Substituted phenyloxazolone compounds

Abstract

This invention provides compounds useful for treating viral infections and proliferative diseases such as cancer. [Solution] Formula (I): JPEG2026113468000056.jpg45153 Compounds of the formula (wherein each R is independently H or D), or stereoisomers, tautomers, or salts thereof are provided. Methods of using the compound to reduce the level of the IKZF1-4 protein are also disclosed; and pharmaceutical compositions comprising the compound are also disclosed. The compound is useful in the treatment of viral infections and proliferative disorders such as cancer.

Description

[Technical Field]

[0001] (cross reference) This application claims the interests of U.S. Provisional Application No. 63 / 500,727, filed on 8 May 2023, and U.S. Provisional Application No. 63 / 632,070, filed on 10 April 2024, both of which are incorporated herein by reference in their entirety.

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

[0003] The Ikaros zinc finger family (IKZF) of transcription factors (TFs) plays a crucial role in lymphocyte development and function (Heizmann et al, 2018, Curr Opin Immunol. 51:14-23). ​​In mammals, the following five members of this TF family are expressed in immune cells: Ikaros (encoded by IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5). The amino acid sequences of these proteins are highly homologous, with Ikaros and Aiolos, and Helios and Eos being the most homologous pairs, while Pegasus is the most distantly related IKZF member. These TFs perform both overlapping and unique functions in lymphocytes (Read et al, 2020, Immunological Reviews, 300:1). Decreasing IKZF TF protein levels may enhance the antitumor T cell response.

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

[0005] IKZF2 encodes Helios, which exhibits a more limited expression profile, restricted to human and mouse regulatory T (Treg) cells, some CD8+ T cells and MAIT cells, and NK cells (Akimova et al, 2011, PLoS One, 6:e24226; Dias et al, 2017, Proceedings of the National Academy of Sciences USA, 114:E5434-E5443; Thornton and Shevach, 2019, Immunology, 158:161-170).

[0006] IKZF3 encodes Aiolos, which is widely and abundantly expressed in human and mouse B lymphocytes, and widely expressed at low levels in T cells and NK cells. In T cells, the repressor targets of the Aiolos gene were found to overlap significantly with the target genes of Ikaros (Powell et al, 2019, Frontiers in Immunology, 10:1299). Compared to Ikaros, Aiolos may have a stronger influence on tissue immune responses and, in some cases, on the responses of follicular helper T cells and T helper type 17 involved in antitumor immunity (Quintana et al., 2012, Nature Immunology, 13:770-777; Read et al., 2017 Journal of Immunology, 7:2377-2387).

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

[0008] A common function of IKZF TFs is the repression of gene expression at specific loci within cells. IKZF TFs can bind to genomic loci as homodimers or heterodimers (e.g., Ikaros:Ikaros or Ikaros:Helios). Both of these dimeric TFs 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 can all associate with centromere heterochromatin and participate in the expression of genes located at centromere loci (Brown et al., 1997, Cell, 91:845-854; Thompson et al., 2007, Immunity, 26:335-344). Eos cooperates with Ikaros but not with Aiolos, and interacts with transcription repressor C-terminal binding protein 1 (CtBP1) in lymphocytes (Koipally et al., 2002, Journal of Biological Chemistry, 277:27697-27705; Pan et al. 2009, Science, 325:1142-1146). Thus, the overlapping functions of IKZF TFs may partially compensate for the deletion or degradation of one or more TFs. Therefore, in cells expressing multiple IKZF members, broad therapeutic degradation of this TF family is expected to result in stronger phenotypic changes compared to selective degradation of one or two IKZF TFs.

[0009] In T cells and Treg cells, a common role of IKZF TFs in regulating key loci for antitumor immune responses has been exemplified by their regulation of genes encoding interleukin-2 (IL-2). Ikaros can directly bind to the IL-2 locus on CD4+ T cells and recruit HDAC complexes; deletion of Ikaros increases IL-2 production by CD4+ and CD8+ T cells (Bandyopadhyay et al., 2007, Blood, 109:2671-2672; Thomas et al., 2007, Journal of Immunology, 179:7305-7315; O'Brien et al., 2014, Journal of Immunology, 192:5118-5129). Helios directly binds to the IL-2 locus in Treg cells, recruiting the HDAC complex and silencing the IL-2 gene (Blaine et al., 2013, Journal of Immunology, 190:1008-1016). Eos also suppresses IL-2 expression in Treg cells and may act through mechanisms including interaction with TF FoxP3 (Pan et al., 2009, Science, 325:1142-1146; Sharma et al., 2013, Immunity, 38:998-1012). The role of Aiolos binding directly to IL-2 deletion is not well understood, but it has been reported that Aiolos siRNA knockdown in human Treg cells increases IL-2 production (Gandhi et al, 2010, Nature Immunology, 11:846-853). In summary, IKZF TFs act to regulate IL-2 production by Treg cells, and all of the multiple lymphocyte subtypes (especially these four IKZF TFs) are richly expressed intracellularly, and IL-2 production is usually negligible.

[0010] Treg cells, characterized by the expression of the transcription factor FoxP3, are a subset of immunosuppressive lymphocytes that employ 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 adverse mutations in the gene encoding FoxP3 lack functional Treg cells and exhibit immunodysregulation, polyendocrine disorders, X-linked enteropathy (IPEX) syndrome, and multi-organ autoimmune diseases. 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, capturing cytokines (e.g., IL-2), and directly inhibiting the activation of T cells and antigen-presenting cells, Treg cells can promote resistance to TME-mediated immunotherapy by modulating multiple pathways in the cancer immune cycle (Chen and Mellman, 2013, Immunity, 39:1-10). In preclinical models, elimination of Treg cells led to regression of progressive, established tumors (Bos et al., 2013, Journal of Experimental Medicine, 210:2435-2466).

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

[0012] Clinically, increased Treg cell abundance in TMEs correlates with worsening outcomes in several solid tumor indications (Shang et al, 2015, Scientific Reports, 5:15179). Furthermore, the correlation between PD-L1+ Treg cell abundance and responsiveness to anti-PD-1 therapy in non-small cell lung cancer (NSCLC) patients strongly suggests the therapeutic potential of Treg cell targeting in TMEs (Wu et al., 2018, Journal of Thoracic Oncology, 13:521-532). Modulating the activity of key factors that control Treg cell differentiation may offer potential therapeutic strategies for treating specific diseases (e.g., cancer and viral infections).

[0013] Furthermore, it has been reported that removal of Foxp3+ Treg cells enhances vaccine-induced antitumor T cell responses (Nishikawa et al., 2010, Int. J. Cancer 127:759-767), suggesting that reducing Helios levels may be effective in enhancing the efficacy of cancer vaccines. Antitumor immunotherapy during viral infection may limit the immunopathological response of Treg cells caused by excessive inflammation and inhibit effective antiviral T cell responses, thereby promoting viral resistance (Schmitz et al., 2013, PLOS Pathogens 9:e1003362). When mice were chronically, rather than acutely, infected with lymphocytic choriomeningitis virus, Foxp3+ Treg cells proliferated significantly, implicitly suggesting a potential mechanism by which certain infectious agents can evade the host immune response by activating and proliferating Treg cells (Punkosdy et al., 2011, PNAS 108:3677-3682). In situations involving chronic viral infection, therapeutic effects can be achieved by reducing the Helios levels of activated Treg cells.

[0014] Approaches targeting tumor Treg cells include antibody-mediated depletion and functional regulation of Treg cells (Tanaka and Sakaguchi, 2019, European Journal of Immunology, 49:1140-1146) and small molecule-mediated "reprogramming" of Treg cells to induce immunosuppressive phenotypes through altered gene expression in cells (Kim et al., 2015, Science, 350:334-339; Sebastian et al., 2016, Journal of Immunology, 196:144-155). Mice carrying Treg cells genetically engineered to lack Helios do not develop the characteristic IPEX-like immunopathology associated with FoxP3 deletion or complete excision of Treg cells, but instead possess Treg cells that exhibit a transcriptional program more closely resembling effector T cells (Fu et al., 2012, Nature Immunology, 13:972-980; Yates et al., 2018, Proceedings of the National Academy of Sciences USA, 115:2162-2167). Importantly, Helios regulates the activity of key Treg cells in TME, as evidenced by the improved control of B16F10 and MC38 tumors in mice with Helios-deficient Treg cells (Nakagawa et al., 2016, Proceedings of the National Academy of Sciences USA, 113:6248-6253). Therefore, therapeutic modulation of Helios may promote anti-tumor immunity by reprogramming tumor Treg cells to a more effector-like phenotype. In particular, since mice lacking Eos expression in FoxP3 Treg cells more effectively control syngeneic tumors compared to controls in preclinical tumor models (Gokhale et al, 2019, Journal of Autoimmunity, 105:102300), Eos also drives immunosuppressive Treg cell activity in TMEs.Similarly, humans with loss-of-function IKZF2 mutations in the germline do not exhibit IPEX-like symptoms (e.g., diabetes, dermatitis, hepatitis, and generalized lymphadenopathy), but instead show an immunophenotype associated with enhanced T cell activation and increased inflammatory cytokine production (Hetemaeki et al., 2021, Science Immunology, 6:eabe3454; Shahin et al., 2021, Science Immunology, 6:eabe3981). These data indicate that reduced levels of Helios and Eos proteins in Treg cells result in the loss of suppression of antitumor T cell responses in solid tumor patients.

