Beneficial treatments for disorders mediated by IKAROS or AIOLOS

Abstract

New treatments for Ikaros- and / or Aiolos-mediated disorders are provided, comprising administering an effective amount of a cereblon-binding agent that degrades Ikaros or Aiolos via the ubiquitin-proteasome pathway.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the interests of U.S. Provisional Patent Application No. 63 / 063,011 filed 7 August 2020, U.S. Provisional Patent Application No. 63 / 173,160 filed 9 April 2021, and U.S. Provisional Patent Application No. 63 / 212,463 filed 18 June 2021. These applications in whole constitute part of this specification by reference for all purposes.

[0002] The present invention provides therapeutic compositions, combinations, and uses thereof for treating disorders mediated by the transcription proteins Ikaros (IKZF1) and / or Aiolos (IKZF3) via the degradation of these proteins through the ubiquitin-proteasome pathway. [Background technology]

[0003] The Ikaros family consists of a series of zinc finger protein transcription factors crucial for certain physiological processes, particularly hematopoietic and lymphocyte development (see Non-Patent Literature 1). Ikaros (IKZF1) was first discovered in 1992 (see Non-Patent Literature 2), and over the following 20 years, four additional homologs—Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5)—have been identified (see Non-Patent Literature 3). The distribution of the various members of the Ikaros protein family in the body is highly variable.

[0004] Ikaros, Helios, and Aiolos are primarily found in lymphoid cells and their corresponding progenitor cells, with Ikaros being additionally detected in the brain, and Ikaros and Helios being detected in erythroid cells. Eos and Pegasus are more widespread and are found in skeletal muscle, liver, brain, and heart (see Non-Patent Documents 4, 5, and 6).

[0005] Ikaros is important for proper lymphocyte development. Deletion of the exons encoding the first three N-terminal zinc fingers results in mice lacking T cells, B cells, natural killer (NK) cells, and their precursor cells. Genetic alterations in Ikaros are associated with poor outcomes in the treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells and lymphoma cells.

[0006] Multiple myeloma (MM) is a plasma cell malignancy typically characterized by abnormal production of monoclonal immunoglobulins, bone marrow lesions, renal dysfunction, immune dysfunction, and skeletal damage. In the United States, MM accounts for nearly 1.8% of all new cancers. While outcomes for subjects with MM have improved considerably over the past few decades, the current projected 5-year relative survival rate is 53.9%, and it remains incurable. With no available treatments to cure it, almost all patients eventually progress.

[0007] Historically, the management of myeloma (MM) involved chemotherapy with corticosteroids and alkylating agents. In the 1980s, treatment with autologous stem cell transplantation advanced further. In the 1990s, the discovery of the efficacy of thalidomide (a first-in-class immunomodulatory imid, IMiD®) in myeloma significantly altered treatment regimens and improved patient outcomes. Subsequent approved IMiDs, lenalidomide and pomalidomide, are now widely used in the treatment of MM, similar to the first-in-class drug thalidomide. This class of drugs binds to the E3 ligase substrate-recognizing adapter protein cereblon (CRBN), promoting the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in antitumor effects, effects on the tumor microenvironment, and immunomodulation that leads to T-cell priming and antitumor activity. Many patients with MM are treated with multiple regimens, including one of these IMiDs. Currently, these drugs, in combination with drugs including dexamethasone, anti-differentiation antigen group 38 (CD38) antibodies, and proteasome inhibitors such as bortezomib, are considered standard treatments for multimyeloma (MM) in many therapies. While these drugs have successfully extended progression-free survival in patients with MM, patients generally relapse, and progression-free survival after each relapse is shorter. Recent studies using the novel drugs velantamab and selinexol have shown improved outcomes in multiclass refractory myeloma, which has recently led to accelerated FDA approval. However, the low response rate (26%–31%) and short progression-free survival (3.7–4.9 months) highlight the continued unmet medical needs in these patients.

[0008] Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies derived from T cells, B cells, or NK cells. NHL includes diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, follicular lymphoma, cutaneous T-cell lymphoma, lymphoplasmacytic lymphoma, marginal zone B-cell lymphoma, MALT lymphoma, and small cell lymphocytic lymphoma. B-cell NHL is dominant, while T-cell lymphoma is less common. Among newly diagnosed patients with rapidly progressing NHL, chemotherapy regimens including cyclophosphamide, vincristine, prednisone, and daunorubicin (known as CHOP) remain the primary treatment. In rapidly progressive B-cell lymphoma, rituximab and CHOP combination therapy is the primary treatment for newly diagnosed patients. Some patients, particularly those with T-cell NHL, undergo autologous stem cell rescue after initial chemotherapy. In the relapsed / refractory population, various targeted therapies have been developed, improving treatment options across multiple NHL subtypes, although these treatments tend not to be curative. Furthermore, NHL subtypes are biologically heterogeneous, limiting the development of therapies across a wide range of indications.

[0009] In patients newly diagnosed with rapidly progressive lymphoma, initial treatment is often aggressive and administered with the aim of curative treatment. Aside from the addition of rituximab to CHOP in B-cell NHL and brentuximab to CHOP in anaplastic large cell lymphoma (ALCL), other novel targeted therapies have not shown improvements in survival rates, and therefore, there are no other approved drugs for the treatment of treatment-naive patients. Recent advances in the treatment of relapsed NHL include Bruton's tyrosine kinase (BTK) inhibitors, particularly for mantle cell lymphoma (MCL) and slower forms of NHL; chimeric antigen receptor T-cell (CAR-T) therapies approved for diffuse large B-cell lymphoma (DBLCL) and MCL; and novel antibody-drug conjugates such as polatuzumab, verantamab, or tafacitamab, approved for DLBCL. Recently approved drugs for T-cell NHL include romidepsin, bellinostat, and brentuximab. In relation to the NHL population studied in this protocol, lenalidomide has demonstrated clinical activity in both B-cell and T-cell NHL, including MCL, DLBCL, and peripheral T-cell lymphoma (PTCL). Lenalidomide was studied in the relapsed / refractory (r / r) MCL population and was approved by the U.S. Food and Drug Administration (FDA) in June 2013, following the results of the Phase II EMERGE trial, which investigated the efficacy and safety of lenalidomide in r / r subjects with MCL after bortezomib administration (overall response rate [ORR] 28%, median duration of response [DOR] 16.6 months). Lenalidomide also shows activity in DLBCL and PTCL. Lenalidomide and other novel targeted therapies have moderate to good response rates, but the duration of response tends to be short in most NHL subtypes. When patients relapse after one or two treatment regimens, the median duration of response tends to be lower and depends on whether the patient has sufficient performance status and organ function to tolerate these treatments. Therefore, there remains an unmet medical need in patients with r / rNHL.

[0010] Proteolysis is a highly regulated and essential process that maintains cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins are achieved via the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biosynthesis, the cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, nerve and muscle degradation, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, responses to stress and extracellular modulators, ribosome biosynthesis, and viral infection. Covalent attachment of numerous ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases marks proteins for proteasome degradation, where they are digested into smaller peptides, ultimately becoming constituent amino acids that act as building blocks for new proteins. Deficiencies in proteasome degradation are associated with a variety of clinical disorders, particularly Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0011] Patent applications describing a specific protein-degrading agent include Patent Document 1, Patent Document 2, Patent Document 3, and Patent Document 4.

[0012] Patent applications filed by C4 Therapeutics, Inc. describing E3 ubiquitin ligases and compounds capable of binding to target proteins for degradation include: Patent Document 5, titled "Isoindrinone and Indoazole Compounds for EGFR Degradation"; Patent Document 6, titled "Difunctional Compounds"; Patent Document 7, titled "Difunctional Compounds for Cancer Therapy"; Patent Document 1, titled "Tricyclic Degradation Products of Ikaros and Aiolos"; Patent Document 8, titled "Heterocyclic Compounds for Medical Treatment"; Patent Document 9, titled "Target Protein Degradation"; Patent Document 10, titled "Spirocyclic Compounds"; Patent Document 11, titled "Compounds for the Degradation of BRD9 or MTH1"; and Patent Document 11, titled "Cerebron Binding Agent for Ikaros Degradation". Patent document 12; Patent document 13 titled "Spiro-ring compound"; Patent document 14 titled "Degrader and degron for targeted protein degradation"; Patent document 15 titled "N / O-bonded degron and deglonimer for protein degradation"; Patent document 16 titled "Amine-bonded C3-glutarimide deglonimer for targeted protein degradation"; Patent document 17 titled "Heterocyclic deglonimer for targeted protein degradation"; Patent document 18 titled "Spiro-ring deglonimer for targeted protein degradation"; Patent document 19 titled "C3-carbon-bonded glutarimide deglonimer for targeted protein degradation"; and Patent document 20 titled "Bromodomain targeting a deglonimer for targeted protein degradation".

[0013] The object of the present invention is to provide novel compositions, combinations, formulations and uses thereof of substances for the treatment of medical disorders mediated by Ikaros or Aiolos, as well as processes for preparing compounds therefor. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] International Publication No. 2020 / 210630 [Patent Document 2] International Publication No. 2020 / 006262 [Patent Document 3] International Publication No. 2020 / 010227 [Patent Document 4] International Publication No. 2020 / 010177 [Patent Document 5] International Publication No. 2021 / 127561 [Patent Document 6] International Publication No. 2021 / 086785 [Patent Document 7] International Publication No. 2021 / 083949 [Patent Document 8] International Publication No. 2020 / 181232 [Patent Document 9] International Publication No. 2020 / 132561 [Patent Document 10] International Publication No. 2019 / 236483 [Patent Document 11] International Publication No. 2020 / 051235 [Patent Document 12] International Publication No. 2019 / 191112 [Patent Document 13] International Publication No. 2019 / 204354 [Patent Document 14] International Publication No. 2019 / 099868 [Patent Document 15] International Publication No. 2018 / 237026 [Patent Document 16] International Publication No. 2017 / 197051 [Patent Document 17] International Publication No. 2017 / 197055 [Patent Document 18] International Publication No. 2017 / 197036 [Patent Document 19] International Publication No. 2017 / 197046 [Patent Document 20] International Publication No. 2017 / 197056 [Non-patent literature]

[0015] [Non-Patent Document 1] Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521 [Non-Patent Document 2] Georgopoulos, K. et al. "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment" Science, 1992, 258:802-812 [Non-Patent Document 3] John, LB, and Ward, AC "The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity" Mol Immunol, 2011, 48:1272-1278 [Non-Patent Document 4] Perdomo, J. et al. "Eos and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities: J Biol Chem, 2000, 275:38347-38354 [Non-Patent Document 5] Schmitt, C. et al. "Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation" Apoptosis, 2002, 7:277-284 [Non-Patent Document 6] Yoshida, T. and Georgopoulos, K. "Ikaros fingers on lymphocyte differentiation" Int J Hematol, 2014, 100:220-229 [Overview of the project]

[0016] Compound 1 is a low-molecular-weight anticancer agent that binds to cereblon E3 ligase with high affinity, thereby creating a new surface on cereblon that interacts with IKZF1 and IKZF3 (see Patent Document 1). As a result, IKZF1 and IKZF3 are efficiently ubiquitinated by cereblon E3 ligase and degraded by the proteasome. The high cereblon-binding affinity of Compound 1 enables rapid, deep, and sustained degradation of IKZF1 / 3, resulting in potent activity in cancer cells, including, but not limited to, hematopoietic malignancies such as multiple myeloma and multiple non-Hodgkin lymphoma. [ka]

[0017] Compound 1 and other compounds described herein have now been found to be highly effective therapeutic regimens for treating disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), and can be administered once or twice daily in low-dose regimens, with optional drug-free periods. For example, anticancer therapy has been found to be effective in patients using one of the compounds described herein at doses of approximately 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, or even 100 μg, 75 μg, 50 μg, 45 μg, 40 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, or 1 μg or less, once daily (QD) or twice daily (BID). In certain embodiments, the patient is an adult (typically a human being weighing at least 100 pounds or more, sometimes 125 pounds or 150 pounds (e.g., 70 kg or more), and typically at least 18 years of age). In alternative embodiments, the patient is a child (may be under £100, £125, or £150, and typically under 18 years of age). Compound 1 has not only been found to be effective as a low-dose therapy, but can also be delivered with a drug-free interval, which is advantageous for the patient. For example, Compound 1 can be delivered once or twice daily for 21 days, followed by a 7-day drug-free interval. Alternative dosing regimens are also useful, for example, but are not limited to, those involving increasing or decreasing the drug-free interval by 1, 2, 3, 4, 5, 6, or 7 days.

