Substituted phenyloxyoxazolyl piperidinedione compounds

Abstract

Disclosed are compounds of Formula (I): or a stereoisomer, tautomer or salt thereof, wherein R is defined herein. The invention also discloses methods of using such compounds to reduce the levels of Ikaros protein, Helios protein, Ailos protein, and Eos protein, and methods of using such compounds to reduce the levels of Ikaros protein, Helios protein, Ailos protein, and Eos protein; and pharmaceutical compositions comprising such compounds. Such compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.

Description

CROSS-REFERENCE

[0001] This application claims the benefit of Indian provisional application serial number 202311058935, filed September 2, 2023, which is incorporated herein in its entirety. TECHNICAL FIELD

[0002] The present invention relates generally to substituted phenyloxazepipidinones compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. Provided herein are substituted phenyloxazepipidinones compounds, compositions comprising such compounds, and methods of using the same. The invention also relates to pharmaceutical compositions comprising at least one compound according to the invention, which are useful for treating proliferative disorders, such as cancer, and viral infections. BACKGROUND

[0003] The Ikaros zinc finger family (IKZF) of transcription factors (TFs) plays a critical role in lymphocyte development and function (Heizmann et al., 2018, Curr Opin Immunol. 51: 14-23). In mammals, the following five members of this TF family are expressed in immune cells: Ikaros (encoded by IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). The amino acid sequences of these proteins are highly homologous, 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). Reduction of protein levels of IKZF TFs can potentiate anti-tumor 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 types, including myeloid cells. In T cells, loss of Ikaros protein or expression of a dominant-negative protein relieves suppression of loci associated with differentiation into effector T cell states, leading to increased expression of effector cytokines, including IFN-g, TNF-a, 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 in 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 widely expressed at lower levels in T and NK cells. In T cells, Aiolos gene targets show substantial overlap with Ikaros target genes (Powell et al., 2019, Frontiers in Immunology, 10: 1299). In contrast to Ikaros, Aiolos can have a stronger effect on follicular helper T cells and T helper type 17 responses (Quintana et al., 2012, Nature Immunology, 13: 770-777; Read et al., 2017 Journal of Immunology, 7: 2377-2387), which have been implicated in tissue immune responses, and in some cases, anti-tumor immunity.

[0007] IKZF4 encodes Eos, which is abundantly expressed in Treg cells and also widely expressed at low levels in B, NK, and T lymphocytes. In Treg cells, loss of Eos expression in FoxP3+ Treg cells drives improved anti-tumor responses in preclinical syngeneic tumor models (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Additionally, Eos expression levels can increase upon T cell activation in conventional CD4+ and CD8+ T cells, where it can limit effector T cell responses (Rieder et al., 2015, Journal of Immunology, 195:553-563).

[0008] The common function shared among the IKZF TFs is related to the repression of gene expression at specific loci in the cell. IKZF TFs can bind to loci as homodimers or heterodimers (each such as Ikaros:Ikaros or Ikaros:Helios). These dimeric TFs both bind to DNA and interact with complexes that regulate histone acetylation and nucleosomes, which in turn leads to modulation of gene expression. Mechanistically, karos, Helios, and Aiolos have each been shown to interact with nucleosome remodeling and deacetylase (NuRD) and Sin3 histone deacetylase (HDAC) complexes to repress gene expression (Zhang et al., 2011, Nature Immunology, 13:86-94; Georgopoulos et al., 2017, Genes and Development, 31:439-450). Similarly, Ikaros, Helios, and Aiolos can all associate with centromeric heterochromatin and contribute to expression of genes located at centromeric loci (Brown et al., 1997, Cell, 91:845-854; Thompson et al., 2007, Immunity, 26:335-344). Eos cooperates with Ikaros, but not Aiolos, to interact with the transcriptional repressor C-terminal binding protein 1 (CtBP1) in lymphocytes (Koipally et al., 2002, Journal of Biological Chemistry, 277:27697-27705; Pan et al., 2009, Science, 325:1142-1146). Taken together, the overlapping functions of IKZF TFs can partially compensate for loss or degradation of one or several TFs. Thus, broad therapeutic degradation of this TF family is expected to drive stronger phenotypic changes in cells expressing multiple IKZF members compared to selective degradation of one or two IKZF TFs.

[0009] The shared role of IKZF TFs in modulating loci important for anti-tumor immune responses in both T cells and Treg cells is exemplified by the 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; loss of Ikaros results in increased IL-2 production by CD4+ and CD8+ T cells (Bandyopadhyay et al., 2007, Blood, 109: 2671-2672; Thomas et al., 2007, Journal of Immunology, 179: 7305-7315; O'Brien et al., 2014, Journal of Immunology, 192: 5118-5129). Helios directly binds to the IL-2 locus in Treg cells to recruit HDAC complexes and enforce IL-2 gene silencing (Blaine et al., 2013, Journal of Immunology, 190: 1008-1016). Eos also inhibits IL-2 expression in Treg cells and can act via a mechanism 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 to IL-2 loss is not 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). In summary, IKZF TFs serve to regulate IL-2 production by multiple lymphocyte subsets, particularly Treg cells, where all four of these IKZF TFs are abundantly expressed and IL-2 production is normally negligible.

[0010] Treg cells, marked by expression of the transcription factor FoxP3, are a subset of immunosuppressive lymphocytes that maintain immune homeostasis using several mechanisms (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, polyendocrine disease, enteropathy, X-linked (IPEX) syndrome, a multi-organ autoimmune disorder. In the tumor microenvironment (TME), the activity of Treg cells is selected for 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 impeding T cell and antigen presenting cell activation, Treg cells can contribute to TME-mediated resistance to immunotherapy by modulating multiple axes in the cancer-immune cycle (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, depletion of Treg cells leads to regression of established invasive tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

[0011] Once activated by specific antigens, Treg cells can suppress reactive T cells in an antigen-nonspecific and bystander manner in vitro (Takahashi et al., 1998, Int Immunol. 10: 1969-80; Thornton et al., 1998, J Exp. Med. 188: 287-96). FoxP3+CD25+CD4+Treg cells are able to suppress a broad anti-tumor immune response involving 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, intratumoral depletion of CD25+CD4+Treg cells induced regression of established tumors with changes in the cytokine environment at the tumor site (Yu et al., 2005, J Exp Med. 201: 779-91). Moreover, transfer of Treg cell-depleted CD4+T cells significantly enhanced the anti-tumor immune response compared to transfer of Treg cell-replete CD4+T cells (Antony et al., 2005, J Immunol 174: 2591-601). Tumor-infiltrating Treg cells activated by tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific anti-tumor immune responses.

[0012] Clinically, increased Treg cell frequency in the TME is associated with worse outcomes in multiple solid tumor indications (Shang et al., 2015, Scientific Reports, 5: 15179). Moreover, the correlation between PD-L1+Treg cell frequency and response to anti-PD-1 therapy in non-small cell lung cancer (NSCLC) patients (Wu et al., 2018, Journal of Thoracic Oncology, 13: 521-532) highlights the therapeutic potential of targeting Treg cells of the TME. Modulation of the activity of key factors that control Treg cell differentiation and / or functional suppressive state can represent a potential therapeutic strategy for treating certain diseases, including cancer and viral infections.

[0013] Furthermore, it has also been reported that removal of FoxP3+ Treg cells enhances vaccine-induced anti-tumor T-cell responses (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767), suggesting that reducing Helios levels can be beneficial to enhance the efficacy of cancer vaccines. In addition to anti-tumor immunotherapy, during viral infection, Treg cells can limit immunopathology due to excessive inflammation, yet potentially suppress effective anti-viral T-cell responses and promote viral persistence (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). Chronic but not acute infection of mice with lymphocytic choriomeningitis virus leads to a significant expansion of FoxP3+ Treg cells, suggesting a potential mechanism by which certain infectious agents can evade host immune responses by activating and expanding Treg cells (Punkosdy et al., 2011, PNAS 108: 3677-3682). Therapeutic benefit can be achieved by reducing Helios levels in activated Treg cells in the context of chronic viral infection-related background.

[0014] Methods targeting tumor Treg cells include antibody-mediated depletion and / or functional modulation (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146), as well as small molecule-mediated “reprogramming” of the immunosuppressive phenotype of Treg cells by altering gene expression in these cells (Kim et al., 2015, Science, 350:334-339; Sebastian et al., 2016, Journal of Immunology, 196:144-155). Mice with Treg cells engineered to lack Helios do not develop IPEX-like immunopathological features of FoxP3 deficiency or complete Treg cell removal, but rather have Treg cells that show more T effector-like transcriptional programs (Fu et al., 2012, Nature Immunology, 13:972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). Importantly, Helios controls the activity of Treg cells that are critical in the TME, as mice with Treg cells lacking Helios show improved B16F10 and MC38 tumor control (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Thus, therapeutic modulation of Helios has the potential to reprogram tumor Treg cells toward a more effector-like phenotype to drive anti-tumor immunity. It should be noted that Eos also drives immunosuppressive Treg cell activity in the TME in preclinical tumor models, as mice lacking Eos expression in FoxP3 Treg cells control syngeneic tumors more effectively compared to controls (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Humans with loss-of-function IKZF2 mutations similarly do not exhibit IPEX-like symptoms, including diabetes, dermatitis, liver inflammation, and systemic lymphadenopathy, but rather show an immune phenotype associated with enhanced T cell activation and proinflammatory cytokine production (Hetemaki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981).These data indicate that a reduction in Helios and Eos protein levels in Treg cells would make them less suppressive of anti-tumor T cell responses in patients with solid tumors.

[0015] Small molecules that degrade Ikaros and Aiolos in Treg cells also reduce the suppressive function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In an engineered mouse model, the Ikaros and Aiolos degrader lenalidomide modestly increased the anti-tumor immune response against a highly immunogenic syngeneic tumor (Geng et al., 2022, Cell Chemical Biology, 29:1260-1272). Degraders targeting Ikaros and Aiolos have also been tested in patients with solid tumors, which sometimes resulted in modest responses leading to stable disease. These studies include avadomide (CC-122) (Rasco et al., 2019, Clin Cancer Research, 25:90-98), lenalidomide (Semeraro et al., 2013, OncoImmunology, 2:11), and pomalidomide (Cooney et al., 2012, Cancer Chemotherapy and Pharmacology, 70, 755) in advanced malignancies. In addition, lenalidomide has been shown to enhance T and NK cell function in preclinical and clinical studies (Hideshima et al., Leukemia, 2021; D’Souza et al., Frontiers in Immunology, 2021).

[0016] In summary, IKZF TFs, Ikaros, Helios, Aiolos, and Eos are abundantly expressed in Treg cells. A combined reduction in the individual protein levels of these four TFs in Treg cells would better reverse the immunosuppressive program, including suppression of IL-2 transcription and other T cell effector genes, compared to approaches that selectively target a single IKZF TF or pair of TFs, i.e., Ikaros and Aiolos or Helios and Eos. In addition to Treg cells, a pan-IKZF1-4 degrader would be expected to increase conventional CD4+ and CD8+ T cell effector function and potentiate NK cell activity to drive robust anti-tumor 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 addresses the aforementioned needs by providing compounds useful for reducing the levels of the four IKZF1-4 proteins Ikaros, Helios, Aiolos, and Eos. SUMMARY

[0019] The present invention provides substituted phenyloxazolidinylpiperidinedione compounds of Formula (I), including stereoisomers, tautomers, salts, and prodrugs thereof, which are useful for reducing the levels of the four proteins Ikaros, Helios, Aiolos, and Eos.

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

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

[0022] The present invention also provides methods and intermediates for preparing a compound of Formula (I), a stereoisomer, tautomer, or salt 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 the levels of Ikaros, Helios, Aiolos, and Eos proteins for the treatment of certain diseases, including cancer, and viral infections.

[0024] Compounds of Formula (I) and compositions comprising compounds of Formula (I) are useful for treating, preventing, or curing various proliferative disorders, such as cancer. Pharmaceutical compositions comprising these compounds are useful for treating, preventing, or slowing the progression of various diseases or disorders in the field of therapy, such as cancer.

[0025] Compounds of Formula (I) and compositions comprising compounds of Formula (I) are useful for treating, preventing, or curing viral infections. Pharmaceutical compositions comprising these 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 will be set forth in the continuation of the specification that follows, in expanded form. DETAILED DESCRIPTION

[0027] Applicants have discovered substituted phenyloxazepipidinones compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. It is believed that the substituted phenyloxazepipidinones compounds facilitate the interaction between Ikaros, Helios, Aiolos, and Eos proteins and the corresponding E3 ubiquitin ligase complex (Cullin4-Cereblon, CUL4-CRBN) with concomitant degradation of the Ikaros, Helios, Aiolos, and Eos proteins. These compounds reduce the levels of Ikaros protein, Helios protein, Aiolos protein, and Eos protein. These compounds are useful in the treatment of certain diseases, including cancer, and viral infections. The provision of the compounds are useful as agents having desirable stability, bioavailability, therapeutic index, and toxicity values important to their druggability.

[0028] A second aspect of the application provides at least one compound of Formula (I): or a stereoisomer, tautomer, or salt thereof, wherein: R is:

[0029] A second aspect of the application provides at least one compound of Formula (I): or a stereoisomer, tautomer, or salt thereof, wherein: R is:

[0030] One embodiment provides a compound of Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

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

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

[0034] One embodiment provides a compound of Formula (I), or a stereoisomer, tautomer, or salt thereof, wherein R is:

[0035] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein R is:

[0036] Included in this embodiment are compounds of Formula (I) or a pharmaceutically acceptable salt thereof. Also included in this embodiment are compounds of Formula (I). In addition, included in this embodiment are pharmaceutically acceptable salts of compounds of Formula (I).

[0037] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or salt thereof.

[0038] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or salt thereof.

[0039] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or salt thereof.

[0040] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or salt thereof.

[0041] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or salt thereof.

[0042] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is: 3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (1); trans 3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4-methylpyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (2); 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)- 2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (3); 3-(5-(4-(6-amino-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2- oxooxazol-3(2H)-yl)piperidine-2,6-dione (4); or 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)- 2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (3);

[0043] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is trans 3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0044] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0045] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0046] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is trans 3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0047] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is trans (R)-3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0048] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is trans (S)-3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0049] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6- dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0050] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6- dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0051] One embodiment provides a compound of Formula (I) or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6- dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0052] One embodiment provides a compound of Formula (I) or a stereoisomer, tautomer, or salt thereof, wherein the compound is 3-(5-(4-(6-amino-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2- yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. Included in this embodiment are one or more pharmaceutically acceptable salts.

[0053] One embodiment provides a compound of Formula (I), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-5-((4-methoxy piperidin-1-yl)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0054] One embodiment provides a compound of Formula (I), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-5-((4-methoxy piperidin-1-yl)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0055] One embodiment provides a compound of Formula (I), or a stereoisomer, tautomer, or salt thereof, wherein the compound is 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0056] One embodiment provides a compound of Formula (I), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0057] One embodiment provides a compound of Formula (I), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione. One or more pharmaceutically acceptable salts are included in this embodiment.

[0058] One embodiment provides a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0059] One embodiment provides a compound having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0060] One embodiment provides a compound having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0061] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0062] One embodiment provides a compound of Formula (I) having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0063] One embodiment provides a compound of Formula (I) having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0064] One embodiment provides a compound of Formula (I) having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0065] One embodiment provides a compound of Formula (I) having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0066] One embodiment provides a compound of Formula (I) having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0067] One embodiment provides a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0068] One embodiment provides a compound having the structure: or a tautomer or pharmaceutically acceptable salt thereof.

