Spirocyclic-substituted oxoisoindlinylpiperidine-2,6-dione compounds

Abstract

Equation (I): Disclosed are the compounds of TIFF2026521443000058.tif61153, their stereoisomers, tautomers, or salts. Also disclosed are the compounds for reducing the levels of IKZF1-4 proteins, as well as methods for using pharmaceutical compositions containing the compounds. The compounds are useful in the treatment of viral infections and proliferative diseases (e.g., cancer).

Description

[Technical Field]

[0001] [Related applications] This application claims priority to U.S. Provisional Application No. 63 / 506,618, filed 7 June 2023, which is incorporated herein by reference in its entirety.

[0002] [explanation] This invention relates to spirocyclic substituted oxoisoindolinylpiperidine-2,6-dione compounds that generally reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. This specification describes spirocyclic substituted oxoisoindolinylpiperidine-2,6-dione compounds, compound compositions containing the compounds, and methods of use thereof. Furthermore, this invention relates to pharmaceutical compositions containing the compounds of the present invention that are useful for the treatment of proliferative disorders (e.g., cancer and viral infections). [Background technology]

[0003] Transcription factors (TFs) of the Ikaros zinc finger family (IKZF) play crucial roles in lymphocyte differentiation and function (Heizmann et al., 2018, Curr. Opin. Immunol. 51: 14-23). ​​In mammalian immune cells, five members of this family are expressed: Ikaros (encoded by IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). These proteins exhibit very high amino acid sequence homology, with Ikaros and Aiolos, and Helios and Eos, being the most homologous pairs, while Pegasus is the most phylogenetically distant IKZF member. These TFs perform both overlapping and unique functions in lymphocytes (Read et al., 2020, Immunological Reviews, 300:1). Decreased levels of the IKZF transcription factor may enhance the antitumor T cell response.

[0004] IKZF1 encodes Ikaros, which is widely and highly expressed in lymphocytes such as human and mouse B cells, NK cells, and T cells. It is also moderately expressed in other immune cells, including myeloid cells. In T cells, deletion of the Ikaros protein or expression of the dominant-negative protein releases repression of loci associated with differentiation into effector T cells, resulting in increased expression of effector cytokines, including IFN-γ, TNF-α, and GM-CSF (Lyon de Ana, et al., 2019, Journal of Immunology 202: 1112-1123; Heller et al., 2014, Journal of Immunology, 193: 3934-3946); Wang et al., 2020, Cell Transplantation, 29).

[0005] IKZF2 encodes Helios, which is expressed exclusively in human and mouse regulatory T cells (Tregs), certain CD8+ T cells and MAIT cells, and NK cells (Akimova et al., 2011, PLoS One, 6:e24226; Dias et al., 2017, Proceedings of the National Academy of Sciences USA, 114:E5434-E5443; Thornton and Shevach, 2019, Immunology, 158:161-170).

[0006] IKZF3 encodes Aiolos, which is widely and highly expressed in human and mouse B lymphocytes, as well as widely and at low levels in T cells and NK cells. In T cells, the targets of Aiolos-mediated gene repression largely overlap with those of Ikaros (Powell et al., 2019, Frontiers in Immunology, 10:1299). Compared to Ikaros, Aiolos may have a stronger influence on the response of follicular helper T cells and Th17 cells, which are involved in tissue immune responses and, in some cases, anti-tumor immunity (Quintana et al., 2012, Nature Immunology, 13:770-777; Read et al., 2017 Journal of Immunology, 7:2377-2387).

[0007] IKZF4 encodes Eos and is highly expressed in Treg cells, as well as widely expressed at low levels in lymphocytes, including B cells, NK cells, and T cells. In preclinical syngeneic tumor models, FoxP3 is expressed among Treg cells. + Deletion of Eos expression in Treg cells leads to an enhanced antitumor response (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Furthermore, conventional CD4 + T cells and CD8 + In T cells, Eos expression levels increase after T cell activation, which may limit the effector T cell response (Rieder et al., 2015, Journal of Immunology, 195:553-563).

[0008] A common function of IKZF transcription factors is the repression of gene expression at specific loci. IKZF transcription factors can bind to genomic loci as homodimers or heterodimers, such as Ikaros:Ikaros or Ikaros:Helios. These dimeric transcription factors all bind to DNA and interact with complexes that regulate histone acetylation and nucleosomes, thereby regulating gene expression. Mechanisms have been shown to involve Ikaros, Helios, and Aiolos interacting with the nucleosome rearrangement and deacetylation complex (NuRD) and the Sin3 histone deacetylase complex (HDAC), respectively, to repress gene expression (Zhang et al., 2011, Nature Immunology, 13:86-94; Georgopoulos et al., 2017, Genes and Development, 31: 439-450). Similarly, Ikaros, Helios, and Aiolos all associate with centromere heterochromatin and can contribute to the expression of genes located at centromere loci (Brown et al., 1997, Cell, 91:845-854; Thompson et al., 2007, Immunity, 26:335-344). Eos interacts with C-terminal binding protein 1 (CtBP1), a lymphocyte transcription repressor, in cooperation with Ikaros, not Aiolos (Koipally et al., 2002, Journal of Biological Chemistry, 277:27697-27705; Pan et al., 2009, Science, 325:1142-1146). Taken together, the IKZF transcription factors share common overlapping functions that can partially compensate for the deletion or degradation of one or more transcription factors. Therefore, in cells expressing multiple IKZF members, it is expected that broadly degrading this transcription factor family during treatment will induce a stronger phenotypic change compared to selectively degrading one or two IKZF transcription factors.

[0009] In T cells and Treg cells, one common role of IKZF transcription factors in regulating gene loci important for antitumor immune responses is the regulation of genes encoding interleukin-2 (IL-2). Ikaros is CD4 + It can directly bind to the IL-2 locus of T cells and recruit the HDAC complex. When Ikaros is deficient, CD4 + and CD8 + T cell-mediated IL-2 production increases (Bandyopadhyay et al., 2007, Blood, 109: 2671-2672; Thomas et al., 2007, Journal of Immunology, 179: 7305-7315; O'Brien et al., 2014, Journal of Immunology, 192:5118-5129). Helios directly binds to the IL-2 gene locus of Treg cells and recruits the HDAC complex, thereby silencing the IL-2 gene (Blaine et al., 2013, Journal of Immunology, 190:1008-1016). Furthermore, Eos may suppress IL-2 expression in Treg cells and act through a mechanism involving interaction with the transcription factor FoxP3 (Pan et al., 2009, Science, 325: 1142-1146; Sharma et al., 2013, Immunity, 38:998-1012). The role of Aiolos' direct binding to the IL-2 locus is not clear, but it has been reported that knockdown of Aiolos by siRNA in human Treg cells increases IL-2 production (Gandhi et al., 2010, Nature Immunology, 11:846-853). In summary, IKZF transcription factors regulate IL-2 production in multiple lymphocyte subtypes, with this role being particularly pronounced in Treg cells. In Treg cells, all four IKZF transcription factors are expressed at high levels, and IL-2 production is usually almost nonexistent.

[0010] Treg cells, characterized by the expression of the transcription factor FoxP3, are a type of lymphocyte that exhibits immunosuppressive effects through multiple mechanisms to maintain immune homeostasis (Sakaguchi et al., 2020, Annual Review of Immunology, 38:541-566; Whibley et al., 2019, Nature Immunology, 20:386-396). Patients with harmful mutations in the gene encoding FoxP3 have a lack of Treg cell function and develop X-linked recessive immunodysregulation syndrome (IPEX syndrome), a multi-organ autoimmune disease with multiple endocrine disorders and intestinal diseases. In the tumor microenvironment (TME), Treg cell function is utilized to promote and maintain an immunosuppressive state (Plitas and Rudensky, 2020, Annual Review of Cancer Biology, 4:459-477). By secreting inhibitory molecules, sequestering cytokines (e.g., IL-2), and directly inhibiting the activation of T cells and antigen-presenting cells, Treg cells can modulate multiple cancer-immune pathways and increase resistance to immunotherapy through TME involvement (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, removal of Treg cells leads to regression of highly advanced tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

[0011] Once activated by a specific antigen, Treg cells can suppress other T cells responding to immune stimulation in vitro in an antigen-nonspecific and bystander manner (Takahashi et al., 1998, Int Immunol. 10:1969-80; Thornton et al., 1998, J Exp. Med. 188:287-96). FoxP3+CD25+CD4+Treg cells are CD4 + Helper T cells, CD8 +It has the ability to suppress a wide range of anti-tumor immune responses involving T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, Cell Research 27:109-118). In preclinical models, the removal of CD25+CD4+ Treg cells within tumors changed the cytokine environment at the tumor site and induced regression of existing tumors (Yu et al., 2005, J Exp Med. 201: 779-91). Furthermore, when Treg cells were removed and CD4 + T cells were transplanted, the anti-tumor immune response was significantly enhanced compared to the case when CD4 + T cells containing Treg cells were transplanted (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrating Treg cells activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific anti-tumor immune responses.

[0012] Clinically, an increase in the number of Treg cells in the TME is correlated with poor clinical outcomes in multiple solid tumors (Shang et al., 2015, Scientific Reports, 5:15179). Furthermore, in patients with non-small cell lung cancer (NSCLC), the correlation between the number of PD-L1+ Treg cells and the response to anti-PD-1 therapy suggests the therapeutic potential of targeting Treg cells in the TME (Wu et al., 2018, Journal of Thoracic Oncology, 13:521-532). Modulating the activity of factors important in controlling the differentiation and / or functionally suppressive state of Treg cells can be a promising therapeutic strategy in the treatment of certain diseases such as cancer and viral infections.

[0013] Furthermore, it has been reported that removing FoxP3+ Treg cells enhances the vaccine-induced antitumor T cell response (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767). This suggests that reducing Helios levels may be effective in enhancing the efficacy of cancer vaccines. In addition to their use in antitumor immunotherapy, Treg cells can suppress immune diseases caused by excessive inflammation during viral infections, while also potentially inhibiting effective antiviral T cell responses and promoting viral persistence (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). Chronic infection of mice with lymphocytic choriomeningitis virus significantly increases FoxP3+ Treg cells. This suggests the existence of a potential mechanism by which certain infectious agents can activate and increase Treg cells, thereby evading the host immune response (Punkosdy et al., 2011, PNAS 108: 3677-3682). In situations associated with chronic viral infection, reducing Helios levels in activated Treg cells may yield therapeutic effects.

[0014] Methods targeting tumor Treg cells include methods that use antibodies to remove Treg cells or regulate their function (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146), as well as methods that alter gene expression within Treg cells, thereby "reprogramming" the immunosuppressive phenotype of Treg cells with small molecule compounds (Kim et al., 2015, Science, 350:334-339; Sebastian et al., 2016, Journal of Immunology, 196:144-155). Mice with Helios-deficient Treg cells do not develop IPEX-like immune disorders characterized by FoxP3 deficiency or complete elimination of Treg cells, but they exhibit Treg cells with transcriptional programs more similar to effector T cells (Fu et al., 2012, Nature Immunology, 13: 972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). It is noteworthy that Helios regulates the activity of Treg cells important in TME, and mice with Helios-deficient Treg cells show improved control of B16F10 tumors and MC38 tumors (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Therefore, regulating Helios activity for therapeutic purposes may transform tumor Treg cells into a phenotype more similar to effector T cells, thereby promoting anti-tumor immunity. Furthermore, in the preclinical tumor model TME, Eos also promotes immunosuppressive Treg cell activity, and it is noteworthy that syngeneic tumors are more effectively controlled in mice lacking Eos expression in FoxP3 Treg cells compared to the control group (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300).Similarly, humans with loss-of-function mutations in IKZF2 in the germline do not exhibit IPEX-like symptoms including diabetes, dermatitis, liver inflammation, and generalized lymph node swelling, but exhibit an immunophenotype associated with enhanced T cell activation and increased production of inflammatory cytokines (Hetemaeki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981). These data indicate that the reduced protein levels of Helios and Eos in Treg cells make antitumor T cell responses less likely to be suppressed by Treg cells in solid tumor patients.