[0018] In certain embodiments, compound 1 or another compound described herein modulates the patient's immune activity. For example, compound 1 has been found to activate the proliferation of cytotoxic T cells, which may be essential for anticancer therapy.

[0019] Compound 1 or other compounds described herein may be administered daily or intermittently with dexamethasone in non-limiting embodiments. In certain embodiments, dexamethasone or other corticosteroids, or other immunosuppressants or anti-inflammatory agents are administered daily without a 28-day rest period. In other embodiments, dexamethasone or other corticosteroids, or other immunosuppressants or anti-inflammatory agents are administered with a rest period that may be the same as or different from the rest period of Compound 1 or other compounds described herein.

[0020] In one embodiment of the present invention, the low-dose Ikaros(IKZF1) and / or Aiolos(IKZF3) degradation compound is compound 1 or a pharmaceutically acceptable salt thereof.

[0021] Compound 1 has a high binding affinity to cereblon (dissociation constant K d Compound 1 promotes over 75% degradation of steady-state IKZF1 in multiple myeloma cells within 1.5 hours at 0.3 nM. The high binding affinity and degradation catalytic activity of Compound 1 demonstrates 96% maximum growth inhibition in previously untreated NCIH929 multiple myeloma cell lines (mean maximum half-percentage inhibitory concentration IC50 = 0.071 nM). 50 ), as well as NCIH929 cells that became resistant to both lenalidomide and pomalidomide (70% maximum growth inhibition, average IC2.3nM). 50 It enables potent cell growth inhibition in both of these areas.

[0022] The compounds described herein can be used to treat cancer cells that are resistant, refractory, or unresponsive to standard treatments for cancer mediated by IKZF1 or IKZF3, including IMiD containing pomalidomide, or any of those described in the background art or detailed description.

[0023] As shown in Example 12, Compound 1 demonstrated strong anticancer activity in a panel of multiple myeloma cell lines (8 of the 12 lines were responsive, and the average IC50 was 0.3 nM among the responsive lines). 50 The anticancer activity of compound 1 was observed in mantle cell lymphoma (MCL) (of the 6 strains tested, 4 strains showed a responsive mean IC of 13 nM between responsive strains). 50 (In the case of diffuse large B-cell lymphoma (DLBCL), 6 out of 11 germinal center B-cell-like DLBCL strains and 3 out of 6 activated B-cell DLBCL strains were responsive, and the mean IC was found among the responsive strains.) 50 (The values ​​were 12 nM and 1.6 nM), Anaplastic Large Cell Lymphoma (ALCL) (4 out of 6 cell lines were responsive, and the average IC was between the responsive lines) 50 (The saturation level was 1.7 nM), and cutaneous T-cell lymphoma (CTCL) (3 out of 4 cell lines tested were responsive, and the mean IC was between the responsive lines). 50 This was also demonstrated in several cell line models of various non-Hodgkin lymphoma subtypes, including those with a concentration of 30 nM. In mouse xenograft tumor models, compound 1 demonstrated dose-dependent efficacy from 3 μg / kg / day to 100 μg / kg / day (see Example 13). In several tumor xenografts, daily administration of compound 1 at doses of 30 μg / kg / day to 100 μg / kg / day resulted in sustained tumor regression. As shown in Figures 45A, 45B, 45C, 52 and others, compound 1 is more than 100 times potent than pomalidomide in various cancer assays.

[0024] In a mouse xenograft model, compound 1 maintained measurable plasma and tumor concentrations for a longer period than CC-92480 (currently in human clinical trials by Celgene, a subsidiary of Bristol Myers Squibb), despite being administered at a 10-fold lower dose. Furthermore, it took significantly longer for IKZF3 levels to return to normal after treatment with compound 1 compared to pomalidomide or CC-92480. For example, in the NCI-H929 tumor model, it took over 48 hours for IKZF3 levels to reach 50% of pre-treatment levels after administration of compound 1, compared to both CC-92480 (10-fold higher dose) and pomalidomide (30-fold higher dose), where IKZF3 reached pre-treatment levels within 48 hours of treatment.

[0025] As a result of the remarkable efficacy of Compound 1 and the other compounds described herein, novel and advantageous therapeutic methods for disorders mediated by Ikaros(IKZF1) and / or Aiolos(IKZF3) have been discovered. In non-limiting embodiments of the present invention, the Ikaros(IKZF1) and / or Aiolos(IKZF3) degradation compounds described herein can be used in the following non-limiting examples.

[0026] 1. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compound is administered in a low dose. For example, the dosage may be approximately 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, 100 μg, 95 μg, 90 μg, 85 μg, 80 μg, 75 μg, 70 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, or 1 μg or less, with optional drug-free periods.

[0027] 2. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are administered in effective doses in a dosing regimen that includes drug-free periods, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, during a 28-day treatment cycle.

[0028] 3. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising first taking a blood or tissue sample from a patient, determining the concentration of one or more biomarkers, e.g., tumor immune markers (e.g., cytokines, tumor-infiltrating lymphocytes, T cell activation and / or proliferation, or B cell markers such as BCMA or M protein, or combinations thereof); apoptosis markers (e.g., total and / or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM or survivin, or combinations thereof); or zinc finger proteins (e.g., IKZF1, IKZF3, ZFP91, WIZ or SALL4, or combinations thereof), and administering compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, to the patient if the patient has concentrations of biomarkers that are statistically different from those of a healthy person, including, but not limited to, differences of about 5%, 10%, 15%, or 20%.

[0029] 4. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising first taking a blood or tissue sample from the patient, determining the concentration of one or more biomarkers, e.g., IRF-1, caspase-3, IL-2, and / or IFN-γ, and administering compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, to the patient if the patient has statistically lower concentrations of biomarkers than a healthy person, including, but not limited to, up to approximately 5%, 10%, 15%, or 20% lower biomarkers.

[0030] 5. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising first taking a blood or tissue sample from the patient, determining the concentration of one or more biomarkers, e.g., cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC, and administering compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, to the patient if the patient has statistically higher concentrations of biomarkers than a healthy person, including, but not limited to, up to approximately 5%, 10%, 15%, or 20% higher biomarkers.

[0031] 6. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering to a patient compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, then taking a blood or tissue sample from the patient, determining the concentration of one or more biomarkers, e.g., IRF-1, caspase-3, IL-2, and / or IFN-γ, and increasing the dose of the compound if the concentration of the biomarkers has not increased significantly, e.g., by at least about 1.25 times, 1.5 times, 1.75 times, or 2 times. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, to a patient, then taking a blood or tissue sample from the patient, determining the concentration of one or more biomarkers, e.g., cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC, and increasing the dose of the compound if the concentration of the biomarker has not decreased significantly, e.g., by about 1.25 times, 1.5 times, 1.75 times, or 2 times.

[0032] 7. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, to a patient, then taking a blood or tissue sample from the patient, determining the concentration of one or more biomarkers, e.g., tumor immune markers (e.g., cytokines, tumor-infiltrating lymphocytes, T cell activation and / or proliferation, and B cell markers such as BCMA or M protein, or a combination thereof); apoptosis markers (e.g., total and / or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM or Survivin, or a combination thereof); or zinc finger proteins (e.g., IKZF1, IKZF3, ZFP91, WIZ or SALL4, or a combination thereof), and increasing the dose of the compound if the concentration of the biomarker has not changed significantly, e.g., by at least about 1.25 times, 1.5 times, 1.75 times, or 2 times.

[0033] 8. Treatment of activated diffuse large B-cell lymphoma, embryonic diffuse large B-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma by an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0034] 9. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compound is administered in low doses. For example, the dose is approximately 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, or even 100 μg, 75 μg, 50 μg, or 25 μg or less, once daily (QD) or twice daily (BID), with optional drug-free intervals.

[0035] 10. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with a BTK inhibitor selected from, for example, acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

[0036] 11. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with a CD38 antibody selected from, for example, ferzaltamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0037] 12. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with proteasome inhibitors selected from, for example, bortezomib, carfilzomib, ixazomib citrate, oprozomib, delanzomib, lactacystine, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0038] 13. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with IMiDs selected from, for example, thalidomide, pomalidomide, lenalidomide, ibertomide, CC-92480, CC-90009, and CC-99282.

[0039] 14. Therapy of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with HDAC inhibitors selected from, for example, trapoxin B, sodium phenylbutyrate, tasedinarin, mosetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzmat A, spritomycin, LMK-235, sodium butyrate, pivaloyloxymethylbutyrate, pyroxamide, avexinostat, resminostat, zivinostat, xinostat, psammaprin A, KD5170, 1-alanine clamidosin, depdesin, panobinostat, licorinostat, vorinostat, and CUDC-101.

[0040] 15. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with other compounds selected from, for example, selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuplumab, and urerumab.

[0041] 16. Therapy of cancer mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering an effective amount of compound 1 to activate T cell proliferation.

[0042] These new therapies offer advantages over currently approved cancer treatments. For example, the compounds described herein can be administered at lower doses than first-generation IMiDs, can cross the blood-brain barrier to treat central nervous system (CNS) cancers, such as CNS-affected lymphoma, can treat relapsed or refractory cancers with standard treatment regimens including first-generation IMiD therapies, and / or can provide patients with longer progression-free survival than first-generation IMiDs, such as thalidomide, pomalidomide, and lenalidomide. In certain embodiments, the compounds described herein are about 30, 40, 50, 60, 70, 80, 90, 100, 500, or even 1000 times more potent in vivo than thalidomide, pomalidomide, lenalidomide, or CC-92480. In certain embodiments, the compounds described herein induce sustained degradation of IKZF1 and / or IKZF3 (for example, IKZF1 and / or IKZF3 levels may take 12, 18, 24, 36, 48 hours, or longer, to return to pre-treatment levels). This sustained degradation is a result of high in vivo efficacy, metabolic stability, and / or selectivity.

[0043] In one embodiment, the compounds used in the treatment described herein are selected from the following: [ka] TIFF0007846086000003.tif148170 or a pharmaceutically acceptable salt thereof.

[0044] The compounds described herein modulate immune system activity, such as activating IFN-alpha, IFN-beta, or IFN-gamma. By activating the immune system, these compounds can treat cancer more effectively. This immunomodulatory activity enhances the efficacy of the compounds described herein when used with other anticancer agents such as daratumumab.

[0045] In certain embodiments, the degradation of IKZF1 and IKZF3 from malignant B cells or T cells leads to tumor cell death, and their depletion from the tumor microenvironment leads to T cell activation.

[0046] The compounds may be provided, for example, for oral, parenteral, or topical delivery. In certain embodiments, the compounds may be provided in solid, gel, or liquid dosage forms for oral delivery, or intravenously. In some embodiments, selected compounds may be provided as softshell capsules or solid dosage tablets for oral administration. In certain embodiments, the dosages of the pharmaceutical compositions may be approximately 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, and 450 μg. The dosage may be 475 μg, 500 μg, 525 μg, 550 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, or 800 μg, and in one non-limiting embodiment, it may be administered once daily (QD) or twice daily (BID) on days 1 to 21 of a 28-day treatment cycle.

