Spiro-substituted oxoisoindolinyl piperidine-2, 6-dione compounds

Abstract

Disclosed are compounds of Formula I: I, or a stereoisomer, tautomer, or salt thereof. Also disclosed are methods of using such compounds to reduce the level of the IKZF1-4 protein; and a pharmaceutical composition comprising the compound. The compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer. (I)

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 506,618, filed June 7, 2023, which is incorporated herein in its entirety.

[0003] describe

[0004] This invention generally relates to spirocyclic-substituted oxoisoindolinylpiperidine-2,6-dione compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. This document provides spirocyclic-substituted oxoisoindolinylpiperidine-2,6-dione compounds, compositions comprising said compounds, and methods of use. The invention further relates to pharmaceutical compositions comprising compounds according to the invention, said pharmaceutical compositions being used to treat proliferative disorders such as cancer and viral infections. Background Technology

[0005] The Ikaros zinc finger family of transcription factors (TFs) plays a crucial role in lymphocyte development and function (Heizmann et al., 2018, Curr. Opin. Immunol. 51: 14-23). ​​In mammals, the following five members of this TF family are expressed in immune cells: Ikaros (encoded by IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). These proteins are highly homologous in amino acid sequences, with Ikaros and Aiolos, and Helios and Eos being the most homologous pairs, and Pegasus being the most distantly related IKZF member. These TFs have overlapping and unique functions in lymphocytes (Read et al., 2020, Immunological Reviews, 300:1). Decreased levels of IKZF TF proteins can enhance anti-tumor T cell responses.

[0006] IKZF1 encodes Ikaros, which is widely and abundantly expressed in human and mouse B, NK, and T lymphocyte populations, and moderately expressed in other immune cell types, including myeloid cells. In T cells, the loss of Ikaros protein or the expression of dominant or negative Ikaros proteins alleviates the suppression of loci associated with effector T cell state differentiation, leading to 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).

[0007] IKZF2 encodes Helios, which shows a more restricted expression profile limited to human and mouse regulatory T (Treg) cells, some 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).

[0008] IKZF3 encodes Aiolos, which is widely and abundantly expressed in human and mouse B lymphocytes, and extensively expressed at lower levels in T and NK cells. In T cells, the repressive targets of the Aiolos gene show significant overlap with those of Ikaros (Powell et al., 2019, Frontiers in Immunology, 10:1299). Compared to Ikaros, Aiolos may have a stronger effect on follicular helper T cell and T helper type 17 responses (Quintana et al., 2012, Nature Immunology, 13:770-777; Read et al., 2017 Journal of Immunology, 7:2377-2387), responses already involved in tissue immune responses and, in some cases, antitumor immunity.

[0009] IKZF4 encodes Eos, which is highly expressed in Treg cells and also widely expressed at low levels in B, NK, and T lymphocytes. In Treg cells, loss of Eos expression in FoxP3+ Treg cells drives improved antitumor responses in preclinical syngeneic tumor models (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Furthermore, in conventional CD4+ and CD8+ T cells, Eos expression levels can increase upon T cell activation, where this increase can limit effector T cell responses (Rieder et al., 2015, Journal of Immunology, 195:553-563).

[0010] The common function shared by IKZF TFs involves the repression of gene expression at specific loci in cells. IKZF TFs can bind to genomic loci in homodimer or heterodimer form (e.g., Ikaros:Ikaros or Ikaros:Helios, respectively). These dimeric TFs bind to DNA and interact with complexes that regulate histone acetylation and nucleosomes, thereby leading to the regulation of gene expression. Mechanistically, Ikaros, Helios, and Aiolos have each been shown to interact with nucleosome remodeling and deacetylase (NuRD) and Sin3 histone deacetylase (HDAC) complexes to repress gene expression (Zhang et al., 2011, Nature Immunology, 13:86-94; Georgopoulos et al., 2017, Genesand Development, 31:439-450). Similarly, Ikaros, Helios, and Aiolos can all associate with centromere heterochromatin and promote 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 collaborates with Ikaros but not with Aiolos to interact with the transcriptional repressor C-terminal binding protein 1 (CtBP1) in lymphocytes (Koipally et al., 2002, Journal of Biological Chemistry, 277:27697-27705; Pan et al., 2009, Science, 325:1142-1146). In summary, the overlapping functions of IKZF TFs can partially compensate for the loss or degradation of one or more TFs. Therefore, in cells expressing multiple IKZF members, extensive therapeutic degradation of this TF family is expected to drive stronger phenotypic changes compared to selective degradation of one or two IKZF TFs.

[0011] In T cells and Treg cells, the combined role of IKZF TFs in regulating important loci for anti-tumor immune responses is illustrated by regulating genes encoding interleukin-2 (IL-2). Ikaros can directly bind to the IL-2 locus in CD4+ T cells and recruit the HDAC complex; loss of Ikaros leads to increased IL-2 production by CD4+ and CD8+ T cells (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 binds directly to the IL-2 locus in Treg cells to recruit the HDAC complex and force IL-2 gene silencing (Blaine et al., 2013, Journal of Immunology, 190:1008-1016). Eos also inhibits IL-2 expression in Treg cells, and this can be achieved through a mechanism involving interaction with TF FoxP3 (Pan et al., 2009, Science, 325: 1142-1146; Sharma et al., 2013, Immunity, 38:998-1012). The role of direct binding of Aiolos in IL-2 loss is less clear, but knockdown of Aiolos siRNA in human Treg cells has been reported to increase IL-2 production (Gandhi et al., 2010, Nature Immunology, 11:846-853). In summary, IKZF TFs are used to regulate IL-2 production in multiple lymphocyte subtypes, particularly Treg cells, in which all four IKZF TFs are highly expressed and IL-2 production is usually negligible.

[0012] Treg cells, characterized by the expression of the transcription factor FoxP3, are a subset of immunosuppressive lymphocytes that utilize several 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 detrimental mutations in the gene encoding FoxP3 lack functional Treg cells and exhibit immune dysregulation, polyendocrine disorders, enteropathy, and IPEX syndrome (a multi-organ autoimmune disorder). In the tumor microenvironment (TME), Treg cell activity is supplemented to promote and maintain the immunosuppressive state (Plitas and Rudensky, 2020, Annual Review of Cancer Biology, 4:459-477). By secreting inhibitory molecules, chelating cytokines (e.g., IL-2), and directly inhibiting T cell and antigen-presenting cell activation, Treg cells can promote TME-mediated resistance to immunotherapy by modulating multiple axes in the cancer-immune cycle (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, ablation of Treg cells led to regression of established invasive tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

[0013] Once activated by specific antigens, Treg cells can suppress responding T cells in vitro in an antigen-nonspecific and bystander manner (Takahashi et al., 1998, Int Immunol. 10:1969-80; Thornton et al., 1998, JExp. Med. 188:287-96). FoxP3+CD25+CD4+Treg cells can suppress a broad range of antitumor immune responses involving CD4+ helper T cells, CD8+ T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, CellResearch 27:109-118). In preclinical models, depletion of intratumoral CD25+CD4+Treg cells can induce tumor regression, accompanied by alterations in the cytokine environment at the tumor site (Yu et al., 2005, J Exp Med. 201:779-91). Furthermore, the migration of CD4+ T cells depleted by Treg cells significantly enhanced the antitumor immune response compared to the migration of CD4+ T cells with sufficient Treg cells (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrating Treg cells activated by tumor-derived autoantigens or tumor-associated antigens can similarly suppress specific antitumor immune responses.

[0014] Clinically, increased Treg cell frequency in the tumor microenvironment (TME) is associated with poorer outcomes in various solid tumor indications (Shang et al., 2015, Scientific Reports, 5:15179). Furthermore, the correlation between PD-L1+ Treg cell frequency and response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC) patients (Wu et al., 2018, Journal of Thoracic Oncology, 13:521-532) highlights the therapeutic potential of Treg cell targeting in the TME. Regulating the activity of key factors controlling Treg cell differentiation and / or functional repressor status could represent a potential therapeutic strategy for certain diseases, including cancer and viral infections.

[0015] Furthermore, it has been reported that the removal of FoxP3+ Treg cells can enhance vaccine-induced anti-tumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767), suggesting that reducing Helios levels may be beneficial in improving the efficacy of cancer vaccines. In addition to anti-tumor immunotherapy, during viral infection, Tregs can limit immunopathology caused by excessive inflammation, but may suppress effective antiviral T cell responses and promote viral persistence (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). Chronic (but not acute) infection with lymphocytic choroid plexus meningitis virus in mice leads to a significant expansion of FoxP3+ Treg cells, suggesting a potential mechanism by which certain infectious agents can evade host immune responses by activating and expanding Treg cells (Punkosdy et al., 2011, PNAS 108: 3677-3682). In contexts associated with chronic viral infection, therapeutic benefits can be obtained by reducing Helios levels in activated Treg cells.

[0016] Targeting tumor Treg cells include antibody-mediated depletion and / or functional modulation (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146), and small molecule-mediated “reprogramming” of Treg cell immunosuppressive phenotypes by altering gene expression in these cells (Kim et al., 2015, Science, 350:334-339; Sebastian et al., 2016, Journal of Immunology, 196:144-155). Mice with Treg cells engineered to lack Helios do not develop IPEX-like immunopathology characterized by FoxP3 deficiency or complete Treg cell ablation, but instead have Treg cells exhibiting a more T-effector-like transcriptional program (Fu et al., 2012, Nature Immunology, 13: 972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). Importantly, Helios controls the activity of Treg cells, which is crucial in the TME, as mice with Helios-deficient Treg cells showed improved control over B16F10 and MC38 tumors (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Therefore, therapeutic modulation of Helios has the potential to reprogram tumor Treg cells to a more effector-like phenotype to drive anti-tumor immunity. Notably, in preclinical tumor models, Eos also drives immunosuppressive Treg cell activity in the TME, as mice lacking Eos expression in FoxP3 Treg cells more effectively control syngeneic tumors compared to controls (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Individuals with loss-of-germ IKZF2 mutations also do not exhibit IPEX-like symptoms (including diabetes, dermatitis, liver inflammation, and systemic lymphadenopathy), but instead display an immunophenotype associated with enhanced T cell activation and pro-inflammatory cytokine production (Hetemäki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981).These data suggest that reduced levels of Helios and Eos proteins in Treg cells will result in less suppression of antitumor T-cell responses in patients with solid tumors.

[0017] Small molecules that degrade Ikaros and Aiolos in Treg cells can also reduce the inhibitory function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In engineered mouse models, lenalidomide, an Ikaros and Aiolos degrader, can moderately increase antitumor immune responses against highly immunogenic syngeneic tumors (Geng et al., 2022, Cell Chemical Biology, 29:1260-1272). Ikaros and Aiolos-targeting degraders have also been clinically tested in patients with solid tumors, sometimes resulting in moderate responses in stable disease. These studies include avalidomide (CC-122) for the treatment of advanced malignancies (Rasco et al., 2019, ClinCancer Research, 25:90-98), lenalidomide (Semeraro et al., 2013, OncoImmunology, 2:11), and pomalidomide (Cooney et al., 2012, Cancer Chemotherapy and Pharmacology, 70, 755). Furthermore, lenalidomide has been shown to enhance T and NK cell function in preclinical and clinical studies (Hideshima et al., Leukemia, 2021; D'Souza et al., Frontiers in Immunology, 2021).