[0015] Small molecule compounds that degrade Ikaros and Aiolos in Treg cells have also been shown to reduce the inhibitory function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In genetically modified mouse models, lenalidomide, which induces degradation of Ikaros and Aiolos, can slightly enhance the antitumor immune response against highly immunogenic syngeneic tumors (Geng et al., 2022, Cell Chemical Biology, 29:1260-1272). Degrading agents targeting Ikaros and Aiolos have also been clinically evaluated in patients with solid tumors, and in some cases, limited therapeutic responses such as disease stabilization have been observed. These clinical studies include the use of abadomide (CC-122) (Rasco et al., 2019, Clin Cancer Research, 25:90-98), lenalidomide (Semeraro et al., 2013, OncoImmunology, 2:11), and pomalidomide (Cooney et al., 2012, Cancer Chemotherapy and Pharmacology, 70, 755) in patients with advanced malignancies. Furthermore, lenalidomide has been shown to enhance T cell and NK cell function in preclinical and clinical studies (Hideshima et al., Leukemia, 2021; D'Souza et al., Frontiers in Immunology, 2021).

[0016] In summary, the IKZF transcription factors Ikaros, Helios, Aiolos, and Eos are highly expressed in Treg cells. Simultaneous reduction of the protein levels of each of these four transcription factors in Treg cells is thought to mitigate immunosuppressive programs, including repression of IL-2 transcription and other effector T cell-related genes, compared to selectively targeting only a single IKZF transcription factor or a pair of transcription factors such as Ikaros and Aiolos or Helios and Eos. Beyond Treg cells, pan IKZF1-IKZF4 degradation agents are also effective against conventional CD4 + T cells and CD8 + By enhancing the effector function of T cells and further increasing the activity of NK cells, it is expected that a strong antitumor response will be induced in patients.

[0017] There is still a need for therapies that can reduce the levels of the four proteins IKZF1-IKZF4: Ikaros, Helios, Aiolos, and Eos.

[0018] The present invention solves the aforementioned problems by providing compounds useful for reducing the levels of four proteins, Ikaros, Helios, Aiolos, and Eos, which are IKZF1 to IKZF4.

[0019] [Overview of the prefecture] The present invention provides a spirocyclic-substituted oxoisoindolinylpiperidine-2,6-dione compound of formula (I) that is useful for reducing the levels of four proteins (Ikaros, Helios, Aiolos, and Eos), including its stereoisomers, tautomers, salts, and prodrugs.

[0020] The present invention also provides pharmaceutical compositions comprising a compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs; and pharmaceutically acceptable carriers.

[0021] Furthermore, the present invention provides a method for treating a disease or disorder by reducing the levels of four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos), characterized by administering a compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs to a patient.

[0022] Furthermore, the present invention provides methods and intermediates for preparing compounds of formula (I), stereoisomers, tautomers, or salts thereof.

[0023] Furthermore, the present invention provides for the use of a compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs, for the manufacture of a pharmacopoeia for reducing Ikaros, Helios, Aiolos, and Eos protein levels in the treatment of certain diseases, including cancer and viral infections.

[0024] Compounds of formula (I) and compositions containing compounds of formula (I) may be used to treat, prevent, or cure various proliferative disorders (e.g., cancer). Pharmaceutical compositions containing the compound are useful for treating, preventing, or slowing the progression of diseases or disorders (e.g., cancer) at various treatment sites.

[0025] Compounds of formula (I) and compositions containing compounds of formula (I) may be used for the treatment, prevention, or cure of viral infections. Pharmaceutical compositions containing such compounds are useful for treating, preventing, or slowing the progression of diseases or disorders (e.g., viral infections).

[0026] These and other features of the present invention will be described in more detail as they are disclosed. [Modes for carrying out the invention]

[0027] The applicant has discovered spirocyclic substituted oxoisoindlinylpiperidine-2,6-dione compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. These substituted oxazolone compounds are thought to promote the interaction between the Ikaros, Helios, Aiolos, and Eos proteins and the corresponding E3 ubiquitin ligase complex (Cullin4-cerebron, CUL4-CRBN), thereby leading to the degradation of these proteins. These compounds reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. These compounds are useful in the treatment of certain diseases (such as cancer and viral infections). The compounds are provided as useful pharmaceuticals possessing desirable stability, bioavailability, therapeutic index, and toxicity ratings, which are important for drugability.

[0028] A first aspect of the present invention is formula (I): [ka] The present invention provides compounds thereof, or their stereoisomers, tautomers, or salts.

[0029] One embodiment provides a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0030] One embodiment provides a compound of formula (I), or its stereoisomers or tautomers.

[0031] One embodiment provides a salt of the compound of formula (I), or a stereoisomer or tautomer thereof.

[0032] One embodiment provides a pharmaceutically acceptable salt of a compound of formula (I), or a stereoisomer or tautomer thereof.

[0033] One embodiment provides a compound of formula (I), or a tautomer thereof, or a salt thereof, the compound being (S)-3-(5-(5-((6-oxa-2-azaspiro[3.5]nonanane-2-yl)methyl)-6-aminopyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0034] One embodiment provides a compound of formula (I), a tautomer thereof, or a salt thereof, the compound being (R)-3-(5-(5-((6-oxa-2-azaspiro[3.5]nonanane-2-yl)methyl)-6-aminopyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0035] One embodiment has the following structure: [ka] The present invention provides a compound of formula (I) having, or its stereoisomer, tautomer, or salt.

[0036] One embodiment has the following structure: [ka] The present invention provides a compound of formula (I) having, or its stereoisomer, tautomer, or salt.

[0037] One embodiment has the following structure: [ka] The present invention provides a compound of formula (I) having, or its stereoisomer, tautomer, or salt.

[0038] Compounds of formula (I), or their stereoisomers, tautomers, or salts, are useful for reducing the levels of the four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0039] In this specification, "reducing the level" of any of the IKZF1-IKZF4 proteins means reducing the level of the protein compared to the initial protein level before contact with or treatment by a compound of formula (I), or its stereoisomers, tautomers, or salts, by degradation, and / or inactivation, and / or inhibition, and / or reduction of the protein's expression level, or a combination thereof.

[0040] To measure the decrease in protein levels of IKZF1-IKZF4 proteins, use the following assay described herein: (i) (IKZF1) Human CD8 + T cell reprogramming assay, (ii) (IKZF2) Jurkat cell degradation assay, (iii) (IKZF3) Human CD8 + Various methods may be used, including T cell reprogramming assays and (iv)(IKZF4) human regulatory T cell reprogramming assays.

[0041] The present invention may be implemented in other specific forms without departing from its spirit or essential parts. The present invention shall encompass all combinations of the aspects and / or embodiments of the present invention described herein. It is understood that any embodiment of the present invention may be combined with any other embodiment to illustrate yet another embodiment. Furthermore, the individual elements constituting each embodiment are intended to be combined with all other elements included in any other embodiment to illustrate yet another embodiment.

[0042] The features and advantages of the present invention will be more readily understood by those skilled in the art by reading the following detailed description. For clarity, some features of the present invention are described in the context of separate embodiments, but these features can also be combined to constitute a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment can also be combined to constitute a subcombination. The examples or preferred embodiments shown herein are for illustrative purposes only and are not intended to limit the present invention.

[0043] Unless otherwise specified in this specification, terms written in the singular form are understood to include plural forms. For example, "a" and "an" may refer to either "1" or "one or more."

[0044] As used herein, the phrase “compound and / or salt thereof” means the compound of the Application, a salt of at least one compound, or a combination thereof. For example, the compound and / or salt of formula (I) includes the compound of formula (I); a salt of the compound of formula (I); a salt of the compound of formula (I) and one or more compounds of formula (I); and a salt of two or more compounds of formula (I).

[0045] Unless otherwise specified, any atom whose valence is not met is assumed to contain enough hydrogen atoms to satisfy its valence.

[0046] The definitions set forth herein supersede any definitions contained in any patent, patent application, or published patent application incorporated herein by reference.

[0047] The following are definitions of the terms used to describe the present invention. These definitions apply to the terms used throughout this specification, individually or as part of a larger set of terms, unless otherwise specified.

[0048] Throughout this specification, each group and its substituents may be selected by those skilled in the art to form stable substructures and compounds.

[0049] In accordance with the conventions used in this field, the structural formulas in this specification [ka] This is used to indicate the bonding point where a substructure or substituent attaches to the core structure or skeletal structure.

[0050] The term "amino" refers to the group -NH2.

[0051] The term "oxo" refers to the base element = oxygen (O).

[0052] The compounds of the present invention contain all isotopes of the atoms contained in the compounds of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example, but not limited to the following, hydrogen isotopes include deuterium (D) and tritium (T). Carbon isotopes include 13 C and 14 It contains C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of other unlabeled reagents.

[0053] As used herein, the term "tautomer" refers to two or more isomers of a compound that coexist simultaneously in equilibrium and readily interchange with each other by the movement of atoms or groups within the molecule. For example, those skilled in the art will know that 1,2,3-triazole has two tautomers as defined below: [ka] It is easy to understand that it exists as such. Therefore, even if only the structure of one tautomer is described in this disclosure, it is assumed that all possible tautomers are included. For example, the compound of formula (I) has the following tautomers: [ka] It can exist as such.

[0054] Other examples of tautomers include: [ka] It includes.

[0055] As used herein, the term “medically acceptable” means a compound, substance, composition, and / or dosage form that, within the bounds of ordinary medical judgment, provides a reasonable benefit-to-risk ratio without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and is suitable for use in contact with human and animal tissues.

[0056] Compounds of formula (I) may form salts, and these salts are also within the scope of the present invention. Unless otherwise specified, references to compounds of the present invention are understood to include references to one or more salts thereof. The term “salt” refers to an acid addition salt formed with an inorganic acid and / or an organic acid. Medicinally acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred. However, other salts are also considered to be within the scope of the present invention, for example, because they may be useful in isolation or purification steps that may be performed in the manufacturing process. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with an acid (e.g., 1 equivalent) in a medium in which the salt precipitates, or in an aqueous medium, followed by freeze-drying.

[0057] Examples of acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipines, alginates, ascorbic acid, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides (formed with hydrochloric acid), and hydrobroms (formed with hydrogen bromide). Examples include hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonic acid (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionic acid, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), and undecanoate.

[0058] The compound of formula (I) is provided as an amorphous solid or crystalline form. Freeze-drying may be performed to obtain the compound of formula (I) as a solid.

[0059] Furthermore, solvates (e.g., hydrates) of compounds of formula (I) are understood to be within the scope of the present invention. The term “solvate” means a state in which a compound of formula (I), whether in an organic or inorganic solvent, is physically associated with one or more solvent molecules. This physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” encompasses both solvates present in the solution phase and solvates that can be isolated. Examples of solvates include hydrates, ethanolates, methanelates, isopropanolates, acetonitrile solvate, and ethyl acetate solvate. Methods of solvation are known to those skilled in the art.

[0060] Various forms of prodrugs are well known in this field and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0061] Furthermore, the compound of formula (I) may be isolated and purified after preparation to obtain a composition containing 99% or more of the compound of formula (I) by weight ("substantially pure"), which may then be used or formulated as described herein. Such a "substantially pure" compound of formula (I) is also envisioned herein as part of the present invention.

[0062] "Stable compound" and "stable structure" refer to compounds that possess sufficient stability to withstand the process of isolation from a reaction mixture to a useful purity, and the process of formulation into an effective therapeutic agent. This invention is intended to encompass such stable compounds.