[0069] One embodiment provides a compound having the following structure: Or its tautomers or pharmaceutically acceptable salts.

[0070] One embodiment provides a compound having the following structure: Or its stereoisomers, tautomers or pharmaceutically acceptable salts.

[0071] One embodiment provides a compound having the following structure: Or its tautomers or pharmaceutically acceptable salts.

[0072] One embodiment provides a compound having the following structure: Or its tautomers or pharmaceutically acceptable salts.

[0073] One embodiment provides a salt of a compound having the following structure: Or its stereoisomers or tautomers. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0074] One embodiment provides a salt of a compound having the following structure: Or its stereoisomers or tautomers. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0075] One embodiment provides a salt of a compound having the following structure: Or its stereoisomers or tautomers. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0076] One embodiment provides a salt of a compound having the following structure: Or its stereoisomers or tautomers. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0077] One embodiment provides a salt of a compound having the following structure: or a stereoisomer or tautomer thereof. Included in this embodiment are one or more pharmaceutically acceptable salts of the compound.

[0078] The compound of Formula (I) or a stereoisomer, tautomer, or salt thereof can be used to reduce the level of four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos.

[0079] As used herein, "reducing the level of one of the IKZF1-4 proteins" means reducing the level of the protein by degradation and / or inactivation and / or inhibiting and / or reducing the level of expression of the protein or a combination thereof, as compared to the initial protein level prior to contact with or treatment with the compound of Formula (I) or a stereoisomer, tautomer, or salt thereof.

[0080] Various methods can be employed to measure the protein level of the IKZF1-4 proteins, including the following assays described below: (i) IKZF1: CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell degradation assay; (iii) IKZF3: human CD8 + T cell reprogramming assay; and (iv) IKZF4: human regulatory T cell reprogramming assay.

[0081] The application can take other specific forms in addition to those explicitly described herein without departing from the spirit or essential attributes thereof. The application encompasses all combinations of aspects and / or embodiments of the application specified herein. It is to be understood that any and every embodiment of the application can be employed with any and every other embodiment to describe still other embodiments. It is also to be understood that each individual element of the described embodiments is intended to be combined with any and all other elements from any and all other embodiments to describe additional embodiments.

[0082] The features and advantages of the application can be better understood with respect to the following embodiments. It should be understood that certain features of the application described above and below in the context of separate embodiments can also be combined to form single embodiments. Conversely, various features described in the context of a single embodiment can also be combined or removed to form additional embodiments. Embodiments identified herein as examples or preferred are intended to be illustrative and not limiting.

[0083] Unless otherwise explicitly specified herein, reference to a singular can include a plural. For example, "a" or "an" can refer to one or more.

[0084] As used herein, the phrase "compound and / or salts thereof" means at least one compound, a salt of at least one compound, or a combination thereof. For example, a compound of Formula (I) and / or salts thereof includes a compound of Formula (I); two compounds of Formula (I); a salt of a compound of Formula (I); a compound of Formula (I) and one or more salts of a compound of Formula (I); and two or more salts of a compound of Formula (I).

[0085] Unless otherwise specified, it is assumed that any atom with an unsatisfied valence is considered to bear a hydrogen atom sufficient to satisfy its valence.

[0086] The definitions set forth herein control over any definitions set forth in any patents, patent applications and / or patent application publications incorporated herein by reference.

[0087] The following definitions are set forth to facilitate understanding of certain terms used frequently herein and are not meant to limit the present application.

[0088] Throughout this application, groups and substituents can be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0089] According to the usual practice in the art, A bond used in structural formulas herein to depict a point of attachment of a moiety or substituent to a parent or backbone structure.

[0090] The term "amino" means the group -NH2.

[0091] The term "oxo" means the group =0.

[0092] The compounds of the present application include all isotopes of atoms occurring in the compounds of the present application. Isotopes include those 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 present application can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0093] As used herein, the term "tautomer" means each of two or more isomers of a compound that exist in equilibrium and are readily interconvertible by the migration of an atom or a group within the molecule. For example, one of skill in the art will readily appreciate that a 1,2,3-triazole exists in two tautomeric forms as defined above: .

[0094] Thus, the present disclosure is intended to embrace all possible tautomers, even if only one tautomer is depicted by the structure. For example, the compound of Formula (I) can exist in tautomeric form: .

[0095] Other examples of tautomeric forms include:

[0096] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0097] The compounds of Formula (I) can form salts, and such salts are within the scope of the application. Unless otherwise specified, reference to a compound of the present application shall be understood to include reference to one or more salts thereof. The term "salt" denotes acidic salts formed with inorganic and / or organic acids. In addition, the term "salt" can include zwitterions (inner salts), for example, when a compound of Formula (I) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic physiologically acceptable) salts are preferred, such as, for example, salts of metals including alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), and aluminum, and salts of amines including, for example, N-methyl-glucamine, choline, and ammonium. However, other salts can be useful, for example, in isolation or purification steps, and thus, are contemplated within the scope of the application. Salts of the compounds of Formula (I) can be formed, for example, by reacting a compound of Formula (I) with an amount of an acid or base (such as an equivalent amount), in a medium such as, for example, one in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0098] Exemplary acid addition salts include acetates (such as those formed with acetic acid or a trihalogenacetic acid, e.g. trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (formed with methanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0099] The compound of formula (I) can be provided as an amorphous solid or a crystalline solid. Lyophilization can be employed to provide the compound of formula (I) as a solid.

[0100] It is further understood that solvates (e.g., hydrates) of the compound of formula (I) are within the scope of the present application. The term “solvate” means the physical association of a compound of formula (I) with one or more solvent molecules (whether organic or inorganic), whether or not the solvent is a hydrate. This physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” includes both solution-phase and isolatable solvates. Exemplary solvates include hydrates, glycolates, methanolates, isopropylates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0101] Various forms of prodrugs are well-known in the art and described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0102] Further, upon preparation of the compound of formula (I), it can be isolated and purified to obtain a composition containing the compound of formula (I) in an amount equal to or greater than 99% by weight (“substantially pure”), which is then used or formulated as described herein. Such “substantially pure” compounds of formula (I) are also contemplated herein as part of the present application.

[0103] "Stable compound" and "stable structure" are intended to refer to compounds that are sufficiently robust to survive isolation from a reaction mixture into a usable purity and formulation into an efficacious therapeutic agent. The present application is intended to embody stable compounds.

[0104] The term "IKZF1 degrader" and "Ikaros degrader" refers to an agent that is capable of reducing 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.

[0105] The term "IKZF2 degrader" and "Helios degrader" refers to an agent that is capable of reducing 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.

[0106] The term "IKZF3 degrader" and "Aiolos degrader" refers to an agent that is capable of reducing 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.

[0107] The term "IKZF4 degrader" and "Eos degrader" refers to an agent that is capable of reducing 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.

[0108] The term "IKZF1-4 protein" refers to Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and Eos (IKZF4) proteins.

[0109] The term "pan-IKZF1-4 degrader" refers to an agent that is capable of reducing the protein level of the four IKZF1-4 proteins Ikaros, Helios, Aiolos, and Eos.

[0110] As used herein, the "Ikaros" protein is encoded by the IKZF1 gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFN1A1, Zinc Finger Protein Subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, 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 following human isoforms listed below: Isoform 1 (UniPort Q13422-1) Isoform 2 (UniProt Q13422-2) Isoform 3 (UniProt Q13422-3) Isoform 4 (UniProt Q13422-4) Isoform 7 (UniProt Q13422-7) Isoform 8 (UniProt Q13422-8)

[0111] The above-listed isoforms 1, 2, 3, 4, 7, and 8 of the “Ikaros” protein comprise a degradation determinant which is the same as the degradation determinant of the “Aiolos” protein. The Ikaros protein also comprises isoforms encoded by the amino acid sequences Q13422-5 and Q13422-6.

[0112] As used herein, the “Helios” protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. In humans, Helios is encoded by the IKZF2 gene. Helios is also known as IKAROS family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2, zinc finger protein subfamily 1A, 2, and Ikaros family zinc finger protein 2. As used herein, the Helios protein comprises various isoforms, including the following-listed isoforms. Isoform 1 (UniProt Q9UKS7-1) Isoform 2 (UniProt Q9UKS7-2) Isoform 4 (UniProt Q9UKS7-4) Isoform 6 (UniProt Q9UKS7-6) Isoform 7 (UniProt Q9UKS7-7)

[0113] The "Helios" isoforms 1, 2, 4, 6, and 7 listed above comprise the degradation determinant FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 23). A degradation determinant is a portion of a protein that functions in regulating the rate of protein degradation. The Helios protein also comprises isoforms encoded by the amino acid sequences Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0114] As used herein, the "Aiolos" protein is encoded by the IKZF3 gene. The Aiolos protein is also known as IKAROS family zinc finger 3, ZNFN1A3, zinc finger protein subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. The Aiolos protein comprises the following human isoforms listed below: Isoform 1 (UniProt Q9UKT9-1) Isoform 3 (UniProt Q9UKT9-3) Isoform 4 (UniProt Q9UKT9-4) Isoform 6 (UniProt Q9UKT9-6) Isoform 7 (UniProt Q9UKT9-7) Isoform 8 (UniProt Q9UKT9-8) Isoform 9 (UniProt Q9UKT9-9) Isoform 14 (UniProt Q9UKT9-14)

[0115] The "Aiolos" protein isoforms 1, 3, 4, 6, 7, 8, 9, and 14 listed above comprise the degradation determinant FQCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 24), which is identical to the degradation determinant of the "Ikaros" protein. The Aiolos protein also comprises 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.

[0116] 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 comprises isoforms encoded by the following two human isoforms 1 (Q9H2S9-1) and 2 (Q9H2S9-2): Isoform 1 (UniProt Q9H2S9-1) Isoform 2 (UniProt Q9H2S9-2)

[0117] The "Eos" protein isoforms 1 and 2 listed above comprise the degradation determinant FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 25), which is identical to the degradation determinant of the "Helios" protein.

[0118] 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.

[0119] As used herein, the term "contacting" refers to bringing the specified moieties together in an in vitro system or in an in vivo system. For example, "contacting" an IKZF1-4 protein with a compound of Formula (I) includes administering a compound of the application to an individual or patient (such as a human) having an Ikaros protein, a Helios protein, an Aiolos protein, and an Eos protein, and, for example, introducing a compound of Formula (I) into a sample containing a cell preparation or a purified preparation containing an Ikaros protein, a Helios protein, an Aiolos protein, and an Eos protein.

[0120] As used herein, the terms "treat," "treating," and "treatment" refer to any type of intervention or treatment on a subject, or administration of an active agent to a subject, with the goal of reversing, alleviating, improving, inhibiting, or slowing or preventing the progression, development, severity or recurrence of symptoms, complications, conditions or biochemical indicia associated with a disease. In contrast, "prophylaxis" or "prevention" refers to the administration of an agent to a subject who does not yet exhibit symptoms of a disease with the goal of preventing the disease from occurring. "Treat," "treating," and "treatment" do not encompass prophylaxis or prevention.

[0121] A "therapeutically effective amount" is intended to include an amount of the compounds of the application alone or in combination with other active ingredients effective to reduce the level of IKZF1-4 proteins in a cell or to treat or prevent viral infections and proliferative disorders, such as cancer.

[0122] As used herein, the term "cell" means a cell in vitro, ex vivo, or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, an in vitro cell is a cell in cell culture. In some embodiments, an in vivo cell is a cell living in an organism, such as a mammal.

[0123] The term "patient" includes a human individual.

[0124] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc, magnesium stearate, calcium stearate or zinc stearate, or stearic acid), or solvent encapsulating material, involved in

[0125] The term "pharmaceutical composition" means a composition comprising a compound of the application in combination with at least one additional pharmaceutically acceptable carrier. Utility

[0126] The compounds of Formula (I) are useful in the treatment of cancer.

[0127] The compounds of Formula (I) are useful in treating viral infections.

[0128] In one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0129] In one embodiment, a method of treating a viral infection in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0130] In one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0131] In one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0132] In one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0133] In one embodiment, a method of treating cancer in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound having the structure: or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0134] One aspect provides a method of treating a disease or disorder by reducing the levels of four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos, the method comprising administering to a patient a therapeutically effective amount of an agent for reducing 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 further embodiments, the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0135] In one embodiment, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: a) the Ikaros protein is an amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6; b) the Helios protein is an amino acid sequence encoded by SEQ ID NO: 7, 8, 9, 10, or 11; c) the Aiolos protein is an amino acid sequence encoded by SEQ ID NO: 12, 13, 14, 15, 16, 17, 18, or 19; and d) the Eos protein is an amino acid sequence encoded by SEQ ID NO: 20 or 21.

[0136] In embodiment 1, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce 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%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0137] In embodiment 2, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce 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%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0138] In embodiment 3, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 50%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 50%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0139] In embodiment 4, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 50%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 50%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0140] In embodiment 5, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0141] In embodiment 6, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0142] In embodiment 7, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0143] In embodiment 8, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0144] In embodiment 9, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0145] In embodiment 10, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0146] In embodiment 11, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0147] In embodiment 12, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0148] In embodiment 13, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0149] In embodiment 14, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0150] In embodiment 15, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0151] In embodiment 16, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0152] In embodiment 17, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 85%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0153] In embodiment 18, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 85%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0154] In embodiment 19, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 85%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0155] In embodiment 20, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 85%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0156] In embodiment 21, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0157] In embodiment 22, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0158] In embodiment 23, there is provided a method of treating a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0159] In embodiment 24, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0160] In embodiment 25, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 30%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 30%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0161] In embodiment 26, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 40%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 40%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0162] In embodiment 27, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 50%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 50%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0163] In embodiment 28, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by at least 60%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by at least 60%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0164] In embodiment 29, a method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 50%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 50%. Included in this embodiment are methods wherein the disease or disorder is cancer. Also included in this embodiment are methods wherein the disease or disorder is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0165] In embodiment 30, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by a range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced by a range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0166] In embodiment 31, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by a range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by a range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0167] In embodiment 32, a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by a range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced by a range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 70%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0168] In embodiment 33, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by a range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced by a range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0169] In embodiment 34, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced by a range of 40 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced by a range of 40 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0170] In embodiment 35, there is provided a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 50%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 50%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0171] In embodiment 36, there is provided a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 60%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 60%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0172] In embodiment 37, there is provided a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. In addition, included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0173] In embodiment 38, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 70%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 70%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0174] In embodiment 39, a method of treating a disease or condition in a patient is provided, comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 80%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 65%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0175] In embodiment 40, there is provided a method of treating a disease or condition in a patient comprising administering to the patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels, wherein: (i) the Ikaros (IKZF1) protein levels are reduced in the range of 50 to 70%; (ii) the Helios (IKZF2) protein levels are reduced by at least 90%; (iii) the Aiolos (IKZF3) protein levels are reduced in the range of 50 to 70%; and (iv) the Eos (IKZF4) protein levels are reduced by at least 90%. Included in this embodiment are methods wherein the disease or condition is cancer. Also included in this embodiment are methods wherein the disease or condition is a viral infection. Further included in this embodiment are methods wherein the agent is a compound of Formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0176] In embodiments 1 to 40, the reduction in protein levels of the IKZF1-4 proteins can be measured using the following assays described below: (i) IKZF1: Human CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell degradation assay; (iii) IKZF3: Human CD8 + T cell reprogramming assay; and (iv) IKZF4: Human regulatory T cell reprogramming assay.

