynecological cancers, head and neck cancer, hemangioblastoma, Hodgkin's disease, immune amyloidosis leukemia, kidney cancer, laryngeal cancer, leukemia, liver cancer (including hepatocellular carcinoma), lobular carcinoma, lung cancer, lymphoma, malignant carcinoid tumors, malignant hypercalcemia, malignant islet tumors, medullary thyroid carcinoma, neuroblastoma, melanoma, brain tumors, mesothelioma, multiple myeloma, myeloma, endocrine or exocrine pancreatic lesions, neuroblastoma, non-Hodgkin's lymphoma, oligodendroglioma, oral cancer, ovarian cancer, Paget's nipple disease. Disease of the Nipple), pancreatic cancer, papillary thyroid carcinoma, peripheral nervous system cancer, phyllodes tumor, pineal tumor, precancerous skin lesions, primary macroglobulinemia, primary thrombocytosis, prostate cancer, kidney cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine or appendix cancer, stomach cancer, testicular cancer, thyroid cancer, bladder cancer, uterine cancer, Waldenstrom's macroglobulinemia.

[0269] This document discloses a method for generating leukocytes with enhanced ability to kill target cells, the method comprising contacting leukocytes with a PTPN2 degrading agent disclosed herein under conditions such that the inhibitor is able to inactivate PTPN2 in the leukocytes, thereby generating leukocytes with enhanced ability to kill target cells. Preferably, the leukocytes are contacted with the PTPN2 inhibitor in the absence of helper T cells.

[0270] This document discloses a method for generating leukocytes with enhanced ability to kill target cells. The method comprises ex vivo contact of leukocytes with a PTPN2 degrading agent disclosed herein for a sufficient duration and under conditions that deactivate PTPN2 in the leukocytes, thereby generating leukocytes with enhanced ability to kill target cells. Preferably, the leukocytes are not exposed to CD4 helper T cells in vitro.

[0271] This article discloses a method for preparing an ex vivo T cell population exhibiting at least one cytotoxic T cell characteristic, the method comprising culturing T cells in the presence of the PTPN2 degrading agent disclosed herein.

[0272] This document discloses a method for preparing an in vitro T cell population exhibiting at least one cytotoxic T cell characteristic, the method comprising the steps of: culturing a T cell population derived from a biological sample in the presence of a PTPN2 degrading agent disclosed herein; expanding the cells in the culture medium; thereby preparing an in vitro T cell population exhibiting cytotoxic characteristics. In some embodiments, the biological sample is derived from a subject with cancer or has been modulated or engineered to be cancer-specific.

[0273] This article discloses an in vitro method for preparing compositions comprising antigen-specific cytotoxic T cells, the method comprising: providing a biological sample containing T cells; culturing an antigenic substance with a population of T cells in the presence of a PTPN2 degrading agent disclosed herein; and expanding the cells in the culture medium, thereby preparing the composition comprising antigen-specific cytotoxic T cells in vitro.

[0274] This article discloses a method for increasing the number of T cells exhibiting an effector memory phenotype in subjects, the method comprising the following steps: culturing a population of T cells derived from a biological sample in vitro in the presence of the PTPN2 degrading agent disclosed herein; expanding the cells in the culture medium; administering the cultured cells to the subject; thereby increasing the number of T cells exhibiting an effector memory phenotype in the subject.

[0275] This article discloses a method for generating an immune response suitable for cancer treatment in a subject, the method comprising the steps of: obtaining T cells from a subject or a tissue-compatible donor; culturing the T cells in vitro for an adequate time and under conditions for generating a population of T cells exhibiting at least one cytotoxic T cell characteristic in the presence of the PTPN2 degrading agent disclosed herein, thereby generating a cytotoxic T cell population; and administering the cytotoxic T cell population to the subject, thereby generating an immune response suitable for cancer treatment in the subject.

[0276] This article discloses a method for enhancing CD8+ T cell-mediated immunity in subjects with a disease, the method comprising: ex vivo contact of CD8+ T cells with a PTPN2 degrading agent disclosed herein for a sufficient duration and under conditions for generating a population of CD8+ T cells exhibiting at least one cytotoxic T cell characteristic; administering the CD8+ T cell population to the subject, thereby enhancing the subject's CD8+ T cell-mediated immunity.

[0277] This article discloses a method for enhancing CD8+ T cell-mediated immunity in subjects with a disease. The method includes: isolating the subject's CD8+ T cell population; introducing a nucleic acid molecule encoding siRNA or shRNA targeting PTPN2 into the isolated CD8+ T cells, thereby reducing the PTPN2 content in the CD8+ T cells; and reintroducing the CD8+ T cells into the subject; thereby enhancing the subject's CD8+ T cell-mediated immunity.

[0278] This article discloses a method for promoting cancer regression in a subject, comprising the following steps: culturing T cells obtained from the subject in the presence of the PTPN2 degrader disclosed herein, administering the cultured T cells to the subject, and then promoting cancer regression.

[0279] This article discloses a method for promoting cancer regression in subjects with cancer, comprising the following steps: culturing CAR T cells specific to tumor antigens expressed by cancer in the presence of the PTPN2 degrader disclosed herein; administering the cultured CAR T cells to the subject; and then promoting cancer regression. In some embodiments, the cancer is Her-2 positive and the CAR T cells are specific to Her-2.

[0280] This article discloses a method for prolonging the survival of subjects with cancer, comprising the following steps: culturing CAR T cells specific to tumor antigens expressed by cancer in the presence of the PTPN2 degrading agent disclosed herein; administering the cultured CAR T cells to the subject; and then prolonging the subject's survival. Preferably, the cancer is Her-2 positive and the CAR T cells are specific to Her-2.

[0281] In some implementations, T cells are selected from the group consisting of: tumor-infiltrating lymphocytes; peripheral blood lymphocytes genetically engineered to express anti-tumor T cell receptors or chimeric antigen receptors (CARs); and γδ T cells enriched from mixed lymphocyte tumor cell cultures (MLCs) or using autologous antigen-presenting cells and tumor-derived peptide clones. In some implementations, lymphocytes are isolated from tissue-compatible donors or cancer-carrying subjects.

[0282] In some embodiments, leukocytes or T cells are purified or substantially purified prior to culture in the presence of the PTPN2 degrading agent disclosed herein. This step enriches leukocytes or T cells by removing other cell types from the biological sample.

[0283] In some embodiments, CAR T cells are Her-2 specific CAR CD8+ T cells. In some embodiments, T cells are a population comprising more than one type of T cell (including any one or more types described herein). For example, the T cell population may include native T cells, activated T cells, and / or memory T cells.

[0284] Metabolic diseases In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are used to treat metabolic diseases.

[0285] As used herein, the term "metabolic disease" refers to a disease or condition in a subject that affects metabolic processes. Exemplary metabolic diseases include nonalcoholic fatty liver disease (NASH), nonalcoholic fatty liver disease (NAFLD), liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinemia, diabetes (e.g., type 1 diabetes, type 2 diabetes, or gestational diabetes), metabolic syndrome, phenylketonuria, proliferative retinopathy, or Kearns-Sayre disease. In some embodiments, the compounds disclosed herein are used to treat metabolic diseases (such as those described herein) by reducing or eliminating symptoms of the disease. In some embodiments, the treatment includes reducing or eliminating symptoms including elevated blood pressure, elevated blood glucose levels, weight gain, fatigue, blurred vision, abdominal pain, flatulence, constipation, diarrhea, jaundice, and similar symptoms.

[0286] Dosage In some embodiments, a composition containing a compound described herein is administered for therapeutic treatment. In some therapeutic applications, the composition is administered to a patient suffering from a disease or symptom in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or symptom. The effective amount for this use depends on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight and response to the drug, and the diagnosis of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0287] In some implementation schemes where the patient’s condition has not improved, the compound may be administered for a long period of time, i.e., for a prolonged period of time, including the entire duration of the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the physician’s judgment.

[0288] In some implementation schemes where the patient’s condition has indeed improved, the dose of the medication being administered is temporarily reduced or temporarily suspended for a period of time (i.e., a “medication holiday”).

[0289] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain implementations, the dose or frequency of administration, or both, is reduced as symptoms change.

[0290] The amount of a given reagent corresponding to this quantity varies depending on factors such as the specific compound, the disease symptoms and their severity, and the identity (e.g., weight, sex) of the subject or host requiring treatment, but is still determined based on the specific circumstances surrounding factors including, for example, the specific reagent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0291] In some embodiments, the dosage for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In some embodiments, the daily dose suitable for the compound described herein or a pharmaceutically acceptable salt thereof is from about 0.01 mg / kg body weight to about 50 mg / kg body weight. In various embodiments, the daily dose and unit dose vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual subject's needs, the severity of the disease or condition being treated, and the physician's judgment.

[0292] Application route Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nasal, and local administration. Additionally, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0293] In some embodiments, the compounds described herein are administered locally rather than systemically, often as reservoir products or sustained-release formulations via direct injection into an organ. In certain embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or via intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In other embodiments, the compounds described herein are provided as rapid-release formulations, extended-release formulations, or intermediate-release formulations.

[0294] Pharmaceutical Compositions / Formulations In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as pharmaceutical compositions to subjects in need. In some embodiments, the compounds described herein are administered to animals.

[0295] In another aspect, this document provides pharmaceutical compositions comprising the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable article. Appropriate formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the contents of which are incorporated herein by reference.

[0296] In some implementations, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0297] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-dissolving formulations, tablets, capsules, pills, powders, sugar-coated pills, effervescent formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-microparticle formulations, and mixed immediate-release and controlled-release formulations.

[0298] combination This document discloses a method for treating cancer in a subject of need, comprising administering to the subject an effective amount of: (a) the PTPN2 / N1 degrader disclosed herein; and (b) an additional therapeutic agent. In some embodiments, combination therapy improves patient outcomes.

[0299] In some implementations, the additional treatment agent is an anticancer agent.

[0300] In some implementations, the additional therapeutic agent is an immunotherapy agent. Combining immunotherapy agents with other cancer treatment regimens has become a promising approach to address limitations such as suboptimal efficacy, dose-dependent toxicity, and acquired resistance, while simultaneously generating a durable anti-tumor immune response and improving patient outcomes. In some implementations, combining PTPN2 / N1 degraders with checkpoint inhibitors can enhance therapeutic efficacy and improve tumor clearance in in vivo tumor models. In some implementations, combining the PTPN2 / N1 degraders disclosed herein with clinically approved immune checkpoint inhibitors has therapeutic benefits. These immune checkpoint inhibitors are, but are not limited to, atezolizumab, avelumab, cimipilimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toribalimab. Other examples of checkpoint inhibitors are AMG-404, camrelizumab, ezabenlimab, pidilizumab, or spartalizumab.

[0301] Because multiple published studies have confirmed that PTPN2 deficiency in tumor or immune compartments significantly enhances antitumor immunity and sensitivity to other immunotherapies such as checkpoint inhibitors, PTPN2 has become a validated immunotherapy target (Manguso et al., 2017; LaFleur et al., 2019; Weide et al., 2020). Emerging data also indicate that PTPN1 acts as an intracellular checkpoint and that PTPN1 deficiency in T cells improves tumor clearance (Weide et al., 2022). More recently, it has been shown that small molecule PTPN2 / N1 inhibitors enhance T cell activation and proliferation and inhibit tumor growth in murine syngeneic models (Liang et al., 2023).

[0302] In some implementations, the additional therapeutic agent is a chemotherapy agent. Chemotherapy induces cytotoxic effects on tumor cells, but is also considered to restore immune surveillance of cancer cells and act as an adjuvant for anti-tumor immunity (Liu et al., 2020). In some implementations, chemotherapy agents include, but are not limited to, cisplatin, cyclophosphamide, doxorubicin, gemcitabine, methotrexate, oxaliplatin, paclitaxel, or vinblastine, or combinations thereof.

[0303] In some implementations, the additional therapeutic agent is radiotherapy (RT). Radiotherapy (RT) can induce tumor cells to release antigens and trigger local or systemic antitumor immunity (Demaria et al., 2016).

[0304] In some implementations, the additional therapeutic agent is a VEGF inhibitor. Previous clinical studies have demonstrated a synergistic effect between immune checkpoint inhibitors and anti-angiogenic agents, and several of these combinations have recently been approved for the treatment of advanced renal cell carcinoma (Motzer et al., 2021; Makker et al., 2019; Jonasch et al., 2022). In some implementations, VEGF inhibitors include, but are not limited to, aflibercept, axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, ponatinib, ramucirumab, regorafenib, sorafenib, sunitinib, tivozanib, and vandetanib, potentially enhancing the clinical efficacy of these agents.

[0305] In some implementations, the additional therapeutic agent is a bispecific antibody or a T-cell adaptor.

