Substituted phenyloxooxazolylpiperidinedione compounds

Abstract

Formula (I): Disclosed is a compound of formula TIFF2026502937000121.tif42153, where R is as defined herein, or a stereoisomer, tautomer, or salt thereof. Also disclosed is a method of using the compound, and pharmaceutical compositions containing the compound, to reduce levels of Ikaros, Helios, Aiolos, and Eos proteins. These compounds are useful for treating viral infections and proliferative diseases (e.g., cancer).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to Indian Provisional Application No. 202311058935, filed September 2, 2023, the entire contents of which are incorporated herein by reference.

[0002] explanation The present invention generally relates to substituted phenyloxooxazolylpiperidinedione compounds that reduce levels of Ikaros, Helios, Aiolos, and Eos proteins. The present specification provides substituted phenyloxooxazolylpiperidinedione compounds, compositions containing such compounds, and methods of using the same. The present invention also relates to pharmaceutical compositions containing at least one compound described herein, which are useful for treating proliferative diseases (e.g., cancer and viral infections). [Background technology]

[0003] The Ikaros zinc finger family of transcription factors (IKZFs) plays an important role in lymphocyte differentiation and function (Heizmann et al., 2018, Curr Opin Immunol. 51: 14-23). ​​Five members of this family are expressed in mammalian immune cells: Ikaros (encoded by IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). These proteins share highly homologous amino acid sequences, with Ikaros and Aiolos, and Helios and Eos, being the most homologous pairs, and Pegasus being the most distantly related IKZF member. These TFs have both overlapping and unique functions in lymphocytes (Read et al., 2020, Immunological Reviews, 300:1). Decreased protein levels of IKZF transcription factors can enhance anti-tumor T cell responses.

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

[0005] IKZF2 encodes Helios, which more specifically regulates human and mouse regulatory T cells (Tregs), some CD8 + It is expressed on T cells, 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, a gene that is widely and abundantly expressed in human and mouse B-cell lymphocytes and widely expressed at lower levels in T and NK cells. In T cells, the regulatory targets of Aiolos largely overlap with those of Ikaros (Powell et al., 2019, Frontiers in Immunology, 10:1299). Compared to Ikaros, Aiolos may have a stronger effect on follicular helper T cell and Th17 cell responses, which are involved in tissue immune responses and, in some cases, antitumor immunity (Quintana et al., 2012, Nature Immunology, 13:770-777; Read et al., 2017 Journal of Immunology, 7:2377-2387).

[0007] IKZF4 encodes Eos, which is expressed in large amounts in Treg cells and in smaller amounts in lymphocytes of B cells, NK cells, and T cells. In preclinical syngeneic tumor models, FoxP3 expression was observed in Treg cells. + Loss of Eos expression in Treg cells improves anti-tumor responses (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300). Furthermore, conventional CD4 + T cells and CD8 + In T cells, Eos expression levels increase after T cell activation and can limit effector T cell responses (Rieder et al., 2015, Journal of Immunology, 195:553-563).

[0008] A common function of IKZF transcription factors is the repression of gene expression in specific cellular regions. IKZF transcription factors can bind to genomic loci as homodimers or heterodimers, such as Ikaros:Ikaros or Ikaros:Helios, respectively. These dimeric transcription factors bind to DNA and interact with complexes that regulate histone acetylation and nucleosomes, thereby regulating gene expression. Mechanistically, Ikaros, Helios, and Aiolos have been shown to interact with nucleosome-remodeling deacetylase (NuRD) and Sin3 histone deacetylase (HDAC) complexes, respectively, to repress gene expression (Zhang et al., 2011, Nature Immunology, 13:86-94; Georgopoulos et al., 2017, Genes and Development, 31: 439-450). Similarly, Ikaros, Helios, and Aiolos all associate with centromeric heterochromatin and may contribute to the expression of genes located at centromeric loci (Brown et al., 1997, Cell, 91:845-854; Thompson et al., 2007, Immunity, 26:335-344). Eos interacts with Ikaros, but not Aiolos, to interact with the lymphocyte transcriptional repressor C-terminal binding protein 1 (CtBP1) (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 transcription factors may partially compensate for the loss or degradation of one or several transcription factors. Therefore, in cells expressing multiple IKZF members, therapeutic broad degradation of this transcription factor family is expected to induce stronger phenotypic changes than selective degradation of one or two IKZF transcription factors.

[0009] The shared role of IKZF transcription factors in regulating loci important in antitumor immune responses in T cells and Treg cells also includes the regulation of the gene encoding interleukin-2 (IL-2). + It can directly bind to the IL-2 locus on T cells and recruit HDAC complexes. + and CD8 + Helios increases IL-2 production by 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 gene locus in Treg cells, recruiting HDAC complexes and suppressing the IL-2 gene (Blaine et al., 2013, Journal of Immunology, 190:1008-1016). Eos also suppresses IL-2 expression in Treg cells, possibly through a mechanism involving interaction with the transcription factor FoxP3 (Pan et al., 2009, Science, 325: 1142-1146; Sharma et al., 2013, Immunity, 38:998-1012). Although the role of direct binding of Aiolos in IL-2 depletion remains unclear, 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 transcription factors regulate IL-2 production by multiple lymphocyte types, particularly Treg cells. Treg cells express high levels of the four IKZF transcription factors mentioned above, but normally produce very little IL-2.

[0010] Treg cells, marked by expression of the transcription factor FoxP3, are a type of lymphocyte that suppress the immune system through several mechanisms to maintain immune homeostasis (Sakaguchi et al., 2020, Annual Review of Immunology, 38:541-566; Whibley et al., 2019, Nature Immunology, 20:386-396). Patients with deleterious mutations in the gene encoding FoxP3 lack functional Treg cells and exhibit the multisystem autoimmune disorder X-linked recessive immune dysregulation syndrome with polyendocrinopathy and enteropathy (IPEX syndrome). In the tumor microenvironment (TME), Treg cell activity is utilized to promote and maintain an immunosuppressive state (Plitas and Rudensky, 2020, Annual Review of Cancer Biology, 4:459-477). By secreting inhibitory molecules, sequestering cytokines (e.g., IL-2), and directly inhibiting the activation of T cells and antigen-presenting cells, Treg cells can promote TME-mediated resistance to immunotherapy by regulating multiple factors in the cancer-immunity cycle (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, ablation of Treg cells results in the regression of invasive, established tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

[0011] Once activated by a specific antigen, Treg cells behave non-specifically in vitro and can suppress killer T cells by overlooking them (Takahashi et al., 1998, Int Immunol. 10:1969-80; Thornton et al., 1998, J Exp. Med. 188:287-96). Foxp3+CD25+CD4+ Treg cells are CD4 + Helper T cells, CD8 +It can suppress a broad range of antitumor immune responses, including T cells, natural killer cells, and natural killer T cells (Tanaka et al., 2017, Cell Research 27:109-118). In preclinical models, depletion of intratumor CD25+CD4+ Treg cells alters the cytokine environment in the tumor area and leads to regression of established tumors (Yu et al., 2005, J Exp Med. 201: 779-91). Furthermore, Treg cell-deficient CD4 + T cell transplantation is performed in patients with sufficient Treg cells and CD4 + Compared with T cell transplantation, antitumor immune responses are significantly increased (Antony et al., 2005, J Immunol 174:2591-601). Tumor-infiltrating Tregs activated by either tumor-derived self-antigens or tumor-associated antigens can similarly suppress specific antitumor immune responses.

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

[0013] Furthermore, it has been reported that depletion of Foxp3+ Treg cells enhances vaccine-induced antitumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127: 759-767). This suggests that reducing Helios levels may be effective in enhancing the efficacy of cancer vaccines. Antitumor immunotherapy during viral infection may limit the immune response of Treg cells driven by excessive inflammation and inhibit effective antiviral T cell responses, promoting viral persistence (Schmitz et al., 2013, PLOS Pathogens 9: e1003362). Chronic infection of mice with lymphocytic choriomeningitis virus resulted in a significant expansion of Foxp3+ Treg cells. This suggests that there exists a potential mechanism by which certain infectious agents may evade the host immune response by activating and expanding Treg cells (Punkosdy et al., 2011, PNAS 108: 3677-3682). In chronic viral infection-associated diseases, reducing the Helios level of activated Treg cells may have a therapeutic effect.

[0014] Approaches to targeting tumor Treg cells include antibody-mediated depletion and / or functional modulation (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146) and small molecule-mediated "reprogramming" of Treg cells to an immunosuppressive phenotype by altering their gene expression (Kim et al., 2015, Science, 350:334-339; Sebastian et al., 2016, Journal of Immunology, 196:144-155). Mice engineered to lack Helios in their Treg cells do not develop IPEX-like immune disorders characterized by FoxP3 deficiency or complete Treg cell ablation, but have Treg cells that display a transcriptional program more similar to that of effector T cells (Fu et al., 2012, Nature Immunology, 13: 972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). Notably, Helios regulates the activity of critical Treg cells in the TME, as mice with Helios-deficient Treg cells showed improved control of B16F10 and MC38 tumors (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Therefore, therapeutic modulation of Helios may reconfigure tumor Treg cells to a more effector T cell-like phenotype and promote antitumor immunity. Notably, Eos also promotes the activity of immunosuppressive Treg cells in the TME of preclinical tumor models, as mice lacking Eos expression in FoxP3 Treg cells more effectively control syngeneic tumors compared to controls (Gokhale et al., 2019, Journal of Autoimmunity, 105:102300).Similarly, humans with germline IKZF2 loss-of-function mutations do not display IPEX-like symptoms (e.g., diabetes, dermatitis, hepatitis, and generalized lymphadenopathy) but instead display an immune phenotype associated with increased T cell activation and proinflammatory cytokine production (Hetemaeki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981). These data suggest that reduced Helios and Eos protein levels in Treg cells compromise the suppression of antitumor T cell responses in patients with solid tumors.

[0015] Small molecules that degrade Ikaros and Aiolos in Treg cells can also reduce the suppressive function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In genetically engineered mouse models, lenalidomide, an Ikaros and Aiolos degrader, can modestly enhance antitumor immune responses against highly immunogenic syngeneic tumors (Geng et al., 2022, Cell Chemical Biology, 29:1260-1272). Degraders targeting Ikaros and Aiolos are also undergoing clinical trials in patients with solid tumors, sometimes resulting in stable disease and abatement of responses. These studies include the use of 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. Additionally, lenalidomide has been shown to enhance T cell and NK cell function in preclinical and clinical trials (Hideshima et al., Leukemia, 2021; D'Souza et al., Frontiers in Immunology, 2021).

[0016] In summary, the IKZF transcription factors Ikaros, Helios, Aiolos, and Eos are abundantly expressed in Treg cells. Combined reduction of the protein levels of these four transcription factors in Treg cells appears to effectively reverse the immune suppressive program, including the repression of IL-2 transcription and other effector T cell genes, compared with approaches that selectively target a single IKZF transcription factor or a pair of transcription factors (i.e., Ikaros and Aiolos or Helios and Eos). Pan-IKZF1-IKZF4 degraders not only target Treg cells but also conventional CD4 T cells. + T cells and CD8 + It is expected to enhance the effector function of T cells, activate NK cells, and promote a stable anti-tumor response in patients.

[0017] There is a need for therapeutic methods that can reduce the levels of the four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0018] The present invention fulfills this need by providing compounds useful for reducing the levels of the four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0019] Summary of the Invention The present invention provides substituted phenyloxooxazolylpiperidinedione compounds of formula (I), including their stereoisomers, tautomers, salts, and prodrugs, that are useful for decreasing the levels of four proteins (Ikaros, Helios, Aiolos, and Eos).

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

[0021] The present invention also provides a method for treating a disease or disorder by decreasing the levels of four IKZF1 to IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos), 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 processes and intermediates for preparing compounds of formula (I), their stereoisomers, tautomers, or salts.

[0023] The present invention also provides the use of a compound of formula (I), or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, for the manufacture of a medicament for reducing Ikaros, Helios, Aiolos, and Eos protein levels in the treatment of certain diseases, including cancer and viral infections.

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

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

[0026] These and other features of the present invention are set forth in the broader disclosure that follows. DETAILED DESCRIPTION OF THE INVENTION

[0027] The applicant has discovered substituted phenyloxooxazolylpiperidinedione compounds that reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. The substituted phenyloxooxazolylpiperidinedione compounds are believed to promote the interaction of Ikaros, Helios, Aiolos, and Eos proteins with the corresponding E3 ubiquitin ligase complexes (Cullin4-cereblon, CUL4-CRBN), resulting in the degradation of Ikaros, Helios, Aiolos, and Eos proteins. These compounds reduce the levels of Ikaros, Helios, Aiolos, and Eos proteins. These compounds are useful for treating certain diseases (such as cancer and viral infections). These compounds are provided as useful pharmaceuticals, possessing desirable stability, bioavailability, therapeutic index, and toxicity profile, all of which are important for druggability.

[0028] A second aspect of the present invention relates to a compound having at least one formula (I): [ka] [In the formula, R is [ka] is] or a stereoisomer, tautomer, or salt thereof.

[0029] A second aspect of the present invention relates to a compound having at least one formula (I): [ka] [In the formula, R is [ka] is] or a stereoisomer, tautomer, or salt thereof.

[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] In one embodiment, the compound of formula (I): wherein R is [ka] or a stereoisomer, tautomer, or salt thereof.

[0035] In one embodiment, the compound of formula (I) wherein R is [ka] is] or a stereoisomer, tautomer, or salt thereof.

[0036] This embodiment includes a compound of formula (I) or a pharmaceutically acceptable salt thereof. This embodiment also includes a compound of formula (I). This embodiment further includes a pharmaceutically acceptable salt of a compound of formula (I).

[0037] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or salt thereof.

[0038] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or salt thereof.

[0039] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or salt thereof.