[0177] Types of cancer that can 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 types of cancer include neuroblastoma, intestinal cancer such as rectal cancer, colon cancer, anal cancer, familial adenomatous polyposis cancer, and hereditary nonpolyposis colorectal cancer, esophageal cancer, nasopharyngeal cancer, lip cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, salivary gland cancer, thymus cancer, esophagogastric cancer, gastric cancer, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, kidney cancer, renal parenchymal carcinoma, ovarian cancer, cervical cancer, uterine body cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urethral cancer, melanoma, brain tumor such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.

[0178] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is melanoma.

[0179] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC).

[0180] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is mesothelioma.

[0181] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, including ductal carcinoma, invasive ductal carcinoma, metastatic breast cancer, triple negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, hormone receptor positive breast cancer, and hormone receptor negative breast cancer.

[0182] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is prostate cancer, including adenocarcinoma of the prostate and castration-resistant prostate cancer.

[0183] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer, including pancreatic adenocarcinoma, exocrine pancreatic cancer, and neuroendocrine pancreatic cancer.

[0184] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is kidney cancer, including renal cell carcinoma, clear cell renal cell carcinoma and non-clear cell renal cell carcinoma, papillary renal cell carcinoma, Wilms tumor, and renal sarcoma.

[0185] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is gastric cancer, including gastric carcinoma.

[0186] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is kidney cancer, including renal carcinoma and renal parenchymal carcinoma.

[0187] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is liver cancer, including hepatocellular carcinoma.

[0188] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer, including ovarian carcinoma.

[0189] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is lymphoma, including Hodgkin’s 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, and diffuse large B-cell lymphoma (DLBCL).

[0190] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is leukemia, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, and diffuse large B-cell lymphoma (DLBCL).

[0191] In one embodiment, there is provided a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is multiple myeloma.

[0192] The compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) can be used in the treatment or prevention of any disease or condition associated with the activity of IKZF1-4 proteins. These include viral and other infections (e.g., skin infections, GI infections, urinary tract infections, urogenital tract infections, systemic infections), and proliferative diseases (e.g., cancer). The compounds or pharmaceutical compositions can be delivered to a patient using any method of administration. In certain embodiments, the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered orally. In other embodiments, the compound of Formula (I) or pharmaceutical composition comprising at least one compound of Formula (I) is administered parenterally.

[0193] In one embodiment, a method of treating a viral infection in a patient is provided, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the viral infection is caused by exposure to HIV, hepatitis (A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackie virus, 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, and arboviral encephalitis virus.

[0194] The compounds of Formula (I) can selectively reduce the protein levels of the four IKZF1-4 proteins in a cell to control Treg differentiation and / or immunoregulatory status. For example, by administering an effective amount of a compound of Formula (I), or a stereoisomer, tautomer, or salt thereof, the compounds of Formula (I) can be used to selectively reduce the protein levels, reduce the activity levels, and / or inhibit the expression levels of each of the four IKZF1-4 proteins in a cell or individual in need of reducing the protein levels, reducing the activity levels, and / or inhibiting the expression levels of each of the four IKZF1-4 proteins to control Treg differentiation and / or immunoregulatory status in the cell or individual.

[0195] In one embodiment, the present application provides a combination formulation of 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 a variety of diseases or conditions associated with the activity of IKZF1-4 proteins. The combination formulation can be used to reduce the protein levels, reduce the activity levels, and / or inhibit the expression levels of each of the four IKZF1-4 proteins.

[0196] In one aspect, the compound(s) of Formula (I) are administered sequentially prior to administration of the immuno-oncology agent. In another aspect, the compound(s) of Formula (I) are administered concurrently with the immuno-oncology agent. In yet another aspect, the compound(s) of Formula (I) are administered sequentially after administration of the immuno-oncology agent.

[0197] In another aspect, the compound(s) of Formula (I) can be co-formulated with the immuno-oncology agent.

[0198] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological or small molecules. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.

[0199] In one aspect, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in amplification of antigen-specific T cell responses (often referred to as immune checkpoint modulators).

[0200] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, Lymphotoxin a / TNF b, TNFR2, TNFa, LTβR, Lymphotoxin a1b2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0201] In one aspect, a T cell response can be stimulated by a combination of a compound of Formula (I) and one or more of (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), 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) an agonist of a protein that stimulates 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.

[0202] Other agents that can be used in combination with a compound of Formula (I) for the treatment of cancer include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, a compound of Formula (I) can be combined with an antagonist of KIR, such as lirilumab.

[0203] Yet other 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 CSF-1R antagonist antibodies, including RG7155 (WO 11 / 70024, WO 11 / 107553, WO 11 / 131407, WO 13 / 87699, WO 13 / 119716, WO 13 / 132044) or FPA-008 (WO 11 / 140249, WO 13 / 169264, WO 14 / 036357).

[0204] In another aspect, a compound of Formula (I) can be used with one or more of: agonists that engage positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and agents that increase the frequency of systemic anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell anergy or exhaustion), and agents that trigger innate immune activation and / or inflammation at the site of the tumor.

[0205] In one aspect, the immuno-oncology agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, YERVOY (ipilimumab) or tremelimumab.

[0206] In another aspect, the immuno-oncology agent is a PD-1 antagonist, such as an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), LIBTAYO (cemiplimab), JEMPERLI (dostarlimab), and ZYNYZ (retifanlimab). An immuno-oncology agent can also include pidilizumab (CT-011), although the specificity of its binding to PD-1 has been discussed. 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 IgGl, known as AMP-224.

[0207] In another aspect, the immuno-oncology agent is 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), MSB0010718C (WO2013 / 79174), TECENTRIQ (atezolizumab), and BAVENCIO (avelumab).

[0208] In another aspect, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0209] In another aspect, 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 (WO 12 / 32433).

[0210] In another aspect, the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06 / 105021, WO 09 / 009116), and MK-4166 (WO 11 / 028683).

[0211] In another aspect, the immuno-oncology agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO 20 / 122150, WO 07 / 75598, WO 08 / 36653, WO 08 / 36642), indoximod or NLG-919 (WO 09 / 73620, WO 09 / 1156652, WO 11 / 56652, WO 12 / 142237).

[0212] In another aspect, the immuno-oncology agent is an OX40 agonist, such as an agonistic OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383 or MEDI-6469.

[0213] In another aspect, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO 06 / 029879).

[0214] In another aspect, the immuno-oncology agent is a CD40 agonist, such as an agonistic CD40 antibody. In yet another embodiment, the immuno-oncology agent is a CD40 antagonist, such as an antagonistic CD40 antibody. Suitable CD40 antibodies include, for example, lucatumumab or dacetuzumab.

[0215] In another aspect, the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0216] In another aspect, the immuno-oncology agent is MGA271 (to B7H3) (WO 11 / 109400).

[0217] In another aspect, the immuno-oncology agent is an anti-TIGIT agent. Suitable anti-TIGIT agents include antibodies such as BMS-986207, tiragolumab, or MK-7684.

[0218] In another aspect, the immuno-oncology agent is a KRAS G12C inhibitor. Suitable KRAS G12C inhibitors include LUMAKRAS (sotorasib) or KRAZATI (adagrasib).

[0219] Combination therapy is intended to embrace administration of these therapeutic agents in sequential regimen, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of these therapeutic agents, in a substantially simultaneous regimen. Substantially simultaneous administration can be accomplished, for example, by administering the therapeutic agents to the subject as a single entity, or in multiple entities. Sequential or substantially simultaneous administration of the therapeutic agents can be effected by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all of the therapeutic agents can be administered orally or all of the therapeutic agents can be administered by intravenous injection. Combination therapy can also embrace administration of therapeutic agents as described above in further combination with other biological agents and non-drug therapies (e.g., surgery or radiation therapy). Where the combination therapy further comprises a non-drug treatment, the non-drug treatment can be conducted at any appropriate time, so long as a beneficial result from the combination of the therapeutic agents and the non-drug treatment is achieved. For example, where appropriate, a beneficial result is still achieved when the non-drug treatment is removed for a period of time, which can be days or even weeks, from the administration of the therapeutic agents.

[0220] One or more additional pharmaceutical agents or treatment methods, such as, for example, antiviral agents, chemotherapeutic or other anticancer agents, immunopotentiators, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL-2 and GM-CSF), and / or tyrosine kinase inhibitors can optionally be used in combination with the compounds of Formula (I) for the treatment of IKZF1-4 protein-related diseases, disorders, or conditions. The agents can be combined with the compounds of the present application in a single dosage form, or the agents can be administered simultaneously or sequentially in separate dosage forms.

[0221] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-thyclcol, triethylenemelamine, triethylenephosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0222] In treating melanoma, suitable agents for use in combination with the compounds of Formula (I) include dacarbazine (DTIC), optionally along with other chemotherapeutic drugs such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen," which consists of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC, temozolomide, or YERVOY™. The compounds of Formula (I) can also be used in combination with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) to treat melanoma.

[0223] The compounds of Formula (I) can also be used in combination with vaccine therapy to treat melanoma. Anti-melanoma vaccines are similar in some respects to anti-viral vaccines used to prevent disease caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells, called antigens, can be injected into a patient to stimulate the body's immune system to recognize and destroy melanoma cells.

[0224] Melanomas localized to an arm or leg can also be treated using a combination of agents including one or more compounds of Formula (I) with hyperthermic isolated limb perfusion techniques. This treatment protocol temporarily separates the circulation of the affected limb from the rest of the body and injects high doses of chemotherapeutic agents into the artery feeding the limb, thus providing high doses to the tumor area without exposing internal organs to such doses, which can otherwise cause severe side effects. Typically, the fluid is warmed to 38.9°C to 40°C. Melphalan is the most commonly used drug in this chemotherapy procedure. This can be provided with another agent called tumor necrosis factor (TNF).

[0225] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, without limitation, folate antagonists, pyrimidine analogues, purine analogues, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine.

[0226] 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, deoxyco-formycin, mitomycin-C, L- asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0227] Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, relotxafine, and droloxafine.

[0228] Also suitable are cytotoxic agents such as epidophyllotoxins, antitumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes (such as cisplatin and carboplatin), biological response modifiers, growth inhibitors, anti-hormone therapies, leucovorin, tegafur, and hematopoietic growth factors.

[0229] Other anti-cancer agents include antibody therapeutics, such as trastuzumab (HERCEPTIN®), antibodies to co-stimulatory molecules (such as CTLA-4, 4-1BB, and PD-1), or antibodies to cytokines (IL-10 or TGF-beta).

[0230] Other anti-cancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4.

[0231] Other anti-cancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer.

[0232] Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses.

[0233] The pharmaceutical compositions of the present application can optionally comprise at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in the signaling pathway in the normal functioning of a cancer cell, resulting in apoptosis of the cell. Suitable STIs include, but are not limited to: (i) bcr / abl kinase inhibitors such as, for example, STI 571 (GLEEVEC®); (ii) epidermal growth factor (EGF) receptor inhibitors such as, for example, kinase inhibitors (IRESSA®, SSI-774) and antibodies (Imclone: C225 [Goldstein et al., Clin. Cancer Res., 1 :1311-1318 (1995)], and Abgenix: ABX-EGF); (iii) her-2 / neu receptor inhibitors such as farnesyl transferase inhibitors (FTIs) such as, for example, L-744,832 (Kohl et al., Nat. Med., 1(8):792-797 (1995)); (iv) inhibitors of the Akt family kinases or the Akt pathway such as, for example, rapamycin (see, for example, Sekulic et al., Cancer Res., 60:3504-3513 (2000)); (v) cell cycle kinase inhibitors such as, for example, flavopiridol and UCN-Ol (see, for example, Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (2003)); and (vi) phosphotidylinositol kinase inhibitors such as, for example, LY294002 (see, for example, Vlahos et al., J. Biol. Chem., 269:5241-5248 (1994)). Alternatively, at least one STI and at least one compound of Formula (I) can be in separate pharmaceutical compositions. In particular embodiments of the present application, at least one compound of Formula (I) and at least one STI can be administered to a patient simultaneously or sequentially. In other words, at least one compound of Formula (I) can be administered first, at least one STI can be administered first, or at least one compound of Formula (I) and at least one STI can be administered simultaneously. In addition, when more than one compound of Formula (I) and / or STI is used, the compounds can be administered in any order.

[0234] The present application further provides a pharmaceutical composition for treating a chronic viral infection in a patient, comprising at least one compound of Formula (I), optionally, at least one chemotherapeutic agent, and optionally, at least one antiviral agent in a pharmaceutically acceptable carrier.

[0235] Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the above pharmaceutical composition.

[0236] In certain embodiments of the application, at least one compound of formula (I) and at least one chemotherapeutic agent are administered to the patient simultaneously or sequentially. In other words, at least one compound of formula (I) can be administered first, at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one STI can be administered simultaneously. In addition, when more than one compound of formula (I) and / or chemotherapeutic agent is used, the compounds can be administered in any order. Similarly, any antiviral agent or STI can also be administered at any point compared to the administration of the compound of formula (I).

[0237] Chronic viral infections that can be treated using the combination therapies of the present application include, but are not limited to, diseases caused by Hepatitis C Virus (HCV), Human Papilloma Virus (HPV), Cytomegalovirus (CMV), Herpes Simplex Virus (HSV), Epstein-Barr Virus (EBV), Varicella Zoster Virus, Coxsackie Virus, and Human Immunodeficiency Virus (HIV).

[0238] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) can include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral drugs.

[0239] Examples of suitable NRTIs include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir (BMS-180194), BCH-I0652, emitricitabine [(-)-FTC], β-L-FD4 (also known as β-L-D4C and as β-L-2',3'-dideoxy-5-fluoro-cytidine), DAPD ((-)-β-D-2,6-diamino-purine dioxolane), and lodenosine (FddA). Typical suitable NNRTIs include nevirapine (BI-RG-587), delaviradine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethyloxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)- pyrimidinedione), and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfnavir (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 Number 11607.

[0240] The combination therapy is intended to encompass administration of these therapeutic agents in sequential regimen, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous regimen. Substantially simultaneous administration can be accomplished, for example, by administering the therapeutic agents to the individual as a single dosage form having a fixed ratio of the therapeutic agents, or in multiple, separate dosage forms for administration at the same time. Sequential or substantially simultaneous administration of the therapeutic agents can be effected by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues, for example. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all of the therapeutic agents can be administered orally or all of the therapeutic agents can be administered by intravenous injection. The combination therapy can also encompass administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-pharmaceutical therapies, e.g., surgery or radiation therapy. Where the combination therapy further comprises a non-pharmaceutical treatment, the non-pharmaceutical treatment can be performed at any appropriate time, so long as a beneficial result from the combined action of the therapeutic agents and the non-pharmaceutical treatment is achieved. For example, where appropriate, a beneficial result is still achieved when the non-pharmaceutical treatment is removed for a period of time, e.g., days or even weeks, from the administration of the therapeutic agents. Pharmaceutical compositions

[0241] The present application also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the compounds of Formula (I), together with one or more pharmaceutically acceptable carriers (additives) and / or diluents; and optionally, one or more additional therapeutic agents as described above.