[0306] In some embodiments, the bispecific antibody or T-cell adaptor is (but not limited to) bintrafusp alfa, blinatumomab, elranatamab, epcoritamab, erfeonrilimab, glofitamab, mosunetuzumab, SHR-1701, tebentafusp, or teclistamab. In some embodiments, because most of these bispecific antibodies are designed to redirect T cells, the combinations disclosed herein enhance T-cell-mediated tumor immunity.

[0307] In some implementations, the additional therapeutic agent is CAR-T cell therapy. Wiede et al. recently demonstrated that PTPN2 deficiency in T cells enhances cancer immune surveillance and improves the potency of CAR-T therapy by enhancing CAR-T cell activation and homing to tumors expressing CXCL9 / CXCL10 via STAT5 signaling (Wiede et al., 2020). In some implementations, the CAR-T cell therapy is (but is not limited to) azithromycin, brecicalenol, cidazolinone, icotinone, lisoxalenol, or texalunenol. In some implementations, the combinations disclosed herein enhance the clinical efficacy of human CAR-T cells.

[0308] In some implementations, the additional therapeutic agent is a KRAS G12C inhibitor. Recently, it has been demonstrated that the KRAS G12C inhibitor adagrasib sensitizes tumors to immunotherapies that alter the immune cell population in the tumor microenvironment (Briere et al., 2021). In some implementations, the KRAS G12C inhibitor is (but not limited to) adagrasib or sotorasib. Other examples of KRAS G12C inhibitors are disclosed in WO2021 / 245051, WO2021 / 245055, and WO2023 / 099612, which are incorporated herein by reference in their entirety. Specifically, other examples of KRAS G12C inhibitors that can be used according to the present invention are represented by compounds Ib-1 to Ib-16, Ic-1 to Ic-9, Id-1 to Id-9 and Ie-1 of WO2021 / 245051, compounds Ia-1 to Ia-170 of WO2021 / 245055 and compounds Ia-1 to Ia-4 and Ib-1 to Ib-9 of WO2023 / 099612. Other examples of KRAS G12C inhibitors are compounds known as: divarasib (GDC-6036), opnurasib (also known as JDQ443), garsorasib (D-1553), glecirasib (JAC-21822), GFH925 / GF105 / IBI351, RMC-6291, LY3537982, JNJ-74699157, and LY3499446. In some embodiments, the combinations disclosed herein enhance antitumor immunomodulation and potentially improve patient outcomes.

[0309] In some implementations, the additional therapeutic agent is a cancer vaccine. Cancer vaccines, such as, but not limited to, BCG, sipuleucel-T, and talimogene laherparepvec (T-VEC), where T-VEC is an FDA-approved oncolytic virus that activates both local and systemic immune responses, ensuring better induction of tumor-specific effector T cell function (Vafaei et al., 2021; Ferrucci et al., 2021). Current clinical trials utilize a combination of DC-based mRNA vaccines and ipilimumab to stimulate a strong T cell response (De Keersmaecker et al., 2020). In some implementations, the combinations disclosed herein promote an additive or synergistic effect against tumor immunity, thus potentially improving clinical outcomes.

[0310] In some implementations, additional therapeutic agents are HER2-targeted therapies. Recent reports have shown that HER2-targeted therapies can enhance anti-tumor immunity by increasing the expression of dendritic (DC) markers, enhancing MHC I expression on cancer cells to facilitate recognition by the immune system, and enhancing the recruitment of tumor-infiltrating CD4+ cells and CD8+ T cells (Iwata et al., 2018 and 2019). Consistent with this idea, HER2-targeted therapies, such as, but not limited to, lapatinib, margetuximab, neratinib, pertuzumab, trastuzumab emtansine (T-DM1), trastuzumab, tucatinib, and zongertinib, can also be combined with PTPN2 / N1 degraders to achieve a more robust anti-tumor immune response (Vafaei et al., 2022).

[0311] In some embodiments, the additional therapeutic agent is a CXCR4 antagonist. CXCR4 antagonists have been developed to impair pathological processes and disrupt the adhesion of cancer cells to stromal cells, promoting the release of cancer cells into circulation (Otsuka et al., 2008; Schrader et al., 2002). In some embodiments, the combinations disclosed herein confer a strong immune response and attack circulating cancer cells to delay tumor development and induce tumor regression. In some embodiments, the CXCR4 antagonist is (but is not limited to) plerixafor.

[0312] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered at a lower frequency than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered at a higher frequency than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein. Example

[0313] Synthesis of 2-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-((2-methoxyethoxy)methoxy)phenyl)acetaldehyde

[0314] Procedure for Compounds 1-2 To a solution of 1-1 (120 g, 508 mmol, 1 equivalent) in DMSO (1.67 L), 10 M NaOH (100 mL, 2 equivalents) was added and the mixture was stirred at room temperature for 12 h. Then, 1 M HCl (30 L) was added, followed by extraction with ethyl acetate (10 L × 3). The combined organic phases were washed with brine (10 L × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-2 (75 g, 320 mmol, 63% yield) was isolated as a yellow crude solid. LCMS (ESI-): m / z = 236.0 (MH) - . 1 H NMR (400 MHz, CDCl3) δ 10.62(s, 1H), 7.20 (t, J =1.90 Hz, 1H), 6.99 (dd, J =10.64, 2.08 Hz, 1H).

[0315] Procedures for compounds 1-3 Triethylamine (64.3 g, 635 mmol, 88.4 mL, 1.5 equivalent) and 1-(chloromethoxy)-2-methoxy-ethane (58 mL, 508 mmol, 1.2 equivalent) were added to a solution of 1-2 (100 g, 423 mmol, 1 equivalent) in CH2Cl2 (1.52 L) at 0 °C under a N2 atmosphere. The reaction mixture was then stirred at 0 °C for 2 h. The reaction mixture was then washed with H2O (5 L) and brine (2 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compound 1-3 (130 g, 397 mmol, 94% yield) was isolated as a yellow crude solid. 1 H NMR (400 MHz, CDCl3) δ 7.35 (t, J =1.67 Hz, 1H), 7.09 (dd, J =8.58,1.79 Hz, 1H), 5.35 (s,2H), 3.83-3.88 (m, 2H), 3.55-3.59 (m, 2H), 3.39 (s, 3H).

[0316] Procedure for compounds 1-4 Fe (51.7 g, 925 mmol, 5 equivalents) and NH4Cl (99 g, 1.85 mol, 10 equivalents) were added to a mixture of 1-3 (60 g, 185 mmol, 1 equivalent) in EtOH (600 mL) and H2O (600 mL) and stirred at 80 °C for 1 h. The reaction mixture was then filtered and concentrated under reduced pressure to remove EtOH. The aqueous mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phases were then washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compounds 1-4 (38.5 g, 131 mmol, 70% yield) were isolated as a brown crude oil. 1 H NMR (400 MHz, CDCl3) δ 6.98 (t, J =1.75 Hz, 1H) 6.82 (dd, J =9.88, 2.00 Hz,1H) 5.21 (s, 2H) 3.75-3.79 (m, 2H) 3.49-3.53 (m, 2H) 3.33 (s, 3H).

[0317] Procedure for compounds 1-6 Diisopropylethylamine (52.7 g, 408 mmol, 71.1 mL, 1.2 equivalents), sodium iodide (10.2 g, 68 mmol, 0.2 equivalents), and 1-5 (73 g, 374 mmol, 55.2 mL, 1.1 equivalents) were added to a solution of 1-4 (100 g, 340 mmol, 1 equivalent) in DMF (1 L), and the mixture was stirred at 80 °C for 6 h. The reaction mixture was then filtered and concentrated under reduced pressure. The crude product was added with H2O (6 L) and extracted with ethyl acetate (1 L × 3). The combined organic phases were then washed with brine (1 L × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give 1-6 (89 g, 217 mmol, 64% yield) as a brown oil. LCMS (ESI+): m / z = 410.1 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ 7.07 (t, J =1.75 Hz, 1H) 6.88(dd, J =11.51, 2.00 Hz, 1H) 5.29 (s, 2H) 3.97 (dd, J=6.07, 2.56 Hz, 2H) 3.82-3.87 (m, 2H) 3.56-3.60 (m, 2H) 3.39-3.42 (m, 3H) 1.46 (s, 9H).

[0318] Procedure for compounds 1-7 At 0℃, towards N A solution of 1-(oxomethylene)aminosulfonyl chloride (48 g, 339 mmol, 29.5 mL, 1.15 equivalents) in CH2Cl2 (1 L) was mixed with propan-2-en-1-ol (20 g, 343 mmol, 23.4 mL, 1.17 equivalents) and stirred for 30 min under a nitrogen atmosphere. Then, a solution of 1-6 (120 g, 294 mmol, 1 equivalent) and triethylamine (89.2 g, 881 mmol, 122 mL, 3 equivalents) in CH2Cl2 (200 mL) was added and stirred for another 30 min. H2O (2 L) was added to the reaction mixture and it was extracted with CH2Cl2 (500 mL × 3). The combined organic phases were then washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compounds 1-7 were isolated as a yellow, crude solid (154 g, 269 mmol, 91% yield). LCMS (ESI-): m / z = 570.8 (MH) - . 1 H NMR (400 MHz, CDCl3) δ 7.20 (t, J =1.81 Hz, 1H) 6.94 (dd, J =8.76, 2.13 Hz, 1H)5.88-5.96 (m, 1H) 5.31-5.33 (m, 1H) 5.27 (d, J =1.63 Hz, 2H) 5.16-5.21 (m, 1H)4.83 (d, J =17.76 Hz, 1H) 4.53-4.58 (m, 2H) 4.27 (d, J =17.76 Hz, 1H) 3.85-3.88(m, 2H) 3.56 (dd, J =5.32, 3.81 Hz, 2H) 3.38 (s, 3H) 1.38 (s, 9H).

[0319] Procedure for compounds 1-8 To a solution of 1-7 (180 g, 315 mmol, 1 equivalent) in MeOH (1.3 L), NaOMe (170 g, 945 mmol, 30% purity, 3 equivalents) was added, followed by degassing under vacuum and purging with N2 gas. This degassing and purging process was repeated a total of 3 times. Then, Pd(PPh3)4 (3.64 g, 3.15 mmol, 0.01 equivalents) was added to the reaction mixture, followed by degassing and purging with N2 gas three more times. The reaction mixture was then heated to 60 °C and stirred for 2 h. The reaction mixture was then filtered and concentrated under reduced pressure. 1 M HCl (4 L) was added to the reaction mixture, followed by extraction with ethyl acetate (1 L × 5). The combined organic phases were then washed with brine (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compounds 1-8 were isolated as a yellow, crude solid (100 g, 242 mmol, 77% yield). LCMS (ESI-): m / z = 413.1 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.31 (t, J =1.81 Hz, 1H) 7.16 (dd, J =8.94,2.06 Hz, 1H) 5.35 (s, 2H) 4.45 (s, 2H) 3.82-3.85 (m, 2H) 3.54-3.57 (m, 2H)3.32-3.34 (m, 3H).

[0320] Procedure for compounds 1-10 K₂CO₃ (20 g, 48 mmol, 1 equivalent) and Pd(dppf)Cl₂ (708 mg, 968 μmol, 0.02 equivalent) were added to a mixture of 1-8 (20 g, 48.40 mmol, 1 equivalent) and 1-9 (9.6 g, 48.40 mmol, 1 equivalent) in DME (2 L) and H₂O (200 mL), and the mixture was stirred at 95 °C for 1 h. The reaction mixture was filtered, followed by the addition of 1 M HCl (1.5 L) and extraction with ethyl acetate (500 mL × 3). The combined organic phases were then washed with brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was used directly without purification. Compounds 1-10 (17.5 g, 43.4 mmol, 90% yield) were isolated as a yellow crude solid. LCMS (ESI-): m / z = 403.2 (MH) - . 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J =12.9 Hz, 1H), 6.78 (s, 1H), 6.55 (d, J =10.4 Hz, 1H), 5.65 (d, J =12.8 Hz, 1H), 5.21 (s, 2H), 4.39-4.18 (m, 2H), 3.96-3.80 (m,2H), 3.72 (s, 2H), 3.47-3.34 (m, 2H), 3.32-3.16 (m, 3H), 1.32 (t, J =7.0 Hz, 3H).

[0321] Procedure for Compounds 1-11 A solution of 1-10 (310 mg, 766 μmol, 1 equivalent) in acetonitrile (6 mL) was added with 12 M HCl (0.6 mL, 9.4 equivalents) and stirred at 0 °C for 20 min. Diisopropylethylamine was added to the reaction mixture to adjust the pH to 8-9. The mixture was then concentrated and used directly in the next step without purification. Compound 1-11 (280 mg, 743 μmol, 97% yield) was isolated as a yellow liquid. LCMS (ESI-): m / z = 375.2 (MH) - .