[0040] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or salt thereof.

[0041] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or salt thereof.

[0042]

[0013] Certain embodiments provide 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-methoxycyclobutoxy)-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)oxy)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione is.

[0043] 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. This embodiment includes one or more pharmaceutically acceptable salts.

[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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0045] One embodiment provides a compound of Formula (I), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(7-amino-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes 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-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[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-oxoxazol-3(2H)-yl)piperidine-2,6-dione. This embodiment includes one or more pharmaceutically acceptable salts.

[0058] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0059] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0061] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0063] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0065] In one embodiment, the compound has the following structure: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0066] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0067] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0068] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0069] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0070] In one embodiment, the compound has the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0071] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0072] In one embodiment, the compound has the following structure: [ka] or a tautomer or a pharmaceutically acceptable salt thereof.

[0073] In one embodiment, the compound has the following structure: [ka] or a stereoisomer or tautomer thereof. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0074] In one embodiment, the compound has the following structure: [ka] or a stereoisomer or tautomer thereof. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0075] In one embodiment, the compound has the following structure: [ka] or a stereoisomer or tautomer thereof. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0076] In one embodiment, the compound has the following structure: [ka] or a stereoisomer or tautomer thereof. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0077] In one embodiment, the compound has the following structure: [ka] or a stereoisomer or tautomer thereof. This embodiment includes one or more pharmaceutically acceptable salts of the compound.

[0078] The compounds of formula (I) or stereoisomers, tautomers, or salts thereof are useful for decreasing the levels of the four IKZF1 to IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0079] As used herein, "reducing the level" of one of the IKZF1 to IKZF4 proteins refers to reducing the level of the protein by degradation and / or inactivation and / or inhibition and / or reducing the expression level of the protein, or a combination thereof, compared to the initial protein level before contact or treatment with a compound of formula (I) or a stereoisomer, tautomer, or salt thereof.

[0080] To measure the reduction in protein levels of IKZF1 to IKZF4 proteins, the following assays were performed as described herein: (i) (IKZF1) human CD8 + T cell reprogramming assay, (ii) (IKZF2) Jurkat cell lysis assay, (iii) (IKZF3) human CD8 + A variety of methods can be used, including (iv) a T cell reprogramming assay, and (iv) a (IKZF4) human regulatory T cell reprogramming assay.

[0081] The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The present invention includes any and all combinations of the aspects and / or embodiments of the present invention described herein. It is understood that any embodiment of the present invention may be combined with any other embodiment to describe additional embodiments. It is also understood that individual elements of an embodiment are meant to be combined with any and all other elements of any embodiment to describe additional embodiments.

[0082] The features and advantages of the present invention will be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described before or after the context of another embodiment may be combined to form a single embodiment. Conversely, various features of the invention that are described in a single embodiment for brevity may also be combined to form subcombinations thereof. Examples or preferred embodiments set forth herein are intended to be illustrative and not limiting.

[0083] Unless otherwise stated herein, words referred to in the singular may also include the plural. For example, "a" and "an" can refer to either "one" or "one or more."

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

[0085] Unless otherwise specified, any atom with unsatisfied valences is assumed to contain enough hydrogen atoms to satisfy the valences.

[0086] The definitions set forth herein supersede any definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0087] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used in the specification, either individually or as part of a larger group (unless otherwise limited in specific instances).

[0088] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0089] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to the core or backbone structure.

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

[0091] The term "oxo" refers to the group =O.

[0092] The compounds of the present invention include all isotopes of atoms contained in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 Contains C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the unlabeled reagent otherwise used.

[0093] As used herein, the term "tautomer" refers to each of two or more isomers of a compound that exist simultaneously in equilibrium and are readily interchangeable by the movement of atoms or groups within the molecule. For example, one skilled in the art would recognize that 1,2,3-triazole exists in two tautomers defined below: [ka] It is easy to understand that it exists as such. Thus, all possible tautomers are intended to be included, even if the structure of only one tautomer is depicted in the present disclosure. For example, compounds of formula (I) may exist in the following tautomers: [ka] It can exist as.

[0094] Other examples of tautomers include: [ka] Includes:

[0095] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, substances, compositions, and / or preparations that are, within the scope of ordinary medical judgment, suitable for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and that are present at a reasonable benefit / risk ratio.

[0096] The compound of formula (I) can form salts, and such salts are also within the scope of the present invention. Unless otherwise specified, reference to a compound of the invention is understood to include reference to one or more salts thereof. The term "salt" refers to acid salts formed with inorganic and / or organic acids. Furthermore, the term "salt" can include zwitterions (internal salts), for example, when a compound of formula (I) contains both a basic moiety (e.g., an amine or a pyridine or imidazole ring) and an acidic moiety (e.g., a carboxylic acid). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, for example, acceptable metal salts and amine salts that do not significantly contribute to the toxicity or biological activity of the salt. However, other salts are also considered within the scope of the present invention, as they may be useful, for example, in isolation or purification steps that may be performed during manufacturing processes. Salts of compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with a certain amount of acid or base (e.g., 1 equivalent) in a solvent (e.g., a solvent in which the salt precipitates or an aqueous solution which is subsequently lyophilized).

[0097] Examples of acid addition salts include acetates (e.g., salts formed with acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), and the like. ), hydroiodide, maleate (formed with maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed with methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate (e.g., those described herein), tartrate, thiocyanate, toluenesulfonate (e.g., tosylate), undecanoate, and the like.

[0098] The compound of formula (I) may be provided as an amorphous or crystalline solid. Lyophilization may be used to obtain the compound of formula (I) as a solid.

[0099] Additionally, solvates (e.g., hydrates) of the compounds of formula (I) are also considered to be within the scope of the present invention. The term "solvate" refers to a physical association with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and separable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0100] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0101] Furthermore, after the compound of formula (I) has been prepared, it may be isolated and purified to provide a composition comprising at least 99% by weight of the compound of formula (I) ("substantially pure"), which may then be used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0102] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, or upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0103] The terms "IKZF1 degrading agent" and "Ikaros degrading agent" refer to an agent that has the effect 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.

[0104] The terms "IKZF2 degrading agent" and "Helios degrading agent" refer to an agent that has the effect 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.

[0105] The terms "IKZF3 degrading agent" and "Aiolos degrading agent" refer to an agent that has the effect 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.

[0106] The terms "IKZF4 degrading agent" and "Eos degrading agent" refer to an agent that has the effect 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.

[0107] The term "IKZF1 to IKZF4 proteins" refers to Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), and Eos (IKZF4) proteins.

[0108] The term "pan IKZF1 to IKZF4 degrading agent" refers to an agent that has the effect of decreasing the protein levels of the four IKZF1 to IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

[0109] As used herein, the "Ikaros" protein is encoded by the IKZF1 gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFNlAl, zinc finger protein, subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL-associated antigen KW-6. The "Ikaros" protein includes isoforms encoded by the human isoforms listed below.

[0110] Isoform 1 (UniPort Q13422-1) [ka]

[0111] Isoform 2 (UniProt Q13422-2) [ka]

[0112] Isoform 3 (UniProt Q13422-3) [ka]

[0113] Isoform 4 (UniProt Q13422-4) [ka]

[0114] Isoform 7 (UniProt Q13422-7) [ka]

[0115] Isoform 8 (UniProt Q13422-8) [ka]

[0116] The above-mentioned "Ikaros" protein isoforms 1, 2, 3, 4, 7, and 8 contain the degron sequence FQCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 22), which is identical to the degron sequence of the "Aiolos" protein. The Ikaros protein also includes isoforms encoded by the amino acid sequences Q13422-5 and Q13422-6.

[0117] As used herein, the term "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 term "Helios" protein includes various isoforms, including the isoforms listed below.

[0118] Isoform 1 (UniProt Q9UKS7-1) [ka]

[0119] Isoform 2 (UniProt Q9UKS7-2) [ka]

[0120] Isoform 4 (UniProt Q9UKS7-4) [ka]

[0121] Isoform 6 (UniProt Q9UKS7-6) [ka]

[0122] Isoform 7 (UniProt Q9UKS7-7) [ka]

[0123] The above-mentioned "Helios" isoforms 1, 2, 4, 6, and 7 contain the degron sequence: FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 23). A degron sequence is a part of a protein that is responsible for regulating the rate of protein degradation. The Helios protein also includes isoforms encoded by the amino acid sequences: Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0124] As used herein, the "Aiolos" protein is encoded by the IKZF3 gene. Aiolos proteins are also known as IKAROS family zinc finger 3, ZNFNlA3, zinc finger protein, subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. Aiolos proteins include the human isoforms listed below.

[0125] Isoform 1 (UniProt Q9UKT9-1) [ka]

[0126] Isoform 3 (UniProt Q9UKT9-3) [ka]

[0127] Isoform 4 (UniProt Q9UKT9-4) [ka]

[0128] Isoform 6 (UniProt Q9UKT9-6) [ka]

[0129] Isoform 7 (UniProt Q9UKT9-7) [ka]

[0130] Isoform 8 (UniProt Q9UKT9-8) [ka]

[0131] Isoform 9 (UniProt Q9UKT9-9) [ka]

[0132] Isoform 14 (UniProt Q9UKT9-14) [ka]

[0133] The aforementioned "Aiolos" protein isoforms 1, 3, 4, 6, 7, 8, 9, and 14 contain the degron sequence FQCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 24), which is identical to the degron sequence of the "Ikaros" protein. Aiolos proteins also include isoforms encoded by the amino acid sequences Q9UKT9-2, Q9UKT9-5, Q9UKT9-10, Q9UKT9-11, Q9UKT9-12, and Q9UKT9-13, Q9UKT9-15, and Q9UKT9-16.

[0134] As used herein, the "Eos" protein is encoded by the IKZF4 gene and is also known as IKAROS family zinc finger 4, ZNFNlA4, zinc finger protein, subfamily 1A, 4, Ikaros family zinc finger protein 4, and KIAAl782. The "Eos" protein includes isoforms encoded by the following two human isoforms: 1 (Q9H2S9-1) and 2 (Q9H2S9-2).

[0135] Isoform 1 (UniProt Q9H2S9-1) [ka]

[0136] Isoform 2 (UniProt Q9H2S9-2) [ka]

[0137] The above-mentioned "Eos" protein isoforms 1 and 2 contain the degron sequence: FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 25), which is identical to the degron sequence of the "Helios" protein.

[0138] 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.

[0139] As used herein, the term "contact" refers to bringing the specified moieties together in vitro or in vivo. For example, "contacting" an IKZF1 to IKZF4 protein with a compound of formula (I) includes administering a compound of the present invention to an individual or patient (e.g., a human) having Ikaros protein, Helios protein, Aiolos protein, or Eos protein, as well as introducing a compound of formula (I) into, for example, a sample containing cells or a purified product containing Ikaros protein, Helios protein, Aiolos protein, or Eos protein.

[0140] As used herein, the terms "treat" and "treatment" refer to any intervention, method, or administration of an active agent to a subject for the purpose of ameliorating, alleviating, ameliorating, inhibiting, delaying, or suppressing the progression, onset, severity, or recurrence of a symptom, complication, condition, or biochemical manifestation of a disease. In contrast, "prophylaxis" or "prevention" refers to administration to a non-affected subject to prevent the onset of a disease. "Treating" and "treatment" do not include prophylaxis or prevention.

[0141] A "therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with the claimed compounds, or an amount of a compound of the invention in combination with other active ingredients that is effective in reducing the level of IKZF1-IKZF4 proteins in cells or in treating or preventing viral infections and proliferative diseases (e.g., cancer).

[0142] As used herein, the term "cell" refers to in vitro, ex vivo, or in vivo cells. In some embodiments, ex vivo cells can be part of a tissue sample removed from an organism (e.g., a mammal). In some embodiments, in vitro cells can be cells in cell culture. In some embodiments, in vivo cells are living cells in an organism (e.g., a mammal).

[0143] The term "patient" includes human subjects.

[0144] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, processing aid (e.g., lubricant, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulant, which is involved in the transport or delivery of a particular compound from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation (i.e., including adjuvants, excipients, or vehicles (e.g., diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, perfumes, antibacterial agents, antifungal agents, lubricants, and dispersing agents) depending on the method of administration and the nature of the dosage form), and not deleterious to the patient.

[0145] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one other pharmaceutically acceptable carrier.

[0146] usefulness The compounds of formula (I) are useful in the treatment of cancer.

[0147] The compounds of formula (I) are useful in the treatment of viral infections.

[0148] In certain embodiments, there is provided a method for treating cancer, comprising administering to a patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, provided herein is a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0150] In certain embodiments, a method of treating cancer in a patient comprises administering to the patient a therapeutically effective amount of a compound having the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0151] In certain embodiments, a method of treating cancer in a patient comprises administering to the patient a therapeutically effective amount of a compound having the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0152] In certain embodiments, a method of treating cancer in a patient comprises administering to the patient a therapeutically effective amount of a compound having the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0153] In certain embodiments, a method of treating cancer in a patient comprises administering to the patient a therapeutically effective amount of a compound having the following structure: [ka] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0154] In one embodiment, a method for treating a disease or disorder by reducing the levels of four IKZF1 to IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos) is provided, comprising administering to a patient a therapeutically effective amount of an agent to reduce Ikaros, Helios, Aiolos, and Eos protein levels. In one embodiment, the disease or disorder is cancer. In another embodiment, the disease or disorder is a viral infection. In yet another embodiment, the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0155] In one embodiment, there is provided a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for decreasing Ikaros, Helios, Aiolos, and Eos protein levels, wherein a) the Ikaros protein is the amino acid sequence encoded by SEQ ID NO: 1, 2, 3, 4, 5, or 6, b) the Helios protein is the amino acid sequence encoded by SEQ ID NO: 7, 8, 9, 10, or 11, c) the Aiolos protein is the amino acid sequence encoded by SEQ ID NO: 12, 13, 14, 15, 16, 17, 18, or 19, and d) the Eos protein is the amino acid sequence encoded by SEQ ID NO: 20 or 21.