[0015] Small molecules that degrade Ikaros and Aiolos in Treg cells can also reduce the inhibitory function of these cells in vitro (Galustian et al., 2008, Cancer Immunology, Immunotherapy, 58:1033-1045). In genetically modified mouse models, lenalidomide, which degrades Ikaros and Aiolos, can moderately enhance the antitumor immune response against highly immunogenic syngeneic tumors (Geng et al, 2022, Cell Chemical Biology, 29:1260-1272). Ikaros and Aiolos-targeted degraders have also been clinically tested in patients with solid tumors, sometimes leading to a moderate and stable response. These studies include those on abadomide (CC-122) (Rasco et al., 2019, Clin Cancer Research, 25:90-98), lenalidomide (Semeraro et al., 2013, OncoImmunology, 2:11), and pomalidomide (Cooney et al., 2012, Cancer Chemotherapy and Pharmacology, 70, 755) in advanced malignancies. Furthermore, 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 four IKZF TFs, Ikaros, Helios, Aiolos, and Eos, are highly expressed in Treg cells. A complex reduction in the individual protein levels of these four TFs in Treg cells would better reverse the immunosuppressive program, including the suppression of IL-2 transcription, compared to approaches that selectively target a single IKZF TF or pairs of TFs (i.e., Ikaros and Aiolos or Helios and Eos). In addition to Treg cells, pan-IKZF1-4 degraders are expected to enhance the effector functions of conventional CD4+ and CD8+ T cells, enhance NK cell activity, and promote a strong anti-tumor response in patients.

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

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

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

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

[0021] The present invention also provides a method for treating a disease or disorder by reducing the levels of four IKZF1-4 proteins, namely Ikaros, Helios, Aiolos, and Eos, characterized by administering a compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs, to a patient.

[0022] The present invention also provides methods and intermediates for producing a compound of formula (I), or its stereoisomers, tautomers, or salts.

[0023] The present invention also provides the use of a compound of formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, or prodrugs, for the manufacture of pharmaceuticals that reduce Ikaros, Helios, Aiolos, and Eos protein levels for the treatment of specific diseases (e.g., cancer and viral infections).

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

[0025] Compounds of formula (I) and compositions containing 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 such as viral infections.

[0026] These and other features of the present invention will be described in more detail as disclosed. Detailed description of the invention

[0027] The applicant has discovered a substituted phenyloxazolone compound that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins. This substituted phenyloxazolone compound is thought to promote the interaction between the Ikaros, Helios, Aiolos, and Eos proteins and the corresponding E3 ubiquitin ligase complex (Cullin4-Cereblon, CUL4-CRBN), thereby degrading the Ikaros, Helios, Aiolos, and Eos proteins. The compound reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins. The compound is useful for the treatment of certain diseases (e.g., cancer and viral infections). The compound provides a useful pharmaceutical with desirable stability, bioavailability, therapeutic index, and important toxicity values ​​for their drugability.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0048] One embodiment provides a compound of formula (Ia), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione. Furthermore, this embodiment includes one or more pharmaceutically acceptable salts.

[0049] One embodiment provides a compound of formula (Ia), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione. Furthermore, this embodiment includes one or more pharmaceutically acceptable salts.

[0050] One embodiment provides a compound of formula (Ib), or a tautomer or salt thereof, wherein the compound is (S)-3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-dione. Furthermore, this embodiment includes one or more pharmaceutically acceptable salts.

[0051] One embodiment provides a compound of formula (Ib), or a tautomer or salt thereof, wherein the compound is (R)-3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione-3,4,4,5,5-d5. Furthermore, this embodiment includes one or more pharmaceutically acceptable salts.

[0052] One embodiment has the following structure: [ka] The present invention provides a compound of formula (I) having, or its stereoisomer, tautomer, or salt.

[0053] One embodiment has the following structure: [ka] The present invention provides a compound of formula (I) having, or its stereoisomer, tautomer, or salt.

[0054] Compounds of formula (I), or their stereoisomers, tautomers, or salts, are useful in reducing the levels of the four IKZF1-4 proteins: Ikaros, Helios, Aiolos, and Eos.

[0055] As used herein, “reducing the level” of one of the IKZF1-4 proteins means reducing the level of the protein by degradation and / or inactivation and / or inhibition and / or a decrease in the expression level of the protein, or a combination thereof, compared to the initial protein level before contact with or treatment with the compound of formula (I), or its stereoisomers, tautomers, or salts.

[0056] Various methods can be used to measure the decrease in protein levels of IKZF1-4 proteins, including the assays described below: (i) IKZF1: Human CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell degradation assay; (iii) IKZF3: Human CD8 + T cell reprogramming assay; and (iv) IKZF4: Human regulatory T cell reprogramming assay.

[0057] The present invention may be implemented in other specific forms without deviating from its essence or essential characteristics. The present invention encompasses any combination of the aspects and / or embodiments of the present invention described herein. It is understood that any embodiment of the present invention may be combined with any other embodiment to illustrate further embodiments. It is also understood that individual elements of an embodiment may be combined with any other elements from any embodiment to illustrate further embodiments.

[0058] The features and usefulness of the present invention can be more readily understood by those skilled in the art by reading the detailed description below. For clarity, it is understood that certain features of the present invention described before or after the context of another embodiment may be combined to form a single embodiment. Conversely, for brevity, various features of the present invention described in the context of a single embodiment may also be combined to form a subcombination thereof. Embodiments described herein as examples or preferred are intended to be illustrative and not limiting.

[0059] Unless otherwise specified in this specification, singular nouns may include plural nouns. For example, "a" and "an" may refer to either "one" or "one or more."

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

[0061] Unless otherwise specified, any atom whose valence is not met is assumed to contain enough hydrogen atoms to satisfy the valence requirement.

[0062] The definitions contained herein supersede any definitions contained in any patent, patent application and / or patent application publication incorporated herein by reference.

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

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

[0065] In accordance with the conventions used in that field, [ka] The symbol is used in the structural formulas of this specification to represent a bond that is a bonding point of a partial or substituent to the core or skeletal structure.

[0066] The term "amino" refers to the -NH2 group.

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

[0068] The present invention intends to contain all isotopes of the atoms contained in the compound of the present invention. Isotopes include atoms that have the same atomic number but different mass numbers. As a general example, but not limited to the following, hydrogen isotopes include deuterium (D) and tritium (T). Carbon isotopes include 13 C and 14 It contains C. The isotope-labeled compounds of the present invention can be prepared by conventional methods generally known to those skilled in the art, or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of the unlabeled reagent used in other methods.

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

[0070] Therefore, the present invention is intended to cover all possible tautomers, even if the structure describes only one of them. For example, the compound of formula (I) may exist in the form of a tautomer: [ka]

[0071] Similarly, the compound of formula (Ia) may exist in the form of a tautomer: [ka]

[0072] Another example of tautomer morphology is: [ka] and [ka] These are some examples.

[0073] As used herein, the phrase "pharmaceutically acceptable" means a compound, substance, composition and / or dosage form that is suitable for use in contact with human and animal tissues without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of ordinary medical judgment, and that provides a reasonable benefit-risk ratio.

[0074] Compounds of formula (I) can form salts, and these salts are also within the scope of the present invention. Unless otherwise specified, references to compounds relating to the invention are understood to include references to one or more salts thereof. The term “salt” refers to an acid salt formed by inorganic and / or organic acids. Salts that are pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) are preferred. However, other salts may also be useful, for example, in isolation or purification steps that may be used in the manufacturing process, and therefore other salts are also considered to be within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by reacting the compound of formula (I) with a certain amount of acid (e.g., 1 equivalent), thereby precipitating the salt in a solvent, for example, or by subsequently freeze-drying an aqueous solution.

[0075] Examples of acid addition salts include acetates (e.g., acetates formed using acetic acid or trihaloacetic acid (e.g., trifluoroacetic acid)), adipines, alginates, ascorbic acid, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed using hydrochloric acid), and hydrobroms (formed using hydrogen bromide). Examples include hydroiodide, maleate (formed using maleic acid), 2-hydroxyethanesulfonate, lactate, methanesulfonate (formed using methanesulfonic acid), 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (formed using sulfuric acid, for example), sulfonate (for example, those described herein), tartrate, thiocyanate, toluenesulfonate (for example, tosylate), and undecanoate.