[0018] In summary, IKZF TFs, namely Ikaros, Helios, Aiolos, and Eos, are highly expressed in Treg cells. Compared to approaches that selectively target a single IKZF TF or TF pairs (i.e., Ikaros and Aiolos or Helios and Eos), the combined reduction of individual protein levels of these four TFs in Treg cells will better reverse immunosuppressive programs, including the inhibition of IL-2 transcription and other T cell effector genes. In addition to Treg cells, pan-IKZF1-4 degraders are expected to increase the function of conventional CD4+ and CD8+ T cell effectors and enhance NK cell activity to drive robust antitumor responses in patients.

[0019] Therapies that can reduce the levels of the four IKZF1-4 proteins—Ikaros, Helios, Aiolos, and Eos—are still needed.

[0020] This invention addresses the aforementioned need by providing compounds that can be used to reduce the levels of four IKZF1-4 proteins: Ikaros, Helios, Aiolos, and Eos. Summary of the Invention

[0021] The present invention provides a spirocyclic substituted oxoisoindolinylpiperidine-2,6-dione compound of formula (I), comprising its stereoisomers, tautomers, salts and prodrugs, said compound being used to reduce the levels of four proteins Ikaros, Helios, Aiolos and Eos.

[0022] The present invention also provides pharmaceutical compositions comprising a compound of formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.

[0023] The present invention also provides a method for treating a disease or disorder by reducing the levels of four IKZF1-4 proteins Ikaros, Helios, Aiolos and Eos, the method comprising administering to a patient a compound of formula (I), its stereoisomers, tautomers, pharmaceutically acceptable salts or prodrugs.

[0024] The present invention also provides methods and intermediates for preparing compounds of formula (I), their stereoisomers, tautomers or salts.

[0025] The present invention also provides the use of a compound of formula (I) or a stereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof for the manufacture of a medicament for reducing the levels of Ikaros, Helios, Aiolos and Eos proteins, said medicament for the treatment of certain diseases, including cancer and viral infections.

[0026] Compounds of formula (I) and compositions comprising compounds of formula (I) can be used to treat, prevent, or cure a variety of proliferative disorders, such as cancer. Pharmaceutical compositions comprising said compounds can be used to treat, prevent, or slow the progression of diseases or disorders in a variety of therapeutic areas, such as cancer.

[0027] Compounds of formula (I) and compositions comprising compounds of formula (I) can be used to treat, prevent, or cure viral infections. Pharmaceutical compositions comprising said compounds can be used to treat or prevent diseases or disorders such as viral infections or to slow the progression of said diseases or disorders.

[0028] As this disclosure continues, these and other features of the invention will be set forth in an expanded form. Detailed Implementation

[0029] The applicant has discovered spirocyclic-substituted oxoisoindolinylpiperidine-2,6-dione compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The substituted oxazolone compounds are believed to promote the interaction of Ikaros, Helios, Aiolos, and Eos proteins with their corresponding E3 ubiquitin ligase complexes (Cullin4-Cereblon, CUL4-CRBN), accompanied by the degradation of Ikaros, Helios, Aiolos, and Eos proteins. The compounds reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The compounds may be used to treat certain diseases, including cancer and viral infections. The provided compounds are intended for use as pharmaceuticals with desired stability, bioavailability, therapeutic index, and toxicity values ​​important for their druggability.

[0030] A first aspect of the present invention provides a compound of formula (I):

[0031] (I)

[0032] Or its stereoisomers, tautomers or salts.

[0033] One embodiment provides a compound of formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0034] One embodiment provides a compound of formula (I) or a stereoisomer or tautomer thereof.

[0035] One embodiment provides a salt of a compound of formula (I) or a stereoisomer or tautomer thereof.

[0036] One embodiment provides a pharmaceutically acceptable salt of a compound of formula (I) or a stereoisomer or tautomer thereof.

[0037] One embodiment provides a compound of formula (I) or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0038] One embodiment provides a compound of formula (I) or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0039] One embodiment provides a compound of formula (I) having the following structure:

[0040]

[0041] Or its stereoisomers, tautomers or salts.

[0042] One embodiment provides a compound of formula (I) having the following structure:

[0043]

[0044] Or its stereoisomers, tautomers or salts.

[0045] One embodiment provides a compound of formula (I) having the following structure:

[0046]

[0047] Or its stereoisomers, tautomers or salts.

[0048] Compounds of formula (I) or their stereoisomers, tautomers or salts can be used to reduce the levels of four IKZF1-4 proteins: Ikaros, Helios, Aiolos and Eos.

[0049] As used herein, “reducing” the level of one of the IKZF1-4 proteins means reducing the protein level by degradation and / or inactivation and / or inhibition and / or reduction of the expression level of the protein or a combination thereof, compared to the initial protein level prior to contact with or treatment with a compound of formula (I) or its stereoisomers, tautomers or salts.

[0050] The reduction in protein levels of IKZF1-4 protein can be measured using various methods, including the following assays described below: (i) IKZF1: human CD8 + (ii) T cell reprogramming assay; (iii) IKZF2:Jurkat cell degradation assay; + (iv) IKZF4: Human T Regulatory Cell Reprogramming Assay;

[0051] The invention may be embodied in other specific forms without departing from the spirit or essential attributes of the invention. The invention encompasses all combinations of aspects and / or embodiments of the invention described herein. It should be understood that any and all embodiments of the invention may be combined with any other one or more embodiments to describe further embodiments. It should also be understood that each individual element in the embodiments is intended to be combined with any and all other elements from any embodiment to describe further embodiments.

[0052] By reading the following detailed description, those skilled in the art will more readily understand the features and advantages of the invention. It should be understood that, for clarity, certain features of the invention described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be combined to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative rather than restrictive.

[0053] Unless otherwise expressly stated herein, references to the singular may also include the plural. For example, “a” and “an” can refer to one or more or more.

[0054] As used herein, the phrase “compound and / or salt thereof” means a compound, at least one salt of said compound, or a combination thereof. For example, a compound of formula (I) and / or salt thereof includes a compound of formula (I); a salt of a compound of formula (I); a compound of formula (I) and one or more salts of a compound of formula (I); and two or more salts of a compound of formula (I).

[0055] Unless otherwise indicated, any atom with an unsaturated valence is assumed to have a hydrogen atom that satisfies the valence.

[0056] The definitions set forth herein take precedence over those set forth in any patent, patent application and / or patent application publication incorporated herein by reference.

[0057] The following are definitions of various terms used to describe the present invention. These definitions apply to terms used alone throughout the specification or as part of a larger group (unless otherwise limited in specific cases).

[0058] Throughout the specification, those skilled in the art can select its groups and substituents to provide stable moieties and compounds.

[0059] According to the conventions used in this field,

[0060]

[0061] To describe the bond as a part or substituent attachment point to the core or skeletal structure.

[0062] The term "amino" refers to the -NH2 group.

[0063] The term "oxo" refers to the =O group.

[0064] The compounds of this invention comprise all isotopes of the atoms present in the compounds of this invention. Isotopes include atoms that have the same number of atoms but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include... 13 C and 14 C. The isotopically 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 appropriate isotopically labeled reagents instead of the originally used unlabeled reagents.

[0065] As used herein, the term "tautomer" refers to each of two or more isomers of a compound, which exist together in equilibrium and are readily interchangeable by the migration of atoms or groups within the molecule. For example, those skilled in the art will readily understand that 1,2,3-triazole exists in two tautomeric forms as defined above:

[0066] .

[0067] Therefore, this disclosure is intended to cover all possible tautomers, even when the structure describes only one of them. For example, compounds of formula (I) can exist in tautomer form:

[0068]

[0069]

[0070] Another example of tautomerism includes:

[0071]

[0072] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that, to the extent of reasonable medical judgment, are suitable for contact with tissues in humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0073] Compounds of formula (I) can form salts, which are also within the scope of this invention. Unless otherwise indicated, reference to compounds of this invention should be understood to include reference to one or more of their salts. The term "one or more salts" means an acidic salt formed with an inorganic acid and / or an organic acid. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred. However, other salts may be used, for example, in separation or purification steps that may be employed during preparation, and are therefore contemplated within the scope of this invention. Salts of compounds of formula (I) can be formed, for example, by reacting a compound of formula (I) with an amount (e.g., an equivalent amount) of an acid in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, followed by lyophilization.

[0074] Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionate, diglucuronide, dodecyl sulfate, ethanesulfonate, fumarate, glucohepanoate, glycerophosphates, hemisulfates, heptarates, hexanoates, hydrochlorides (forming with hydrochloric acid), hydrobromide (forming with hydrogen bromide), hydroiodides, and maleates. (Forms with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (forms with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, salicylate, succinate, sulfate (such as those that form with sulfuric acid), sulfonate (such as those mentioned in this article), tartrate, thiocyanate, toluenesulfonate (such as tosylate), undecanoate, etc.

[0075] The compound of formula (I) can be provided as an amorphous solid or a crystalline solid. Lyophilization can be used to provide the compound of formula (I) as a solid.

[0076] It should be further understood that solvates (e.g., hydrates) of compounds of formula (I) are also within the scope of this invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more solvent molecules (whether organic or inorganic). This physical association contains hydrogen bonds. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both the solution phase and the separable solvate. Exemplary solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Solvation methods are known in the art.

[0077] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0078] Furthermore, the prepared compound of formula (I) can be isolated and purified to obtain a composition containing an amount equal to or greater than 99% by weight of the compound of formula (I) (“substantially pure”), which can then be used or formulated as described herein. Such “substantially pure” compounds of formula (I) are also considered herein as part of the invention.

[0079] "Stable compound" and "stable structure" are intended to indicate that a compound is robust enough to withstand separation from the reaction mixture to a useful level of purity and to be formulated into an effective therapeutic agent. This invention aims to implement stable compounds.

[0080] The terms “IKZF1 degrader” and “Ikaros degrader” refer to agents that can reduce the level of IKZF1 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of IKZF1 protein or a combination thereof.

[0081] The terms “IKZF2 degrader” and “Helios degrader” refer to agents that can reduce the level of IKZF2 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of IKZF2 protein or a combination thereof.

[0082] The terms “IKZF3 degrader” and “Aiolos degrader” refer to agents that can reduce the level of IKZF3 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of IKZF3 protein or a combination thereof.

[0083] The terms “IKZF4 degrader” and “Eos degrader” refer to agents that can reduce the level of IKZF4 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of IKZF4 protein or a combination thereof.

[0084] The term "IKZF1-4 protein" refers to the proteins Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and Eos (IKZF4).

[0085] The term "pan-IKZF1-4 degrader" refers to a drug that can reduce the protein levels of four IKZF1-4 proteins: Ikaros, Helios, Aiolos, and Eos.

[0086] As used in this article, the “Ikaros” protein is 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, lymphocyte 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 allotropes encoded by the following human allotropes listed below.