[0156] In embodiment 1, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing 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%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0157] In embodiment 2, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing 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%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0158] In embodiment 3, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) the Helios (IKZF2) protein level is reduced by at least 50%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0159] In embodiment 4, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) the Helios (IKZF2) protein level is reduced by at least 50%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0160] In embodiment 5, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) the Helios (IKZF2) protein level is reduced by at least 60%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0161] In embodiment 6, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) The Helios (IKZF2) protein level is reduced by at least 60%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0162] In embodiment 7, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) The Helios (IKZF2) protein level is reduced by at least 60%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0163] In embodiment 8, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) The Helios (IKZF2) protein level is reduced by at least 60%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0164] In embodiment 9, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0165] In embodiment 10, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0166] In embodiment 11, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment also includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0167] In embodiment 12, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) the Helios (IKZF2) protein level is reduced by at least 70%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0168] In embodiment 13, there is provided a method for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) The Helios (IKZF2) protein level is reduced by at least 80%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0169] In embodiment 14, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) The Helios (IKZF2) protein level is reduced by at least 80%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0170] In embodiment 15, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) the Helios (IKZF2) protein level is reduced by at least 80%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0171] In embodiment 16, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) The Helios (IKZF2) protein level is reduced by at least 80%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0172] In embodiment 17, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) The Helios (IKZF2) protein level is reduced by at least 85%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0173] In embodiment 18, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) The Helios (IKZF2) protein level is reduced by at least 85%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0174] In embodiment 19, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) The Helios (IKZF2) protein level is reduced by at least 85%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0175] In embodiment 20, there is provided a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) the Helios (IKZF2) protein level is reduced by at least 85%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0176] In embodiment 21, there is provided a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) the Helios (IKZF2) protein level is reduced by at least 90%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0177] In embodiment 22, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) the Helios (IKZF2) protein level is reduced by at least 90%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0178] In embodiment 23, there is provided a method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) the Helios (IKZF2) protein level is reduced by at least 90%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0179] In embodiment 24, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) the Helios (IKZF2) protein level is reduced by at least 90%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0180] In embodiment 25, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 30%, (ii) The Helios (IKZF2) protein level is reduced by at least 90%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 30%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0181] In embodiment 26, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 40%, (ii) The Helios (IKZF2) protein level is reduced by at least 90%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 40%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0182] In embodiment 27, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%, (ii) the Helios (IKZF2) protein level is reduced by at least 90%, (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%, and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0183] In embodiment 28, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by at least 60%, (ii) The Helios (IKZF2) protein level is reduced by at least 90%, (iii) The Aiolos (IKZF3) protein level is reduced by at least 60%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment also includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0184] In embodiment 29, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 50%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0185] In embodiment 30, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 60%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0186] In embodiment 31, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0187] In embodiment 32, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 70%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0188] In embodiment 33, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 80%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0189] In embodiment 34, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 40-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 90%, (iii) The Aiolos (IKZF3) protein level is reduced by 40-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0190] In embodiment 35, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 50%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 50%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0191] In embodiment 36, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 60%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 60%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0192] In embodiment 37, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0193] In embodiment 38, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 70%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 70%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0194] In embodiment 39, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 80%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 65%. This embodiment includes a method wherein the disease or disorder is cancer. This embodiment also includes a method wherein the disease or disorder is a viral infection. This embodiment further includes a method wherein the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0195] In embodiment 40, a method is provided for treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of an agent for reducing Ikaros, Helios, Aiolos, and Eos protein levels. (i) The Ikaros (IKZF1) protein level is reduced by 50-70%, (ii) The Helios (IKZF2) protein level is reduced by at least 90%, (iii) The Aiolos (IKZF3) protein level is reduced by 50-70%, and (iv) The Eos (IKZF4) protein level is reduced by at least 90%. This embodiment includes a method in which the disease or disorder is cancer. This embodiment also includes a method in which the disease or disorder is a viral infection. This embodiment further includes a method in which the agent is a compound of Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

[0196] In embodiments 1 to 40, the reduction in protein levels of IKZF1 to IKZF4 proteins is measured using the following assays described herein: (i) IKZF1: human CD8 +T cell reprogramming assay; (ii) IKZF2: Jurkat cell lysis assay; (iii) IKZF3: human CD8 + T cell reprogramming assay; and (iv) IKZF4: may be measured using a human regulatory T cell reprogramming assay.

[0197] Types of cancer that may be treated with the compounds of formula (I) include, but are not limited to, brain cancer, skin cancer, bladder cancer, ovarian cancer, breast cancer, stomach cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer, lung cancer and osteosarcoma. Examples of such cancer types include neuroblastoma, intestinal cancer (e.g., rectal cancer, colon cancer, anal cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer), esophageal cancer, nasopharyngeal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, thymic cancer, esophagogastric cancer, gastric cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancer, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumors), Hodgkin's lymphoma, non-Hodgkin's lymphoma, and thyroid cancer. These include: Burkitt's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung cancer, non-small cell lung cancer, mesothelioma, multiple myeloma, basal cell carcinoma, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0198] In certain embodiments, provided are methods for treating melanoma in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0199] In certain embodiments, provided are methods for treating lung cancer (e.g., small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC)) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0200] In certain embodiments, provided are methods for treating mesothelioma in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0201] In certain embodiments, provided is a method of treating breast cancer (e.g., ductal carcinoma, invasive ductal carcinoma metastatic breast cancer, triple-negative breast cancer, human epidermal growth factor receptor 2 (HER2)-positive breast cancer, estrogen receptor (ER)-positive breast cancer, hormone receptor-positive breast cancer, and hormone receptor-negative breast cancer) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0202] In certain embodiments, provided are methods for treating prostate cancer (e.g., prostate cancer and castration-resistant prostate cancer) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0203] In certain embodiments, provided are methods for treating pancreatic cancer (e.g., pancreatic adenocarcinoma, exocrine pancreatic cancer, and neuroendocrine pancreatic cancer) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0204] In certain embodiments, provided are methods for treating kidney cancer (e.g., renal cell carcinoma, clear cell renal cell carcinoma, and non-clear cell renal cell carcinoma, papillary renal cell carcinoma, Wilms' tumor, and renal sarcoma) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0205] In certain embodiments, provided are methods for treating stomach cancer (e.g., gastric cancer) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0206] In certain embodiments, provided are methods for treating cancer of the kidney (e.g., renal carcinoma and renal parenchymal carcinoma) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0207] In certain embodiments, provided is a method for treating liver cancer (e.g., hepatocellular carcinoma) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0208] In certain embodiments, provided are methods for treating cancer of the ovary (e.g., ovarian cancer) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0209] In certain embodiments, provided is a method of treating lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL)) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0210] In certain embodiments, provided are methods of treating leukemia (e.g., acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia-lymphoma, and diffuse large B-cell lymphoma (DLBCL)) in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0211] In certain embodiments, provided are methods for treating multiple myeloma in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0212] The compounds of Formula (I) and pharmaceutical compositions comprising at least one compound of Formula (I) are useful for treating or preventing any disease or condition associated with the activity of the IKZF1-IKZF4 protein. Such diseases include viral and other infectious diseases (e.g., skin infections, GI infections, urinary tract infections, urinary-gastrointestinal infections, and systemic infections), and proliferative diseases (e.g., cancer). Any administration method may be used to administer the compounds or pharmaceutical compositions to a patient. In some embodiments, the compounds of Formula (I) or pharmaceutical compositions comprising at least a compound of Formula (I) are administered orally. In other embodiments, the compounds of Formula (I) or pharmaceutical compositions comprising at least a compound of Formula (I) are administered parenterally.

[0213] In certain embodiments, there is provided a method of treating a viral infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to Formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the viral infection is caused by exposure to HIV, hepatitis (A, B, or C), herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviridae, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, cowpox virus, HTLV, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0214] The compound of formula (I) can selectively reduce the protein levels of the four IKZF1 to IKZF4 proteins in cells to control Treg differentiation and / or immunomodulation. For example, the compound of formula (I) can be used to selectively reduce the protein levels, activity levels, and expression levels of each of the four IKZF1 to IKZF4 proteins in cells to control Treg differentiation and / or immunomodulation in cells or individuals, which are necessary to reduce the protein levels, activity levels, and / or suppress the expression levels of each of the four IKZF1 to IKZF4 proteins, by administering an effective amount of the compound of formula (I) or a stereoisomer, tautomer, or salt thereof.

[0215] In certain embodiments, the present invention provides a combination preparation of a compound of Formula (I) and / or a pharmaceutically acceptable salt thereof with another therapeutic agent for simultaneous, separate, or sequential use in the treatment and / or prevention of multiple diseases or disorders associated with the activity of the IKZF1 to IKZF4 proteins. The combination preparation can be used to reduce protein levels, reduce protein activity levels, and / or suppress the expression levels of each of the four IKZF1 to IKZF4 proteins.

[0216] In some embodiments, the compound of Formula (I) is administered sequentially prior to the administration of the immuno-oncology agent. In other embodiments, the compound of Formula (I) is administered simultaneously with the immuno-oncology agent. In yet other embodiments, the compound of Formula (I) is administered sequentially after the administration of the immuno-oncology agent.

[0217] In another embodiment, the compound of formula (I) may be formulated with an immuno-oncology agent.

[0218] Immuno-oncology agents include, for example, small molecule drugs, antibodies, or other biological or small molecule drugs. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In one embodiment, the antibody is a monoclonal antibody. In another embodiment, the monoclonal antibody is a humanized or human antibody.

[0219] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory receptor (including a costimulatory receptor) or (ii) an antagonist of an inhibitory signal (including a co-inhibitory signal) on a T cell, both of which result in amplification of an antigen-specific T cell response (often referred to as an immune checkpoint regulator).

[0220] Certain stimulatory and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors includes the TNF family molecules that bind to the cognate TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, and OPG. , RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APR, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, Includes EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0221] In certain embodiments, T cell responses can be stimulated by a combination of a compound of Formula (I) and one or more of the following: (i) antagonists of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and (ii) agonists of proteins that stimulate T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0222] For cancer treatment, other drugs that can be combined with the compound of formula (I) can include antagonists of inhibitory receptors on NK cells or agonists of activating receptors on NK cells. For example, the compound of formula (I) can be combined with antagonists of KIR, such as lirilumab.

[0223] Further agents for use in combination therapy include agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-1R antagonist antibodies (e.g., RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044)) or CSF-1R antagonists, including FPA-008 (WO11 / 140249, WO13169264, WO14 / 036357).

[0224] In another embodiment, the compounds of formula (I) may be used in conjunction with one or more of agonistic agents that bind positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Treg cells (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo depletion with anti-CD25 beads), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or T cell exhaustion), and agents that activate innate immunity and / or cause inflammation in the tumor area.

[0225] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist, e.g., an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab) or tremelimumab.

[0226] In another embodiment, the immuno-oncology agent is a PD-1 antagonist, e.g., an antagonistic PD-1 antibody. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), MEDI-0680 (AMP-514; WO2012 / 145493), Libtayo (cemiplimab), Gemperli (dostallimab), and ZYNYZ (retifanlimab). Immuno-oncology agents also include pidilizumab (CT-011), although its specificity for PD-1 binding has been questioned. Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated AMP-224.

[0227] In another embodiment, the immuno-oncology agent includes a PD-L1 antagonist, such as an antagonistic PD-L1 antibody. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), MSB0010718C (WO2013 / 79174), Tecentriq (atezolizumab), and Bavencio (avelumab).

[0228] In another embodiment, the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG-3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

[0229] In another embodiment, the immuno-oncology agent is a CD137 (4-1BB) agonist, such as an agonistic CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO12 / 32433).

[0230] In another embodiment, the immuno-oncology agent is a GITR agonist, for example, an agonistic GITR antibody. Suitable CD137 antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06 / 105021, WO09 / 009116) and MK-4166 (WO11 / 028683).

[0231] In another embodiment, the immuno-oncology agent is an IDO antagonist.Suitable IDO antagonists include, for example, INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

[0232] In another embodiment, 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.

[0233] In another embodiment, the immuno-oncology agent is an OX40L antagonist, such as an antagonistic OX40 antibody. Suitable OX40L antagonists include, for example, RG-7888 (WO06 / 029879).

[0234] In another embodiment, 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.

[0235] In another embodiment, the immuno-oncology agent is a CD27 agonist, such as an antagonistic CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0236] In another embodiment, the immuno-oncology agent (against B7H3) is MGA271 (WO11 / 109400).

[0237] In another embodiment, the immuno-oncology agent is an anti-TIGIT agent. Suitable anti-TIGIT agents include antibodies such as BMS-986207, tiragolumab, or MK-7684.

[0238] In another embodiment, the immuno-oncology agent is a KRAS G12C inhibitor. Suitable KRAS G12C inhibitors include Lumakelas (sotorasib) or Clazati (adagrasib).

[0239] Combination therapy includes sequential administration of the therapeutic agents, i.e., administration of each therapeutic agent at different times, as well as substantially simultaneous administration of the therapeutic agents or at least two therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single, fixed-ratio dosage form of each therapeutic agent or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any suitable route, including, but not limited to, oral, intravenous, intratumoral, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The administration of the therapeutic agents described above can also be combined with other biologically active ingredients and non-drug treatments (e.g., surgery or radiation therapy) to achieve combination therapy. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as a beneficial effect results from the interaction of the combination of the therapeutic agent and the non-drug treatment, e.g., in appropriate cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended (perhaps for days or weeks) from the administration of the therapeutic agent.

