Substituted phenyloxazolone compounds

Abstract

Formula (I): TIFF2026501039000057.tif45153 (wherein each R is independently H or D) The present invention relates to a compound of formula (I), or a stereoisomer, tautomer, or salt thereof. Also disclosed are methods of using the compound to reduce the level of IKZF1-4 protein; and pharmaceutical compositions containing the compound. The compound is useful for treating proliferative diseases such as viral infections and cancer.

Description

[Technical Field]

[0001] (cross reference) This application claims the benefit of U.S. Provisional Application No. 63 / 500,727, filed May 8, 2023, and U.S. Provisional Application No. 63 / 632,070, filed April 10, 2024, each of which is incorporated herein in its entirety.

[0002] Description of the Invention The present invention generally relates to substituted phenyloxazolone compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. Provided herein are substituted phenyloxazolone compounds, compositions containing the compounds, and methods of use. The present invention further relates to pharmaceutical compositions containing the compounds that are useful for treating proliferative disorders such as cancer and viral infections. [Background technology]

[0003] The Ikaros zinc finger family of transcription factors (IKZFs) plays an important role in lymphocyte development and function (Heizmann et al., 2018, Curr Opin Immunol. 51:14-23). ​​In mammals, 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 share high amino acid sequence homology, 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 both overlapping and unique functions in lymphocytes (Read et al., 2020, Immunological Reviews, 300:1). Reducing IKZF TF protein levels can enhance antitumor T cell responses.

[0004] 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 lineages, including myeloid cells. In T cells, deletion of Ikaros or expression of a dominant-negative protein derepresses loci associated with the differentiation of effector T cell states and increases the expression of effector cytokines, including IFN-γ, TNF-α, and GM-CSF (Lyon de Ana, et al., 2019, Journal of Immunology 202:1112-1123; Heller et al., 2014, Journal of Immunology 193:3934-3946; Wang et al., 2020, Cell Transplantation 29).

[0005] IKZF2 encodes Helios, which shows a more restricted expression profile, restricted 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).

[0006] IKZF3 encodes Aiolos, which is widely and abundantly expressed in human and mouse B lymphocytes and at lower levels in T and NK cells. In T cells, the Aiolos gene's inhibitory targets were found to overlap extensively with those of Ikaros (Powell et al., 2019, Frontiers in Immunology, 10:1299). Compared to Ikaros, Aiolos may have a stronger effect on tissue immune responses and, potentially, on follicular helper T and T helper type 17 responses, which are involved in antitumor immunity (Quintana et al., 2012, Nature Immunology, 13:770-777; Read et al., 2017 Journal of Immunology, 7:2377-2387).

[0007] IKZF4 encodes Eos, which is abundantly expressed in Treg cells and widely expressed at lower levels among B, NK, and T lymphocytes. Loss of Eos expression in FoxP3+ Treg cells improved antitumor responses in preclinical syngeneic tumor models (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Furthermore, Eos expression levels increase in conventional CD4+ and CD8+ T cells after T cell activation, potentially limiting effector T cell responses (Rieder et al., 2015, Journal of Immunology, 195:553-563).

[0008] A common function of IKZF TFs is the repression of gene expression at specific loci within cells. IKZF TFs can bind to genomic loci as homodimers or heterodimers (e.g., Ikaros:Ikaros or Ikaros:Helios). These dimeric TFs both bind to DNA and interact with complexes that regulate histone acetylation and nucleosomes, thereby regulating gene expression. Mechanistically, Ikaros, Helios, and Aiolos have been shown to interact with nucleosome remodeling deacetylase (NuRD) and Sin3 histone deacetylase (HDAC) complexes, respectively, to repress gene expression (Zhang et al., 2011, Nature Immunology, 13:86-94; Georgopoulos et al., 2017, Genes and Development, 31:439-450). Similarly, Ikaros, Helios, and Aiolos all associate with centromeric heterochromatin and can mediate the expression of genes located at centromeric loci (Brown et al., 1997, Cell, 91:845-854; Thompson et al., 2007, Immunity, 26:335-344). Eos interacts with Ikaros, but not Aiolos, and 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). Thus, the overlapping functions of IKZF TFs may partially compensate for the loss or degradation of one or more TFs. Thus, in cells expressing multiple IKZF members, broad therapeutic degradation of this TF family is expected to result in stronger phenotypic changes compared with selective degradation of one or two IKZF TFs.

[0009] The common role of IKZF TFs in regulating loci important for antitumor immune responses in T cells and Treg cells is illustrated by their regulation of the gene encoding interleukin-2 (IL-2). Ikaros can directly bind to the IL-2 locus in CD4+ T cells and recruit HDAC complexes; deletion of Ikaros increases 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 directly binds to the IL-2 locus in Treg cells, recruiting HDAC complexes and silencing the IL-2 gene (Blaine et al., 2013, Journal of Immunology, 190:1008-1016). Eos also suppresses IL-2 expression in Treg cells, possibly through mechanisms involving interaction with the TF FoxP3 (Pan et al., 2009, Science, 325:1142-1146; Sharma et al., 2013, Immunity, 38:998-1012). The role of direct Aiolos binding in IL-2 deficiency is less clear, but siRNA knockdown of Aiolos in human Treg cells has been reported to increase IL-2 production (Gandhi et al., 2010, Nature Immunology, 11:846-853). Taken together, IKZF TFs act to regulate IL-2 production by Treg cells, cells in which multiple lymphocyte subtypes (especially all four of these IKZF TFs) are abundantly expressed and in which IL-2 production is normally negligible.

[0010] Treg cells, characterized by expression of the transcription factor FoxP3, are a subset of immunosuppressive lymphocytes that use 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 deleterious mutations in the gene encoding FoxP3 lack functional Treg cells and exhibit immune dysregulation, polyendocrinopathy, X-linked enteropathy (IPEX) syndrome, and multisystem autoimmune disease. In the tumor microenvironment (TME), Treg cell activity is utilized to promote and maintain an immunosuppressive state (Plitas and Rudensky, 2020, Annual Review of Cancer Biology, 4:459-477). By secreting inhibitory molecules, sequestering cytokines (e.g., IL-2), and directly inhibiting the activation of T cells and antigen-presenting cells, Treg cells can promote resistance to immunotherapy through the TME by regulating multiple pathways in the cancer-immunity cycle (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, elimination of Treg cells resulted in regression of aggressive, established tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

[0011] Once activated by a specific antigen, Treg cells behave nonspecifically in vitro and suppress responder T cells by ignoring them (Takahashi et al., 1998, Int Immunol. 10:1969-80; Thornton et al., 1998, J Exp. Med. 188:287-96). Foxp3+CD25+CD4+ Treg cells can suppress a broad range of antitumor immune responses, including CD4+ helper T cells, CD8+ T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, Cell Research 27:109-118). In preclinical models, depletion of intratumor CD25+CD4+ Tregs altered the cytokine environment in the tumor and induced regression of established tumors (Yu et al., 2005, J Exp. Med. 201:779-91). Furthermore, transplantation of Treg-depleted CD4+ T cells significantly enhanced antitumor immune responses compared with transplantation of Treg-sufficient CD4+ T cells (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrated Treg cells activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific antitumor immune responses.

[0012] Clinically, increased Treg cell abundance in the TME correlates with worse outcomes in multiple solid cancer indications (Shang et al., 2015, Scientific Reports, 5:15179). Furthermore, the correlation between PD-L1+ Treg cell abundance and response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC) patients strongly suggests the therapeutic potential of targeting Treg cells in the TME (Wu et al., 2018, Journal of Thoracic Oncology, 13:521-532). Modulating the activity of key factors regulating Treg cell differentiation may represent a potential therapeutic strategy for treating certain diseases (e.g., cancer and viral infections).

[0013] Furthermore, it has been reported that depletion of Foxp3+ Tregs enhances vaccine-induced antitumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127:759-767), suggesting that reducing Helios levels may be effective in enhancing the efficacy of cancer vaccines. Antitumor immunotherapy during viral infection may limit the immunopathological reactions of Treg cells caused by excessive inflammation and may inhibit effective antiviral T cell responses, promoting viral resistance (Schmitz et al., 2013, PLOS Pathogens 9:e1003362). Chronic, but not acute, infection of mice with lymphocytic choriomeningitis virus resulted in a significant expansion of Foxp3+ Treg cells, suggesting a potential mechanism by which certain infectious agents may evade host immune responses by activating and expanding Treg cells (Punkosdy et al., 2011, PNAS 108:3677-3682). In situations involving chronic viral infection, reducing Helios levels in activated Treg cells can have a therapeutic effect.

[0014] Approaches to targeting tumor Treg cells include antibody-mediated depletion and functional modulation of Treg cells (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146) and small molecule-mediated "reprogramming" of Treg cells to an immunosuppressive phenotype by altering gene expression in the 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 the IPEX-like immunopathology characteristic of FoxP3 deletion or complete ablation of Treg cells, but instead have Treg cells that display a transcriptional program more similar to that of effector T cells (Fu et al., 2012, Nature Immunology, 13:972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). Importantly, Helios regulates the activity of Treg cells, which are critical in the TME, such that mice with Helios-deficient Treg cells have improved control of B16F10 and MC38 tumors (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Therefore, therapeutic modulation of Helios may reprogram tumor Treg cells toward a more effector-like phenotype to promote antitumor immunity. Notably, Eos also drives immunosuppressive Treg cell activity in the TME, as mice lacking Eos expression in FoxP3 Treg cells more effectively controlled syngeneic tumors compared with controls in preclinical tumor models (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300).Humans with germline loss-of-function IKZF2 mutations similarly lack IPEX-like symptoms (e.g., diabetes, dermatitis, hepatitis, and generalized lymphadenopathy) and instead display an immune phenotype associated with enhanced T cell activation and proinflammatory cytokine production (Hetemaeki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981). These data indicate that reduced Helios and Eos protein levels in Treg cells result in disinhibited antitumor T cell responses in patients with solid tumors.