[0047] The compound may be provided, for example, for oral or parenteral delivery. In certain embodiments, the compound may be provided in solid, gel, or liquid dosage forms for oral delivery, or intravenously. In some embodiments, the selected compound is provided as a softshell capsule or tablet for oral administration. In certain embodiments, the dose size of the solid or gel dosage form is 25 μg, 50 μg, 100 μg, 200 μg, 300 μg, or 400 μg, and in one non-limiting embodiment, it may be administered once daily (QD) from day 1 to day 21 of a 28-day cycle.

[0048] In the primary embodiments, the compound used in the treatment described herein is Compound 1 or a pharmaceutically acceptable salt thereof.

[0049] In certain embodiments, any of the compounds described herein have, i.e., are enriched, at least one desired isotopic substitution of an atom in an amount equivalent to the natural abundance of the isotope. In certain embodiments, the compound comprises one or more deuterium atoms.

[0050] Other features and advantages of the present invention will become apparent from the following detailed description and claims. [Brief explanation of the drawing]

[0051] [Figure 1A] This figure shows a dose-response curve illustrating the effect of Compound 1 on H929 cell viability compared to pomalidomide as described in Example 9. The x-axis represents the concentration of Compound 1 or pomalidomide in nM units, and the y-axis represents the H929 cell viability % after 96 hours. [Figure 1B] This figure shows a dose-response curve illustrating the effect of Compound 1 on IKZF1 degradation compared to pomalidomide as described in Example 9. The x-axis represents the concentration of Compound 1 or pomalidomide in nM units, and the y-axis represents the percentage of IKZF1 remaining after 1.5 hours. [Figure 2A] This scatter plot shows data from tumor lysates analyzed by multiplexing proteomics in mice treated with compound 1 for 4 hours. The scatter plot shows the relative abundance changes compared to treatment with DMSO control and compound 1, based on the analysis of tumor lysates by multiplexing proteomics. The x-axis represents the Log2 abundance change, and the y-axis represents the negative Log10 adjusted p-value. Horizontal dashed lines indicate statistical significance (adjusted p ≤ 0.01), and vertical lines indicate abundance changes of 2 or greater. IKZF1 and IKZF3 are the only significantly downregulated proteins with abundance changes of 5.5 and 4.1, respectively. The data shown are from biological replicas measured in a single 10-plex TMT experiment quantifying a total of 7903 proteins. P-values ​​were derived from appropriate t-statistics and corrected using multiple hypothesis testing with the Benjamini-Hochberg approach. The experimental procedure is provided in Example 10. [Figure 2B] This figure shows a scatter plot of data from tumor lysates analyzed by multiplexing proteomics in mice treated with compound 1 for 24 hours. The scatter plot shows the relative abundance changes compared to DMSO control and treatment with compound 1, based on the analysis of tumor lysates by multiplexing proteomics. The x-axis shows the Log2 ratio change, and the y-axis shows the negative Log10 adjusted p-value. The horizontal dashed line indicates statistical significance (adjusted P ≤ 0.01), and the vertical line indicates a ratio change of 2 or greater. The experimental procedure is provided in Example 10. [Figure 3] This figure shows dose-response curves illustrating the effect of compound 1 on Ikaros degradation with and without bortezomib (a proteasome inhibitor) or MLN-4924 (a NEDD inhibitor). As described in Example 11, Ki-JK cells were exposed to compound 1 with and without bortezomib or MLN-4924, and IKZF1 concentrations were determined by flow cytometry at 1.5 hours, 3 hours, and 6 hours for compound 1, and at 6 hours for compound 1 in combination with bortezomib or MLN-4924. The x-axis represents the concentration of compound 1 alone or in combination with bortezomib or MLN-4924. The y-axis represents the residual concentration of IKZF1-488, measured as a percentage of DMSO. [Figure 4] This figure shows a graph of the effect of compound 1 in mice carrying multiple myeloma NCI-H929 cells as described in Example 13. Compound 1 was administered orally (PO) daily (QD) at four different concentrations (3 μg / kg, 10 μg / kg, 30 μg / kg, and 100 μg / kg) and compared to pomalidomide. The x-axis represents time measured in days, and the y-axis represents NCI-H929 tumor volume measured in mm³. [Figure 5]This figure shows a graph of the effect of compound 1 in mice carrying multiple myeloma RPMI-8226 cells as described in Example 13. Compound 1 was administered orally (PO) daily (QD) at four different concentrations (3 μg / kg, 10 μg / kg, 30 μg / kg, and 100 μg / kg) and compared to pomalidomide. The x-axis represents time measured in days, and the y-axis represents the RPMI-8226 tumor volume measured in mm³. [Figure 6] This figure shows images comparing mice administered with compound 1 and the vehicle. The mice were imaged using IVIS Lumina II, as described in Example 14. [Figure 7] This figure shows a graph of the bioluminescence signal of mice imaged using IVIS Lumina II after daily oral (PO) administration of compound 1 (QD) or administration of a vehicle, as described in Example 14. The x-axis represents time measured in days, and the y-axis represents MM1S-Luc whole-body BLI (total bioluminescence signal) measured in photons / 10⁶. [Figure 8] This figure shows a graph of tumor volume in mice injected with NCI-H929 pomalidomide-resistant cells and administered compound 1 (100 μg / kg) or pomalidomide (3000 μg / kg) orally (PO) daily (QD), as described in Example 15. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 9] This figure shows a graph of tumor volume in mice injected with the refractory multiple myeloma cell line RPMI-8226. As described in Example 15, RPMI-8226 tumors were injected into mice and allowed to grow to a volume of 109 mm³ to 158 mm³ (28 days post-transplant). Vehicle-treated animals continued treatment until the tumor reached an MTV (mean tumor volume) of 2211 mm³. On day 17, pomalidomide-treated animals were switched to compound 1 (100 μg / kg / day) and treated for a further 21 days. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 10]This figure shows a graph of tumor volume in mice injected with lymphoma REC1 mantle cells and administered compound 1 or pomalidomide, as described in Example 16. Compound 1 was administered at four different concentrations (3 μg / kg, 10 μg / kg, 30 μg / kg, or 100 μg / kg), and pomalidomide was administered at a dose of 3000 μg / kg. Both drugs were administered orally (PO) daily (QD). The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 11] This figure shows a graph of tumor volume in mice that were injected with lymphoma TMD8 DLBCL and administered compound 1 (100 μg / kg) or pomalidomide (3000 μg / kg) orally (PO) daily (QD), as described in Example 16. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 12] This figure shows a graph of tumor volume in mice that were injected with KI-JK ALCL tumors as described in Example 17 and administered either 30 μg / kg or 100 μg / kg of compound 1 in PO QD (daily orally), pomalidomide (3000 μg / kg, QD PO), or CC-92480 (1000 μg / kg, QD PO). The mice were administered for 21 days. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 13A] This figure shows a bar graph of IKZF1 protein expression in mice injected with KI-JK ALCL tumors and administered compound 1 or pomalidomide, as described in Example 17. Mice were sacrificed 6 and 24 hours after a single dose, and tumors were collected. The x-axis is labeled with the time after administration to the sacrifice of the animals, and the y-axis is the percentage of IKZF1 protein compared to a vehicle control normalized to GAPDH. [Figure 13B]This figure shows a bar graph of IRF4 protein expression in mice injected with KI-JK ALCL tumors and administered compound 1 or pomalidomide, as described in Example 17. Mice were sacrificed 6 and 24 hours after a single dose, and tumors were collected. The x-axis is labeled with the time after administration to the sacrifice of the animals, and the y-axis is the percentage of IRF4 protein compared to a vehicle control normalized to GAPDH. [Figure 14] This figure shows a graph of tumor volume in mice injected with DL-40 ALCL tumors and administered compound 1, pomalidomide, or CC-92480, as described in Example 18. Compound 1 was administered daily (QD) orally (PO) at three different concentrations (10 μg / kg, 30 μg / kg, or 100 μg / kg). Pomalidomide was administered daily orally at a dose of 3000 μg / kg. CC-92480 was administered daily orally at a dose of 300 μg / kg. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 15A] This figure shows a graph of IKZF1 protein expression in mice injected with DL-40 ALCL tumors and administered compound 1 or pomalidomide, as described in Example 18. Mice were sacrificed and tumors were collected 1, 4, and 24 hours after a single dose. The x-axis is labeled with the time after administration at which the animals were sacrificed, and the y-axis is the percentage of IKZF1 protein compared to a vehicle control normalized to GAPDH. [Figure 15B] This figure shows Western blots measuring the concentrations of IKZF1 and IKZF3 in mice injected with DL-40 ALCL tumors and administered compound 1 or pomalidomide, as described in Example 18. The concentrations were determined when mice were sacrificed 1 hour, 4 hours, and 24 hours after a single dose. DL-40 ALCL tumors [Figure 16]This figure shows a graph of tumor volume in mice injected with DL-40 ALCL tumors and administered with compound 1 or pomalidomide, as described in Example 19. Compound 1 was administered orally (PO) daily (QD) at five different concentrations (3 μg / kg, 10 μg / kg, 30 μg / kg, 100 μg / kg, or 300 μg / kg). Pomalidomide was administered orally daily at a dose of 3000 μg / kg. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 17] This figure shows a graph of tumor volume in mice injected with DL-40 ALCL tumors and administered compound 1, as described in Example 19. Compound 1 was administered orally (PO) daily (QD) at three different concentrations (30 μg / kg, 100 μg / kg, or 300 μg / kg). The x-axis represents time measured in days, and the y-axis represents body weight change measured as a percentage. [Figure 18] This figure shows a graph of tumor volume in mice that were injected with KI-JK ALCL tumors and administered compound 1 (100 μg / kg orally (PO) daily (QD)) as described in Example 20. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 19] This figure shows graphs of protein expression for IKZF1, IKZF3, IRF-4, caspase-3, and IRF-1 in mice injected with KI-JK ALCL tumors and administered compound 1, as described in Example 20. The x-axis is labeled with time after administration to sacrifice of the animals, and the y-axis is the percentage of protein compared to the vehicle control normalized to GAPDH. [Figure 20] This figure shows a graph comparing the effects of compound 1, ibrutinib, and a combination of compound 1 and ibrutinib on TMD8 tumor volume in mice, as described in Example 13. Compound 1 was administered orally daily at a dose of 50 μg / kg, and ibrutinib was administered orally daily at a dose of 12.5 mg / kg. The combination was administered at the respective doses of each drug. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 21]This figure shows the survival rates of TMD8 DLBCL-carrying mice administered with Compound 1, ibrutinib, and a combination of Compound 1 and ibrutinib, as described in Example 21. Compound 1 was administered orally daily at a dose of 50 μg / kg, and ibrutinib was administered orally daily at a dose of 12.5 mg / kg. The combination was administered at the respective doses of each drug. The x-axis represents the number of days after administration, and the y-axis represents the survival rate. [Figure 22] This figure shows a graph comparing the effects of compound 1, dexamethasone, and a combination of compound 1 and dexamethasone on the tumor volume of RPMI-8226 multiple myeloma in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) weekly (QW) at a dose of 5 mg / kg, and compound 1 was administered orally daily at a dose of 10 μg / kg. Compound 1 was administered in combination with dexamethasone at the respective dose levels and schedules of each drug. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 23] This figure shows the survival rates of RPMI-8226 multiple myeloma tumor-bearing mice administered with compound 1, dexamethasone, and a combination of compound 1 and dexamethasone, as described in Example 22. Dexamethasone was administered intravenously (IV) weekly (QW) at a dose of 5 mg / kg, and compound 1 was administered orally daily at a dose of 10 μg / kg. Compound 1 was administered in combination with dexamethasone at the respective dose levels and schedules of each drug. The x-axis represents the number of days after administration, and the y-axis represents the survival rate. [Figure 24] This figure shows a graph measuring the concentrations of IKZF1 and IKZF3 in monkeys administered compound 1. As described in Example 23, compound 1 was administered to one monkey, and blood samples were collected at 0, 4, and 24 hours after administration to determine the concentrations of IKZF1 and IKZF3. The x-axis represents the time after administration as measured in time, and the y-axis represents the average fluorescence intensity of IKZF1 and IKZF3. [Figure 25A]This figure shows a graph measuring the plasma concentration of compound 1 or compound 14 after administering compound 1 (60 μg / kg or 100 μg / kg) to monkeys using polyoxygen injection (PO). The x-axis represents the time measured, and the y-axis represents the plasma concentration measured in ng / mL. [Figure 25B] This figure shows a graph measuring the plasma concentration of compound 1 or compound 14 after administering compound 1 (30 mg / kg) to rats using polyoxygen injection (PO). The x-axis represents the time measured, and the y-axis represents the plasma concentration measured in ng / mL. [Figure 26A] This figure shows a graph measuring the effect of compound 1 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26B] This figure shows a graph measuring the effect of compound 2 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26C] This figure shows a graph measuring the effect of compound 3 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26D] This figure shows a graph measuring the effect of compound 4 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26E]This figure shows a graph measuring the effect of compound 5 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26F] This figure shows a graph measuring the effect of compound 6 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26G] This figure shows a graph measuring the effect of compound 7 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26H] This figure shows a graph measuring the effect of compound 8 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26I] This figure shows a graph measuring the effect of compound 9 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26J] This figure shows a graph measuring the effect of compound 10 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26K]This figure shows a graph measuring the effect of compound 11 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26L] This figure shows a graph measuring the effect of compound 12 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with DL-40 ALCL tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 26M] This figure shows a graph measuring the effect of compound 13 (100 μg / kg, QD PO) compared to the vehicle on tumor volume in mice injected with H929 tumors, as described in Example 25. The x-axis represents the treatment period measured in days, and the y-axis represents the H929 tumor volume measured in mm³. [Figure 27] This figure shows a graph demonstrating the in-vitro binding of compound 1 to purified cereblon-DDB1, measured by fluorescence polarization experiment. Compound 1 (circle) or the reference compound (pomalidomide) competes with the Alexa-647-based fluorescent probe for binding to cereblon-DDB1. Probe substitution reduces the level of fluorescence polarization, which is used to calculate the proportion of bound probes using signals from positive and negative controls. Error bars represent the standard deviation (SD). The measured Kd values ​​are as follows: Compound 1: Kd = 0.9 ± 0.5 nM; Pomalidomide: Kd = 712 ± 140 nM. The fluorescence polarization experiment is described in Example 26. [Figure 28]This figure shows dose-response curves illustrating the substitution of cereblon-binding tracer molecules with compound 1 or pomalidomide in 293T cells expressing a cereblon-NanoLuc fusion, as described in Example 27. The x-axis represents the concentration of compound 1 or pomalidomide in nM units, and the y-axis represents the %NanoBRET signal for cells treated with cereblon-binding tracer only (100%) or without tracer (0%). 