[0242] The compounds of Formula (I) can be administered by any appropriate route, preferably in the form of a pharmaceutical composition adapted to such a route, and in dosages effective for the treatment intended. The compounds and compositions of the compounds of Formula (I) can be administered by any appropriate means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried suspensions) syrups, and emulsions; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including by inhalation spray; topically, such as in creams, ointments, or drops; or rectally such as in suppositories; alone or in combination with another agent. Compositions suitable for oral administration include lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, hard or soft capsules, syrups, elixirs, or candies. Preferred compositions are tablets or capsules submitted to enteric coating.

[0243] For oral administration, the pharmaceutical composition can be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. For example, the pharmaceutical composition can be provided in the form of a tablet or capsule comprising an amount of the active ingredient ranging, for example, 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. A suitable daily dose for a human or other mammal can vary widely depending on the condition of the patient and other factors, but can be determined using routine methods.

[0244] Any of the pharmaceutical compositions contemplated herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Exemplary oral formulations include, but are not limited to, for example, tablets, troches, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions intended for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions intended for oral administration. To provide a pharmaceutically palatable preparation, a pharmaceutical composition according to the application can contain at least one agent selected from a sweetening agent, a flavoring agent, a coloring agent, a soothing agent, an antioxidant, and a preserving agent.

[0245] Tablets can be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient that is suitable for the manufacture of tablets. Exemplary excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium starch glycolate, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, acacia, and

[0246] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate, calcium phosphate, and kaolin.

[0247] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier, such as, for example, polyethylene glycol, and at least one oily medium, such as, for example, peanut oil, liquid paraffin and olive oil.

[0248] Aqueous suspensions can be prepared, for example, by mixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension. Exemplary excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum and gum acacia; dispersing or wetting agents, such as, for example, naturally occurring phosphatides, e.g., lecithin; condensation products of alkylene oxides with fatty acids, such as, for example, polyoxyethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example, heptadecaethylene-oxycetanol; condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as, for example, polyoxyethylene sorbitol monooleate; and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as, for example, polyoxyethylene dehydrated sorbitol monooleate. The aqueous suspensions can also contain at least one preservative, such as, for example, ethyl and n-propyl p-hydroxybenzoate; at least one colorant; at least one flavoring agent; and / or at least one sweetening agent, including, but not limited to, for example, sucrose, saccharin and aspartame.

[0249] Oil suspensions can be prepared, for example, by suspending at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, peanut oil, olive oil, sesame oil and coconut oil, or a mineral oil, such as, for example, liquid paraffin. Oil suspensions can also contain at least one thickening agent, such as, for example, beeswax, hard paraffin and cetyl alcohol. To provide an oil suspension with mouthcoating properties, at least one of the sweetening agents already described above and / or at least one flavoring agent can be added to the oil suspension. The oil suspensions can further contain at least one preservative, including, but not limited to, for example, antioxidants, such as, for example, butylated hydroxyanisole and alpha-tocopherol.

[0250] Dispersible powders and granules can be prepared, for example, by admixing at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersing and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing and wetting agents and suspending agents have already been described above. Exemplary preservatives include, but are not limited to, for example, antioxidants, e.g., ascorbic acid. Furthermore, dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, a sweetening agent, a flavoring agent and a colorant.

[0251] Emulsions of at least one 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 an emulsion comprising a compound of Formula (I) can be constituted from known ingredients in known fashion. The oil phase can be provided by, but is not limited to, for example, vegetable oils, such as, for example, olive oil and peanut oil, mineral oil such as, for example, liquid paraffin, and mixtures thereof. While this phase can contain only the emulsifier, it can contain a mixture of at least one emulsifier with a fat or an oil, or both. Suitable emulsifiers include, but are not limited to, for example, naturally occurring phosphatides, e.g., soybean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monoleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxyethylene sorbitan monoleate. Preferably, a hydrophilic emulsifier is included along with a lipophilic emulsifier which acts as a stabilizer. It is also preferable to include both an oil and a fat. In contemplation, the emulsifier(s), with or without stabilizer, constitute so-called emulsifying wax, and the wax, together with the oil and the fat, constitute so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Emulsions can also contain sweetening agents, flavoring agents, preservatives and / or antioxidants. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the application include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with wax, or other materials well known in the art.

[0252] The compounds of Formula (I) and / or at least one pharmaceutically acceptable salt thereof can also be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injectable form. Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water microemulsions; and aqueous or oleaginous suspensions.

[0253] Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be formulated according to the known art, using one or more of the agents described above for oral administration or other suitable agents well known in the art. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art and are readily available. The active ingredient can also be administered by injection as a composition with suitable carriers, including saline, dextrose or water, or with cyclodextrin (i.e., Captisol), cosolvent solubilization (i.e., propylene glycol), or micellar solubilization (i.e., Tween 80).

[0254] The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0255] Sterile injectable aqueous and oleaginous suspensions can be formulated according to the known art. For example, sterile injectable solutions or suspensions can be prepared using a non-toxic parenterally acceptable diluent or solvent, such as, for example, 1,3-butanediol; and sterile injectable suspensions can be formulated using a non-toxic parenterally acceptable diluent or solvent such as, for example, a sterile fixed oil, such as, for example, synthetic mono- or diglycerides, and fatty acids, such as, for example, oleic acid.

[0256] Sterile aqueous or oleaginous suspensions can be prepared according to methods known in the art. For example, sterile aqueous solutions or suspensions can be prepared using a non-toxic parenterally acceptable diluent or solvent such as, for example, 1,3-butanediol; and sterile oleaginous suspensions can be prepared using a sterile non-toxic acceptable diluent or suspending medium such as, for example, a sterile fixed oil, such as, for example, synthetic mono- or diglycerides, and fatty acids such as, for example, oleic acid.

[0257] Pharmaceutically acceptable carriers are formulated in accordance with the routine methods of those skilled in the art. These include, without limitation: the type and nature of the active agent being formulated, the individual to whom the dosage composition is to be administered, the intended route of administration of the composition, and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can comprise a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons (e.g., to stabilize the active agent, to bind the agent, etc.) well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection are found in various readily available resources, such as, for example, Allen, L. V. Jr. et al., Remington: The Science and Practice of Pharmacy (2 volumes), 22ndedition (2012), Pharmaceutical Press.

[0258] Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of this application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethyleneoxy castor oil derivatives such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerol, 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, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl cyclodextrin, or other solubilized derivatives can also be advantageously used to enhance delivery of compounds of the formulae described herein.

[0259] The pharmaceutically active compounds of this application can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients including humans and other mammals. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and / or can contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings if desired. Such compositions can also comprise adjuvants such as wetting agents, sweetening agents, flavoring agents, and perfuming agents.

[0260] For therapeutic purposes, the active compounds of this application are generally combined with one or more adjuvants appropriate for the specified route of administration. If administered orally, the compounds can be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphates, and sulphates of sodium and calcium, gelatine, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain release controlling formulations, as provided by a dispersion of the active compound in hydroxypropylmethylcellulose.

[0261] The amount of compound administered and dosage regimen for treating a condition with the compounds and / or compositions of this application will depend on a variety of factors, including age, body weight, sex, medical condition of the subject, type of disease, severity of the disease, administration route and frequency, and the particular compound employed. Thus, the dosage regimen can vary widely, but can be determined in a routine manner using standard methods. Daily dosages of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 and about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, can be appropriate. The daily dose can be administered in 1 to 4 doses per day. Other dosing schedules include one dose per week and one dose per two-day period.

[0262] Pharmaceutical compositions of the present application comprise at least one compound of Formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle. Alternative compositions of the present application comprise a compound of Formula (I) or a prodrug thereof as described herein, and a pharmaceutically acceptable carrier, adjuvant, and vehicle.

[0263] The present application also includes pharmaceutical kits useful, for example, in the treatment or prevention of IKZF1-4 protein-related diseases or disorders and other diseases mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits can further comprise, if desired, one or more of the other components of a variety of conventional pharmaceutical kits, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, as will be apparent to those of skill in the art. Instructions, in the form of an insert or a label, indicating that the components are to be used for the indicated amount, administration instructions, and / or instructions for mixing the components can also be included in the kit.

[0264] The dosage regimen for compounds of the present application will, of course, vary depending upon, for example, the pharmacokinetic properties of the particular agent, its mode and route of administration, the species, age, sex, health, medical condition, and weight of the recipient, the nature and severity of the symptoms, the kind of concurrent treatment, the frequency with which treatment is to be effected, the route of administration, and the renal and hepatic function of the patient.

[0265] By way of general guidance, the daily oral dosage of each active ingredient 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, when used for the indicated effects. The most preferred dosage range, intravenously, during a constant rate infusion, is from about 0.01 to about 10 mg / kg / minute. The compound of Formula (I) can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, or four times per day.

[0266] The compounds are typically administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (collectively referred to as a pharmaceutical carrier) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups for oral administration, and consistent with conventional pharmaceutical practices.

[0267] Dosage forms (pharmaceutical compositions) suitable for administration of the present application can contain from about 1 milligram to about 200 milligrams of the active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of from about 0.1 to 95% by weight based on the total weight of the composition.

[0268] A typical capsule for oral administration contains at least one of the compounds of Formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

[0269] A typical injectable formulation is produced by aseptically placing at least one of the compounds of Formula (I) (250 mg) into a vial, aseptically lyophilizing, and sealing. For use, the contents of the vial are mixed with 2 mL of normal saline to create an injectable formulation.

[0270] The present application includes within its scope pharmaceutical compositions comprising an active ingredient, a therapeutically effective amount of at least one of the compounds of Formula (I) alone or in combination with a pharmaceutical carrier. Optionally, the compounds of Formula (I) can be used alone, in combination with other compounds of Formula (I), or in combination with one or more other therapeutic agents, e.g., anti-cancer agents or other pharmaceutically active substances.

[0271] Regardless of the route of administration selected, the compounds of Formula (I) and / or the pharmaceutical compositions of the present application, which can be used in a suitable hydrated form, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0272] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this application can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0273] The selected dosage level will depend on a variety of factors including the activity of the particular compound of Formula (I) employed, or of its esters, salts or amides, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0274] An ordinarily skilled medical or veterinary practitioner can readily determine the effective amount and prescribe the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compound of formula (I) employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0275] In general, a suitable daily dose of a compound of formula (I) will be that amount of the compound that is the lowest to produce a therapeutic effect. Such an effective dose is generally determined by consideration of factors relevant to pharmaceutical administration. In general, oral, intravenous, intracerebroventricular, and subcutaneous dosages of a compound of formula (I) for a patient range from about 0.01 to about 50 mg / kg body weight per day.

[0276] If desired, the effective daily dose of the active compound can be administered in two, three, four, five, six or more sub-doses administered separately at appropriate intervals, optionally, in unit dosage forms. In certain aspects of the application, dosing is one administration per day.

[0277] While it is possible for a compound of formula (I) to be administered alone, it is preferable to present the compound as a pharmaceutical formulation (composition).

[0278] The above other therapeutic agents, when employed in combination with a compound of formula (I), can be used, for example, in the amounts dictated by the Physicians’ Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the application, such other therapeutic agents can be administered prior to, simultaneously with, or following the administration of a compound of the application. Methods of preparation

[0279] The compounds of the application can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof, as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The entire texts of all references cited herein are incorporated by reference in their entireties.

[0280] The compounds of the present application can be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the descriptions of the synthetic methods described below, it is understood that the choice of appropriate solvent, reaction atmosphere, reaction temperature, duration of the experiment and the work-up procedure are made according to the particular reaction conditions selected. It will be appreciated by a person skilled in the art that functional groups present on various moieties of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents compatible with the reaction conditions will be readily apparent to a person skilled in the art, and alternative methods must then be used. This sometimes requires judgement as to the order of the synthetic steps or the choice of one particular process scheme over another to obtain the compounds of the present application. It is further understood that another major consideration in planning a Examples

[0281] The following examples illustrate particular embodiments of the present application and do not limit the scope of the application. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their usual and customary meanings unless otherwise specified. Additional abbreviations employed above and elsewhere in the application are defined above. Common intermediates are often useful in preparing more than one example. Compounds of the examples are identified by the example and step in which they were prepared (e.g.,“1-A” denotes Example 1, Step A) or by the example alone if the compound is the title compound of the example (e.g.,“1” denotes the title compound of Example 1). In some instances, alternative preparations of intermediates or examples are described. Often, a chemist skilled in synthesis can design alternative preparations based on one or more considerations, such as shorter reaction time, less expensive starting materials, ease of operation or isolation, improved yield, suitability for catalysis, avoidance of toxic reagents, availability of specialized equipment, and reduced linear step count, among others, which can be desirable. The intent of describing alternative preparations is to further enable the preparation of the examples of the present application. In some instances, some functional groups outlined in the examples and claims can be replaced by well-known bioisosteric replacements known in the art, for example, replacing a carboxylic acid group with a tetrazole or phosphate moiety. Abbreviations Analytical LCMS Conditions

[0282] 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 NH4OAc; mobile phase B: 5:95 water:acetonitrile with 2.5 mM NH4OAc; temperature: 40 °C; gradient: 20%B to 100%B over 2 minutes; flow rate: 0.7 mL / min; detection: MS and UV (220 nm). Method B: Column: XBridge BEH XP C18 (50 x 2.1) mm, 2.5 μm; mobile phase A: 95:5 water:acetonitrile with 10 mM NH4OAc; mobile phase B: 5:95 water:acetonitrile with 10 mM NH4OAc; temperature: 50 °C; gradient: 0%B to 100%B over 3 minutes; flow rate: 1.1 mL / min; detection: MS and UV (220 nm). Synthesis of oxazolone intermediate A

[0283] 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- oxooxazol-3(2H)-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione Preparation of Int-A1: 2-bromo-l-(4-bromo-2-fluorophenyl)ethan-l-one To a stirred solution of l-(4-bromo-2-fluorophenyl)ethan-l-one (7.5 g, 34.6 mmol) in THF (75 mL) was added pyridine hydrobromide perbromide (13.26 g, 41.47 mmol) slowly at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Then, 20% aqueous sodium bisulfite solution was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (SiO2, 10 to 50% DCM / pet. ether) to give 2-bromo-l-(4-bromo-2-fluorophenyl)ethan-l-one (6.5 g, 57%). LCMS (Method A) retention time 1.64 min, [M-H] + 294.8; 1H NMR (400 MHz, CDC13) δ ppm 7.84 (t, J = 8.0 Hz, 1H), 7.50-7.35 (m, 2H), 4.49 (d, J = 2.5 Hz, 2H).

[0284] Preparation of Int-A2: 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine- 2,6-dione To a stirred solution of 3-amino piperidine-2,6-dione, HC1 (22.25 g, 135 mmol) in THF (200 mL) was added K2C03(20 g, 145 mmol) and the reaction mixture was stirred for 15 min at room temperature under nitrogen atmosphere. Next, 2-bromo-l-(4-bromo-2-fluorophenyl)ethan-l-one (20 g, 67.6 mmol) was added portion wise to the reaction mixture and heated at 70 °C for 2 h. Then, the reaction mixture was cooled to room temperature and concentrated in vacuum. Water (200 mL) was added to get a solid precipitate which was filtered through a Buchner funnel and dried in vacuum to get 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione (19 g, 71%) as off-white solid. LCMS (Method A): Retention time 0.87 min, [M+H] 371.0. + 343.0.

[0285] Preparation of Int-A3: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine- 2,6-dione 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 K2C03(12.08 g, 87 mmol) and CDI (28.4 g, 175 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuum to remove excess solvent. Water (400 mL) was added to get a solid precipitate which was filtered through a Buchner funnel and dried in vacuum to get 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (21.1 g, 50%) as brown solid. LCMS (Method A): Retention time 1.79 min, [M+H] 371.0. + 371.0.