[0015] Small molecules that degrade Ikaros and Aiolos in Treg cells can also reduce the suppressive function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In genetically engineered mouse models, lenalidomide, which degrades Ikaros and Aiolos, can modestly enhance antitumor immune responses against highly immunogenic syngeneic tumors (Geng et al., 2022, Cell Chemical Biology, 29:1260-1272). Ikaros- and Aiolos-targeted degraders are also undergoing clinical trials in patients with solid tumors, sometimes leading to modest, stable responses. These studies include avadomide (CC-122) in advanced malignancies (Rasco et al., 2019, Clin Cancer Research, 25:90-98), lenalidomide (Semeraro et al., 2013, OncoImmunology, 2:11), and pomalidomide (Cooney et al., 2012, Cancer Chemotherapy and Pharmacology, 70, 755). Additionally, lenalidomide has been shown to enhance T cell and NK cell function in preclinical and clinical trials (Hideshima et al., Leukemia, 2021; D'Souza et al., Frontiers in Immunology, 2021).

[0016] In summary, four IKZF TFs, Ikaros, Helios, Aiolos, and Eos, are abundantly expressed in Treg cells. Combined reduction of the individual protein levels of these four TFs in Treg cells may better reverse the immunosuppressive program, including the suppression of IL-2 transcription, compared with approaches that selectively target single IKZF TFs or TF pairs (i.e., Ikaros and Aiolos or Helios and Eos). In addition to Treg cells, pan-IKZF1-4 degraders are expected to enhance the effector function of conventional CD4+ and CD8+ T cells, enhance NK cell activity, and promote robust antitumor responses in patients.

[0017] There remains a need for therapies that can reduce the levels of the four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos.

[0018] The present invention fulfills the above-mentioned needs by providing compounds useful for reducing the levels of the four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos.

[0019] (Summary of the Invention) The present invention provides substituted phenyloxazolone compounds of formula (I) (e.g., stereoisomers, tautomers, salts and prodrugs thereof) that are useful for reducing the levels of four proteins: Ikaros, Helios, Aiolos and Eos.

[0020] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof; and a pharmaceutically acceptable carrier.

[0021] The present invention also provides a method for treating a disease or disorder by decreasing the levels of the four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos, comprising administering to a patient a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof.

[0022] The present invention also provides processes and intermediates for making compounds of formula (I), or stereoisomers, tautomers or salts thereof.

[0023] 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 Ikaros, Helios, Aiolos and Eos protein levels for the treatment of certain diseases (e.g., cancer and viral infections).

[0024] The compounds of formula (I) and compositions comprising the compounds of formula (I) can be used to treat, prevent or cure various proliferative diseases, such as cancer. Pharmaceutical compositions comprising the compounds are useful for treating, preventing or slowing the progression of diseases or disorders in various therapeutic areas, such as cancer.

[0025] The compounds of formula (I) and compositions comprising the compounds of formula (I) can be used to treat, prevent or cure viral infections. Pharmaceutical compositions comprising the compounds are useful for treating, preventing or slowing the progression of diseases or disorders such as viral infections.

[0026] These and other features of the present invention are set forth in the broader disclosure.

[0027] The applicant has discovered substituted phenyloxazolone compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. These substituted phenyloxazolone compounds are believed to promote the interaction of Ikaros, Helios, Aiolos, and Eos proteins with the corresponding E3 ubiquitin ligase complexes (Cullin4-Cereblon, CUL4-CRBN), resulting in the degradation of Ikaros, Helios, Aiolos, and Eos proteins. The compounds reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The compounds are useful for treating certain diseases (e.g., cancer and viral infections). The compounds provide useful pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values ​​important for their druggability.

[0028] A first aspect of the present invention provides a compound having at least one formula (I): [ka] wherein each R is independently hydrogen (H) or deuterium (D). or a stereoisomer, tautomer or salt thereof.

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

[0030] One embodiment provides a compound of formula (I), or a stereoisomer or tautomer thereof:

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

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

[0033] A second aspect of the present invention is a compound of formula (Ia): [ka] or a stereoisomer, tautomer or salt thereof.

[0034] One embodiment provides a compound of formula (Ia), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0035] One embodiment provides a compound of formula (Ia), or a stereoisomer or tautomer thereof:

[0036] One embodiment provides a salt of a compound of formula (Ia), or a stereoisomer or tautomer thereof.

[0037] One embodiment provides a pharmaceutically acceptable salt of a compound of formula (Ia), or a stereoisomer or tautomer thereof.

[0038] A third aspect of the present invention is a compound of formula (Ib): [ka] or a stereoisomer, tautomer or salt thereof.

[0039] One embodiment provides a compound of formula (Ib), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0040] One embodiment provides a compound of formula (Ib), or a stereoisomer or tautomer thereof:

[0041] One embodiment provides a salt of a compound of formula (Ib), or a stereoisomer or tautomer thereof.

[0042] One embodiment provides a pharmaceutically acceptable salt of a compound of formula (Ib), or a stereoisomer or tautomer thereof.

[0043] One embodiment provides compounds of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least one R is D.

[0044] One embodiment provides a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least two R's are D.

[0045] One embodiment provides a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least three R are D.

[0046] One embodiment provides a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein at least four R are D.

[0047] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is selected from 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione and 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-d5.

[0048] One embodiment provides a compound of Formula (Ia), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. Further included within this embodiment is one or more pharmaceutically acceptable salts.

[0049] One embodiment provides a compound of Formula (Ia), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. Also included in this embodiment are one or more pharmaceutically acceptable salts.

[0050] One embodiment provides a compound of Formula (Ib), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-dione. Also included in this embodiment are one or more pharmaceutically acceptable salts.

[0051] One embodiment provides a compound of Formula (Ib), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-d5. Also included in this embodiment are one or more pharmaceutically acceptable salts.

[0052] One embodiment has the following structure: [ka] or a stereoisomer, tautomer or salt thereof.

[0053] One embodiment has the following structure: [ka] or a stereoisomer, tautomer or salt thereof.

[0054] The compounds of formula (I), or stereoisomers, tautomers or salts thereof, are useful for reducing the levels of the four IKZF1-4 proteins, Ikaros, Helios, Aiolos and Eos.

[0055] As used herein, "reducing the level" of one of the IKZF1-4 proteins refers to reducing the level of the protein by degradation and / or inactivation and / or inhibition and / or reduction in expression level of the protein, or a combination thereof, compared to the starting protein level before contact or treatment with a compound of formula (I), or a stereoisomer, tautomer or salt thereof.

[0056] To measure the reduction in protein levels of IKZF1 to IKZF4 proteins, various methods can be used, including the assays described below: (i) IKZF1:human CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell lysis assay; (iii) IKZF3: human CD8 + T cell reprogramming assay; and (iv) IKZF4: human regulatory T cell reprogramming assay.

[0057] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes any combination of the aspects and / or embodiments of the present invention described herein. It is understood that any embodiment of the present invention may be combined with any other embodiment to describe additional embodiments. It is also understood that individual elements of an embodiment are meant to be combined with any other element from any embodiment to describe additional embodiments.

[0058] The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described before or after the context of separate embodiments may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment may also be combined to form subcombinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative, not limiting.

[0059] Unless otherwise stated herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

[0060] As used herein, the phrase "compound and / or salt thereof" refers to a compound, a salt of at least one compound, or a combination thereof. For example, compounds of formula (I) and / or salts thereof include compounds of formula (I); salts of compounds of formula (I); salts of compounds of formula (I) and one or more compounds of formula (I); and salts of two or more compounds of formula (I).

[0061] Unless otherwise specified, any atom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0062] The definitions set forth herein supersede any definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0063] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification, either individually or as part of a larger group (unless they are limited in specific instances).

[0064] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0065] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to the core or backbone structure.

[0066] The term "amino" refers to the group --NH.sub.2.

[0067] The term "oxo" refers to the group =O.

[0068] The present invention is intended to include all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described herein, using an appropriate isotopically labeled reagent in place of an otherwise unlabeled reagent.

[0069] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the movement of atoms or groups within the molecule. For example, one skilled in the art will readily recognize that 1,2,3-triazole exists in two tautomeric forms, as defined above: [ka]

[0070] Thus, the present invention is intended to cover all possible tautomers, even if the structure depicts only one of them. For example, compounds of formula (I) may exist in tautomeric forms: [ka]

[0071] Likewise, compounds of formula (Ia) may exist in tautomeric forms: [ka]

[0072] Another example of a tautomeric form is the following: [ka] and [ka] Examples include:

[0073] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that are, within the scope of ordinary medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and that offer a reasonable benefit / risk ratio.

[0074] The compound of formula (I) can form salts, and such salts are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the invention is understood to include reference to one or more salts thereof. The term "salt" refers to an acid salt formed with an inorganic and / or organic acid. Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred. However, other salts may also be useful, for example, in isolation or purification steps that may be used in manufacturing processes, and therefore, other salts are also considered to be within the scope of the present invention. A salt of a compound of formula (I) may be formed, for example, by reacting a compound of formula (I) with a certain amount of acid (e.g., 1 equivalent) and precipitating the salt in a solvent, for example, or by subsequent lyophilization of the aqueous solution.

[0075] Examples of acid addition salts include acetate (e.g., acetate formed with acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, hydrogensulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride (formed with hydrochloric acid), and hydrobromide (formed with hydrogen bromide). , hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (formed, for example, with sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), undecanoate, and the like.

[0076] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as a solid by lyophilization.

[0077] Additionally, solvates (e.g., hydrates) of the compounds of formula (I) are also considered to be within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0078] 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).

[0079] Additionally, after the compound of formula (I) is prepared, it can be isolated and purified to obtain a composition containing 99% or more 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 to be part of this invention.

[0080] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, nor upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0081] The terms "IKZF1 degrading agent" and "Ikaros degrading agent" refer to an agent 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.

[0082] The terms "IKZF2 degrading agent" and "Helios degrading agent" refer to an agent 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.

[0083] The terms "IKZF3 degrading agent" and "Aiolos degrading agent" refer to an agent 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.

[0084] The terms "IKZF4 degrading agent" and "Eos degrading agent" refer to an agent 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.

[0085] The term "IKZF1-4 proteins" refers to Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and Eos (IKZF4) proteins.