50% of the tracer was substituted with compound 1 with an IC50 of 0.4 nM and pomalidomide with an IC50 of 644 nM. [Figure 29] This figure shows a dose-response curve illustrating the effect of compound 1 on IKZF1 degradation compared to pomalidomide as described in Example 9. The x-axis represents the concentration of compound 1 or pomalidomide in nM units, and the y-axis represents the %IKZF1 remaining after treatment with compound 1 or pomalidomide for 1 or 2 hours. [Figure 30] This figure shows a Western blot illustrating the levels of Aiolos and Ikaros remaining in H929 cells after treatment with compound 1 or pomalidomide for 4 hours in a dose-response experiment. The method for this experiment is described in Example 28. [Figure 31] This figure shows a dose-response curve illustrating the effect of compound 1 on caspase 3 / 7 activity in the NCIH929 multiple myeloma cell line compared to pomalidomide after 72 hours of treatment, as described in Example 29. The x-axis represents the concentration of compound 1 or pomalidomide in nM units, and the y-axis represents the luminescence signal (RLU) measured after the addition of the caspase 3 / 7 substrate reagent. The method for this experiment is described in Example 29. [Figure 32] This figure shows a plot illustrating the effect of compound 1 on the growth of eight multiple myeloma cell lines compared to pomalidomide as described in Example 30. The x-axis represents the concentration of compound 1 or pomalidomide in nM units (IC50) that inhibited cell proliferation by up to 50% in 96 hours, and the y-axis represents the cell lines tested. [Figure 33]This figure shows the in vivo efficacy of compound 1 and pomalidomide in the treatment of female NOD SCID mice carrying NCI-H929 multiple myeloma xenograft tumors. Mice were treated for 21 days with either compound 1 or 3000 μg / kg / day of pomalidomide as a vehicle control or in dose-response (3 μg / kg / day, 10 μg / kg / day, 30 μg / kg / day, and 100 μg / kg / day) of compound 1. All compounds were administered daily (QD) orally (PO), and tumor regrowth was monitored 21 days after administration. The arrows indicate a re-challenge starting from day 40 with compound 1 at 30 μg / kg / day. The x-axis represents time measured in days, and the y-axis represents NCI-H929 tumor volume measured in mm3. This assay is described in Example 31. [Figure 34] This figure shows a graph of the bioluminescence signal of mice imaged using IVIS Lumina II after daily oral (PO) administration of compound 1 (QD) or administration of a vehicle, as described in Example 14. The x-axis represents time measured in days, and the y-axis represents MM1S-Luc whole-body BLI (total bioluminescence signal) measured in photons / 10⁶. [Figure 35] This figure shows the in vivo efficacy of compound 1 and pomalidomide in the treatment of female CB17 SCID mice carrying RPM-8226 multiple myeloma xenograft tumors. Mice were treated for 21 days with a vehicle control, compound 1 at doses (3 μg / kg / day, 10 μg / kg / day, 30 μg / kg / day, and 100 μg / kg / day), or pomalidomide at 3000 μg / kg / day. All compounds were administered orally (PO) daily (QD). Tumors are graphed individually and expressed as a percentage of their original volume, as shown on the y-axis. [Figure 36] This figure shows a graph of IKZF3 protein expression in mice injected with RPMI-8226 tumor and administered compound 1 in a dose-response manner, as described in Example 32. The x-axis is labeled with time after administration to sacrifice of the animals, and the y-axis is the percentage of protein compared to the vehicle control normalized to GAPDH. [Figure 37]This figure shows graphs of tumor protein expression for IKZF1, IKZF3, and IRF-4 in mice injected with RPMI-8226 MM tumors and administered compound 1, as described in Example 32. The x-axis is labeled with time after administration to sacrifice of the animals, and the y-axis is the percentage of protein compared to the vehicle control normalized to GAPDH. [Figure 38] This figure shows Western blots evaluating the levels of cereblon, IKZF1, and IKZF3 in H929 cells treated with untreated (parent) cells, DMSO (LTC; long-term culture), lenalidomide, or pomalidomide for 4 months. Vinculin was used as a loading control. Western blotting was performed using the method described in Example 33. [Figure 39] This figure shows the effect of Compound 1 on the growth of IMiD-resistant NCIH929 multiple myeloma cells compared to pomalidomide as described in Example 34. The x-axis represents the concentration of Compound 1 or pomalidomide in nM units, and the y-axis represents the % viability of IMiD-resistant NCIH929 cells after 96 hours compared to untreated cells. [Figure 40] This figure shows a graph of tumor volume in mice injected with the refractory multiple myeloma cell line RPMI-8226. Mice were orally administered daily for 35 days either as a vehicle control, pomalidomide (3000 μg / kg / day), or compound 1 (100 μg / kg / day), except in the pomalidomide group. In this group, pomalidomide administration was discontinued on day 17, and compound 1 (100 μg / kg / day) was administered for the remainder of the experiment. This experiment is described in detail in Example 15. [Figure 41] This figure shows a graph comparing the effects of compound 1, dexamethasone, and a combination of compound 1 and dexamethasone on the tumor volume of RPMI-8226 multiple myeloma in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) weekly (QW) at a dose of 5 mg / kg, and compound 1 was administered orally daily at a dose of 10 μg / kg or 100 μg / kg. Compound 1 at 10 μg / kg was administered in combination with dexamethasone at the respective dose levels and schedules of each drug. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. [Figure 42] This figure shows a graph comparing the effects of compound 1, dexamethasone, and a combination of compound 1 and dexamethasone on RPMI-8226 multiple myeloma tumor volume in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) weekly (QW) at a dose of 5 mg / kg, and compound 1 was administered orally daily at a dose of 10 μg / kg. Compound 1 was administered in combination with dexamethasone at the respective dose levels and schedules of each drug. When the tumor volume reached 1000 mm3, the animals were removed from the study and recorded as dead. The y-axis represents the probability of survival of the animal with a particular treatment, and the x-axis represents the number of days the animal survived. [Figure 43] This figure shows graphs of tumor protein expression for IKZF1, IKZF3, and IRF-4 in mice injected with REC1 MCL tumors and administered compound 1, as described in Example 35. The x-axis is labeled with time after administration to sacrifice of the animals, and the y-axis is the percentage of protein compared to a vehicle control normalized to GAPDH. [Figure 44] This figure shows graphs of E2F1 and cyclin D1 protein expression in mice injected with REC1 MCL tumors and administered compound 1, as described in Example 35. The x-axis is labeled with time after administration to sacrifice of the animals, and the y-axis is the percentage of protein compared to the vehicle control normalized to GAPDH. [Figure 45] Figures 45A, 45B, and 45C are dot bar graphs illustrating the effect of compound 1 on the growth of NHL cell lines compared to pomalidomide, as described in Example 37. The x-axis represents the concentration of compound 1 or pomalidomide in nM units (IC50) that inhibited cell proliferation by up to 50% at 96 hours, and the y-axis represents the cell lines tested. White symbols indicate that growth was not inhibited by more than 50% at the highest test concentration (100 nM or 10 μM for compound 1, 10 μM for pomalidomide, and 10 μM for CC-92480), and therefore the IC50 could not be determined. [Figure 46]This figure shows Western blots taken from mice carrying established KI-JK xenografts that received a single dose of compound 1 (100 μg / kg) or daily for 5 days. Tumors were collected 4 and 24 hours after the single dose, and 24 hours after the five daily doses. Tumors were analyzed by Western blotting for IKZF1 and IRF-4 levels. The experimental procedure is described in Example 38. [Figure 47] This figure shows a line graph illustrating the change in tumor volume in mice carrying Mino xenograft tumors treated with either compound 1 (100 μg / kg) orally once daily, rituximab IV (10 mg / kg) once weekly, or a combination of both at their respective doses. The data is expressed as mean tumor volume ± SEM value. The experimental procedure is described in Example 39. [Figure 48] This figure shows a line graph illustrating the time course of concentration changes after treating mice carrying established NCI-H929 xenograft tumors with a single dose of compound 1 (100 μg / kg) or CC-92480 (1000 μg / kg). Plasma and tumor samples were collected 1, 4, 24, and 48 hours after the single dose and analyzed by LC-MS / MS. Data are expressed as total compound concentration ± SEM value. The experimental procedure is provided in Example 40. [Figure 49] This figure shows a line graph illustrating the time course of concentration changes after treating mice carrying established NCI-H929 xenograft tumors with a single dose of compound 1 (100 μg / kg), CC-92480 (1000 μg / kg), or pomalidomide (3000 μg / kg). Tumor samples were collected 1, 4, 24, and 48 hours after a single dose and analyzed for IKZF3 levels by Western blotting. Data were expressed as the percentage of remaining IKZF3 compared to the vehicle control and normalized to GAPDH ± SEM values. The experimental procedure is provided in Example 40. [Figure 50]This figure shows a line graph illustrating the change in tumor volume over time after treating mice carrying established NCI-H929 xenograft tumors orally with compound 1 (100 μg / kg), CC-92480 (1000 μg / kg), or pomalidomide (3000 μg / kg) daily for 18 days. Tumor volume and body weight were measured twice a week. Data are expressed as mean tumor volume ± SEM value. The experimental procedure is provided in Example 40. [Figure 51] This figure shows a dose-response curve illustrating the effect of compound 1 on caspase 3 / 7 activity in the TMD8 cell line compared to pomalidomide after 48 hours of treatment, as described in Example 41. The x-axis represents the concentration of compound 1 or pomalidomide in nM units, and the y-axis represents the luminescence signal (RLU) compared to a DMSO-treated control, measured after the addition of the caspase 3 / 7 substrate reagent. [Figure 52] This figure shows a dose-response curve illustrating the effect of compound 1 on TMD8 cell viability compared to pomalidomide after 96 hours of treatment, as described in Example 42. The x-axis represents the concentration of compound 1 or pomalidomide in nM units, and the y-axis represents the cell viability % compared to the DMSO-treated control, measured after the addition of CellTiter Glo reagent. [Figure 53] This figure shows line graphs illustrating the effects of compound 1, ibrutinib, and the combination of compound 1 and ibrutinib on Mino mantle cell lymphoma xenograft tumors. Mice were orally administered daily for 34 days at doses of compound 1 (30 μg / kg / day), ibrutinib (25 mg / kg), or the combination of ibrutinib and compound 1, at their respective dose levels, or as a vehicle control. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. Statistics were performed using paired t-tests in GraphPad Prism software. The experimental procedure is provided in Example 44. [Figure 54]This figure shows line graphs illustrating the effects of compound 1, CC-92480, pomalidomide, or a vehicle control on RPMI-8226 multiple myeloma xenograft tumors. Mice were orally administered daily for 19 days at a dose of 100 μg / kg / day of compound 1, 1000 μg / kg / day of CC-92480, or 3000 μg / kg / day of pomalidomide. The x-axis represents time measured in days, and the y-axis represents tumor volume measured in mm³. Statistics were performed using paired t-tests in GraphPad Prism software. The experimental procedure is provided in Example 45. [Figure 55] This figure shows line graphs illustrating the effects of compound 1, CC-92480, pomalidomide, or vehicle control on IKZF3 levels in RPMI-8226 multiple myeloma xenograft tumors. Mice were orally administered compound 1 at a dose of 100 μg / kg / day, CC-92480 at a dose of 1000 μg / kg / day, or pomalidomide at a dose of 3000 μg / kg / day daily for 7 days. Tumors were collected 4 and 24 hours after a single dose, and 24 hours after daily administration for 3, 5, and 7 days. Data are expressed as a percentage of the target present in the vehicle control and normalized for total protein. Error bars represent ±SEM values. The experimental procedure is provided in Example 45. [Figure 56] This figure shows line graphs illustrating the effects of compound 1, bortezomib, and a combination of compound 1 and bortezomib on NCI-H929 xenografts. Mice carrying established NCI-H929 xenografts were administered compound 1 (10 μg / kg), bortezomib (0.5 mg / kg), a combination of compound 1 and bortezomib, or a vehicle control dose for 14 days. Compound 1 was administered orally daily, while bortezomib was administered intravenously every other week. Statistical analysis was performed on day 14 (the last day for all animals studied) using two-way ANOVA with GraphPad Prism software. Data are expressed as mean tumor volume ± SEM. [Figure 57]This figure shows line graphs illustrating the effects of compound 1, bortezomib, and a combination of compound 1 and bortezomib on NCI-H929 xenografts. Mice carrying established NCI-H929 xenografts were administered compound 1 (10 μg / kg), bortezomib (0.25 mg / kg), a combination of compound 1 and bortezomib, or a vehicle control dose for 14 days. Compound 1 was administered orally daily, while bortezomib was administered intravenously twice a week. Statistical analysis was performed on day 14 (the last day for all animals studied) using two-way ANOVA with GraphPad Prism software. Data are expressed as mean tumor volume ± SEM. [Figure 58] This figure shows a line graph illustrating the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL2 secreted from anti-CD3 stimulated T cells after a 6-day incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 59] This figure shows a line graph illustrating the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IFNg secreted from anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 60] This figure shows a line graph illustrating the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL21 secreted from anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 61]This figure shows a line graph illustrating the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL9 secreted from anti-CD3 stimulated T cells after a 6-day incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 62] This figure shows a line graph illustrating the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL4 secreted from anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 63] This figure shows a line graph illustrating the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of TNF-alpha secreted from anti-CD3 stimulated T cells after a 6-day incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Figure 64] This figure shows a line graph illustrating the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL17A secreted from anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the concentration of the compound in nM units, and the y-axis represents the ratio change relative to the DMSO-treated control well. The experimental procedure is provided in Example 46. [Modes for carrying out the invention]