[0063] The terms "IKZF1 degrader" and "Ikaros degrader" refer to drugs that have the effect of reducing the level of IKZF1 protein by degradation, inactivation, inhibition, reduction of IKZF1 protein expression levels, or a combination of these.

[0064] The terms "IKZF2 degrading agent" and "Helios degrading agent" refer to drugs that reduce the level of IKZF2 protein by degradation, inactivation, inhibition, reduction of IKZF2 protein expression levels, or a combination of these.

[0065] The terms "IKZF3 degrader" and "Aiolos degrader" refer to drugs that reduce the level of IKZF3 protein by degradation, inactivation, inhibition, reduction of IKZF3 protein expression levels, or a combination of these.

[0066] The terms "IKZF4 degrader" and "Eos degrader" refer to drugs that have the effect of reducing the level of IKZF4 protein by degradation, inactivation, inhibition, reduction of IKZF4 protein expression levels, or a combination of these.

[0067] The term "IKZF1-IKZF4 proteins" refers to the Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and Eos (IKZF4) proteins.

[0068] The term "pan IKZF1-IKZF4 degrading agent" refers to a drug that has the effect of lowering the protein levels of the four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0069] As used herein, the “Ikaros” protein refers to the protein encoded by the IKZF1 gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFN1A1 (zinc finger protein subfamily 1A,1), Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92 (protein phosphatase 1 regulatory subunit 92), PRO0758, CVID13, and CLL-associated antigen KW-6. The “Ikaros” protein includes each isoform encoded by the human-derived isoforms listed below.

[0070] Isoform 1 (UniPort Q13422-1) [ka]

[0071] Isoform 2 (UniProt Q13422-2) [ka]

[0072] Isoform 3 (UniProt Q13422-3) [ka]

[0073] Isoform 4 (UniProt Q13422-4) [ka]

[0074] Isoform 7 (UniProt Q13422-7) [ka]

[0075] Isoform 8 (UniProt Q13422-8) [ka]

[0076] The isoforms 1, 2, 3, 4, 7, and 8 of the "Ikaros" protein listed above are degron sequences. [ka] This includes the degron sequence of the "Aiolos" protein, which is identical to that of the "Aiolos" protein. The Ikaros protein also contains isoforms encoded by amino acid sequences Q13422-5 and Q13422-6.

[0077] As used herein, the "Helios" protein is a zinc finger protein belonging to the Ikaros family. In humans, Helios is encoded by the IKZF2 gene. Helios is also known as IKAROS family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2 (zinc finger protein subfamily 1A,2), and Ikaros family zinc finger protein 2. The Helios protein as used herein includes multiple isoforms, including those listed below.

[0078] Isoform 1 (UniProt Q9UKS7-1) [ka]

[0079] Isoform 2 (UniProt Q9UKS7-2) [ka]

[0080] Isoform 4 (UniProt Q9UKS7-4) [ka]

[0081] Isoform 6 (UniProt Q9UKS7-6) [ka]

[0082] Isoform 7 (UniProt Q9UKS7-7) [ka]

[0083] The isoforms 1, 2, 4, 6, and 7 of the "Helios" protein listed above are degron sequences. [ka] This includes the degron sequence, which refers to a part of a protein involved in controlling the rate of protein degradation. Furthermore, the Helios protein also includes isoforms encoded by the amino acid sequences: Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0084] As used herein, the "Aiolos" protein refers to the protein encoded by the IKZF3 gene. The Aiolos protein is also known as IKAROS family zinc finger 3, ZNFN1A3 (zinc finger protein subfamily 1A,3), Ikaros family zinc finger protein 3, and AIO. The Aiolos protein includes the following human-derived isoforms:

[0085] Isoform 1 (UniProt Q9UKT9-1) [ka]

[0086] Isoform 3 (UniProt Q9UKT9-3) TIFF2026521443000024.tif58153

[0087] Isoform 4 (UniProt Q9UKT9-4) [ka]

[0088] Isoform 6 (UniProt Q9UKT9-6) [ka]

[0089] Isoform 7 (UniProt Q9UKT9-7) [ka]

[0090] Isoform 8 (UniProt Q9UKT9-8) TIFF2026521443000028.tif58153

[0091] Isoform 9 (UniProt Q9UKT9-9) [ka]

[0092] Isoform 14 (UniProt Q9UKT9-14) [ka]

[0093] The isoforms 1, 3, 4, 6, 7, 8, 9, and 14 of the "Aiolos" protein listed above are degron sequences. [ka] This includes the degron sequence of the "Ikaros" protein, which is identical. The Aiolos protein also includes isoforms encoded by the amino acid sequences: Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0094] The "Eos" protein as used herein is encoded by the IKZF4 gene and is also known as IKAROS family zinc finger 4, ZNFN1A4 (zinc finger protein subfamily 1A,4), Ikaros family zinc finger protein 4, and KIAAl782. The "Eos" protein includes isoforms encoded by the following two human-derived isoforms 1 (Q9H2S9-1) and 2 (Q9H2S9-2).

[0095] Isoform 1 (UniProt Q9H2S9-1) [ka]

[0096] Isoform 2 (UniProt Q9H2S9-2) TIFF2026521443000033.tif70153

[0097] The isoforms 1 and 2 of the "Eos" protein listed above are degron sequences. [ka] This includes the degron sequence of the "Helios" protein, which is identical to that of the degron sequence.

[0098] The "Pegasus" protein as used herein is also known as IKAROS family zinc finger 5, ZNFN1A5 (zinc finger protein subfamily 1A,5), and Ikaros family zinc finger protein 5. Pegasus is encoded by the IKZF5 gene.

[0099] As used herein, the term "contact" means bringing together a predetermined substructure in vitro or in vivo. For example, "contacting" IKZF1-IKZF4 proteins with the compound of formula (I) includes administering the compound of the present invention to an individual or patient (e.g., a human) having the Ikaros, Helios, Aiolos, and Eos proteins. This also includes introducing the compound of formula (I) into a cell sample or a sample containing purified preparations containing the Ikaros, Helios, Aiolos, and Eos proteins, for example.

[0100] As used herein, the term “treatment” means any intervention or procedure, or administration of an activator, performed on a subject with the aim of restoring, reducing, improving, inhibiting, delaying, or preventing the progression, onset, severity, or recurrence of any symptom, complication, condition, or biochemical indicator associated with a disease. In contrast, “prevention” or “prevention” means administration to a subject who does not have the disease, with the aim of preventing the onset of the disease. “Treatment” does not include prevention or prevention.

[0101] "Therapeutically effective dose" means an amount of the compound of the present invention alone, or an amount of the compound of the present invention combined with other active ingredients, that is effective in reducing the levels of IKZF1-IKZF4 proteins in cells, or an amount that is effective in treating or preventing proliferative disorders such as viral infections and cancer.

[0102] As used herein, the term "cell" refers to a cell in vitro, ex vivo, or in vivo state. In some embodiments, ex vivo cells may be part of a tissue sample extracted from an organism such as a mammal. In some embodiments, in vitro cells may be cells in cell culture. In even more embodiments, in vivo cells may be cells living within an organism such as a mammal.

[0103] The term "patient" includes human subjects.

[0104] As used herein, “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or vehicle, and includes, for example, liquid or solid fillers, diluents, excipients, processing aids (e.g., lubricants, talc, magnesium stearate, calcium stearate, or zinc stearate, or stearic acid), or solvent encapsulants. These are involved in transporting or delivering the target compound from one organ or part of the body to another organ or a different part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components in a formulation, including adjuvants, excipients, or vehicles used depending on the route of administration and the nature of the dosage form, and is not harmful to the patient, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobial agents, antifungal agents, lubricants, and dispersants.

[0105] The term "pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one other pharmaceutically acceptable carrier.

[0106] [Usefulness] The compound of formula (I) is useful in the treatment of cancer.

[0107] The compound of formula (I) is useful in treating viral infections.

[0108] In one embodiment, a method for treating cancer is provided, characterized by administering to a patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0109] In one embodiment, a method for treating a viral infection is provided, characterized by administering to a patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0110] In one embodiment, a therapeutically effective amount of the following structure: [ka] The present invention provides a method for treating cancer, characterized by administering to a patient a compound having such a compound, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0111] In one embodiment, a method is provided for treating a disease or disorder by reducing the levels of four IKZF1-4 proteins (Ikaros, Helios, Aiolos, and Eos). The method is characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of the Ikaros, Helios, Aiolos, and Eos proteins. In one embodiment, the disease or disorder is cancer. In another embodiment, the disease or disorder is a viral infection. In yet another embodiment, the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0112] In one embodiment, a method is provided for treating a patient's disease or disorder. The method is characterized by administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein a) the Ikaros protein is the amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; b) the Helios protein is the amino acid sequence encoded by SEQ ID NO: 7, 8, 9, 10, or 11; c) the Aiolos protein is the amino acid sequence encoded by SEQ ID NO: 12, 13, 14, 15, 16, 17, 18, or 19; and d) the Eos protein is the amino acid sequence encoded by SEQ ID NO: 20 or 21.

[0113] Embodiment 1 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 30%, (ii) reduces the level of the Helios (IKZF2) protein by at least 50%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 30%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0114] Embodiment 2 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 40%, (ii) reduces the level of the Helios (IKZF2) protein by at least 50%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 40%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0115] Embodiment 3 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) the level of the Ikaros (IKZF1) protein is reduced by at least 50%, (ii) the level of the Helios (IKZF2) protein is reduced by at least 50%, (iii) the level of the Aiolos (IKZF3) protein is reduced by at least 50%, and (iv) the level of the Eos (IKZF4) protein is reduced by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0116] Embodiment 4 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 50%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0117] Embodiment 5 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 30%, (ii) reduces the level of the Helios (IKZF2) protein by at least 60%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 30%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0118] Embodiment 6 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the level of the Ikaros (IKZF1) protein is reduced by at least 40%, (ii) the level of the Helios (IKZF2) protein is reduced by at least 60%, (iii) the level of the Aiolos (IKZF3) protein is reduced by at least 40%, and (iv) the level of the Eos (IKZF4) protein is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0119] Embodiment 7 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 50%, (ii) reduces the level of the Helios (IKZF2) protein by at least 60%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 50%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0120] Embodiment 8 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 60%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0121] Embodiment 9 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) the level of the Ikaros (IKZF1) protein is reduced by at least 30%, (ii) the level of the Helios (IKZF2) protein is reduced by at least 70%, (iii) the level of the Aiolos (IKZF3) protein is reduced by at least 30%, and (iv) the level of the Eos (IKZF4) protein is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0122] Embodiment 10 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 40%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 40%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0123] Embodiment 11 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) the level of the Ikaros (IKZF1) protein is reduced by at least 50%, (ii) the level of the Helios (IKZF2) protein is reduced by at least 70%, (iii) the level of the Aiolos (IKZF3) protein is reduced by at least 50%, and (iv) the level of the Eos (IKZF4) protein is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0124] Embodiment 12 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0125] Embodiment 13 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 30%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 30%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0126] Embodiment 14 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 40%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 40%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0127] Embodiment 15 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 50%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 50%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0128] Embodiment 16 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0129] Embodiment 17 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 30%, (ii) reduces the level of the Helios (IKZF2) protein by at least 85%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 30%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0130] Embodiment 18 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 40%, (ii) reduces the level of the Helios (IKZF2) protein by at least 85%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 40%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0131] Embodiment 19 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 50%, (ii) reduces the level of the Helios (IKZF2) protein by at least 85%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 50%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0132] Embodiment 20 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 85%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0133] Embodiment 21 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 30%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 30%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0134] Embodiment 22 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 40%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 40%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0135] Embodiment 23 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 50%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 50%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0136] Embodiment 24 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by at least 60%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by at least 60%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0137] Embodiment 25 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, reduces the level of the Ikaros (IKZF1) protein by at least 30%, the level of the Helios (IKZF2) protein by at least 90%, the level of the Aiolos (IKZF3) protein by at least 30%, and the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0138] Embodiment 26 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, reduces the level of the Ikaros (IKZF1) protein by at least 40%, the level of the Helios (IKZF2) protein by at least 90%, the level of the Aiolos (IKZF3) protein by at least 40%, and the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0139] Embodiment 27 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, reduces (i) the level of the Ikaros (IKZF1) protein by at least 50%, (ii) the level of the Helios (IKZF2) protein by at least 90%, (iii) the level of the Aiolos (IKZF3) protein by at least 50%, and (iv) the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0140] Embodiment 28 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, reduces the level of the Ikaros (IKZF1) protein by at least 60%, the level of the Helios (IKZF2) protein by at least 90%, the level of the Aiolos (IKZF3) protein by at least 60%, and the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0141] Embodiment 29 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40–70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 50%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40–70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0142] Embodiment 30 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 60%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0143] Embodiment 31 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0144] Embodiment 32 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 70%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0145] Embodiment 33 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40–70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40–70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0146] Embodiment 34 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 40-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by 40-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0147] Embodiment 35 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 50%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0148] Embodiment 36 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 60%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0149] Embodiment 37 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0150] Embodiment 38 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 70%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 70%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0151] Embodiment 39 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 80%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0152] Embodiment 40 provides a method for treating a disease or disorder, characterized by administering to a patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The method, in this case, (i) reduces the level of the Ikaros (IKZF1) protein by 50-70%, (ii) reduces the level of the Helios (IKZF2) protein by at least 90%, (iii) reduces the level of the Aiolos (IKZF3) protein by 50-70%, and (iv) reduces the level of the Eos (IKZF4) protein by at least 90%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. Furthermore, this embodiment includes a method in which the agent is a compound of formula (I), its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0153] In embodiments 1 to 40, the decrease in the protein levels of IKZF1 to IKZF4 proteins can be measured using the following assays described herein: (i) IKZF1: Human CD8 +(ii) T cell reprogramming assay; (ii) IKZF2: Human regulatory T cell reprogramming assay; (iii) IKZF3: Human CD8 + T cell reprogramming assay; and (iv) IKZF4: Human regulatory T cell reprogramming assay