[0286] Preparation of Int-A4: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione 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 -48 °C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with the addition of water. The reaction mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography (Biotage, SiO2, 0 to 60% EtOAc / pet. ether) to afford 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (6.2 g, 45%) as a light brown solid. LCMS (Method A): Retention time 2.04 min, [M-H]- + 498.0; 1 H NMR (400 MHz, CDCl3) δ ppm 7.52 (t, J = 8.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 10.6, 1.6 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 5.29-5.17 (m, 2H), 4.87 (dd, J = 12.6, 6.1 Hz, 1H), 3.67-3.58 (m, 2H), 3.10-3.00 (m, 1H), 2.92-2.78 (m, 1H), 2.48-2.30 (m, 2H), 1.02-0.85 (m, 2H), 0.01 (s, 9H).

[0287] Preparation of Int-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 To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7 g, 14 mmol) in 1,4- dioxane (70 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.34 g, 21 mmol) and potassium acetate (1.65 g, 16.8 mmol) at room temperature. The solution was flushed with nitrogen for 10 minutes and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1.0 g, 1.4 mmol) was added. The resulting reaction mixture was heated at 80 °C for 1 hour, cooled to room temperature, and diluted with EtOAc (70 mL). The suspension was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting residue was purified by flash column chromatography (Biotage, SiO2, 0 to 70% EtOAc / pet. ether) to afford 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 (7 g, 81%) as a white solid. LCMS (Method A): Retention time 2.19 min, [M-H] + 545.2; 1 H NMR (400 MHz, CDCl3) δppm 7.68-7.60 (m, 2H), 7.51 (d, J = 11.8 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H),5.30-5.17 (m, 2H), 4.88 (dd, J = 12.6, 6.1 Hz, 1H), 3.67-3.59 (m, 2H), 3.10-2.99 (m, 1H), 2.94-2.78 (m, 1H), 2.48-2.30 (m, 2H), 1.36-1.13 (m, 12H), 1.03-0.85 (m, 2H), 0.07 (s, 9H)。 Synthesis of oxazolone intermediate B

[0288] 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 Preparation of Int-B1 : tert-Butyl 5-amino-4-((2-(4-bromo-2-fluorophenyl)-2- oxoethyl)amino)-5-oxopentanoate To a stirred solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (Int-A1) (2 g, 6.76 mmol) in acetonitrile (15 mL) was added tert-butyl 4,5-diamino-5- oxopentanoate, HC1 (2.42 g, 11.97 mmol) at room temperature. The reaction mixture was cooled to 0 °C and sodium iodide (1.22 g, 8.11 mmol) and DIPEA (2.36 mL, 13.52 mmol) were added. The reaction mixture was stirred for 5 h. The reaction was quenched with the addition of 10% sodium bisulfite solution. The reaction mixture was extracted with DCM (3 x 25 mL). The combined organic phase was washed with water, brine solution, dried over anhydrous Na2S04, filtered and concentrated in vacuo to afford tert-butyl 5-amino-4-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)-5- oxopentanoate (2.82 g, crude) as a yellow oil. LCMS (Method A) retention time 1.43 min, [M+H] 460.2. + 417.2.

[0289] Preparation of Int-B2: tert-Butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxo- oxazol-3(2H)-yl)-5-oxopentanoate To a stirred solution of tert-butyl 5-amino-4-((2-(4-bromo-2-fluorophenyl)-2- oxoethyl)amino)-5-oxopentanoate (2.82 g, 4.53 mmol) in DMF (28 mL) was added CDI (1.84 g, 11.32 mmol) and triethylamine (1.89 mL, 13.58 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was cooled to 0 °C. The reaction was quenched with the addition of ice cold water. The reaction mixture was filtered. The precipitate was washed with ice cold water, 20% DCM / pet. ether and dried in vacuo to afford tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoate (1.57 g, 66%) as a light brown solid. LCMS (Method A) retention time 1.64 min, [M-H] 460.2. + 440.8; 1H NMR (300 MHz, DMSO-d6) δ ppm 7.81-7.68 (m, 2H), 7.58-7.46 (m, 3H), 7.44-7.32 (m, 1H), 4.60-4.48 (m, 1H), 2.33-2.06 (m, 4H), 1.37 (s, 9H).

[0290] Preparation of Int-B: 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 To a stirred solution of tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2- oxooxazol-3(2H)-yl)-5-oxopentanoate (1.31 g, 2.75 mmol) in 1,4-dioxane (26 mL) was added bis(pinacolato)diboron (105 g, 412 mmol) and potassium acetate (53.9 g, 550 mmol) at room temperature. The reaction mixture was flushed with argon for 10 minutes and [1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (0.22 g, 0.27 mmol) was added. The reaction mixture was heated at 90 °C for 3 hours, cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (SiO2, 0 to 40% EtOAc / petroleum ether) to give 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 (0.96 g, 68%) as a light brown solid. LCMS (Method B) retention time 3.23 min, [M+H] + 491.15; 1 H NMR (500 MHz, DMSO-d6) δ ppm 7.79 (br s, 1H), 7.63-7.52 (m, 3H), 7.45 (d, J = 11.3 Hz, 1H), 7.40 (br s, 1H), 4.58-4.53 (m, 1H), 2.27-2.11 (m, 4H), 1.36 (s, 9H), 1.31 (s, 12H). Synthesis of Intermediate C

[0291] cis-3-(benzyloxy)cyclobutan-1-ol Preparation of Int-C: cis-3-(benzyloxy)cyclobutan-l-ol To a stirred solution of 3-(benzyloxy)cyclobutan-l-one (4 g, 22.7 mmol) in methanol (200 mL) was added sodium borohydride (1.35 g, 35.6 mmol) in small portions at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with EtOAc. The organic layer was washed with 10% aqueous ammonium chloride solution, water and brine solution. The organic layer was separated, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 24 g column, 0 to 70% EtOAc / pet. ether) to give a mixture of cis / trans isomers of 3-(benzyloxy)cyclobutan-l-ol. This isomeric mixture was purified using preparative SFC [(column: Chiral-I amylose straight 3 (250 X 50) mm, 5 μm; %C02: 90%; %Co solvent: 10% of 0.2% 7 mM methanamine in methanol; total flow rate: 250 g / min; back pressure: 100 bar; temperature: 40 °C; UV: 220 nm)] to give cis-3-(benzyloxy)cyclobutan-l-ol as an off-white solid (2.3 g, 57%) and trans-3-(benzyloxy)cyclobutan-l-ol as a viscous liquid (0.15 g, 4%). Cis isomer: LCMS (Method A) Retention time 1.02 min, [M+H] + 179.4; 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.25 (m, 5H), 4.97 (d, J = 5.0 Hz, 1H), 4.35-4.24 (m, 3H), 4.18-4.11 (m, 1H), 2.22-2.14 (m, 2H), 2.09-1.95 (m, 2H). Trans isomer: LCMS (Method A) Retention time 1.06 min, [M+H] + 179.0; 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.26 (m, 5H), 5.00 (d, J = 6.5 Hz, 1H), 4.34 (s, 2H), 3.73-3.64 (m, 1H), 3.58-3.49 (m, 1H), 2.57-2.52 (m, 2H), 1.79-1.69 (m, 2H).

[0292] Example 1 3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluorophenyl)- 2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation 1A: 3-bromo-2,6-dichloro-4-methylpyridine To a stirred solution of 2,6-dichloro-4-methylpyridin-3-amine (20 g, 113 mmol) in hydrobromic acid (100 mL, 866 mmol) was added slowly a solution of sodium nitrite (21.44 g, 124 mmol) in water (20 mL) at 0 °C. The reaction mixture was stirred at the same temperature for an additional 30 minutes. Then, a solution of copper(I) bromide (19.45 g, 136 mmol) in hydrobromic acid (40 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. After 2 hours, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with a brine solution, dried over anhydrous Na2S04, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 220 g column, 0 to 30% EtOAc / pet. ether) to give 3-bromo-2,6-dichloro-4-methylpyridine as an off-white solid (22 g, 81%). LCMS (Method A) Retention time 1.85 min, [M+H] + 241.0; 1 H NMR (400MHz, CDCl3) δ ppm 7.29 (s, 1H), 2.48-2.48 (s, 3H).

[0293] Preparation 1B: l-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylpropan-2-ol To a stirred solution of diisopropylamine (9.47 mL, 66.4 mmol) in dry THF (150 mL) was added 2.5 M n-BuLi in hexanes (23.25 mL, 58.1 mmol) at -78 °C under nitrogen atmosphere over a period of 20 min. The reaction mixture was stirred at -78 °C for 30 min, warmed to 0 °C and stirred for another 30 min. The reaction mixture was again cooled to -78 °C and a solution of 3-bromo-2,6-dichloro-4-methylpyridine (10 g, 41.5 mmol) in dry THF (20 mL) was added. After 1 h, acetone (12.19 mL, 166 mmol) in dry THF (10 mL) was added and the reaction mixture was stirred for another 1 h. The reaction was quenched with the addition of 100 mL of ice cold water. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to get a crude residue which was purified by flash column chromatography (SiO2, 220 g column, 0 to 70% EtOAc in petroleum ether) to get 1-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylpropan-2-ol (3 g, 24%) as off-white solid. LCMS (Method A) Retention time 1.54 min, [M+H] + 297.8; 1 H NMR (400 MHz, CDCl3) δ ppm 7.39 (s, 1H), 3.08 (s, 2H), 1.41 (br s, 1H), 1.29 (s, 6H).

[0294] Preparation 1C: 1-(3-bromo-6-chloro-2-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2- methylpropan-2-ol At room temperature, 2,4-dimethoxyphenyl)methylamine (0.9 mL, 6.02 mmol) and DIPEA (1.402 mL, 8.03 mmol) were added to a stirred solution of 1-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylprop-2-ol (0.6 g, 2.007 mmol) in NMP (30 mL). The resulting reaction mixture was heated in a microwave reactor at 160 °C for 1.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with ice-cold water and a saline solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain a crude residue. This residue was purified by rapid column chromatography (SiO₂, 40 g column, 0 to 70% EtOAc / petroleum ether) to give 1-(3-bromo-6-chloro-2-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2-methylprop-2-ol (0.35 g, 41%) as a pale yellow liquid (LCMS (Method A) retention time 1.89 min, [M+H)). + 429.0; 1 ¹H NMR (400 MHz, CDCl₃) δ ppm 7.33–7.30 (m, 1H), 6.59 (s, 1H), 6.51 (d, J = 2.5 Hz, 1H), 6.49–6.45 (m, 1H), 5.86–5.76 (m, 1H), 4.58 (d, J = 5.5 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.91 (s, 2H), 1.44 (s, 1H), 1.31 (s, 6H)); and 1-(3-bromo-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2-methylprop-2-ol (0.15 g, 17%) as a pale yellow liquid (LCMS). (Method A) Retention time 1.83 min, [M+H] + 429.0; 1 H NMR (400MHz, CDCl3) δ ppm 7.17-6.96 (m, 1H), 6.42-6.22 (m, 3H), 4.99 (br t, J = 5.7Hz, 1H), 4.57 (s, 1H), 4.29 (s, 2H), 3.75 (s, 3H), 3.72 (s, 3H), 2.85 (s, 2H), 1.26 (s, 6H)).

[0295] Preparation 1D: 5-chloro-N-(2,4-dimethoxybenzyl)-2,2-dimethyl-2,3- dihydrofuro[2,3-c]pyridin-7-amine To a stirred solution of 1-(3-bromo-6-chloro-2-((2,4-dimethoxybenzyl)amino)pyridin- 4-yl)-2-methylpropan-2-ol (200 mg, 0.465 mmol) in toluene (10 mL) was added sodium tert-butoxide (90 mg, 0.93 mmol) and 1,2,3,4,5-pentaphenyl-1'-(di-tert- butylphosphino)ferrocene (66 mg, 0.093 mmol) at room temperature in a pressure tube. The reaction mixture was flushed with argon for 15 minutes and Pd2(dba)3 (85 mg, 0.093 mmol) was added and heated at 90 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 40 g column, 0 to 70% EtOAc / pet. ether) to give 5-chloro-N-(2,4-dimethoxybenzyl)-2,2-dimethyl-2,3-dihydrofuro[2,3- c]pyridin-7-amine (50 mg, 31%) as a colourless viscous liquid. LCMS (Method A) RT 1.96 min, [M+H] 410.2. + 349.2; 1 H NMR (300 MHz, CDCl3)δ ppm 7.30 (d, J = 7.9 Hz, 1H), 6.47-6.39 (m, 3H), 4.67 (br s, 1H), 4.54 (d,J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.90 (s, 2H), 1.44 (s, 6H).

[0296] Preparation 1E: 3-(5-(4-(7-((2,4-dimethoxybenzyl)amino)-2,2-dimethyl-2,3- dihydrofuro[2,3-c]pyridin-5-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione To a stirred solution of 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-oxooxazol-3(2H)-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6- dione (Int-A) (260 mg, 0.48 mmol) in 1,4-dioxane (20 mL)-water (0.5 mL) was added 6-chloro-N-(2,4-dimethoxybenzyl)-2-methyl-2H-[l,2,3]triazolo[4,5-c]pyridin-4-amine (183 mg, 0.523 mmol) and cesium carbonate (310 mg, 0.952 mmol) at room temperature. The reaction mixture was flushed with argon for 10 min and added with Catacxium Pd G3 (34.6 mg, 0.048 mmol). The reaction mixture was heated at 85 °C for 3 h, cooled to room temperature, diluted with EtOAc, and filtered through a pad of celite. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography (SiO2, 330 g column, 0 to 80% EtOAc / DCM) to afford 3-(5-(4-(7-((2,4-dimethoxybenzyl)amino)-2,2-dimethyl-2,3-dihydrofuro[2,3- c]pyridin-5-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (180 mg, 51.6%) as off-white solid. LCMS (Method A) Retention time 2.30 min, [M+H] + 733.4.

[0297] Example 1: 3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione To a stirred solution of 3-(5-(4-(7-((2,4-dimethoxybenzyl)amino)-2,2-dimethyl- 2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (0.1 g, 0.14 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL, 64.9 mmol) at 0 °C. The reaction mixture was warmed to room temperature, stirred for 16 h, and then concentrated in vacuo. The resulting residue was dissolved in DME (5 mL) and cooled to 0 °C. N,N'-dimethylethylenediamine (0.07 mL, 0.682 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 30 min. The reaction was quenched with the addition of acetic acid (0.5 mL, 8.73 mmol). The reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was concentrated in vacuo to give a crude residue which was purified by preparative HPLC (column: Sun Fire C18 (250*19*5) mobile phase A: water with 10 mM ammonium acetate (pH: 4.5); mobile phase B: ACN; gradient: A hold at 10% B for 0 min, 15 to 50% B over 10 min, followed by a hold at 50% B for 2 min; flow rate: 20 mL / min; column temperature: 25 °C) to give 3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (40 mg, 65%) as a white solid. LCMS (Method A) Retention time 1.40 min, [M+H] + 453.1; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (br s, 1H), 7.87 (s, 1H), 7.85 (d,J = 5.0 Hz, 1H), 7.62-7.55 (m, 2H), 7.21 (s, 1H), 5.70 (s, 2H), 5.07 (dd, J =13.0, 5.3 Hz, 1H), 3.03 (s, 2H), 2.95-2.82 (m, 1H), 2.65-2.53 (m, 2H), 2.13(dt, J = 10.4, 5.2 Hz, 1H), 1.47 (s, 6H). Example 2 Trans 3-(5-(4-(6-amino-5-(3-methoxyoxanylyl)-4-methylpyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation 2A: 2,6-Dichloro-4-methylpyridin-3-ol To a stirred solution of 4-methylpyridin-3-ol (12.5 g, 115 mmol) in acetonitrile (250 mL) was added NCS (33.6 g, 252 mmol) in small portions at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered through a pad of celite and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 220 g column, 0 to 50% EtOAc / pet. ether) to give 2,6-dichloro-4-methylpyridin-3-ol as a bright yellow solid (10 g, 49%). LCMS (Method A): Retention time 1.07 min, [M+H] + 177.9; 1 H NMR (300MHz, CDCL3) δ ppm 7.08 (s, 1H), 5.54 (br s, 1H), 2.31 (s, 3H).