[0087] Alien 1 (UniPro Q13422-1)

[0088] MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVASNVKVETQSDEENGRACEMNGEECAEDLRMLDASGEKMNGSHRDQGSSALSGVGGIRLPNGKLKCDICGIICIGP NVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSVGKPHKCGYCGRSYKQRSSLEEHKERCHNYLESMGLPGTLYPVIKEETNHSEMAEDLCKIGSE RSLVLDRRLASNVAKRKSSMPQKFLGDKGLSDTPYDSSASYEKENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPRSNHSAQDSAVENLLLLSKAKLVPSEREAS PSNSCQDSTDTESNNEEQRSGLIYLTNHIAPHARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIHMGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS (SEQ ID NO: 1)

[0089] Alien 2 (UniProt Q13422-2)

[0090] MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVGERP FQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSVGKPHKCGYCGRSYKQRSSLEEHKERCHNYLESMGLPGTLYPVIKEETNHSEMAEDLCKIGSERSLVLDRLASNVAKRKSSMPQKFLGDKGLSDTPYDSSASYEKENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPRSNHSAQDSAVENLLLLSKAKLVPSEREASPSNSCQDSTDTESNNEEQRSGLIYLTNHIAPHARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIHMGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS (SEQ ID NO: 2)

[0091] Isoform 3 (UniProt Q13422-3)

[0092] MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVASNVKVETQSDEENGRACEMNGEECAEDLRMLDASGEKMNGSHRDQGSSALSGVGGIRLPNGKLKCDICGIICIGPNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSGDKGLSDTPYDSSASYEKENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPRSNHSAQDSAVENLLLLSKAKLVPSEREASPSNSCQDSTDTESNNEEQRSGLIYLTNHIAPHARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIHMGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS (SEQ ID NO: 3)

[0093] Isoform 4 (UniProt Q13422-4)

[0094] MDADEGQDMASNVKVETQSDEENGRACEMNGEECAEDLRMLDASGEKMNGSHRDQGSSALSGVGGIRLPNGKLKCDICGIICIGPNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSGDKGLSDTPYDSSASYEKENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPRSNHSAQDSAVENLLLLSKAKLVPSEREASPSNSCQDSTDTESNNEEQRSGLIYLTNHIAPHARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIHMGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS (SEQ ID NO: 4)

[0095] Isoform 7 (UniProt Q13422-7)

[0096] MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVASNVKVETQSDEENGRACEMNGEECAEDLRMLDASGEKMNGSHRDQGSSALSGVGGIRLPNGKLKCDICGIICIGPNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSVIKEETNHSEMAEDLCKIGSERSLVLDRLASNVAKRKSSMPQKFLGDKGLSDTPYDSSASYEKENEMMKSHVMDQAINNAINYLGAESLRPLVQTPPGGSEVVPVISPMYQLHKPLAEGTPRSNHSAQDSAVENLLLLSKAKLVPSEREASPSNSCQDSTDTESNNEEQRSGLIYLTNHIAPHARNGLSLKEEHRAYDLLRAASENSQDALRVVSTSGEQMKVYKCEHCRVLFLDHVMYTIHMGCHGFRDPFECNMCGYHSQDRYEFSSHITRGEHRFHMS (SEQ ID NO: 5)

[0097] UniProt Q13422-8

[0098] MDADEGQDMSQVSGKESPPVSDTPDEGDEPMPIPEDLSTTSGGQQSSKSDRVVASNVKVETQSDEENGRACEMNGEECAEDLRMLDASGEKMNNGSHRDQGSSALSGVGGIRLP NGKLKCDICGIICIGPNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHSGEKPFKCHLCNYACRRRDALTGHLRTHSVIKEETNHSEMAEDLCKIGSEISRAGQTSK (SEQ ID NO: 6)

[0099] The “Eos” protein isoforms 1, 2, 3, 4, 7, and 8 listed above include the degradation determinant FQCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 22), which is identical to the degradation determinant of the “Aiolos” protein. The Ikaros protein also includes isoforms encoded by the amino acid sequences Q13422-5 and Q13422-6.

[0100] As used herein, "Helios" protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. 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. As used herein, Helios protein includes several variants, including those listed below.

[0101] Alien 1 (UniProt Q9UKS7-1)

[0102] METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDH\ / MYT IHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 7)

[0103] Variant 2 (UniProt Q9UKS7-2)

[0104] METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHT / MYTIHMGCHGYRDPLECNICGYRSQDRYE FS SHIVRG EHTFH (SEQ ID NO: 8)

[0105] Variant 4 (UniProt Q9UKS7-4)

[0106] METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 9)

[0107] Isoform 6 (UniProt Q9UKS7-6)

[0108] METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHDS (SEQ ID NO: 10)

[0109] Isoform 7 (UniProt Q9UKS7-7)

[0110] METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP FHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCSYACRRRDALLTGHLRTHSVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHF DMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSES SHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 11)

[0111] The Helios variants 1, 2, 4, 6, and 7 listed above include the degradation determinant FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 23). Degradation determinants are parts of a protein that play a role in regulating the rate of protein degradation. The Helios protein also includes variants encoded by the amino acid sequences Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0112] As used in this article, the "Aiolos" protein is encoded by the IKZF3 gene. Aiolos proteins are also known as IKAROS family zinc finger 3, ZNFN1A3, zinc finger protein subfamily 1A,3, Ikaros family zinc finger protein 3, and AIO. Aiolos proteins include the following human allotypes:

[0113] Alien 1 (UniProt Q9UKT9-1)

[0114] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGDDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSVEKPYKCEFCGRSYKQRSSLEEHKERCRTFLQSTDPGDTASAEARHIKAEMGSERALVLDRLASNVAKRKSSMPQKFIGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 12)

[0115] Isoform 3 (UniProt Q9UKT9-3)

[0116] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGDDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSASAEARHIKAEMGSERALVLDRLASNVAKRKSSMPQKFIGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 13)

[0117] Isoform 4 (UniProt Q9UKT9-4)

[0118] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGDDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSVEKPYKCEFCGRSYKQRSSLEEHKERCRTFLQSTDPGDTGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 14)

[0119] Isoform 6 (UniProt Q9UKT9-6)

[0120] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGDDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 15)

[0121] Isoform 7 (UniProt Q9UKT9-7)

[0122] MEDIQTNAELKSTQEQSVPADDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSVEKPYKCEFCGRSYKQRSSLEEHKERCRTFLQSTDPGDTASAEARHIKAEMGSERALVLDRLASNVAKRKSSMPQKFIGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 16)

[0123] Isoform 8 (UniProt Q9UKT9-8)

[0124] MEDIQTNAELKSTQEQSVPADDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCISFNVLMVHKRSHTGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSASAEARHIKAEMGSERALVLDRLASNVAKRKSSMPQKFIGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO:17)

[0125] Variant 9 (UniProt Q9UKT9-9)

[0126] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGGERPFQCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSVEKPYKCEFCGRSYKQRSSLEEHKERCRTFLQSTDPGDTASAEARHIKAEMGSERALVLDRLASNVAKRKSSMPQKFIGEKRHCFDVNYNSSYMYEKESELIQTRMMDQAINNAISYLGAEALRPLVQTPPAPTSEMVPVISSMYPIALTRAEMSNGAPQELEKKSIHLPEKSVPSERGLSPNNSGHDSTDTDSNHEERQNHIYQQNHMVLSRARNGMPLLKEVPRSYELLKPPPICPRDSVKVINKEGEVMDVYRCDHCRVLFLDYVMFTIHMGCHGFRDPFECNMCGYRSHDRYEFSSHIARGEHRALLK (SEQ ID NO: 18)

[0127] Alien 14 (UniProt Q9UKT9-14)

[0128] MEDIQTNAELKSTQEQSVPAESAAVLNDYSLTKSHEMENVDSGEGPANEDEDIGDDSMKVKDEYSERDENVLKSEPMGNAEEPEIPYSYSREYNEYENIKLERHVVSFDSSRPTSGKMNCDVCGLSCIFNVLMVHKRSHTGERP F QCNQCGASFTQKGNLLRHIKLHTGEKPFKCHLCNYACQRRDALTGHLRTHSVEKPYKCEFCGRSYKQRSSLEEHKERCRTFLQSTDPGDTGTGWGWVELSHLGIRLQDLNVPWCRLH (SEQ ID NO: 19)

[0129] The “Aiolos” protein subtypes 1, 3, 4, 6, 7, 8, 9, and 14 listed above include the degradation determinant FQCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 24), which is identical to the degradation determinant of the “Ikaros” protein. The Aiolos protein also includes an variant encoded by the amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0130] As used in this article, the “Eos” protein is encoded by the IKZF4 gene, also known as IKAROS family zinc finger 4, ZNFNlA4, zinc finger protein subfamily 1A,4, Ikaros family zinc finger protein 4, and KIAAl782. The “Eos” protein includes variants encoded by two human variants: 1 (Q9H2S9-1) and 2 (Q9H2S9-2).

[0131] Alien 1 (UniProt Q9H2S9-1)

[0132] MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFIMESLFCESSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGWSLPQGPPPQPPPTIWGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRWGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 20)

[0133] Variant 2 (UniProt Q9H2S9-2)

[0134] MDSRYLQLQLYLPSCSLLQGSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVC GMVCIGPNVLMVHKRSHTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQ PGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLP GRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGWSLPQGPPPQPPPTIWGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRWGESGEPVKAFKCEHCR ILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 21)

[0135] The “Eos” protein isomorphs 1 and 2 listed above include the degradation determinant FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 25), which is the same as the degradation determinant of the “Helios” protein.

[0136] As used in this article, the "Pegasus" protein 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.

[0137] As used herein, the term "contact" means bringing together the indicated portions of an in vitro or in vivo system. For example, "contacting" the IKZF1-4 protein with a compound of formula (I) includes administering the compound of the invention to an individual or patient (e.g., a human) having Ikaros, Helios, Aiolos, and Eos proteins, and, for example, introducing a compound of formula (I) into a sample containing a cell preparation or purified formulation containing Ikaros, Helios, Aiolos, and Eos proteins.

[0138] As used herein, the terms “treat,” “treating,” and “treatment” refer to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, with the aim of reversing, reducing, improving, inhibiting, or slowing down or preventing the progression, development, severity, or recurrence of symptoms, complications, symptom patterns, or disease-related biochemical indicators. In contrast, “prophylaxis” or “prevention” refers to administration to a subject who does not have a disease to prevent the onset of the disease. “Treatment,” “treating,” and “treatment” do not encompass “prophylaxis” or “prevention.”

[0139] "Therapeutic effective amount" is intended to include the amount of the compound of the invention alone, or the amount of the compound of the invention in combination with other active ingredients, which effectively reduce the level of IKZF1-4 protein in cells or effectively treat or prevent viral infections and proliferative disorders (such as cancer).

[0140] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells may be part of a tissue sample excised from an organism (such as a mammal). In some embodiments, ex vivo cells may be cells in a cell culture. In some embodiments, in vivo cells are cells living in an organism (such as a mammal).

[0141] The term "patient" includes human subjects.

[0142] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, magnesium talc, calcium stearate, zinc stearate, or stearic acid), or solvent encapsulating material, which participates in carrying or transporting the subject compound from one organ or body part to another. Each carrier must be “acceptable” in the sense that it is compatible with other components of the formulation, including adjuvants, excipients, or mediators such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispensing agents, depending on the manner of administration and the nature of the dosage form; and is harmless to the patient.