[0154] The types of cancers that can be treated with compounds of formula (I) include, but are not limited to, malignant brain tumors, skin cancers, bladder cancers, ovarian cancers, breast cancers, stomach cancers, pancreatic cancers, prostate cancers, colon cancers, hematological cancers, lung cancers, and bone cancers. Examples of such cancer types include neuroblastoma, intestinal cancers (e.g., rectal cancer, colon cancer, anal cancer, cancer associated with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer), esophageal cancers, nasopharyngeal cancers, lip cancers, laryngeal cancers, hypopharyngeal cancers, tongue cancers, salivary gland cancers, thymic cancers, esophageal and gastric cancers, stomach cancers, adenocarcinomas, medullary thyroid cancers, papillary thyroid cancers, kidney cancers, renal parenchymal cancers, ovarian cancers, cervical cancers, uterine cancers, endometrial cancers, choriocarcinomas, pancreatic cancers, prostate cancers, testicular cancers, breast cancers, cancers of the urinary tract, melanomas, and brain tumors (e.g., glioblastomas, astrocytomas, meningiomas, medulloblastomas, and peripheral neuroectodermal tumors). These include Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminomas, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0155] In one embodiment, a method is provided for treating a patient's melanoma, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0156] In one embodiment, a method is provided for treating a patient's lung cancer (e.g., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0157] In one embodiment, a method for treating mesothelioma in a patient is provided, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0158] In one embodiment, a method is provided for treating a patient's breast cancer (e.g., ductal carcinoma, invasive ductal carcinoma, metastatic breast cancer, triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, hormone receptor-positive breast cancer, and hormone receptor-negative breast cancer), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0159] In one embodiment, a method is provided for treating a patient's prostate cancer (e.g., prostate adenocarcinoma and castration-resistant prostate cancer), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0160] In one embodiment, a method is provided for treating a patient's pancreatic cancer (e.g., pancreatic adenocarcinoma, exocrine pancreatic cancer, and neuroendocrine pancreatic cancer), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0161] In one embodiment, a method is provided for treating a patient's renal cancer (e.g., renal cell carcinoma, clear cell renal cell carcinoma, and non-clear cell renal cell carcinoma, papillary renal cell carcinoma, Wilms' tumor, and renal sarcoma), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0162] In one embodiment, a method for treating gastric cancer (e.g., gastric cancer) in a patient is provided, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0163] In one embodiment, a method is provided for treating a patient's kidney cancer (e.g., renal cancer and renal parenchymal cancer), characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0164] In one embodiment, a method for treating a patient's liver cancer (e.g., hepatocellular carcinoma) is provided, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0165] In one embodiment, a method is provided for treating ovarian cancer (e.g., ovarian cancer) in a patient, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0166] In one embodiment, a method is provided for treating a patient's lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL)) characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0167] In one embodiment, a method is provided for treating a patient's leukemia (e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, and diffuse large B-cell lymphoma (DLBCL)) characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomers, tautomers, or pharmaceutically acceptable salts.

[0168] In one embodiment, a method for treating a patient's multiple myeloma is provided, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt.

[0169] A compound of formula (I) and a pharmaceutical composition comprising at least one compound of formula (I) are useful for the treatment or prevention of any disease or condition related to the activity of IKZF1-IKZF4 proteins. Such diseases include viral infections and other infections (e.g., skin infections, gastrointestinal infections, urinary tract infections, genitourinary tract infections, systemic infections) and proliferative disorders (e.g., cancer). Any method of administration may be used to administer the compound or pharmaceutical composition to a patient. In one embodiment, the compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered orally. In another embodiment, the compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) is administered parenterally.

[0170] In one embodiment, a method is provided for treating a viral infection in a patient, characterized by administering to the patient a therapeutically effective amount of the compound described in formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The viral infection is caused by exposure to HIV, hepatitis viruses (A, B, or C), herpesviruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, RSV, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, cowpox virus, HTLV, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0171] Compounds of formula (I) can selectively reduce the protein levels of four intracellular IKZF1-IKZF4 proteins to control Treg differentiation and / or immunomodulation. For example, by administering an effective dose of compound (I), or its stereoisomers, tautomers, or salts, compounds of formula (I) can be used to control Treg differentiation and / or immunomodulation in cells or individuals where a reduction in protein levels, activity levels, and / or suppression of expression levels is required for each of the four IKZF1-IKZF4 proteins.

[0172] In one embodiment, the present invention provides combination formulations of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof with other therapeutic agents used simultaneously, separately, or sequentially in the treatment and / or prevention of a number of diseases or disorders related to the activity of IKZF1-4 proteins. These combination formulations may be used to reduce protein levels, reduce protein activity levels, and / or suppress the expression levels of each of the four IKZF1-4 proteins.

[0173] In one embodiment, the compound of formula (I) is administered immediately before the administration of the immunotumor drug. In another embodiment, the compound of formula (I) is administered simultaneously with the immunotumor drug. In yet another embodiment, the compound of formula (I) is administered immediately after the administration of the immunotumor drug.

[0174] In another embodiment, the compound of formula (I) may be formulated together with an immunotumor agent.

[0175] Immuno-oncological drugs include, for example, small molecule drugs, antibodies, or other biological agents or small molecule compounds. Examples of biological immuno-oncological drugs include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized antibody or human antibody.

[0176] In one embodiment, immunotumor drugs are (i) agonists of stimulative receptors (including costimulatory receptors) on T cells, or (ii) antagonists of inhibitory signals (including coinhibitory signals) on T cells, both of which amplify antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0177] Certain stimulant and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). The B7 family is one of the important families of membrane-bound ligands that bind to costimulatory or coinhibitory receptors, and includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or coinhibitory receptors includes TNF family molecules that bind to the same TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, R ANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, Includes EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0178] In some embodiments, the T cell response may be stimulated by combining a compound of formula (I) with one or more protein agonists that (i) inhibit T cell activation (e.g., immune checkpoint inhibitors) and / or (ii) stimulate T cell activation. Examples of the antagonists in (i) include CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4. Examples of the agonists in (ii) above include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0179] Other drugs that can be combined with the compound of formula (I) for the treatment of cancer include inhibitory receptor antagonists on NK cells or activating receptor agonists on NK cells. For example, the compound of formula (I) can be used in combination with a KIR antagonist such as lirilumab.

[0180] Further drugs used in combination therapy include drugs that inhibit or deplete macrophages or monocytes, and include, but are not limited to, CSF-1R antagonist antibodies (RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357)) and CSF-1R antagonists.

[0181] In another embodiment, the compound of formula (I) may be used in combination with agonistic agents that bind to positive costimulatory receptors, blockers that attenuate signaling mediated by inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of antitumor T cells. Furthermore, the compound of formula (I) may be used in combination with agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blockade of inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depletion or inhibition of Tregs (e.g., use of anti-CD25 monoclonal antibodies (e.g., daclizumab), or depletion by anti-CD25 beads ex vivo), inhibition of metabolic enzymes such as IDO, or restoration or prevention of T cell anergy or exhaustion), and agents that activate innate immunity and / or induce inflammation at the tumor site.

[0182] In one embodiment, the immunotumor drug is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Examples of suitable CTLA-4 antibodies include Yervoy (ipilimumab) or tremelimumab.

[0183] In another embodiment, immunotumor drugs are PD-1 antagonists, such as antagonistic PD-1 antibodies. Examples of suitable PD-1 antibodies include Opdivo (nivolumab), Keytruda (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), Ributayo (semiprimab), Jenperli (dostallimab), and ZYNYZ (retifanlimab). Another immunotumor drug that has been questioned regarding its binding specificity to PD-1 is pidilizumab (CT-011). Another approach targeting the PD-1 receptor is a recombinant protein called AMP-224, which fuses the extracellular domain of PD-L2 (B7-DC) to the Fc portion of IgG1.

[0184] In another embodiment, the immunotumor drug is a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Examples of suitable PD-L1 antibodies include MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), MSB0010718C (WO2013 / 79174), Tecentriq (atezolizumab), and Bavencio (avelumab).

[0185] In another embodiment, the immunotumor agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Examples of suitable LAG3 antibodies include BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0186] In another embodiment, the immunotumor drug is a CD137(4-1BB) agonist, such as an agonistic CD137 antibody. Examples of suitable CD137 antibodies include urelumab and PF-05082566(WO12 / 32433).

[0187] In another embodiment, the immunotumor agent is a GITR agonist, such as an agonistic GITR antibody. Examples of suitable CD137 antibodies include BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116), and MK-4166 (WO11 / 028683).

[0188] In another embodiment, immunotumor agents are IDO antagonists. Examples of suitable IDO antagonists include INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0189] In another embodiment, the immunotumor drug is an OX40 agonist, such as an agonistic OX40 antibody. Examples of suitable OX40 antibodies include MEDI-6383 or MEDI-6469.

[0190] In another embodiment, the immunotumor drug is an OX40L antagonist, such as an antagonistic OX40 antibody. An example of a suitable OX40L antagonist is RG-7888 (WO06 / 029879).

[0191] In another embodiment, the immunotumor drug is a CD40 agonist, for example, an agonistic CD40 antibody. In yet another embodiment, the immunotumor drug is a CD40 antagonist, for example, an antagonistic CD40 antibody. Examples of suitable CD40 antibodies include lucatumumab or dacetuzumab.

[0192] In another embodiment, the immunotumor drug is a CD27 agonist, such as an antagonistic CD27 antibody. An example of a suitable CD27 antibody is valrirumab.

[0193] In another embodiment, the immunotumor drug is MGA271 (WO11 / 109400) against B7H3.