[0298] Preparation 2B: Trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4- methylpyridine To a stirred solution of 2,6-dichloro-4-methylpyridin-3-ol (1.0 g, 5.62 mmol) in anhydrous THF (2 mL) was added cis-3-(benzyloxy)cyclobutan-1-ol (Int-C) (1.20 g, 6.74 mmol) and triphenylphosphine (1.77 g, 6.74 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C and DIAD (1.31 mL, 6.74 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. Next, the reaction mixture was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 24 g column, 0 to 40% EtOAc / pet. ether) to give trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4-methylpyridine as a colourless liquid (1.3 g, 68%). LCMS (Method A) retention time 1.52 min, [M+H] + 338.1; 1H NMR (300 MHz, CDC13) δ ppm 7.39-7.28 (m, 5H), 7.09 (s, 1H), 4.81 (tt, J = 7.0, 5.1 Hz, 1H), 4.44 (s, 2H), 4.42-4.32 (m, 1H), 2.60-2.40 (m, 4H), 2.30 (s, 3H).

[0299] Preparation 2C: Trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4- methylpyridine 3-((2,6-Dichloro-4-methylpyridin-3-yl)oxy)cyclobutan-1-ol To a stirred solution of trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4- methylpyridine (1.3 g, 3.84 mmol) in THF (15 mL) was added 50% wet Pd / C (10% w / w) (1.08 g, 10.18 mmol) under nitrogen. The reaction mixture was flushed with hydrogen and then stirred under an atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was filtered through a pad of celite and the celite pad was washed with THF and MeOH. The combined filtrates were concentrated in vacuo and the resulting residue was purified by flash column chromatography (Si02, 24 g column, 0 to 50% EtOAc / petroleum ether) to give trans 3-((2,6-dichloro-4-methylpyridin-3-yl)oxy)cyclobutan-1-ol (600 mg, 63%) as a colourless sticky mass. LCMS (Method A) Retention time 1.26 min, [M+H] 279.0;1H NMR (300 MHz, CDC13) δ ppm 7.09 (s, 1H), 4.85 (tt, J = 6.9, 5.0 Hz, 1H), 4.72-4.64 (m, 1H), 3.49 (br s, 1H), 2.67-2.54 (m, 2H), 2.39-2.31 (m, 2H), 2.30 (s, 3H). + 248.2; 1 H NMR (300 MHz, CDC13) δ ppm 7.09 (s, 1H), 4.85 (tt, J = 6.9, 5.0 Hz, 1H), 4.72-4.64 (m, 1H), 3.49 (br s, 1H), 2.67-2.54 (m, 2H), 2.39-2.31 (m, 2H), 2.30 (s, 3H).

[0300] Preparation 2D: Trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4- methylpyridine 2,6-Dichloro-3-(3-methoxycyclobutyloxy)-4-methylpyridine To a stirred solution of trans-3-((2,6-dichloro-4-methylpyridin-3- yl)oxy)cyclobutan-l-ol (600 mg, 2.42 mmol) in dry THF (5 mL) was added NaH (60% in mineral oil) (145 mg, 3.63 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min and iodomethane (0.151 mL, 2.42 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with the addition of ice cold water. The reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine solution, dried over Na2S04, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 40 g column, 0 to 20% EtOAc / petroleum ether) to give trans-2,6-dichloro-3-(3- methoxycyclobutoxy)-4-methylpyridine (400 mg, 63%) as an off-white solid. LCMS (Method A) Retention time 1.74 min, [M+H] 323.0; 325.0. + 262.2; 1 H NMR (300MHz, CDCl3) δ ppm 7.09 (s, 1H), 4.77 (tt, J = 7.0, 5.3 Hz, 1H), 4.14 (tt, J =6.8, 3.6 Hz, 1H), 3.26 (s, 3H), 2.57-2.48 (m, 2H), 2.45-2.35 (m, 2H), 2.31(s, 3H).

[0301] Preparation 2E: trans-3-(3-(benzyloxy)cyclobutoxy)-2,6-dichloro-4- methylpyridine 6-chloro-N-(2,4-dimethoxybenzyl)-3-(3-methoxycyclobutoxy)-4- methylpyridin-2-amine To a stirred solution of trans 2,6-dichloro-3-(3-methoxy cyclobutyloxy)-4- methylpyridine (400 mg, 1.526 mmol) and (2,4-dimethoxyphenyl)methanamine (255 mg, 1.526 mmol) in anhydrous 1,4-oxane (5 mL) at room temperature was added cesium carbonate (994 mg, 3.05 mmol). The reaction mixture was flushed with argon for 10 minutes and palladium(II) acetate (34 mg, 0.153 mmol) and BINAP (143 mg, 0.229 mmol) were added. The reaction mixture was heated at 90 °C for 16 hours, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography (SiO2, 24 g column, 0 to 50% EtOAc / pet. ether) to give trans 6-chloro-N-(2,4-dimethoxybenzyl)-3-(3- methoxycyclobutyloxy)-4-methylpyridin-2-amine (230 mg, 38%) as an off-white solid. LCMS (Method A) Retention time 2.07 min, [M+H] + 393.3; 1 H NMR (300 MHz, CDCl3) δ ppm 7.26 (d, J = 6 Hz, 1H), 6.47-6.41 (m, 2H), 6.33 (s, 1H), 5.23 (br t, J = 5.4 Hz, 1H), 4.54-4.45 (m, 3H), 4.06-3.97 (m, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.20 (s, 3H), 2.40-2.25 (m, 4H), 2.11 (s, 3H).

[0302] Preparation 2F: trans 3-(3-(benzyloxy)cyclobutyloxy)-2,6-dichloro-4- methylpyridine 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-5-(3-methoxycyclobutyloxy)- 4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoic acid tert-butyl ester To a stirred solution of trans 6-chloro-N-(2,4-dimethoxybenzyl)-3-(3- methoxycyclobutyloxy)-4-methylpyridin-2-amine (230 mg, 0.585 mmol) in 1,4- dioxane (8 mL)-water (2.0 mL) was added 5-amino-4-(5-(2-fluoro-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoic acid tert-butyl ester (Int-B) (316 mg, 0.644 mmol) and potassium phosphate tribasic (311 mg, 1.46 mmol) at room temperature. The reaction mixture was flushed with argon for 10 minutes and XPhos Pd G2 (46 mg, 0.059 mmol) was added. The reaction mixture was then heated at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, dried over anhydrous Na2SO4and filtered through a pad of celite. The filtrate was concentrated in vacuo to give a crude residue which was purified by flash chromatography (SiO2, 12 g cartridge, 0 to 4% MeOH / DCM) to give trans 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-5-(3- methoxycyclobutyloxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoic acid tert-butyl ester (200 mg, 47%) as a light brown solid. LCMS (Method B) Retention time 2.04 min, [M+H] + 721.4; 1 H NMR (300 MHz, DMSO-d6) δ ppm 7.95-7.83 (m, 2H), 7.77 (s, 1H), 7.57 (t, J = 8.3 Hz, 1H), 7.48 (d, J = 2.9 Hz, 1H), 7.40 (s, 1H), 7.19 (d, J = 8.3 Hz, 1H), 7.09 (s, 1H), 6.57 (d, J = 2.2 Hz, 1H), 6.44 (dd, J = 8.4, 2.3 Hz, 1H), 6.31 (s, 1H), 4.64 (s, 1H), 4.59-4.51 (m, 3H), 4.11 (br dd, J = 4.3, 2.9 Hz, 1H), 3.92 (s, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.15 (s, 3H), 2.47-2.36 (m, 2H), 2.30-2.20 (m, 7H), 1.38 (s, 9H).

[0303] Example 2: Trans 3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione To a stirred solution of trans tert-butyl 5-amino-4-(5-(4-(6-((2,4- dimethoxybenzyl)amino)-5-(3-methoxycyclobutyloxy)-4-methylpyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate (200 mg, 0.277 mmol) in acetonitrile (5 mL) was added methanesulfonic acid (0.054 mL, 0.832 mmol) at room temperature and heated at 90 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to get a crude residue which was purified by reverse phase preparative HPLC (column: YMC EXRS C18 ( 250 mm*20 mm) 5 μm; mobile phase A: water with 10 mM ammonium acetate pH-4.5; mobile phase B: ACN; flow rate: 20.0 mL / min) to get trans 3-(5-(4-(6-amino-5-(3-methoxycyclobutyloxy)-4- methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (50 mg, 36%) as off-white solid. LCMS (Method B) Retention time 1.89 min, [M+H] + 497.15; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (br s, 1H), 7.91 (s, 1H), 7.89-7.87 (m,1H), 7.63-7.58 (m, 2H), 7.11 (s, 1H), 5.81 (br s, 2H), 5.07 (dd, J = 13.0,5.3 Hz, 1H), 4.68-4.61 (m, 1H), 4.14-4.08 (m, 1H), 3.15 (s, 3H), 2.95-2.83(m, 1H), 2.65-2.53 (m, 2H), 2.46-2.37 (m, 2H), 2.26-2.22 (m, 2H), 2.21 (s,3H), 2.17-2.10 (m, 1H).

[0304] Example 3 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation 3A: 2,6-dichloro-4-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-3-amine To a stirred solution of 2,6-dichloro-4-methylpyridin-3-amine (1 g, 5.65 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (0.96 g, 8.47 mmol) in EtOAc (10 mL) was added TFA (0.87 mL, 11.3 mmol) at room temperature. The reaction mixture was stirred for 30 min. Then, sodium triacetoxyborohydride (2.4 g, 11.3 mmol) was added and the reaction mixture was stirred overnight. The reaction was quenched with the addition of saturated aqueous NaHC03solution. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic phase was washed with water and brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 40 g column, 0 to 20% EtOAc / petroleum ether) to give 6-dichloro-4-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-3-amine (0.75 g, 48%) as a yellow oil. LCMS (Method A): Retention time 1.65 min, [M+H] + 275.2; 1 H NMR (400 MHz, CDC13) δ ppm 7.04 (s, 1H), 4.02 (br dd, J = 11.5, 4.0 Hz, 2H), 3.76 (br s, 1H), 3.46-3.36 (m, 2H), 2.99 (d, J = 6.0 Hz, 2H), 2.35 (s, 3H), 1.75-1.71 (m, 2H), 1.64-1.57 (m, 1H), 1.48-1.32 (m, 2H).

[0305] Preparation 3B: 6-chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3 -((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,3-diamine To a stirred solution of 2,6-dichloro-4-methyl-N-((tetrahydro-2H-pyran-4- yl)methyl)pyridin-3-amine (0.67 g, 2.44 mmol) and 2,4-dimethoxybenzylamine (0.36 mL, 2.44 mmol) in anhydrous 1,4-dioxane (5 mL) at room temperature was added cesium carbonate (1.6 g, 4.87 mmol). The reaction mixture was flushed with argon for 10 minutes and BINAP (227 mg, 0.365 mmol) and palladium(II) acetate (55 mg, 0.24 mmol) were added. The reaction mixture was heated at 90 °C for 3 hours, cooled to room temperature, diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (Si02, 24 g column, 0 to 30% EtOAc / petroleum ether) to give 6-chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3 -((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2,3-diamine (0.42 g, 43%). LCMS (Method A) Retention time 2.03 min, [M-H] + 404.1; 1 H NMR (400 MHz, CDCl3) δ ppm 7.28 (d, J = 7.1 Hz, 1H), 6.48 (s, 1H), 6.45 (br d, J = 8.5 Hz, 1H), 6.36 (s, 1H), 5.65 (br s, 1H), 4.54 (br d, J = 5.5 Hz, 2H), 3.98 (br dd, J = 11.0, 3.5 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 3.39 (br t, J = 11.8 Hz, 2H), 2.64 (br d, J = 6.0 Hz, 2H), 2.44 (br s, 1H), 2.14 (s, 3H), 1.70 (br d, J = 11.0 Hz, 3H), 1.41-1.29 (m, 2H).

[0306] Preparation 3C: tert-Butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate To a stirred solution of 6-chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3 -((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,3-diamine (300 mg, 0.739 mmol) was added tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate (Int-B) (364 mg, 0.739 mmol) and potassium phosphate tribasic (392 mg, 1.848 mmol). The reaction mixture was flushed with argon for 10 minutes and XPhos Pd G2 (58 mg, 0.074 mmol) was added. The reaction mixture was heated at 95 °C for 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, dried over anhydrous Na2SO4, and filtered through a pad of celite. The filtrate was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (SiO2, 24 g column, 0 to 5% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate (0.45 g, 83%). LCMS (Method A) Ret Time 1.92 min, [M+H] + 734.5.

[0307] Example 3: 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione To a stirred solution of tert-butyl 5-amino-4-(5-(4-(6-((2,4- dimethoxybenzyl)amino)-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoate (300 mg, 0.409 mmol) in acetonitrile (2 mL) was added methanesulfonic acid (66 µL, 1.02 mmol) at room temperature. The reaction mixture was heated at 90 °C for 2 h, cooled to room temperature and concentrated in vacuo to give a crude residue which was purified by reverse phase preparative HPLC (column: YMC Triartec18 EXRS1 (250*20*5); mobile phase A: water with 10 mM ammonium acetate; mobile phase B: ACN; time / %B: 00 / 20, 15 / 60, 17 / 95) to give 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4- yl)methyl)amino)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine- 2,6-dione (19 mg, 9%) as off-white solid. LCMS (Method B) Retention time 1.45 min, [M+H] + 510.20; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (br s, 1H), 7.89 (s, 1H), 7.86 (d, J = 4.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.10 (s, 1H), 5.63 (s, 2H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 3.92-3.82 (m, 3H), 3.28-3.23 (m, 2H), 2.94-2.83 (m, 1H), 2.76 (br t, J = 6.6 Hz, 2H), 2.65-2.54 (m, 2H), 2.23 (s, 3H), 2.17-2.08 (m, 1H), 1.70 (br d, J = 10.8 Hz, 3H), 1.26-1.15 (m, 2H).