[0086] The term "panIKZF1 to 4 degrading agent" refers to an agent that can reduce the protein levels of the four IKZF1 to 4 proteins, Ikaros, Helios, Aiolos, and Eos.

[0087] As used herein, the "Ikaros" protein is encoded by the IKZF1 gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFNlAl, zinc finger protein 1, subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL-associated antigen KW-6. The "Ikaros" protein includes isoforms encoded by the human isoforms listed below: [Table 1] [Table 2]

[0088] The "Ikaros" protein isoforms 1, 2, 3, 4, 7 and 8 listed above are the same degrons as the "Aiolos" protein degrons: [Table 3] The Ikaros protein also includes isoforms encoded by the amino acid sequences Q13422-5 and Q13422-6.

[0089] As used herein, the term "Helios" 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, the term "Helios" includes various isoforms, including isoforms 1 to 5 listed below. [Table 4] [Table 5]

[0090] The Helios isoforms 1, 2, 4, 6, and 7 mentioned above are degrons: [Table 6] A degron is a portion of a protein that plays a role in regulating the rate of protein degradation. The Helios protein also includes isoforms encoded by the amino acid sequences Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0091] As used herein, the "Aiolos" protein is encoded by the IKZF3 gene. The Aiolos protein is also known as IKAROS family zinc finger 3, ZNFNlA3, zinc finger protein, subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. The Aiolos protein includes the following human isoforms: [Table 7] [Table 8] [Table 9]

[0092] The "Aiolos" protein isoforms 1, 3, 4, 6, 7, 8, 9 and 14 described above are degrons identical to those of the "Ikaros" protein: [Table 10] Aiolos proteins also include isoforms encoded by the amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12 and Q9UKT9-13, Q9UKT9-15 and Q9UKT9-16.

[0093] As used herein, the "Eos" protein is encoded by the IKZF4 gene and is also known as IKAROS family zinc finger 4, ZNFN1A4, zinc finger protein, subfamily 1A, 4, Ikaros family zinc finger protein 4, and KIAA1782. The "Eos" protein includes isoforms encoded by the following two human isoforms, 1 (Q9H2S9-1) and 2 (Q9H2S9-2): [Table 11]

[0094] The "Eos" protein isoforms 1 and 2 listed above are degrons identical to the "Helios" protein degrons: [Table 12] Includes.

[0095] As used herein, 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.

[0096] As used herein, the term "contact" refers to bringing together a predetermined moiety in an in vitro or in vivo system. For example, "contacting" an IKZF1-4 protein with a compound of formula (I) includes administering a compound of the present invention to an individual or patient (e.g., a human) having Ikaros protein, Helios protein, Aiolos protein, or Eos protein, as well as introducing a compound of formula (I) into a sample or purified product containing cells containing Ikaros protein, Helios protein, Aiolos protein, or Eos protein.

[0097] As used herein, the terms "treating" and "treatment" refer to any intervention, method, or administration of an active agent to a subject for the purpose of ameliorating, alleviating, ameliorating, inhibiting, delaying, or suppressing the progression, onset, severity, or recurrence of symptoms, complications, medical conditions, or biochemical manifestations of a disease. In contrast, "prophylaxis" or "prevention" refers to administration to a non-affected subject to prevent the onset of a disease. "Treating" and "treatment" do not include prophylaxis or prevention.

[0098] A "therapeutically effective amount" is intended to include an amount of a compound of the present invention, alone or in combination with other active ingredients, that is effective in reducing IKZF1-4 protein levels in cells or that is effective in treating or preventing viral infections and proliferative diseases (e.g., cancer).

[0099] As used herein, the term "cell" is intended to refer to an in vitro, ex vivo, or in vivo cell. In some embodiments, an ex vivo cell may be part of a tissue sample removed from an organism (e.g., a mammal). In some embodiments, an in vitro cell may be a cell in cell culture. In some embodiments, an in vivo cell is a living cell in an organism (e.g., a mammal).

[0100] The term "patient" includes human subjects.

[0101] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, processing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulant, which is involved in the transport or delivery of a particular compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation (i.e., including adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispensing agents), depending on the method of administration and the nature of the dosage form), and not deleterious to the patient.

[0102] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional pharmaceutically acceptable carrier.

[0103] (usefulness) The compounds of formula (I) are useful in the treatment of cancer.

[0104] The compounds of formula (I) are useful in the treatment of viral infections.

[0105] In one embodiment, a method is provided for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0106] In one embodiment, there is provided a method for treating a viral infection in a patient, 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.

[0107] In one embodiment, a therapeutically effective amount of the following structure: [ka]

[0010] A method is provided for treating cancer in a patient, comprising administering to the patient a compound having the formula:

[0108] One embodiment provides a method for treating a disease or disorder by reducing the levels of the four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos, comprising administering to a patient a therapeutically effective amount of an agent that reduces the levels of 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 a further embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0109] In one embodiment, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein a) the Ikaros protein has the amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; b) the Helios protein has the amino acid sequence encoded by SEQ ID NO: 7, 8, 9, 10, or 11; c) the Aiolos protein has the amino acid sequence encoded by SEQ ID NO: 12, 13, 14, 15, 16, 17, 18, or 19; and d) the Eos protein has the amino acid sequence encoded by SEQ ID NO: 20 or 21.

[0110] In embodiment 1, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method within this embodiment, the disease or disorder is cancer. Also within this embodiment, the disease or disorder is a viral infection. Furthermore, in a method within this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0111] In embodiment 2, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Also in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0112] In embodiment 3, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0113] In embodiment 4, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0114] In embodiment 5, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0115] In embodiment 6, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0116] In embodiment 7, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0117] In embodiment 8, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0118] In embodiment 9, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0119] In embodiment 10, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0120] In embodiment 11, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0121] In embodiment 12, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0122] In embodiment 13, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0123] In embodiment 14, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0124] In embodiment 15, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0125] In embodiment 16, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0126] In embodiment 17, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0127] In embodiment 18, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0128] In embodiment 19, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0129] In embodiment 20, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0130] In embodiment 21, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0131] In embodiment 22, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0132] In embodiment 23, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0133] In embodiment 24, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0134] In embodiment 25, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0135] In embodiment 26, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0136] In embodiment 27, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0137] In embodiment 28, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, 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%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0138] In embodiment 29, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0139] In embodiment 30, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0140] In embodiment 31, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In a method according to this embodiment, the disease or disorder is cancer. Also, in a method according to this embodiment, the disease or disorder is a viral infection. Furthermore, in a method according to this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0141] In embodiment 32, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 70%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0142] In embodiment 33, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0143] In embodiment 34, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 40-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by 40-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0144] In embodiment 35, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0145] In embodiment 36, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0146] In embodiment 37, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0147] In embodiment 38, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 70%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0148] In embodiment 39, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0149] In embodiment 40, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent that reduces Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by 50-70%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by 50-70%; and (iv) the Eos (IKZF4) protein level is reduced by at least 90%. In a method of this embodiment, the disease or disorder is cancer. Also in a method of this embodiment, the disease or disorder is a viral infection. Furthermore, in a method of this embodiment, the agent is a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0150] In embodiments 1 to 40, the reduction in the protein levels of IKZF1 to IKZF4 proteins can be measured using the following assays described herein: (i) IKZF1:human CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell lysis assay; (iii) IKZF3: human CD8 + T cell reprogramming assay; and (iv) IKZF4: human regulatory T cell reprogramming assay.

[0151] Cancer types that may be treated with the 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 (e.g., rectal cancer, colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor), Hodgkin's disease, and urinary tract cancer. Lymphoma, Non-Hodgkin's Lymphoma, Burkitt's 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, Multiple Myeloma, Basal Cell Carcinoma, Teratoma, Retinoblastoma, Choroidal Melanoma, Seminoma, Rhabdomyosarcoma, Craniopharyngioma, Osteosarcoma, Chondrosarcoma, Myosarcoma, Liposarcoma, Fibrosarcoma, Ewing's Sarcoma and Plasmacytoma.

[0152] In one embodiment, provided is a method of treating cancer in a patient, wherein the cancer is melanoma, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0153] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, e.g., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0154] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is mesothelioma.

[0155] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, e.g., ductal carcinoma, invasive ductal carcinoma-metastatic breast cancer, triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, hormone receptor-positive breast cancer, and hormone receptor-negative breast cancer.

[0156] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is prostate cancer, e.g., adenocarcinoma of the prostate and castration-resistant prostate cancer.

[0157] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, e.g., pancreatic adenocarcinoma, exocrine pancreatic cancer, and neuroendocrine pancreatic cancer.

[0158] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is kidney cancer, e.g., renal cell carcinoma, clear cell renal cell carcinoma and non-clear cell renal cell carcinoma, papillary renal cell carcinoma, Wilms' tumor, and renal sarcoma.

[0159] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is gastric cancer, such as gastric carcinoma.

[0160] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is renal cancer, e.g., renal cancer and renal parenchymal cancer.

[0161] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is liver cancer, e.g., hepatocellular carcinoma.

[0162] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, e.g., ovarian carcinoma.

[0163] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is a lymphoma, e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL).

[0164] In one embodiment, there is provided a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is a leukemia, e.g., acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia-lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0165] In one embodiment, there is provided a method for treating cancer in a patient, wherein the cancer is multiple myeloma, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0166] The compound of Formula (I) and pharmaceutical compositions comprising the compound of Formula (I) are useful for treating or preventing any disease or condition associated with the activity of IKZF1-4 protein. These include viral and other infectious diseases (e.g., skin infections, gastrointestinal infections, urinary tract infections, urogenital infections, systemic infections), and proliferative diseases (e.g., cancer). Any administration method can be used to deliver the compound or pharmaceutical composition to a patient. In certain embodiments, the compound of Formula (I) or pharmaceutical compositions comprising the compound of Formula (I) are administered orally. In other embodiments, the compound of Formula (I) or pharmaceutical compositions comprising the compound of Formula (I) are administered parenterally.

[0167] In one embodiment, there is provided a method for treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the viral infection is HIV, hepatitis (A, B, or C), herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, CMV, and Epstein-Barr virus), 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 virus, poliovirus, rabies virus, JC virus, arbovirus, and encephalitis virus.