[0240] In treating diseases, disorders, or conditions related to the IKZF1 to IKZF4 proteins, one or more other pharmaceutical agents or therapeutic methods (e.g., antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compounds of Formula (I), as appropriate. The above agents may be combined with the compounds of the present application in a single dosage form, or may be administered simultaneously or sequentially in different dosage forms.

[0241] Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including but not limited to, nitrogen mustards, ethyleneimine derivatives, alkylsulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0242] In the treatment of melanoma, suitable agents for use in combination with the compounds of formula (I) include dacarbazine (DTIC), optionally with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; cisplatin, vinblastine, and DTIC, temozolomide, or Yervoy. TM The compounds of formula (I) may also be combined with immunotherapeutic agents, such as cytokines (such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF)), in the treatment of melanoma.

[0243] The compounds of formula (I) can also be used in combination with vaccine therapy in the treatment of melanoma. Anti-melanoma vaccines are similar in some respects to antiviral vaccines used to prevent diseases caused by viruses (e.g., polio, measles, and mumps). Attenuated melanoma cells or parts of melanoma cells, called antigens, can be injected into patients to stimulate the body's immune system to recognize and destroy melanoma cells.

[0244] Melanoma limited to the arms or legs can also be treated using hyperthermic perfusion therapy with a combination of drugs containing one or more compounds of Formula (I). This treatment protocol involves temporarily isolating the circulatory system of the affected limb from the rest of the body, and then infusing high concentrations of chemotherapy drugs into the arteries of the affected limb, delivering high doses to the tumor site that would otherwise cause serious side effects if exposed to internal organs. This treatment typically involves warming bodily fluids to 38.9°C to 40°C. Melphalan is the drug most frequently used in this chemotherapy. Another agent called tumor necrosis factor (TNF) inhibitors may also be used.

[0245] Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0246] 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, cytarabine, paclitaxel (taxol), mithramycin, deoxycoformycin, mitomycin C, L-asparaginase, interferons (especially IFNα), etoposide, and teniposide.

[0247] Other cytotoxic agents include navelbine, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, and droloxifene.

[0248] Suitable cytotoxic agents also include, for example, epipodophyllotoxins; anti-neoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes (e.g., cisplatin and carboplatin); biological response modifiers; growth inhibitory agents; antihormonal therapeutic agents; leucovorin; tegafur; and hematopoietic growth factors.

[0249] Other anti-cancer agents include antibody drugs such as trastuzumab (Herceptin®), antibodies against costimulatory molecules (e.g., CTLA-4, 4-1BB, and PD-1), or antibodies against cytokines (IL-1O or TGF-β).

[0250] Other anti-cancer agents also include those that inhibit immune cell migration, such as antagonists to chemokine receptors (eg, CCR2 and CCR4).

[0251] Other anti-cancer drugs also include those that enhance the immune system, such as adjuvants or adoptive T-cell transfer.

[0252] Anti-cancer vaccines include dendritic cell vaccines, synthetic peptide vaccines, DNA vaccines and recombinant viral vaccines.

[0253] The pharmaceutical compositions of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is an agent that selectively inhibits one or more critical steps in a signal transduction pathway in the normal function of cancer cells, thereby inducing apoptosis. Suitable STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774) and antibodies (ImClone's C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)], and Abgenix's ABX-EGF); (iii) Her2 / neu receptor inhibitors, such as farnesyltransferase inhibitors (FTIs) (e.g., L-744,832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) inhibitors of Akt family kinases or the Akt pathway (e.g., rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513 (1995)]). (200)); (v) cell cycle kinase inhibitors (e.g., flavopiridol and UCN-O1 (see, e.g., Sausville, Curr. Med. Chem. Anti-Canc. Agents, 3:47-56(203)); and (vi) phosphatidylinositol kinase inhibitors (e.g., LY294002 (see, e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248(1994))). Alternatively, at least one STI and at least one compound of formula (I) may be formulated in separate pharmaceutical compositions. In certain embodiments of the present invention, at least one compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) or at least one STI may be administered first, or at least one compound of formula (I) and at least one STI may be administered simultaneously.Furthermore, when more than one compound of formula (I) and / or STI is used, the compounds may be administered in any order.

[0254] The present invention further provides pharmaceutical compositions 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 for treating a chronic viral infection in a patient.

[0255] Also provided is a method of treating a chronic viral infection in a patient by administering an effective amount of the pharmaceutical composition.

[0256] In certain embodiments of the present invention, at least one compound of formula (I) and at least one chemotherapeutic agent can be administered to patients simultaneously or sequentially.In other words, at least one compound of formula (I) or at least one chemotherapeutic agent can be administered first, or at least one compound of formula (I) and at least one chemotherapeutic agent can be administered simultaneously.In addition, when more than one compound of formula (I) and / or chemotherapeutic agent are used, the compounds can be administered in any order.Similarly, any antiviral drug or STI can be administered at any time when administering the compound of formula (I).

[0257] Chronic viral infections that may be treated using the combination therapy of the present application include, but are not limited to, diseases caused by hepatitis C virus (HCV), human papillomavirus (HPV), cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV), varicella-zoster virus, coxsackievirus, and human immunodeficiency virus (HIV).

[0258] Suitable antiviral agents contemplated for use in combination with the compounds of formula (I) may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and other antiviral agents.

[0259] Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also called β-L-D4C, named 2',3'-dideoxy-2',3'-didehydro-β-L-5-fluorocytidine); DAPD, ((-)-β-D-2,6-diamino-purine dioxolane); and rhodenosine (FddA). Representative and suitable NNRTIs include nevirapine (BI-RG-587); delavirdine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative and suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lacinavir (BMS-234475); DMP-450; Other antiviral medications include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, and Yissum Project No. 11607.

[0260] Combination therapy includes sequential administration of the therapeutic agents, i.e., administration of each therapeutic agent at different times, as well as substantially simultaneous administration of the therapeutic agents or at least two therapeutic agents. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single, fixed-ratio dosage form of each therapeutic agent or a single dosage form of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be by any suitable route, including, but not limited to, oral, intravenous, intratumoral, intramuscular, and direct absorption through mucosal membranes. The therapeutic agents can be administered by the same or different routes. For example, a first therapeutic agent in a selected combination can be administered by intravenous injection, while another therapeutic agent in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The administration of the therapeutic agents described above can also be combined with other biologically active ingredients and non-drug treatments (e.g., surgery or radiation therapy) to achieve combination therapy. If the combination therapy further includes a non-drug treatment, the non-drug treatment can be administered at any suitable time, so long as a beneficial effect results from the interaction of the combination of the therapeutic agent and the non-drug treatment, e.g., in appropriate cases, this beneficial effect is achieved even when the non-drug treatment is temporarily suspended (perhaps for days or weeks) from the administration of the therapeutic agent.

[0261] Pharmaceutical Composition The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of formula (I), formulated together with one or more pharmaceutically acceptable carriers (excipients), and / or diluents, and optionally one or more additional therapeutic agents as described above.

[0262] The compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route, and in a dosage effective for the intended treatment. For any of the uses described herein, the compounds of formula (I) and compositions of compounds of formula (I) may be administered by any suitable method, such as oral administration (e.g., tablets, capsules (each including sustained-release or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions); sublingual administration; buccal administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous solutions or suspensions); nasal administration, including administration to the nasal mucosa (e.g., inhalation spray); topical administration (e.g., in the form of a cream or ointment); or rectal administration (e.g., in the form of a suppository)). They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0263] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably formulated in a dosage unit form containing a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose for administration to humans or other mammals may vary greatly depending on the patient's condition and other factors, but can be determined using conventional methods.

[0264] Any pharmaceutical composition discussed herein can be orally administered, for example, by any suitable acceptable oral preparation. Examples of oral preparations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. In order to provide a medicament that is easy to swallow, the pharmaceutical compositions described in the present invention can include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0265] 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 additive suitable for tablet manufacture. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binders (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). Furthermore, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the gastrointestinal tract, thereby prolonging the effect of the active ingredient. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropylmethylcellulose and hydroxypropylcellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0266] 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 (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0267] 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 (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0268] 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 additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, tragacanth gum, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and fatty acids and and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0269] Oily 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 vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspensions can also contain at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide an oily suspension that is easy to drink, at least one sweetener and / or at least one flavoring agent as described above can be added to the oily suspension. Oily suspensions can further contain at least one preservative, including, but not limited to, an antioxidant (e.g., butylhydroxyanisole and α-tocopherol).

[0270] Dispersible powders and granules 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 dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules can also contain at least one excipient (e.g., but not limited to, sweeteners, flavoring agents, and coloring agents).

[0271] 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 emulsions containing a compound of formula (I) can be composed of known ingredients in a known manner. The oil phase can be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase can contain only an emulsifier, or a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier, with or without a stabilizer, makes up what is called an emulsifying wax, and the wax, together with the oil and fat, forms the oily dispersed phase of the cream, making up what is called an emulsifying ointment base. The emulsion may also include sweeteners, flavorings, preservatives, and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or in combination with wax; or other substances known in the art.

[0272] In addition, the compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharmaceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0273] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in oral preparations, or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrins (i.e., Captisol), solubilizing cosolvents (i.e., propylene glycol), or solubilizing micelles (i.e., Tween 80).

[0274] Alternatively, a sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (for example, a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used, water, Ringer's solution, and isotonic sodium chloride solution are used. Furthermore, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used in injectable preparations.

[0275] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the oil phase containing formula (I) with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0276] Sterile aqueous suspensions or sterile oily suspensions can be prepared according to methods known to those skilled in the art. For example, sterile aqueous solutions or sterile aqueous suspensions can be prepared using non-toxic, parenterally acceptable diluents or solvents (e.g., 1,3-butanediol), and sterile oily suspensions can be prepared using sterile, non-toxic, acceptable solvents or suspension media (e.g., sterile fixed oils (e.g., synthetic monoglycerides or diglycerides), and fatty acids (e.g., oleic acid).

[0277] Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. Such carriers can contain many different components and additives in addition to the active agent, and such additional components are included in the formulation for various reasons (e.g., stabilization of the active agent, binders, etc.) known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and the factors involved in selecting them can be found in a variety of readily available references, such as Allen, LV Jr. et al. Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition (2012), Pharmaceutical Press.

[0278] Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphate, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts, or electrolytes (e.g., protamine sulfate), Examples of suitable carriers include cyclodextrins (e.g., alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrin, or other solubilizing derivatives) and cyclodextrins (e.g., alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrin, or other solubilizing derivatives) may also be used effectively to enhance delivery of the compounds of the formulae described herein.

[0279] The pharmaceutically active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or may contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills may additionally be prepared with enteric coatings. Such compositions may also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and perfumes).

[0280] For treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphate and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then be tableted or encapsulated for convenient administration.Such capsule or tablet can also contain controlled release formulation, and can be provided by dispersing the active compound in hydroxypropylmethylcellulose.

[0281] The amount of compound and dosage regimen administered to treat a condition using the compounds and / or compositions of the present invention depend on various factors, such as age, weight, sex, the patient's condition, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used. Therefore, dosage regimens may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably about 0.0025 to about 50 mg / kg body weight, and most preferably about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered one to four times daily. Other dosage regimens include weekly and biday cycles.

[0282] Pharmaceutical compositions of the present invention include at least one compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof, and optionally, an additive selected from a pharmaceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0283] The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of IKZF1-IKZF4 protein-associated diseases or disorders, and other diseases described herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I). Such kits may further optionally include one or more of a variety of conventional pharmaceutical kit components (e.g., a container containing one or more pharmaceutically acceptable carriers, a separate container), which will be readily apparent to those of skill in the art. Instructions, either in the form of a package insert or label, indicating the amounts of components to be administered, dosage guidelines, and / or mixing guidelines for the components may also be included in the kit.

[0284] Dosage regimens for the compounds of the present invention will, of course, vary depending on known factors, such as the pharmacodynamic properties of the particular drug and its method and route of administration; the recipient's species, age, sex, health, condition, and weight; the nature and extent of the condition; type of concomitant treatment; frequency of treatment; route of administration, the patient's renal and hepatic function, and the desired effect.

[0285] As a general guideline, the daily oral dose of each active ingredient, when used to achieve the intended effect, will range from about 0.001 to about 5000 mg / day, preferably from about 0.01 to about 1000 mg / day, and most preferably from about 0.1 to about 250 mg / day. The most preferred dose for intravenous constant rate infusion is in the range of about 0.01 to about 10 mg / kg / min. The compound of formula (I) may be administered in a single daily dose, or in divided doses with the total daily dose being 2, 3, or 4 times a day.

[0286] The compounds are generally selected appropriately for the intended form of administration (e.g., oral tablets, capsules, elixirs, and syrups) and are administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers), consistent with conventional pharmaceutical practice.

[0287] Dosage forms (pharmaceutical compositions) suitable for administration may contain about 1 mg to about 200 mg of the active ingredient per dosage unit. In these pharmaceutical compositions, the active ingredient is typically present in an amount of about 0.1 to 95% by weight of the total weight of the composition.

[0288] A typical capsule for oral administration contains at least one compound of Formula (I) (250 mg), lactose (75 mg), and magnesium stearate (15 mg), which mixture is passed through a 60 mesh sieve and filled into a No. 1 gelatin capsule.

[0289] A typical injectable formulation is prepared by aseptically adding at least one compound of formula (I) (250 mg) to a vial, aseptically lyophilizing and sealing it, and then mixing the contents of the vial with saline (2 mL) to prepare the injectable formulation.

[0290] The scope of the present invention includes pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one compound of formula (I), alone or in combination with a pharmaceutical carrier. Compounds of formula (I) may 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), as appropriate.

[0291] The compounds of formula (I) and / or pharmaceutical compositions of the present invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art, regardless of the route of administration selected.