[0322] Example 1: 2-((S)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenylethyl)pyrrolidine-3-yl)-N-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)amino)methyl)benzyl)acetamide)

[0323] Procedure for compound 1-14A Diisopropylethylamine (1.9 mL, 10.86 mmol, 2 equivalents) was added to a solution of 1-12 (1.5 g, 5.43 mmol, 1 equivalent) and 1-13 (5.97 mmol, 1.1 equivalent) in NMP (15 mL), followed by heating to 90 °C and stirring for 12 hours. H₂O (100 mL) was then added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1 to 1 / 1) to give 1-14A (2.6 g, 1.62 mmol, 30% yield) as a yellow oil. LCMS (ESI+): m / z = 493.2 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.53(d, J =8.28 Hz, 1H), 6.97 (d, J =2.01 Hz, 1H), 6.86 (dd, J =8.41, 2.13 Hz, 1H), 5.02 (dd, J =12.49, 5.46 Hz, 1H), 4.43 (s, 2H), 4.21 (d, J =5.14 Hz, 2H), 2.59-2.80 (m, 3H), 2.33-2.39 (m, 5H), 2.03 (d, J =8.03 Hz, 3H), 1.44 (s, 9H) Intermediates 1-14B and 1-14I are prepared using appropriate intermediates according to the procedure described in 1-14A.

[0324]

[0325]

[0326] Procedure for compound 1-15A At room temperature, TFA (1.5 mL, 20.2 mmol, 19 equivalents) was added to a mixture of 1-14A (0.52 g, 1.06 mmol, 1 equivalent) and CH2Cl2 (6 mL), and the mixture was stirred for 1 h. The reaction mixture was then concentrated under reduced pressure to give a crude product. The crude product was used in the next step without further purification. Compound 1-15A (0.41 g, 1 mmol, 95% yield) was obtained as a yellow oil. LCMS (ESI+): m / z = 393.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (s,2H), 7.56 (d, J =8.4 Hz, 1H), 7.41 (s, 4H), 6.97-6.82 (m, 1H), 4.58-4.36 (m,2H), 4.08-3.94 (m, 2H), 3.30 (t, J =7.0 Hz, 4H), 2.24-2.12 (m, 4H).

[0327] Intermediates 1-15B and 1-15I are prepared using appropriate intermediates according to the procedure described in 1-15A.

[0328]

[0329]

[0330] Procedure for compound 1-17A Diisopropylethylamine (1 mL, 5 mmol, 1 equivalent), HOAt (168 mL, 1.2 mmol, 1.2 equivalent), and HATU (571 mg, 1.5 mmol, 1.5 equivalent) were added to solutions of 1-15A (0.41 g, 1 mmol, 1 equivalent) in DMF (5 mL), and the mixture was stirred at 20 °C for 2 h. H₂O (10 mL) was then added, followed by extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2) and 1 M NaOH (15 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then dissolved in MeOH (minimum amount), followed by the addition of H₂O to form a precipitate. The precipitate was separated and dried under reduced pressure. The crude product was subsequently purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40 mm×10 μm; mobile phase: [A: H2O (10mM NH4CO3), B: acetonitrile]; gradient: 1%–35% B, duration 8.0 min). Compound 1-17A (0.1 g, 0.16 mmol, 16% yield) was obtained as a brown oil. LCMS (ESI+): m / z = 604.2 (M+H) + .

[0331] Intermediates 1-17B-1-17J are prepared using appropriate intermediates according to the procedure described in 1-17A.

[0332]

[0333]

[0334] Procedure for compound 1-18A TFA (235 mL g, 3.17 mmol, 20 equivalents) was added to a solution of 1-17A (0.1 g, 0.16 mmol, 1 equivalent) in CH₂Cl₂ (5 mL) and stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure to give a crude product. The crude product was used in the next step without further purification. Compound 1-18A (83 mg, 0.15 mmol, 95% yield) was obtained as a yellow oil. LCMS (ESI+): m / z = 504.2 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.49(m, 1H), 8.39 (s, 1H), 7.74-7.69 (m, 1H), 7.69-7.64 (m, 1H), 7.33-7.27 (m,1H), 7.21 (d, J =8.0 Hz, 1H), 6.95-6.82 (m, 1H), 5.01 (dd, J =5.3, 12.7 Hz,1H), 3.37-3.28 (m, 1H), 3.27-3.14 (m, 1H), 3.14-2.98 (m, 1H), 2.96-2.63 (m,2H), 2.60-2.52 (m, 2H), 2.45-2.40 (m, 1H), 2.38-2.25 (m, 2H), 2.10-1.85 (m,2H), 1.69-1.58 (m, 2H), 1.57-1.45 (m, 1H), 1.43-1.32 (m, 2H), 1.23 (s, 1H),0.91 (t, J =7.4 Hz, 3H).

[0335] Intermediates 1-18B-1-18J are prepared using appropriate intermediates according to the procedure described in 1-18A.

[0336]

[0337]

[0338]

[0339] Procedure for compound 1-19A Diisopropylethylamine (37 μL, 216 μmol, 3 equivalents) was added to a solution of 1-18A (80 mg, 129 μmol, 1.2 equivalents) and 1-11 (41 mg, 107 μmol, 1 equivalent) in acetonitrile (2 mL), and the mixture was stirred at room temperature for 30 min. Then, NaBH3CN (20 mg, 323 μmol, 3 equivalents) was added, and the mixture was stirred for another 2 h. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 100×40 mm×5 μm; mobile phase: [A: H2O (0.04% HCl), B: acetonitrile]; gradient: 15%–45% B, duration 8.0 min). Product 1-19A (93 mg, 34 μmol, 32% yield) was obtained as a brown oil. 1 H NMR (400 MHz, DMSO-d6) δ 11.19-10.91 (m, 1H), 10.04-9.50 (m, 2H), 8.41 (s, 1H), 7.77-7.49 (m, 2H), 7.37-7.08 (m, 5H), 6.97-6.81 (m, 2H), 6.74-6.58 (m, 2H), 5.04-4.99 (m, 1H), 4.43 (s, 2H), 4.24 (d, J =1.0 Hz, 2H), 4.13 (d, J =2.5 Hz, 2H), 3.79-3.67 (m, 1H), 3.26-3.19 (m, 4H), 2.97-2.77 (m, 4H), 2.68-2.66 (m, 2H), 2.38-2.30 (m, 5H), 2.26-1.94 (m, 5H),1.75-1.62 (m, 1H), 1.61-1.45 (m, 1H), 1.32-1.20 (m, 1H), 1.15 (s, 1H). LCMS(ESI-): m / z = 862.6 (MH) - . 1H NMR (400 MHz, DMSO-d6) δ 11.19-10.91 (m, 1H), 10.04-9.50 (m, 2H), 8.41 (s, 1H), 7.77-7.49 (m, 2H), 7.37-7.08 (m, 5H), 6.97-6.81 (m, 2H), 6.74-6.58 (m, 2H), 5.04-4.99 (m, 1H), 4.43 (s, 2H), 4.24 (br d, J =1.0 Hz, 2H), 4.13 (d, J =2.5 Hz, 2H), 3.79-3.67 (m, 1H), 3.26-3.19 (m, 4H), 2.97-2.77 (m, 4H), 2.68-2.66 (m, 2H), 2.38-2.30 (m, 5H), 2.26-1.94 (m, 5H), 1.75-1.62 (m, 1H), 1.61-1.45 (m, 1H), 1.32-1.20 (m, 1H), 1.15 (s, 1H).

[0340] Intermediates 1-19B-1-19J are prepared using appropriate intermediates according to the procedure described in 1-19A.

[0341]

[0342]

[0343]

[0344]

[0345] Example 1 program 4 M HCl (EtOAc solution, 3 mL) was added to a flask containing 1-19A (30 mg, 34 μmol, 1 equivalent), and the mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [A: H₂O (10 mM NH₄CO₃), B: acetonitrile]; gradient: 10%–40% B, 8.0 min). Product Example 1 was obtained (5 mg, 6.4 μmol, 18% yield). LCMS (ESI-): m / z = 774.2 (MH) - . 1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H),7.70 (t, J =5.8 Hz, 1H), 7.55 (d, J =8.4 Hz, 1H), 7.33-7.26 (m, 2H), 7.21 (d, J =8.1 Hz, 2H), 6.93 (s, 1H), 6.87 (d, J =8.6 Hz, 1H), 6.58 (s, 2H), 5.01 (dd, J =5.4, 12.8 Hz, 1H), 4.43 (d, J =5.0 Hz, 2H), 4.29-4.18 (m, 2H), 3.93 (s, 2H), 3.30 (s, 6H), 2.91-2.80 (m, 2H), 2.78-2.72 (m, 1H), 2.68-2.65 (m, 1H), 2.58(s, 2H), 2.54 (s, 3H), 2.39-2.21 (m, 3H), 2.06-1.88 (m, 2H).

[0346] Examples 2-7 are prepared using appropriate intermediates according to the procedure described in Example 1.

[0347]

[0348]

[0349] Example 11: 2-((S)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenethyl)pyrrolidine-3-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)acetamide

[0350] Procedure for compound 11-3A Add 11-2 (1.81 g, 7.32 mmol, 1 equivalent) to a solution of 11-1 (2 g, 7.32 mmol, 1 equivalent) in THF (70 mL), and then stir at room temperature for 1 h. Filter the reaction mixture, then separate the filtrate and concentrate under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0, 10 / 1, 2 / 1). Compound 11-3A (1.5 g, 3.10 mmol, 59% yield), present as a yellow oil, was isolated. LCMS (ESI-): m / z = 483.4 (MH) - . 1 H NMR (400MHz, CD3OD) δ 8.61 (d, J =8.38 Hz, 1H), 7.78 (t, J =7.88 Hz, 1H), 7.59 (d, J =7.38 Hz, 1H) 5.13 (dd, J =12.63, 5.50 Hz, 1H), 3.55-3.69 (m, 2H), 3.46 (d, J =8.38 Hz, 1H), 3.00-3.08 (m, 1H), 2.68-2.96 (m, 5H), 2.12-2.19 (m, 2H), 1.77-1.88 (m, 1H), 1.65-1.74 (m, 1H), 1.46 (s, 9H).

[0351] Compound 11-3B was prepared using appropriate intermediates according to the procedure described in Compound 11-3A.

[0352]

[0353] Procedure for compound 11-4A TFA (2 mL) was added to a solution of 11-3A (600 mg, 1.24 mmol, 1 equivalent) in CH₂Cl₂ (8 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure and used in the next step without further purification. Compound 11-4A (1.2 g, crude, TFA) was obtained as a brown oil. LCMS (ESI+): m / z = 385.1 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.60 (d, J=8.4 Hz, 1H), 7.89-7.74 (m, 1H),7.62 (d, J =7.3 Hz, 1H), 5.14 (dd, J =5.4, 12.4 Hz, 1H), 3.69-3.56 (m, 2H), 3.29-3.19 (m, 1H), 2.86-2.71 (m, 6H), 2.33 (dt, J =4.4, 6.6 Hz, 1H), 2.18-2.11(m, 1H), 1.90-1.75 (m, 2H).

[0354] Compound 11-4B was prepared using appropriate intermediates according to the procedure described in Compound 11-4A.

[0355]

[0356] Procedure for compound 11-5A Diisopropylethylamine (740 μL, 4.25 mmol, 2 equivalents) and 11-4A (1.17 g, 2.34 mmol, 1.1 equivalents) were added to a solution of 1-11 (800 mg, 2.13 mmol, 1 equivalent) in acetonitrile (10 mL), and the mixture was stirred at room temperature for 30 min. NaBH3CN (400 mg, 6.38 mmol, 3 equivalents) was then added and the mixture was stirred for another 30 min. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 180 × 70 mm × 10 μm; mobile phase: [A: H2O (0.2% formic acid), B: acetonitrile]; gradient: 11%–41% B, duration: 20.0 min). Compound 11-5A (300 mg, 402 μmol, 19% yield) was given as a yellow solid. LCMS (ESI-): m / z = 743.5 (MH) - . 1 H NMR (400 MHz, DMSO-d6) δ 8.38-8.21 (m, 1H), 7.67-7.59 (m, 1H), 6.93-6.80 (m, 3H), 5.25 (s, 2H), 4.78-4.52 (m, 1H), 3.92 (s, 2H), 3.76 (d, J =4.5 Hz, 2H), 3.46 (d, J=4.8 Hz, 2H), 3.22-3.21 (m, 3H), 3.14-3.00 (m, 4H), 2.94-2.81 (m, 4H), 2.69-2.59 (m, 4H), 2.24-1.90 (m, 4H), 1.69-1.55 (m, 1H).

[0357] Compound 11-5B was prepared using appropriate intermediates according to the procedure described in Compound 11-5A.