[0168] The compound of formula (I) can selectively reduce the protein levels of the four IKZF1 to IKZF4 proteins in cells to control Treg differentiation. For example, the compound of formula (I) can be used to selectively reduce the protein levels, activity levels, and / or inhibition of expression levels of each of the four IKZF1 to IKZF4 proteins in cells to control Treg differentiation in cells or individuals in need of reduced protein levels, reduced activity levels, and / or inhibition of expression levels of each of the four IKZF1 to IKZF4 proteins by administering an effective amount of the compound of formula (I), or a stereoisomer, tautomer, or salt thereof.

[0169] In one embodiment, the present invention provides a combined preparation comprising a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof and an additional therapeutic agent for simultaneous, separate, or sequential use in the treatment and / or prevention of multiple diseases or disorders associated with the activity of IKZF1 to IKZF4 proteins. The combined preparation can be used to reduce the protein levels, reduce the protein activity levels, and / or inhibit the expression levels of the four IKZF1 to IKZF4 proteins.

[0170] In some embodiments, the compound of Formula (I) is administered sequentially prior to the administration of the immuno-oncology agent. In other embodiments, the compound of Formula (I) is administered simultaneously with the immuno-oncology agent. In yet other embodiments, the compound of Formula (I) is administered sequentially following the administration of the immuno-oncology agent.

[0171] In another embodiment, the compound of formula (I) may be formulated with an immuno-oncology agent.

[0172] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In other embodiments, the monoclonal antibody is a humanized antibody or a human antibody.

[0173] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory receptor (including costimulatory) or (ii) an antagonist of an inhibitory signal (including co-inhibitory) on a T cell, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint regulators).

[0174] Certain stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory 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 costimulatory or coinhibitory receptors are the TNF family molecules that bind to the cognate 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, and RAN. K, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, E Examples include DAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0175] In certain embodiments, T cell responses may be stimulated by a combination of a compound of Formula (I) of the present invention and one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; and (ii) agonists of proteins that stimulate T cell activation, 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.

[0176] For cancer treatment, other drugs that can be combined with the compound of formula (I) can include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells.For example, the compound of formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0177] Further agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or CSF-1R antagonist antibodies, including FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0178] In another embodiment, the compounds of Formula (I) may be used in conjunction with one or more of agonistic agents that bind positive costimulatory receptors, blocking agents that reduce signaling through inhibitory receptors, antagonists, 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 engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Treg cells (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo depletion with anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or T cell depletion), and agents that cause innate immune activation and / or inflammation in the tumor area.

[0179] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab) or tremelimumab.

[0180] In another embodiment, the immuno-oncology agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). The immuno-oncology agent may also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

[0181] In another embodiment, the immuno-oncology agent includes a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), and MSB0010718C (WO2013 / 79174).

[0182] In another embodiment, the immuno-oncology agent is a LAG-3 antagonist, for example, an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0183] In another embodiment, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0184] In another embodiment, the immuno-oncology agent is a GITR agonist, for example, an agonistic GITR antibody. Suitable CD137 antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0185] In another embodiment, the immuno-oncology agent is an IDO antagonist.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).

[0186] In another embodiment, the immuno-oncology agent is an OX40 agonist, e.g., an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0187] In another embodiment, the immuno-oncology agent is an OX40L antagonist, e.g., an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0188] In another embodiment, the immuno-oncology agent is a CD40 agonist, for example, an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, for example, an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0189] In another embodiment, the immuno-oncology agent is a CD27 agonist, for example, an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0190] In another embodiment, the immuno-oncology agent (against B7H3) is MGA271 (WO11 / 109400).

[0191] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, and the therapeutic agents, or at least two therapeutic agents, are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single, fixed-ratio dosage form of each therapeutic agent or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered intravenously, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The administration of the above therapeutic agents can also be combined with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) to achieve combination therapy. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the interaction of the combined therapeutic agent and non-drug treatment is achieved, e.g., in suitable cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from the administration of the therapeutic agent.

[0192] One or more additional pharmaceutical agents or therapeutic methods (e.g., antiviral agents, chemotherapeutic agents or other anti-cancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compounds of Formula (I) to treat diseases, disorders, or conditions associated with IKZF1-4 proteins. The agents may be combined with the compounds in a single dosage form, or the agents may be administered simultaneously or sequentially in different dosage forms.

[0193] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0194] Suitable agents for use in combination with compounds of Formula (I) in the treatment of melanoma include dacarbazine (DTIC), optionally with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; combinations of cisplatin, vinblastine, and DTIC, temozolomide, or Yervoy®). Compounds of Formula (I) may also be combined with immunotherapeutic agents (e.g., cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF)) in the treatment of melanoma.

[0195] The compound of formula (I) can also be used in combination with vaccine therapy in the treatment of melanoma.Anti-melanoma vaccines are similar in some respects to antiviral vaccines used to prevent diseases caused by viruses (e.g., polio, measles, and mumps).Attenuated melanoma cells or parts of melanoma cells called antigens can be injected into patients to stimulate the body's immune system and destroy melanoma cells.

[0196] Melanomas confined to the arms or legs can also be treated using hyperthermic perfusion therapy in combination with drugs containing the compound of Formula (I). This treatment protocol involves temporarily isolating the circulatory system of the affected limb from the rest of the body, and then infusing high doses of chemotherapy into the arteries of the affected limb, delivering the high doses to the tumor site without exposing internal organs to potentially serious side effects. Typically, body fluids are heated to 38.9°C to 40°C during this treatment. Melphalan is the drug most frequently used in this chemotherapy. Another agent called tumor necrosis factor (TNF) inhibitors can also be used in this therapy.

[0197] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0198] Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (especially IFNα), etoposide, and teniposide.

[0199] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene and droloxifene.

[0200] Suitable cytotoxic agents also include, for example, epipodophyllotoxins; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes (e.g., cisplatin and carboplatin); biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0201] Other anti-cancer agents include antibody drugs such as trastuzumab (Herceptin®), antibodies against costimulatory molecules (e.g., CTLA-4, 4-1BB, and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0202] Other anti-cancer agents also include those that block immune cell migration, such as antagonists to chemokine receptors (eg, CCR2 and CCR4).

[0203] Other anti-cancer agents also include agents that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0204] Anti-cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines and recombinant viral vaccines.

[0205] The pharmaceutical compositions of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in a signal transduction pathway in the normal function of cancer cells, thereby inducing apoptosis. Suitable STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitor (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 (e.g., farnesyltransferase inhibitors (FTIs) (e.g., L-744,832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513 (1995)]). (200)); (v) cell cycle kinase inhibitors (e.g., flavopiridol and UCN-O1 (see, e.g., Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203)); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and the compound of formula (I) may be contained in separate pharmaceutical compositions. In certain embodiments of the present invention, the compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, or at least one STI may be administered first, or the compound of formula (I) and at least one STI may be administered simultaneously. Furthermore, when the compound of formula (I) and / or one or more STIs are used, the compounds may be administered in any order.

[0206] The present invention further provides a pharmaceutical composition comprising a compound of formula (I), optionally at least one chemotherapeutic agent, and optionally at least one antiviral agent, in a pharmaceutically acceptable carrier for treating a chronic viral infection in a patient.

[0207] Also provided is a method for treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0208] In certain embodiments of the present invention, the compound of formula (I) and at least one chemotherapeutic agent are administered to patients simultaneously or sequentially.In other words, the compound of formula (I) can be administered first, or at least one chemotherapeutic agent can be administered first, or the compound of formula (I) and at least one chemotherapeutic agent can be administered simultaneously.In addition, when one or more chemotherapeutic agents are used, the compound and one or more chemotherapeutic agents can be administered in any order.Similarly, any antiviral drug or STI can be administered at any time compared with the administration of the compound of formula (I).

[0209] Chronic viral infections that may be treated using the combination therapies of the present application include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).

[0210] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0211] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, which is β-L-2',3'-dideoxy-5-fluoro-cytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Representative and suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative and suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (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 No. 11607.

[0212] Combination therapy is intended to include administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, and the therapeutic agents, or at least two therapeutic agents, are administered in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the patient a single, fixed-ratio dosage form of each therapeutic agent or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be achieved by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered intravenously, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The administration of the above therapeutic agents can also be combined with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation therapy) to achieve combination therapy. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as the beneficial effect resulting from the interaction of the combined therapeutic agent and non-drug treatment is achieved, e.g., in suitable cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended, perhaps for days or weeks, from the administration of the therapeutic agent.

[0213] (Pharmaceutical composition) The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I), formulated together with one or more pharmaceutically acceptable carriers (excipients) and / or diluents, and optionally one or more further therapeutic agents as described above.

[0214] The compound of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition compatible with such a route, and in a dosage effective for the intended treatment. The compound of formula (I) and compositions comprising the compound of formula (I) may be administered for any of the uses described herein by any suitable method (e.g., oral administration (e.g., tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions)); nasal administration, including administration to the nasal membranes (e.g., inhalation spray); topical administration (e.g., in the form of a cream or ointment); or rectal administration (e.g., in the form of a suppository)). They may be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0215] For oral administration, pharmaceutical compositions may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. Pharmaceutical compositions are preferably formulated in dosage unit forms containing a specific amount of active ingredient. For example, pharmaceutical compositions may be provided as tablets or capsules containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg. The appropriate daily dose for administration to humans or other mammals may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0216] Any pharmaceutical composition discussed herein can be orally delivered, for example, through any acceptable and suitable oral formulation.Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups and elixirs.Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration.In order to provide a pharmaceutical preparation that is easy to swallow, the pharmaceutical composition described in the present invention can contain at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants and preservatives.

[0217] Tablets can be prepared, for example, by mixing the compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant-tasting drugs or to delay the disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0218] Hard gelatin capsules may be prepared, for example, by mixing the compound of formula (I) and / or at least one salt thereof with at least one inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0219] 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).