[0194] In another embodiment, the immunotumor drug is an anti-TIGIT agent. Suitable anti-TIGIT agents include antibodies such as BMS-986207, tilagolumab, or MK-7684.

[0195] In another embodiment, the immunotumor drug is a KRAS G12C inhibitor. Suitable KRAS G12C inhibitors include Lumakeras (sotrasib) or Clazati (adaglasib).

[0196] Combination therapy includes modes in which these therapeutic agents are administered sequentially, i.e., by administering each therapeutic agent at a different time, as well as modes in which these therapeutic agents, or at least two therapeutic agents, are administered substantially simultaneously. Substantially simultaneous administration can be achieved, for example, by administering to a subject a single dosage form containing each therapeutic agent in a fixed ratio, or by administering a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but is not limited to, oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent in a selected combination may be administered by intravenous injection while other therapeutic agents are administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. In addition to administering therapeutic agents as described above, the therapy also includes modes in which other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiotherapy) are further combined. In combination therapy, if non-pharmacological therapy is included, it may be administered at any appropriate time, as long as an effective effect is obtained through the synergistic action of the therapeutic and non-pharmacological therapies. For example, when appropriate, an effective effect can still be obtained even if the non-pharmacological therapy is administered at an interval from the administration of the therapeutic drug (e.g., several days or several weeks later).

[0197] For the treatment of diseases, disorders, or conditions related to IKZF1-IKZF4 proteins, one or more other pharmaceuticals or therapeutic methods, such as antiviral agents, chemotherapeutic agents or other anticancer drugs, immunostimulants, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (e.g., IL-2 and GM-CSF), and / or tyrosine kinase inhibitors, may be used in combination with the compound of formula (I) as appropriate. These agents may be used in combination with the compound of the present invention as a single dosage form, or administered simultaneously or sequentially as individual dosage forms.

[0198] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonic acids, nitrosoureas, and triazenes), specifically including uracil mustard, chlormetine, cyclophosphamide (cytoxane®), ifosfamide, melphalan, chlorambucil, pipobromane, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozosin, dacarbazine, and temozolomide.

[0199] Appropriate agents to use in combination with the compound of formula (I) in the treatment of melanoma include: dacarbazine (DTIC) (as appropriate, in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; the three agents cisplatin, vinblastine, and DTIC; temozolomide; or YERVOY TM These include the compounds of formula (I), which can also be used in combination with immunotherapy agents (e.g., cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF)) in the treatment of melanoma.

[0200] Furthermore, the compound of formula (I) can be used in combination with vaccine therapy in the treatment of melanoma. Antimelanoma vaccines are similar in some respects to antiviral vaccines used to prevent diseases caused by viruses such as polio, measles, and mumps. By injecting a patient with attenuated melanoma cells, or a portion of melanoma cells called an antigen, the body's immune system is stimulated to recognize and destroy the melanoma cells.

[0201] Furthermore, melanomas localized to the arms or legs can also be treated with a combination of a drug containing the compound of formula (I) and thermotherapy with isolated limb perfusion. In this treatment protocol, the blood circulation of the affected limb is temporarily separated from the systemic circulation, and a high dose of chemotherapeutic agent is injected into the arterial system of that limb. This allows for the selective delivery of high doses of chemotherapeutic agent, which would normally cause serious side effects if exposed to internal organs, to the tumor site. Typically, this perfusion fluid is heated to 38.9°C to 40°C. The most frequently used drug in this chemotherapy procedure is melphalan. This procedure can also be performed in combination with another drug called tumor necrosis factor (TNF).

[0202] Appropriate chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (such as folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, but not limited to those listed below), specifically methotrexate, 5-fluorouracil, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0203] Further suitable chemotherapeutic agents or other anticancer agents include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), specifically including vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, cytarabine, paclitaxel (Taxol), mitramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferon (especially IFNα), etoposide, and teniposide.

[0204] Other cytotoxic drugs include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and doroxifene.

[0205] Appropriate cytotoxic agents include, for example, epipodophyllotoxin, antitumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum-coordinated complexes such as cisplatin and carboplatin, biological response modifiers, proliferation inhibitors, antihormone therapies, leucovorin, tegafur, and hematopoietic growth factors.

[0206] Other anticancer drugs include antibody drugs, specifically trastuzumab (Herceptin®), antibodies against costimulatory molecules (e.g., CTLA-4, 4-1BB, and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0207] Other anticancer agents include those that inhibit the migration of immune cells, such as antagonists targeting chemokine receptors including CCR2 and CCR4.

[0208] Other anticancer treatments include therapies that enhance the immune system, such as adjuvants or adoptive T cell transplantation.

[0209] Anti-cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines, and recombinant virus vaccines.

[0210] The pharmaceutical composition of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is a drug that induces apoptosis by selectively inhibiting one or more important steps in the signal transduction pathway in the normal function of cancer cells. Appropriate STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774) and antibodies (ImClone's C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix's ABX-EGF); (iii) Her2 / neu receptor inhibitors such as farnesyltransferase inhibitors (FTIs) (e.g., L-744, 832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin [e.g., Sekulic et al., Cancer Res., 60:3504-3513 Examples include (v) cell cycle kinase inhibitors (e.g., flavopyridol and UCN-O1 (e.g., see Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203))); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (e.g., see Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994))). Alternatively, at least one STI and a compound of formula (I) may each be included in a separate pharmaceutical composition. In certain embodiments of the present invention, a compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. That is, either a compound of formula (I) or at least one STI may be administered first, or a compound of formula (I) and at least one STI may be administered simultaneously.Furthermore, when a compound of formula (I) and two or more STIs are used, these compounds may be administered in any order.

[0211] Furthermore, the present invention provides a pharmaceutical composition for treating a patient's chronic viral infection, comprising a compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent, in a pharmaceutically acceptable carrier.

[0212] Furthermore, a method for treating a patient's chronic viral infection is also provided, which involves administering an effective amount of the above-mentioned pharmaceutical composition.

[0213] In certain embodiments of the present invention, the compound of formula (I) and at least one chemotherapeutic agent may be administered to the patient simultaneously or sequentially. That is, the compound of formula (I) or at least one chemotherapeutic agent may be administered first, or the compound of formula (I) and at least one chemotherapeutic agent may be administered simultaneously. Furthermore, when two or more chemotherapeutic agents are used, the compound of the present invention and the multiple chemotherapeutic agents may be administered in any order. Similarly, any antiviral agent or STI may be administered at any time when administered with the compound of formula (I).

[0214] Chronic viral infections that can be treated using the combination therapy of this invention include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).

[0215] Suitable antiviral agents intended for use in combination with the compound of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0216] Appropriate NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stabudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, named 2',3'-dideoxy-2',3'-didehydro-β-L-5-fluorocytidine); DAPD, ((-)-β-D-2,6-diaminopurine dioxolane); and rhodenosine (FddA). Representative and appropriate NNRTIs include nevirapine (BI-RG-587); delavirdin (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolid A (NSC-675451) and calanolid B. Representative and appropriate protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; Examples include BMS-2322623; ABT-378; and AG-1549. Other antiviral drugs include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0217] Combination therapy includes sequential administration of each therapeutic agent at different time points, as well as substantially simultaneous administration of each therapeutic agent, or at least two therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to a subject a single dosage form containing each therapeutic agent in a fixed ratio, or by administering a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent may be carried out by any suitable route, including, but is not limited to, oral, intravenous, intramuscular, and direct absorption via mucosal tissue. Therapeutics may be administered by the same or different routes. For example, the first therapeutic agent in a selected combination may be administered by intravenous injection while the other therapeutic agents are administered orally. Alternatively, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Furthermore, combination therapy may include, in addition to the administration of the therapeutic agents described above, further combinations with other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiation therapy). In combination therapy, if non-pharmacological therapy is included, the non-pharmacological therapy may be administered at any appropriate time, as long as an effective effect is obtained through the synergistic action of the therapeutic and non-pharmacological therapies. For example, in appropriate cases, an effective effect can still be obtained even if the non-pharmacological therapy is administered at an interval from the administration of the therapeutic drug (e.g., several days or weeks later).

[0218] [Pharmaceutical composition] Furthermore, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) together with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and further optionally comprising one or more of the above-mentioned therapeutic agents.

[0219] The compound of formula (I) may be administered by any suitable route of administration, preferably in the form of a pharmaceutical composition suitable for that route, and in a dose effective for the intended treatment. The compound of formula (I) and its pharmaceutical compositions may be administered by any suitable method for any of the uses described herein, for example, by oral administration such as tablets, capsules (including sustained-release and time-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingual administration; buccal administration; parenteral administration by subcutaneous, intravenous, intramuscular, or intrasternal injection, or by drip infusion (e.g., sterile aqueous or non-aqueous solution for injection, or suspension); nasal administration, including administration to the nasal mucosa by inhalation spray; topical administration by cream or ointment; and rectal administration in the form of suppositories. These may be administered alone, but are generally administered with a pharmaceutical carrier selected based on the selected route of administration and standard pharmaceutical criteria.

[0220] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably formulated as a dosage unit containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing the active ingredient in an amount ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The appropriate daily dose in humans or other mammals may vary considerably depending on the subject's condition and other factors, but can be determined by conventional methods.

[0221] Any pharmaceutical composition envisioned herein may be administered orally, for example, by an optional and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration may be manufactured according to any method known in the art. To provide a pharmaceutical formulation that is easy to take, the pharmaceutical compositions according to the present invention may contain at least one substance selected from sweeteners, flavorings, colorants, lubricants, antioxidants, and preservatives.

[0222] Tablets may be manufactured, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic, pharmaceutically acceptable additive suitable for the manufacture of tablets. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulators and disintegrants (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets may be uncoated or coated by known methods to mask the taste of drugs with unpleasant tastes, or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble, taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropylcellulose. Examples of materials that delay disintegration and absorption include, but are not limited to, ethylcellulose and cellulose acetate-butyrate.

[0223] Hard gelatin capsules can be produced, for example, by mixing a compound of formula (I) and / or at least one salt thereof with at least one inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.

[0224] Soft gelatin capsules can be manufactured, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier such as polyethylene glycol, and at least one oily medium such as peanut oil, liquid paraffin, or olive oil.

[0225] Aqueous suspensions can be prepared, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one suitable additive for the preparation of the aqueous suspension. Examples of suitable additives for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersants, or wetting agents (e.g., naturally derived phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), ethylene oxide, fatty acids, and hexyl Examples include condensation products with partial esters derived from thol (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoic acid), at least one colorant, at least one flavoring, and / or at least one sweetener (but not limited to, e.g., sucrose, saccharin, and aspartame).

[0226] An oily suspension can be prepared, for example, by suspending a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in a vegetable oil (such as peanut oil, olive oil, sesame oil, and coconut oil), or a mineral oil (such as liquid paraffin). The oily suspension may also contain at least one thickening agent (such as beeswax, solid paraffin, and cetyl alcohol). To provide an easily administrable oily suspension, at least one of the above-mentioned sweetening agents and / or at least one flavoring agent may be added. The oily suspension may further contain at least one preservative (including but not limited to antioxidants such as butyl hydroxyanisole and α-tocopherol).

[0227] Dispersible powders and granules can be prepared, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents include those already mentioned above. Examples of preservatives include, but are not limited to, antioxidants (such as ascorbic acid). Furthermore, the dispersible powders and granules may contain at least one excipient such as a sweetening agent, a flavoring agent, and a coloring agent, but are not limited thereto.

[0228] Emulsions of compounds of formula (I) and / or at least one pharmaceutically acceptable salt thereof may be prepared, for example, as oil-in-water emulsions. The oil phase of an emulsion containing a compound of formula (I) may be composed of known components by known methods. The oil phase may be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase may contain only emulsifiers, or it may contain at least one emulsifier and fats or oils, or mixtures of both fats and oils. Suitable emulsifiers include, but is not limited to, naturally occurring phospholipids (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Furthermore, it is preferable to contain both oil and fat. In addition, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, which, together with the oil and fat, forms a so-called emulsifying ointment base that forms the oily dispersion phase of the cream. The emulsion may further contain sweeteners, fragrances, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, or other substances known in the art, which may be used alone or in combination with wax.