[0143] The term "pharmaceutical composition" means a composition comprising a combination of the compounds of the present invention with at least one other pharmaceutically acceptable carrier.

[0144] practicality

[0145] The compound of formula (I) can be used to treat cancer.

[0146] The compound of formula (I) can be used to treat viral infections.

[0147] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0148] In one embodiment, a method for treating a patient with a viral infection is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0149] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound having the following structure:

[0150]

[0151] Or its stereoisomers, tautomers or pharmaceutically acceptable salts.

[0152] One aspect provides a method for treating a disease or disorder by reducing levels of four IKZF1-4 proteins: Ikaros, Helios, Aiolos, and Eos. The method comprises administering a therapeutically effective amount of an agent to a patient 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 a pharmaceutically acceptable salt.

[0153] In one embodiment, a method for treating a disease or disorder in a patient is provided, the method comprising 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 an amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; b) the Helios protein is an 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 NO: 12, 13, 14, 15, 16, 17, 18, or 19; and d) the Eos protein is an amino acid sequence encoded by SEQ ID NO: 20 or 21.

[0154] In embodiment 1, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0155] In embodiment 2, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0156] In embodiment 3, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0157] In embodiment 4, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0158] In embodiment 5, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0159] In embodiment 6, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0160] In embodiment 7, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0161] In embodiment 8, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0162] In embodiment 9, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0163] In embodiment 10, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0164] In embodiment 11, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0165] In embodiment 12, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0166] In embodiment 13, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0167] In embodiment 14, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0168] In embodiment 15, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0169] In embodiment 16, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0170] In embodiment 17, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0171] In embodiment 18, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0172] In embodiment 19, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0173] In embodiment 20, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0174] In embodiment 21, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0175] In embodiment 22, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0176] In embodiment 23, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0177] In embodiment 24, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0178] In embodiment 25, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0179] In embodiment 26, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0180] In embodiment 27, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0181] In embodiment 28, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0182] In embodiment 29, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0183] In embodiment 30, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0184] In embodiment 31, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0185] In embodiment 32, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 70%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0186] In embodiment 33, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0187] In embodiment 34, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 40% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by 40% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0188] In embodiment 35, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0189] In embodiment 36, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0190] In embodiment 37, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0191] In embodiment 38, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 70%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0192] In embodiment 39, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0193] In embodiment 40, a method for treating a patient's disease or disorder is provided, the method comprising administering to the patient a therapeutically effective amount of an agent to reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein: (i) the Ikaros (IKZF1) protein level is reduced by 50% to 70%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by 50% to 70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 90%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. Additionally, this embodiment includes a method wherein the agent is a compound of formula (I), its stereoisomers, tautomers, or a pharmaceutically acceptable salt.

[0194] In embodiments 1 to 40, the decrease in protein levels of IKZF1-4 protein can be measured using the following assays: (i) IKZF1: human CD8 + (ii) IKZF2: Human regulatory T cell reprogramming assay; (iii) IKZF3: Human CD8 + (iv) IKZF4: Human regulatory T cell reprogramming assay.

[0195] Types of cancer that can be treated with compounds of formula (I) include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer, and bone cancer. Examples of such cancer types include neuroblastoma, colorectal cancer (such as rectal cancer, colon cancer, anal cancer, common adenomatous polyposis carcinoma, and hereditary nonpolyposis colorectal cancer), esophageal cancer, nasopharyngeal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, thymic cancer, esophageal and gastric cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), and Hodgkin's tumor. Golden lymphoma, non-Hodgkin lymphoma, Burkily 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 carcinoma, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0196] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is melanoma.

[0197] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0198] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is mesothelioma.

[0199] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, including 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.

[0200] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is prostate cancer, including prostate adenocarcinoma and castration-resistant prostate cancer.

[0201] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, including pancreatic adenocarcinoma, exocrine pancreatic cancer, and neuroendocrine pancreatic cancer.

[0202] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is renal cancer, including renal cell carcinoma, clear cell renal cell carcinoma, non-clear cell renal cell carcinoma, papillary renal cell carcinoma, nephroblastoma, and renal sarcoma.

[0203] In one embodiment, a method for treating a patient with cancer is provided, comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is gastric cancer, including gastric carcinoma.

[0204] In one embodiment, a method for treating a patient with cancer is provided, comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is kidney cancer, including renal carcinoma and renal parenchymal carcinoma.

[0205] In one embodiment, a method for treating a patient with cancer is provided, comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is liver cancer, including hepatocellular carcinoma.

[0206] In one embodiment, a method for treating a patient with cancer is provided, comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, including ovarian carcinoma.

[0207] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is a lymphoma, including Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL).

[0208] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is leukemia, including acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0209] In one embodiment, a method for treating a patient with cancer is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is multiple myeloma.

[0210] Compounds of formula (I) and pharmaceutical compositions containing compounds of formula (I) may be used to treat or prevent any disease or condition associated with the activity of the IKZF1-4 protein. These diseases or conditions include viral infections and other infections (e.g., skin infections, GI infections, urinary tract infections, genitourinary infections, systemic infections) and proliferative diseases (e.g., cancer). The compound or pharmaceutical composition may be delivered to a patient using any method of administration. In some embodiments, the compound of formula (I) or the pharmaceutical composition containing a compound of formula (I) is administered orally. In other embodiments, the compound of formula (I) or the pharmaceutical composition containing a compound of formula (I) is administered parenterally.

[0211] In one embodiment, a method for treating a patient with a viral infection is provided, the method comprising administering to the patient a therapeutically effective amount of a compound according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the viral infection is caused by exposure to viruses including: HIV, hepatitis A, B, or C, herpesviruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, EBV), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, Coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arbovirus encephalitis virus.

[0212] Compounds of Formula (I) can selectively reduce the protein levels of four IKZF1-4 proteins in cells to control Treg differentiation and / or immune regulatory status. For example, compounds of Formula (I) can be used to selectively reduce the protein level of each of the four IKZF1-4 proteins in cells, reduce the activity level of said proteins, and / or inhibit the expression level of said proteins by administering an effective amount of the compound of Formula (I) or its stereoisomers, tautomers, or salts, to control Treg differentiation and / or immune regulatory status in cells or individuals where it is necessary to reduce the protein level of each of the four IKZF1-4 proteins, reduce the activity level of said proteins, and / or inhibit the expression level of said proteins.

[0213] In one embodiment, the present invention provides a combination formulation of a compound of formula (I) and / or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents, said combination formulation for simultaneous, separate, or sequential use in the treatment and / or prevention of a variety of diseases or disorders associated with the activity of IKZF1-4 proteins. The combination formulation can be used to reduce the protein level of each of the four IKZF1-4 proteins, reduce the activity level of said proteins, and / or inhibit the expression level of said proteins.

[0214] In one aspect, the compound of formula (I) is administered sequentially before the administration of an immuno-oncology agent. In another aspect, the compound of formula (I) is administered concurrently with an immuno-oncology agent. In yet another aspect, the compound of formula (I) is administered sequentially after the administration of an immuno-oncology agent.

[0215] In another aspect, compounds of formula (I) can be co-formulated with immuno-oncology agents.

[0216] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological molecules or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one respect, antibodies are monoclonal antibodies. In another respect, monoclonal antibodies are humanized or human-derived.

[0217] In one respect, immuno-oncology agents are either (i) agonists of receptors that stimulate (including co-stimulatory) or (ii) antagonists of inhibitory (including co-inhibitory) signals on T cells, both of which lead to amplification of antigen-specific T cell responses (commonly referred to as immune checkpoint modulators).

[0218] Some stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which 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 co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the homologous 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, RANK, and RAN. KL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR 3. EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0219] In one aspect, T cell responses can be stimulated by a compound of formula (I) and a combination of one or more of the following: (i) antagonists (e.g., immune checkpoint inhibitors) that inhibit T cell-activated proteins such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactagogue 9, CEACAM-1, BTLA, CD69, galactagogue-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) agonists that stimulate T cell-activated proteins such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0220] Other agents that can be combined with compounds of formula (I) for the treatment of cancer include antagonists of receptors that inhibit NK cells or agonists of receptors that activate NK cells. For example, compounds of formula (I) can be combined with antagonists of KIRs, such as lirilumab.

[0221] Other agents used in combination therapy include agents that inhibit or deplete macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0222] In another aspect, the compound of formula (I) may be used in conjunction with one or more of the following: an agonist that connects to a positive co-stimulatory receptor, an inhibitor that attenuates signal transduction via an inhibitory receptor, an antagonist, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor binding (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or depleting them via ex vivo anti-CD25 beads), inhibiting metabolic enzymes (e.g., IDO), or reversing / preventing T cell anergy or exhaustion), and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0223] In one aspect, immuno-oncology agents are CTLA-4 antagonists, such as antagonistic CTLA-4 antibodies. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0224] On the other hand, immuno-oncology agents are PD-1 antagonists, such as antagonistic PD-1 antibodies. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), LIBTAYO (cimiprizumab), JEMPERLI (dotalipimab), and ZYNYZ (refulimab). Immuno-oncology agents may also include pidilimumab (CT-011), although its specificity for PD-1 binding is questionable. Another approach to targeting the PD-1 receptor is a recombinant protein called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0225] On the other hand, immuno-oncology agents are PD-L1 antagonists, such as antagonistic PD-L1 antibodies. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), duvarubib (MEDI4736), BMS-936559 (WO 207 / 005874), MSB0010718C (WO2013 / 79174), TECENTRIQ (atezolizumab), and BAVENCIO (atezolizumab).

[0226] On the other hand, immuno-oncology agents are LAG-3 antagonists, such as antagonistic LAG-3 antibodies. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0227] On the other hand, immuno-oncology agents are CD137 (4-1BB) agonists, such as agonist CD137 antibodies. Suitable CD137 antibodies include, for example, uroselumab and PF-05082566 (WO12 / 32433).

[0228] On the other hand, immuno-oncology agents are GITR agonists, such as GITR-stimulating antibodies. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0229] On the other hand, immuno-oncology agents are IDO antagonists. Suitable IDO antagonists include, for example, INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0230] On the other hand, immuno-oncology agents are OX40 agonists, such as agonistic OX40 antibodies. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0231] On the other hand, immuno-oncology agents are OX40L antagonists, such as antagonistic OX40 antibodies. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0232] In another aspect, immuno-oncology agents are CD40 agonists, such as agonist CD40 antibodies. In yet another embodiment, immuno-oncology agents are CD40 antagonists, such as antagonist CD40 antibodies. Suitable CD40 antibodies include, for example, rucatumumab or dasatumumab.

[0233] On the other hand, immuno-oncology agents are CD27 agonists, such as agonist CD27 antibodies. Suitable CD27 antibodies include, for example, varlilumab.

[0234] On the other hand, the immuno-oncology agent is MGA271 (targeting B7H3) (WO11 / 109400).

[0235] On the other hand, immuno-oncology agents are anti-TIGIT agents. Suitable anti-TIGIT agents include antibodies such as BMS-986207, tilagomalumab, or MK-7684.

[0236] On the other hand, immuno-oncology agents are KRAS G12C inhibitors. Suitable KRAS G12C inhibitors include LUMAKRAS (sottorazib) or KRAZATI (adagrasisib).