[0220] Aqueous suspensions can be prepared, for example, by mixing the compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one additive suitable for preparing aqueous suspensions. Examples of additives suitable for preparing aqueous suspensions include, but are not limited to, suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and acacia gum; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin); condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate; condensation products of ethylene oxide and long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol; condensation products of ethylene oxide and partial esters obtained from fatty acids and hexitols, such as polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide and partial esters obtained from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (for example, but not limited to, sucrose, saccharin, and aspartame).

[0221] Oily suspensions can be prepared, for example, by suspending the compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions can also contain at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To make oily suspensions easier to swallow, at least one sweetener as described above and / or at least one flavoring agent can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant (e.g., butylhydroxyanisole and α-tocopherol).

[0222] 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 have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). In addition, dispersible powders and granules can also contain at least one excipient (e.g., but not limited to, sweeteners, flavoring agents, and coloring agents).

[0223] Emulsions of the compound 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 emulsions containing the 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. The oil phase can contain only an emulsifier, or a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oils and fats. Together, the emulsifiers, with or without stabilizers, form what is called an emulsifying wax, which, together with the oils and fats, forms a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. The emulsion may also contain sweeteners, flavorings, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with waxes or other materials known to those skilled in the art.

[0224] The compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0225] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents described for use in oral preparations, or other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with a suitable carrier (e.g., saline, dextrose, or water), or a cyclodextrin (e.g., Captisol), a solubilizing cosolvent (e.g., propylene glycol), or a solubilizing micelle (e.g., Tween 80).

[0226] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used, water, Ringer's solution, and isotonic sodium chloride solution are used. Furthermore, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland, fixed oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used as injectables.

[0227] Sterile 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.

[0228] Sterile aqueous suspensions or sterile oily suspensions can be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions can be prepared using non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol), and sterile oily suspensions can be prepared using sterile, non-toxic, acceptable solvents or suspension media (e.g., sterile fixed oils (e.g., synthetic monoglycerides or diglycerides), and fatty acids (e.g., oleic acid).

[0229] Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the targeted therapeutic index. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such additional components are included in the formulation for various reasons, such as stabilization of the active agent, binders, etc., as known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors for selecting them can be found in various readily available literature, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0230] Pharmaceutically acceptable carriers, adjuvants, and vehicles 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) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat). Cyclodextrins (e.g., α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilizing derivatives) may also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0231] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to produce medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may further be prepared with enteric coatings. Such compositions may also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and perfumes).

[0232] For treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for the intended route of administration.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then be tableted or encapsulated for convenient administration.Such capsules or tablets can contain sustained-release preparations, such as those provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0233] The amount of compound and dosing regimen administered to treat a medical condition using the compounds and / or compositions of the present invention will depend on a variety of factors, such as age, weight, sex, the patient's medical condition, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound being used. Therefore, dosing regimens may vary widely but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosing regimens include weekly and biday cycles.

[0234] The pharmaceutical compositions of the present invention include a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additive selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (I) as described herein or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0235] The present invention includes pharmaceutical kits useful, for example, in the treatment or prevention of IKZF1-4 protein-associated diseases or disorders, and other diseases described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). The kit may further optionally include one or more of a variety of conventional pharmaceutical kit components (e.g., a container containing one or more pharmaceutically acceptable carriers, a separate container), which will be readily apparent to those skilled in the art. Instructions, either in the form of a package insert or label, indicating the amounts of components to be administered, administration guidelines, and / or guidelines for mixing the components may also be included in the kit.

[0236] Dosage regimens for the compounds of the present invention will, of course, vary depending on known factors (e.g., the pharmacodynamic properties of the particular drug and its method and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the condition; type of concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect).

[0237] As a general guideline, the daily oral dose of each active ingredient, when used to achieve the intended effect, ranges 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. The most preferred dose for intravenous constant rate infusion is in the range of about 0.01 to about 10 mg / kg / min. Compounds of formula (I) may be administered in a single daily dose, or the total daily dose may be divided into two, three, or four doses.

[0238] The compounds are generally selected appropriately for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to herein as pharmaceutical carriers), which is consistent with conventional pharmaceutical practice.

[0239] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 mg to about 200 mg of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.1 to 95% by weight of the total weight of the composition.

[0240] A typical capsule for oral administration contains 250 mg of a compound of Formula (I), 75 mg of lactose, and 15 mg of magnesium stearate, which is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

[0241] A typical injectable formulation is prepared by aseptically adding 250 mg of the compound of formula (I) to a vial, aseptically lyophilizing and sealing the vial, and then mixing the contents of the vial with 2 mL of saline to prepare the injectable formulation.

[0242] The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) as the active ingredient, alone or in combination with a pharmaceutical carrier. If desired, the compound of formula (I) may be used in combination with one or more other therapeutic agents (e.g., anti-cancer agents or other pharmaceutically active substances).

[0243] Regardless of the route of administration selected, the compounds of formula (I) and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0244] Actual dosage levels of the active ingredient in the pharmaceutical compositions of formula (I) may be varied to contain an amount of the active ingredient that is non-toxic to the patient and effective to produce a therapeutic effect for a particular patient, composition, and mode of administration.

[0245] The selected dosage level will depend upon a variety of factors, including the activity of the compound of formula (I) or its ester, salt, or amide employed, the route of administration of the particular compound employed, the time of administration, rate of excretion or metabolism, rate and extent of absorption, duration of treatment, other drugs, compounds, and / or substances used in combination with the particular compound employed, the age, sex, weight, symptoms, health, and medical history of the patient being treated, and factors well known in the medical arts.

[0246] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a level lower than required to achieve a therapeutic effect, and gradually increase the dosage until the effect is achieved.

[0247] Generally, a suitable daily dose of a compound of formula (I) is the lowest effective dose of the compound to achieve a therapeutic effect. Such an effective dose is generally determined by the factors described above. Generally, the dose of a compound of formula (I) administered to a patient is about 0.01 to about 50 mg / kg body weight / day for oral, intravenous, intracerebroventricular, and subcutaneous administration.

[0248] If desired, the effective daily dose of the active compound may be administered in two, three, four, five, six or more divided doses at appropriate intervals throughout the day, optionally in unit dosage forms. In some embodiments of the invention, dosing is once daily.

[0249] While it is possible for a compound of formula (I) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0250] The other therapeutic agents described above, when used in combination with a compound of Formula (I), may be used, for example, in amounts set forth in the Pharmaceutical and Medical Devices Manual (PDR) or as determined by one of ordinary skill in the art. In the methods of the invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of a compound of the invention.

[0251] (Manufacturing method) The compounds of the present invention can be prepared by a number of methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known to those skilled in the art of organic synthetic chemistry, or by variations thereon that will be recognized by those skilled in the art. Preferred methods include, but are not limited to, the following: All documents cited herein are incorporated by reference in their entirety.

[0252] The compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the reagents and materials used and are suitable for the transformations being effected. Furthermore, in describing the synthetic methods set forth below, all proposed reaction conditions (e.g., solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup) are selected to be standard conditions for the reactions, 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 portions of the molecule must be compatible with the proposed reagents and reactants. Such limitations on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods should be used, if necessary. This may necessitate the determination of altering the order of synthetic steps or selecting a different course of action for certain reactions to obtain the desired compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this field is the determination of the appropriate selection of protecting groups used to protect reactive functional groups present in the compounds described herein. For the experienced experimenter, an authoritative account describing many protecting group alternatives is Greene and Wuts (Protective Groups In Organic Synthesis, Fourth Edition, Wiley & Sons, 2007). [Example]

[0253] The following examples illustrate specific embodiments of the present invention and are not intended to limit the scope of the invention. Chemical and scientific abbreviations and symbols have their common and accustomed meanings unless otherwise specified. Additional abbreviations used in the examples and elsewhere in this specification are defined below. Example compounds and intermediates are identified by the example and step by which they are prepared (e.g., "1-A" refers to Step A of Example 1), or by the example only if the compound is the title compound of the example (e.g., "1" refers to the title compound of Example 1). In some instances, alternative methods of preparing intermediates or examples are described. Chemists skilled in the synthetic arts frequently devise desirable alternative methods of preparation based on one or more considerations (e.g., shorter reaction times, less expensive starting materials, ease of handling and purification, higher yields, catalyst operability, avoidance of toxic reagents, availability of specialized equipment, and reduced number of steps). The intent of describing alternative methods of preparation is to make the examples of the present invention more accessible to manufacture. In some cases, some functional groups in the outlined examples and claims may be substituted with bioisosteric substitutions known to those skilled in the art (e.g., replacing a carboxylic acid group with a tetrazole or phosphate moiety).

[0254] [Table 13]

[0255] Analytical LCMS conditions Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: 95:5 water:acetonitrile (with 2.5 mM NHOAc); Mobile Phase B: 5:95 water:acetonitrile (with 2.5 mM NHOAc); Temperature: 40 °C; Gradient: 20% B to 100% B over 2 min; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column - Kinetex XB-C18 (75 x 3 mm - 2.6 μm); Mobile phase A: 10 mM NH4COOH / water; Mobile phase B: acetonitrile; Gradient: 20% B to 100% B over 4.6 min; Flow rate: 1.0 mL / min Method C: Column: Waters Acquity BEH C18 1.7 μm 2.1 x 50 mm; Start % B: 0; Final % B: 100; Gradient time: 1.0 min; Stop time: 1.50 min; Flow rate: 1.0 mL / min; Solvent A:A2 = 0.05% TFA / CH3CN:water (5:95); Solvent B:B2 = 0.05% TFA / CH3CN:water (95:5); Oven temperature: 50 °C

[0256] Intermediate A 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka]

[0257] Preparation of Intermediate A1: 2-Bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one [ka] To a stirred solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (44 g, 203 mmol) in EtOAc (1000 mL) was added copper(II) bromide (91 g, 405 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16 h under an argon atmosphere, cooled to room temperature, and filtered through a Celite pad. The filtrate was concentrated in vacuo. The resulting crude product was purified by flash chromatography (SiO2, 330 g column, 0–10% EtOAc / petroleum ether) to give 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (32.8 g, 51%). 1 H-NMR (400 MHz, CDCl3): δ 4.50 (s, 2H), 7.40-7.48 (m, 2H), 7.83-7.87 (m, 1H).