[0308] Example 4 3-(5-(4-(6-amino-5-((4-methoxy piperidin-1-yl)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation 4A: tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate To a stirred solution of tert-butyl (6-chloropyridin-2-yl)carbamate (20 g, 87 mmol) and TEMED (33 mL, 219 mmol) in dry THF (300 mL) was added 1.6 M n-BuLi in hexanes (137 mL, 219 mmol) at -78 °C under nitrogen atmosphere over a period of 30 min. The reaction mixture was gradually warmed to -10 °C and stirred at the same temperature for 2 h. The reaction mixture was again cooled to -78 °C, added with dry DMF (34 mL, 437 mmol) and gradually warmed to room temperature. The reaction mixture was stirred for another 2 h, quenched with 1 N hydrochloric acid (0.5 L) and diluted with EtOAc (1 L) and stirred for 15 min. The organic phase was washed with water and saturated NaHC03solution, dried over anhydrous Na2S04, filtered and concentrated in vacuo to get a crude residue which was triturated with 10% isopropanol in petroleum ether, filtered and dried in vacuo to get tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (15 g, 67%) as off-white solid. LCMS (Method A): Retention time 1.45 min, [M-tBu] 279.0; 1H NMR (300 MHz, CDC13) δ ppm 10.17 (br s, 1H), 9.90 (s, 1H), 7.94 (br d, J = 8.3 Hz, 1H), 7.26-7.02 (m, 1H), 1.55 (s, 9H). + 201.1; 1 H NMR (300 MHz, CDCl3) δ ppm 10.17(br s, 1H), 9.90 (s, 1H), 7.94 (br d, J = 8.3 Hz, 1H), 7.26-7.02 (m, 1H),1.55 (s, 9H)。

[0309] Preparation 4B: tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5- formylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate To a stirred solution of 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)-2-oxooxazol-3(2H)-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2,6-dione (Int-B) (4.78 g, 9.74 mmol) in 1,4-dioxane (60 mL)-water (4.5 mL) was added 6-chloro-N-(2,4-dimethoxybenzyl)-2-methyl-2H-[l,2,3]triazolo[4,5- c]pyridin-4-amine (2.5 g, 9.74 mmol) and cesium carbonate (4.76 g, 14.6 mmol) at room temperature. The reaction mixture was flushed with argon for 10 min and added with Catacxium Pd G3 (0.36 g, 0.49 mmol). The reaction mixture was heated at 85 °C for 3 h, cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated in vacuo to give a crude residue which was purified by flash column chromatography (SiO2, 80 g column, 0 to 80% EtOAc / petroleum ether) to give tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5- formylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate (5.0 g, 88%) as a light brown solid. LCMS (Method A) Retention time 1.81 min, [M-H] + 583.5.

[0310] Preparation 4C: tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-((4- methoxy piperidin- 1 -yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoate At room temperature, triethylamine (0.024 mL, 0.41 mmol) was added to a stirred solution containing 4-methoxypiperidine (47.3 mg, 0.41 mmol) and 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxovalerate tert-butyl ester (120 mg, 0.20 mmol) in DCE (5 mL)-DMF (1 mL). The reaction mixture was stirred overnight. Then, MP-cyanoborohydride (200 mg) was added and the reaction mixture was stirred again overnight. The reaction mixture was filtered through a diatomaceous earth pad and concentrated under vacuum to obtain a crude residue, which was purified by rapid column chromatography (SiO2, 12 g column, 0 to 10% MeOH / DCM) to give tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxovalerate (120 mg, 58%) as a yellow solid. LCMS (Method A): retention time 2.01 min, [M+H] + 684.5.

[0311] Example 4: 3-(5-(4-(6-amino-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidin-2,6-dione To a stirred solution of tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5- ((4-methoxy piperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoate (120 mg, 0.18 mmol) in acetonitrile (5 mL) was added benzenesulfonic acid (0.04 mL, 0.36 mmol) at room temperature. The reaction mixture was heated at 90 °C for 16 h, cooled to room temperature and concentrated in vacuo to give a crude residue which was purified by reverse phase preparative HPLC (Column: Waters XBridge C18, 150 mm x 19 mm, 5-μm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: stay at 10% B for 0 min, 10 to 48% B over 10 min, then stay at 48% B for 5 min; flow rate: 20 mL / min; column temperature: 25 °C) to give 3-(5-(4-(6-amino-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (50 mg, 55%) as a white solid. LCMS (Method A): Retention time 1.62 min, [M+H] + 510.2; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (s, 1H), 7.98-7.93 (m,2H), 7.66-7.61 (m, 2H), 7.39 (br d, J = 7.5 Hz, 1H), 7.20 (d, J = 7.5 Hz,1H), 6.22 (br s, 2H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 3.45-3.38 (m, 2H),3.23 (s, 3H), 3.22-3.16 (m, 1H), 2.94-2.84 (m, 1H), 2.69-2.56 (m, 4H), 2.19-2.07 (m, 3H), 1.83 (br s, 2H), 1.45 (br d, J = 9.0 Hz, 2H)。

[0312] Example 5 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation of 5A: (2,6-dichloro-4-methylpyridin-3-yl)methanol At 0°C under nitrogen atmosphere, a 2M solution (6.07 ml, 12.13 mmol) of lithium aluminum hydride in THF was slowly added to a stirred solution of 1.0 g (4.85 mmol) of 2,6-dichloro-4-methylnicotinic acid in anhydrous THF (30 ml). The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched at 0°C by the slow addition of water (2.3 mL) followed by 2.3 mL of 15% NaOH solution. The reaction mixture was stirred for 5 minutes and then water (6.9 mL) was added, followed by THF (50 mL). The reaction mixture was stirred vigorously for 10 minutes, dried over anhydrous Na2SO4, and filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum, and the resulting crude residue was purified by rapid column chromatography (SiO2, 0 to 80% EtOAc / petroleum ether) to give (2,6-dichloro-4-methylpyridin-3-yl)methanol (440 mg, 47%) as a light-colored amorphous solid. LCMS (Method A): retention time 1.03 min, [M+H] + 192.1; 1 H NMR (300 MHz, CDCl3) δ ppm 7.15 (s,1H), 4.83 (s, 2H), 2.49 (s, 3H), 1.95 (br s, 1H).

[0313] Preparation of 5B: 2,6-dichloro-3-(chloromethyl)-4-methylpyridine At room temperature, triethylamine (0.54 ml, 3.91 mmol) was added to a stirred solution of (2,6-dichloro-4-methylpyridin-3-yl)methanol (500 mg, 2.6 mmol) in anhydrous DCM (26 ml), followed by DMAP (32 mg, 0.26 mmol). Methanesulfonyl chloride (243 µL, 3.12 mmol) was added at 0 °C under nitrogen. The reaction mixture was heated to room temperature and stirred for 16 hours. The reaction mixture was then concentrated under vacuum, and the resulting crude residue was purified by rapid column chromatography (SiO2, 0 to 50% EtOAc / petroleum ether) to give 2,6-dichloro-3-(chloromethyl)-4-methylpyridine (345 mg, 63%) as a pale yellow oil. LCMS (Method A): retention time 1.70 min, [M+H] + 210.1;1 H NMR (300 MHz, CDCl3) δ ppm 7.14 (s, 1H), 4.68 (s,2H), 3.96 (dt, J = 11.7, 4.6 Hz, 2H), 3.62 (dt, J = 8.5, 4.5 Hz, 1H), 3.53-3.41 (m, 2H), 2.46 (s, 3H), 1.96 (br dd, J = 13.3, 3.9 Hz, 2H), 1.70-1.61 (m,2H).

[0314] Preparation 5C: 2,6-dichloro-4-methyl-3-(((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridine To a stirred solution of tetrahydro-2H-pyran-4-ol (580 mg, 5.7 mmol) in anhydrous THF (30 mL) at 0 °C was added 60% sodium hydride in mineral oil (285 mg, 7.13 mmol). The reaction mixture was stirred at 0 °C for 30 min. Next, 2,6-dichloro-3-(chloromethyl)-4-methylpyridine (1 g, 4.75 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with the addition of ice cold water at 0 °C. The reaction mixture was extracted with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The obtained crude residue was purified by flash column chromatography (SiO2, 0 to 80% EtOAc / petroleum ether) to give 2,6-dichloro-4-methyl-3-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridine (1.1 g, 84%) as a colorless oil. LCMS (Method A): Retention time 1.48 min, [M+H] 313.0;1H NMR (300 MHz, CDCl3) δ ppm 7.16 (s, 1H), 4.72 (s, 2H), 2.49 (s, 3H). + 276.0; 1 H NMR (300 MHz, CDCl3) δ ppm 7.14 (s, 1H), 4.68 (s,2H), 3.96 (dt, J = 11.7, 4.6 Hz, 2H), 3.62 (dt, J = 8.5, 4.5 Hz, 1H), 3.53-3.41 (m, 2H), 2.46 (s, 3H), 1.96 (br dd, J = 13.3, 3.9 Hz, 2H), 1.70-1.61 (m,2H).

[0315] Preparation 5D: 6-chloro-N-(2,4-dimethoxybenzyl)-4-methyl-3-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-amine To a stirred solution of 2,6-dichloro-4-methyl-3-(((tetrahydro-2H-pyran-4- yl)oxy)methyl)pyridine (1 g, 3.62 mmol) and (2,4-dimethoxyphenyl)methanamine (0.7 g, 4.16 mmol) in anhydrous 1,4-dioxane (12 ml) was added cesium carbonate (2.95 g, 9.05 mmol) at room temperature. The reaction mixture was flushed with argon for 10 minutes at room temperature. Next, palladium(II) acetate (81 mg, 0.36 mmol) and BINAP (338 mg, 0.54 mmol) were added. The reaction mixture was heated at 90 °C for 1.5 hours and then cooled to room temperature. The reaction mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated in vacuo and the obtained crude residue was purified by reverse-phase flash column chromatography (column C18 750 g, mobile phase A: water with ammonium acetate, pH 7; mobile phase B: acetonitrile; gradient: time (min) / %B - 0 / 0%, 40 / 40%, 90 / 40%, 95 / 100%) to give 6-chloro-N-(2,4-dimethoxybenzyl)-4-methyl-3-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-amine (450 mg, 31%) as a light viscous solid. LCMS (Method A): Retention time 1.98 min, [M-H] + 405.4; 1 H NMR (300 MHz, CDCl3) δ ppm 7.29 (d, J =7.9 Hz, 1H), 6.47-6.38 (m, 3H), 5.88 (br t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.7Hz, 2H), 4.47 (s, 2H), 3.87 (dt, J = 11.8, 4.5 Hz, 2H), 3.82 (s, 3H), 3.79(s, 3H), 3.49-3.34 (m, 3H), 2.19 (s, 3H), 1.87-1.74 (m, 2H), 1.54-1.46 (m,2H).

[0316] Preparation 5E: tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate To a stirred solution of 6-chloro-N-(2,4-dimethoxybenzyl)-4-methyl-3-(((tetrahydro- 2H-pyran-4-yl)oxy)methyl)pyridin-2-amine (150 mg, 0.37 mmol) and tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-2- oxooxazol-3(2H)-yl)-5-oxopentanoate (Int-B) (181 mg, 0.37 mmol) in 1,4- dioxane (2 mL)-water (0.5 mL) was added cesium carbonate (300 mg, 0.92 mmol) at room temperature. The reaction mixture was flushed with argon for 10 minutes. Next, Xphos Pd G2 (29 mg, 0.04 mmol) was added and the reaction mixture was heated at 90 °C for 2.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, dried over anhydrous Na2SO4and filtered through a pad of celite. The filtrate was concentrated in vacuo and the resulting crude residue was purified by flash column chromatography (SiO2, 0 to 100% EtOAc (containing 15% EtOH) / DCM) to afford tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-4-methyl-5-(((tetrahydro- 2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5- oxopentanoate (250 mg, 92%). LCMS (Method A): Retention time 2.02 min, [M-H] + 735.5; 1H NMR (300 MHz, CDCl3) δ ppm 7.92-7.81 (m, 2H), 7.68-7.61 (m, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 6.87 (s, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.42 (dd, J = 8.3, 2.5 Hz, 1H), 6.35 (br s, 1H), 5.89 (t, J = 5.4 Hz, 1H), 5.51 (br s, 1H), 4.78-4.72 (m, 1H), 4.70 (d, J = 5.4 Hz, 2H), 4.58 (s, 2H), 3.88 (s, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.51 (tt, J = 8.7, 4.1 Hz, 1H), 3.40 (ddd, J = 11.8, 9.5, 2.7 Hz, 2H), 2.37 (br d, J = 3.6 Hz, 3H), 2.30 (s, 3H), 2.23-2.12 (m, 1H), 1.91-1.80 (m, 2H), 1.57 (br d, J = 9.3 Hz, 2H), 1.46 (s, 9H).

[0317] Example 5: 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione To a stirred solution of tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-4- methyl-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2- oxooxazol-3(2H)-yl)-5-oxopentanoate (230 mg, 0.31 mmol) in acetonitrile (2 mL) was added methanesulfonic acid (102 µL, 1.56 mmol) at room temperature. The reaction mixture was heated at 90 °C for 2 h. Next, the reaction mixture was cooled to room temperature, concentrated in vacuo to give a crude residue which was purified by reverse-phase preparative HPLC (XSelect CSH C18 (250 mm x 19 mm x 5 µm); mobile phase A: water with 10 mM ammonium acetate (pH 4.5); mobile phase B: acetonitrile; gradient: T / %B - 0 / 20%, 3 / 30%, 15 / 55%, 13 / 95%; flow rate: 20 mL / min) to give 3-(5-(4-(6-amino-4-methyl-5-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-yl)-2- fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (37 mg, 27%) as a white amorphous solid. LCMS (Method B) Retention time 1.66 min, [M+H] + 511.15; 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 7.97 (s, 1H), 7.96-7.93 (m, 1H),7.66-7.60 (m, 2H), 7.14 (s, 1H), 5.83 (s, 2H), 5.07 (dd, J = 12.9, 5.1 Hz,1H), 4.50 (s, 2H), 3.84-3.78 (m, 2H), 3.59 (dt, J = 8.8, 4.5 Hz, 1H), 3.35(br s, 2H), 2.88 (br d, J = 4.5 Hz, 1H), 2.69-2.54 (m, 2H), 2.30 (s, 3H),2.17-2.09 (m, 1H), 1.94-1.86 (m, 2H), 1.50-1.41 (m, 2H)。

[0318] Comparative Compound A 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione is disclosed in WO 2019 / 060693 Al as compound number I-33.

[0319] Preparation 1A: tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate To a stirred suspension of 2-bromo-l-phenylethan-l-one (200 mg, 1.0 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate HC1 (360 mg, 1.5 mmol) in dry 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 min. DIPEA (351 pL, 2.01 mmol) was added dropwise to the reaction mixture. The reaction mixture was continued to stir at 0 °C for 2 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with the addition of 10% sodium bisulfite solution. The mixture was extracted with DCM (3 x 10 mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2S04, filtered and concentrated under vacuum to afford 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.

[0320] Preparation IB: tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate 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 x 15 mL). The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 24 g cartridge, 0 to 100% EtOAc in 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 (300MHz, DMSO-d6) δ ppm 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).

[0321] 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 h, cooled to room temperature, concentrated under vacuum and the residue was purified by reverse phase preparative HPLC (X-Bridge Phenyl C18 (250 mm*19 mm) 5 µm; mobile phase A: water with 10 mM ammonium acetate, 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; 1H NMR (400 MHz, DMSO-d6) δ ppm 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).

[0322] Comparative Compound B 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione Preparation 1A: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- (hydroxymethyl)piperidine-2,6-dione To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.4 mmol) in dry DCM (2.0 mL) was added TFA (0.154 mL, 2.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, concentrated under vacuum and the residue co-evaporated with DME (4 x) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1- (hydroxymethyl)piperidine-2,6-dione (150 mg, 94%). LCMS (Method A): Retention time 1.37 min, [M+Na] + 423.1.