[0292] Actual dosage levels of the active ingredient in the pharmaceutical compositions of the present invention may be varied to contain an amount of the active ingredient that is non-toxic to the patient and effective to produce a therapeutic effect for a particular patient, composition, and mode of administration.

[0293] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of formula (I) or ester, salt, or amide thereof employed, the route of administration of the particular compound employed, the time of administration, rate of excretion or metabolism, rate and extent of absorption, duration of treatment, other drugs, compounds, and / or substances used in combination with the particular compound employed, the age, sex, weight, symptoms, health, and medical history of the patient being treated, and factors well known in the medical arts.

[0294] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a level lower than required to achieve a therapeutic effect, and gradually increase the dosage until the effect is achieved.

[0295] Generally, a suitable daily dose of a compound of formula (I) is the lowest effective dose of the compound to achieve a therapeutic effect. Such an effective dose is generally determined by the factors described above. Generally, the dose of a compound of formula (I) administered to a patient is about 0.01 to about 50 mg / kg body weight / day for oral, intravenous, intracerebroventricular, and subcutaneous administration.

[0296] If desired, the effective daily dose of the active compound may be administered in two, three, four, five, six or more divided doses at appropriate intervals throughout the day, conveniently in unit dosage forms. In some embodiments of the invention, dosing is once daily.

[0297] While it is possible for a compound of formula (I) to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).

[0298] The other therapeutic agents described above, when used in combination with a compound of Formula (I), may be used, for example, in amounts set forth in the Pharmaceutical and Medical Devices Manual (PDR) or as determined by one of ordinary skill in the art. In the methods of the invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of a compound of the invention.

[0299] Manufacturing method The compounds of the present invention can be prepared by many methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods, synthetic methods known in the art of organic synthetic chemistry, or analogous synthetic methods appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following methods. All references cited herein are incorporated by reference in their entirety.

[0300] The compounds of the present invention may be prepared using the reactions and techniques described in this section. The reactions are carried out in solvents appropriate to the reagents and materials used and are suitable for the transformations being effected. It is also understood that in describing the synthetic methods set forth below, all proposed reaction conditions (including solvent selection, reaction atmosphere, reaction temperature, experimental time, and workup method) have been selected to be standard conditions for the reactions in question, and should be readily recognized by those skilled in the art. Those skilled in the art of organic synthesis will understand that functional groups present on various portions of the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used. The reactions may require the determination to alter the order of synthetic steps or to select a different course of action for certain reactions in order to obtain the compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this field is the selection of appropriate protecting groups to protect reactive functional groups contained in the compounds described herein. An authoritative reference that suggests many protecting group options to those skilled in the art is Protective Groups in Organic Synthesis by Greene and Wuts (Fourth Edition, Wiley & Sons, 2007).

[0301] Example The following examples illustrate specific embodiments of the present invention and are not intended to limit the scope of the invention. Chemical and scientific abbreviations and symbols have their common and accustomed meanings unless otherwise specified. Additional abbreviations used in the examples and elsewhere in this specification are defined above. Common intermediates are generally useful in the preparation of one or more examples. Example compounds are identified by the example and step by which they are prepared (e.g., "1-A" refers to Step A of Example 1), or by the example only if the compound is the title compound of the example (e.g., "1" refers to the title compound of Example 1). In some cases, alternative methods of preparation of intermediates or examples are described. Chemists skilled in the synthetic arts will frequently devise desirable alternative preparation methods based on one or more considerations (e.g., shorter reaction times, less expensive starting materials, ease of manipulation and purification, higher yields, ease of catalyst, avoidance of toxic reagents, availability of specialized equipment, and reduced number of steps). The intent of describing alternative preparation methods is to facilitate the further preparation of examples of the present invention. In some cases, some functional groups in the outlined examples and claims may be substituted with bioisosteric substitutions known to those skilled in the art (e.g., replacing a carboxylic acid group with a tetrazole or phosphate moiety).

[0302] Abbreviation [Table 1]

[0303] Analytical LCMS conditions Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile Phase A: 95:5 (water:acetonitrile containing 2.5 mM NH4OAc); Mobile Phase B: 5:95 (water:acetonitrile containing 2.5 mM NH4OAc); Temperature: 40°C; Gradient: 20% B to 100% B over 2 min; Flow Rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column: XBridge BEH XP C18 (50x2.1) 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 min; Flow rate: 1.1 mL / min; Detection: MS and UV (220 nm).

[0304] Synthesis of oxazolone intermediate A 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka]

[0305] Intermediate A1: Preparation of 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one [ka] To a stirred solution of 1-(4-bromo-2-fluorophenyl)ethan-1-one (7.5 g, 34.6 mmol) in THF (75 mL) at 0 °C, pyridinium bromide perbromide (13.26 g, 41.47 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. 20% aqueous sodium bisulfite was then added and 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 extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 10-50% DCM / petroleum ether) to give 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (6.5 g, 57%). LCMS (Method A): Retention time 1.64 min, [MH] + 294.8; 1H NMR(400MHz, CDCl3) δ ppm 7.84(t, J=8.0Hz, 1H), 7.50-7.35(m, 2H), 4.49(d, J=2.5Hz, 2H)

[0306] Preparation of Intermediate A2: 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione [ka] To a stirred solution of 3-aminopiperidine-2,6-dione·HCl (22.25 g, 135 mmol) in THF (200 mL) was added KCO (20 g, 145 mmol) at room temperature under a nitrogen atmosphere and stirred for 15 minutes. 2-Bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (20 g, 67.6 mmol) was then added portionwise to the reaction mixture and heated at 70 °C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. Water (200 mL) was added to give a precipitated solid, which was filtered through a Buchner funnel and dried under reduced pressure to give 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione (19 g, 71%) as an off-white solid. LCMS (Method A): Retention time 0.87 min, [M+H] + 343.0

[0307] Preparation of Intermediate A3: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione [ka] To a stirred solution of 3-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)piperidine-2,6-dione (30 g, 87 mmol) in THF (300 mL) was added K2CO3 (12.08 g, 87 mmol) and CDI (28.4 g, 175 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to remove excess solvent. Water (400 mL) was added to give a precipitated solid which was filtered through a Buchner funnel and dried under reduced pressure to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (21.1 g, 50%) as a brown solid. LCMS (Method A): Retention time 1.79 min, [M+H] + 371.0

[0308] Intermediate A4: Preparation of 3-(5-(4-bromo2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-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) under a nitrogen atmosphere at −48° C. and stirred at the same temperature for 1 h. Water was added to quench the reaction, and the reaction mixture was extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (Biotage, SiO, 0-60% EtOAc / petroleum ether) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (6.2 g, 45%) as a light brown solid. LCMS (Method A): Retention time 2.04 min, [MH] + 498.0;1 H NMR(400MHz, CDCl3) δ ppm 7.52(t, J=8.1Hz, 1H), 7.37(d, J=8.5Hz, 1H), 7.31(dd, J=10.6, 1.6Hz, 1H), 6.91(d, J=2.5Hz, 1H), 5.29-5.17(m, 2H), 4.87(dd, J=12.6, 6.1Hz, 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)

[0309] Preparation of Intermediate A: 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7 g, 14 mmol) in 1,4-dioxane (70 mL) at room temperature, 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) were added. The mixture was purged with nitrogen for 10 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.0 g, 1.4 mmol) was added. The 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 Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (Biotage, SiO2, 0-70% EtOAc / petroleum ether) to give 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7 g, 81%) as a white solid. LCMS (Method A): Retention time 2.19 min, [MH] + 545.2; 1 H NMR (400MHz, CDCl3) δ ppm 7.68-7.60(m, 2H), 7.51(d, J=11.8Hz, 1H), 6.96(d, J=2.5Hz, 1H), 5.30-5.17(m, 2H), 4.88(dd, J=12.6, 6.1Hz, 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)

[0310] Synthesis of oxazolone intermediate 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 [ka]

[0311] Intermediate B1: Preparation of tert-butyl 5-amino-4-((2-(4-bromo-2-fluorophenyl)-2-oxoethyl)amino)-5-oxopentanoate [ka] To a stirred solution of 2-bromo-1-(4-bromo-2-fluorophenyl)ethan-1-one (Intermediate A1) (2 g, 6.76 mmol) in acetonitrile (15 mL) at room temperature, tert-butyl 4,5-diamino-5-oxopentanoate·HCl (2.42 g, 11.97 mmol) was added, cooled to 0 °C, and sodium iodide (1.22 g, 8.11 mmol) and DIPEA (2.36 mL, 13.52 mmol) were added and stirred for 5 h. The reaction was quenched by the addition of 10% sodium sulfite solution. The reaction mixture was extracted with DCM (3 x 25 mL) and the combined organic extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 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] + 417.2

[0312] Intermediate B2: Preparation of tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate [ka] 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) under a nitrogen atmosphere at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0° C. and quenched by the addition of ice-cold water. The mixture was filtered, and the precipitate was washed with ice-cold water and 20% DCM / petroleum ether and dried under vacuum to give 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, [MH] + 440.8; 1 H NMR (300MHz, 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)

[0313] Intermediate B: Preparation of 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-oxoxoxazol-3(2H)-yl)-5-oxopentanoate (1.31 g, 2.75 mmol) in 1,4-dioxane (26 mL) at room temperature, bis(pinacolato)diboron (105 g, 412 mmol) and potassium acetate (53.9 g, 550 mmol) were added. The reaction mixture was purged with argon for 10 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)·DCM adduct (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 Celite. The filtrate was concentrated under reduced pressure to give a crude residue. This was purified by flash column chromatography (SiO2, 0-40% 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-oxoxazol-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 (500MHz, DMSO-d6) δ ppm 7.79(br s, 1H), 7.63-7.52(m, 3H), 7.45(d, J=11.3Hz, 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)

[0314] Synthesis of intermediate C cis-3-(benzyloxy)cyclobutan-1-ol [ka]

[0315] Preparation of Intermediate C: cis-3-(benzyloxy)cyclobutan-1-ol To a stirred solution of 3-(benzyloxy)cyclobutan-1-one (4 g, 22.7 mmol) in methanol (200 mL) was added sodium borohydride (1.35 g, 35.6 mmol) in portions at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with EtOAc. The organic layer was washed with 10% aqueous ammonium chloride, water, and brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 24 g column, 0–70% EtOAc / petroleum ether) to give a mixture of cis / trans isomers of 3-(benzyloxy)cyclobutan-1-ol. This isomeric mixture was purified by preparative SFC [(Column: Chiral-I Amylose 3 (250 × 50) mm, 5 μm; CO: 90%; Cosolvent: 10% (0.2% 7 mM methanolic ammonia / methanol); Total flow rate: 250 g / min; Back pressure: 100 bar; Temperature: 40 °C; UV: 220 nm)] to give cis-3-(benzyloxy)cyclobutan-1-ol (2.3 g, 57%) as an off-white solid and trans-3-(benzyloxy)cyclobutan-1-ol (0.15 g, 4%) as a viscous liquid. Cis isomer: LCMS (Method A), retention time 1.02 min, [M+H] + 179.4; 1 H NMR (400MHz, DMSO-d6) δ ppm 7.37-7.25(m, 5H), 4.97(d, J=5.0Hz, 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; 1H NMR (400MHz, DMSO-d6) δ ppm 7.37-7.26(m, 5H), 5.00(d, J=6.5Hz, 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)

[0316] 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 [ka]

[0317] 1A: Preparation of 3-bromo-2,6-dichloro-4-methylpyridine [ka] To a stirred solution of 2,6-dichloro-4-methylpyridin-3-amine (20 g, 113 mmol) in hydrobromic acid (100 mL, 866 mmol), a solution of sodium nitrite (21.44 g, 124 mmol) in water (20 mL) was slowly added at 0 °C and stirred for 30 minutes at the same temperature. Then, a solution of copper(I) bromide (19.45 g, 136 mmol) in hydrobromic acid (40 mL) was added dropwise and 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 brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 220 g column, 0-30% EtOAc / petroleum ether) to give 3-bromo-2,6-dichloro-4-methylpyridine (22 g, 81%) as an off-white solid. LCMS (Method A): Retention time 1.85 min, [M+H] + 241.0; 1H NMR (400MHz, CDCl3) δ ppm 7.29(s, 1H), 2.48-2.48(s, 3H)

[0318] 1B: Preparation of 1-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylpropan-2-ol [ka] To a stirred solution of diisopropylamine (9.47 mL, 66.4 mmol) in anhydrous THF (150 mL) was added n-BuLi / hexane (2.5 M, 23.25 mL, 58.1 mmol) over 20 minutes at −78°C under a nitrogen atmosphere, stirred at −78°C for 30 minutes, warmed to 0°C, and stirred for an additional 30 minutes. The reaction mixture was cooled again to −78°C, and a solution of 3-bromo-2,6-dichloro-4-methylpyridine (10 g, 41.5 mmol) in anhydrous THF (20 mL) was added. After 1 hour, acetone (12.19 mL, 166 mmol) in anhydrous THF (10 mL) was added, and the reaction mixture was stirred for an additional hour. The reaction was quenched by the addition of ice-cold water (100 mL). The reaction mixture was extracted with EtOAc (2x100 mL), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue which was purified by flash column chromatography (SiO2, 220 g column, 0-70% EtOAc / petroleum ether) to give 1-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylpropan-2-ol (3 g, 24%) as an off-white solid. LCMS (Method A): Retention time 1.54 min, [M+H] + 297.8; 1 H NMR (400MHz, CDCl3) δ ppm 7.39(s, 1H), 3.08(s, 2H), 1.41(br s, 1H), 1.29(s, 6H)