[0052] The novel therapies described herein, such as low-dose regimens, are based on the discovery that the compounds described are abnormally active degraders of Ikaros and Aiolos. Compound 1 is considered to be the most potent IKZF1 / 3 degrader currently available. Data described herein and other data demonstrate a significant improvement in the antitumor effect of the combination of Compound 1 and dexamethasone. The compounds described herein, in particular Compound 1, are significantly more effective than pomalidomide both in vitro and in vivo across all NHL models, including PTCL and MCL. Therefore, in NHL subtypes (MCL, DLBCL, PTCL, etc.) where classical IMiD shows clinical activity but is not widely adopted as standard treatment, these compounds can be preferred over thalidomide, lenalidomide, and pomalidomide.

[0053] The compounds described herein have been found to be highly effective therapeutic modalities for treating disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), and can be administered in low-dose regimens once or twice daily, with optional drug-free periods. For example, treatment may be effective in patients using one of the compounds described herein at doses of approximately 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, or even 100 μg, 75 μg, 50 μg, or 25 μg or less, once daily (QD) or twice daily (BID). In certain embodiments, the patient is an adult (typically weighing at least 100 pounds, sometimes 125 pounds or 150 pounds (e.g., 70 kg or more, and typically at least 18 years of age)). In alternative embodiments, the patient is a child (may be less than 100 pounds, 125 pounds or 150 pounds, and typically under 18 years of age).

[0054] In certain embodiments, the dosage includes a drug-free period. The drug-free period is a period during which the patient is not administered the active compound. For the purposes of this disclosure, the treatment cycle is typically based on a 28-day cycle. For example, the patient may be administered the active compound or a pharmaceutically acceptable salt thereof for 21 consecutive days, with no chemotherapy for 7 days during the 28-day cycle, and then optionally this regimen may be repeated once or more times. In certain examples, one of the compounds described herein may be administered once or twice daily for at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days, followed by a drug-free period until the next 28-day cycle. In some embodiments, the compound is administered once or twice daily for at least 20, 21, 22, 23, or 24 consecutive days, followed by a rest period until the end of a 28-day cycle. In yet another embodiment, the drug is administered daily without rest periods to achieve continuous administration during a dosing regimen that may be continuous or periodic for one, two, three, or four weeks, or even one, two, three, four, five, or six months or more. In yet another embodiment, the use of the compounds described herein eliminates the need for off-cycle periods, rest periods, or reductions in the concentration of concurrently administered antitumor compounds during treatment. In yet another embodiment, the cycle period is longer than 28 days, for example, more than 30 or 35 days, and appropriate on-cycle and off-cycle regimens are determined by the patient's healthcare professional.

[0055] In certain embodiments, the Ikaros(IKZF1) and / or Aiolos(IKZF3) degrading agents are administered in combination with one or more additional therapeutic agents. Non-limiting examples of therapeutic agents that may be used in combination with the degrading agents described herein include:

[0056] 1. BTK inhibitors selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

[0057] 2. A CD38 antibody selected from ferzaltamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0058] 3. A proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0059] 4. IMiD selected from pomalidomide, lenalidomide, thalidomide, iverdamide, CC-92480, CC-90009, and CC-99282.

[0060] 5. HDAC inhibitors selected from Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinostat, Cay10603, HPOB, TMP269, Nextulastat A, Santacruzmat A, Spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, Pyroxamide, Abexinostat, Resminostat, Divinostat, Xynostat, Psammaprin A, KD5170, 1-Alanine Chlamydosin, Depdesin, and CUDC-101.

[0061] 6. Compounds selected from selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plelixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afrecertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuplumab, and urerumab.

[0062] I. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this application pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Methods and materials similar to or equivalent to those described herein may be used in the implementation and testing of this application, but preferred methods and materials are described below. All publications, patent applications, patents and other references referenced herein constitute part of this specification by reference. References cited herein are not considered prior art to this application. In case of conflict, this specification, including definitions, shall prevail. In addition, materials, methods and examples are illustrative and not intended to be limiting.

[0063] Compounds are described using their formal names. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this invention pertains.

[0064] In certain embodiments of each compound described herein, the compound may be in the form of an isomer such as a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, or rotational isomer, as each is specifically described, unless otherwise explicitly excluded by the context.

[0065] The terms "a" and "an" are not intended to limit quantity but rather to indicate the presence of at least one of the item(s) being referred to. The term "or" means "and / or". The recitation of a range of values is intended to serve simply as a convenient method of referring individually to each separate value falling within the range, and each separate value is hereby incorporated into the specification as if it were individually recited herein. All endpoints of ranges are included within the range and may be combined independently. All methods and treatments described herein can be performed in a suitable order, unless otherwise specified herein or clearly precluded by context. The use of the words "example" or "exemplary" (such as "such as") is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention, unless otherwise claimed.

[0066] The present invention includes the compounds described herein having isotope substitution of at least one desired atom at an amount exceeding the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., having the same number of protons but different numbers of neutrons. When isotope substitution is used, substitution of hydrogen by at least one deuterium is common.

[0067] More generally, examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, and fluorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O and 18 F, respectively. In a non-limiting embodiment, the isotope-labeled compound is used for metabolic studies (e.g., 14 using 2 C), kinetic studies (e.g., 3It can be used in detection or imaging techniques, including drug or substrate tissue distribution assays or radiotherapy for patients, such as positron emission tomography (PET) or single-photon emission tomography (SPECT), using H. Additionally, any hydrogen atom present in the compound of the present invention can be used 18 Substitution with a fluorine atom is also possible, and this substitution may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention and their prodrugs can generally be prepared by replacing the non-isotope-labeled reagent with a readily available isotope-labeled reagent, by following the procedures disclosed in the scheme or in the following examples and preparations.

[0068] As a general example, though not limited to them, hydrogen isotopes, for example, deuterium ( 2 H) and tritium ( 3 H) can be used in any part of the described structure in which the desired result is achieved. Alternatively or additionally, carbon isotopes, for example 13 C and 14 You can use C.

[0069] Isotope substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is replaced by deuterium. In certain embodiments, the isotope is enriched to 90%, 95%, 99%, or more at any position of the target. In one non-limiting embodiment, deuterium is enriched to 90%, 95%, or 99% at a desired position.

[0070] In one non-limiting embodiment, the substitution of a hydrogen atom with a deuterium atom can occur in any of the compounds described herein. For example, if any of the groups is methyl or ethyl, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, etc.).

[0071] The compounds of the present invention can form solvates with a solvent (including water). Therefore, in one non-limiting embodiment, the present invention includes compounds in the solvated form described herein. The term "solvate" refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Non-limiting examples of solvents include water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex containing a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent may be isotope-substituted, such as D2O, d6-acetone, and d6-DMSO. Solvates may be in liquid or solid form.

[0072] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, oral forms, sublingual forms, topical forms, gels, and mucosal forms. "Dosage form" may also include implants, such as optical implants.

[0073] As used herein, “endogenous” means any substance that originates from or is produced within an organism, cell, tissue, or system.

[0074] As used herein, the term “exogenous” refers to any substance introduced from or produced outside of an organism, cell, tissue, or system.

[0075] As used herein, the term “modulate” means mediating a detectable increase or decrease in the level of response in a patient compared to the level of response in the patient in the absence of the treatment or compound, and / or otherwise identical, but compared to the level of response in an untreated patient. The term encompasses mediating a beneficial therapeutic response in a patient, preferably a human, by disrupting and / or affecting an inherent signal or response.

[0076] Parenteral administration of compounds includes, for example, subcutaneous (sc), intravenous (iv), intramuscular (im), or intrasternal injection, or infusion methods.