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

[0077] Furthermore, solvates (e.g., hydrates) of compounds of formula (I) should also be considered within the scope of the present invention. The term “solvate” means a physical bond between a compound of formula (I) and one or more organic or inorganic solvent molecules. This physical bond includes hydrogen bonds. In some cases, solvates can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. “Solvate” includes both the solution phase and the separable solvate. Examples of solvates include hydrates, ethanolates, methanelates, isopropanolates, acetonitrile solvate, and ethyl acetate solvate. Methods of solvation are known in the art.

[0078] Various forms of prodrugs are well known in this field and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0079] In addition, after being manufactured, the compound of formula (I) is isolated and purified to obtain a composition containing 99% or more of the compound of formula (I) ("substantially pure"), which is then used or formulated as described herein. Such "substantially pure" compound of formula (I) is also considered to be part of the present invention.

[0080] A "stable compound" and a "stable structure" are intended to be compounds that are sufficiently robust to not degrade even when isolated from a reaction mixture to a useful purity or when formulated into an effective therapeutic agent. This invention aims to embody such stable compounds.

[0081] The terms "IKZF1 degrading agent" and "Ikaros degrading agent" refer to drugs that can reduce the level of IKZF1 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of the IKZF1 protein, or a combination thereof.

[0082] The terms "IKZF2 degrading agent" and "Helios degrading agent" refer to drugs that can reduce the level of IKZF2 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of the IKZF2 protein, or a combination thereof.

[0083] The terms "IKZF3 degrading agent" and "Aiolos degrading agent" refer to drugs that can reduce the level of IKZF3 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of the IKZF3 protein, or a combination thereof.

[0084] The terms "IKZF4 degrading agent" and "Eos degrading agent" refer to drugs that can reduce the level of IKZF4 protein by degrading and / or inactivating and / or inhibiting and / or reducing the expression level of the IKZF4 protein, or a combination thereof.

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

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

[0087] As used herein, the “Ikaros” protein is encoded by the IKZFl gene. Ikaros is also known as IKAROS family zinc finger 1, ZNFN1Al, zinc finger protein 1, subfamily 1A, 1, Ikaros family zinc finger protein 1, IK1, lymphoid transcription factor LyF-1, Hs.54452, PPP1R92, protein phosphatase 1, regulatory subunit 92, PRO0758, CVID13, and CLL-associated antigen KW-6. The “Ikaros” protein includes isoforms encoded by the human isoforms listed below: [Table 1] [Table 2]

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

[0089] As used herein, the “Helios” protein refers to a protein that is a member of the Ikaros family of zinc finger proteins. In humans, Helios is encoded by the IKZF2 gene. Helios is also known as Ikaros family zinc finger 2, ANF1A2, ZNF1A2, ZNFN1A2, zinc finger protein, subfamilies 1A and 2, and Ikaros family zinc finger protein 2. As used herein, the Helios protein includes various isoforms, including isoforms 1-5 listed below. [Table 4] [Table 5]

[0090] The above-mentioned isoforms 1, 2, 4, 6, and 7 of "Helios" are from Degron: [Table 6] It includes degron, a part of the protein that plays a role in regulating the rate of proteolysis. The Helios protein also includes isoforms encoded by amino acid sequences Q9UKS7-3, Q9UKS7-5, and Q9UKS7-8.

[0091] As used herein, the "Aiolos" protein is encoded by the IKZF3 gene. The Aiolos protein is also known as Ikaros family zinc finger 3, ZNFN1A3, zinc finger protein, subfamily 1A, 3, Ikaros family zinc finger protein 3, and AIO. The Aiolos protein includes the following human isoforms: [Table 7] [Table 8] [Table 9]

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

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

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

[0095] The "Pegasus" protein as used herein is also known as IKAROS family zinc finger 5, ZNFN1A5, zinc finger protein, subfamily 1A, 5, and Ikaros family zinc finger protein 5. Pegasus is encoded by the IKZF5 gene.

[0096] As used herein, the term “contact” means bringing a given part into contact with a given part in an in vitro or in vivo system. For example, “contact” the IKZF1-4 protein with the compound of formula (I) includes administering the compound of the present invention to an individual or patient (e.g., a human) having the Ikaros, Helios, Aiolos, and Eos proteins, or similarly, introducing the compound of formula (I) into a sample or purified product containing cells containing the Ikaros, Helios, Aiolos, and Eos proteins.

[0097] As used herein, the terms “to treat” and “treatment” refer to any intervention, method, or administration of an active agent performed on a subject for the purpose of improving, reducing, improving, inhibiting, delaying, or suppressing the progression, onset, worsening, or recurrence of symptoms, complications, conditions, or biochemical signs relating to a disease. In contrast, “prevention” or “prevention” refers to administration to an unaffected subject in order to prevent the onset of a disease. “To treat” and “treatment” do not include prevention or prevention.

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

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

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

[0101] As used herein, the phrase “pharmaceutically acceptable carrier” means a pharmaceutically acceptable substance, composition, or vehicle, such as liquid or solid extenders, diluents, excipients, processing aids (e.g., lubricants, magnesium talc, calcium or zinc stearate, or stearic acid), or solvent encapsulants, which are involved in the transport or delivery of a particular compound from one organ or part of the body to another organ, or to another part of the body. Each carrier must be “acceptable” in the sense that it is compatible with other components in the formulation [i.e., including adjuvants, excipients, or vehicles (e.g., diluents, preservatives, extenders, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobial agents, antifungal agents, lubricants, and compounding agents) as determined by the method and form of administration] and is not harmful to the patient.

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

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

[0104] The compound of formula (I) is useful in treating viral infections.

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

[0106] One embodiment provides a method for treating a viral infection in a patient, characterized by administering to the patient a therapeutically effective amount of a compound according to formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0107] In one embodiment, the following structure in a therapeutically effective amount: [ka] A method for treating cancer in a patient is provided, characterized by administering a compound having to the patient.

[0108] One embodiment provides a method for treating a disease or disorder by reducing the levels of four IKZF1-4 proteins, Ikaros, Helios, Aiolos, and Eos, the method characterized by administering to a patient a therapeutically effective amount of a drug that reduces the levels of the Ikaros, Helios, Aiolos, and Eos proteins. In one embodiment, the disease or disorder is cancer. In another embodiment, the disease or disorder is a viral infection. In a further embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

[0110] Embodiment 1 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0111] Embodiment 2 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0112] Embodiment 3 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0113] Embodiment 4 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 50%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 50%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0114] Embodiment 5 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0115] Embodiment 6 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0116] Embodiment 7 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0117] Embodiment 8 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 60%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0118] Embodiment 9 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0119] Embodiment 10 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0120] Embodiment 11 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0121] Embodiment 12 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 70%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0122] Embodiment 13 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0123] Embodiment 14 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0124] Embodiment 15 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0125] Embodiment 16 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 80%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0126] Embodiment 17 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0127] Embodiment 18 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0128] Embodiment 19 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0129] Embodiment 20 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 85%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0130] Embodiment 21 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0131] Embodiment 22 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0132] Embodiment 23 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0133] Embodiment 24 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 60%. In the method included in this embodiment, the disease or disorder is cancer. Also in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0134] Embodiment 25 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 30%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 30%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0135] Embodiment 26 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 40%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 40%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0136] Embodiment 27 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 50%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 50%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0137] Embodiment 28 provides a method for treating a disease or disorder in a patient, characterized by administering to the patient a therapeutically effective amount of a drug that reduces the levels of Ikaros, Helios, Aiolos, and Eos proteins, wherein (i) the Ikaros (IKZF1) protein level is reduced by at least 60%; (ii) the Helios (IKZF2) protein level is reduced by at least 90%; (iii) the Aiolos (IKZF3) protein level is reduced by at least 60%; and (iv) the Eos (IKZF4) protein level is reduced by at least 65%. In the method included in this embodiment, the disease or disorder is cancer. Also included in the method included in this embodiment, the disease or disorder is a viral infection. Furthermore, in the method included in this embodiment, the drug is a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

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

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

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

[0150] In embodiments 1 to 40, the decrease in protein levels of IKZF1 to 4 proteins can be measured using the following assays described herein: (i) IKZF1: Human CD8 + T cell reprogramming assay; (ii) IKZF2: Jurkat cell degradation assay; (iii) IKZF3: Human CD8 + T cell reprogramming assay; and (iv) IKZF4: Human regulatory T cell reprogramming assay.

[0151] The types of cancer that can be treated with compounds of formula (I) include, but are not limited to, brain tumors, skin cancers, bladder cancers, ovarian cancers, breast cancers, stomach cancers, pancreatic cancers, prostate cancers, colon cancers, hematological cancers, lung cancers, and bone cancers. Examples of such cancer types include neuroblastoma, colorectal cancer (e.g., rectal cancer, colon cancer, familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer), esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, urinary tract cancers, melanoma, brain tumors (e.g., glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors), and Hodgkin's cancer. Lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia / lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminomas, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

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

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

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

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

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

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

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

[0159] One embodiment provides a method for treating cancer in a patient, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is gastric cancer such as gastric carcinoma.

[0160] In one embodiment, a method is provided for treating cancer in a patient, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is renal cancer, such as kidney cancer and renal parenchymal cancer.