[0358]

[0359] Program of Example 11 4 M HCl (EtOAc solution, 5 mL) was added to a flask containing 11-5A (220 mg, 295 μmol, 1 equivalent) and stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [A: H₂O (0.04% HCl), B: acetonitrile]; gradient: 1%–33% B, 8.0 min). Compound Example 11 was obtained (24 mg, 33 μmol, 11% yield). LCMS (ESI-): m / z = 655.2 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 8.58 (d, J =8.4 Hz, 1H), 7.81 (dt, J =4.3, 7.9 Hz, 1H), 7.62 (d, J =7.1 Hz, 1H), 6.82-6.65 (m, 2H), 5.14(dd, J =5.4, 12.6 Hz, 1H), 4.39 (s, 2H), 4.05-3.90 (m, 1H), 3.81-3.64 (m, 1H), 3.56-3.45 (m, 3H), 3.29-3.10 (m, 1H), 3.08-2.94 (m, 3H), 2.90-2.68 (m, 5H), 2.54-2.27 (m, 1H), 2.22-2.08 (m, 1H), 2.02-1.71 (m, 1H).

[0360] Example 12 is prepared using appropriate intermediates according to the procedure described in Example 11.

[0361]

[0362] Synthesis of (S)-3-(2-bromoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0363] Procedure for compound 13-2 At 0°C, 1M BH3-THF (130 mL, 3 equivalents) was slowly added to a solution of 13-1 (10 g, 43.62 mmol, 1 equivalent) in 30 mL of THF. The reaction mixture was then stirred at room temperature for 2 h. MeOH (30 mL) was then added and the mixture was stirred again at 0°C for 30 min. The mixture was then concentrated under reduced pressure and used in the next step without further purification. Compound 13-2 (10 g, crude) was obtained as an oil. 1 H NMR (400 MHz, CDCl3) δ 3.66-3.86 (m, 2H), 3.34-3.62 (m, 3H), 3.24 (d, J =5.25 Hz, 1H), 2.79-2.99 (m, 1H), 2.11-2.33 (m,1H), 1.94-2.06 (m, 1H), 1.72-1.89 (m, 1H), 1.57-1.70 (m, 2H), 1.45 (s, 9H).

[0364] Procedure for compound 13-3 At 0 °C, CBr4 (7.95 g, 23.97 mmol, 1.3 equivalent) and PPh3 (6.34 g, 24.15 mmol, 1.3 equivalent) were added to a solution of 13-2 (4 g, 18.58 mmol, 1 equivalent) in CH2Cl2 (350 mL). The reaction mixture was then stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1). Compound 13-3 (3.3 g, 11.9 mmol, 64% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 3.57 (dd, J =10.48, 7.47 Hz, 1H), 3.44-3.50 (m, 1H), 3.39-3.44 (m,2H), 3.28 (td, J =9.98, 7.15 Hz, 1H), 2.90 (dd, J=10.48, 8.60 Hz, 1H), 2.35(dt, J =15.69, 7.84 Hz, 1H), 2.00-2.09 (m, 1H), 1.95 (q, J=7.11 Hz, 2H), 1.48-1.56 (m, 1H), 1.46 (s, 9H).

[0365] Example 13: 5-((2-((R)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenethyl)pyrrolidine-3-yl)ethyl)amino)-2-(2,6-dioxopiridine-3-yl)isoindoline-1,3-dione

[0366] Procedure for compound 13-5A K₂CO₃ (607 mg, 4.39 mmol, 2 equivalents) was added to solutions of 13-4 (600 mg, 2.20 mmol, 1 equivalent) in DMF (10 mL), and the mixture was stirred at room temperature for 12 h. H₂O (50 mL) was then added, followed by extraction with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (40 mL × 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was used in the next step without further purification. Compound 13-5A (1.5 g, crude) was isolated as a yellow oil. LCMS (ESI-): m / z = 469.4 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.45 (dd, J =7.2, 8.3 Hz, 1H), 7.09-6.94 (m, 2H), 5.09 (dd, J =5.6, 12.8 Hz, 1H), 3.83 (t, J =7.1 Hz, 2H), 3.54 (dd, J =7.3, 10.4Hz, 1H), 3.45-3.37 (m, 1H), 3.28-3.18 (m, 1H), 2.96-2.82 (m, 4H), 2.23-2.02(m, 3H), 1.69-1.52 (m, 3H), 1.45 (d, J =1.6 Hz, 9H).

[0367] Intermediates 13-5B and 13-5C are prepared using appropriate intermediates according to the procedure described in 13-5A.

[0368]

[0369] Procedure for compound 13-6A TFA (2 mL) was added to a solution of 13-5A (600 mg, 1.28 mmol, 1 equivalent) in CH₂Cl₂ (8 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and used in the next step without further purification. Compound 13-6A (1 g, crude) was obtained as a yellow oil. LCMS (ESI+): m / z = 371.1 (M+H) + . LCMS(ESI+): m / z = 371.1 (M+H) + .

[0370] Intermediates 13-6B-13-6C are prepared using appropriate intermediates according to the procedure described in 13-6A.

[0371]

[0372] Procedure for compound 13-7A Diisopropylethylamine (648 μL, 3.72 mmol, 2 equivalents) and 13-6A (991 mg, 2.05 mmol, 1.1 equivalents) were added to a solution of 1-11 (700 mg, 1.86 mmol, 1 equivalent) in acetonitrile (15 mL), and the mixture was stirred at room temperature for 30 min. NaBH3CN (350 mg, 5.58 mmol, 3 equivalents) was then added and the mixture was stirred for another 30 min. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (column: Welch Xtimate C18 180 × 70 mm × 10 μm; mobile phase: [A: H2O (10 mM NH4HCO3), B: acetonitrile]; gradient: 15%–45% B, duration 20.0 min). Compound 13-7A (340 mg, 465 μmol, 25% yield) was given as a yellow solid. LCMS (ESI-): m / z = 729.5 (MH) - . 1H NMR (400 MHz, DMSO-d6) δ 7.52-7.43 (m, 1H), 7.07-6.95 (m, 2H), 6.93-6.80 (m, 2H), 6.52 (s, 2H), 5.26 (s, 2H), 5.15 (dd, J =5.4, 13.0 Hz, 1H),3.92 (s, 2H), 3.75 (dd, J =3.9, 5.5 Hz, 2H), 3.68 (t, J =6.6 Hz, 2H), 3.45 (dd, J =3.9, 5.6 Hz, 2H), 3.22 (s, 4H), 3.06-2.83 (m, 4H), 2.81-2.64 (m, 2H), 2.53(s, 2H), 2.47 (s, 2H), 2.26-2.01 (m, 3H), 1.69-1.30 (m, 3H).

[0373] Intermediates 13-7B-13-7C are prepared using appropriate intermediates according to the procedure described in 13-7A.

[0374]

[0375] Program of Example 13 To a flask containing 13-7A (80 mg, 109 μmol, 1 equivalent), 4 M HCl (EtOAc solution, 1 mL) was added and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (column: Phenomenex Luna C18 100×40 mm×5 μm; mobile phase: [A: H₂O (0.04% HCl), B: acetonitrile]; gradient: 10%–30% B, 8.0 min). Compound Example 13 was obtained (25 mg, 36 μmol, 33% yield). LCMS (ESI+): m / z = 643.2 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.54-7.36 (m, 1H), 7.10-6.93 (m, 2H), 6.77-6.59 (m, 2H), 5.11 (tdd, J =2.6, 5.3, 10.2 Hz, 1H), 4.43 (d, J=1.9 Hz, 2H), 3.92-3.81 (m, 2H), 3.79-3.59 (m, 1H), 3.56-3.37 (m, 3H), 3.30-3.07 (m, 2H), 3.04-2.79 (m, 4H), 2.75 - 2.59 (m, 1H), 2.58 - 2.19 (m, 2H), 2.17 - 2.03 (m, 1H), 1.95 - 1.58 (m, 3H).

[0376] Examples 14 and 15 are prepared using appropriate intermediates according to the procedure described in Example 13.

[0377]

[0378] Synthesis of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0379] Procedure for compound 16-3 Diisopropylethylamine (22.06 g, 170.7 mmol, 29.7 mL, 3.1 equivalents) was added to a solution of 16-1 (10 g, 55.06 mmol, 1 equivalent, HCl), 16-2 (13.37 g, 57.81 mmol, 1.05 equivalents), and HATU (31.40 g, 82.59 mmol, 1.5 equivalents) in CH2Cl2 (500 mL), and the mixture was stirred at room temperature for 12 h. Citric acid was then used. (水溶液) The reaction mixture was washed with 5% NaOH (500 mL × 3), 1 M NaOH (500 mL), and brine (500 mL). The organic layer was then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to give 16-3 (13 g, 35.7 mmol, 65% yield) as a yellow oil. 1 H NMR (400MHz, CD3OD) δ 6.41(d, J =9.4 Hz, 1H), 4.54 (dd, J =8.1, 9.1 Hz, 1H), 4.47 (br s, 1H), 4.30 (d, J=9.5 Hz, 1H), 3.71 (s, 3H), 2.32-2.19 (m, 1H), 2.06-1.98 (m, 2H), 1.44 (s, 9H), 1.02 (s, 9H).

[0380] Procedure for compound 16-4 LiOH-H2O (3.04 g, 72.54 mmol, 2 equivalents) was added to a solution of 16-3 (13 g, 36.27 mmol, 1 equivalent) in MeOH (180 mL), THF (180 mL), and H2O (180 mL), and the mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated under reduced pressure and resuspended in 0.1 M NaOH (1 L). The aqueous mixture was acidified to pH 1 with 1 M HCl and then extracted with ethyl acetate (500 mL × 3). The combined organic phases were then washed with brine (1 L), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound 16-4 (11.3 g, 32.9 mmol, 90% yield) was given as a colorless oil. 1 HNMR (400MHz, CD3OD) δ 4.61-4.43 (m, 2H), 4.30 (s, 1H), 3.90-3.73 (m, 2H), 2.34-2.24 (m, 1H), 2.06 (ddd, J =4.5, 9.1,13.4 Hz, 1H), 1.44 (s, 9H), 1.03 (s, 9H).

[0381] Procedure for compounds 16-7 16-6 (6.61 g, 66.62 mmol, 1 equivalent) was added to a solution of 16-5 (10 g, 33.31 mmol, 1 equivalent), potassium acetate (6.54 g, 66.62 mmol, 2.00 equivalent), and Pd(OAc)2 (74.79 mg, 333.12 μmol, 0.01 equivalent) in DMA (65 mL). The solution was then heated to 120 °C for 2 h under a N2 atmosphere. H2O (500 mL) was then added to form a precipitate. The precipitate was filtered and washed with H2O (500 mL). The precipitate was separated, dried, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 99 / 1 to 87 / 13) to give 16-7 (27.9 g, 87.6 mmol, 87% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H) 6.40-6.73 (m, 5H) 3.76-3.94 (m, 1H) 1.63 (s, 3H) 0.45-0.62 (m, 12H).

[0382] Procedure for compound 16-8 A solution of 16-7 (4.65 g, 14.6 mmol, 1 equivalent) in CH2Cl2 (320 mL) was added with 4 M HCl (dialkylene solution, 53.5 mL, 14.65 equivalents) and stirred at room temperature for 3 h. MTBE (200 mL) was then added to the reaction mixture to form a precipitate. The precipitate was separated and dried under reduced pressure. The crude product was used in the next step without further purification. Compound 14-8 (2.9 g, 11.6 mmol, 80% yield) was given as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H) 7.66 (d, J =8.34 Hz, 2H) 7.56 (d, J =8.23 Hz, 2H) 4.44(br d, J =3.46 Hz, 1H) 2.47 (s, 3H) 1.55 (d, J =6.79 Hz, 3H).

[0383] Procedure for compound 16-9 HATU (3.6 g, 9.4 mmol, 1 equivalent) and diisopropylethylamine (4.06 g, 31.4 mmol, 5.4 mL, 5 equivalent) were added to a solution of 16-4 (2.1 g, 6.3 mmol, 1 equivalent) in CH2Cl2 (80 mL), and the solution was stirred at room temperature for 20 h. Citric acid was then used. (水溶液) The reaction mixture was washed with 5% NaOH (200 mL), 1 M NaOH (500 mL × 2), and brine (300 mL). The organic layer was then dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then dissolved in MeOH (minimum amount), followed by the addition of H₂O to form a precipitate. The precipitate was separated, dried under reduced pressure, and used in the next step without further purification. Compound 16-9 was given as a white solid (2.9 g, 5.4 mmol, 86% yield). 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H) 7.61 (d, J =7.75 Hz, 1H) 7.32-7.46 (m, 4H) 5.21-5.35 (m, 1H) 5.08 (quin, J =7.06 Hz, 1H)4.77 (s, 1H) 4.50 (s, 1H) 4.23 (d, J =9.30 Hz, 1H) 4.09 (d, J =11.44 Hz, 1H)3.58 (dd, J =11.44, 3.34 Hz, 1H) 2.44-2.62 (m, 4H) 1.98-2.15 (m, 1H) 1.29-1.55 (m, 12H) 0.92-1.12 (m, 9H).