[0319] 1C: Preparation of 1-(3-bromo-6-chloro-2-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2-methylpropan-2-ol [ka] To a stirred solution of 1-(3-bromo-2,6-dichloropyridin-4-yl)-2-methylpropan-2-ol (0.6 g, 2.007 mmol) in NMP (30 mL) at room temperature, (2,4-dimethoxyphenyl)methanamine (0.9 mL, 6.02 mmol) and DIPEA (1.402 mL, 8.03 mmol) were added and heated in a microwave synthesizer 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 brine. The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 40 g column, 0–70% EtOAc / petroleum ether) to give 1-(3-bromo-6-chloro-2-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2-methylpropan-2-ol (0.35 g, 41%) as a pale yellow liquid. LCMS (Method A): Retention time 1.89 min, [M+H] + 429.0; 1 H NMR (400MHz, CDCl3) δ ppm 7.33-7.30(m, 1H), 6.59(s, 1H), 6.51(d, J=2.5Hz, 1H), 6.49-6.45(m, 1H), 5.86-5.76(m, 1H), 4.58(d, J=5.5Hz, 2H), 3.88(s, 3H), 3.83(s, 3H), 2.91(s, 2H), 1.44(s, 1H), 1.31(s, 6H) Additionally, 1-(3-bromo-2-chloro-6-((2,4-dimethoxybenzyl)amino)pyridin-4-yl)-2-methylpropan-2-ol (0.15 g, 17%) was obtained as a pale yellow liquid. LCMS (Method A) Retention time 1.83 min, [M+H] + 429.0; 1H 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)

[0320] 1D: Preparation of 5-chloro-N-(2,4-dimethoxybenzyl)-2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-7-amine [ka] 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) in a pressure tube at room temperature, 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) were added. The reaction mixture was purged with argon for 15 minutes, and Pd(dba) (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 Celite, and concentrated under reduced pressure to provide a crude residue. This was purified by flash column chromatography (SiO2, 40 g column, 0-70% EtOAc / petroleum 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 colorless viscous liquid. LCMS (Method A): Retention time 1.96 min, [M+H] + 349.2; 1 H NMR(300MHz, CDCl3) δ ppm 7.30(d, J=7.9Hz, 1H), 6.47-6.39(m, 3H), 4.67(br s, 1H), 4.54(d, J=5.8Hz, 2H), 3.83(s, 3H), 3.80(s, 3H), 2.90(s, 2H), 1.44(s, 6H)

[0321] 1E: Preparation 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 [ka] To a stirred solution of 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Intermediate 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-[1,2,3]triazolo[4,5-c]pyridin-4-amine (183 mg, 0.523 mmol) and cesium carbonate (310 mg, 0.952 mmol) at room temperature. The mixture was purged with argon for 10 minutes, and Catacxium Pd G3 (34.6 mg, 0.048 mmol) was added. The mixture was heated at 85 °C for 3 hours, cooled to room temperature, diluted with EtOAc, and filtered through Celite. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 330 g column, 0-80% 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)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (180 mg, 51.6%) as an off-white solid. LCMS (Method A) retention time 2.30 minutes, [M+H] + 733.4

[0322] 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., warmed to room temperature, and stirred for 16 hours. After concentration under reduced pressure, 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 mixture was stirred at 0° C. for 30 minutes. The reaction was quenched by the addition of acetic acid (0.5 mL, 8.73 mmol), and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to give a crude residue. This was purified by preparative HPLC (column: Sun Fire C18 (250*19*5); mobile phase A: 10 mM ammonium acetate aqueous solution (pH: 4.5); mobile phase B: ACN; gradient: 10% B for 0 min, then 15-50% B over 10 min, then 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; 1H NMR (400MHz, DMSO-d6) δ ppm 11.13(br s, 1H), 7.87(s, 1H), 7.85(d, J=5.0Hz, 1H), 7.62-7.55(m, 2H), 7.21(s, 1H), 5.70(s, 2H), 5.07(dd, J=13.0, 5.3Hz, 1H), 3.03(s, 2H), 2.95-2.82(m, 1H), 2.65-2.53(m, 2H), 2.13(dt, J=10.4, 5.2Hz, 1H), 1.47(s, 6H)

[0323] Example 2 trans-3-(5-(4-(6-amino-5-(3-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione [ka]

[0324] 2A: Preparation of 2,6-dichloro-4-methylpyridin-3-ol [ka] To a stirred solution of 4-methylpyridin-3-ol (12.5 g, 115 mmol) in acetonitrile (250 mL) at 0 °C, NCS (33.6 g, 252 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (SiO2, 220 g column, 0-50% EtOAc / petroleum ether) to give 2,6-dichloro-4-methylpyridin-3-ol (10 g, 49%) as a pale yellow solid. 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)

[0325] 2B: Preparation of trans-3-(3-(benzyloxy)cyclobutoxy)-2,6-dichloro-4-methylpyridine [ka] To a stirred solution of 2,6-dichloro-4-methylpyridin-3-ol (1.0 g, 5.62 mmol) in anhydrous THF (2 mL) at room temperature under a nitrogen atmosphere, cis-3-(benzyloxy)cyclobutan-1-ol (Intermediate C, 1.20 g, 6.74 mmol) and triphenylphosphine (1.77 g, 6.74 mmol) were added. The mixture was cooled to 0 °C, and DIAD (1.31 mL, 6.74 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to give a crude residue. This was purified by flash column chromatography (SiO2, 24 g column, 0–40% EtOAc / petroleum ether) to give trans-3-(3-(benzyloxy)cyclobutoxy)-2,6-dichloro-4-methylpyridine (1.3 g, 68%) as a colorless liquid. LCMS (Method A): Retention time 1.52 min, [M+H] + 338.1; 1 H NMR (300MHz, CDCl3) δ ppm 7.39-7.28(m, 5H), 7.09(s, 1H), 4.81(tt, J=7.0, 5.1Hz, 1H), 4.44(s, 2H), 4.42-4.32(m, 1H), 2.60-2.40(m, 4H), 2.30(s, 3H)

[0326] 2C: Preparation of 3-((2,6-dichloro-4-methylpyridin-3-yl)oxy)cyclobutan-1-ol [ka] To a stirred solution of trans-3-(3-(benzyloxy)cyclobutoxy)-2,6-dichloro-4-methylpyridine (1.3 g, 3.84 mmol) in THF (15 mL) under a nitrogen atmosphere was added Pd / C (10% w / w, 50% wet, 1.08 g, 10.18 mmol). The mixture was purged with hydrogen and then stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through Celite, and the Celite was washed with THF and MeOH. The combined filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (SiO2, 24 g column, 0-50% EtOAc / petroleum ether) to afford trans-3-((2,6-dichloro-4-methylpyridin-3-yl)oxy)cyclobutan-1-ol (600 mg, 63%) as a colorless gum. LCMS (Method A): Retention time 1.26 min, [M+H] + 248.2; 1 H NMR (300MHz, CDCl3) δ ppm 7.09(s, 1H), 4.85(tt, J=6.9, 5.0Hz, 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)

[0327] 2D: Preparation of 2,6-dichloro-3-(3-methoxycyclobutoxy)-4-methylpyridine [ka] To a stirred solution of trans-3-((2,6-dichloro-4-methylpyridin-3-yl)oxy)cyclobutan-1-ol (600 mg, 2.42 mmol) in anhydrous THF (5 mL) was added NaH (60% mineral oil, 145 mg, 3.63 mmol) under nitrogen atmosphere at 0°C, and the mixture was stirred at the same temperature for 30 minutes. Methyl iodide (0.151 mL, 2.42 mmol) was then added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by the addition of ice-cold water, and the reaction mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 40 g column, 0-20% 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] + 262.2; 1 H NMR (300MHz, CDCl3) δ ppm 7.09(s, 1H), 4.77(tt, J=7.0, 5.3Hz, 1H), 4.14(tt, J=6.8, 3.6Hz, 1H), 3.26(s, 3H), 2.57-2.48(m, 2H), 2.45-2.35(m, 2H), 2.31(s, 3H)

[0328] 2E: Preparation of 6-chloro-N-(2,4-dimethoxybenzyl)-3-(3-methoxycyclobutoxy)-4-methylpyridin-2-amine [ka] To a stirred solution of trans-2,6-dichloro-3-(3-methoxycyclobutoxy)-4-methylpyridine (400 mg, 1.526 mmol) and (2,4-dimethoxyphenyl)methanamine (255 mg, 1.526 mmol) in anhydrous 1,4-dioxane (5 mL) was added cesium carbonate (994 mg, 3.05 mmol) at room temperature. The reaction mixture was purged 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 Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (SiO2, 24 g column, 0-50% EtOAc / petroleum ether) to afford trans-6-chloro-N-(2,4-dimethoxybenzyl)-3-(3-methoxycyclobutoxy)-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(300MHz, CDCl3) δ ppm 7.26(d, J=6Hz, 1H), 6.47-6.41(m, 2H), 6.33(s, 1H), 5.23(br t, J=5.4Hz, 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)

[0329] 2F: Preparation of tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-5-(3-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate [ka] To a stirred solution of trans-6-chloro-N-(2,4-dimethoxybenzyl)-3-(3-methoxycyclobutoxy)-4-methylpyridin-2-amine (230 mg, 0.585 mmol) in 1,4-dioxane (8 mL)-water (2.0 mL) at room temperature was added tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (Intermediate B, 316 mg, 0.644 mmol) and potassium phosphate tripotassium (311 mg, 1.46 mmol). The reaction mixture was purged 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, cooled to room temperature, diluted with EtOAc, dried over anhydrous Na2SO4, and filtered through Celite. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash chromatography (SiO2, 12 g column, 0-4% MeOH / DCM) to give trans-tert-butyl 5-amino-4-(5-(4-(6-((2,4-dimethoxybenzyl)amino)-5-(3-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (200 mg, 47%) as a light brown solid. LCMS (Method B): Retention time 2.04 min, [M+H] + 721.4; 1H NMR (300MHz, DMSO-d6) δ ppm 7.95-7.83(m, 2H), 7.77(s, 1H), 7.57(t, J=8.3Hz, 1H), 7.48(d, J=2.9Hz, 1H), 7.40(s, 1H), 7.19(d, J=8.3Hz, 1H), 7.09(s, 1H), 6.57(d, J=2.2Hz, 1H), 6.44(dd, J=8.4, 2.3Hz, 1H), 6.31(s, 1H), 4.64(s, 1H), 4.59-4.51(m, 3H), 4.11(br dd, J=4.3, 2.9Hz, 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)

[0330] Example 2: trans-3-(5-(4-(6-amino-5-(3-methoxycyclobutoxy)-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-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (200 mg, 0.277 mmol) in acetonitrile (5 mL) at room temperature was added methanesulfonic acid (0.054 mL, 0.832 mmol) and heated at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide a crude residue. This was purified by reverse-phase preparative HPLC (column: YMC EXRS C18 (250 mm * 20 mm) 5 μm; mobile phase A: 10 mM ammonium acetate aqueous solution (pH ~ 4.5); mobile phase B: ACN; flow rate: 20.0 mL / min) to give trans-3-(5-(4-(6-amino-5-(3-methoxycyclobutoxy)-4-methylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione (50 mg, 36%) as an off-white solid. LCMS (Method B): Retention time 1.89 min, [M + H] + 497.15; 1 H NMR (400MHz, 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, 5.3Hz, 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)

[0331] 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 [ka]

[0332] 3A: Preparation of 2,6-dichloro-4-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-3-amine [ka] 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 and stirred for 30 minutes. Sodium triacetoxyborohydride (2.4 g, 11.3 mmol) was then added and stirred overnight, and the reaction was quenched by the addition of saturated aqueous NaHCO3. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 40 g column, 0-20% 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(400MHz, CDCl3) δ ppm 7.04(s, 1H), 4.02(br dd, J=11.5, 4.0Hz, 2H), 3.76(br s, 1H), 3.46-3.36(m, 2H), 2.99(d, J=6.0Hz, 2H), 2.35(s, 3H), 1.75-1.71(m, 2H), 1.64-1.57(m, 1H), 1.48-1.32(m, 2H)

[0333] 3B: 6-chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3Preparation of -((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,3-diamine [ka] 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) was added cesium carbonate (1.6 g, 4.87 mmol) at room temperature. The mixture was purged with argon for 10 minutes, and BINAP (227 mg, 0.365 mmol) and palladium(II) acetate (55 mg, 0.24 mmol) were added and heated at 90 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. This was purified by flash column chromatography (SiO2, 24 g column, 0–30% EtOAc / petroleum ether) to give 6-chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3 -((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,3-diamine (0.42 g, 43%) was obtained as a yellow syrup. LCMS (Method A): Retention time 2.03 min, [MH] + 404.1; 1 H NMR(400MHz, CDCl3) δ ppm 7.28(d, J=7.1Hz, 1H), 6.48(s, 1H), 6.45(br d, J=8.5Hz, 1H), 6.36(s, 1H), 5.65(br s, 1H), 4.54(br d, J=5.5Hz, 2H), 3.98(br dd, J=11.0, 3.5Hz, 2H), 3.85(s, 3H), 3.81(s, 3H), 3.39(br t, J=11.8Hz, 2H), 2.64(br d, J=6.0Hz, 2H), 2.44(br s, 1H), 2.14(s, 3H), 1.70(br d, J=11.0Hz, 3H), 1.41-1.29(m, 2H)

[0334] 3C: Preparation 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 [ka] 6-Chloro-N 2 -(2,4-dimethoxybenzyl)-4-methyl-N 3 To a stirred solution of -((tetrahydro-2H-pyran-4-yl)methyl)pyridine-2,3-diamine (300 mg, 0.739 mmol), 1,4-dioxane (2.9 mL), and water (0.74 mL) at room temperature was added tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (Intermediate B, 364 mg, 0.739 mmol) and potassium phosphate tripotassium (392 mg, 1.848 mmol). The mixture was purged with argon for 10 minutes, and XPhos Pd G2 (58 mg, 0.074 mmol) was added. The 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 Celite. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (SiO2, 24 g column, 0-5% 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-oxoxazol-3(2H)-yl)-5-oxopentanoate (0.45 g, 83%). LCMS (Method A): Retention time 1.92 min, [M+H] + 734.5