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

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

[0163] In one embodiment, a method is provided for treating cancer in a patient, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the cancer is a lymphoma, such as Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia, and diffuse large B-cell lymphoma (DLBCL).

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

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

[0166] Compounds of formula (I) and pharmaceutical compositions containing compounds of formula (I) are useful for the treatment or prevention of any disease or condition related to the activity of the IKZF1-4 protein. These include viral and other infections (e.g., skin infections, gastrointestinal infections, urinary tract infections, genitourinary tract infections, systemic infections), and proliferative disorders (e.g., cancer). Any method of administration can be used to deliver the compound or pharmaceutical composition to a patient. In certain embodiments, the compound of formula (I) or pharmaceutical compositions containing compounds of formula (I) are administered orally. In other embodiments, the compound of formula (I) or pharmaceutical compositions containing compounds of formula (I) are administered parenterally.

[0167] In one embodiment, a method is provided for treating a viral infection in a patient, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the viral infection is HIV, hepatitis (A, B, or C), herpesvirus (e.g., VZV, HSV-1, HAV-6, HSV-II, CMV, and Epstein-Barr virus), adenovirus, influenza virus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, arbovirus, and encephalitis virus.

[0168] Compounds of formula (I) can selectively reduce the protein levels of four IKZF1-4 proteins in cells to control Treg differentiation. For example, compounds of formula (I) can be used to selectively reduce the protein levels, activity levels, and / or inhibition of the expression levels of each of the four IKZF1-4 proteins in cells to control Treg differentiation by administering an effective amount of compound (I), or its stereoisomers, tautomers, or salts.

[0169] In one embodiment, the present invention provides a compound of formula (I) and / or a pharmaceutically acceptable salt thereof; and a formulation combining additional therapeutic agents for simultaneous, separate, or sequential use in the treatment and / or prevention of a plurality of diseases or disorders related to the activity of IKZF1-4 proteins. The combined formulation can be used to reduce protein levels, reduce protein activity levels, and / or inhibit the expression levels of the four IKZF1-4 proteins.

[0170] In one embodiment, the compound of formula (I) is administered sequentially before the administration of an immunotumor drug. In another embodiment, the compound of formula (I) is administered simultaneously with the immunotumor drug. In yet another embodiment, the compound of formula (I) is administered sequentially after the administration of an immunotumor drug.

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

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

[0173] In one embodiment, an immunotumor drug is either an (i) agonist of a stimulating receptor (including co-stimulation) or an (ii) antagonist of an inhibitory signal (including co-inhibition) on T cells, both of which result in the amplification of an antigen-specific T cell response (often referred to as an immune checkpoint regulator).

[0174] Certain stimulating and inhibitory molecules belong to the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or coinhibitory 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 is the TNF family of molecules that bind to the homogeneous TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, and RAN. K, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, E Examples include DAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0175] In one embodiment, the T cell response may be stimulated by a combination of a compound of formula (I) of the present invention and one or more of the following: (i) an antagonist of a protein that inhibits T cell activation (e.g., immune checkpoint inhibitors); e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin 1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4; and (ii) an agonist of a protein that stimulates T cell activation; e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H

[0176] Other drugs that may be combined with the compound of formula (I) for cancer treatment may include inhibitory receptor antagonists on NK cells or activating receptor agonists on NK cells. For example, the compound of formula (I) may be combined with a KIR antagonist such as lirilumab.

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

[0178] In another embodiment, the compound of formula (I) may be used with one or more agents that conjugate positive costimulatory receptors, blocking agents that reduce inhibitory receptor-mediated signaling, antagonists, and one or more agents that systemically increase the frequency of antitumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Treg cells (e.g., by the use of anti-CD25 monoclonal antibodies (e.g., daclizumab), or by depletion of anti-CD25 beads in vitro), inhibiting metabolic enzymes such as IDO, or restoring / inhibiting T cell anergy or T cell depletion), and agents that activate innate immunity and / or induce inflammation of the tumor portion.

[0179] In one aspect, the immunotumor agent is a CTLA-4 antagonist, such as an antagonistic CTLA-4 antibody. Suitable CTLA-4 antibodies include, for example, Yervoy (ipilimumab) or tremelimumab.

[0180] In another embodiment, immunotumor agents are PD-1 antagonists, such as antagonistic PD-1 antibodies. Suitable PD-1 antibodies include, for example, Opdivo (nivolumab), Keytruda (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). Another immunotumor agent, although its specificity for PD-1 binding is questionable, is pidilizumab (CT-011). Another approach targeting the PD-1 receptor is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused with the Fc portion of IgG1, referred to as AMP-224.

[0181] In another embodiment, immunotumor agents include PD-L1 antagonists, such as antagonistic PD-L1 antibodies. Suitable PD-L1 antibodies include, for example, MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO207 / 005874), and MSB0010718C (WO2013 / 79174).

[0182] In another embodiment, the immunotumor agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody. Suitable LAG3 antibodies include, for example, BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO09 / 44273).

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

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

[0185] In another embodiment, the immunotumor agent is an IDO antagonist. Suitable IDO antagonists include, for example, INCB-024360 (WO206 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO09 / 1156652, WO11 / 56652, WO12 / 142237).

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

[0187] In another embodiment, the immunotumor agent is an OX40L antagonist, such as an antagonistic OX40 antibody. A suitable OX40L antagonist is, for example, RG-7888 (WO06 / 029879).

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

[0189] In another embodiment, the immunotumor agent is a CD27 agonist, such as an agonistic CD27 antibody. A suitable CD27 antibody is, for example, valrirumab.

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

[0191] Combination therapy is intended to involve the administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, and these therapeutic agents, or at least two therapeutic agents, are administered substantially concurrently. Substantial concurrent administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or a single dosage form of each therapeutic agent. Sequential or substantially concurrent administration of each therapeutic agent can be carried out by any suitable route, including, but is not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membrane tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent in a selected combination may be administered by intravenous injection, while another therapeutic agent in this combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Combination therapy can also be performed by further combining the administration of the above therapeutic agents with other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiation therapy). If this combination therapy also includes non-pharmacological treatments, the non-pharmacological treatments can be performed at any appropriate time, as long as the beneficial effects resulting from the interaction between the therapeutic and non-pharmacological treatments are achieved. For example, in favorable cases, these beneficial effects can be achieved even if the non-pharmacological treatment is temporarily discontinued from the administration of the therapeutic drug, perhaps for several days or weeks.

[0192] For the treatment of diseases, disorders, or conditions related to the IKZF1-4 protein, one or more other pharmaceuticals or therapies (e.g., antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (e.g., IL2 and GM-CSF), and / or tyrosine kinase inhibitors) may be used in combination with the compound of formula (I) as appropriate. The above-mentioned agents may be combined with the compound in a single dosage form, or the agents may be administered simultaneously or sequentially in different dosage forms.

[0193] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonic acids, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (cytoxane®), ifosfamide, melphalan, chlorambucil, pipobromane, triethylene-melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozosin, dacarbazine, and temozolomide.

[0194] In the treatment of melanoma, suitable agents to be used in combination with the compound of formula (I) include dacarbazine (DTIC), which may be used as appropriate with other chemotherapeutic agents (e.g., carmustine (BCNU) and cisplatin); the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; and combinations of cisplatin, vinblastine, and DTIC, temozolomide, or Yervoy®). The compound of formula (I) may also be used in combination with immunotherapy agents (e.g., cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF)) in the treatment of melanoma.

[0195] Furthermore, the compound of formula (I) can be used in combination with vaccine therapy in the treatment of melanoma. Antimelanoma vaccines are similar in some respects to antiviral vaccines used to prevent diseases caused by viruses (e.g., polio, measles, and mumps). Attenuated melanoma cells or a portion of melanoma cells called an antigen may be injected into the patient to stimulate the body's immune system and destroy the melanoma cells.

[0196] Melanomas limited to the arms or legs can also be treated with hyperthermic perfusion therapy using a combination of drugs containing the compound of formula (I). In this treatment protocol, the circulatory system of the affected limb is temporarily isolated from the rest of the body's circulatory system, and high doses of chemotherapeutic agents are injected into the arteries of the affected limb, thereby delivering high doses that could cause serious side effects to the tumor site without exposing the internal organs. Typically, the body fluids are heated to 38.9°C to 40°C during this treatment. Melphalan is the most frequently used drug in this chemotherapy. Another drug called tumor necrosis factor (TNF) may also be used in this therapy.

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

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

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

[0200] Appropriate cytotoxic agents include, for example, epipodophyllotoxin; anti-tumor enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum-based complexes (e.g., cisplatin and carboplatin); bioreaction modifiers; growth inhibitors; anti-hormone therapies; leucovorin; tegafur; and hematopoietic growth factors.

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

[0202] Other anticancer drugs include those that block immune cell migration, such as antagonists targeting chemokine receptors (e.g., CCR2 and CCR4).

[0203] Other anticancer drugs include those that enhance the immune system, such as adjuvants or adoptive T-cell transplants.