[0384] Procedure for Compounds 16-10 To a solution of 16-9 (3.7 g, 6.79 mmol, 1 equivalent) in CH₂Cl₂ (24 mL), 4 M HCl (dialkyl solution, 24 mL, 14.1 equivalents) was added, followed by stirring at room temperature for 15 min. Then, MeOH (18 mL) was added and the mixture was stirred for another 30 min. The reaction mixture was then concentrated under reduced pressure to give the crude product. The crude product was used in the next step without further purification. Compound 16-10 (3.2 g, 6.7 mmol, 99% yield) was given as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H) 8.62 (d, J =7.70 Hz, 1H) 8.16 (d, J =3.79 Hz, 2H) 7.29-7.55 (m, 4H) 4.91 (quin, J =7.09 Hz, 1H) 4.54 (t, J =8.38Hz, 1H) 4.30 (s, 1H) 3.87 (d, J =5.01 Hz, 1H) 3.75 (d, J =11.13 Hz, 1H) 3.49(dd, J =10.94, 3.73 Hz, 1H) 3.16 (s, 1H) 2.47 (s, 3H) 2.11 (dd, J=12.72, 7.83Hz, 1H) 1.74 (ddd, J =12.93, 8.96, 4.28 Hz, 1H) 1.37 (d, J =6.97 Hz, 3H) 1.02(s, 8H).

[0385] Example 16: (2S,4R)-1-((S)-2-(2-(4-((2-((S)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolyl-2-yl)-3-fluoro-5-hydroxyphenylethyl)pyrrolidine-3-yl)acetamido)methyl)phenyl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0386] Procedure for compound 16-12A To a solution of 16-11 (0.5 g, 1.88 mmol, 1 equivalent) and 16-10 (1 g, 2.07 mmol, 1.1 equivalent, HCl) in DMF (15 mL), HOAt (316 μL, 2.26 mmol, 1.2 equivalent), diisopropylethylamine (1.31 mL, 7.54 mmol, 4 equivalent), and HATU (1.07 g, 2.83 mmol, 1.5 equivalent) were added, followed by stirring at room temperature for 2 h. The reaction mixture was diluted with citric acid. (水溶液) The product was diluted (5%, 500 mL) and then extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with 1 M NaOH (300 mL × 2) and brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then dissolved in MeOH (minimum amount), followed by the addition of H₂O to form a precipitate. The precipitate was separated and dried under reduced pressure. The crude product was used in the next step without further purification. Compound 16-12A (1.19 g, 1.73 mol, 92% yield) was given as a pale brown solid. LCMS (ESI+): m / z = 692.5 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1 H), 8.39 (d, J =7.63 Hz, 1H), 8.03 (d, J=9.06 Hz, 1H),7.35-7.50 (m, 4H), 7.19-7.26 (m, 1H), 7.13 (d, J =10.49 Hz, 2H), 7.07 (d, J =7.03 Hz, 1H), 5.09 (d, J =3.46 Hz, 1H), 4.88-4.99 (m, 1H), 4.37-4.55 (m, 2H), 4.27 (s, 1H), 4.09 (d, J =5.72 Hz, 2H), 3.50-3.69 (m, 3H), 3.30 (s, 1H) 2.45(s, 3H), 1.98-2.05 (m, 1H), 1.79 (d, J =4.41 Hz, 1H), 1.34-1.45 (m, 12H), 0.68-1.05 (m, 9H).

[0387] Intermediates 16-12B-16-12F are prepared using appropriate intermediates according to the procedure described in 16-12A.

[0388]

[0389]

[0390] Procedure for compound 16-13A A solution of 16-12A (6.50 g, 9.39 mmol, 1 equivalent) in CH₂Cl₂ (65 mL) was added with 4 M HCl (dialkyl solution, 65 mL, 27 equivalents) and MeOH (52 mL), and then stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and used in the next step without further purification. Compound 16-13A (5.9 g, 9.3 mmol, 99% yield) was given as a yellow solid. LCMS (ESI+): m / z = 592.4 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ9.10 (s, 1H), 8.45 (s, 1H), 8.11 (d, J=9.30 Hz, 1H), 7.37-7.46 (m, 4H), 7.31-7.37 (m, 4H), 4.85-4.98 (m, 1H), 4.34-4.54 (m, 2H), 3.94-3.99 (m, 2H), 3.59-3.72 (m, 3H), 3.46-3.53 (m, 1H).

[0391] Intermediates 16-13B-16-13F are prepared using appropriate intermediates according to the procedure described in 16-13A.

[0392]

[0393]

[0394] Procedure for compound 16-14A Triethylamine (470 μL, 3.38 mmol, 1 equivalent), HOAt (141 μL, 1.01 mmol, 1.2 equivalent), and HATU (482 mg, 1.27 mmol, 1.5 equivalent) were added to a solution of 16-13A (500 mg, 0.84 mmol, 1 equivalent) in DMF (5 mL), followed by stirring at room temperature for 1 h. The reaction mixture was diluted with citric acid. (水溶液) The product was diluted (5%, 20 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 1 M NaOH (15 mL × 2) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / ethyl acetate = 1 / 1) to give 16-14A as a yellow oil (445 mg, 0.55 mmol, 65% yield). LCMS (ESI+): m / z = 803.3 (M+H) + . 1 H NMR (400MHz, CD3OD) δ 8.87 (s, 1H), 8.39-8.60 (m, 1H), 7.85 (d, J =8.70 Hz, 1H), 7.37-7.47 (m, 4H), 7.26-7.31 (m, 1H), 7.15-7.25 (m, 3H), 5.00 (t, J=7.09 Hz, 1H),4.52-4.64 (m, 2H), 4.32-4.46 (m, 3H), 3.80-3.88 (m, 1H), 3.68-3.77 (m, 1H),3.50-3.64 (m, 3H), 3.38-3.47 (m, 1H), 2.93-2.99 (m, 1H), 2.52-2.66 (m, 1H), 2.48 (s, 3H), 2.33 (d, J =6.79 Hz, 2H), 2.13-2.22 (m, 1H), 2.05 (d, J =6.08 Hz,1H), 1.90-1.99 (m, 1H), 1.51 (d, J =6.91 Hz, 2H), 1.45 (s, 11H), 0.96-1.03 (m, 8H).

[0395] Intermediates 16-14B-16-14F are prepared using appropriate intermediates according to the procedure described in 16-14A.

[0396]

[0397]

[0398]

[0399] Procedure for compound 16-15A TFA (1.5 mL, 20.2 mmol, 1 equivalent) was added to a solution of 16-14A (612 mg, 0.76 mmol, 1 equivalent) in CH₂Cl₂ (6 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and used in the next step without further purification. Compound 16-15A (600 mg [TFA salt], 0.73 mmol, 96% yield) was given as a green oil. LCMS (ESI+): m / z = 703.3 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 9.10-9.20(m, 1H), 7.42-7.49 (m, 4H), 7.26-7.34 (m, 1H), 7.13-7.24 (m, 3H), 5.00 (q, J=6.83 Hz, 1H), 4.49-4.66 (m, 2H), 4.29-4.44 (m, 3H), 3.85 (d, J =10.85 Hz, 1H),3.69-3.78 (m, 1H), 3.47-3.66 (m, 4H), 3.35-3.42 (m, 1H), 3.20-3.27 (m, 1H),2.85-3.01 (m, 2H), 2.62-2.72 (m, 1H), 2.51 (s, 3H), 2.48 (d, J =6.32 Hz, 1H),2.36-2.44 (m, 1H), 2.15-2.30 (m, 2H), 1.89-1.99 (m, 1H), 1.64-1.75 (m, 1H),1.57 (s, 1H), 1.46-1.54 (m, 3H), 0.97-1.05 (m, 9H).

[0400] Intermediates 16-15B-16-15F are prepared using appropriate intermediates according to the procedure described in 16-15A.

[0401]

[0402]

[0403] Procedure for compound 16-16A Diisopropylethylamine (383 μL, 2.20 mmol, 1 equivalent) was added to a solution of 16-15A (600 mg, 0.73 mmol, 1 equivalent) and 1-11 (303 mg, 0.73 mmol, 1 equivalent) in acetonitrile (4 mL), and the mixture was stirred at room temperature for 30 min. Then, NaBH3CN (184 mg, 2.94 mmol, 4 equivalent) was added, and the mixture was stirred for another 4 h. The reaction mixture was then concentrated under reduced pressure. The crude product was subsequently purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [A: H2O (10 mM NH4CO3), B: acetonitrile]; gradient: 20%–50% B, duration 8.0 min). Compound 16-16A (95 mg, 0.09 mmol, 12% yield) was given as a white solid. LCMS (ESI-): m / z = 1061.8 (MH) - . 1H NMR (400 MHz, DMSO-d6) δ 9.28-9.76 (m, 1H), 8.98 (s, 1H),8.31-8.50 (m, 2H), 8.04 (d, J =9.26 Hz, 1H), 7.34-7.49 (m, 4H), 7.21-7.28 (m,1H), 7.06-7.17 (m, 3H), 6.84-6.93 (m, 2H), 5.27 (s, 2H), 5.04-5.13 (m, 1H),4.86-4.99 (m, 1H), 4.49 (d, J =9.26 Hz, 1H), 4.42 (t, J =8.07 Hz, 1H), 4.25 (d, J =6.00 Hz, 3H), 3.93 (s, 2H) 3.72-3.80 (m, 2H), 3.53-3.67 (m, 4H), 3.34-3.48(m, 6H), 3.21-3.24 (m, 1H), 3.23 (s, 2H), 2.91 (s, 2H), 2.51-2.55 (m, 2H), 2.47-2.48 (m, 1H), 2.45 (s, 3H), 2.28-2.40 (m, 2H), 2.07-2.24 (m, 1H), 1.96-2.05 (m, 1H), 1.79 (ddd, J =12.85, 8.47, 4.57 Hz, 1H), 1.34-1.44 (m, 3H), 1.03-1.28 (m, 1H), 0.87-0.97 (m, 9H).

[0404] Intermediates 16-16B-16-16F are prepared using appropriate intermediates according to the procedure described in 16-16A.

[0405]

[0406]

[0407] Program of Example 16 To a flask containing 16-16A (95 mg, 0.09 mmol, 1 equivalent), 4 M HCl (EtOAc solution, 950 μL) was added, followed by stirring at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure and then purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [A: H₂O (10 mM NH₄CO₃), B: acetonitrile]; gradient: 20%–70% B, 8.0 min). Product Example 16 was obtained (47 mg, 47 mmol, 52% yield). LCMS (ESI-): m / z = 973.4 (MH) - . 1 H NMR (400 MHz, DMSO-d6) δ 9.06-9.94 (m,2H), 8.98 (s, 1H), 8.35-8.48 (m, 2H), 8.04 (d, J =9.01 Hz, 1H), 7.30-7.49 (m,4H), 7.05 (s, 4H), 6.51-6.74 (m, 2H), 5.10 (d, J =3.25 Hz, 1H), 4.86-4.98 (m,1H), 4.38-4.52 (m, 2H), 4.25 (d, J =5.88 Hz, 3H), 3.94 (s, 2H), 3.50-3.70 (m,4H), 3.43 (d, J =14.13 Hz, 2H), 3.07-3.27 (m, 3H), 2.59-2.99 (m, 4H), 2.43-2.48 (m, 3H), 2.36 (s, 1H), 2.24-2.30 (m, 1H), 1.95-2.24 (m, 2H), 1.50-1.85(m, 2H), 1.38(d, J =7.00 Hz, 3H), 0.92 (s, 9H).

[0408] Examples 17-21 are prepared using appropriate intermediates according to the procedure described in Example 16.

[0409]

[0410] Example 22: (2S,4R)-1-((S)-2-(2-((S)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenylethyl)pyrrolidine-3-yl)acetamido)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0411] Procedure for compound 22-1 Triethylamine (4.48 mmol, 4 equivalents), HOAt (1.34 mmol, 1.2 equivalents), and HATU (1.68 mmol, 1.5 equivalents) were added to solutions of 16-10 (500 mg, 1.12 mmol, 1 equivalent) in DMF (5 mL), followed by stirring at room temperature for 1 h. The reaction mixture was then diluted with citric acid. (水溶液) The product was diluted (5%, 20 mL) and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with 1 M NaOH (15 mL × 2) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 10 / 1 to dichloromethane / ethyl acetate = 1 / 1) to give 22-1 (541 mg, 0.78 mmol, 70% yield) as a yellow oil. LCMS (ESI+): m / z = 656.4 (M+H) + .