[0229] In addition, the compound of formula (I) and / or at least one of its pharmaceutically acceptable salts can be administered intravenously, subcutaneously, and / or intramuscularly, for example, via any pharmaceutically acceptable and appropriate injection form. Examples of injectable preparations include, but are not limited to, for example, sterile aqueous solutions, sterile water-in-oil microemulsions, and aqueous or oily suspensions containing acceptable vehicles and solvents (such as water, Ringer's solution, and sodium chloride isotonic solution).

[0230] The formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions can be prepared from sterile powders or granules by using one or more of the carriers or diluents described above as used in formulations for oral administration, or by using other appropriate dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffer solutions. Other adjuvants and administration forms are known and widely known in the pharmaceutical field. Also, the active ingredient may be administered by injection as a composition with an appropriate carrier (such as physiological saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing cosolvent (i.e., propylene glycol), or micelle solubilizing agent (i.e., Tween 80).

[0231] In addition, a sterile injectable preparation may be a sterile injectable solution or suspension prepared in a non-toxic diluent or solvent suitable for parenteral administration, and can be prepared, for example, as a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used include water, Ringer's solution, and sodium chloride isotonic solution. Furthermore, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any low-irritancy fixed oil containing synthetic monoglycerides or diglycerides may be used. In addition, fatty acids such as oleic acid are also used in the preparation of injectable preparations.

[0232] A sterile oil-in-water microemulsion for injection can be produced, for example, by the following steps: 1) dissolve the compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) mix the oil phase containing the compound of formula (I) with a mixture of water and glycerol; and 3) process the resulting mixture to form a microemulsion.

[0233] Sterile aqueous suspensions or sterile oily suspensions can be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions can be prepared using a non-toxic diluent or solvent suitable for parenteral administration (e.g., 1,3-butanediol). On the other hand, sterile oily suspensions can be prepared using a sterile, non-toxic, and acceptable solvent or suspension medium (e.g., sterile fixative oils such as synthetic monoglycerides or diglycerides, and fatty acids such as oleic acid).

[0234] Medicinally acceptable carriers are selected based on a number of factors that fall within the ordinary expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the activator being formulated, the patients to whom the composition containing the activator will be administered, the intended route of administration of the composition, and the target therapeutic indicators. Medicinally acceptable carriers include a variety of solid and semi-solid dosage forms, as well as both aqueous and non-aqueous liquid media. Such carriers may contain a variety of components and additives in addition to the activator, and the added components may be included in the formulation for various purposes known to those skilled in the art, such as stabilizing the activator or functioning as a binder. A description of suitable pharmaceutically acceptable carriers and the factors involved in their selection can be found in various readily available publications, e.g., Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0235] pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween compounds, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymer delivery matrices), serum proteins (e.g., human serum) Examples include albumin, buffering agents (e.g., phosphates, glycine, sorbic acid, potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin. Cyclodextrins (e.g., α-, β-, and γ-cyclodextrins, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins containing 2- and 3-hydroxypropyl cyclodextrins, or other solubilized derivatives)) may also be effectively used to improve the deliverability of compounds of the formulas described herein.

[0236] The pharmaceutically active compounds of the present invention may be processed according to conventional pharmaceutical methods to produce pharmaceuticals for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain conventionally used adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may be further prepared by enteric coating. Such compositions may also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and fragrances).

[0237] The active compound of the present invention is used for therapeutic purposes in combination with one or more adjuvants suitable for the commonly assumed route of administration. When administered orally, the compound may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then formulated into tablets or capsules for convenience of administration. Such capsules or tablets may contain a controlled-release formulation in which the active compound is dispersed in hydroxypropyl methylcellulose.

[0238] The amount of compound administered when treating a disease condition with the compounds and / or compositions of the present invention, as well as the administration regimen, depends on various factors, including age, weight, sex, the patient's condition, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used. Therefore, the administration regimen can vary considerably, but it can be determined according to standard methods. A daily dose of about 0.001 to 100 mg / kg body weight may be appropriate, preferably about 0.0025 to about 50 mg / kg body weight, and more preferably about 0.005 to 10 mg / kg body weight. The daily dose may be administered once to four times a day. Other administration plans include weekly and every-other-day administration cycles.

[0239] The pharmaceutical compositions of the present invention comprise a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally any additive selected from pharmaceutically acceptable carriers, adjuvants, and vehicles. Another composition of the present invention comprises a compound of formula (I) as described herein, or its prodrug, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0240] The present invention also includes, for example, a pharmaceutical kit useful in the treatment or prevention of IKZF1-IKZF4 protein-related diseases or disorders and other diseases described herein, the kit comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I). Furthermore, such a kit may optionally include one or more components of various conventional pharmaceutical kits (e.g., a container containing a pharmaceutically acceptable carrier, another container), which are readily understood by those skilled in the art. In addition, instructions indicating the amount of the component to be administered, guidance for administration, and / or guidance for mixing the components may be included in the kit as either a package insert or a label.

[0241] The administration regimen for the compounds of the present invention will naturally vary depending on known factors such as the pharmacodynamic properties of the specific drug, its method and route of administration, the species, age, sex, health status, medical condition and weight of the recipient, the nature and severity of symptoms, the type of concomitant therapy, the frequency of treatment, the route of administration, the patient's renal and hepatic function, and the desired effect.

[0242] As a general guideline, the daily oral dose of each active ingredient, when used to obtain the desired effect, is in the range of approximately 0.001 to approximately 5000 mg / day, preferably approximately 0.01 to approximately 1000 mg / day, and most preferably approximately 0.1 to approximately 250 mg / day. For intravenous administration, the most preferred dose at constant-rate infusion is in the range of approximately 0.01 to approximately 10 mg / kg / min. The compound of formula (I) may be administered in a once-daily dose, or the total daily dose may be divided into two, three, or four doses.

[0243] This compound is typically administered in a mixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier) that is appropriately selected according to the intended dosage form (e.g., oral tablets, capsules, elixirs, and syrups) and conforms to conventional pharmaceutical practice.

[0244] Suitable dosage forms (pharmaceutical compositions) may contain approximately 1 mg to 200 mg of the active ingredient per dose. In these pharmaceutical compositions, the active ingredient typically accounts for approximately 0.1 to 95% by weight based on the total weight of the composition.

[0245] A typical oral capsule contains the compound of formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). This mixture is sieved through a 60-mesh sieve and then filled into No. 1 gelatin capsules.

[0246] A typical injectable formulation is manufactured by filling a vial with the compound of formula (I) (250 mg) under sterile conditions, lyophilizing it under sterile conditions, and then sealing it. When using, the contents of the vial are mixed with physiological saline (2 mL) to prepare the injectable formulation.

[0247] The scope of the present invention includes pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of the compound of formula (I) alone or in combination with a pharmaceutical carrier. The compound of formula (I) may be used in appropriate combination with one or more other therapeutic agents (e.g., anticancer agents or other pharmaceutically active substances).

[0248] Compounds of formula (I) and / or pharmaceutical compositions of the present invention, which can be used in an appropriate hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art, regardless of the selected route of administration.

[0249] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention may be adjusted to contain an amount of the active ingredient that is non-toxic to the patient and effective in obtaining therapeutic effects according to a specific patient, composition, and dosage form.

[0250] The selected dosage level varies depending on a variety of factors, including the activity of the compound of formula (I) used, or its ester, salt or amide, the route of administration of the compound, the time of administration, the excretion rate or metabolic rate, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or substances used in combination with the compound, the age, sex, weight, symptoms, health status, and medical history of the patient to be treated, and other factors known in the medical field.

[0251] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a level lower than the required amount to obtain a therapeutic effect and gradually increase the dosage until the effect is obtained.

[0252] Generally, an appropriate daily dosage of the compound of formula (I) is the minimum amount of the compound effective to obtain a therapeutic effect. Such effective dosages are usually determined by the factors described above. Generally, the dosage of the compound of formula (I) for a patient is about 0.01 to about 50 mg / kg body weight / day in oral administration, intravenous administration, intracerebroventricular administration and subcutaneous administration.

[0253] If necessary, the effective daily dosage of the active compound can be administered in divided doses two, three, four, five, six or more times at appropriate intervals throughout the day in appropriate unit dosage forms. In certain embodiments of the invention, the dosing is once a day.

[0254] Although it is possible to administer the compound of formula (I) alone, it is preferred to administer the compound as a pharmaceutical formulation (composition).

[0255] When used in combination with the compound of formula (I), the other therapeutic agents described above may be used, for example, in the amounts described in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, these other therapeutic agents may be administered before, simultaneously with, or after the administration of the compounds of the present invention.

[0256] [Manufacturing method] The compounds of the present invention can be produced by various methods known to those skilled in the art in the field of organic synthesis. In addition to the methods described below, the compounds of the present invention can be synthesized using synthetic methods known in the field of organic synthesis chemistry, or similar synthetic methods appreciated by those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are incorporated herein by reference in their entirety.

[0257] The compounds of the present invention can be prepared using the reactions and techniques described in this section. The reactions described below are carried out in solvents suitable for the reagents and substances used, and under conditions suitable for the desired transformation. Furthermore, in the description of the synthesis methods below, all reaction conditions presented (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and work-up method) are selected as standard conditions for the reaction and are readily understandable to those skilled in the art. It is understood by those skilled in the field of organic synthesis that the functional groups present at each part of the molecule must be compatible with the presented reagents and reactions. It is obvious to those skilled in the art that the substituents that can be compatible with the reaction conditions are limited, and alternative methods may be necessary. For this reason, it may be necessary to change the order of the synthesis steps or change a particular reaction route to obtain the compounds of the present invention. Furthermore, it is recognized that one of the important considerations in planning synthetic routes in the art is the selection of appropriate protecting groups to be used to protect the reactive functional groups contained in the compounds of the present invention. For those skilled in the art, a highly authoritative publication presenting a diverse range of protecting group options is *Protective Groups In Organic Synthesis* (Fourth Edition, Wiley & Sons, 2007) by Greene and Wuts.

[0258] [Examples] The following examples illustrate specific embodiments of the present invention and do not limit the scope of the invention. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their general and conventional meanings unless otherwise specified. Other abbreviations used in the examples and elsewhere in this specification are defined below. The compounds and intermediates of the examples are identified by the example and step in which they were prepared (e.g., "1-A" represents step A of Example 1), or, if the compound is the title compound of that example, by the example number alone (e.g., "1" represents the title compound of Example 1). In some cases, alternative preparation methods for intermediates or examples may be described. A chemist skilled in the art of synthesis may devise a desirable alternative preparation method based on one or more considerations such as reduced reaction time, lower starting material costs, ease of handling or isolation, improved yield, compatibility with catalysts, avoidance of toxic reagents, availability with specialized equipment, and reduction of the number of steps. The intention of describing alternative preparation methods is to make the examples of the present invention even easier to prepare. In some cases, some of the functional groups in the described examples and claims may be substituted with biologically equivalent substituents known to those skilled in the art. For example, a carboxylic acid group may be substituted with a tetrazole group or a phosphate group.