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

[0205] The pharmaceutical composition of the present invention may optionally contain at least one signal transduction inhibitor (STI). A "signal transduction inhibitor" is a drug that selectively inhibits one or more important steps in the signal transduction pathway during the normal function of cancer cells, thereby inducing apoptosis. Appropriate STIs include, but are not limited to, (i) bcr / abl kinase inhibitors (e.g., STI 571 (GLEEVEC®)); (ii) epidermal growth factor (EGF) receptor inhibitors (e.g., kinase inhibitors (IRESSA®, SSI-774)) and antibodies (Imclone:C225 [Goldstein et al., Clin. Cancer Res., 1:1311-1318 (1995)] and Abgenix:ABX-EGF); (iii) HER-2 / neu receptor inhibitors (e.g., farnesyltransferase inhibitors (FTIs) (e.g., L-744, 832 [Kohl et al., Nat. Med., 1(8):792-797 (1995)]); (iv) Akt family kinase or Akt pathway inhibitors (e.g., rapamycin (e.g., Sekulic et al., Cancer Res., 60:3504-3513)); (See (200)); (v) Cell cycle kinase inhibitors (e.g., flavopyridol and UCN-O1 (e.g., Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (See (203))); and (vi) Phosphatidylinositol kinase inhibitors (e.g., LY294002 (e.g., Vlahos et al., J. Biol. Chem., 269:5241-5248) (See 1994))) Alternatively, at least one STI and a compound of formula (I) may be included in separate pharmaceutical compositions. In certain embodiments of the present invention, a compound of formula (I) and at least one STI may be administered to a patient simultaneously or sequentially. In other words, at least one compound of formula (I) may be administered first, or at least one STI may be administered first, or a compound of formula (I) and at least one STI may be administered simultaneously. Furthermore, when a compound of formula (I) and / or one or more STIs are used, the compounds may be administered in any order.

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

[0207] Furthermore, the present invention provides a method for treating a patient's chronic viral infection by administering an effective amount of the above-mentioned pharmaceutical composition.

[0208] In certain embodiments of the present invention, the compound of formula (I) and at least one chemotherapeutic agent are administered to the patient simultaneously or sequentially. In other words, the compound of formula (I) may be administered first, or at least one chemotherapeutic agent may be administered first, or the compound of formula (I) and at least one chemotherapeutic agent may be administered simultaneously. Furthermore, if one or more chemotherapeutic agents are used, the compound and the one or more chemotherapeutic agents may be administered in any order. Similarly, any antiviral agent or STI may be administered at any time in comparison to the administration of the compound of formula (I).

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

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

[0211] Appropriate NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stabudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir pivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194); BCH-I0652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C, whose name is β-L-2',3'-dideoxy-5-fluorocytidine); DAPD, ((-)-β-D-2,6-diaminopurine dioxolane); and rhodenosine (FddA). Representative and appropriate NNRTIs include nevirapine (BI-RG-587); delavirdin (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B. Representative and appropriate protease inhibitors include saquinavir (Ro Examples include 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfinavir (AG-1343); amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1549. Other antiviral drugs include hydroxyurea, ribavirin, IL-2, IL-12, pentafusid, and Yissum Project No. 11607.

[0212] Combination therapy is intended to involve the administration of these therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at various different times, and these therapeutic agents, or at least two therapeutic agents, are administered substantially concurrently. Substantial concurrent administration can be achieved, for example, by administering to the patient a single dosage form with a fixed ratio of each therapeutic agent, or a single dosage form of each therapeutic agent. Sequential or substantially concurrent administration of each therapeutic agent can be carried out by any suitable route, including, but is not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal membrane tissue. The therapeutic agents can be administered by the same or different routes. For example, the first therapeutic agent in a selected combination may be administered by intravenous injection, while another therapeutic agent in this combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. Combination therapy can also be performed by further combining the administration of the above therapeutic agents with other biologically active ingredients and non-pharmacological therapies (e.g., surgery or radiation therapy). If this combination therapy also includes non-pharmacological treatments, the non-pharmacological treatments can be performed at any appropriate time, as long as the beneficial effects resulting from the interaction between the therapeutic and non-pharmacological treatments are achieved. For example, in favorable cases, these beneficial effects can be achieved even if the non-pharmacological treatment is temporarily discontinued from the administration of the therapeutic drug, perhaps for several days or weeks.

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

[0214] Compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route, and in a dosage effective for the intended treatment. Compounds of formula (I) and compositions comprising compounds of formula (I) may be administered by any suitable method for any use described herein (e.g., oral administration (e.g., tablets, capsules (including sustained-release or time-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions); sublingual administration; oral administration; parenteral administration (e.g., subcutaneous, intravenous, intramuscular or intrasternal injection, or infusion techniques (e.g., sterile injectable aqueous or non-aqueous or suspension)); nasal administration including administration into the nasal membrane (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 are generally administered with a pharmaceutical carrier selected based on a chosen route of administration and standard pharmaceutical criteria.

[0215] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably formulated in dosage units having a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient in the range of about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. An appropriate daily dose for administration to humans or other mammals may be determined using conventional methods, although this may vary considerably depending on the patient's condition and other factors.

[0216] Any pharmaceutical composition discussed herein may be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration may be manufactured according to any method known in the art of manufacturing pharmaceutical compositions for oral administration. To provide a pharmaceutically acceptable formulation, the pharmaceutical compositions described in the present invention may contain at least one substance selected from sweeteners, flavoring agents, coloring agents, lubricants, antioxidants, and preservatives.

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

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

[0219] Soft gelatin capsules can be manufactured, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oily medium (e.g., peanut oil, liquid paraffin, and olive oil).

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

[0221] An oily suspension may be prepared, for example, by suspending a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof in either a vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or a mineral oil (e.g., liquid paraffin). The oily suspension may also contain at least one thickener (e.g., beeswax, solid paraffin, and cetyl alcohol). To provide an easily administered oily suspension, at least one of the sweeteners already described above and / or at least one flavoring agent may be added to the oily suspension. The oily suspension may further contain at least one preservative (but not limited to the following, for example, an antioxidant (e.g., butylhydroxyanisole and α-tocopherol)).

[0222] Dispersible powders and granules may be prepared, for example, by mixing a compound of formula (I) and / or at least one pharmaceutically acceptable salt thereof with at least one dispersant and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersants, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). Furthermore, dispersible powders and granules may also contain at least one excipient (e.g., sweeteners, flavoring agents, and coloring agents, but are not limited to)

[0223] Emulsions of compounds of formula (I) and / or at least one pharmaceutically acceptable salt thereof may be prepared, for example, as oil-in-water emulsions. The oil phase of an emulsion containing a compound of formula (I) may consist of known components in known ways. The oil phase may be provided by, but is not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin) and mixtures thereof. The oil phase may contain only emulsifiers, or it may contain at least one emulsifier and fats or oils, or mixtures of both fats and oils. Suitable emulsifiers include, but is not limited to, naturally occurring phosphatides (e.g., soy lecithin), esters or partial esters obtained from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxides (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier acting as a stabilizer. Furthermore, it is preferable to include both oils and fats. In addition, the emulsifier, together with or without a stabilizer, forms a so-called emulsifying wax, which, together with the oils and fats, forms a so-called emulsifying ointment base that forms the oily dispersion phase of the cream formulation. The emulsion may also contain sweeteners, flavoring agents, preservatives and / or antioxidants. Suitable emulsifiers and emulsion stabilizers for use in the formulations of 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 well known to those skilled in the art.

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

[0225] Parenteral formulations 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 formulations, or by using other suitable dispersants or wetting and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride solution, tragacanth gum, and / or various buffers. Other adjuvants and administration methods are well and extensively known in the pharmaceutical field. The active ingredient may also be administered by injection as a composition with a suitable carrier (e.g., physiological saline, dextrose, or water), or with cyclodextrin (i.e., Captisol), a solubilizing co-solvent (i.e., propylene glycol), or a solubilizing micelle (i.e., Tween 80).

[0226] Furthermore, sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents (e.g., solutions in 1,3-butanediol). Acceptable vehicles and solvents that may be used include water, Ringer's solution, and sodium chloride isotonic solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid are used in injectable formulations.

[0227] Aseptic injection oil-in-water microemulsions can be produced, for example, by 1) dissolving the compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin); 2) combining the oil phase containing the compound of formula (I) with a mixture of water and glycerol; and 3) processing the combination to form a microemulsion.

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

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

[0230] pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactant (BASF), or other similar polymer delivery matrices), serum proteins (e.g., human serum albumin), buffering substances such as phosphoric acid, electrolytes such as glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or protamine sulfates, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol, and lanolinic tallow). Cyclodextrins (e.g., α-, β-, and γ-cyclodextrins, or chemically modified derivatives (e.g., hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl cyclodextrin, or other solubilized derivatives)) may also be advantageously used to enhance the delivery of compounds of the formulas described herein.