[0412] Intermediates 22-2 - 22-3 are prepared using appropriate intermediates according to the procedure described in Example 16.

[0413]

[0414]

[0415] Example 22 is prepared using appropriate intermediates according to the procedure described in Example 16.

[0416]

[0417] Example 23: 2-((S)-1-(4-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-3-fluoro-5-hydroxyphenylethyl)pyrrolidine-3-yl)-N-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl)acetamide

[0418] Procedure for compound 23-2A K₂CO₃ (1.01 g, 7.32 mmol, 1 equivalent) was added to a solution of 11-1 (1 g, 3.66 mmol, 1 equivalent) in DMF (10 mL), and the mixture was stirred at room temperature for 12 h. H₂O (100 mL) was then added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1 to 3 / 1) to give 23-2A (1.5 g, 3.17 mmol, 86% yield) as a yellow oil. LCMS (ESI-): m / z = 471.4 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.44 (dd, J =8.44, 7.07Hz, 1H), 7.04 (d, J =7.00 Hz, 1H), 6.98 (d, J =8.38 Hz, 1H), 5.07 (dd, J =12.82,5.44 Hz, 1H), 3.77 (td, J =7.38, 2.25 Hz, 2H), 3.02 (q, J =6.71 Hz, 2H), 2.81-2.91 (m, 2H), 2.67 (qd, J =12.74, 5.82 Hz, 1H), 2.04-2.13 (m, 1H), 1.53 (quin, J =7.25 Hz, 2H), 1.38-1.49 (m, 11H) 1.27-1.36 (m, 4H).

[0419] Intermediate 23-2B is prepared using an appropriate intermediate according to the procedure described in 23-2A.

[0420]

[0421] Procedure for compound 23-3A TFA (3 mL) was added to a mixture of 23-2A (1.5 g, 3.17 mmol, 1 equivalent) in CH2Cl2 (15 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under reduced pressure and used in the next step without further purification. Compound 23-3A (1.55 g, crude, TFA) was isolated as a colorless oil. LCMS (ESI-): m / z = 371.3 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.44 (dd, J =8.46, 7.15 Hz, 1H), 7.04 (d, J =7.03Hz, 1H), 6.96-7.01 (m, 1H), 5.07 (dd, J =12.87, 5.48 Hz, 1H), 3.79 (td, J =7.27, 2.38 Hz, 2H), 2.80-3.03 (m, 4H), 2.61-2.75 (m, 1H), 2.04-2.16 (m, 1H),1.66 (quin, J =7.45 Hz, 2H), 1.55-1.60 (m, 2H) 1.32-1.46 (m, 4H).

[0422] Intermediate 23-3B is prepared using an appropriate intermediate according to the procedure described in 23-2A.

[0423]

[0424] Procedure for compound 23-4A Triethylamine (1.33 mL, 9.56 mmol, 1 equivalent) and HATU (1.82 g, 4.78 mmol, 1.5 equivalent) were added to a solution of 23-3A (1.55 g, 3.19 mmol, 1 equivalent) and 1-15 (876 mg, 3.82 mmol, 1.2 equivalent) in DMF (15 mL), and the mixture was stirred at room temperature for 12 h. H₂O (100 mL) was then added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1 to 1 / 1) to give 23-4A (1.4 g, 2.40 mmol, 75% yield) as a yellow solid. LCMS (ESI-): m / z = 582.5 (MH) - . 1 HNMR (400 MHz, CD3OD) δ 7.94 (d, J =4.27 Hz, 1H), 7.45 (dd, J =8.41, 7.03 Hz,1H), 6.96-7.11 (m, 2H), 5.08 (dd, J =12.92, 5.52 Hz, 1H), 3.79 (t, J =7.22 Hz,2H), 3.46-3.59 (m, 1H), 3.37-3.45 (m, 1H), 3.11-3.29 (m, 3H), 2.80-2.97 (m,3H), 2.67 (qd, J =12.76, 5.77 Hz, 1H), 2.44-2.59 (m, 1H), 2.16-2.30 (m, 2H), 2.05-2.13 (m, 1H), 1.94-2.05 (m, 2H), 1.49-1.61 (m, 4H), 1.45 (s, 9H), 1.30-1.40 (m, 4H).

[0425] Intermediate 23-4B is prepared using an appropriate intermediate according to the procedure described in 23-4A.

[0426]

[0427] Procedure for compound 23-5A TFA (2 mL) was added to a solution of 23-4A (500 mg, 856 μmol, 1 equivalent) in CH₂Cl₂ (8 mL), and the mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure and used in the next step without further purification. Compound 23-5A (1.1 g, crude, TFA) was obtained as a brown oil. LCMS (ESI+): m / z = 484.2 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.46 (dd, J =7.1, 8.4 Hz, 1H), 7.09-6.96 (m, 2H), 5.08 (dd, J =5.5, 12.9 Hz, 1H), 3.78 (t, J =7.3 Hz, 2H), 3.48 (dd, J =7.8, 11.6Hz, 1H), 3.40-3.33 (m, 1H), 3.27-3.12 (m, 3H), 2.95-2.84 (m, 3H), 2.76-2.58(m, 2H), 2.44-2.28 (m, 2H), 2.25-2.03 (m, 2H), 1.74-1.61 (m, 1H), 1.59-1.48 (m, 4H), 1.40-1.31 (m, 4H).

[0428] Intermediate 23-5B is prepared using an appropriate intermediate according to the procedure described in 23-5A.

[0429]

[0430] Procedure for compound 23-6A Diisopropylethylamine (555 μL, 3.19 mmol, 2 equivalents) and 23-5A (1.05 g, 1.75 mmol, 1.10 equivalents) were added to a solution of 1-11 (600 mg, 1.6 mmol, 1 equivalent) in acetonitrile (15 mL) and stirred at room temperature for 30 min. Then, NaBH3CN (300 mg, 4.78 mmol, 3 equivalents) was added and stirred for another 30 min. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (column: Welch Xtimate C18 180 × 70 mm × 10 μm; mobile phase: [A: H2O (10 mM NH4HCO3), B: acetonitrile]; gradient: 15%–45% B, duration: 20.0 min). Compound 23-6A (110 mg, 130 μmol, 8% yield) was given as a yellow solid. LCMS (ESI-): m / z = 842.6 (MH) - .

[0431] Intermediate 23-6B is prepared using an appropriate intermediate according to the procedure described in 23-6A.

[0432]

[0433] Program of Example 19 To a flask containing 23-6A (90 mg, 106 μmol, 1 equivalent), 4 M HCl (EtOAc solution, 4 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was then concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [A: H₂O (0.04% HCl), B: acetonitrile]; gradient: 1%–43% B, 8.0 min). Example 23 (45 mg, 55 μmol, 52% yield) was obtained as a white solid. LCMS (ESI+): m / z = 756.3 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 7.45 (t, J=7.8 Hz, 1H),7.13-6.89 (m, 2H), 6.79-6.61 (m, 2H), 5.13-5.05 (m, 1H), 4.41 (s, 2H), 3.84-3.62 (m, 3H), 3.49-3.37 (m, 3H), 3.27-3.08 (m, 3H), 3.02-2.93 (m, 2H), 2.90-2.77 (m, 3H), 2.66 (dq, J =5.8, 12.8 Hz, 2H), 2.48-2.18 (m, 3H), 2.14-2.02 (m,1H), 1.91-1.63 (m, 1H), 1.53 (td, J =6.6, 13.1 Hz, 4H), 1.40-1.28 (m, 4H).

[0434] Example 24 is prepared using appropriate intermediates according to the procedure described in Example 23.

[0435]

[0436] Synthesis of 5-(6-fluoro-8-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azacyclohepten-7-yl)-1,2,5-thiadiazolidine-3-one 1,1-dioxide

[0437] Procedure for compound 25-2 A solution of 25-1 (200 g, 858 mmol, 1 equivalent) in CH2Cl2 (1 L) was mixed with (COCl)2 (163.4 g, 1.29 mol, 112 mL, 1.5 equivalent) and DMF (12.5 g, 171.6 mmol, 13.2 mL, 0.2 equivalent) and stirred at 0 °C under a N2 atmosphere for 1 h. The reaction mixture was then concentrated under reduced pressure to give 25-2 (220 g, crude product) as a brown oil. LCMS (ESI+): m / z = 245.1 / 247.1 (M-OCl+MeOH) + .

[0438] Procedure for compound 25-3 At 0 °C, a solution of AlCl3 (349.9 g, 2.62 mol, 143 mL, 3 equivalents) in CH2Cl2 (1.5 L) was added to CH2Cl2 (500 mL) containing 25-2 (220 g, 874 mmol, 1 equivalent), and the mixture was stirred for 1 h. Ethylene was added to the reaction mixture, and the mixture was stirred for another 2 h. H2O (1 L) was then added, followed by extraction with CH2Cl2 (1.2 L × 2). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-3 (130 g, 534 mmol, 61% yield).

[0439] 1 H NMR (CDCl3) δ 7.21 (s, 1H), 7.18-7.12 (m, 1H), 3.51 (s, 2H), 3.08(t, J = 6.8 Hz, 2H), 2.63-2.55 (m, 2H).

[0440] Procedure for compound 25-4 A solution of 25-3 (130 g, 534 mmol, 1 equivalent) in MeOH (1.3 L) was added to NH₂OH-HCl (55.7 g, 802 mmol, 1.5 equivalent) and NaOAc (87.7 g, 1.07 mol, 2 equivalent) and stirred at room temperature for 1.5 h. The reaction mixture was then concentrated under reduced pressure to remove MeOH. H₂O (300 mL) was added to this solution, followed by extraction with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was ground with petroleum ether to give 25-4 (100 g, 387 mmol, 72% yield) as a pale solid. 1 H NMR(CDCl3) δ 9.02-8.39 (m, 1H), 7.16 (s, 1H), 7.14-7.09 (m, 2H), 3.74 (s, 2H), 3.55-3.48 (m, 1H), 2.95-2.84 (m, 3H), 2.79-2.71 (m, 1H), 2.60-2.52 (m, 2H).

[0441] Procedure for compound 25-5 At 0°C and under N2, 1 M DIBALH (116 mL, 5 equivalents) was added dropwise to a solution of 25-4 (6 g, 23.25 mmol, 1 equivalent) in CH2Cl2 (60 mL). The reaction mixture was then stirred at 25°C for 2 h. Next, at 0°C, 20 mL of H2O containing NaF (9.7 g, 232 mmol, 9.7 mL, 10 equivalents) was added. The reaction mixture was then heated to 25°C and stirred for another 2 h. The solution was then saturated with NH4Cl... (水溶液) and 1 M Na2S2O3 (水溶液) The resulting suspension was quenched by a 1:1, 100 mL mixture and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then purified by HPLC to give 25-5 (1 g, 4.10 mmol, 17% yield) as a white solid. 1 HNMR (CD3OD) δ 7.31-7.27 (m, 2H), 3.33-3.29 (m, 4H), 3.22-3.17 (m, 4H).

[0442] Procedure for compound 25-6 Boc₂O (894 mg, 4.1 mmol, 941.2 equivalents) and DMAP (25.02 mg, 204.83 µmol, 0.1 equivalents) were added to a solution of 25-5 (0.5 g, 2.05 mmol, 1 equivalent) in CH₂Cl₂ (5 mL), and the solution was stirred at room temperature for 12 h. The solution was then treated with saturated NH₄Cl₂. (水溶液) and 1 M Na2S2O 3 (水溶液) The suspension was quenched by the (1:1, 10 mL) mixture and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-6 (0.7 g, 2.03 mmol, 99% yield) as a yellow oil. 1 H NMR (CDCl3) δ 7.12-7.07 (m, 2H), 3.59-3.50 (m, 4H), 2.94-2.86 (m, 4H), 1.48 (s, 9H).

[0443] Procedure for compound 25-7 Add 25-7 (1.03 g, 4.07 mmol, 2 equivalents), Pd(dppf)Cl2 (148 mg, 203 μmol, 0.1 equivalents), and KOAc (798 mg, 8.1 mmol, 4 equivalents) to a solution of 25-6 (0.7 g, 2.03 mmol, 1 equivalent) in 1,4-dimethylamine (10 mL), then heat to 90 °C under N2 for 2 h. Separately, use saturated NH4Cl. (水溶液) and 1M Na2S2O 3 (水溶液) The suspension was quenched by the (1:1, 10 mL) mixture and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-8 (1.3 g, crude product) as a yellow solid. 1 H NMR (CDCl3) δ 7.34-7.30 (m, 2H), 3.57-3.51 (m, 4H), 2.99-2.90 (m, 4H), 1.33 (s, 9H), 1.26 (s, 12H).