[0237] Combination therapy is intended to include the sequential administration of these therapeutic agents (i.e., each therapeutic agent is administered at different times) and the substantially simultaneous administration of these therapeutic agents, or at least two of these therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering a single dosage form of each therapeutic agent to the subject at a fixed ratio, or by administering multiple single dosage forms (for each therapeutic agent). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered via the same route or via different routes. For example, the first therapeutic agent of a selected combination can be administered via intravenous injection, while the other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or via intravenous injection. Combination therapy may also include further administration of the therapeutic agents as described above in combination with other bioactive ingredients and non-pharmacological therapies (e.g., surgical or radiation therapy). Where the combination therapy further includes non-pharmacological treatment, the non-pharmacological treatment can be administered at any suitable time, provided that a beneficial effect is achieved from the combined action of the therapeutic agents and the non-pharmacological treatment. For example, in appropriate circumstances, the aforementioned beneficial effects can still be achieved when non-pharmacological treatments are temporarily removed from the administration of the therapeutic agent (perhaps for several days or even weeks).

[0238] One or more other agents or treatments (e.g., antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (e.g., IL-2 and GM-CSF), and / or tyrosine kinase inhibitors) may optionally be combined with compounds of formula (I) for the treatment of diseases, disorders, or conditions related to the IKZF1-4 protein. The agents may be combined with the compounds of the present invention in a single dosage form, or the agents may be administered simultaneously or sequentially as separate dosage forms.

[0239] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including but not limited to nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazine), such as uracil nitrogen mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, piperobromidine, triethylene melamine, triethylene thiophosphamide, busulfan, carmustine, lomustine, streptozotocin, dacarbazine, and temozolomide.

[0240] In the treatment of melanoma, suitable agents used in combination with compounds of formula (I) include: dacarbazine (DTIC), optionally, in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen," consisting of DTIC, BCNU, cisplatin, and tamoxifen; and combinations of cisplatin, vincristine, and DTIC, temozolomide, or YERVOY™. In the treatment of melanoma, compounds of formula (I) may also be combined with immunotherapy agents, including cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF).

[0241] Compounds of formula (I) can also be combined with vaccine therapy for the treatment of melanoma. Anti-melanoma vaccines are in some respects similar to antiviral vaccines used to prevent viral diseases (poliomyelitis, measles, and mumps). Weakened melanoma cells, or portions of melanoma cells, called antigens, can be injected into the patient to stimulate the body's immune system to recognize and destroy the melanoma cells.

[0242] Hyperthermia-isolated limb perfusion techniques can also be used to treat melanoma limited to the arm or leg with a combination of agents including compounds of formula (I). This treatment regimen temporarily isolates the circulation of the affected limb from the rest of the body and injects a high dose of chemotherapy into the arteries supplying the limb, thus delivering a high dose to the tumor area without exposing internal organs to doses that would otherwise cause serious side effects. Typically, the fluid is warmed to 38.9ºC to 40ºC. Melphalan is the most commonly used drug in this chemotherapy. It can be administered in combination with another agent called tumor necrosis factor (TNF).

[0243] Suitable chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (including but not limited to folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, fluorouracil, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0244] Suitable chemotherapeutic agents or other anticancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxin), such as vincristine, vinblastine, bleomycin, danomycin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), scintillans, deoxyco-formycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0245] Other cytotoxic agents include navelbene, CPT-11, anastrozole, letrozole, capecitabine, and droloxafine.

[0246] Also suitable are cytotoxic agents, such as epidophyllotoxin; antitumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes, such as cisplatin and carboplatin; biological response modifiers; growth inhibitors; anti-hormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0247] One or more other anticancer agents include antibody therapeutics such as trastuzumab (HERCEPTIN®), antibodies against co-stimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies against cytokines such as IL-10 or TGF-β.

[0248] Other anticancer agents include those that block the migration of immune cells, such as antagonists of chemokine receptors (including CCR2 and CCR4).

[0249] Other anticancer agents include those that enhance the immune system, such as through helper or adoptive T-cell transfer.

[0250] Cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines, and recombinant viruses.

[0251] The pharmaceutical compositions of the present invention may optionally comprise at least one signal transduction inhibitor (STI). A “signal transduction inhibitor” is an agent that selectively inhibits one or more important steps in the signal transduction pathways in the normal function of cancer cells, thereby leading to apoptosis. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors, such as STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors, such as kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: ​​C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)] and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors, such as farnesyltransferase inhibitors (FTIs), such as L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) Akt family kinases or Akt pathway inhibitors, such as rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (200)); (v) Cell cycle kinase inhibitors, such as frappindo and UCN-O1 (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203)); and (vi) phosphatidylinositol kinase inhibitors, such as LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and a compound of formula (I) may be in a separate pharmaceutical composition. In specific embodiments of the invention, a compound of formula (I) and at least one STI may be administered to a patient in parallel or sequentially. In other words, a compound of formula (I) may be administered first, at least one STI may be administered first, or a compound of formula (I) and at least one STI may be administered simultaneously. Additionally, when using a compound of formula (I) and / or more than one STI, the compounds may be administered in any order.

[0252] The present invention further provides a pharmaceutical composition for treating a patient with a chronic viral infection, the pharmaceutical composition comprising a compound of formula (I) in a pharmaceutically acceptable carrier, optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent.

[0253] A method for treating a patient’s chronic viral infection by administering an effective amount of the above pharmaceutical composition is also provided.

[0254] In specific embodiments of the invention, the compound of formula (I) and at least one chemotherapeutic agent can be administered to the patient in parallel or sequentially. In other words, the compound of formula (I) can be administered first, at least one chemotherapeutic agent can be administered first, or the compound of formula (I) and at least one STI can be administered simultaneously. Furthermore, when more than one chemotherapeutic agent is used, the compound and the more than one chemotherapeutic agent can be administered in any order. Similarly, any antiviral agent or STI can be administered at any point compared to the administration of the compound of formula (I).

[0255] Chronic viral infections that can be treated using the combination therapy of the present 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, Coxsackie virus, and human immunodeficiency virus (HIV).

[0256] Suitable antiviral agents to be considered for use in combination with compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0257] Examples of suitable NRTIs include zidovudine (AZT); didanoxin (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2',3'-dicleoxy-5-fluorocytidine); DAPD ((-)-β-D-2,6-diaminopurine dioxolane); and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587); deraviridine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinidone); and (+)-succinyl lactone A (NSC-675451)) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); ampravir (141W94); lacinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum (project number 11607).

[0258] Combination therapy is intended to include the sequential administration of these therapeutic agents (i.e., each therapeutic agent is administered at different times) and the substantially simultaneous administration of these therapeutic agents, or at least two of these therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single dosage form of each therapeutic agent in a fixed ratio, or by administering multiple single dosage forms (for each therapeutic agent). Sequential or substantially simultaneous administration of each therapeutic agent can be achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered via the same route or via different routes. For example, the first therapeutic agent of a selected combination can be administered via intravenous injection, while the other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or via intravenous injection. Combination therapy may also include further administration of the therapeutic agents as described above in combination with other bioactive ingredients and non-pharmacological therapies (e.g., surgical or radiation therapy). Where the combination therapy also includes non-pharmacological treatment, the non-pharmacological treatment can be administered at any suitable time, provided that a beneficial effect is achieved from the combined action of the therapeutic agents and the non-pharmacological treatment. For example, in appropriate circumstances, the aforementioned beneficial effects can still be achieved when non-pharmacological treatment is temporarily (perhaps for several days or even weeks) removed from the administration of the therapeutic agent.

[0259] Pharmaceutical Composition

[0260] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, and optionally one or more additional therapeutic agents as described above.

[0261] Compounds of formula (I) may be administered via any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and at a dose effective for the intended treatment. Compounds of formula (I) and compositions thereof may be administered in any suitable manner for any of the uses described herein: for example, orally, such as tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension); nasally, including administration to a nasal membrane, such as by inhalation spray; topically, such as in the form of creams or ointments; or rectally, such as in the form of suppositories. They may be administered alone, but will generally be administered in conjunction with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0262] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. Preferably, the pharmaceutical composition is prepared in a dosage unit containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, more preferably about 0.5 to 100 mg. The appropriate daily dose for humans or other mammals may vary considerably depending on the patient's condition and other factors, but can be determined using conventional methods.

[0263] Any pharmaceutical composition considered herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, tablets, lozenges, sugar lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for producing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable formulation, pharmaceutical compositions according to the invention may contain at least one agent selected from sweeteners, flavoring agents, coloring agents, modifiers, antioxidants, and preservatives.

[0264] Tablets 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 non-toxic, pharmaceutically acceptable excipient suitable for manufacturing tablets. Exemplary excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrants such as microcrystalline cellulose, croscarmellose sodium, corn starch, and alginate; binders such as starch, gelatin, polyvinylpyrrolidone, and gum arabic; and lubricants such as magnesium stearate, stearic acid, and talc. Additionally, tablets may be uncoated or coated using known techniques to mask unpleasant tastes of the drug or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby maintaining the action of the active ingredient for a longer period. Exemplary water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Exemplary delay-release materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0265] Hard gelatin capsules can be prepared, 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 and kaolin).

[0266] Soft gelatin capsules 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 water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0267] 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 excipient suitable for the production of aqueous suspensions. Exemplary excipients suitable for manufacturing aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic; dispersants or wetting agents such as naturally occurring phospholipids, such as lecithin; condensation products of alkyl epoxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxides and long-chain aliphatic alcohols, such as heptadecaethylene-oxycetanol; condensation products of ethylene oxides and esters derived from fatty acids and hexitols, such as polyoxyethylene sorbitan monooleate; and condensation products of ethylene oxides and esters derived from fatty acids and hexitol anhydrides, such as polyvinyl dehydrated sorbitan monooleate. Aqueous suspensions may also contain at least one preservative, such as ethylparaben and n-propylparaben; at least one colorant; at least one flavoring agent; and / or at least one sweetener, including but not limited to sucrose, saccharin and aspartame.

[0268] Oily suspensions 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 (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or in a mineral oil (e.g., liquid paraffin). Oily suspensions may also contain at least one thickener, such as beeswax, hard paraffin, and cetyl alcohol. To provide a palatable oily suspension, at least one sweetener and / or at least one flavoring agent described above may be added to the oily suspension. Oily suspensions may further contain at least one preservative, including but not limited to antioxidants such as butylated hydroxyanisole and α-tocopherol.

[0269] 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 dispersant and / or wetting agent, at least one suspending agent and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents are as described above. Exemplary preservatives include, but are not limited to, antioxidants such as ascorbic acid. In addition, dispersible powders and granules may also contain at least one excipient, including but not limited to, sweeteners, flavoring agents, and coloring agents.

[0270] Emulsions of compounds of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be prepared, for example, as oil-in-water emulsions. The oil phase of an emulsion containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can 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. While the phase may contain only an emulsifier, it may contain at least one emulsifier with a fat or oil, or with both fats and oils. Suitable emulsifiers include, but are not limited to, natural phospholipids, such as soybean lecithin; esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Preferably, a hydrophilic emulsifier is included together with the lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oils and fats. One or more emulsifiers, with or without one or more stabilizers, constitute a so-called emulsified wax, and the wax, together with oils and fats, constitutes a so-called emulsified ointment matrix, which forms the oily dispersed phase of the cream formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of this invention include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, distearate alone or with the wax, or other materials well known in the art.