[0231] The pharmaceutically active compounds of the present invention may be processed according to conventional pharmaceutical methods to produce drugs 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, humectants, emulsifiers, buffers, etc.). Tablets and pills may be further produced using enteric coating agents. Such compositions may also contain adjuvants (e.g., humectants, sweeteners, flavorings, and fragrances).

[0232] For therapeutic purposes, the active compounds of the present invention are typically combined with one or more adjuvants appropriate to the intended route of administration. When administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose esters of alkanates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then encapsulated or tableted for convenient administration. Such capsules or tablets may include sustained-release formulations in which the active compound is dispersed in hydroxypropyl methylcellulose.

[0233] The amount of the compound administered to treat a medical condition using the compounds and / or compositions of the present invention, and the dosage schedule, depend on various factors (e.g., age, weight, sex, the patient's medical condition, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound used). Therefore, the dosage schedule may be significantly modified, but it can be determined according to standard methods. The daily dose may be appropriate between about 0.001 and 100 mg / kg body weight, preferably between about 0.0025 and 50 mg / kg body weight, and most preferably between about 0.005 and 10 mg / kg body weight. The daily dose may be administered 1 to 4 times a day. Other dosage schedules include once-weekly and every-other-day cycles.

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

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

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

[0237] General guidance indicates that the daily oral dose of each active ingredient, when used to achieve the desired effect, ranges from approximately 0.001 to approximately 5000 mg / day, preferably approximately 0.01 to approximately 1000 mg / day, and most preferably approximately 0.1 to approximately 250 mg / day. The most preferred dose for constant-rate infusion in intravenous administration is in the range of approximately 0.01 to approximately 10 mg / kg / min. The compound of formula (I) may be administered in a once-daily dose or the total daily dose may be divided into two, three, or four doses.

[0238] This compound is generally administered in a mixture with an appropriate pharmaceutical diluent, excipient, or carrier (collectively referred to herein as a pharmaceutical carrier), which is consistent with conventional pharmaceutical standards, and is appropriately selected for the intended dosage form (e.g., oral tablets, capsules, elixirs, and syrups).

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

[0240] Typical capsules for oral administration contain the compound of formula (I) (250 mg), lactose (75 mg) and magnesium stearate (15 mg). This mixture is sieved through a 60-mesh sieve and filled into No. 1 gelatin capsules.

[0241] Typical injection preparations are produced by adding the compound of formula (I) (250 mg) aseptically to a vial, freeze-drying and sealing it aseptically. When in use, the contents of the vial are mixed with physiological saline (2 mL) to produce an injection preparation.

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

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

[0244] The actual dosage level of the active ingredient in the pharmaceutical composition of formula (I) can be varied so as to be non-toxic to the patient and to include an amount of the active ingredient effective to obtain a therapeutic effect for a particular patient, composition and mode of administration.

[0245] The selected dosage level depends on a variety of factors, including the activity of the compound of formula (I) or its ester, salt, or amide used; the route of administration, time of administration, rate of elimination or metabolism, rate and degree of absorption of the specific compound used; the duration of treatment; other drugs, compounds, and / or substances used in combination with the specific compound used; the age, sex, weight, symptoms, health status, and medical history of the patient being treated; and other factors known in the medical field.

[0246] A physician or veterinarian with common technical knowledge in this field can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, to obtain a therapeutic effect, a physician or veterinarian can start the dosage of the compound of formula (I) used in the pharmaceutical composition at a level lower than the required amount and gradually increase the dosage until the effect is achieved.

[0247] Generally, the appropriate daily dose of the compound of formula (I) is the minimum effective dose of the compound required to obtain a therapeutic effect. Such an effective dose is generally determined by the factors described above. Typically, the dose of the compound of formula (I) to a patient is approximately 0.01 to approximately 50 mg / kg body weight / day, administered orally, intravenously, intraventricularly, and subcutaneously.

[0248] If desired, the effective daily dose of the active compound may be administered in divided doses of 2, 3, 4, 5, 6, or more times at appropriate intervals throughout the day, preferably in a unit dosage form. In one embodiment of the present invention, the medication is administered once daily.

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

[0250] The other therapeutic agents described above, when used in combination with the compound of formula (I), may be used, for example, in the amounts specified in the U.S. Pharmaceutical Handbook (PDR) or in amounts determined by those skilled in the art. In the method of the present invention, the other therapeutic agents may be administered before, simultaneously with, or after the administration of the compound of the present invention.

[0251] (Manufacturing method) The compounds of the present invention can be produced by a number of methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be produced by using the following methods in conjunction with synthetic methods known to those skilled in the art of organic synthesis, or by variations thereof recognized to those skilled in the art. Preferred methods include, but are not limited to, the following. All references cited herein are incorporated herein by reference in their entirety.

[0252] The compounds of the present invention can be prepared using the reactions and techniques described in this section. These reactions are carried out in solvents suitable for the reagents and substances used, and appropriate for the resulting transformations. Furthermore, in the description of the synthesis methods below, all presented reaction conditions (e.g., solvent selection, ambient air, reaction temperature, experimental time, and workup) are selected to be standard conditions for the reaction, readily apparent to those skilled in the art. Those skilled in the field of organic synthesis will understand that functional groups present in various parts of the molecule must be compatible with the presented reagents and reactants. Such limitations on substituents compatible with the reaction conditions are readily apparent to those skilled in the art, and alternative methods should be used if necessary. This may necessitate changes in the order of the synthesis steps or the selection of different reaction processes to obtain the desired compounds of the present invention. It is also recognized that another important consideration in planning any synthetic route in this art is the appropriate selection of protecting groups to be used to protect the reactive functional groups present in the compounds described in the present invention. For experienced experimenters, an authoritative description listing many alternative protecting groups is by Greene and Wuts (Protective Groups In Organic Synthesis, Fourth Edition, Wiley & Sons, 2007). [Examples]

[0253] The following examples illustrate specific embodiments of the present invention and do not limit the scope of the invention. Chemical abbreviations and symbols, as well as scientific abbreviations and symbols, have their general and conventional meanings unless otherwise stated. Additional abbreviations used in the examples and throughout this specification are defined below. Compounds and intermediates of the examples are identified by the example and step in which they are produced (e.g., "1-A" represents step A of Example 1), or by the example only if the compound is the title compound of the example (e.g., "1" represents the title compound of Example 1). Alternative methods for producing intermediates or examples are described as examples. Experienced chemists in the field of synthesis can often devise preferred alternative methods based on one or more considerations (e.g., shorter reaction times, cheaper starting materials, ease of handling and purification, higher yields, catalyst operability, avoidance of toxic reagents, availability with specialized equipment, and reduction in the number of steps). The intention of describing alternative methods is to make the examples of the present invention easier to produce. In some cases, some functional groups in the outlined examples and claims may be substituted by biological equivalence substitutions known to those skilled in the art (e.g., substituting a carboxylic acid group with a tetrazole or phosphate moiety).

[0254] [Table 13]

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

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

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

[0258] Production of Intermediate A2: 3 - ((2 - (4 - Bromo - 2 - fluorophenyl) - 2 - oxoethyl)amino)piperidine - 2,6 - dione

Chemical Structure

[0259] Intermediate A3: Production of 3 - (5 - (4 - bromo - 2 - fluorophenyl) - 2 - oxooxazol - 3(2H) - yl)piperidine 2,6 - dione

Chemical Structure

[0260] Preparation of Intermediate A4: 3-(5-(4-bromo-2-fluorophenyl)-2-oxooxazol-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione

Chemical Structure

[0261] Manufacturing of intermediate A: To a stirred solution of 3-(5-(4-bromo-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (7 g, 14.0 mmol) in anhydrous 1,4-dioxane (70 mL), BISPIN (5.34 g, 21.02 mmol) and potassium acetate (1.651 g, 16.82 mmol) were added at room temperature. The reaction mixture was purged with argon for 10 minutes, and Pd(dppf)Cl2.DCM complex (1.026 g, 1.40 mmol) was added under argon. The resulting mixture was heated at 80°C for 1 hour. The reaction mixture was cooled to room temperature, diluted with ELISA (70 mL), filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 120 g column, 0-70% siRNA / petroleum ether). The isolated product was stirred with diethyl ether for 1 hour, filtered, and vacuum-dried to obtain 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazole-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (4.85 g, 63%) as a white solid. LCMS (Method A): Retention time 2.16 min, [MH] + 545.2; 1H NMR (chloroform-d, 300 MHz) δ 7.5-7.6 (m, 2H), 7.44 (d, 1H, J = 11.7 Hz), 6.90 (d, 1H, J = 2.3 Hz), 5.17 (d, 2H, J = 12.5 Hz), 4.82 (dd, 1H, J = 5.9, 12.7 Hz), 3.56 (t, 2H, J = 8.1 Hz), 2.9-3.1 (m, 1H), 2.7-2.9 (m, 1H), 2.31 (br s, 2H), 1.28 (s, 12H), 0.8-0.9 (m, 2H), -0.07 (s, 9H).