[0444] Procedure for compound 25-9 A solution of 25-8 (1.2 g, 3.07 mmol, 1 equivalent) in acetone (20 mL) was mixed with 20 mL of H₂O containing potassium persulfate complex salt (oxone) (3.77 g, 6.13 mmol, 2 equivalents) and stirred at 0 °C for 0.5 h. Then, 50 mL of H₂O was added, followed by extraction with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-9 as a colorless oil.

[0445] 1 H NMR (CDCl3) δ 6.49-6.43 (m, 2H), 3.58-3.50 (m, 4H), 2.89-2.82 (m,4H), 1.49 (s, 9H).

[0446] Procedure for compound 25-10 NaH (199 mg, 4.9 mmol, 60% purity, 2 equivalents) was added to a solution of 25-9 (0.7 g, 2.49 mmol, 1 equivalent) in THF (10 mL), and the mixture was stirred at 0 °C under N2 for 0.5 h. MEMCl (464 mg, 3.73 mmol, 426 μL, 1.5 equivalents) was then added to the reaction mixture, and the mixture was heated to 25 °C and stirred for another 12 h. The solution was then treated with saturated NH4Cl. The suspension was quenched with a mixture of aqueous solution and 1 M Na₂S₂O₃ (1:1, 20 mL) and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (20 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-10 (0.7 g, 1.89 mmol, 76% yield) as a yellow solid. 1 H NMR (CDCl3) δ 6.69-6.61 (m, 2H), 5.23 (s, 2H), 3.83-3.80 (m,2H), 3.59-3.49 (m, 6H), 3.39 (s, 3H), 2.87 (br d, J = 4.8 Hz, 4H), 1.49 (s, 9H).

[0447] Procedure for compound 25-11 At 0°C, 2.5 M of 2,2,6,6-tetramethylpiperidine (497 mg, 3.5 mmol, 597 μL, 2 equivalents) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine in 6 mL of THF. n -BuLi (1.41 mL, 2 equivalents) was added, followed by stirring under N2 for 0.5 h. The reaction mixture was then cooled to -78 °C, and 3 mL of THF containing 25-10 (0.65 g, 1.76 mmol, 1 equivalent) was added, followed by tetramethylethylenediamine (306 mg, 2.64 mmol, 398 μL, 1.5 equivalents), and the mixture was stirred for another 2 h. Then, 1.5 mL of THF containing I2 (1.12 g, 4.4 mmol, 886 μL, 2.5 equivalents) was added. The reaction mixture was then heated to 25 °C and stirred for another 1 h. The mixture was then treated with saturated NH4Cl. (水溶液) and 1 M Na2S2O 3 (水溶液)The suspension was quenched by the (1:1, 10 mL) mixture and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the crude product. The crude product was then purified by column chromatography to give 25-11 (0.71 g, 1.43 mmol, 81% yield) as a yellow solid. 1 H NMR (CDCl3) δ 6.73 (s, 1H), 5.32 (s, 2H), 3.90-3.84 (m, 2H), 3.59-3.49(m, 6H), 3.38 (s, 3H), 2.96-2.85 (m, 4H), 1.48 (s, 9H).

[0448] Procedure for compounds 25-13 Add 25-12 (258 mg, 1.97 mmol, 1.5 equivalence), Cs₂CO₃ (1.28 g, 3.94 mmol, 3 equivalence), XPhos (125.12 mg, 262.46 μmol, 0.2 equivalence), and BrettPhos Pd G₃ (118 mg, 131 μmol, 0.1 equivalence) to a solution of 25-11 (0.65 g, 1.31 mmol, 1 equivalent) in 1,4-dimethylamine (7 mL), then heat to 90 °C under N₂ for 48 h. Separately, use saturated NH₄Cl. (水溶液) and 1 M Na2S2O 3 (水溶液) The resulting suspension was quenched by a mixture of (1:1, 15 mL) and stirred at 25 °C for 5 min. The reaction mixture was then extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 25-13 (0.5 g, 1.0 mmol, 76% yield) as a yellow oil. 1 H NMR (CDCl3) δ 6.70 (br s, 1H), 5.26 (br s, 2H), 3.95 (br s, 2H), 3.91-3.80 (m, 2H), 3.64-3.48 (m, 6H), 3.47-3.33 (m, 3H), 3.07-2.64 (m, 4H), 1.67-1.41 (m, 18H).

[0449] Procedure for compounds 25-14 Towards N A solution of 191 mg (1.35 mmol, 117 μL, 1.5 equivalents) in CH2Cl2 (5 mL) was mixed with propan-2-en-1-ol (157 mg, 2.7 mmol, 184 μL, 3 equivalents) and stirred at 0 °C for 0.5 h. The reaction mixture was then heated to 25 °C, and CH2Cl2 (2 mL) containing 25-13 (0.45 g, 902 μmol, 1 equivalent) and diisopropylethylamine (116 mg, 902 μmol, 157 μL, 1 equivalent) was added and stirred for another 1 h. H2O (5 mL) was then added to the reaction mixture, followed by extraction with CH2Cl2 (5 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 25-14 (0.5 g, crude) as a yellow oil.

[0450] Procedure for compounds 25-15 To a solution of 25-14 (0.3 g, 453 μmol, 1 equivalent) in MeOH (3 mL), NaOMe (408 mg, 2.27 mmol, 30% purity, 5 equivalents) and Pd(PPh3)4 (52 mg, 45 μmol, 0.1 equivalents) were added, followed by heating to 60 °C under N2 for 1 h. H2O (5 mL) was then added to the reaction mixture, followed by extraction with CH2Cl2 (5 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 25-15. 1 H NMR(CD3OD) δ 6.90 (s, 1H), 5.29 (s, 2H), 4.24 (s, 2H), 3.88-3.81 (m, 2H), 3.62-3.50 (m, 6H), 3.34-3.32 (m, 3H), 3.00-2.87 (m, 4H), 1.46 (s, 9H).

[0451] Procedure for compounds 25-16 A solution of 25-15 (0.15 g, 297 μmol, 1 equivalent) in 4 M HCl (EtOAc solution, 5 mL) was stirred at 25 °C for 1 h. The resulting reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was then purified by HPLC to give 25-16 (0.1 g) as a white solid.

[0452] LCMS (ESI-): m / z = 314.0 (MH) - . 1 H NMR (D2O) δ 6.64 (s, 1H), 4.31 (s,2H), 3.26 (br t, J = 9.4 Hz, 4H), 3.09 - 3.02 (m, 4H).

[0453] Example 25: (2S,4R)-1-((S)-2-(6-(7-(1,1-dioxo-4-oxo-1,2,5-thiadiazolyl-2-yl)-6-fluoro-8-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azacyclohepten-3-yl)hexanoylamino)-3,3-dimethylbutyryl)-4-hydroxy-N-((S)-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0454] Procedure for compound 25-18A Under N2, Pd / C (50 mg, 10% purity) was added to a solution of 25-17A (457 mg, 3.17 mmol, 10 equivalents), 25-16 (100 mg, 317 μmol, 1 equivalent), and triethylamine (441 μL, 3.17 mmol, 10 equivalents) in MeOH (12 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was pressurized with H2 (15 psi) and stirred at room temperature for 12 h. The reaction mixture was then filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters XbridgePrep OBD C18 150 × 40 mm × 10 μm; mobile phase: [A: H2O (10 mM NH4HCO3), B: acetonitrile]; gradient: 1%–30% B, duration 8.0 min). Compound 25-18A was given as a white solid (110 mg, 248 μmol, 78% yield). LCMS (ESI-): m / z = 442.3 (MH) - . 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 2H), 6.59 (s, 1H), 3.92 (d, J =1.5 Hz, 2H), 3.66-3.58 (m, 4H), 3.23-2.92 (m, 7H), 2.88-2.75 (m, 1H), 2.33 (t, J=7.3 Hz, 2H), 1.66 (s, 2H), 1.60-1.52 (m, 2H), 1.35-1.25 (m, 2H).

[0455] Intermediate 25-18B is prepared using an appropriate intermediate according to the procedure described in 25-18A.

[0456]

[0457] Procedure for compound 25-19A LiOH-H2O (6 mg, 135 μmol, 2 equivalents) was added to a solution of 25-18A (30 mg, 67 μmol, 1 equivalent) in H2O (0.3 mL), THF (0.3 mL), and MeOH (0.3 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure and used in the next step without further purification. Compound 25-19A (30 mg, crude) was given as a white solid. LCMS (ESI-): m / z = 428.3 (MH) - .

[0458] Intermediate 25-19B is prepared using an appropriate intermediate according to the procedure described in 25-19A.

[0459]

[0460] Program of Example 21 HOAt (12 μL, 84 μmol, 1.2 equivalence), diisopropylethylamine (61 μL, 349 μmol, 5 equivalence), and HATU (40 mg, 104 μmol, 1.5 equivalence) were added to solutions of 25-19A (30 mg, 69 μmol, 1 equivalence) in DMF (1 mL), followed by stirring at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [A: H2O (10 mM NH4HCO3), B: acetonitrile]; gradient: 10%–45% B, duration 8.0 min). Example 25 (24 mg, 26 μmol, 36% yield) was obtained. LCMS (ESI-): m / z = 854.3 (MH) - . 1H NMR (400 MHz, DMSO-d6) δ 9.31(s, 2H), 8.98 (s, 1H), 8.35 (d, J =7.8 Hz, 1H), 7.81 (d, J =9.3 Hz, 1H), 7.50-7.34 (m, 4H), 6.60 (s, 1H), 5.09 (d, J =3.4 Hz, 1H), 4.97-4.84 (m, 1H), 4.52(d, J =9.3 Hz, 1H), 4.41 (t, J =8.1 Hz, 1H), 4.29 (d, J =1.4 Hz, 1H), 3.92 (s,2H), 3.70-3.49 (m, 4H), 3.20-2.96 (m, 6H), 2.88-2.79 (m, 1H), 2.45 (s, 3H),2.32 (s, 1H), 2.20-2.10 (m, 1H), 2.07-1.94 (m, 1H), 1.86-1.73 (m, 1H), 1.66(d, J =2.3 Hz, 2H), 1.60-1.43 (m, 3H), 1.37 (d, J =7.0 Hz, 3H), 1.31-1.20 (m,2H), 0.94 (s, 9H).

[0461] Example 26 is prepared using appropriate intermediates according to the procedure described for Example 25.

[0462]

[0463] Example 27: 5-((10-(7-(1,1-dioxo-4-oxo-1,2,5-thiadiazolidine-2-yl)-6-fluoro-8-hydroxy-1,2,4,5-tetrahydro-3H-benzo[d]azacyclohepten-3-yl)decyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0464] Procedure for compound 27-3A DIEA (1.03 g, 7.98 mmol, 1 equivalent) was added to a mixture of 27-1 (1.1 g, 3.98 mmol, 1 equivalent) and 27-2A (898 mg, 5.18 mmol, 1.3 equivalent) in NMP (11 mL), and the mixture was stirred at 90 °C for 12 h. No significant changes were observed. H₂O (100 mL) was then added to the reaction mixture, followed by extraction with EtOAc (50 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give 27-3A (1.71 g, 1.4 mmol, 35% yield) as a yellow solid. LCMS (ESI-): m / z = 428.4 (MH) - . 1 H NMR (400 MHz, CD3OD) δ 7.56 (d, J =8.38 Hz, 1 H) 6.97 (d, J =2.13 Hz, 1 H) 6.83 (dd, J =8.50, 2.13 Hz, 1 H) 5.04 (dd, J =12.44, 5.44 Hz, 1 H) 3.53 (t, J =6.69 Hz, 3 H) 3.18-3.22 (m, 2 H) 1.97-2.12 (m, 7 H) 1.61-1.70 (m, 3 H) 1.49-1.56 (m, 3 H) 1.36-1.48 (m, 6 H).

[0465] Intermediate 27-3B is prepared using an appropriate intermediate according to the procedure described in 27-3A.

[0466]

[0467] Procedure for compound 27-4A At room temperature, 27-3A (50 mg, 116 μmol, 1 equivalent) and N -Methylmorpholine NThe mixture of 27 mg (232 μmol, 24.6 μL, 2 equivalents) of the oxide in CH2Cl2 (2 mL), ACN (0.2 mL), and 4A MS (25 mg) was stirred for 10 min. TPAP (6.1 mg, 17 μmol, 0.15 equivalents) was then added and stirred for another 2 h. H2O (10 mL) was then added to the reaction mixture, followed by extraction with CH2Cl2 (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. LCMS (ESI+): m / z = 428.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.65 (s, 1H), 7.55(d, J =8.3 Hz, 1H), 7.10 (br t, J =4.9 Hz, 1H), 6.93 (s, 1H), 6.87-6.80 (m,1H), 5.09-4.95 (m, 1H), 3.55 (t, J =4.6 Hz, 4H), 3.23-3.04 (m, 4H), 2.27 (brs, 4H), 1.53 (br dd, J =6.9, 14.4 Hz, 4H), 1.26 (br s, 6H).