[0323] Comparative Compound B: At 0 °C under nitrogen atmosphere, N,N'-dimethylethane-1,2-diamine (199 mg, 2.26 mmol) was added to a stirred solution containing 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-(hydroxymethyl)piperidin-2,6-dione (180 mg, 0.45 mmol) in anhydrous DME (2255 µL). The reaction mixture was heated to room temperature and stirred for 30 min, cooled to 0 °C, acidified with acetic acid (258 µL, 4.5 mmol), and then concentrated under vacuum (bath temperature < 30 °C). The residue was purified by reverse-phase preparative HPLC (method: column: X-Bridge Phenyl (19 mm x 250 mm*5 μm); mobile phase A: water containing 10 mM ammonium acetate, mobile phase B: ACN; flow rate: 20 mL / min; gradient conditions (time / %B): 0 / 30, 14 / 51, 14.1 / 100) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidin-2,6-dione (67 mg, 40%). LCMS (method A): retention time 2.155 min, [MH] + 366.8; 1 H NMR (400 MHz, DMSO-d6)δ ppm 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). Biological assay

[0324] The pharmacological properties of the compounds of the present invention can be confirmed by a variety of biological assays. The exemplary biological assays shown below have been performed using the compounds of the present invention.

[0325] JURKAT Cell Degradation Assay Jurkat cells were plated at 80,000 cells / well in 384-well cell culture plates in 40 pL RPMI + 10% FBS prior to using acoustic dispensing techniques to add the compound of interest. Cell cultures were incubated at 37 °C with 5% CO2 for 24 hours. To facilitate analysis, cell cultures were centrifuged for 5 minutes at 200 rpm and the supernatant was discarded. After the plate was shaken to remove the cell pellet, the cells were resuspended in 50 pL fixation buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 60 minutes at room temperature. After centrifugation and discarding the supernatant, the cells were permeabilized with 50 pL permeabilization buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 10 minutes at room temperature. After permeabilization, the cells were centrifuged and the supernatant was replaced with 20 pL of 1x permeabilization buffer containing fluorescently labeled anti-Helios, Ikaros, and Aiolos antibodies or corresponding isotype controls (Ikaros-Alexa Fluor® 488 [Biolegend, Cat. No. 368408, 1:50], Helios-PE [CST, Cat. No. 29360, 1:50], Aiolos-Alexa Fluor® 647 [Biolegend, Cat. No. 371106 Biolegend, 1:25]) and the staining reaction was incubated for 1 hour at room temperature while protected from light. Subsequently, 30 pL of 1x permeabilization buffer was added before the cells were centrifuged and the supernatant was discarded. The stained cells were resuspended in 25 pL of flow cytometry staining buffer (PBS + 0.2% bovine serum albumin (BSA)) and analyzed using an Intellicyt iQue Plus flow cytometer. Table A-1 Jurkat cell degradation assay: maximum degradation observed

[0326] Table A-1 lists the maximum degradation observed for IKZF1 protein, IKZF2 protein, and IKZF3 protein as 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 remaining protein or complete degradation of the protein; and a value of 0% indicates that the test compound did not cause detectable degradation of the protein. In the studies reported in Table A-1, at least 89% degradation of IKZF2 (Helios) protein was observed for the compounds of the application as exemplified by Examples 1-5. In contrast, less than 30% degradation of IKZF2 protein was observed for Comparative Compound A and Comparative Compound B. Table A-2 Jurkat cell degradation assay: DC50 * *DC 50 defined as the concentration of compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone. Human regulatory T cell degradation assay

[0327] Freeze-stored human regulatory T cells were thawed in RPMI + 10% FBS + 20 ng / mL IL-2. After centrifugation for 5 minutes at 1200 rpm, cells were resuspended in RPMI + 10% FBS + 20 ng / mL human IL-2 and left to rest for 3 hours at 37°C with 5% CO2. Cells were then plated at 40,000 cells / well in 40 μL RPMI + 10% FBS + 20 ng / mL human IL-2 in a 384-well cell culture plate followed by the addition of compounds of interest using acoustic dispensing technology (ECHO 555). Cell cultures were incubated for 20 hours at 37°C and 5% CO2. To facilitate analysis, cell cultures were centrifuged for 5 minutes at 1200 rpm and the supernatant discarded using an EL406 plate washer. After washing three times with 70 μL PBS, cell pellets were resuspended in 50 μL near-IR live stain solution (Life Technologies, Cat. No. L34975) and incubated for 30 minutes on ice protected from light. Cells were washed three times with 70 μL PBS + 0.5% BSA using an EL406 plate washer. After shaking the plate to dislodge the cell pellets, cells were resuspended in 50 μL fixation buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 60 minutes at room temperature. After centrifugation and discarding the supernatant, cells were permeabilized with 50 μL permeabilization buffer (eBioScience FoxP3 Buffer Set 00-5523-00) for 10 minutes at room temperature. After permeabilization, cells were centrifuged and the supernatant replaced with 30 μL 1x permeabilization buffer containing fluorescently labeled antibodies against intracellular targets Helios (Helios-APC [BioLegend, Cat. No. 137222, 1:50]), Aiolos, and Ikaros and the staining reaction incubated for 1 hour at room temperature; protected from light. Subsequently, 30 μL 1x permeabilization buffer was added before cells were centrifuged and the supernatant discarded. Stained cells were resuspended in 30 μL flow cytometry staining buffer (PBS + 0.5% BSA) and analyzed using an Intellicyt iQue Plus flow cytometer. Table B-1 Human regulatory T cell degradation assay: observed maximum degradation

[0328] Table B-1 lists the observed maximum degradation of IKZF1-4 proteins as measured in the human regulatory T cell degradation assay. The results in Table B-1 have been rounded to two decimal places. In the human regulatory T cell degradation assay, a value of 100% indicates no detectable remaining protein or complete degradation of the protein; and a value of 0% indicates that the test compound did not cause detectable protein degradation. In the studies reported in Table B-1, it was observed that each of the compounds of the application exemplified by Examples 1-5 degraded (i) 51%, 56%, 58%, 67%, and 52% of the IKZF1 (Ikaros) protein; (ii) 98% of the IKZF2 (Helios) protein; (iii) 22%, 25%, 25%, 35%, and 29% of the IKZF3 (Aiolos) protein; and (iv) 56%, 62%, 59%, 62%, and 67% of the IKZF4 (Eos) protein. Table B-2 Human regulatory T cell degradation assay: DC 50 * *DC 50 Defined as the concentration of compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone. Human regulatory T cell reprogramming assay

[0329] Human CD4 + T cells were isolated from fresh healthy leukopak (Stemcell Technologies) using RosetteSep Human CD4 + T Cell Enrichment Cocktail (Stemcell Technologies) and Ficoll density gradient centrifugation. Leukopaks were diluted with an equal volume of phosphate-buffered saline (PBS [Gibco]) supplemented with 2% fetal bovine serum (FBS, VWR Lifescience) and incubated with RosetteSep Human CD4 + T Cell Enrichment Cocktail for 20 minutes before layering over Ficoll-Paque Plus solution (GE Health Care). The enriched cell interface layer was harvested and washed twice with PBS supplemented with 2% FBS. EasySep Human CD4 + CD127 低 CD25+ Regulatory T cell isolation kits (Stemcell Technologies) were used to manually isolate regulatory T cells according to the manufacturer’s instructions. Cells were rested overnight in a humidified incubator (37 °C, 5% CO2) in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco). Cells were then stained for CD4 (clone: RPA-T4, Biolegend), CD25 (clone: 2A3, BD Biosciences), and CD127 (clone: hIL-7R-M21, BD Biosciences). CD4 + CD127 低 CD25 + Cells were sorted on a BD FACS Aria Fusion sorter to 95% or greater purity. Sorted cells were used immediately or cryopreserved for downstream assays.

[0330] Fresh or cryopreserved FACS-sorted CD4 + CD127 低 CD25 + Treg cells were cultured in RPMI 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) at 25,000 to 50,000 cells per well of a 96-well round-bottom plate. Cells were stimulated with Treg Xpander beads (Thermo Fisher) at a 1:4 cell-to-bead ratio in the presence of 500 U / mL recombinant human IL-2 (Proleukin). Compounds were added at titrated doses and cells were incubated at 37 °C, 5% CO2 for 12 to 13 days. Recombinant human IL-2 and compounds were replenished every 2 to 3 days throughout the duration of the culture. On day 12 or 13, cells were restimulated with 12-myristate 13-acetate phorbol ester (PMA) and ionomycin in the presence of protein transport inhibitors brefeldin A and monensin (eBioscience Cell Stimulation Cocktail plus Protein Transport Inhibitors, 500x, Cat#00-4975-93) before flow cytometry staining and analysis.

[0331] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated in human Tru-Stain Fc Block (Biolegend) for 10 minutes before adding eFluor780 viability dye (Thermo Fisher) and a surface marker antibody cocktail for 30 minutes at 4°C. Cells were then fixed and permeabilized by incubating with FoxP3 Transcription Factor Staining Buffer (Thermo Fisher) for 30 minutes at 4°C, following the kit manufacturer’s instructions. Cells were washed twice with the permeabilization / wash buffer supplied in the kit and incubated with an intracellular antibody cocktail containing antibodies specific for the transcription factors shown in Table C overnight at 4°C, following the manufacturer’s instructions. Prior to acquisition, cells were washed twice with the permeabilization / wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher). Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometry analyzer. Single stain controls for each fluorescent dye were prepared using UltraComp eBead compensation beads (Thermo Fisher). Data were analyzed using FlowJo version 10 and GraphPad Prism software. Table C Antibodies for flow sorting and analysis Table C-1 Human regulatory T cell reprogramming assay - observed maximum degradation

[0332] Table C-1 lists the observed maximum degradation of IKZF2 protein and IKZF4 protein as measured in the human regulatory T cell reprogramming assay. 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 remaining protein or complete degradation of the protein; and a value of 0% indicates that the test compound did not cause detectable protein degradation. Table C-2 Human regulatory T cell reprogramming assay: DC 50 * *DC 50 Defined as the concentration of compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone. Human CD8 + T cell degradation assay

[0333] Cryopreserved healthy donor human peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and seeded at 500,000 cells per well of a 96-well round bottom plate in RPMI 1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco). Cells were treated with titrated doses of compounds for 24 hours at 37°C, 5% CO2, after which they were analyzed by flow cytometry.

[0334] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated in human Tru-Stain Fc Block (Biolegend) for 10 minutes, after which eFluor780 viability dye (Thermo Fisher) and a surface marker antibody cocktail containing LD-eFluor780, CD3-BUV-395, CD4-BUV805, CD8-FITC, and CD25-BV605 were added for 30 minutes at 4°C. Cells were then fixed and permeabilized by incubation with permeabilization buffer (eBioscience FoxP3 Buffer Set 00-5523-00) for 30 minutes at 4°C, following the kit manufacturer’s instructions. Cells were washed twice with the permeabilization / wash buffer supplied in the kit and incubated with an intracellular antibody cocktail containing antibodies specific for transcription factors (i.e., Foxp3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PE CF594, AIOLOS-AF647) overnight at 4°C, following the manufacturer’s instructions. Prior to acquisition, cells were washed twice with permeabilization / wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher). Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometry analyzer. Single stain controls for each fluorescent dye were prepared using UltraComp eBead compensation beads (Thermo Fisher). Data were analyzed using FlowJo version 10 and GraphPad Prism software. Table D-1 Human CD8 + T cell reprogramming assay - maximum degradation observed Table D-2 Human CD8 + T cell reprogramming assay: DC 50 * *DC 50 defined as the concentration of compound required to reduce the level of a given protein by 50% compared to treatment with DMSO alone.

[0335] Table D-1 lists the observed maximum degradation of IKZF1 protein and IKZF3 protein as measured in the human CD8 + T cell reprogramming assay. Results in Table D-1 have been rounded to two decimal places. In the human CD8 + T cell reprogramming assay, a value of 100% indicates no detectable remaining protein or complete degradation of the protein; and a value of 0% indicates that the test compound did not cause detectable protein degradation. Table E Comparison of observed maximum degradation of IKZF1-4: Examples 1-5 compared to comparative compounds A and B * IKZF1 and IKZF3: human CD8 + T cell reprogramming assay (D-1) ** IKZF2: Jurkat cell degradation assay (A-1) *** IKZF4: human regulatory T cell reprogramming assay (C-1)

[0336] Examples 1-5 have been compared to comparative compound A and comparative compound B disclosed in WO 2019 / 060693 Al and have been found to be particularly advantageous. Examples 1-5 have the surprising advantage of reducing the levels of four IKZF1-4 proteins Ikaros, Helios, Aiolos, and Eos. As shown in Tables A-1, C-1, and D-1 in the assays reported: (i) Examples 1-5 reduced the level of IKZF1 (Ikaros) by at least 53% (Table D-1); (ii) Examples 1-4 reduced the level of IKZF2 (Helios) protein by at least 89% (Table A-1); (iii) Examples 1-4 reduced the level of IKZF3 (Aiolos) by at least 58% (Table D-1); and (iv) Examples 1-4 reduced the level of IKZF4 (Eos) by at least 46% (Table C-1). In contrast, in similar tests, comparative compound A and comparative compound B were observed to degrade the IKZF2 (Helios) protein (Table A-1) by 27% or less; and the IKZF4 (Eos) protein (Table C-1) by 11% or less.

[0337] The present invention meets the aforementioned needs by providing compounds useful for reducing the levels of four IKZF1-4 proteins Ikaros, Helios, Aiolos, and Eos.

Claims

1. A compound of formula (I): Or its stereoisomers, tautomers, or salts, wherein: R is:

2. The compound according to claim 1, or its stereoisomers, tautomers, or salts thereof, wherein the compound is: 。 3. The compound according to claim 1, or its stereoisomers, tautomers, or salts thereof, wherein the compound is: 。 4. The compound according to claim 1, or its stereoisomers, tautomers, or salts thereof, wherein the compound is: 。 5. The compound according to claim 1, or its stereoisomers, tautomers, or salts thereof, wherein the compound is: 。 6. The compound according to claim 1, or its stereoisomers, tautomers, or salts thereof, wherein the compound is: 。 7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, or pharmaceutically acceptable salts, for the treatment of cancer.

9. The use according to claim 8, 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.

10. A method for treating a patient with cancer, the method comprising administering to the patient a therapeutically effective amount of a compound, stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6.

11. The method of claim 10, 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.

12. The method of claim 10, further comprising administering a therapeutically effective amount of a second agent to the patient before, simultaneously with, or after the administration of the compound, wherein the second agent is selected from PD1 / PD-L1 axis antagonists, CTLA4 antagonists, chemotherapeutic agents, radiation, or antitumor vaccines.

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

14. The use according to claim 11, wherein a) The Ikaros protein level is reduced by at least 30%; b) The Helios protein level is reduced by at least 50%; c) The Aiolos protein level is reduced by at least 20%; and d) The Eos protein level is reduced by at least 50%.

15. The method of claim 12, further comprising administering to the patient a therapeutically effective amount of a second agent before, simultaneously with, or after the administration of the compound, wherein the second agent is selected from PD1 / PD-L1 axis antagonists, CTLA4 antagonists, chemotherapeutic agents, radiation, or antitumor vaccines.

16. A method for reducing the levels of Ikaros, Helios, Aiolos, and Eos proteins in cells, comprising contacting the cells with a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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