[0262] Example 1 3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione [ka] Preparation of intermediate 1A: 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazole-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione [ka] 6-chloro-3,4-dimethylpyridine-2-amine (1.24 g, 7.91 mmol), 3-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazole-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Int-A, 3.93 g, 7.19 mmol), cesium carbonate (3.51 g, 10.79 mmol), dioxane (32 mL), and water (80 μL) were added to a vial at room temperature. The reaction mixture was purged with argon for 10 minutes, and CatacXium Pd G3 (0.157 g, 0.22 mmol) was added. The reaction mixture was heated at 100°C for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a Celite pad. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 80 g column, 0-4% MeOH / DCM), and the isolated product was recrystallized from ethyl acetate to obtain 3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (2.10 g, 54%) as a white solid. LCMS (Method A): Retention time 1.86 min, [M+H] + 541.3; 1 H NMR (chloroform-d, 300 MHz) δ 7.76 (br d, 2H, J = 10.6 Hz), 7.6-7.7 (m, 1H), 6.9-7.0 (m, 2H), 5.2-5.3 (m, 2H), 4.89 (dd, 1H, J = 6.0, 12.5 Hz), 4.46 (br s, 2H), 3.6-3.7 (m, 2H), 3.0-3.1 (m, 1H), 2.8-3.0 (m, 1H), 2.3-2.5 (m, 2H), 2.30 (s, 3H), 2.10 (s, 3H), 0.9-1.0 (m, 2H), 0.00 (s, 9H).

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

[0264] Example 1: To a stirred solution of 3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-1-(hydroxymethyl)piperidine-2,6-dione (1.385 g, 3.14 mmol) in anhydrous DME (21 mL), N,N'-dimethylethylenediamine (1.692 mL, 15.7 mmol) was added at 0°C under a nitrogen atmosphere. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The reaction mixture was cooled to 0°C, acidified with acetic acid (1.8 mL, 31.4 mmol), and concentrated under reduced pressure (bath temperature <30°C). The residue was purified by flash chromatography (SiO2, 40 g column, 0-6% MeOH / DCM), and the isolated product was recrystallized from ethyl ether to obtain 3-(5-(4-(6-amino-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)piperidine-2,6-dione (0.48 g, 37%) as a white solid. LCMS (Method C): Retention time 1.33 min, [M+H] + 411.15; 1 H NMR (DMSO-d6, 400 MHz) δ 11.13 (br s, 1H), 7.9-8.0 (m, 2H), 7.6-7.6 (m, 2H), 7.11 (s, 1H), 5.74 (s, 2H), 5.07 (dd, 1H, J = 5.3, 13.0 Hz), 2.8-2.9 (m, 1H), 2.6-2.7 (m, 2H), 2.23 (s, 3H), 2.1-2.2 (m, 1H), 2.02 (s, 3H).

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

[0266] Preparation of intermediate 2B: tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] In a 25 mL round-bottom flask containing 230 mg, 0.77 mmol of 2-bromo-1-(4-bromo-2-fluorophenyl)ethane-1-one and 208 mg, 0.86 mmol of tert-butyl 4,5-diamino-5-oxopentanoate-2,2,3,3,4-D5 hydrochloride (208 mg, 0.86 mmol) in anhydrous DMF (2.4 mL), NaI (128 mg, 0.86 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes, after which DIPEA was added dropwise at 0°C (0.35 mL, 1.94 mmol). The reaction mixture was stirred at 0°C for 3 hours. After 3 hours, CDI (315 mg, 1.94 mmol) was added at 0°C, followed by the dropwise addition of TEA (0.54 mL, 3.9 mmol). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with Depositphotos (7 mL) and H₂O (5 mL) and stirred at room temperature for 2 minutes. The organic layer was separated and back-extracted with Depositphotos (1 × 3 mL) water. The organic layers were combined, concentrated to dry, and purified by ISCO (24 g silica gel) eluting at 100% Hex ~ 90% Depositphotos / Hex; the product eluted at 40 ~ 45% Depositphotos / Hex. The fractions containing the product were combined, concentrated, and allowed to dry overnight to obtain tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 as an orange solid (79 mg, yield 23%). LC-MS (Method C): Retention time 1.006 min, [M+H-Boc] + 391.8 / 393.7 (bromide isotope).

[0267] Preparation of intermediate 2C: tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] A stirred solution of tert-butyl 5-amino-4-(5-(4-bromo-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 (127 mg, 0.29 mmol) / 1,4-dioxane (2.5 ml) in a 10 mL reaction vial was degassed with N2 for 5 minutes, and then bis(pinacolato)diborone (108 mg, 0.43 mmol) and potassium acetate (56 mg, 0.57 mmol) were added. The solution was purged under a nitrogen stream for 5 minutes, and then 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (21 mg, 0.029 mmol) was added. The solution was purged under nitrogen for another 5 minutes. The reaction mixture was heated at 80°C for 16 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The mother liquor was concentrated to dryness to obtain a black oily substance. The crude residue was purified on ISCO (24 g silica gel) and eluted with 100% Hex to 80% ethyl acetate / hexolate. The product was eluted with 70% ethyl acetate / hexolate. The fractions containing the product were combined, concentrated to dryness, and dried overnight under vacuum to obtain tert-butyl 5-amino-4-(5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 as a brown foam (98 mg, 69% yield). LCMS (Method C): Retention time 1.056 min, [M+H-Boc] + 439.8.

[0268] Preparation of intermediate 2D: tert-butyl 5-amino-4-(5-(4-(6-(bis(tert-butoxycarbonyl)amino)-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,3,4-D5 [ka] To a solution of tert-butyl 5-amino-4-(5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,4-D5 (98 mg, 0.2 mmol) and tert-butyl (tert-butoxycarbonyl)(6-chloro-3,4-dimethylpyridine-2-yl)carbamate (67.2 mg, 0.19 mmol), K3PO4 (120 mg, 0.57 mmol) and XPhos Pd G2 (14.8 mg, 0.019 mmol) were added. The reaction mixture was degassed under N2 for 5 minutes. The reaction mixture was heated at 90°C for 3 hours. After 3 hours, the reaction mixture was cooled to 0°C. The reaction was quenched by adding H2O (1.8 mL). The reaction mixture was extracted with ethyl acetate, the organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness to obtain a black oily substance. The crude product was purified over ISCO (12 g silica gel) and eluted with 100% Hex to 90% ethyl acetate / Hex. The product was eluted with 50 to 65% ethyl acetate / Hex. The products were combined, concentrated to dryness, and vacuum-dried overnight to obtain tert-butyl 5-amino-4-(5-(4-(6-(bis(tert-butoxycarbonyl)amino)-4,5-dimethylpyridine-2-yl)-2-fluorophenyl)-2-oxoxazole-3(2H)-yl)-5-oxopentanoate-2,2,3,4-D5 as a yellow foam (90 mg, 69% yield). (Method C): Retention time 1.106 min, [M+H] + 690.1.

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

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

[0271] Preparation of intermediate 3A: tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate [ka] To a stirred suspension of 2-bromo-1-phenylethane-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), sodium iodide (181 mg, 1.21 mmol) was added under argon at 0°C. The reaction mixture was stirred at the same temperature for 5 minutes. DIPEA (351 μL, 2.01 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was warmed to room temperature and stirred overnight. This reaction was quenched by adding a 10% sodium bisulfite solution. The mixture was extracted with DCM (3 × 10 mL). The organic phases were combined, washed with water and saline solution, dried on anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl 5-amino-5-oxo-4-((2-oxo-2-phenylethyl)amino)pentanoate (322 mg, crude). LC-MS (Method A): Retention time 1.215 min, [M+H] + 321.1.

[0272] Preparation of intermediate 3B: tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazole-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), CDI (407 mg, 2.5 mmol) and triethylamine (420 μL, 3.0 mmol) were added under argon at 0°C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with ice water. The reaction mixture was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, washed with water and saline, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (SiO2, 24 g column, 0-100% ethyl acetate / petroleum ether) to obtain tert-butyl 5-amino-5-oxo-4-(2-oxo-5-phenyloxazole-3(2H)-yl)pentanoate (155 mg, 44%). LC-MS (Method A): Retention time 1.33 min, [M+Na] + 369.2; 1 H NMR (DMSO-d6, 300 MHz) δ 7.75 (s, 2H), 7.5-7.6 (m, 2H), 7.42 (t, 2H, J = 7.5 Hz), 7.3-7.4 (m, 2H), 4.50 (dd, 1H, J = 4.3, 10.1 Hz), 2.2-2.3 (m, 3H), 2.0-2.1 (m, 1H), 1.38 (s, 9H).

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

[0274] Analytical LC-MS 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 minutes; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column-Kinetex XB-C18 (75 x 3 mm - 2.6 μm); Mobile phase A: 10 mM NH4COOH / water; Mobile phase B: Acetonitrile; Gradient: 20% B to 100% B over 4.6 minutes, Flow rate: 1.0 mL / min.