[0271] Compounds of formula (I) and / or at least one pharmaceutically acceptable salt thereof may also be delivered intravenously, subcutaneously, and / or intramuscularly, for example, by any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, sterile aqueous solutions containing acceptable media and solvents, such as water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oily suspensions.

[0272] Formulations intended for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more carriers or diluents mentioned for use in formulations intended for oral administration, or by using other suitable dispersants or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, astragalus gum, and / or various buffer solutions. Other adjuvants and methods of administration are well known in the pharmaceutical industry. The active ingredient may also be administered by injection as a composition with a suitable carrier (including saline, dextran, or water) or with cyclodextrin (i.e., Captisol), a cosolvent solubilizer (i.e., propylene glycol), or a micellar solubilizer (i.e., Tween 80).

[0273] Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile fixative oils are routinely used as solvents or suspending media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can be used in the preparation of injectable formulations.

[0274] Aseptic injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving a compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining the oil phase containing the compound of formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

[0275] Sterile aqueous or oily suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared with non-toxic, parenteral-acceptable diluents or solvents (e.g., 1,3-butanediol); and sterile oily suspensions can be prepared with sterile, non-toxic, acceptable solvents or suspending media (e.g., sterile fixative oils (e.g., synthetic monoglycerides or diglycerides) and fatty acids (e.g., oleic acid)).

[0276] Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated; the subject to be administered the composition containing the agent; the intended route of administration of the composition; and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may also include a number of different components and additives in addition to the active agent, such additional components being included in the formulation for a variety of reasons well known to those skilled in the art (e.g., stabilization of the active agent, binder, etc.). Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in their selection are found in several readily available sources, such as Allen, LV Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd edition (2012), Pharmaceutical Press.

[0277] Pharmaceutically acceptable carriers, adjuvants, and mediators that can 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) (such as d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (such as Tween, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF) or other similar polymer delivery matrices), serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine), sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins (such as α-, β- and γ-cyclodextrins) or chemically modified derivatives (such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-cyclodextrins or other solubilized derivatives) can also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0278] The pharmaceutically active compounds of this invention can be processed using conventional pharmaceutical methods to produce medical agents for administration to patients (including humans and other mammals). The pharmaceutical compositions can undergo conventional pharmaceutical processes such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Tablets and pills can be additionally prepared using enteric coating. Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and aromatizers.

[0279] For therapeutic purposes, the active compounds of the present invention are typically combined with one or more adjuvants suitable for the indicated route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkyl cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain controlled-release formulations, which may be provided as a dispersion of the active compound in hydroxypropyl methylcellulose.

[0280] The amount of compound applied and the dosing regimen for treating symptoms with the compounds and / or compositions of the present invention depend on a variety of factors, including the subject's age, weight, sex, medical condition, disease type, disease severity, route and frequency of administration, and the specific compound used. Therefore, dosing regimens can vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight, and most preferably between about 0.005 and 10 mg / kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. Other dosing schedules include weekly and every two days.

[0281] The pharmaceutical compositions of the present invention comprise a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally another agent selected from any pharmaceutically acceptable carrier, adjuvant, and mediator. Alternative compositions of the present invention comprise a compound of formula (I) as described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator.

[0282] The present invention also includes pharmaceutical kits for the treatment or prevention of, for example, IKZF1-4 protein-related diseases or disorders, as well as other diseases mentioned herein, said pharmaceutical kits comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I). If desired, such kits may further include one or more of the following: various conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, which will be readily apparent to those skilled in the art. The kit may also include instructions for use as inserts or labels, indicating the amount of components to be administered, instructions for administration, and / or instructions for mixing components.

[0283] Of course, the dosage regimen of the compounds of the present invention will vary according to known factors, such as: the pharmacokinetic characteristics of the particular agent and its administration mode and route; the recipient's species, age, sex, health, medical condition and weight; the nature and severity of symptoms; the types of concurrent treatments; the frequency of treatment; the route of administration, the patient's renal and hepatic function, and the desired effect.

[0284] As a general guideline, when used for the indicated effects, the daily oral dose of each active ingredient will range from about 0.001 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. Intravenously, during a constant rate infusion, the most preferred dose range will be from about 0.01 to about 10 mg / kg / min. The compounds of formula (I) can be administered as a single daily dose, or the total daily dose can be administered in divided doses twice, three, or four times daily.

[0285] Compounds are typically administered in combination with a suitable drug diluent, excipient, or carrier (collectively referred to herein as a drug carrier), which is appropriately selected with regard to the planned form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and in accordance with standard pharmaceutical practice.

[0286] Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 mg to about 200 mg of active ingredient per dose unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of about 0.1% to 95% by weight based on the total weight of the composition.

[0287] Typical capsules for oral administration contain a compound of formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0288] A typical injectable formulation is produced by aseptically placing the compound of formula (I) (250 mg) into a vial, aseptically freeze-drying and sealing it. For use, the contents of the vial are mixed with 2 mL of physiological saline to produce the injectable formulation.

[0289] This invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) (alone or in combination with a drug carrier) as an active ingredient. Optionally, the compound of formula (I) may be used in combination with one or more other therapeutic agents (e.g., anticancer drugs or other pharmaceutically active substances).

[0290] Regardless of the chosen route of administration, the compounds of formula (I) (which may be used in a suitable hydrated form) and / or the pharmaceutical compositions of the present invention can be formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

[0291] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be changed in order to obtain an amount of active ingredient that effectively achieves a therapeutic response for a particular patient, composition and administration method without causing toxicity to the patient.

[0292] The selected dose level will depend on a variety of factors, including the activity of the compound of formula (I) or its esters, salts or amides, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound, the rate and extent of absorption, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field.

[0293] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian can start with a dose of a compound of formula (I) used in the pharmaceutical composition at a level below that required to achieve a therapeutic effect, and gradually increase the dose until the effect is achieved.

[0294] Generally, the appropriate daily dose of a compound of formula (I) will be the lowest dose at which the compound effectively produces a therapeutic effect. This effective dose will typically depend on the factors mentioned above. Generally, the oral, intravenous, intraventricular, and subcutaneous doses of a compound of formula (I) for a patient will range from approximately 0.01 mg to approximately 50 mg / kg body weight per day.

[0295] If desired, the effective daily dose of the active compound can be administered as two, three, four, five, six or more sub-dose at appropriate intervals throughout the day, optionally in unit dosage form. In some aspects of the invention, administration is once daily.

[0296] While it is possible to administer the compound of formula (I) alone, it is preferred to administer the compound as a pharmaceutical formulation (composition).

[0297] When used in combination with compounds of formula (I), the other therapeutic agents described above may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR), or in amounts otherwise determined by those skilled in the art. In the methods of the invention, one or more such other therapeutic agents may be administered before, simultaneously with, or after the application of the compounds of the invention.

[0298] Preparation method

[0299] The compounds of this invention can be prepared by a variety of methods well known to those skilled in the art of organic synthesis. The compounds of this invention can be synthesized using the methods described below, together with synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are incorporated herein by reference in their entirety.

[0300] The compounds of the present invention can be prepared using the reactions and techniques described in this section. These reactions are carried out in solvents suitable for the reagents and materials used and are applicable to the transformations achieved. Furthermore, in the description of the synthetic methods described below, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment, and post-treatment procedures, are selected as standard conditions for the stated reactions, and this should be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that the functional groups present on the various parts of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with these reaction conditions will be readily apparent to those skilled in the art, and thus alternative methods must be used. This will sometimes require judgment to modify the order of synthetic steps or to choose a particular methodological scheme instead of another in order to obtain the compounds of the present invention. It will also be recognized that another important consideration when planning any synthetic route in the art is the prudent choice of protecting groups, which are used to protect the reactive functional groups present in the compounds described in this invention. The authoritative explanation of the many alternatives for trained practitioners is that of Greene and Wuts (Protective Groups in Organic Synthesis, 4th Edition, Wiley and Sons, 2007).

[0301] Example

[0302] The following examples illustrate specific embodiments of the invention and do not limit the scope of the invention. Unless otherwise stated, chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their usual and conventional meanings. Additional abbreviations used elsewhere in this application are defined below in the Examples section. The compounds and intermediates of the examples are identified by the examples and steps in which they are prepared (e.g., "1-A" indicates Example 1, step A), or simply by the example in which the compound is the title compound of the example (e.g., "1" indicates the title compound of Example 1). In some cases, alternative preparations of intermediates or examples are described. Often, chemists skilled in the art of synthesis can design potentially desirable alternative preparations based on one or more considerations such as shorter reaction times, lower cost of starting materials, ease of operation or separation, increased yield, suitability for catalysis, avoidance of toxic reagents, availability of specialized instruments, and a reduced number of linear steps. The purpose of describing alternative formulations is to further realize the preparation of the examples of the invention. In some cases, some functional groups in the outlined examples and claims can be replaced by well-known bioisosteric substitutes known in the art, such as partially replacing the carboxylic acid group with a tetrazolium or phosphate ester.

[0303] abbreviation

[0304] ACN acetonitrile

[0305] DCM dichloromethane

[0306] DME dimethyl ether

[0307] DMF dimethylformamide

[0308] DMSO dimethyl sulfoxide

[0309] dppf bis(diphenylphosphine)ferrocene

[0310] Ethyl acetate (EtOAc)

[0311] HPLC (High Performance Liquid Chromatography)

[0312] Memethyl

[0313] MeOH methanol

[0314] min minutes

[0315] mL / ml

[0316] NaHMDS bis(trimethylsilyl)amide sodium

[0317] n-BuLi n-Butyllithium

[0318] NH4OAc ammonium acetate

[0319] TEMED tetramethylethylenediamine

[0320] TFA (trifluoroacetic acid)

[0321] THF tetrahydrofuran

[0322] Analytical LCMS conditions

[0323] 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: 40ºC; Gradient: 2 min from 20% B to 100% B; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm).

[0324] Intermediate A

[0325] (6-chloro-3-formylpyridin-2-yl)tert-butyl carbamate

[0326] (Intermediate A)

[0327] At -78ºC under nitrogen, a solution of 1.6 Mn-BuLi in hexane (137 mL, 219 mmol) was added dropwise over approximately 30 minutes to a stirred solution of (6-chloropyridin-2-yl)carbamate (20 g, 87 mmol) and TEMED (32.8 mL, 219 mmol) in anhydrous THF (300 mL). The reaction mixture was slowly warmed to -10ºC and maintained at -10ºC for 2 h. The reaction mixture was then cooled again to -78ºC. DMF (33.9 mL, 437 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction mixture was diluted with EtOAc (1 L) and 1 N hydrochloric acid (0.5 L), stirred for 15 min, and the organic phase was separated. The organic phase was washed with water and saturated NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was mixed with 10% IPA in petroleum ether, the separated solid was filtered and dried under vacuum to give tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (15 g, 67%) as a light-colored solid. LCMS (Method A): retention time 1.45 min, [M-56] + 201.1; 1 H 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).