[0335] 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-oxoxazol-3(2H)-yl)-5-oxopentanoate (300 mg, 0.409 mmol) in acetonitrile (2 mL) at room temperature was added methanesulfonic acid (66 μL, 1.02 mmol) and heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide a crude residue. This was purified by reverse phase preparative HPLC (column: YMC Triate c18 EXRS1 (250*20*5); mobile phase A: 10 mM ammonium acetate aqueous solution; 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 an off-white solid. LCMS (Method B): Retention time 1.45 min, [M+H] + 510.20; 1H NMR (400MHz, DMSO-d6) δ ppm 11.12(br s, 1H), 7.89(s, 1H), 7.86(d, J=4.4Hz, 1H), 7.60-7.55(m, 2H), 7.10(s, 1H), 5.63(s, 2H), 5.06(dd, J=12.9, 5.3Hz, 1H), 3.92-3.82(m, 3H), 3.28-3.23(m, 2H), 2.94-2.83(m, 1H), 2.76(br t, J=6.6Hz, 2H), 2.65-2.54(m, 2H), 2.23(s, 3H), 2.17-2.08(m, 1H), 1.70(br d, J=10.8Hz, 3H), 1.26-1.15(m, 2H)

[0336] Example 4 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 [ka]

[0337] 4A: Preparation of tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate [ka] To a stirred solution of tert-butyl (6-chloropyridin-2-yl)carbamate (20 g, 87 mmol) and TEMED (33 mL, 219 mmol) in anhydrous THF (300 mL) was added n-BuLi / hexane (1.6 M, 137 mL, 219 mmol) over 30 min at −78 °C under a nitrogen atmosphere. The reaction mixture was gradually warmed to −10 °C and stirred at the same temperature for 2 h. The reaction mixture was cooled again to −78 °C, and anhydrous DMF (34 mL, 437 mmol) was added and gradually warmed to room temperature. The reaction mixture was stirred for an additional 2 h, quenched with 1 N hydrochloric acid (0.5 L), diluted with EtOAc (1 L), and stirred for 15 min. The organic layer was washed with water and saturated NaHCO solution, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude residue. This was triturated with 10% i-propanol / petroleum ether, filtered, and dried under vacuum to give tert-butyl (6-chloro-3-formylpyridin-2-yl)carbamate (15 g, 67%) as an off-white solid. LCMS (Method A): Retention time 1.45 min, [M-tBu] + 201.1; 1 H NMR (300MHz, CDCl3) δ ppm 10.17(br s, 1H), 9.90(s, 1H), 7.94(br d, J=8.3Hz, 1H), 7.26-7.02(m, 1H), 1.55(s, 9H)

[0338] 4B: Preparation of tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-5-oxopentanoate [ka] To a stirred solution of 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Intermediate 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-[1,2,3]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 purged with argon for 10 minutes, Catacxium Pd G3 (0.36 g, 0.49 mmol) was added, and the mixture was heated at 85 °C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite. The filtrate was concentrated under reduced pressure to give a crude residue, which was purified by flash column chromatography (SiO2, 80 g column, 0-80% EtOAc / petroleum ether) to give tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (5.0 g, 88%) as a light brown solid. LCMS (Method A): Retention time 1.81 min, [MH] + 583.5

[0339] 4C: Preparation of 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-oxopentanoate [ka] To a stirred solution of 4-methoxypiperidine (47.3 mg, 0.41 mmol) and tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-formylpyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (120 mg, 0.20 mmol) in DCE (5 mL)-DMF (1 mL) was added triethylamine (0.024 mL, 0.41 mmol) at room temperature and stirred overnight. MP-cyanoborohydride (200 mg) was then added and the reaction mixture was stirred overnight again. The reaction mixture was filtered through Celite and concentrated under reduced pressure to provide a crude residue. This was purified by flash column chromatography (SiO2, 12 g column, 0-10% 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-oxoxazol-3(2H)-yl)-5-oxopentanoate (120 mg, 58%) as a yellow solid. LCMS (Method A): Retention time 2.01 min, [M+H] + 684.5

[0340] Example 4: 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 To a stirred solution of tert-butyl 5-amino-4-(5-(4-(6-((tert-butoxycarbonyl)amino)-5-((4-methoxypiperidin-1-yl)methyl)pyridin-2-yl)-2-fluorophenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (120 mg, 0.18 mmol) in acetonitrile (5 mL) at room temperature was added benzenesulfonic acid (0.04 mL, 0.36 mmol) and heated at 90° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide a crude residue. This was purified by reverse-phase preparative HPLC (column: Waters XBridge C18; 150 mm x 19 mm; particle size: 5 μm; mobile phase A: 5:95 (acetonitrile:water (containing 10 mM ammonium acetate)); mobile phase B: 95:5 (acetonitrile:water (containing 10 mM ammonium acetate)); gradient: elution with 10% B for 0 minutes, followed by elution with 10 to 48% B over 10 minutes, then elution with 48% B for 5 minutes; 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 (400MHz, 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=7.5Hz, 1H), 7.20(d, J=7.5Hz, 1H), 6.22(br s, 2H), 5.08(dd, J=12.9, 5.4Hz, 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=9.0Hz, 2H)

[0341] 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 [ka]

[0342] 5A: Preparation of (2,6-dichloro-4-methylpyridin-3-yl)methanol [ka] To a stirred solution of 2,6-dichloro-4-methylnicotinic acid (1.0 g, 4.85 mmol) in anhydrous THF (30 mL) was slowly added lithium aluminum hydride (2 M in THF, 6.07 mL, 12.13 mmol) under a nitrogen atmosphere at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched by the slow addition of water (2.3 mL) followed by 15% NaOH solution (2.3 mL) at 0 °C. The reaction mixture was stirred for 5 min, and then water (6.9 mL) was added, followed by THF (50 mL). The reaction mixture was stirred vigorously for 10 min, dried over anhydrous Na2SO4, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash column chromatography (SiO2, 0–80% EtOAc / petroleum ether) to give (2,6-dichloro-4-methylpyridin-3-yl)methanol (440 mg, 47%) as a pale amorphous solid. LCMS (Method A): Retention time 1.03 min, [M+H] + 192.1; 1 H NMR (300MHz, CDCl3) δ ppm 7.15(s, 1H), 4.83(s, 2H), 2.49(s, 3H), 1.95(br s, 1H)

[0343] 5B: Preparation of 2,6-dichloro-3-(chloromethyl)-4-methylpyridine [ka] To a stirred solution of (2,6-dichloro-4-methylpyridin-3-yl)methanol (500 mg, 2.6 mmol) in anhydrous DCM (26 mL) at room temperature, triethylamine (0.54 mL, 3.91 mmol) was added, followed by DMAP (32 mg, 0.26 mmol). Under a nitrogen atmosphere, methanesulfonyl chloride (243 μL, 3.12 mmol) was added at 0 °C, and the mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue was purified by flash column chromatography (SiO2, 0-50% EtOAc / petroleum ether) to afford 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 (300MHz, CDCl3) δ ppm 7.16(s, 1H), 4.72(s, 2H), 2.49(s, 3H)

[0344] 5C: Preparation of 2,6-dichloro-4-methyl-3-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridine [ka] To a stirred solution of tetrahydro-2H-pyran-4-ol (580 mg, 5.7 mmol) in anhydrous THF (30 mL) was added sodium hydride (60% mineral oil, 285 mg, 7.13 mmol) at 0 °C and stirred for 30 min at 0 °C. 2,6-Dichloro-3-(chloromethyl)-4-methylpyridine (1 g, 4.75 mmol) was then added and stirred at 0 °C for 1 h. The reaction mixture was quenched with ice-cold water at 0 °C and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiO2, 0–80% EtOAc / petroleum ether) to afford 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] +276.0; 1 H NMR (300MHz, CDCl3) δ ppm 7.14(s, 1H), 4.68(s, 2H), 3.96(dt, J=11.7, 4.6Hz, 2H), 3.62(dt, J=8.5, 4.5Hz, 1H), 3.53-3.41(m, 2H), 2.46(s, 3H), 1.96(br dd, J=13.3, 3.9Hz, 2H), 1.70-1.61(m, 2H)

[0345] 5D: Preparation of 6-chloro-N-(2,4-dimethoxybenzyl)-4-methyl-3-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)pyridin-2-amine [ka] 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 and purged with argon for 10 minutes at room temperature. Palladium(II) acetate (81 mg, 0.36 mmol) and BINAP (338 mg, 0.54 mmol) were then added, and the 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 Celite. The filtrate was concentrated under reduced pressure, and the resulting crude residue was purified by reverse-phase flash column chromatography (Column: C18 750 g, Mobile phase A: aqueous 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 pale sticky solid. LCMS (Method A): Retention time 1.98 min, [MH] + 405.4; 1H NMR(300MHz, CDCl3) δ ppm 7.29(d, J=7.9Hz, 1H), 6.47-6.38(m, 3H), 5.88(br t, J=5.4Hz, 1H), 4.54(d, J=5.7Hz, 2H), 4.47(s, 2H), 3.87(dt, J=11.8, 4.5Hz, 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)

[0346] 5E: Preparation 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 [ka] 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-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazol-3(2H)-yl)-5-oxopentanoate (Intermediate 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 and purged with argon for 10 minutes. Xphos Pd G2 (29 mg, 0.04 mmol) was then added, and the mixture was heated at 90 °C for 2.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, dried over anhydrous Na2SO4, and filtered through Celite. The filtrate was concentrated under reduced pressure, and the crude residue was purified by flash column chromatography (SiO2, 0–100% EtOAc (containing 15% EtOH) in DCM) to give 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-oxoxazol-3(2H)-yl)-5-oxopentanoate (250 mg, 92%). LCMS (Method A): Retention time 2.02 min, [MH] + 735.5; 1H NMR (300MHz, CDCl3) δ ppm 7.92-7.81(m, 2H), 7.68-7.61(m, 1H), 7.31(d, J=8.3Hz, 1H), 7.22(d, J=2.9Hz, 1H), 6.87(s, 1H), 6.48(d, J=2.5Hz, 1H), 6.42(dd, J=8.3, 2.5Hz, 1H), 6.35(br s, 1H), 5.89(t, J=5.4Hz, 1H), 5.51(br s, 1H), 4.78-4.72(m, 1H), 4.70(d, J=5.4Hz, 2H), 4.58(s, 2H), 3.88(s, 2H), 3.86(s, 3H), 3.79(s, 3H), 3.51(tt, J=8.7, 4.1Hz, 1H), 3.40(ddd, J=11.8, 9.5, 2.7Hz, 2H), 2.37(br d, J=3.6Hz, 3H), 2.30(s, 3H), 2.23-2.12(m, 1H), 1.91-1.80(m, 2H), 1.57(br d, J=9.3Hz, 2H), 1.46(s, 9H)

[0347] 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-oxoxazol-3(2H)-yl)-5-oxopentanoate (230 mg, 0.31 mmol) in acetonitrile (2 mL) at room temperature was added methanesulfonic acid (102 μL, 1.56 mmol) and heated at 90° C. for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to provide a crude residue. This was purified by reverse-phase preparative HPLC (XSelect CSH C18 (250 mm x 19 mm x 5 μm); mobile phase A: 10 mM aqueous ammonium acetate (pH 4.5); mobile phase B: acetonitrile; gradient: time / %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 H NMR (400MHz, 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, 5.1Hz, 1H), 4.50(s, 2H), 3.84-3.78(m, 2H), 3.59(dt, J=8.8, 4.5Hz, 1H), 3.35(br s, 2H), 2.88(br d, J=4.5Hz, 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)

[0348] Comparative compound A 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione [ka] 3-(2-oxo-5-phenyloxazol-3(2H)-yl)piperidine-2,6-dione is disclosed in WO 2019 / 060693 A1 as compound number I-33.

[0349] 1A: Preparation of tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate [ka] To a stirred suspension of 2-bromo-1-phenylethan-1-one (200 mg, 1.0 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate·HCl (360 mg, 1.5 mmol) in anhydrous acetonitrile (4.5 mL) under an argon atmosphere, sodium iodide (181 mg, 1.21 mmol) was added at 0 °C. The mixture was stirred at the same temperature for 5 min, and DIPEA (351 μL, 2.01 mmol) was added dropwise. Stirring was continued at 0 °C for 2 h, then the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of 10% sodium bisulfite solution, and the mixture was extracted with DCM (3 x 10 mL). The combined organic extracts were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate (322 mg, crude). LCMS (Method A): Retention time 1.215 min, [M+H] + 321.1

[0350] 1B: Preparation of tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate [ka] To a stirred solution of tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate (322 mg, 1.0 mmol) in anhydrous DMF (7 mL) was added CDI (407 mg, 2.5 mmol) and triethylamine (420 μL, 3.0 mmol) under an argon atmosphere at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched by the addition of ice-cold water, and the reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (SiO, 24 g column, 0–100% EtOAc / petroleum ether) to give tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazol-3(2H)-yl)pentanoate (155 mg, 44%). LCMS (Method A): Retention time 1.33 min, [M+Na] + 369.2; 1 H NMR (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)

[0351] 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 and heated at 90° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparative HPLC (X-Bridge Phenyl C18 (250 mm*19 mm); 5 μm; Mobile phase A: 10 mM aqueous 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; 1 H NMR (400MHz, 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, 13.3Hz, 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)

[0352] Comparative compound B 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)piperidine-2,6-dione [ka]

[0353] 1A: Preparation of 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione [ka] To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.4 mmol) in anhydrous DCM (2.0 mL) was added TFA (0.154 mL, 2.0 mmol) at room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was co-concentrated with DME (4x) to give 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (150 mg, 94%). LCMS (Method A): Retention time 1.37 min; [M+Na] + 423.1

[0354] Comparative compound B: To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxoxazol-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (180 mg, 0.45 mmol) in anhydrous DME (2255 μL) was added N,N'-dimethylethane-1,2-diamine (199 mg, 2.26 mmol) under a nitrogen atmosphere at 0°C, and the mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, acidified with acetic acid (258 μL, 4.5 mmol), and then concentrated under reduced pressure (bath temperature <30°C). The resulting residue was purified by reverse-phase preparative HPLC (Method: Column: X-Bridge Phenyl (19 mm x 250 mm x 5 μm); Mobile phase A: 10 mM aqueous 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)piperidine-2,6-dione (67 mg, 40%). LCMS (Method A): Retention time 2.155 min, [MH] + 366.8; 1H NMR (400MHz, DMSO-d6) δ ppm 11.13(br s, 1H), 7.75-7.70(m, 1H), 7.66(d, J=3.0Hz, 1H), 7.53(s, 1H), 7.52(d, J=5.1Hz, 1H), 5.06(dd, J=5.3, 13.3Hz, 1H), 2.94-2.80(m, 1H), 2.70-2.54(m, 2H), 2.16-2.08(m, 1H)

[0355] Biological assays The pharmacological action of the compounds of the present invention can be confirmed by a number of biological assays. The following exemplified biological assays are carried out using the compounds of the present invention.