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

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

[0277] Analytical LCMS conditions Method A: ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm; Mobile phase A: 95:5 water:acetonitrile (containing 2.5 mM NH4OAc); Mobile phase B: 5:95 water:acetonitrile (containing 2.5 mM NH4OAc); Temperature: 40°C; Gradient: 20% B to 100% B over 2 minutes; Flow rate: 0.7 mL / min; Detection: MS and UV (220 nm). Method B: Column-Kinetex XB-C18 (75 x 3 mm - 2.6 μm); Mobile phase A: 10 mM NH4COOH / water; Mobile phase B: Acetonitrile; Gradient: 20% B to 100% B over 4.6 minutes; Flow rate: 1.0 mL / min.

[0278] Biological assays The pharmacological properties of the compounds of the present invention can be confirmed by numerous biological assays. The following biological assays were performed using the compounds of the present invention.

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

[0280] Table A-1 shows the observed maximum degradation levels of IKZF1, IKZF2, and IKZF3 proteins measured in the Jurkat cytodegradation assay. The results in Table A-1 have been rounded to two decimal places. In the Jurkat cytodegradation assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that there is no detectable degradation of the protein by the test compound. In the tests reported in Table A-1, the compound of Example 1 was observed to degrade more than 90% of the IKZF2 (Helios) protein. In contrast, comparative compounds A and B were observed to degrade less than 30% of the IKZF2 protein. [Table 15]

[0281] Human regulatory T cell degradation assay Cryopreserved human regulatory T cells were thawed in RPMI + 10% FBS + 20 ng / mL IL-2. After centrifugation at 1200 rpm for 5 minutes, the cells were resuspended in RPMI + 10% FBS + 20 ng / mL and allowed to stand at 37°C in 5% CO2 for 3 hours. Subsequently, the cells were seeded at a density of 40,000 cells / well in 40 pL of RPMI + 10% FBS + 20 ng / mL human IL-2 in a 384-well cell culture plate, and the target compound was added using acoustic dispensing technology (ECHO 555). The cell culture was incubated at 37°C in 5% CO2 for 20 hours. To facilitate analysis, the cell culture was centrifuged at 1200 rpm for 5 minutes, and the supernatant was discarded using an EL406 plate washer. After washing the cell pellet three times with 70 pL of PBS, the cell pellet was resuspended in 50 μL of near-infrared survival staining solution (Life Technologies, Cat# L34975) and incubated on ice for 30 minutes in the dark. The cells were washed three times with 70 pL of PBS + 0.5% BSA using an EL406 plate washer. After shaking the plate to detach the cell pellet, the cells were resuspended in 50 μL of fixation buffer (eBioScience FoxP3 buffer set 00-5523-00) and allowed to stand at room temperature for 60 minutes. After centrifugation and removal of the supernatant, the cells were permeabilized in permeabilization buffer (50 μL, eBioScience FoxP3 buffer set 00-5523-00) for 10 minutes at room temperature. After permeabilization, the cells were centrifuged, and the supernatant was replaced with fluorescently labeled antibody against Helios (30 μL) / 1x permeabilization buffer (Helios APC [Biolegend, Cat# 137222, 1:50]). The cells were incubated at room temperature for 1 hour, shielded from light. Then, before centrifugation and discarding the supernatant, 1x permeabilization buffer (30 μL) was added. The stained cells were resuspended in 30 μL of flow cytometry staining buffer (PBS + 0.5% BSA) and analyzed using an Intellicyt Ique Plus flow cytometer. [Table 16] Table B-1 shows the observed maximum degradation levels of IKZF1 and IKZF2 proteins measured in the human regulatory T cell degradation assay. The results in Table B-1 have been rounded to two decimal places. In the human T regulatory assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that there is no detectable degradation of the protein by the test compound. In the tests reported in Table B-1, the compound in Example 1 was observed to degrade the IKZF1 (Ikaros) protein by 55%. [Table 17]

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

[0283] Fresh or frozen Flowsort CD4 + CD127 low CD25 + Treg cells were cultured at 25,000–50,000 cells / well in RPMI1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) in 96-well round-bottom plates. Cells were stimulated with Treg Xpander beads (Thermo Fisher) with a cell-to-bead ratio of 1:4 in the presence of 500 U / mL recombinant human IL-2 (Proleukin). The compounds were added in escalating doses, and the cells were incubated at 37°C, 5% CO2 for 12–13 days. Recombinant human IL-2 and the compounds were replenished every 2–3 days during the culture period. On day 12 or 13, cells were stimulated again with phorbol 12-myristate 13-acetate (PMA) and ionomycin, and stained and analyzed by flow cytometry.

[0284] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher), incubated for 10 minutes in Human Tru-stain Fc block (Biolegend), then incubated with eFluor780 viability dye (Thermo Fisher) and a surface marker antibody cocktail at 4°C for 30 minutes. Subsequently, cells were fixed and permeabilized by incubation at 4°C for 30 minutes with FoxP3 transcription factor staining buffer (Thermo Fisher) according to the kit manufacturer's instructions. The cells were then washed twice with the Perm / Wash buffer provided in the kit, as per the manufacturer's instructions, and incubated overnight at 4°C with an intracellular antibody cocktail containing antibodies specific to the transcription factors shown in Table C. The cells were washed twice with Perm / Wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher) to obtain the sample. Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stain controls for each fluorescent dye were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). The data were analyzed using FlowJo version 10 and GraphPad Prism Software. [Table 18] [Table 19]

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

[0286] Human CD8 + T-cell degradation assay Cryopreserved healthy donor human peripheral blood mononuclear cells (PBMCs; obtained from Stemcell Technologies or Blood Works Northwest) from two healthy donors were thawed and seeded at 500,000 cells / well in RPMI1640 medium (Gibco) supplemented with 10% FBS, Pen / Strep (Gibco), MEM-NEAA (Gibco), and sodium pyruvate (Gibco) in 96-well round-bottom plates. The cells were treated with gradually increasing doses of the compound at 37°C in 5% CO2 for 24 hours and then analyzed by flow cytometry.

[0287] For flow cytometry staining, cells were washed twice with flow cytometry staining buffer (Thermo Fisher), incubated for 10 minutes on Human Tru-stain Fc block (Biolegend), then a surface marker antibody cocktail containing eFluor780 viability dye (Thermo Fisher), LD-eFluor780, CD3-BUV-395, CD4-BUV805, CD8-FITC, CD25-BV605, FoxP3-BV421, HELIOS-PE-Cy7, EOS-PE, IKAROS-PECF594, and AIOLOS-AF647 was added, and incubated at 4°C for 30 minutes. Subsequently, cells were fixed and permeabilized by incubation at 4°C for 30 minutes with permeabilization buffer (eBioscience FoxP3 buffer set 00-5523-00) according to the kit manufacturer's instructions. Cells were washed twice with the Perm / Wash buffer provided in the kit, according to the manufacturer's instructions, and incubated overnight at 4°C with an intracellular antibody cocktail containing antibodies specific to the transcription factors shown in Table C. The cells were washed twice again with Perm / Wash buffer and resuspended in flow cytometry staining buffer (Thermo Fisher) to obtain samples. Sample acquisition and analysis were performed using a BD LSRFortessa (BD Biosciences) flow cytometer. Single-stain controls for each fluorescent dye were prepared using UltraComp eBead Compensation Beads (Thermo Fisher). Data were analyzed using FlowJo version 10 and GraphPad Prism Software.

[0288] [Table 21] [Table 22]

[0289] Table D-1 shows human CD8 +The observed maximum degradation levels of IKZF1 and IKZF3 proteins measured in the T-cell reprogramming assay are shown. The results in Table D-1 have been rounded to two decimal places. (Human CD8) + In the T cell reprogramming assay, a value of 100% indicates that no detectable protein remains or that the protein has been completely degraded, while a value of 0% indicates that there is no detectable degradation of the protein by the test compound. [Table 23]

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

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

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, each R is independently either H or D) A compound thereof, or its stereoisomer, tautomer, or salt.

2. Structure below: 【Chemistry 2】 A compound according to claim 1, or a stereoisomer, tautomer, or salt thereof, having the same properties.

3. The compound according to claim 1, or its stereoisomer, tautomer, or salt, wherein each R is independently H.

4. The compound according to claim 1, or its stereoisomer or tautomer, wherein each R is independently H.

5. A compound according to claim 1, or a salt of a stereoisomer or tautomer thereof, wherein each R is H.

6. A pharmaceutically acceptable salt of the compound according to claim 1, or a stereoisomer or tautomer thereof, wherein each R is H.

7. The compound according to claim 1, or its stereoisomer, tautomer, or salt, wherein each R is independently D.

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

9. A compound according to claim 1, or a salt of a stereoisomer or tautomer thereof, wherein each R is D.

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

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

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

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

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

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

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

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

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

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

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

21. The use according to claim 18 in combination with a second agent, wherein the second agent is selected from a PD1 / PD-L1 axis antagonist, a CTLA4 antagonist, a chemotherapeutic agent, radiation, or an antitumor vaccine.

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

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