[0328] Intermediate B

[0329] (S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)-5-oxopentanoic acid tert-butyl ester

[0330] (Intermediate B)

[0331] Preparation of intermediate B-1: 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one

[0332] (Intermediate B-1)

[0333] At 0ºC, a solution of 2.5 Mn-BuLi in hexane (16 mL, 40 mmol) was added to a stirred solution of 2,2,6,6-tetramethylpiperidine (7.07 mL, 41.6 mmol) in anhydrous THF (150 mL). The reaction mixture was stirred at 0ºC for 30 min, cooled to -50ºC, and at the same temperature, a solution of 4-bromo-3-fluorobenzoic acid (3.5 g, 15.98 mmol) in anhydrous THF (100 mL) was added dropwise under nitrogen. The reaction mixture was stirred at -50ºC for 3 h under nitrogen. Anhydrous DMF (2.48 mL, 32 mmol) was added at -50ºC, and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction was quenched by adding 1.5 N HCl (100 mL). The reaction mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and evaporated under vacuum. The residue was purified by rapid chromatography (SiO₂, 120 g column, 0-50% EtOAc / petroleum ether) to give a yellow solid of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (1.0 g, 23%). LCMS (Method A): retention time 0.48 min, [MH] + 245.1, 247.1; 1 H NMR (400 MHz, acetonitrile-d3)δ 7.93 (dd, J = 8.0, 5.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 6.74 (br s, 1H), 5.94 (br s, 1H).

[0334] Preparation of intermediate B-2: tert-butyl (S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)-5-oxovalerate

[0335] (Intermediate B-2)

[0336] At 0ºC under nitrogen, sodium triacetoxyborohydride (3.65 g, 17.21 mmol) was added to a stirred solution of 5-bromo-4-fluoro-3-hydroxyisobenzofuran-1(3H)-one (1.7 g, 6.88 mmol) and (S)-4,5-diamino-5-oxovalerate tert-butyl ester HCl (1.67 g, 8.26 mmol) in DMF (30 mL). The reaction mixture was warmed to room temperature and stirred for 48 h. The reaction mixture was diluted with ice water (50 mL), and the resulting white solid was filtered and dried under vacuum to give (S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester (1.6 g, 50%) as a white solid. LCMS (Method A): retention time 1.39 min, [MH] + 413.9; 1 H NMR (400 MHz, DMSO-d6) δ7.85 (dd, J = 8.0, 6.0 Hz, 1H), 7.59 (br s, 1H), 7.51 (d, J = 8.0 Hz, 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).

[0337] Preparation of intermediate B-3: (S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindoline-2-yl)-5-oxopentanoic acid tert-butyl ester

[0338] (Intermediate B-3)

[0339] A mixture of (S)-5-amino-4-(5-bromo-4-fluoro-1-oxoisoindolin-2-yl)-5-oxovalerate tert-butyl ester (10.0 g, 24.1 mmol), potassium acetate (0.355 g, 3.61 mmol), and dihydrogen ester (7.95 g, 31.3 mmol) in anhydrous DME (15 ml) was purged with argon for 10 min at room temperature. Pd(dppf)Cl2-DCM complex (1.97 g, 2.4 mmol) was added under argon atmosphere, the vial was sealed, and the reaction mixture was heated at 90ºC for 16 h. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum. The obtained residue was dissolved in diethyl ether, filtered through a diatomaceous earth mat, and the filtrate was concentrated under vacuum to give (S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)isoindoline-2-yl)-5-oxopentanoic acid tert-butyl ester (11.0 g, crude). LCMS (Method A): retention time 1.6 min, [M+H] + 463.1.

[0340] Preparation of intermediate B:

[0341] At room temperature, tert-butyl (6-chloro-3-carboxypyridin-2-yl)carbamate (7.42 g, 28.9 mmol) and 3 M potassium phosphate aqueous solution (24.08 mL, 72.2 mmol) were added to a stirred solution of (S)-5-amino-4-(4-fluoro-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-1,3,2-dioxane-2-yl)isoindoline-2-yl)-5-oxovalerate (11.0 g, 23.8 mmol) in dioxane (200 mL). The reaction mixture was purged with nitrogen for 10 min, and then 1.556 g (1.81 mmol) of methanesulfonic acid-(2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) was added under nitrogen atmosphere. The reaction mixture was then heated at 85ºC for 2 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (300 mL), and washed with brine. The organic layer was then separated, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The crude compound was purified by rapid chromatography (SiO2, 220 g column, 10%–100% EtOAc (containing 15% EtOH) / DCM) to give (S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-4-fluoro-1-oxoisoindoline-2-yl)-5-oxovalerate tert-butyl ester (7.4 g, 55% yield) as a yellow solid. LCMS (Method A): retention time 1.62 min, [M+H] + 557.2; 1 H NMR (300 MHz, chloroform-d)δ 10.08(br s, 1H), 9.97 (s, 1H), 8.54 (br t, J = 7.2 Hz, 1H), 8.09 (br d, J =7.6 Hz,1H), 7.78 (br d, J = 7.6 Hz, 2H), 6.37 (br s, 1H), 4.94 (br t, J = 6.8 Hz,1H), 4.72 (br d, J =17.4 Hz, H), 4.58 (br d, J =17.8 Hz, 1H), 2.46-2.11 (m,4H), 1.70-1.62 (m, 9H), 1.53-1.37 (m, 9H).

[0342] Example 1

[0343] 3-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[0344] (2)

[0345] Preparation of intermediate 1A: (S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-4-fluoro-1-oxoisoindoline-2-yl)-5-amino-5-oxovalerate tert-butyl ester

[0346] (Intermediate 1A)

[0347] 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 (S)-5-amino-4-(5-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-4-fluoro-1-oxoisoindoline-2-yl)-5-oxovalerate (8.0 g, 14.37 mmol) in DCE (150 mL) and DMF (20 mL). The reaction mixture was stirred overnight at room temperature. MP-cyanoborohydride (8.0 g) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was passed through a diatomaceous earth pad and concentrated under vacuum. The residue was purified by rapid chromatography (SiO2, 220 g column, 10%–100% EtOAc (containing 15% EtOH) / DCM) to give (S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-4-fluoro-1-oxoisoindoline-2-yl)-5-amino-5-oxovalerate tert-butyl ester (5.5 g, 51% yield) as a yellow solid. LCMS (Method A): retention time 1.79 min, [M+H] + 668.3; 1H NMR (300 MHz, DMSO-d6) δ10.07 (s, 1H), 8.18 (br t, J = 7.4 Hz, 1H), 7.80 (br d, J = 7.9 Hz, 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 = 3.4 Hz, 2H), 3.05 (br d, J = 6.4 Hz, 2H), 2.86 (br d, J= 7.2 Hz, 2H), 2.21 (br s, 5H), 1.72 (br d, J = 4.5 Hz, 2H), 1.48 (s, 10H), 1.34 (s, 9H).

[0348] Example 1: 3-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione

[0349] At room temperature, benzenesulfonic acid (1.480 g, 9.36 mmol) was added to a stirred solution of (S)-4-(5-(5-((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-4-fluoro-1-oxoisoindoline-2-yl)-5-amino-5-oxovalerate (2.5 g, 3.74 mmol) in acetonitrile (150 mL). The reaction mixture was heated at 90ºC for 16 h, cooled to room temperature, and concentrated under vacuum. Saturated Na2CO3 solution was added to quench the residue until pH reached 7.0. The suspension was extracted with 10% MeOH (50 mL x 3) in DCM, the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (SiO2, 220 g column, 0-10% MeOH / DCM) to give 1.4 g (65%) of 3-(5-(((6-oxa-2-azaspiro[3.5]non-2-yl)methyl)-6-aminopyridin-2-yl)-4-fluoro-1-oxoisoindololin-2-yl)piperidin-2,6-dione as a white solid. LCMS (Method A): retention time 1.02 min, [M+H] + 494.3; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.06 (t,J = 7.3 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.02(dd, J = 7.4, 2.4 Hz, 1H), 6.16 (s, 2H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 17.4 Hz, 1H), 4.45 (d, J = 17.4 Hz, 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 = 5.4 Hz, 2H).

[0350] Comparison of compound A

[0351] 3-(4-fluoro-1-oxo-5-(4-((3-phenylazacyclobutane-1-yl)methyl)pyridin-2-yl)isoindoline-2-yl)piperidin-2,6-dione

[0352]

[0353] Comparative compound A was prepared according to the procedure described in WO 2021 / 101919 (Example 208).

[0354] Comparison of compound B

[0355] 3-(5-(5-((2-azaspiro[3.3]heptane-2-yl)methyl)-6-aminopyridin-2-yl)-1-oxoisoindolin-2-yl)piperidin-2,6-dione

[0356]

[0357] Comparative compound B was prepared according to the procedure described in WO 2022 / 216573 (Example 286).

[0358] Biological assay

[0359] The pharmacological properties of the compounds of this invention can be confirmed by a number of biological assays. The following exemplified biological assays have been performed using the compounds of this invention.

[0360] Jurkat cell degradation assay

[0361] Jurkat cells were seeded at 80,000 cells / well in 40 µL RPMI + 10% FBS in 384-well cell culture plates, followed by addition of the target compound using acoustic dispensing. The cell cultures were incubated at 37ºC and 5% CO2 for 72 h. For analysis, the cell cultures were vortexed at 200 rpm for 5 min to settle, and the supernatant was discarded. After shaking the plate to detach the cell pellet, the cells were resuspended in 50 µL of fixation buffer (eBioscience FoxP3 buffer set 00-5523-00) at room temperature for 60 min. After centrifugation and discarding the supernatant, the cells were permeabilized with 50 µL of permeabilization buffer (eBioscience FoxP3 buffer set 00-5523-00) at room temperature for 10 min. After permeabilization, cells were rotated to settle, and the supernatant was replaced with 20 µL of fluorescently labeled antibodies against Helios, Ikaros, and Aiolos or their corresponding isotype controls in 1× permeabilization buffer (Ikaros-Alexa488 [Biolegend, catalog number 368408, 1:50], Helios-PE [CST, catalog number 29360, 1:50], Aiolos-Alexa647 [Biolegend, catalog number 371106 Biolegend, 1:25]). The staining reaction was incubated in the dark at room temperature for 1 h. Subsequently, 30 µL of 1× permeabilization buffer was added, followed by centrifugation and discarding of the supernatant. The stained cells were resuspended in 25 µL of flow cytometry staining buffer (PBS + 0.2% bovine serum albumin (BSA)) and analyzed using an Intellicyt Ique Plus flow cytometer.

[0362] Table A-1

[0363] Jurkat cell degradation assay: Maximum observed degradation

[0364]

[0365] Table A-1 lists the maximum observed degradation of IKZF1, IKZF2, and IKZF3 proteins as measured in the Jurkat cell degradation assay. Results in Table A-1 are rounded to two digits. In the Jurkat cell degradation assay, a value of 100% indicates no detectable protein residue or complete protein degradation; and a value of 0% indicates no protein degradation induced by the test compound was detected.

[0366] Table A-2

[0367] Jurkat cell degradation assay: DC50 *

[0368]

[0369] *DC 50 Defined as the concentration of a compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone.