[0356] JURKAT cell lysis assay Jurkat cells were seeded into 384-well cell culture plates at 80,000 cells per well in 40 μL of RPMI + 10% FBS, followed by the addition of compounds of interest using acoustic dispensing technology. Cells were incubated at 37°C and 5% CO2 for 24 hours. To facilitate analysis, cultured cells were spun down at 200 rpm for 5 minutes and the supernatant removed. After rocking the plate to loosen the cell pellet, the cells were resuspended in fixation buffer (50 μL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 60 minutes at room temperature. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 10 minutes at room temperature. After permeabilization, cells were spun down, and the supernatant was replaced with fluorescently labeled antibodies (20 μL) against Helios, Ikaros, and Aiolos or the corresponding isotype controls in 1x permeabilization buffer (Ikaros-Alexa488 [Biolegend, Cat #368408, 1:50], Helios-PE [CST, Cat #29360, 1:50], Aiolos-Alexa647 [Biolegend, Cat #371106, 1:25]). The staining reaction was incubated for 1 h at room temperature protected from light. Next, 1x permeabilization buffer (30 μL) was added, the cells were centrifuged, and the supernatant was removed. Stained cells were resuspended in flow cytometry staining buffer [25 μL, PBS + 0.2% bovine serum albumin (BSA)] and analyzed using an Intellicyt iQue Plus flow cytometer. [Table 2] Table A-1 lists the maximum observed degradation rates of IKZF1, IKZF2, and IKZF3 proteins as measured in the Jurkat cell degradation assay. The results in Table A-1 have been rounded to two decimal places. A value of 100% in the Jurkat cell degradation assay indicates no detectable remaining protein or complete protein degradation, and a value of 0% indicates no detectable protein degradation by the test compound. In the tests shown in Table A-1, the compounds of the present invention were observed to degrade at least 89% of IKZF2 (Helios) protein, as shown in Examples 1 to 5. In contrast, less than 30% degradation of IKZF2 protein was observed with Comparative Compound A and Comparative Compound B. [Table 3]

[0357] Human regulatory T cell lysis assay Cryopreserved human regulatory T cells were thawed in RPMI + 10% FBS + IL-2 (20 ng / mL). After centrifugation at 1200 rpm for 5 minutes, the cells were resuspended in RPMI + 10% FBS + 20 ng / mL and incubated at 37°C and 5% CO2 for 3 hours. Cells were then seeded into a 384-well cell culture plate at 40,000 cells per well in 40 μL of RPMI + 10% FBS + human IL-2 (20 ng / mL). Compounds of interest were then added using an acoustic dispensing device (ECHO 555). The cultured cells were incubated at 37°C and 5% CO2 for 20 hours. To facilitate analysis, the cultured cells were spun down at 1200 rpm for 5 minutes, and the supernatant was discarded using an EL406 plate washer. After washing three times with PBS (70 μL), the cell pellet was resuspended in Near-IR stain (50 μL, Life Technologies, Cat# L34975) and incubated on ice for 30 minutes in the dark to measure viability. Cells were washed three times with PBS (70 μL) + 0.5% BSA using an EL406 plate washer. After shaking the plate to detach the cell pellet, the cells were resuspended in fixation buffer (50 μL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 60 minutes at room temperature. After centrifugation to remove the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 Buffer Set, 00-5523-00) for 10 minutes at room temperature. After permeabilization, cells were spun down, and the supernatant was replaced with fluorescently labeled antibodies (30 μL) against the intracellular targets Helios (Helios-APC [BioLegend, Cat# 137222, 1:50]), Aiolos, and Ikaros (1:1 permeabilization buffer). The staining reaction was incubated for 1 hour at room temperature protected from light. Next, 1:1 permeabilization buffer (30 μL) was added, the cells were centrifuged, and the supernatant was removed. Stained cells were resuspended in flow cytometry staining buffer (30 μL, PBS + 0.5% BSA) and analyzed using an Intellicyt iQue Plus flow cytometer. [Table 4] Table B-1 lists the maximum observed degradation rates of IKZF1-IKZF4 proteins as measured in the human regulatory T cell lysis assay. The results in Table B-1 have been rounded to two decimal places. A value of 100% in the human regulatory T cell lysis assay indicates no detectable remaining protein or complete protein degradation, and a value of 0% indicates no detectable protein degradation by the test compound. In the tests shown in Table B-1, the compounds of the present invention were observed to degrade (i) 51%, 56%, 58%, 67%, and 52% of IKZF1 (Ikaros) protein; (ii) 98% of IKZF2 (Helios) protein; (iii) 22%, 25%, 25%, 35%, and 29% of IKZF3 (Aiolos) protein; and (iv) 56%, 62%, 59%, 62%, and 67% of IKZF4 (Eos) protein, respectively, as shown in Examples 1 to 5. [Table 5]

[0358] Human regulatory T cell reprogramming assay RosetteSep Human CD4 + Human CD4 T Cells were isolated from fresh Leukopaks (Stemcell Technologies) of healthy donors using T Cell Enrichment Cocktail (Stemcell Technologies) and Ficoll density gradient centrifugation. + T cells were isolated by diluting the Leukopak with an equal volume of phosphate-buffered saline (PBS [Gibco], containing 2% fetal bovine serum (FBS, VWR Lifesciences)) and adding RosetteSep Human CD4 + After 20 minutes of incubation with T Cell Enrichment Cocktail, Ficoll-Paque Plus solution (GE Health Care) was added. The cell-rich interface was collected and washed twice with PBS (containing 2% FBS). EasySep Human CD4 + CD127 low CD25 +Regulatory T cells were manually isolated using a regulatory T cell isolation kit (Stemcell Technologies) according to the manufacturer's instructions. Cells were incubated overnight in Roswell Park Memorial Institute (RPMI) 1640 medium (Gibco, containing 10% FBS + Pen / Strep (Gibco) + MEM-NEAA (Gibco) + sodium pyruvate (Gibco)) in a humidified incubator (37°C, 5% CO2). Cells were then stained for CD4 with RPA-T4 (Biolegend), CD25 with 2A3 (BD ​​Biosciences), and CD127 with hIL-7R-M21 (BD Biosciences). CD4 + CD127 low CD25 + Cells were sorted to >95% purity using a BD FACSAria Fusion cell sorter and were either used immediately for subsequent assays or cryopreserved. Freshly isolated by FACS or isolated and cryopreserved CD4 + CD127 low CD25 +Treg cells were cultured in 96-well round-bottom plates at 25,000–50,000 cells per well in RPMI 1640 medium (Gibco, containing 10% FBS + Pen / Strep (Gibco) + MEM-NEAA (Gibco) + sodium pyruvate (Gibco)). Cells were activated using Treg Xpander beads (Thermo Fisher) at a cell-to-bead ratio of 1:4 in the presence of recombinant human IL-2 (500 U / mL, Proleukin). Compounds were added incrementally, and cells were incubated at 37°C, 5% CO2 for 12–13 days. Recombinant human IL-2 and compounds were replenished every 2–3 days during the culture period. On day 12 or 13, cells were reactivated with phorbol 12-myristate 13-acetate (PMA) and ionomycin in the presence of protein transport inhibitors: brefeldin A and monensin (eBioscience Cell Stimulation Cocktail (plus protein transport inhibitors), 500x, catalog number: 00-4975-93), followed by staining and analysis by flow cytometry. For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated in Human TruStain FcX (Biolegend, Fc receptor blocking reagent) for 10 minutes, followed by the addition of Viability Dye eFluor 780 (Thermo Fisher) and a surface marker antibody cocktail for 30 minutes at 4°C. Cells were then fixed and permeabilized by incubation with FoxP3 transcription factor staining buffer (Thermo Fisher) for 30 minutes at 4°C according to the kit manufacturer's instructions. Cells were washed twice with the kit's Perm / Wash buffer and incubated overnight at 4°C with an intracellular antibody cocktail composed of antibodies specific for the transcription factors listed in Table C according to the manufacturer's instructions. Cells were washed twice with Perm / Wash buffer, resuspended in flow cytometry staining buffer (Thermo Fisher), and harvested. Samples were harvested and analyzed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stained controls were prepared for each fluorochrome using UltraComp eBead Compensation Beads (Thermo Fisher). Data were analyzed using FlowJo (version 10) and GraphPad Prism software. [Table 6] [Table 7] Table C-1 lists the maximum observed degradation rates of IKZF2 and IKZF4 proteins measured in the human regulatory T cell reprogramming assay. The results in Table C-1 have been rounded to two decimal places. A value of 100% in the human regulatory T cell reprogramming assay indicates no detectable remaining protein or complete protein degradation, and a value of 0% indicates no detectable protein degradation by the test compound. [Table 8]

[0359] Human CD8 + T cell lysis assay Cryopreserved human peripheral blood mononuclear cells (PBMCs) from healthy donors were thawed and seeded at 500,000 cells per well in 96-well round-bottom plates in RPMI 1640 medium (Gibco, containing 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco)). Cells were treated with increasing concentrations of compounds at 37°C under 5% CO2 for 24 hours, followed by flow cytometry analysis. For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher) and incubated in Human TruStain FcX (Biolegend, Fc receptor blocking reagent) for 10 min, followed by Viability Dye eFluor780 (Thermo Fisher) and a surface marker antibody cocktail (including LD-eFluor780, CD3-BUV-395, CD4-BUV805, CD8-FITC, and CD25-BV605) for 30 min at 4°C. Cells were then fixed and permeabilized by incubation with permeabilization buffer (eBioscience FoxP3 Buffer Set, 00-5523-00) for 30 min at 4°C according to the kit manufacturer's instructions. According to the manufacturer's instructions, cells were washed twice with the kit's Perm / Wash buffer and incubated overnight at 4°C with an intracellular antibody cocktail consisting of antibodies specific for transcription factors (i.e., Foxp3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PECF594, and AIOLOS-AF647). Cells were washed twice with Perm / Wash buffer, resuspended in flow cytometry staining buffer (Thermo Fisher), and then harvested. Samples were harvested and analyzed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stained controls were prepared for each fluorochrome using UltraComp eBead Compensation Beads (Thermo Fisher). Data were analyzed using FlowJo (version 10) and GraphPad Prism software. [Table 9] [Table 10] Table D-1 shows human CD8 + The maximum observed degradation rates of IKZF1 and IKZF3 proteins measured in the T cell reprogramming assay are listed. Results in Table D-1 have been rounded to two decimal places.+ A value of 100% in the T cell reprogramming assay indicates no detectable remaining protein or complete protein degradation, and a value of 0% indicates no detectable protein degradation by the test compound.

[0360] [Table 11] Comparing Examples 1-5 with Comparative Compound A and Comparative Compound B disclosed in WO 2019 / 060693 A1, Examples 1-5 were found to be particularly useful. Examples 1-5 have the significant advantage of reducing the levels of four IKZF1 to IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos). In the above tests, as shown in Tables A-1, C-1, and D-1, (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) 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, comparative compounds A and B reduced IKZF2 (Helios) protein by 27% or less in the same test (Table A-1), and reduced IKZF4 (Eos) protein by 11% or less (Table C-1).

[0361] The present invention fulfills this need by providing compounds useful for reducing the levels of the four IKZF1-IKZF4 proteins (Ikaros, Helios, Aiolos, and Eos).

Claims

1. Formula (I): 【Chemistry 1】 (Wherein R is 【Chemistry 2】 or a stereoisomer, tautomer, or salt thereof.

2. The compound is 【Transformation 3】 2. The compound of claim 1, wherein:

3. The compound is 【Chemistry 4】 2. The compound of claim 1, wherein:

4. The compound is 【Transformation 5】 2. The compound of claim 1, wherein:

5. The compound is 【Transformation 6】 2. The compound of claim 1, wherein:

6. The compound is 【Transformation 7】 2. The compound of claim 1, wherein:

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

8. 10. Use of a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, for treating cancer.

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

11. 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. 11. The method of claim 10, further comprising administering to the patient a therapeutically effective amount of a second agent prior to, concurrently with, or after administration of the compound, wherein the second agent is selected from a PD1 / PD-L1 antagonist, a CTLA4 antagonist, a chemotherapeutic agent, radiation, or an anti-tumor vaccine.

13. 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 method according to claim 10, wherein the Eos protein has an amino acid sequence encoded by SEQ ID NO: 20 or 21.

14. 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%; The method of claim 13.

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

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

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