[0258] Preparation of Intermediate A2: 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione [ka] To a stirred solution of 3-aminopiperidine-2,6-dione, HCl (22.25 g, 135 mmol) in THF (200 mL) was added K2CO3 (20 g, 145 mmol). The reaction mixture was stirred under nitrogen for 15 minutes. 2-Bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (20 g, 67.6 mmol) was added in small portions and the reaction mixture was heated at 70 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with water (200 mL). The separated solid was filtered and dried in vacuo to give 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione (19 g, 71%). LCMS (Method A): Retention time 0.865 min, [M+H] + 344.0.

[0259] Preparation of Intermediate A3: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine 2,6-dione [ka] To a stirred solution of 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione (30 g, 87 mmol) in THF (300 mL) was added K2CO3 (12.08 g, 87 mmol) and CDI (28.4 g, 175 mmol) at room temperature. The reaction mixture was stirred at the same temperature for 16 hours, concentrated in vacuo, and diluted with water (400 mL). The solid precipitate that formed was filtered through a Buchner funnel and dried under vacuum to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (21.1 g, 50%). LCMS (Method A): Retention time 1.79 min, [M+H] + 370.0.

[0260] Preparation of intermediate A4: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (10 g, 27.1 mmol) in THF (100 mL) was added DBU (6.12 mL, 40.6 mmol) and SEM-Cl (5.77 mL, 32.5 mmol) at −50° C. under nitrogen. The reaction was continued at the same temperature for 1 h and quenched with water. The reaction mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, 0–60% EtOAc / petroleum ether) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (6.2 g, 45%). LCMS (Method A): Retention time 1.68 min, [M+H] + 500.1.

[0261] Preparation of Intermediate A: To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7 g, 14.0 mmol) in anhydrous 1,4-dioxane (70 mL) was added BISPIN (5.34 g, 21.02 mmol) and potassium acetate (1.651 g, 16.82 mmol) at room temperature. The reaction mixture was purged with argon for 10 minutes, Pd(dppf)Cl.DCM complex (1.026 g, 1.40 mmol) was added under argon, and the resulting mixture was heated at 80° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with EtOAc (70 mL), filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 120 g column, 0–70% EtOAc / petroleum ether). The isolated product was stirred with diethyl ether for 1 h, filtered, and dried under vacuum to give 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (4.85 g, 63%) as a white solid. LCMS (Method A): Retention time 2.16 min, [MH] + 545.2; 1H NMR (chloroform-d, 300 MHz) δ 7.5-7.6 (m, 2H), 7.44 (d, 1H, J = 11.7 Hz), 6.90 (d, 1H, J = 2.3 Hz), 5.17 (d, 2H, J = 12.5 Hz), 4.82 (dd, 1H, J = 5.9, 12.7 Hz), 3.56 (t, 2H, J = 8.1 Hz), 2.9-3.1 (m, 1H), 2.7-2.9 (m, 1H), 2.31 (br s, 2H), 1.28 (s, 12H), 0.8-0.9 (m, 2H), -0.07 (s, 9H).

[0262] Example 1 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione [ka] Preparation of Intermediate 1A: 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka] To a vial was added 6-chloro-3,4-dimethylpyridin-2-amine (1.24 g, 7.91 mmol), 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Int-A, 3.93 g, 7.19 mmol), cesium carbonate (3.51 g, 10.79 mmol), dioxane (32 mL), and water (80 μL) at room temperature. The reaction mixture was purged with argon for 10 minutes, and CatacXium Pd G3 (0.157 g, 0.22 mmol) was added. The reaction mixture was heated at 100° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 80 g column, 0–4% MeOH / DCM), and the isolated product was recrystallized from EtOAc to give 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.10 g, 54%) as a white solid. LCMS (Method A): Retention time 1.86 min, [M+H] + 541.3; 1 H NMR (chloroform-d, 300 MHz) δ 7.76 (br d, 2H, J = 10.6 Hz), 7.6-7.7 (m, 1H), 6.9-7.0 (m, 2H), 5.2-5.3 (m, 2H), 4.89 (dd, 1H, J = 6.0, 12.5 Hz), 4.46 (br s, 2H), 3.6-3.7 (m, 2H), 3.0-3.1 (m, 1H), 2.8-3.0 (m, 1H), 2.3-2.5 (m, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 0.9-1.0 (m, 2H), 0.00 (s, 9H).

[0263] Preparation of Intermediate 1B: 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7.13 g, 13.18 mmol) in DCM (78 mL) was added TFA (20.3 mL, 264 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 1 h, concentrated under reduced pressure and co-evaporated with DME (4 times). LCMS (Method B): Retention time 1.38 min, [M+H] + 441.5.

[0264] Example 1: To a stirred solution of 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (1.385 g, 3.14 mmol) in anhydrous DME (21 mL) was added N,N'-dimethylethylenediamine (1.692 mL, 15.7 mmol) at 0°C under a nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, acidified with acetic acid (1.8 mL, 31.4 mmol), and concentrated under reduced pressure (bath temperature <30°C). The residue was purified by flash chromatography (SiO, 40 g column, 0-6% MeOH / DCM) and the isolated product was recrystallized from EtOAc / diethyl ether to give 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (0.48 g, 37%) as a white solid. LCMS (Method C): Retention time 1.33 min, [M+H] + 411.15; 1 H NMR (DMSO-d6, 400 MHz) δ 11.13 (br s, 1H), 7.9-8.0 (m, 2H), 7.6-7.6 (m, 2H), 7.11 (s, 1H), 5.74 (s, 2H), 5.07 (dd, 1H, J = 5.3, 13.0 Hz), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 2H), 2.23 (s, 3H), 2.1-2.2 (m, 1H), 2.02 (s, 3H).

[0265] Example 2 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-D5 [ka] Preparation of Intermediate 2A: tert-Butyl 4,5-diamino-5-oxopentanoate-2,2,3,3,4-D5 Hydrochloride [ka] tert-Butyl 4,5-diamino-5-oxopentanoate-2,2,3,3,4-D5 hydrochloride was prepared according to the general method disclosed in WO2014116573 A1.

[0266] Preparation of Intermediate 2B: tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] To a 25 mL round-bottom flask containing 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (230 mg, 0.77 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate-2,2,3,3,4-D5 hydrochloride (208 mg, 0.86 mmol) in anhydrous DMF (2.4 mL) was added NaI (128 mg, 0.86 mmol). The reaction mixture was stirred at 0°C for 10 minutes, and then DIPEA (0.35 mL, 1.94 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 3 hours. After 3 hours, CDI (315 mg, 1.94 mmol) was added at 0°C, followed by the dropwise addition of TEA (0.54 mL, 3.9 mmol). The reaction mixture was allowed to warm slowly to room temperature and stirred for 16 hours. The reaction mixture was diluted with EtOAc (7 mL) and HO (5 mL) and stirred at room temperature for 2 minutes. The organic layer was separated, and the water was back-extracted with EtOAc (1 x 3 mL). The combined organic layers were concentrated to dryness and purified by ISCO (24 g silica gel) eluting with 100% Hex to 90% EtOAc / Hex; the product eluted with 40-45% EtOAc / Hex. The product-containing fractions were combined, concentrated, and dried overnight to afford tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 as an orange solid (79 mg, 23% yield). LCMS (Method C): Retention time 1.006 min, [M+H-Boc] + 391.8 / 393.7 (bromide isotope).

[0267] Preparation of Intermediate 2C: tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] To a stirred solution of tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 (127 mg, 0.29 mmol) in 1,4-dioxane (2.5 ml) in a 10 mL reaction vial was degassed with N for 5 minutes, followed by the addition of bis(pinacolato)diboron (108 mg, 0.43 mmol) and potassium acetate (56 mg, 0.57 mmol). The solution was purged under a stream of nitrogen for 5 minutes, after which 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (21 mg, 0.029 mmol) was added. The solution was purged under nitrogen for an additional 5 minutes. The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was filtered through Celite and rinsed with EtOAc. The mother liquor was concentrated to dryness to give a black oil. The crude residue was purified by ISCO (24 g silica gel) eluting with 100% Hex to 80% EtOAc / Hex. The product eluted with 70% EtOAc / Hex. The product-containing fractions were combined, concentrated to dryness, and dried under vacuum overnight to give tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 as a brown foam (98 mg, 69% yield). LCMS (Method C): Retention time 1.056 min, [M+H-Boc] + 439.8.

[0268] Preparation of Intermediate 2D: tert-butyl 5-amino-4-(5-(4-(6-(bis(tert-butoxycarbonyl)amino)-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] To a solution of tert-butyl 5-amino-4-(5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,4-D5 (98 mg, 0.2 mmol) and tert-butyl (tert-butoxycarbonyl)(6-chloro-3,4-dimethylpyridin-2-yl)carbamate (67.2 mg, 0.19 mmol) in a mixed solvent of dioxane (1.6 mL) and water (0.4 mL) was added KPO (120 mg, 0.57 mmol) and XPhos Pd G (14.8 mg, 0.019 mmol). The reaction mixture was degassed under N for 5 minutes. The reaction mixture was heated at 90 °C for 3 hours. After 3 h, the reaction mixture was cooled to 0 °C. HO (1.8 mL) was added to quench the reaction. The reaction mixture was extracted with EtOAc, and the organic layer was separated, dried over NaSO, filtered, and concentrated to dryness to give a black oil. The resulting crude product was purified by ISCO (12 g silica gel) and eluted with 100% Hex to 90% EtOAc / Hex. The product eluted with 50 to 65% EtOAc / Hex. The combined products were concentrated to dryness and dried under vacuum overnight to give tert-butyl 5-amino-4-(5-(4-(6-(bis(tert-butoxycarbonyl)amino)-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,4-D5 as a yellow foam (90 mg, 69% yield). (Method C): Retention time 1.106 min, [M+H] + 690.1.