[0259] [Abbreviation] TIFF2026521443000036.tif91150

[0260] [Analytical LCMS conditions] Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile phase A: 95:5 (water:acetonitrile (containing 2.5 mM NH4OAc)); Mobile phase B: 5:95 (water:acetonitrile (containing 2.5 mM NH4OAc)); Temperature: 40°C; Gradient: Elute over 2 minutes from 20%B to 100%B; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm)

[0261] Intermediate A tert-butyl(6-chloro-3-formylpyridine-2-yl)carbamate [ka] To a stirred solution of tert-butyl(6-chloropyridine-2-yl)carbamate (20 g, 87 mmol) and TEMED (32.8 mL, 219 mmol) / anhydrous THF (300 mL), n-BuLi (1.6 M, hexane solution, 137 mL, 219 mmol) was added dropwise at -78°C for approximately 30 minutes under a nitrogen atmosphere. The reaction mixture was slowly warmed to -10°C and maintained at -10°C for 2 hours. The reaction mixture was cooled again to -78°C, DMF (33.9 mL, 437 mmol) was added, and the mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with RINKAN (1 L) and 1N hydrochloric acid (0.5 L), and the organic layer was separated by stirring for 15 minutes. The organic layer was washed with water and saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was mixed with 10% IPA / petroleum ether, and the isolated solid was filtered and dried under reduced pressure to obtain tert-butyl(6-chloro-3-formylpyridine-2-yl)carbamate (15 g, 67%) as a pale solid. LC-MS (Method A): Retention time 1.45 min, [M-56] + 201.1; 1 ¹H NMR (300 MHz, chloroform-d) δ 10.17 (br s, 1H), 9.90 (s, 1H), 7.94 (br d, J=8.3 Hz, 1H), 7.26-7.02 (m, 1H), 1.55 (s, 9H)

[0262] Intermediate B tert-butyl(S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka]

[0263] Intermediate B-1: Preparation of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one [ka] To a stirred solution of 2,2,6,6-tetramethylpiperidine (7.07 mL, 41.6 mmol) / anhydrous THF (150 mL), n-BuLi (2.5 M, hexane solution, 16 mL, 40 mmol) was added at 0°C and the mixture was stirred at 0°C for 30 minutes. This mixture was cooled to -50°C, and a solution of 4-bromo-3-fluorobenzoic acid (3.5 g, 15.98 mmol) / anhydrous THF (100 mL) was added dropwise at the same temperature under a nitrogen atmosphere, and the mixture was stirred at -50°C under a nitrogen atmosphere for 3 hours. Anhydrous DMF (2.48 mL, 32 mmol) was added at -50°C, and the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched by adding 1.5N HCl (100 mL). The reaction mixture was extracted with à (3 x 30 mL), the organic layers were washed together with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2, 120 g column, 0-50% Âxy / petroleum ether) to obtain 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (1.0 g, 23%) as a yellow solid. LC-MS (Method A): Retention time 0.48 min, [MH] + 245.1, 247.1; 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 7.93 (dd, J=8.0, 5.5 Hz, 1 H), 7.59 (d, J=8.0 Hz, 1 H), 6.74 (br s, 1 H), 5.94 (br s, 1 H)

[0264] Intermediate B-2: Preparation of tert-butyl(S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate [ka] To a stirred solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (1.7 g, 6.88 mmol) and tert-butyl(S)-4,5-diamino-5-oxopentanoate·HCl (1.67 g, 8.26 mmol) / DMF (30 mL), sodium triacetoxyborohydride (3.65 g, 17.21 mmol) was added at 0°C under a nitrogen atmosphere. This mixture was heated to room temperature and stirred for 48 hours. The reaction mixture was diluted with ice water (50 mL), and the resulting white solid was filtered and dried under reduced pressure to obtain tert-butyl(S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (1.6 g, 50%) as a white solid. LCMS (Method A): Retention time 1.39 min, [MH] + 413.9; 1 H NMR (400MHz, DMSO-d6) δ 7.85(dd, J=8.0, 6.0Hz, 1H), 7.59(br s, 1H), 7.51(d, J=8.0Hz, 1H), 7.23(br s, 1H), 4.77-4.59(m, 3H), 2.26-2.13(m, 3H), 2.08-1.96(m, 1H), 1.34(s, 9H)

[0265] Intermediate B-3: Preparation of tert-butyl(S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-2-yl)-5-oxopentanoate [ka] A mixture of tert-butyl(S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (10.0 g, 24.1 mmol), potassium acetate (0.355 g, 3.61 mmol), and Bispin (7.95 g, 31.3 mmol) / anhydrous DME (15 mL) was purged with argon for 10 minutes at room temperature. Under an argon atmosphere, Pd(dppf)Cl2·DCM complex (1.97 g, 2.4 mmol) was added, the vial was sealed, and the mixture was heated at 90°C for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in diethyl ether and filtered by Celite. The filtrate was concentrated under reduced pressure to obtain tert-butyl(S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-2-yl)-5-oxopentanoate (11.0 g, crude product). LC-MS (Method A): Retention time 1.6 min, [M+H] + 463.1

[0266] Production of intermediate B: To a stirred solution of tert-butyl(S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindorin-2-yl)-5-oxopentanoate (11.0 g, 23.8 mmol) / dioxane (200 mL), tert-butyl(6-chloro-3-formylpyridine-2-yl)carbamate (7.42 g, 28.9 mmol) and 3M potassium phosphate aqueous solution (24.08 mL, 72.2 mmol) were added at room temperature. The reaction mixture was purged with nitrogen for 10 minutes, and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (1.556 g, 1.81 mmol) was added under a nitrogen atmosphere, and the mixture was heated at 85°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with toluene (300 mL), and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude compound was purified by flash chromatography (SiO2, 220g column, 10-100% ethyl(containing 15% EtOH) / DCM) to obtain tert-butyl(S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (7.4g, 55% yield) as a yellow solid. LCMS (Method A): Retention time 1.62 min, [M+H] + 557.2; 1 H NMR (300MHz, chloroform-d) δ 10.08(br s, 1H), 9.97(s, 1H), 8.54(br t, J=7.2Hz, 1H), 8.09(br d, J =7.6Hz, 1H), 7.78(br d, J=7.6Hz, 2H), 6.37(br s, 1H), 4.94(br t, J=6.8Hz, 1H), 4.72(br d, J =17.4Hz, H), 4.58(br d, J =17.8Hz, 1H), 2.46-2.11(m, 4H), 1.70-1.62(m, 9H), 1.53-1.37(m, 9H)

[0267] Example 1 3-(5-(5-((6-oxa-2-azaspiro[3.5]nonanane-2-yl)methyl)-6-aminopyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka]

[0268] Intermediate 1A: Preparation of tert-butyl(S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-amino-5-oxopentanoate [ka] Acetic acid (0.411 mL, 7.19 mmol) was added to a stirred solution of 6-oxa-2-azaspiro[3.5]nonane·HCl (3.53 g, 21.56 mmol) and tert-butyl(S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-oxopentanoate (8.0 g, 14.37 mmol) / DCE (150 mL) and DMF (20 mL), and the mixture was stirred overnight at room temperature. MP-cyanobolohydride (8.0 g) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2, 220g column, 10-100% ethyl(containing 15% EtOH) / DCM) to obtain tert-butyl(S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]nonanane-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-amino-5-oxopentanoate (5.5g, 51%) as a yellow solid. LCMS (Method A): Retention time 1.79 min, [M+H] +668.3; 1 H NMR (300MHz, DMSO-d6) δ 10.07(s, 1H), 8.18(br t, J=7.4Hz, 1H), 7.80(br d, J=7.9Hz, 1H), 7.72-7.57(m, 3H), 7.25(br s, 1H), 4.81-4.61(m, 3H), 3.68(s, 3H), 3.61(s, 2H), 3.49(br d, J=3.4Hz, 2H), 3.05(br d, J=6.4Hz, 2H), 2.86(br d, J=7.2Hz, 2H), 2.21(br s, 5H), 1.72(br d, J=4.5Hz, 2H), 1.48 (s, 10H), 1.34 (s, 9H)

[0269] Example 1: 3-(5-(5-((6-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-6-aminopyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione To a stirred solution of tert-butyl(S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]nonanane-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)-5-amino-5-oxopentanoate (2.5 g, 3.74 mmol) / acetonitrile (150 mL), benzenesulfonic acid (1.480 g, 9.36 mmol) was added at room temperature and heated at 90 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the resulting residue was quenched by adding saturated Na2CO3 solution until the pH was 7.0. This suspension was extracted with 10% MeOH / DCM (50 mL x 3), the organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2, 220g column, 0-10% MeOH / DCM) to obtain 3-(5-(5-((6-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)-6-aminopyridine-2-yl)-4-fluoro-1-oxoisoindorin-2-yl)piperidine-2,6-dione (1.4g, 65%) as a white solid. LCMS (Method A): Retention time 1.02 min, [M+H] + 494.3; 1 H NMR (400MHz, DMSO-d6) δ 11.01(s, 1H), 8.06 (t, J=7.3Hz, 1H), 7.65(d, J=7.9Hz, 1H), 7.43(d, J=7.5Hz, 1H), 7.02(dd, J=7.4, 2.4Hz, 1H), 6.16(s, 2H), 5.14(dd, J=13.3, 5.1Hz, 1H), 4.62(d, J=17.4Hz, 1H), 4.45(d, J=17.4Hz, 1H), 3.58(s, 2H), 3.54-3.44(m, 4H), 3.04-2.81(m, 4H), 2.66-2.56(m, 1H), 2.46-2.36(m, 2H), 2.08-1.99(m, 1H), 1.75-1.67(m, 2H), 1.45(br d, J=5.4Hz, 2H)

[0270] Comparative compound A 3-(4-fluoro-1-oxo-5-(4-((3-phenylazetidine-1-yl)methyl)pyridine-2-yl)isoindorin-2-yl)piperidine-2,6-dione [ka] Comparative compound A was prepared according to the procedure disclosed in WO 2021 / 101919 (Example 208).

[0271] Comparative compound B 3-(5-(5-((2-Azaspiro[3,3]heptan-2-yl)methyl)-6-aminopyridine-2-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione [ka] Comparative compound B was prepared according to the procedure disclosed in WO 2022 / 216573 (Example 286).

[0272] [Biological assay] The pharmacological properties of the compounds of the present invention can be confirmed by multiple biological assays. The biological assays exemplified below have been performed using the compounds of the present invention.

[0273] [JURKAT cell degradation assay] Jurkat cells were seeded in a 384-well cell culture plate at a rate of 80,000 cells per well in RPMI (40 μL) + 10% FBS, and the target compound was added using acoustic dispensing technology. The cell culture was incubated at 37°C and 5% CO2 for 72 hours. To facilitate analysis, the cultured cells were centrifuged at 200 rpm for 5 minutes, and the supernatant was removed. After shaking the plate to disperse the cell pellet, the cells were resuspended in fixation buffer (50 μL, eBioScience FoxP3 buffer set, 00-5523-00) at room temperature for 60 minutes. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 buffer set, 00-5523-00) at room temperature for 10 minutes. After permeabilization, the cells were centrifuged, and the supernatant was replaced with fluorescently labeled antibodies against Helios, Ikaros, and Aiolos, or the corresponding isotype control antibodies (20 μL) / 1x permeabilization buffer (Ikaros-Alexa488 [Biolegend, Cat #368408, 1:50], Helios-PE [CST, Cat #29360, 1:50], Aiolos-Alexa647 [Biolegend, Cat #371106, 1:25]). The staining reaction was incubated at room temperature for 1 hour in the dark. Then, 1x permeabilization buffer (30 μL) was added, the cells were centrifuged, and the supernatant was removed. The stained cells were resuspended in flow cytometry staining buffer [25 μL, PBS + 0.2% bovine serum albumin (BSA)] and analyzed using an Intellicyt iQue Plus flow cytometer. [Table 1] Table A-1 shows the maximum observed degradation rates of IKZF1, IKZF2, and IKZF3 proteins as measured by the Jurkat cytodegradation assay. The results shown in Table A-1 have been rounded to two decimal places. In the Jurkat cytodegradation assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that no protein degradation by the test compound was detected. [Table 2]