[0077] As used herein, “pharmaceutical composition” is a composition comprising at least one activator, such as a selective active compound described herein, and at least one other substance, such as a carrier. “Pharmaceutical combinations” is a combination of at least two activators, which may be combined into a single dosage form or administered together in separate dosage forms, and which are indicated to be used in combination to treat any of the disorders described herein.

[0078] As used herein, “pharmaceutically acceptable salt” is a derivative of the disclosed compound obtained by modifying the parent compound to produce its inorganic and organic salts, acid addition salts, or base addition salts, with a loss of bioacidic toxicity. Salts of the compound can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acid form with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting these compounds in their free base form with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical when practical. Salts of the compound further include solvates of the compound and salts of the compound.

[0079] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n Examples of salts prepared from organic acids such as -COOH (where n is 0 to 4) or using different acids that produce the same counterion. A further list of suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0080] The term "carrier" means a diluent, excipient, or vehicle in which the activator is used or delivered.

[0081] "Pharmacologically acceptable excipients" means excipients that are generally safe and not inappropriate for administration to a host (usually a human) biologically or otherwise, and that are useful in the preparation of a pharmaceutical composition / combination. In certain embodiments, excipients acceptable for veterinary use are used.

[0082] "Patient" or "host" is a human or non-human animal that requires treatment for any of the disorders specifically described herein. Typically, the host is human. "Host" may also alternatively refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0083] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention means an amount that is effective in producing a therapeutic effect such as improvement of symptoms or reduction or mitigation of the disease itself when administered to a host.

[0084] II. Compounds of the present invention In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0086] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0087] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0090] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0091] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0093] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0095] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the compounds used in the present invention are [ka] or a pharmaceutically acceptable salt thereof.

[0097] III. Embodiments of the Invention 1. In certain embodiments, the present invention provides a treatment for Ikaros or Aiolos-mediated disorders comprising administering a low-dose therapeutic regimen in a host requiring treatment, wherein the treatment comprises administering a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13, or a pharmaceutically acceptable salt thereof, once daily (QD) or twice daily (BID) in doses of about 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 300 μg, 250 μg, 200 μg, 150 μg, or even less than 100 μg.

[0098] 2. The treatment of Embodiment 1, wherein the treatment regimen includes a drug-free period.

[0099] 3. The treatment of Embodiment 2, which is carried out by a regimen in which a drug-free period is taken for the next 28-day cycle after a treatment that consists of at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days of treatment once or twice daily.

[0100] 4. The treatment according to Embodiment 3, in which the treatment is administered once or twice a day for 21 days, followed by a 7-day drug-free period.

[0101] 5. Any one of the treatments described in Embodiments 1 to 4, wherein the dose is less than approximately 400 μg.

[0102] 6. Any one of the treatments described in Embodiments 1 to 4, wherein the dose is less than approximately 300 μg.

[0103] 7. Any one of the treatments described in Embodiments 1 to 4, with a dose of less than approximately 200 μg.

[0104] 8. Any one of the treatments described in Embodiments 1 to 4, wherein the dose is less than approximately 100 μg.

[0105] 9. Any one of the treatments from Embodiments 1 to 4, wherein the dose is approximately 50 μg or less than 25 μg.

[0106] 10. A treatment according to any one of Embodiments 1 to 9, wherein the Ikaros or Aiolos-mediated disorder is diffuse large B-cell lymphoma.

[0107] 11. The treatment of embodiment 10, wherein diffuse large B-cell lymphoma is activated B-cell lymphoma.

[0108] 12. The treatment of embodiment 10, wherein diffuse large B-cell lymphoma is germinal center B-cell lymphoma.

[0109] 13. Treatment of embodiments 1-9 in which the Ikaros or Aiolos-mediated disorder is anaplastic large cell lymphoma.

[0110] 14. A treatment according to any one of Embodiments 1 to 9, wherein the Ikaros or Aiolos-mediated disorder is cutaneous T-cell lymphoma.

[0111] 15. A treatment according to any one of Embodiments 1 to 9, wherein the Ikaros or Aiolos-mediated disorder is mantle cell lymphoma.

[0112] 16. A treatment according to any one of Embodiments 1 to 9, wherein the Ikaros or Aiolos-mediated disorder is multiple myeloma.

[0113] 17. The treatment according to any one of embodiments 1 to 16, wherein the disorder is resistant to treatment with a first-generation IMiD drug.

[0114] 18. The treatment according to embodiment 17, wherein the disorder is resistant to treatment with thalidomide.

[0115] 19. The treatment according to embodiment 17, wherein the disorder is resistant to treatment with pomalidomide.

[0116] 20. The treatment according to embodiment 17, wherein the disorder is resistant to treatment with lenalidomide.

[0117] 21. The treatment according to embodiment 17, wherein the disorder is resistant to treatment with iberdomid.

[0118] 22. Treatment of a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising collecting a blood sample or a tissue sample from a patient, determining the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2, and / or IFN-γ, and administering to the patient compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, when the patient has a statistically lower concentration of the biomarker than a healthy person, including, but not limited to, up to about 5%, 10%, 15%, or 20% lower biomarker.

[0119] 23. Treatment of a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising collecting a blood sample or a tissue sample from a patient, determining the concentration of one or more biomarkers, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC, and administering to the patient compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, when the patient has a statistically higher concentration of the biomarker than a healthy person, including, but not limited to, up to about 5%, 10%, 15%, or 20% higher biomarker.

[0120] Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering to a patient a compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, then collecting a blood sample or a tissue sample from the patient, determining the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2, and / or IFN-γ, and increasing the dose of the compound if the concentration of the biomarker does not increase significantly, for example, by at least about 1.25-fold, 1.5-fold, 1.75-fold or 2-fold.

[0121] Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering to a patient a compound 1 or a pharmaceutically acceptable salt thereof, or another compound described herein, then collecting a blood sample or a tissue sample from the patient, determining the concentration of one or more biomarkers, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC, and increasing the dose of the compound if the concentration of the biomarker does not decrease significantly, for example, by at least about 1.25-fold, 1.5-fold, 1.75-fold, or 2-fold.

[0122] Treatment according to any one of embodiments 22-25, wherein the dose is increased when the concentration of the biomarker is less than 150%.

[0123] Treatment according to any one of embodiments 22-25, wherein the dose is increased when the concentration of the biomarker is less than 160%.

[0124] Treatment according to any one of embodiments 22-25, wherein the dose is increased when the concentration of the biomarker is less than 170%.

[0125] Treatment according to any one of embodiments 22-25, wherein the dose is increased when the concentration of the biomarker is less than 180%.

[0126] 30. Treatment of Ikaros and / or Aiolos-mediated disorder comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13 or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the Ikaros or Aiolos-mediated disorder is activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.

[0127] 31. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising using a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, in combination with a BTK inhibitor selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.

[0128] 32. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising using a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, in combination with a CD38 antibody selected from ferzaltamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0129] 33. Therapy for disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising using a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystine, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0130] 34. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising using a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, in combination with an IMiD selected from CC-92480, CC-90009, and CC-99282.

[0131] 35. Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, such as Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinos Therapy using in combination with an HDAC inhibitor selected from TATT, cay10603, HPOB, TMP269, nextulastat A, santacruzmat A, spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, avexinostat, resminostat, zivinostat, xinostat, psammaprin A, KD5170, 1-alanine clamidosin, depdesin, and CUDC-101.

[0132] Treatment of disorders mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising using a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13 or a pharmaceutically acceptable salt thereof in combination with a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilimumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, urolupumab, and urelumab.

[0133] 37. The compound is

Chemical formula

[0134] 38. The compound is

Chemical formula

[0135] 39. The compound is

Chemical formula

[0136] 40. The compound is

Chemical formula

[0137] 41. The compound is [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0138] 42. The compound, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0139] 43. The compound, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0140] 44. The compound, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0141] 45. The compound, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0142] 46. ​​The compound, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0143] 47. Compounds, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0144] 48. Compounds, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0145] 49. Compounds, [ka] A treatment according to any one of embodiments 1 to 36, which is a pharmaceutically acceptable salt thereof.

[0146] 50. Any one of the treatments described in Embodiments 1 to 49, wherein the compound is administered in combination with a Bruton's tyrosine kinase inhibitor.

[0147] 51. The treatment of Embodiment 50, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

[0148] 52. Any one of the treatments described in Embodiments 1 to 49, wherein the compound is administered in combination with a corticosteroid.

[0149] 53. The treatment of embodiment 52, wherein the corticosteroid is dexamethasone.

[0150] 54. Any one of the therapies described in Embodiments 1 to 49, wherein the compound is administered in combination with CAR T-cell therapy.

[0151] 55. Any one of the therapies of Embodiments 1 to 49, wherein the compound is administered in combination with an antibody-drug conjugate.

[0152] 56. Any one of the therapies from Embodiments 1 to 49, wherein the compound is administered in combination with BiTE therapy.

[0153] 57. A treatment according to any one of Embodiments 1 to 49, wherein the compound is administered in combination with a bispecific antibody.

[0154] 58. Any one of the treatments described in Embodiments 1 to 49, wherein the compound is administered in combination with a monoclonal antibody.

[0155] 59. Any one of the treatments of Embodiments 1 to 49, wherein the compound is administered in combination with a BTK inhibitor selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

[0156] 60. Any one of the treatments of Embodiments 1 to 49, wherein the compound is administered in combination with a CD38 antibody selected from ferzaltamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0157] 61. Any one of Embodiments 1 to 49, wherein the compound is administered in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystine, bortezomib, carfilzomib, VLX1570, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0158] 62. Any one of the treatments described in Embodiments 1 to 49, wherein the compound is administered in combination with an IMiD selected from pomalidomide, lenalidomide, thalidomide, iverdamide, CC-92480, CC-90009, and CC-99282.

[0159] 63. Any one of the treatments of Embodiments 1 to 49, wherein the compound is administered in combination with an HDAC inhibitor selected from Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinostat, Cay10603, HPOB, TMP269, Nextulastat A, Santacruzmat A, Spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, Pyroxamide, Abexinostat, Resminostat, Divinostat, Xynostat, Psammaprin A, KD5170, 1-Alanine Clamidosin, Depdesin, and CUDC-101.

[0160] 64. Any one of the treatments of Embodiments 1 to 49, wherein the compound is administered in combination with a compound selected from selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuplumab, and urerumab.

[0161] In a particular embodiment, the above-described treatment is provided in which the dose of compound 1 is about 5 μg or less.

[0162] In a particular embodiment, the above-described treatment is provided in which the dose of compound 1 is about 10 μg or less.

[0163] Further Embodiments 1. In a particular embodiment, a method for treating a disorder mediated by Ikaros and / or Aiolos, comprising a dose of approximately 500 micrograms (μg) or less, once daily (QD) or twice daily (BID). [ka] A method is provided comprising administering a compound selected from TIFF0007846086000031.tif215170 or a pharmaceutically acceptable salt thereof.

[0164] 2. The method of Embodiment 1, wherein the compound is administered in a dose of approximately 500 micrograms to 1 microgram.

[0165] 3. The method of Embodiment 1 or Embodiment 2, wherein the compound is administered for several days with a drug-free period during the subsequent treatment cycle.

[0166] 4. The method of Embodiment 3, wherein the compound is administered once or twice daily for at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days, followed by a drug-free period until the next 28-day cycle.

[0167] 5. The method of Embodiment 3, wherein the compound is administered once or twice daily for 21 days, followed by a 7-day drug-free period.

[0168] 6. Any one of Embodiments 1 to 5, wherein the dose is approximately 400 μg or less.

[0169] 7. One of the methods of Embodiments 1 to 5, wherein the dose is approximately 300 μg or less.

[0170] 8. Any one of the methods of Embodiments 1 to 5, wherein the dose is approximately 200 μg or less.

[0171] 9. Any one of the methods from Embodiments 1 to 5, wherein the dose is approximately 100 μg or less.

[0172] 10. One of the methods from Embodiments 1 to 5, wherein the dose is approximately 50 μg or less.