[0269] Example 2: To a solution of tert-butyl 5-amino-4-(5-(4-(6-(bis(tert-butoxycarbonyl)amino)-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 (90 mg, 0.13 mmol) in anhydrous MeCN (2.1 mL) in a 10 mL reaction vial was added methanesulfonic acid (89 μL, 1.37 mmol). The reaction vial was sealed and heated at 70° C. for 7 hours, followed by an additional 16 hours. The reaction mixture was cooled to room temperature, and additional methanesulfonic acid (76 μL) was added. The reaction mixture was heated at 70° C. for an additional 24 hours. The reaction mixture was cooled to room temperature, diluted with 0.6 mL of MeCN, and purified by semi-preparative HPLC (HPLC conditions: column; Luna C-18 (250 x 10 mm); mobile phase A: 0.1% TFA / water; mobile phase B: MeCN; flow rate: 5 mL / min; wavelength: 220 nm; gradient: 0 min: 10% B, 20 min: 60% B, 21 min: 95% B). The product eluted at 13–13.5 min. The product-containing fractions were combined, concentrated to remove all MeCN, and lyophilized overnight to give 3-(5-(4-(6-amino-4,5-dimethylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione-3,4,5,5-D5 (32 mg, 53% yield). (Method C): Retention time 0.783 min, [M+H] + 415.7. 1 H NMR (400 MHz, DMSO-D6) δ 11.15 (s, 1H), 7.91 (dd, 1H), 7.83 (m, 1H), 7.75 (m, 2H), 7.29 (s, 1H), 5.08 (s, 0.25H exchanged from particle D to H), 2.35 (s, 3H), 2.12 (s, 3H).

[0270] Comparative compound A 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione is disclosed as compound number I-33 in WO 2019 / 060693 A1.

[0271] Preparation of Intermediate 3A: tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate [ka] To a stirred suspension of 2-bromo-1-phenylethan-1-one (200 mg, 1.0 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate, HCl (360 mg, 1.5 mmol) in anhydrous acetonitrile (4.5 mL) was added sodium iodide (181 mg, 1.21 mmol) at 0° C. under argon. The reaction mixture was stirred at the same temperature for 5 minutes. DIPEA (351 μL, 2.01 mmol) was added dropwise to the reaction mixture. The reaction mixture was continued to stir at 0° C. for 2 hours. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of 10% sodium bisulfite solution. The mixture was extracted with DCM (3×10 mL). The combined organic phases were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate (322 mg, crude). LCMS (Method A): Retention time 1.215 min, [M+H] + 321.1.

[0272] Preparation of Intermediate 3B: tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate [ka] To a stirred solution of tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate (322 mg, 1.0 mmol) in anhydrous DMF (7 mL) was added CDI (407 mg, 2.5 mmol) and triethylamine (420 μL, 3.0 mmol) at 0 °C under argon. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold water. The reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic phase was washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 24 g column, 0-100% EtOAc / petroleum ether) to give tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate (155 mg, 44%). LCMS (Method A): Retention time 1.33 min, [M+Na] + 369.2; 1 H NMR (DMSO-d6, 300 MHz) δ 7.75 (s, 2H), 7.5-7.6 (m, 2H), 7.42 (t, 2H, J = 7.5 Hz), 7.3-7.4 (m, 2H), 4.50 (dd, 1H, J = 4.3, 10.1 Hz), 2.2-2.3 (m, 3H), 2.0-2.1 (m, 1H), 1.38 (s, 9H).

[0273] Comparative compound A To a stirred solution of tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate (150 mg, 0.43 mmol) in acetonitrile (3.0 mL) was added methanesulfonic acid (42 μL, 0.65 mmol) at room temperature. The reaction mixture was heated at 90°C for 1 hour, cooled to room temperature, concentrated in vacuo, and the residue purified using reverse-phase prep-HPLC (X-Bridge Phenyl C18 (250 mm*19 mm) 5 µm; Mobile phase A: 10 mM ammonium acetate / water; Mobile phase B: ACN; Flow rate: 20.0 mL / min; Gradient time / % B: 0 / 30, 15 / 43, 15.1 / 100) to give 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione (25 mg, 21%) as a white solid. LCMS (Method A): Retention time 1.582 min, [M+H] + 273.20; 1 H NMR (400 MHz, DMSO-d6) δ = 11.02 (br s, 1H), 7.70 (s, 1H), 7.52-7.47 (m, 2H), 7.47-7.42 (m, 2H), 7.35-7.30 (m, 1H), 5.03 (dd, J = 5.3, 13.3 Hz, 1H), 2.95-2.84 (m, 1H), 2.68-2.60 (m, 1H), 2.48-2.35 (m, 1H), 2.21-2.11 (m, 1H).

[0274] Analytical LCMS conditions: Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: 95:5 water:acetonitrile (containing 2.5 mM NHOAc); Mobile Phase B: 5:95 water:acetonitrile (containing 2.5 mM NHOAc); Temperature: 40 °C; Gradient: 20% B to 100% B over 2 min; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column - Kinetex XB-C18 (75 x 3 mm - 2.6 μm); Mobile phase A: 10 mM NH₄COOH / water; Mobile phase B: acetonitrile; Gradient: 20% B to 100% B over 4.6 min; Flow rate: 1.0 mL / min.

[0275] Comparative compound B 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione [ka] Preparation of Intermediate 4A: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.4 mmol) in anhydrous DCM (2.0 mL) at room temperature was added TFA (0.154 mL, 2.0 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo, and the residue was co-evaporated with DME (4×) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (150 mg, 94%). LCMS (Method A): Retention time 1.37 min, [M+Na]+ 423.1.

[0276] Comparative compound B: To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoozole-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (180 mg, 0.45 mmol) in anhydrous DME (2255 μL) was added N,N′-dimethylethane-1,2-diamine (199 mg, 2.26 mmol) under nitrogen at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes before being cooled to 0° C., acidified with acetic acid (258 μL, 4.5 mmol), and concentrated in vacuo (bath temperature <30° C.). The residue was purified by reverse phase prep-HPLC (Method: Column: X-Bridge Phenyl (19 mm x 250 mm*5 μm); Mobile phase A: 10 mM ammonium acetate / water; Mobile phase B: ACN; Flow rate: 20 mL / min; Gradient conditions (time / %B): 0 / 30, 14 / 51, 14.1 / 100). 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-3(2 H)-yl)piperidine-2,6-dione (67 mg, 40%) was obtained. LCMS (Method A): Retention time 2.155 min, [M-H] + 366.8; 1 H NMR (400 MHz, DMSO-d6) δ = 11.13 (br s, 1H), 7.75-7.70 (m, 1H), 7.66 (d, J = 3.0 Hz, 1H), 7.53 (s, 1H), 7.52 (d, J = 5.1 Hz, 1H), 5.06 (dd, J = 5.3, 13.3 Hz, 1H), 2.94-2.80 (m, 1H), 2.70-2.54 (m, 2H), 2.16-2.08 (m, 1H).

[0277] Analytical LCMS conditions Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: 95:5 water:acetonitrile (containing 2.5 mM NHOAc); Mobile Phase B: 5:95 water:acetonitrile (containing 2.5 mM NHOAc); Temperature: 40 °C; Gradient: 20% B to 100% B over 2 min; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column - Kinetex XB-C18 (75 x 3 mm - 2.6 μm); Mobile phase A: 10 mM NH₄COOH / water; Mobile phase B: acetonitrile; Gradient: 20% B to 100% B over 4.6 min; Flow rate: 1.0 mL / min.

[0278] Biological assays The pharmacological properties of the compounds of the present invention may be confirmed by a number of biological assays. The following biological assays have been carried out with the compounds of the present invention.

[0279] Jurkat cell lysis assay Jurkat cells were seeded at 80,000 cells per well in 40 pL of RPMI + 10% FBS in a 384-well cell culture plate, and compounds of interest were added using acoustic dispensing. Cell cultures were incubated at 37°C and 5% CO2 for 72 hours. To facilitate analysis, cultured cells were spun down at 200 rpm for 5 minutes and the supernatant removed. After shaking the plate to detach the cell pellet, the cells were resuspended in fixation buffer (50 uL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 60 minutes at room temperature. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 10 minutes at room temperature. After permeabilization, cells were spun down, and the supernatant was replaced with fluorescently labeled antibodies (20 μL) against Helios, Ikaros, and Aiolos, or the corresponding isotype controls, in 1x permeabilization buffer (Ikaros-Alexa488 [Biolegend, Cat #368408, 1:50], Helios-PE [CST, Cat #29360, 1:50], Aiolos-Alexa647 [Biolegend, Cat #371106, 1:25]). The staining reaction was incubated for 1 hour at room temperature protected from light. Then, 1x permeabilization buffer (30 μL) was added, the cells were centrifuged, and the supernatant was removed. Stained cells were resuspended in flow cytometry staining buffer [25 μL, PBS + 0.2% bovine serum albumin (BSA)] and analyzed using an Intellicyt Ique Plus flow cytometer. [Table 14]

[0280] Table A-1 shows the maximum observed degradation of IKZF1, IKZF2, and IKZF3 proteins measured in the Jurkat cell degradation assay. The results in Table A-1 have been rounded to two decimal places. In the Jurkat cell degradation assay, a value of 100% indicates no detectable protein remaining or complete degradation of the protein, and a value of 0% indicates no detectable degradation of the protein by the test compound. In the tests reported in Table A-1, the compound of Example 1 was observed to degrade more than 90% of the IKZF2 (Helios) protein. In contrast, Comparative Compound A and Comparative Compound B were observed to degrade less than 30% of the IKZF2 protein. [Table 15]