[0370] Human regulatory T cell degradation assay

[0371] Cryopreserved human regulatory T cells were thawed in RPMI + 10% FBS + 20 ng / mL IL-2. After sedimentation at 1200 rpm for 5 min, the cells were resuspended in RPMI + 10% FBS + 20 ng / mL and incubated at 37ºC for 3 h at 5% CO2. Cells were then seeded at 40,000 cells / well in 40 µL of RPMI + 10% FBS + 20 ng / mL human IL-2 in 384-well cell culture plates, followed by addition of the target compound using an acoustic dispensing technique (ECHO 555). The cell culture was incubated at 37ºC and 5% CO2 for 20 h. For analysis, the cell culture was sedimented at 1200 rpm for 5 min, and the supernatant was discarded using an EL406 washer. After washing three times with 70 μL PBS, the cell pellet was resuspended in 50 μL of near-IR viability staining solution (Life Technologies, catalog number L34975) and incubated on ice in the dark for 30 minutes. Using an EL406 washer, the cells were washed three times with 70 μL PBS + 0.5% BSA. After shaking the plate to detach the cell pellet, the cells were resuspended in 50 µL of fixation buffer (eBioScience FoxP3 buffer set 00-5523-00) at room temperature for 60 minutes. After centrifugation and discarding the supernatant, the cells were permeabilized with 50 µL of permeabilization buffer (eBioScience FoxP3 buffer set 00-5523-00) at room temperature for 10 minutes. After permeabilization, cells were rotated to settle, and the supernatant was replaced with 30 µL of fluorescently labeled antibodies against Helios (Helios-APC [BioLegend, catalog number 137222, 1:50]), Aiolos, and Ikaros in 1x permeabilization buffer. The staining reaction was incubated in the dark at room temperature for 1 hour. Subsequently, 30 µL of 1x permeabilization buffer was added, followed by centrifugation and discarding of the supernatant. The stained cells were resuspended in 30 µL of flow cytometry staining buffer (PBS + 0.5% BSA) and analyzed using an Intellicyt Ique Plus flow cytometer.

[0372] Table B-1

[0373] Human regulatory T cell degradation assay: maximum observed degradation

[0374]

[0375] Table B-1 lists the maximum observed degradation of IKZF1 and IKZF2 proteins as measured in the human regulatory T cell degradation assay. Results in Table B-1 are rounded to two digits. In the human regulatory T cell degradation assay, a value of 100% indicates no detectable protein residue or complete protein degradation; and a value of 0% indicates no protein degradation induced by the test compound was detected.

[0376] Table B-2

[0377] Human regulatory T cell degradation assay: DC 50 *

[0378]

[0379] *DC50 is defined as the concentration of a compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone.

[0380] Human regulatory T cell reprogramming assay

[0381] Use RosetteSep CD4 + Human CD4 was isolated from fresh healthy leukocyte apheresis products (leukopaks) (Stemcell Technologies) using T cell enrichment mixture (Stemcell Technologies) and Ficoll density gradient centrifugation. + T cells. The leukocyte apheresis product was diluted with an equal volume of phosphate-buffered saline (PBS [Gibco]) supplemented with 2% fetal bovine serum (FBS, VWR Lifescience) and then mixed with RosetteSep human CD4. + The T-cell enrichment mixture was incubated together for 20 minutes, then separated on Ficoll-Paque Plus solution (GE Health Care). The cell-rich interfacial layer was harvested and washed twice with PBS supplemented with 2% FBS. Then, EasySep human CD4 was used according to the manufacturer's instructions. + CD127 低 CD25 +Regulatory T cells were manually isolated using a regulatory T cell isolation kit (Stemcell Technologies). Cells were incubated overnight in a humidified incubator (37ºC, 5% CO2) in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco). Cells were then stained with CD4 (clone: ​​RPA-T4, Biolegend), CD25 (clone: ​​2A3, BD Biosciences), and CD127 (clone: ​​hIL-7R-M21, BD Biosciences). + CD127 低 CD25 + Cells were sorted to 95% purity or higher using a BD FACS Aria fusion sorter. Sorted cells were used immediately or cryopreserved for downstream assays.

[0382] CD4 sorted from fresh or frozen FACS + CD127 低 CD25 + Treg cells were cultured in RPMI 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) at a density of 25,000–50,000 cells per well in 96-well round-bottom plates. Cells were stimulated with Treg Xpander beads (Thermo Fisher) at a cell-to-bead ratio of 1:4 in the presence of 500 U / mL recombinant human IL-2 (Proleukin). The compound was added titrated, and cells were incubated at 37ºC and 5% CO2 for 12–13 days. Recombinant human IL-2 and the compound were supplemented every 2–3 days throughout the culture period. On day 12 or 13, cells were restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin in the presence of the protein transport inhibitors brefeldtamicin A and monensin (eBioscience cell stimulation mixture plus protein transport inhibitor, 500x, catalog number 00-4975-93), followed by flow cytometry staining and analysis.

[0383] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated for 10 min in human Tru-stain Fc blocking agent (Biolegend), followed by incubation at 4ºC for 30 min with a mixture of eFluor 780 viability dye (Thermo Fisher) and surface marker antibody. Cells were then fixed and permeabilized by incubation at 4ºC for 30 min with FoxP3 transcription factor staining buffer (Thermo Fisher) according to the kit manufacturer's instructions. Cells were washed twice with the permeabilization / washing buffer provided in the kit and incubated overnight at 4ºC with an intracellular antibody mixture consisting of antibodies specific to transcription factors as shown in Table C, according to the manufacturer's instructions. Prior to collection, cells were washed twice with permeabilization / washing buffer and resuspended in flow cytometry staining buffer (Thermo Fisher). Sample collection and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-staining controls for each fluorescent dye were prepared using UltraComp eBeads (Thermo Fisher). Data were analyzed using FlowJo version 10 and GraphPad Prism software.

[0384] Table C

[0385] Antibodies for flow cytometry sorting and analysis

[0386]

[0387] Table C-1

[0388] Human Regulatory T Cell Reprogramming Assay - Maximum Observed Degradation

[0389]

[0390] Table C-1 lists the maximum observed degradation of IKZF2 and IKZF4 proteins as measured in the human regulatory T cell reprogramming assay. Results in Table C-1 are rounded to two digits. In the human regulatory T cell reprogramming assay, a value of 100% indicates no detectable protein residue or complete protein degradation; and a value of 0% indicates no protein degradation induced by the test compound was detected.

[0391] Table C-2

[0392] Human regulatory T cell reprogramming assay: DC 50 *

[0393]

[0394] *DC50 is defined as the concentration of a compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone.

[0395] Human CD8 + T cell degradation assay

[0396] Cryopreserved healthy donor peripheral blood mononuclear cells (PBMCs) were thawed and seeded at 500,000 cells per well in RPMI 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) in 96-well round-bottom plates. Cells were treated with titrated amounts of the compounds at 37ºC and 5% CO2 for 24 hours, followed by flow cytometry analysis.

[0397] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated for 10 minutes in human Tru-stain Fc blocking agent (Biolegend). Then, eFluor780 viable dye (Thermo Fisher) and a mixture of surface marker antibodies containing LD-eFluor780, CD3-BUV-395, CD4-BUV805, CD8-FITC, and CD25-BV605 were added at 4ºC for 30 minutes. Cells were then fixed and permeabilized by incubation at 4ºC for 30 minutes 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 permeation / wash buffer provided in the kit and incubated overnight at 4ºC with an intracellular antibody mixture consisting of antibodies specific to transcription factors (i.e., Foxp3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PECF594, AIOLOS-AF647). Prior to collection, cells were washed twice with permeation / wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher). Samples were collected and analyzed using a BDLSLRFortessa (BD Biosciences) flow cytometer. Single-staining controls for each fluorescent dye were prepared using UltraComp eBeads (Thermo Fisher). Data were analyzed using FlowJo version 10 and GraphPadPrism software.

[0398] Table D-1

[0399] Human CD8 +T cell reprogramming assay - maximum observed degradation

[0400]

[0401] Table D-2

[0402] Human CD8 + T cell reprogramming assay: DC 50 *

[0403]

[0404] *DC 50 Defined as the concentration of a compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone.

[0405] Table D-1 lists examples such as CD8 in humans. + The maximum observed degradation of IKZF1 and IKZF3 proteins was measured in the T-cell reprogramming assay. Results in Table D-1 are rounded to two decimal places. In human CD8... + In the T-cell reprogramming assay, a 100% value indicates no detectable protein residue or complete protein degradation; and a 0% value indicates no protein degradation caused by the test compound was detected.

[0406] Table E

[0407] Maximum observed degradation of IKZF1-4: Example 1 compared with control compounds A and B

[0408]

[0409] IKZF1 and IKZF3: Human CD8+ T cell reprogramming assay (Table D-1)

[0410] IKZF2 and IKZF4: Assay for Reprogramming Human T Regulatory Cells (Table C-1)

[0411] As shown in Tables C-1 and D-1 of the reported tests: (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). Conversely, in similar tests, control compounds A and B reduced the level of IKZF1 (Ikaros) by 20% or less; and control compound B reduced the level of IKZF3 (Aiolos) by 2%.

[0412] This invention addresses the aforementioned need by providing compounds that can be used to reduce the levels of four IKZF1-4 proteins: Ikaros, Helios, Aiolos, and Eos.

Claims

1. A compound of Formula (I): or a stereoisomer, a tautomer, or a salt thereof. (I) 2. The compound of claim 1, or a stereoisomer or a tautomer thereof.

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

4. A pharmaceutical salt of the compound of claim 1, or a stereoisomer or a tautomer thereof.

5. The compound of claim 1, or a stereoisomer, a tautomer, or a salt thereof, having the structure:

6. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 。 7. A pharmaceutical composition comprising a compound of claim 2, or a stereoisomer or a tautomer thereof; and a pharmaceutically acceptable carrier.

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

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

10. The use of claim 9, wherein the cancer is selected from the group consisting of colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

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

12. The method of claim 11, wherein the cancer is selected from the group consisting of colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia, and melanoma.

13. The method of claim 11, wherein the cancer is selected from the group consisting of lymphoma, leukemia, and multiple myeloma.

14. The method of claim 11, further comprising administering to the patient a therapeutically effective amount of a second agent prior to, concurrently with, or after administration of the compound, wherein the second agent is selected from the group consisting of an antagonist of the PD1 / PD-L1 axis, an antagonist of CTLA4, a chemotherapeutic agent, radiation, or an anti-tumor vaccine.

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

16. The method of claim 15, wherein: a) the Ikaros protein is an amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; ​ b) the Helios protein is an 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 NO: 12, 13, 14, 15, 16, 17, 18, or 19; and d) the Eos protein is an amino acid sequence encoded by SEQ ID NO: 20 or 21.

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

18. The method of claim 15, further comprising administering to the patient a therapeutically effective amount of a second agent prior to, concurrently with, or after administering the compound, wherein the second agent is selected from an antagonist of the PD1 / PD-L1 axis, an antagonist of CTLA4, a chemotherapeutic agent, radiation, or an anti-tumor vaccine.

19. A method of reducing the level of Ikaros, Helios, Aiolos, and Eos proteins in a cell, the method comprising contacting the cell with a compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Images