[0173] 11. Any one of Embodiments 1 to 5, wherein the dose is approximately 25 μg or less.

[0174] 12. Any one of Embodiments 1 to 5, wherein the dose is approximately 10 μg or less.

[0175] 13. One of the methods of Embodiments 1 to 5, wherein the dose is approximately 5 μg or less.

[0176] 14. One of the methods of Embodiments 1 to 5, wherein the dose is approximately 50 μg.

[0177] 15. Any one of Embodiments 1 to 5, wherein the dose is approximately 25 μg.

[0178] 16. Any one of Embodiments 1 to 5, wherein the dose is approximately 10 μg.

[0179] 17. Any one of Embodiments 1 to 5, wherein the dose is approximately 5 μg.

[0180] 18. Any one of Embodiments 1 to 17, wherein the disorder is diffuse large B-cell lymphoma.

[0181] 19. The method of Embodiment 18, wherein diffuse large B-cell lymphoma is activated B-cell lymphoma.

[0182] 20. The method of Embodiment 18, wherein diffuse large B-cell lymphoma is germinal center B-cell lymphoma.

[0183] 21. Any one of Embodiments 1 to 17, wherein the disorder is anaplastic large cell lymphoma.

[0184] 22. Any one of Embodiments 1 to 17, wherein the disorder is cutaneous T-cell lymphoma.

[0185] 23. Any one of Embodiments 1 to 17, wherein the disorder is mantle cell lymphoma.

[0186] 24. Any one of Embodiments 1 to 17, wherein the disorder is multiple myeloma.

[0187] 25. Any one of Embodiments 1 to 24, wherein the disorder is resistant to treatment with first-generation IMiD drugs.

[0188] 26. The method of Embodiment 25, wherein the disorder is resistant to treatment with thalidomide.

[0189] 27. The method of Embodiment 25, wherein the disorder is resistant to treatment with pomalidomide.

[0190] 28. The method of Embodiment 25, wherein the disorder is resistant to treatment with lenalidomide.

[0191] 29. The method of Embodiment 25, wherein the disorder is resistant to treatment with iverdide.

[0192] 30. In a particular embodiment, a method is provided for treating a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising: taking a blood or tissue sample from a patient; determining the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN-γ; and administering to the patient a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, if the patient has statistically lower concentrations of the biomarker(s) than a healthy person.

[0193] 31. The method of Embodiment 30, wherein the statistically low concentration of biomarkers (which may be multiple) is 5% lower than that of the average healthy patient.

[0194] 32. The method of Embodiment 30, wherein the statistically low concentration of biomarkers (which may be multiple) is 20% lower than that of the average healthy patient.

[0195] 33. A method for treating a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising: taking a blood or tissue sample from a patient; determining the concentration of one or more biomarkers selected from cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and MYC; and, if the patient has statistically higher concentrations of biomarkers(s) than a healthy person, administering to the patient a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof.

[0196] 34. The method of Embodiment 33, wherein the statistically elevated concentration of biomarkers (which may be multiple) is 5% higher than that of the average healthy patient.

[0197] 35. The method of Embodiment 33, wherein the statistically elevated concentration of biomarkers (which may be multiple) is 20% higher than that of the average healthy patient.

[0198] 36. In a particular embodiment, a method is provided for treating a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering to a patient a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof; then taking a blood or tissue sample from the patient; determining the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN-γ; and increasing the dose of the compound if the concentration of the biomarker(s) has not increased significantly.

[0199] 37. The method of Embodiment 36, wherein if the concentration of a biomarker (which may be multiple) has not increased by at least about 25%, the dose of the compound is increased.

[0200] 38. The method of Embodiment 36, wherein if the concentration of a biomarker(s) has not increased by at least about 100%, the dose of the compound is increased.

[0201] 39. The method of Embodiment 36, wherein if the concentration of a biomarker(s) has not increased by at least about 200%, the dose of the compound is increased.

[0202] 40. In a particular embodiment, a method is provided for treating a disorder mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), comprising administering to a patient a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof; then taking a blood or tissue sample from the patient; determining the concentration of one or more biomarkers selected from cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and MYC; and increasing the dose of the compound if the concentration of the biomarker(s) has not decreased significantly.

[0203] 41. The method of Embodiment 40, wherein the dose of the compound is increased if the concentration of the biomarker(s) has not decreased by at least about 10%.

[0204] 42. The method of Embodiment 40, wherein the dose of the compound is increased if the concentration of the biomarker(s) has not decreased by at least about 25%.

[0205] 43. The method of Embodiment 40, wherein the dose of the compound is increased if the concentration of the biomarker(s) has not decreased by at least about 50%.

[0206] 44. In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13 or a pharmaceutically acceptable salt thereof to a patient in need thereof, wherein the Ikaros or Aiolos-mediated disorder is activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.

[0207] 45. In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, wherein the patient also receives a BTK inhibitor selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.

[0208] 46. ​​In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, wherein the patient also receives a CD38 antibody selected from ferzaltamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0209] 47. In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, wherein the patient also receives a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystine, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0210] 48. In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient also receives an IMiD selected from CC-92480, CC-90009, and CC-99282.

[0211] 49. In certain embodiments, a method for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient is a patient who has received trapoxin B, sodium phenylbutyrate, tasedinarin, mosetinostat, BR A method is also provided that involves receiving an HDAC inhibitor selected from D73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzmat A, spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, avexinostat, resminostat, zivinostat, xinostat, psammaprin A, KD5170, 1-alanine clamidosin, depdesin, and CUDC-101.

[0212] 50. In certain embodiments, a method is provided for treating a disorder mediated by Ikaros and / or Aiolos, comprising administering an effective amount of a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13, or a pharmaceutically acceptable salt thereof, to a patient in need thereof, wherein the patient also receives a compound selected from selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuprumab, and urerumab.

[0213] 51. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0214] 52. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0215] 53. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0216] 54. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0217] 55. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0218] 56. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0219] 57. Compounds, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0220] 58. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0221] 59. Compounds, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0222] 60. Compounds, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0223] 61. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0224] 62. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0225] 63. The compound, [ka] A method according to any one of Embodiments 1 to 50, or a pharmaceutically acceptable salt thereof.

[0226] 64. Any one of embodiments 1 to 63, wherein a Bruton's tyrosine kinase inhibitor is also administered to the patient.

[0227] 65. The method of Embodiment 64, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

[0228] 66. Any one of embodiments 1 to 65, wherein a corticosteroid is also administered to the patient.

[0229] 67. The method of embodiment 66, wherein the corticosteroid is dexamethasone.

[0230] 68. Any one of embodiments 1 to 67, wherein CAR T-cell therapy is also administered to the patient.

[0231] 69. Any one of embodiments 1 to 67, wherein an antibody-drug conjugate is also administered to the patient.

[0232] 70. One of the embodiments 1 to 67, wherein BiTE therapy is also administered to the patient.

[0233] 71. Any one of Embodiments 1 to 67, wherein a bispecific antibody is also administered to the patient.

[0234] 72. Any one of embodiments 1 to 67, wherein a monoclonal antibody is also administered to the patient.

[0235] 73. Any one of Embodiments 1 to 67, wherein a BTK inhibitor selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib is also administered to the patient.

[0236] 74. Any one of Embodiments 1 to 67, wherein a CD38 antibody selected from ferzaltamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient.

[0237] 75. Any one of Embodiments 1 to 67, wherein a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616 is also administered to the patient.

[0238] 76. Any one of Embodiments 1 to 67, wherein an IMiD selected from pomalidomide, lenalidomide, thalidomide, iverdamide, CC-92480, CC-90009, and CC-99282 is also administered to the patient.

[0239] 77. Any one of Embodiments 1 to 67, wherein an HDAC inhibitor selected from Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinostat, Cay10603, HPOB, TMP269, Nextulastat A, Santacruzmat A, Spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, Pyroxamide, Abexinostat, Resminostat, Divinostat, Xynostat, Psammaprin A, KD5170, 1-Alanine Chlamydosin, Depdesin, and CUDC-101 is also administered to the patient.

[0240] 78. Any one of Embodiments 1 to 67, wherein a compound selected from selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plelixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuprumab, and urerumab is also administered to the patient.

[0241] 79. Any one of Embodiments 1 to 78, comprising administering a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, once daily.

[0242] 80. Any one of Embodiments 1 to 78, comprising administering a compound selected from Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, and Compound 13, or a pharmaceutically acceptable salt thereof, twice daily.

[0243] 81. Any one of Embodiments 1 to 80, wherein the disorder is non-Hodgkin lymphoma.

[0244] 82. Any one of Embodiments 1 to 80, wherein the disorder is multiple myeloma.

[0245] 83. Any one of Embodiments 1 to 82, wherein the disorder is recurrent.

[0246] 84. Any one of Embodiments 1 to 82, wherein the disorder is intractable.

[0247] 85. Any one of Embodiments 1 to 82, wherein the disorder is recurrent and refractory.

[0248] IV. Treatment of disorders mediated by Ikaros and / or Aiolos A favorable treatment for disorders mediated by Ikaros and / or Aiolos is provided. In certain embodiments, the treatment comprises administering a low-dose form once or twice daily, with optionally drug-free intervals, which is a very effective treatment modality. For example, the treatment has been found to be effective in patients using one of the compounds described herein, once daily (QD) or twice daily (BID), with optionally treatment breaks, at doses of approximately 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, or even 100 μg, 75 μg, 50 μg, or 25 μg or less. In some embodiments, the patient is an adult (usually weighing at least 100 pounds and usually 18 years of age or older). In another embodiment, the patient is a child (may be under 100 pounds and typically under 18 years of age).

[0249] The selected compound, for example, compound 1, can be administered as a monotherapy, or in combination with a standard treatment for the target tumor or cancer, including but not limited to any of those described in the background of the present invention, or with a proteasome inhibitor and / or an anti-CD38 monoclonal antibody (mAb), etc. In MCL, the selected compound can be used in combination with, for example, a Bruton's tyrosine kinase (BTK) inhibitor or an anti-CD20 monoclonal antibody. In PTCL, particularly ALCL, the selected compound can be administered in combination with, for example, an anti-CD30 or anti-CD38 monoclonal antibody.

[0250] In certain embodiments, compound 1 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0251] In certain embodiments, compound 2 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0252] In certain embodiments, compound 3 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0253] In certain embodiments, compound 4 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0254] In certain embodiments, compound 5 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0255] In certain embodiments, compound 6 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0256] In certain embodiments, compound 7 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0257] In certain embodiments, compound 8 is used to treat a disorder mediated by Ikaros or Aiolos in accordance with the therapeutic regimen described herein.

[0258] In certain embodiments, compound 9 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0259] In certain embodiments, compound 10 is used to treat Ikaros or Aiolos-mediated disorders in accordance with the therapeutic regimens described herein.

[0260] In certain embodiments, compound 11 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0261] In certain embodiments, compound 12 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0262] In certain embodiments, compound 13 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the therapeutic regimens described herein.

[0263] In certain embodiments, the compounds described herein, for example, compound 1, are used to treat metastatic cancer. In certain embodiments, the compounds described herein, for example, compound 1, are used to treat cancer that has metastasized to the brain.

[0264] Treatment cycle In certain embodiments, the dosage includes a drug-free period. The drug-free period is a period during which the patient is not administered the active compound. For example, the patient may be administered the active compound or a pharmaceutically acceptable salt thereof for 21 consecutive days, followed by a 7-day period without chemotherapy during a 28-day cycle, after which this regimen may be optionally repeated once, several times, or more times. In certain examples, one of the compounds described herein may be administered once or twice daily for at least 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days, followed by a drug-free period until the next 28-day cycle. In some embodiments, the compound is administered once or twice daily for at least 20, 21, 22, 23, or 24 consecutive days, followed by a drug-free period until the end of the 28-day cycle. In yet another embodiment, the drug is administered daily without any breaks to achieve continuous administration during a drug regimen that may last for two, three, or four weeks, or even longer, such as one, two, three, four, five, or six months or more. In yet another embodiment, the use of the compounds described herein eliminates the need for off-cycle periods, drug-free periods, or reductions in the concentration of concurrently administered antitumor compounds during treatment. In yet another embodiment, the cycle period exceeds 28 days, for example, 30 or 35 days.