[0281] Degradation assay of human regulatory T cells Cryopreserved human regulatory T cells were thawed in RPMI + 10% FBS + 20 ng / mL IL-2. After centrifugation at 1200 rpm for 5 minutes, the cells were resuspended in RPMI + 10% FBS + 20 ng / mL and incubated at 37°C and 5% CO2 for 3 hours. Cells were then seeded at 40,000 cells / well in 40 pL of RPMI + 10% FBS + 20 ng / mL human IL-2 in a 384-well cell culture plate, and the compound of interest was added using acoustic dispensing technology (ECHO 555). The cell culture was incubated at 37°C and 5% CO2 for 20 hours. To facilitate analysis, the cell culture was spun down at 1200 rpm for 5 minutes, and the supernatant was discarded using an EL406 plate washer. After washing three times with 70 μL of PBS, the cell pellet was resuspended in 50 μL of near-infrared viability staining solution (Life Technologies, Cat# L34975) and incubated on ice for 30 minutes, protected from light. Using an EL406 plate washer, the cells were washed three times with 70 μL of 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) and incubated at room temperature for 60 minutes. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 Buffer Set 00-5523-00) for 10 minutes at room temperature. After permeabilization, cells were spun down and the supernatant was replaced with 30 μL of fluorescently labeled antibody against Helios in 1:1 permeabilization buffer (Helios APC [Biolegend, Cat# 137222, 1:50]). The staining reaction was incubated for 1 hour at room temperature protected from light. 1:1 permeabilization buffer (30 μL) was then added before the cells were centrifuged and the supernatant discarded. 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. [Table 16] Table B-1 shows the maximum observed degradation of IKZF1 and IKZF2 proteins measured in a human regulatory T cell degradation assay. The results in Table B-1 have been rounded to two decimal places. In the human T regulatory assay, a value of 100% indicates no detectable protein remaining or complete degradation of the protein, and a value of 0% indicates no detectable degradation of the protein by the test compound. In the tests reported in Table B-1, the compound of Example 1 was observed to degrade IKZF1 (Ikaros) protein by 55%. [Table 17]

[0282] Human regulatory T cell reprogramming assay Human CD4+ T cells were isolated from fresh, normal leukopacks (Stemcell Technologies) using RosetteSep Human CD4+ T Cell Enrichment Cocktail (Stemcell Technologies) and Ficoll density gradient centrifugation. Leukopacks were diluted with an equal volume of phosphate-buffered saline (PBS [Gibco]) supplemented with 2% fetal bovine serum (FBS, VWR Lifescience) and then enriched in RosetteSep Human CD4 + After 20 minutes of incubation with the T cell enrichment cocktail, the cells were layered with Ficoll-Paque Plus solution (GE Health Care). The cell-rich interface layer was collected and washed twice with PBS containing 2% FBS. Then, cells were transferred to EasySep Human CD4 T cells according to the manufacturer's instructions. + CD127 low CD25 +Regulatory T cells were manually isolated using a regulatory T cell isolation kit (Stemcell Technologies). Cells were rested overnight in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) in a humidified incubator (37°C, 5% CO2). Cells were then stained for CD4 (clone: ​​RPA-T4, Biolegend), CD25 (clone: ​​2A3, BD Biosciences), and CD127 (clone: ​​hIL-7R-M21, BD Biosciences). CD4 + CD127 low CD25 + Cells were sorted on a BD FACS Aria Fusion sorter and were either used immediately or cryopreserved for downstream assays.

[0283] Fresh or cryopreserved flow-sorted CD4 + CD127 low CD25 + Treg cells were cultured at 25,000–50,000 cells / 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 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). Compounds were added at increasing doses, and cells were incubated at 37°C, 5% CO2 for 12–13 days. Recombinant human IL-2 and compounds were replenished every 2–3 days during the culture period. On days 12 or 13, cells were restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin for staining and analysis by flow cytometry.

[0284] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated with Human Tru-stain Fc block (Biolegend) for 10 minutes, followed by incubation with eFluor 780 viability dye (Thermo Fisher) and a surface marker antibody cocktail at 4°C for 30 minutes. Cells were then fixed and permeabilized by incubation with FoxP3 transcription factor staining buffer (Thermo Fisher) for 30 minutes at 4°C according to the kit manufacturer's instructions. Cells were then washed twice with the Perm / Wash buffer provided with the kit and incubated overnight at 4°C with an intracellular antibody cocktail containing antibodies specific for the transcription factors listed in Table C. Cells were washed twice with Perm / Wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher) before sample acquisition. Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stained controls for each fluorochrome were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). Data were analyzed using Flow Jo version 10 and GraphPad Prism Software. [Table 18] [Table 19]

[0285] Table C-1 shows the maximum observed degradation of IKZF2 and IKZF4 proteins measured in a human regulatory T cell reprogramming assay. The results in Table C-1 have been rounded to two decimal places. In the human regulatory T cell reprogramming assay, a value of 100% indicates no detectable protein remaining or complete protein degradation, and a value of 0% indicates no detectable protein degradation by the test compound. In the tests reported in Table D-1, the compounds of Examples 1 and 2 reduced IKZF2 (Helios) protein levels by at least 83% and IKZF4 (Eos) protein levels by at least 73%. In contrast, Comparative Compound A and Comparative Compound B reduced IKZF2 (Helios) protein levels by 6% or less and IKZF4 (Eos) protein levels by 11% or less. [Table 20]

[0286] Human CD8 + T cell lysis assay Cryopreserved healthy donor human peripheral blood mononuclear cells (PBMCs; obtained from Stemcell Technologies or Blood Works Northwest) from two healthy donors were thawed and seeded at 500,000 cells / well in 96-well round-bottom plates in RPMI 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco). Cells were treated with increasing doses of compounds for 24 hours at 37°C in 5% CO2 before analysis by flow cytometry.

[0287] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher Scientific) and incubated with Human Tru-stain Fc block (Biolegend) for 10 min. Then, eFluor 780 viability dye (Thermo Fisher Scientific) and a surface marker antibody cocktail containing LD-eFluor 780, CD3-BUV-395, CD4-BUV805, CD8-FITC, CD25-BV605, FoxP3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PECF594, and AIOLOS-AF647 were added and incubated for 30 min at 4 °C. Cells were then fixed and permeabilized by incubation with permeabilization buffer (eBioscience FoxP3 buffer set 00-5523-00) for 30 min at 4 °C according to the kit manufacturer's instructions. The cells were washed twice with the Perm / Wash buffer provided with the kit according to the manufacturer's instructions and incubated overnight at 4°C with an intracellular antibody cocktail containing antibodies specific to the transcription factors listed in Table C. The cells were washed twice with Perm / Wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher) before sample acquisition. Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stained controls for each fluorochrome were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). Data were analyzed using Flow Jo version 10 and GraphPad Prism Software.

[0288] [Table 21] [Table 22]

[0289] Table D-1 shows human CD8 +The maximum observed degradation of IKZF1 and IKZF3 proteins measured in the T cell reprogramming assay is shown in Table D-1. The results in Table D-1 have been rounded to two decimal places. + For the T cell reprogramming assay, a value of 100% indicates no detectable protein remaining or complete degradation of the protein, and a value of 0% indicates no detectable degradation of the protein by the test compound. [Table 23]

[0290] When the compounds of Examples 1 and 2 are compared with Comparative Compound A and Comparative Compound B disclosed in WO 2019 / 060693 A1, the compounds of Examples 1 and 2 are found to be particularly advantageous. The compounds of Examples 1 and 2 have the surprising advantage of reducing the levels of the four IKZF1-4 proteins Ikaros, Helios, Aiolos, and Eos. In the reported tests, as shown in Tables C-1 and D-1, (i) the compounds of Examples 1 and 2 reduced the IKZF1 (Ikaros) level by 74% and 66%, respectively (Table D-1); (ii) the compounds of Examples 1 and 2 reduced the IKZF2 (Helios) protein level by 83% and 88%, respectively (Table C-1); (iii) the compounds of Examples 1 and 2 reduced the IKZF3 (Aiolos) level by 77% and 71%, respectively (Table D-1); and (iv) the compounds of Examples 1 and 2 reduced the IKZF4 (Eos) level by 73% and 96%, respectively (Table C-1). In contrast, in the same tests, Comparative Compound A and Comparative Compound B reduced the IKZF2 (Helios) protein level by 6% or less (Table C-1); and reduced the IKZF4 (Eos) protein level by 11% or less (Table C-1).

[0291] The present invention fulfills the above-mentioned need by providing compounds useful for reducing the levels of the four IKZF1-4 proteins Ikaros, Helios, Aiolos and Eos.

Claims

1. Formula (I): 【Chemistry 1】 wherein each R is independently H or D. or a stereoisomer, tautomer or salt thereof.

2. The following structure: 【Chemistry 2】 2. The compound of claim 1, or a stereoisomer, tautomer, or salt thereof, having the formula:

3. 2. The compound of claim 1, or a stereoisomer, tautomer, or salt thereof, wherein each R is independently H.

4. 2. The compound of claim 1, or a stereoisomer or tautomer thereof, wherein each R is independently H.

5. 2. The compound of claim 1, wherein each R is H, or a salt of a stereoisomer or tautomer thereof.

6. 10. The compound of claim 1, wherein each R is H, or a pharmaceutically acceptable salt of a stereoisomer or tautomer thereof.

7. 2. The compound of claim 1, or a stereoisomer, tautomer, or salt thereof, wherein each R is independently D.

8. 2. The compound of claim 1, wherein each R is independently D, or a stereoisomer or tautomer thereof.

9. 2. The compound of claim 1, wherein each R is D, or a salt of a stereoisomer or tautomer thereof.

10. 10. The compound of claim 1, wherein each R is D, or a pharmaceutically acceptable salt of a stereoisomer or tautomer thereof.

11. 11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

12. 4. A pharmaceutical composition comprising the compound of claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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

14. 10. A pharmaceutical composition comprising a compound of claim 6, or a pharmaceutically acceptable salt of a stereoisomer or tautomer thereof; and a pharmaceutically acceptable carrier.

15. 10. A pharmaceutical composition comprising the compound of claim 7, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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

17. 11. A pharmaceutical composition comprising a compound of claim 10, or a pharmaceutically acceptable salt of a stereoisomer or tautomer thereof; and a pharmaceutically acceptable carrier.

18. 11. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, for treating cancer.

19. 19. The use of claim 18, wherein the cancer is selected from colon cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia and melanoma.

20. 19. The use according to claim 18, wherein the cancer is selected from lymphoma, leukemia and multiple myeloma.

21. 20. The use of claim 18 in combination with a second agent, 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 antitumor vaccine.

22. 11. A method for reducing Ikaros, Helios, Aiolos and Eos protein levels in a cell, comprising contacting the cell with a compound of any one of claims 1 to 10, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Images