[0468] Intermediate 27-4B is prepared using an appropriate intermediate according to the procedure described in 27-4A.

[0469]

[0470] Program in Example 27 Et3N (47 μL) was added to a mixture of 25-16 (40 mg, 113 μmol, 1 equivalent) and 27-4A (48 mg, 113 μmol, 1 equivalent) in THF (10 mL), followed by degassing under reduced pressure. Then, 10% Pd / C (30 mg) was added, followed by purging with H2 gas and stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 100 × 40 mm × 5 μm; mobile phase: [A: H2O (0.04% HCl), B: acetonitrile]; gradient: 20%–50% B, duration 8.0 min). Example 27 (5 mg, 6.34 μmol, 6% yield) was obtained. LCMS (ESI+): m / z = 727.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.72 (br dd, J =3.2, 9.3 Hz, 2H), 7.56 (d, J =8.4 Hz, 1H), 7.17-7.06 (m, 1H), 6.93 (s, 1H), 6.84 (br d, J =8.4 Hz, 1H), 6.61 (s, 1H), 5.02 (dd, J =5.4, 12.8 Hz, 1H), 4.07(s, 2H), 3.65-3.59 (m, 2H), 3.19-3.05 (m, 7H), 3.03-2.96 (m, 2H), 2.92-2.83(m, 2H), 2.57 (br d, J =17.1 Hz, 2H), 1.98 (br dd, J =6.0, 11.5 Hz, 1H), 1.66(br d, J =2.3 Hz, 2H), 1.60-1.51 (m, 2H), 1.40-1.23 (m, 12H) Example 28 is prepared using appropriate intermediates according to the procedure described for Example 27.

[0471]

[0472] HiBiT cell degradation assay Parental Jurkat cells (ATCC, TIB-152) were grown in complete RPMI medium consisting of RPMI 1640 medium (Gibco, 61870036) supplemented with 10% fetal bovine serum (Gibco, 10082147) and 1× penicillin-streptomycin antibiotic (Pen Strep) (Gibco, 15140122). The sequence encoding the HiBiT tag (Promega) was integrated into the 5' ends of the coding sequences of the two alleles of the PTPN2 gene in Jurkat cells using CRISPR to generate the Jurkat-PTPN2-N-HiBiT cell line. The HiBiT tag sequence was also integrated into the 3' ends of the coding sequences of the two alleles of the PTPN1 gene in Jurkat cells using CRISPR to generate the Jurkat-PTPN1-C-HiBiT cell line.

[0473] Degradation of HiBiT-tagged proteins was monitored by luminescence using the Nano-Glo® HiBiT lysis detection system (Promega, N3040). Five thousand cells per well of Jurkat-PTPN2-N-HiBit or Jurkat-PTPN1-C-HiBiT were seeded in white, opaque OptiPlate™-384 microplates (Perkin-Elmer, 6007290) in 25 µL of complete RPMI medium. The compound was added to the cells using a Tecan D300e digital dispenser. Cells were incubated for 24 hours in a humidified incubator at 37°C and 5% CO2. After 24 hours of incubation, the Nano-Glo® HiBiT lysis reagent was added to the cells, and the luminescence level was read on a CLARIOstar microplate reader (BMG LABTECH). Each plate included a mediator control (0.1% DMSO), from which the % degradation of the test compound was calculated. DC was determined using a four-parameter curve fitting method. 50 and D max value.

[0474] Table 2 .

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I), wherein: Ring A is heterocycloalkyl or heteroaryl; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; or two R on the same atom 1 combined together to form oxo; or two R on the same carbon 1 combined together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; or two R on different atoms 1 combined together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each optionally substituted with one or more R; n is 0, 1, 2, 3, or 4; each L 1 independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -, -NR 5 C(=O)-, -NR 5 C(=O)NR 5 -, -S(=O)2NR 5 -, -NR 5 S(=O)2-, -NR 5 S(=O)2NR 5 -, C1-C 10 alkylene, C2-C6alkenylene, C2-C6alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R; Each R 5 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is optionally substituted by one or more R. s is 1-20; M is an E3 ligase targeting agent; L 2 is -O-, -S-, -S(=O)-, -S(=O)2-, -NR 2 -, -[C(R 3 )2] m -, -O[C(R 3 )2] m -, -NR 2 [C(R 3 )2] m -, -[C(R 3 )2] m O- or -[C(R 3 )2] m NR 2 -; R 2 is hydrogen, -C(=0)R a , Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6deuteroalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-C6heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R 3 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocyclic alkyl; wherein each alkyl, cycloalkyl and heterocyclic alkyl group is independently and optionally substituted by one or more R; or two R 3 combined together to form a cycloalkyl or heterocycloalkyl; each optionally substituted with one or more R; m is 1, 2, 3, or 4; each R independently is deuterium, halogen, -CN, -OH, -OR 4 independently is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteriumated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; p is 0, 1, or 2; W is CR W or N; R W is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)Ra a , -S(=O)2Ra a , -S(=O)2NRbRc c R d , -NRbRc c R d , -C(=O)Ra a , -C(=O)ORa b , -C(=O)NRbRc c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteriumated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; each R c and R d is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl group independently optionally substituted with one or more R L is absent or C1-C3 alkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterioalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 heteroalkyl; or two R on the same atom are taken together to form oxo.

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4- to 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 4-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 6-membered heterocycloalkyl comprising 1 or 2 heteroatoms selected from O, S, and N.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L 2 is -[C(R 3 )2] m -.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 3 is hydrogen.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 2.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 3.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein p is 0.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

13. A compound of Formula (II): or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (II), wherein: Ring A is 7- to 15-membered cycloalkyl or 7- to 15-membered heterocycloalkyl comprising 1 to 4 heteroatoms selected from O, S, and N; Each R 1 Independently deuterium, halogen, -CN, -NO2, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclicalkyl, aryl or heteroaryl; wherein each alkyl, cycloalkyl, heterocyclicalkyl, aryl and heteroaryl group is independently and optionally substituted by one or more R groups; or two R on the same atom 1 combined together to form oxo; n is 0, 1, 2, 3, or 4; Each L 1 Independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR 5 -, -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)NR 5 -、-NR 5 C(=O)-、-NR 5 C(=O)NR 5 -、-S(=O)2NR 5 -、-NR 5 S(=O)2-、-NR 5 S(=O)2NR 5 -、C1-C 10 Alkylene, C2-C6 alkenylene, C2-C6 alkyneide, cycloalkylene, heteroalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkyneide, cycloalkylene, heteroalkylene, arylene, and heteroarylene is independently and optionally substituted by one or more R. Each R 5 It can be hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocyclicalkyl; s is 1-20; M is an E3 ligase targeting agent; X is CR X or N; R X is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)Ra, a , -S(=O)2Ra, a , -S(=O)2NRaRa, c R d , -NRaRa, c R d , -C(=O)Ra, a , -C(=O)ORa, b , -C(=O)NRaRa, c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Y is CR Y or N; R Y halogen, -CN, -NO2, -OH, -OR a , -S(=O)Ra, a , -S(=O)2Ra, a , -S(=O)2NRbRc, c R d , -NRbRc, c R d , -C(=O)Ra, a , -C(=O)ORa, b , -C(=O)NRbRc, c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Z is CR Z or N; R Z is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)Ra, a , -S(=O)2Ra, a , -S(=O)2NR c R d , -NR c R d , -C(=O)Ra, a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; W is CR W or N; R W is hydrogen, deuterium, halogen, -CN, -NO2, -OH, -OR a , -S(=O)Ra, a -S(=O)2Ra, a -S(=O)2NRbRc, c R d , -NRbRc, c R d -C(=O)Ra, a -C(=O)ORa, b -C(=O)NRbRc, c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteriumated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Each R a Independently, it is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs; Each R b Independently, it is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteralkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, -L-cycloalkyl, -L-heterocyclicalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, ynyl, cycloalkyl, heterocyclicalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; each R c and R d is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6deuteroalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R; or R c and R d taken together with the atom to which they are attached form a heterocycloalkyl group independently optionally substituted with one or more R L is absent or C1-C3 alkylene independently optionally substituted with one or more R; and each R is independently deuterium, halogen, -CN, -OH, -OC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -NHC(=O)OC1-C3 alkyl, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)N(C1-C3 alkyl)2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterioalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, or C1-C3 heteroalkyl; or two R on the same atom are taken together to form oxo.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 7-membered cycloalkyl.

15. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 7-membered heterocycloalkyl comprising 1 heteroatom selected from O, S, and N.

16. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.

17. The compound of any one of claims 13 to 16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein X is CR X .

18. The compound of any one of claims 13 to 17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R X is halogen.

19. The compound of any one of claims 13 to 18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Y is CR Y .

20. The compound of any one of claims 13 to 19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R Y is -OH.

21. The compound of any one of claims 13 to 20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is CR Z .

22. The compound of any one of claims 13 to 21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R Z is hydrogen.

23. The compound of any one of claims 13 to 22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein W is N.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L 1 is independently -0-, -NR 5 -, -C(=0)-, -OC(=0)-, -C(=0)0-, -C(=0)NR 5 -, -NR 5 C(=0)-, C1-C 10 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

25. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L 1 is independently -0-, -NR 5 -, -C(=0)NR 5 -, -NR 5 C(=0)-, C1-C 10 alkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

26. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L 1 is independently -NR 5 -, -C(=O)NR 5 -, -NR 5 C(=O)-, C1-C 10 alkylene, arylene, or heteroarylene; wherein each alkylene, arylene, and heteroarylene is independently optionally substituted with one or more R.

27. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each L 1 is independently -NR 5 -, -C(=O)NR 5 -, -NR 5 C(=O)-, C1-C 10 alkylene or arylene; wherein each alkylene and arylene is independently optionally substituted with one or more R.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 5 is independently hydrogen or Ci-C6alkyl.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1-15.

30. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1-10.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 1-5.

32. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-10.

33. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-15.

34. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5-20.

35. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 2.

36. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 3.

37. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 4.

38. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 5.

39. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 6.

40. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 7.

41. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 8.

42. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 9.

43. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein s is 10.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the E3 ligase targeting agent is a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAP1 ligase, or a IAP ligase.

45. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the E3 ligase targeting agent is .

46. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is selected from the compounds described in Table 1 or the specification.

47. A pharmaceutical composition comprising a compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

48. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

49. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 47.

50. A method of treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

51. A method of treating type 2 diabetes in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 47.

52. A method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

53. A method of treating and / or managing obesity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 47.

54. A method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

55. A method of treating a metabolic disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 47.

56. The method of any one of claims 48-55, further comprising administering an additional therapeutic agent.

57. The method of claim 56, wherein the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

58. The method of claim 56, wherein the additional therapeutic agent is a CAR-T cell therapy.

59. The method of claim 58, wherein the CAR-T cell therapy is axicabtagene ciloleucel, brexucabtagene ciloleucel, ciltacabtagene ciloleucel, idecabtagene vicleucel, lisocabtagene maraleucel, or tisotabtagene celucel.

60. A method for producing a leukocyte with enhanced ability to kill a target cell, the method comprising contacting the leukocyte with a compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, under conditions such that the degrader is able to inactivate PTPN2 in the leukocyte, thereby producing a leukocyte with enhanced ability to kill a target cell.

61. The method of claim 60, wherein the leukocyte is contacted with the compound in the absence of a helper T cell.

62. The method of claim 60, wherein the leukocyte is derived from a subject having a cancer.

63. The method of claim 60, wherein the leukocyte is a neutrophil, eosinophil, basophil, monocyte, or lymphocyte.

64. The method of claim 63, wherein the lymphocyte is a tumor infiltrating lymphocyte.

65. The method of claim 60, wherein the leukocyte is modulated or engineered to have specificity for a cancer antigen.

66. The method of claim 65, wherein the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.

67. The method of claim 60, wherein the target cell is a cancer cell.

68. A method for treating cancer, the method comprising the steps of: culturing ex vivo leukocytes from a cancer subject to be treated or a histocompatible donor of the cancer subject to be treated, in the presence of a compound as described in any one of claims 1 to 46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, under conditions such that the degrader is capable of inactivating PTPN2 in the leukocytes, thereby forming a cellular composition having an enhanced ability to kill target cancer cells; administering the cellular composition to the subject, thereby treating cancer.

69. The method of claim 68, wherein the leukocytes are neutrophils, eosinophils, basophils, monocytes, or lymphocytes.

70. The method of claim 69, wherein the lymphocytes are tumor infiltrating lymphocytes or peripheral blood lymphocytes.

71. The method of claim 68, wherein the leukocytes are modulated or engineered to have specificity for a cancer to be treated.

72. The method of claim 71, wherein the engineered specificity is provided by a recombinant chimeric receptor or T cell receptor that specifically binds to a cancer antigen.

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