[0274] [Human Regulatory T Cell Degradation Assay] Cryopreserved human regulatory T cells were thawed in RPMI + 10% FBS + IL-2 (20 ng / mL). After centrifugation at 1200 rpm for 5 minutes, the cells were resuspended in RPMI + 10% FBS + 20 ng / mL and allowed to stand for 3 hours at 37°C and 5% CO2. Subsequently, cells were seeded into 384-well cell culture plates at a rate of 40,000 cells per well in RPMI (40 μL) + 10% FBS + human IL-2 (20 ng / mL), and the target compound was added using acoustic dispensing technology (ECHO 555). The cultured cells were incubated at 37°C and 5% CO2 for 20 hours. To facilitate analysis, the cultured cells were centrifuged at 1200 rpm for 5 minutes, and the supernatant was removed using an EL406 plate washer. After washing three times with PBS (70 μL), the cell pellet was resuspended in Near-IR stain (50 μL, Life Technologies, Cat# L34975) and incubated on ice for 30 minutes in the dark. The cells were washed three times with PBS (70 μL) + 0.5% BSA using an EL406 plate washer. After shaking the plate to disperse the cell pellet, the cells were resuspended in fixation buffer (50 μL, eBioScience FoxP3 buffer set, 00-5523-00) at room temperature for 60 minutes. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 buffer set, 00-5523-00) at room temperature for 10 minutes. After permeabilization, the cells were centrifuged and the supernatant was removed. Fluorescently labeled antibodies (30 μL) against the intracellular targets Helios (Helios-APC [BioLegend, Cat# 137222, 1:50]), Aiolos, and Ikaros were added in 1x permeabilization buffer, and the cells were incubated at room temperature for 1 hour, shielded from light. Subsequently, 1x permeabilization buffer (30 μL) was added, the cells were centrifuged, and the supernatant was removed. The stained cells were resuspended in flow cytometry staining buffer (30 μL, PBS + 0.5% BSA) and analyzed using an Intellicyt iQue Plus flow cytometer. [Table 3] Table B-1 shows the maximum observed degradation rates of IKZF1 and IKZF2 proteins as measured by the human regulatory T cell degradation assay. The results shown in Table B-1 have been rounded to two decimal places. In the human regulatory T cell degradation assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that no protein degradation by the test compound was detected. [Table 4]

[0275] [Human Regulatory T Cell Reprogramming Assay] RosetteSep Human CD4 + Using T Cell Enrichment Cocktail (Stemcell Technologies) and Ficoll density gradient centrifugation, human CD4 was extracted from fresh Leukopak (Stemcell Technologies) derived from healthy individuals. + T cells were isolated. Leukopak was diluted equally with phosphate-buffered saline (PBS [Gibco], containing 2% fetal bovine serum (FBS, VWR Lifescience)) and RosetteSep Human CD4 + After incubation with T Cell Enrichment Cocktail for 20 minutes, the cells were added to Ficoll-Paque Plus solution (GE Health Care). The interface layer with accumulated cells was collected and washed twice with PBS (containing 2% FBS). Then EasySep Human CD4 was added. + CD127 low CD25 +Regulatory T cells were manually isolated using a regulatory T cell isolation kit (Stemcell Technologies) according to the manufacturer's instructions. The cells were incubated overnight in a humidified incubator (37°C, 5% CO2) in Roswell Park Memorial Institute (RPMI) 1640 medium (containing Gibco, 10% FBS + Pen / Strep (Gibco) + MEM-NEAA (Gibco) + sodium pyruvate (Gibco)). CD4 was then stained with RPA-T4 (Biolegend), CD25 with 2A3 (BD ​​Biosciences), and CD127 with hIL-7R-M21 (BD Biosciences). + CD127 low CD25 + Cells were isolated with a purity of over 95% using a BD FACSAria Fusion cell sorter. The separated cells were either used immediately for subsequent assays or cryopreserved. CD4 immediately after sorting or frozen after sorting using FACS + CD127 low CD25 +Treg cells were seeded in 96-well round-bottom plates at a rate of 25,000–50,000 cells per well and cultured in RPMI 1640 medium (containing Gibco, 10% FBS + Pen / Strep (Gibco) + MEM-NEAA (Gibco) + sodium pyruvate (Gibco)). Cells were stimulated by adding Treg Xpander beads (Thermo Fisher) in a cell-to-bead ratio of 1:4 in the presence of recombinant human IL-2 (500 U / mL, Proleukin). Cells were incubated at 37°C and 5% CO2 for 12–13 days with serially diluted compounds added. Recombinant human IL-2 and compounds were replenished every 2–3 days during the culture period. On day 12 or 13, cells were re-stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin under conditions containing the protein transport inhibitors brefeldin A and monensin (eBioscience Cell Stimulation Cocktail (plus protein transport inhibitors), 500x, catalog number: 00-4975-93), followed by staining and analysis by flow cytometry. For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher), incubated for 10 minutes in Human TruStain FcX (Biolegend, Fc receptor blocking reagent), then Viability Dye eFluor780 (Thermo Fisher) and a surface marker antibody cocktail were added, and incubated for 30 minutes at 4°C. Next, cells were fixed by incubation for 30 minutes at 4°C with FoxP3 transcription factor staining buffer (Thermo Fisher) according to the kit manufacturer's instructions, followed by permeabilization. Following the manufacturer's instructions, cells were washed twice with the kit's Perm / Wash buffer and incubated overnight at 4°C with an intracellular antibody cocktail consisting of antibodies specific to the transcription factors shown in Table C. After washing the cells twice with Perm / Wash buffer and resuspending them in flow cytometry staining buffer (Thermo Fisher), they were collected. Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. For each fluorescent dye, single-stain controls were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). The obtained data were analyzed using FlowJo (version 10) and GraphPad Prism software. [Table 5] [Table 6] Table C-1 shows the maximum observed degradation rates of IKZF2 and IKZF4 proteins as measured by the human regulatory T cell reprogramming assay. The results shown in Table C-1 have been rounded to two decimal places. In the human regulatory T cell reprogramming assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that no protein degradation by the test compound was detected. [Table 7]

[0276] [Human CD8 + [T-cell degradation assay] Human peripheral blood mononuclear cells (PBMCs) derived from healthy donors, which had been cryopreserved, were thawed and seeded at a rate of 500,000 cells per well in 96-well round-bottom plates. They were then cultured in RPMI 1640 medium (containing Gibco, 10% FBS + Pen / Strep (Gibco) + MEM-NEAA (Gibco) + sodium pyruvate (Gibco)). After adding compounds at serially diluted concentrations and treating the cells at 37°C under 5% CO2 for 24 hours, flow cytometry analysis was performed. For staining by flow cytometry, cells were washed twice with flow cytometry staining buffer (Thermo Fisher), incubated for 10 minutes in Human TruStain FcX (Biolegend, Fc receptor blocking reagent), then Viability Dye eFluor780 (Thermo Fisher) and a surface marker antibody cocktail (containing LD-eFluor780, CD3-BUV-395, CD4-BUV805, CD8-FITC, and CD25-BV605) were added, and incubated at 4°C for 30 minutes. Subsequently, cells were fixed and permeabilized by incubation for 30 minutes at 4°C with permeabilization buffer (eBioscience FoxP3 buffer set, 00-5523-00) according to the kit manufacturer's instructions. Following the manufacturer's instructions, cells were washed twice with the kit's Perm / Wash buffer and incubated overnight at 4°C with an intracellular antibody cocktail consisting of antibodies specific to transcription factors (i.e., Foxp3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PECF594, AIOLOS-AF647). The cells were washed twice again with Perm / Wash buffer, resuspended in flow cytometry staining buffer (Thermo Fisher), and then collected. Samples were acquired and analyzed using a BD LSRFortessa (BD Biosciences) flow cytometer. For each fluorescent dye, single-stain controls were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). The obtained data were analyzed using FlowJo (version 10) and GraphPad Prism software. [Table 8] [Table 9] Table D-1 shows human CD8 +The maximum observed degradation rates of IKZF1 and IKZF3 proteins, as measured by T-cell reprogramming assays, are shown. The results shown in Table D-1 have been rounded to two decimal places. (Human CD8) + In the T cell reprogramming assay, a value of 100% indicates that no detectable residual protein remains or that the protein has been completely degraded, while a value of 0% indicates that no protein degradation by the test compound was detected. [Table 10]

[0277] In the above tests, as shown in Tables C-1 and D-1, (i) Example 1 reduced the level of IKZF1 (Ikaros) by 64-65% (Table D-1); (ii) Example 1 reduced the level of IKZF2 (Helios) protein by 85% (Table C-1); (iv) Example 1 reduced the level of IKZF3 (Aiolos) by 62-66% (Table D-1); and (iv) Example 1 reduced the level of IKZF4 (Eos) by 65% ​​(Table C-1). In contrast, in similar tests, comparative compounds A and B reduced the level of IKZF1 (Ikaros) by less than 20%, and comparative compound B reduced the level of IKZF3 (Aiolos) by only 2%.

[0278] The present invention solves the above problem by providing compounds useful for reducing the levels of Ikaros, Helios, Aiolos, and Eos, which are IKZF1-IKZF4 proteins.

Claims

1. Equation (I): 【Chemistry 1】 A compound of the same, or its stereoisomer, tautomer, or salt.

2. The compound described in claim 1, or its stereoisomer or tautomer.

3. A salt of the compound described in claim 1, or a stereoisomer or tautomer thereof.

4. A pharmaceutically acceptable salt of the compound described in claim 1, or a stereoisomer or tautomer thereof.

5. The following structure: 【Chemistry 2】 A compound according to claim 1, or a stereoisomer, tautomer, or salt thereof having the above characteristics.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising the compound described in claim 2, or a stereoisomer or tautomer, and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound described in claim 4, or a stereoisomer or tautomer thereof, and a pharmaceutically acceptable carrier.

9. Use of any one of the compounds described in claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for the treatment of cancer.

10. The use according to claim 9, wherein the cancer is selected from colon cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

11. A method for treating the patient's cancer, characterized by administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

12. The method according to claim 11, wherein the cancer is selected from colon cancer, stomach cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

13. The method according to claim 11, wherein the cancer is selected from lymphoma, leukemia, and multiple myeloma.

14. The method according to claim 11, further characterized by administering a therapeutically effective amount of a second agent to the patient before, simultaneously with, or after administration of the compound, wherein the second agent is selected from a PD1 / PD-L1 antagonist, a CTLA4 antagonist, a chemotherapeutic agent, radiation, or an antitumor vaccine.

15. A method for treating a patient's cancer, characterized by administering to the patient a therapeutically effective amount of an agent to reduce the protein levels of Ikaros, Helios, Aiolos, and Eos, wherein the agent is a compound described in any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

16. a) The Ikaros protein is the amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; b) The Helios protein is the amino acid sequence encoded by SEQ ID NO: 7, 8, 9, 10, or 11; c) The Aiolos protein is an amino acid sequence encoded by SEQ ID NOs: 12, 13, 14, 15, 16, 17, 18, or 19; and d) The Eos protein is the amino acid sequence encoded by SEQ ID NO: 20 or 21. The method according to claim 15.

17. a) The level of the Ikaros protein decreases by at least 30%; b) The level of the Helios protein is reduced by at least 50%; c) The level of the Aiolos protein is reduced by at least 30%; and d) The level of the Eos protein decreases by at least 50%, The method according to claim 15.

18. The method according to claim 15, further characterized by administering a therapeutically effective amount of a second agent to the patient before, simultaneously with, or after administration of the compound, wherein the second agent is selected from a PD1 / PD-L1 antagonist, a CTLA4 antagonist, a chemotherapeutic agent, radiation, or an antitumor vaccine.

19. A method for reducing the protein levels of Ikaros, Helios, Aiolos, and Eos in cells, characterized by contacting the cells with a compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Images