[0265] In certain embodiments, the compound of the present invention is administered for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered for 14 consecutive days, followed by a 14-day rest period. In certain embodiments, the compound of the present invention is administered for 21 consecutive days, followed by a 7-day rest period.

[0266] In certain embodiments, the compound of the present invention is administered once daily for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered daily for 14 consecutive days, followed by a 14-day rest period. In certain embodiments, the compound of the present invention is administered daily for 21 consecutive days, followed by a 7-day rest period.

[0267] In certain embodiments, the compound of the present invention is administered twice daily for 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days of a 28-day treatment cycle. In certain embodiments, the compound of the present invention is administered twice daily for 14 consecutive days, followed by a 14-day rest period. In certain embodiments, the compound of the present invention is administered twice daily for 21 consecutive days, followed by a 7-day rest period.

[0268] In a particular embodiment, compound 1 is administered orally daily for 21 days within each 28-day treatment cycle, followed by a 7-day rest period.

[0269] dosage In certain alternative embodiments, the compound of the present invention is administered in a dose of about 800 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than about 600 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than about 400 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than about 300 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than about 200 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than about 100 μg.

[0270] In certain embodiments, the compound of the present invention is administered in a dose of less than approximately 50 μg. In certain embodiments, the compound of the present invention is administered in a dose of less than approximately 25 μg.

[0271] In certain embodiments, the compound of the present invention is administered in a dose of approximately 50 μg.

[0272] In certain embodiments, the compound of the present invention is administered in a dose of approximately 45 μg.

[0273] In certain embodiments, the compound of the present invention is administered in a dose of approximately 40 μg.

[0274] In certain embodiments, the compound of the present invention is administered in a dose of approximately 35 μg.

[0275] In certain embodiments, the compound of the present invention is administered in a dose of approximately 30 μg.

[0276] In certain embodiments, the compound of the present invention is administered in a dose of approximately 25 μg.

[0277] In certain embodiments, the compound of the present invention is administered in a dose of approximately 20 μg.

[0278] In certain embodiments, the compound of the present invention is administered in a dose of approximately 15 μg.

[0279] In certain embodiments, the compound of the present invention is administered in a dose of approximately 10 μg.

[0280] In certain embodiments, the compound of the present invention is administered in a dose of approximately 5 μg.

[0281] In certain embodiments, the compound of the present invention is administered in a dose of approximately 1 μg.

[0282] In certain embodiments, compound 1 is given in a dose of less than approximately 800 μg. In certain embodiments, compound 1 is given in a dose of less than approximately 600 μg. In certain embodiments, compound 1 is given in a dose of less than approximately 400 μg. In certain embodiments, compound 1 is given in a dose of less than approximately 300 μg. In certain embodiments, compound 1 is given in a dose of less than approximately 200 μg. In certain embodiments, compound 1 is given in a dose of less than approximately 100 μg.

[0283] In certain embodiments, compound 1 is given in a dose of approximately 800 μg. In certain embodiments, compound 1 is given in a dose of approximately 600 μg. In certain embodiments, compound 1 is given in a dose of approximately 400 μg. In certain embodiments, compound 1 is given in a dose of approximately 300 μg. In certain embodiments, compound 1 is given in a dose of approximately 200 μg. In certain embodiments, compound 1 is given in a dose of approximately 100 μg.

[0284] In certain embodiments, compound 1 is present in amounts of at least about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, It is administered in doses of 525 μg, 550 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg, or 1000 μg, or doses in between.

[0285] In certain embodiments, compound 1 is administered in a dose of approximately 25 μg. In certain embodiments, compound 1 is administered in a dose of approximately 50 μg or 75 μg. In certain embodiments, compound 1 is administered in a dose of approximately 100 μg or 150 μg. In certain embodiments, compound 1 is administered in a dose of approximately 175 μg or 200 μg. In certain embodiments, compound 1 is administered in a dose of approximately 225 μg or 250 μg. In certain embodiments, compound 1 is administered in doses of approximately 275 μg, 300 μg, 325 μg or 350 μg. In certain embodiments, compound 1 is administered in a dose of approximately 400 μg or 450 μg. In certain embodiments, compound 1 is administered in a dose of approximately 550 μg. In certain embodiments, compound 1 is administered in a dose of approximately 650 μg. In certain embodiments, compound 1 is administered in a dose of approximately 725 μg. In a particular embodiment, compound 1 is administered in a dose of approximately 800 μg.

[0286] The present invention includes at least the following low-dose features: (a) Low-dose treatment regimens for Ikaros or Aiolos-mediated disorders in the host, comprising administering a compound selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13 to patients in need at doses of 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 300 μg, 250 μg, 200 μg, 150 μg, or even 100 μg or less once daily (QD) or twice daily (BID); (b) The treatment regimen includes a drug-free period; (c) Treatment of (b) carried out by a regimen of treatment, the drug-free period being at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days with one or two doses per day, followed by a drug-free period until the next 28-day cycle; (d) Treatment as described in (c), which is administered once or twice a day for 21 days, followed by a 7-day rest period; (e) Treatment of (a) to (d) with a single dose of 400 micrograms or less; (f) Treatment of (a) to (d) with a single dose of 300 micrograms, 200 micrograms, or 100 micrograms or less; (g) Treatment of (a) to (d) with a single dose of 25 micrograms, 50 micrograms, or 75 micrograms or less; (h) Treatment of (b) which may have drug-free intervals of two, three, four, five, or six weeks, or even one, two, three, four, five, or six months, or longer; (i) Treatment of (a) without a drug-free period; (j) Treatment of (a) with a cycle duration exceeding 28 days (e.g., exceeding 30 or 35 days), including a drug-free period; (k) The treatment of (a) to (j), wherein the disorder is selected from diffuse large B-cell lymphoma, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, mantle cell lymphoma, and multiple myeloma, and comprises administering an effective amount of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13 to a patient in need thereof; (l) Treatment of (a) to (j) the disorder which is resistant to treatment with other cereblon ligands, comprising administering an effective amount of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13 to a patient in need thereof; (m) Treatment of a patient with cereblon-mediated disorder, including monitoring the concentration of one or more biomarkers selected from IRF-1 and caspase-3, as described in (a) to (j); (n) The combination therapy of patients with cereblon-mediated disorders comprises administering an effective amount of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13 in combination with or alternately with a Bruton's tyrosine kinase inhibitor, corticosteroid, CAR T cell therapy, antibody-drug conjugate, BiET therapy, bispecific antibody, or monoclonal antibody to patients in need of such treatment; (o) Low-dose pharmaceutical compositions of the compounds described herein in a pharmaceutically acceptable carrier, or pharmaceutically acceptable salts, isotopic derivatives (including deuterated derivatives) or prodrugs thereof; (p) Treatment of any disorder described herein by (a) to (j), comprising administering an effective amount of compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13 to a patient in need thereof; (q) Compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, for the treatment of disorders mediated by Ikaros or Aiolos as described in (a) to (j); (r) Patients having any of the disorders described herein (including those mediated by Ikaros or Aiolos), typically using an effective amount of the compounds described herein, or their pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, in the treatment of human (a) to (j); (s) A method for producing a low-dose pharmaceutical for the treatment of a disorder described herein in a host, characterized in that the compound described herein is used in the production at a low dose as specified herein; (t) Use of the compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, in the manufacture of a medicament for the treatment of cancer (a) to (j), including any of the cancers described herein; (u) A method for producing a pharmaceutical for the treatment of cancer by (a) to (j) in a host comprising any of the cancers described herein, characterized in that a compound described herein is used in the production; (v) A compound described herein, or a pharmaceutically acceptable salt, isotope derivative, or prodrug thereof, for the treatment of a tumor in a host containing any of the tumors described herein by (a) to (j); (w) Use of the compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, in the manufacture of a medicament for the treatment of tumors (a) to (j) including any of the tumors described herein; (x) A method for producing a pharmaceutical for the treatment of a tumor by (a) to (j) in a host containing any of the tumors described herein, characterized in that a compound described herein is used in the production; (y) Compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, for the treatment of (a) to (j) an immune, autoimmune, or inflammatory disorder in a host; (z) Use of the compounds described herein, or pharmaceutically acceptable salts, isotopic derivatives, or prodrugs thereof, in the manufacture of pharmaceuticals for the treatment of (a) to (j) of immune, autoimmune, or inflammatory disorders; (aa) A method for producing a pharmaceutical product for the treatment of an immune, autoimmune, or inflammatory disorder in a host by (a) to (j), characterized in that a compound described herein is used in the production; (bb) Compounds described herein, or pharmaceutically acceptable salts, isotope derivatives, or prodrugs thereof, for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, as described in (a) to (j); (cc) Use of the compounds described herein, or their pharmaceutically acceptable salts, isotope derivatives, or prodrugs, in the manufacture of pharmaceuticals for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma, by (a) to (j); (dd) A method for producing a pharmaceutical product for the treatment of hematological malignancies in a host such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, or non-Hodgkin lymphoma by (a) to (j), characterized in that the compounds described herein are used in the production; (ee) A pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, in an amount effective for host treatment according to (a) to (j), together with a pharmaceutically acceptable carrier or diluent; (ff) Treatment by (a) to (j) wherein the compound described herein is a mixture of an enantiomer or diastereomer (if applicable) including a racemic mixture; (gg) Treatment by (a) to (j), wherein the compounds described herein are concentrated forms of the enantiomer or diastereomer (if applicable), including isolated enantiomers or diastereomers (i.e., with a purity greater than 85%, 90%, 95%, 97%, or 99%); and (hh) A process for preparing a therapeutic product comprising a low dose of an effective amount of the compound described herein.

[0287] In certain alternative embodiments, the compound of the present invention is given in a dose of less than approximately 800 mg. In certain embodiments, the compound of the present invention is given in a dose of less than approximately 600 mg. In certain embodiments, the compound of the present invention is given in a dose of less than approximately 400 mg. In certain embodiments, the compound of the present invention is given in a dose of less than approximately 300 mg. In certain embodiments, the compound of the present invention is given in a dose of less than approximately 200 mg. In certain embodiments, the compound of the present invention is given in a dose of less than approximately 100 mg.

[0288] In certain embodiments, the compounds of the present invention are administered in doses of approximately 1000 mg, 950 mg, 900 mg, 850 mg, 800 mg, 750 mg, 700 mg, 650 mg, 600 mg, 550 mg, 500 mg, 475 mg, 450 mg, 425 mg, 400 mg, 375 mg, 350 mg, 325 mg, 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 75 mg, 70 mg, 65 mg, 60 mg, 55 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, or 1 mg.

[0289] In certain embodiments, the compounds of the present invention are present in amounts of approximately 1000 μg, 950 μg, 900 μg, 850 μg, 800 μg, 750 μg, 700 μg, 650 μg, 600 μg, 550 μg, 500 μg, 475 μg, 450 μg, 425 μg, 400 μg, 375 μg, 350 μg, 325 μg, 300 μg, and 275 μg. It is administered in doses of 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, 100 μg, 90 μg, 80 μg, 75 μg, 70 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, or 1 μg.

[0290] In certain embodiments, the compounds of the present invention are present in amounts of at least about 1000 μg, 950 μg, 900 μg, 850 μg, 800 μg, 750 μg, 700 μg, 650 μg, 600 μg, 550 μg, 500 μg, 475 μg, 450 μg, 425 μg, 400 μg, 375 μg, 350 μg, 325 μg, 300 μg, and 27 μg. It is administered in doses of 5 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, 100 μg, 90 μg, 80 μg, 75 μg, 70 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, or 1 μg.

[0291] In certain embodiments, the compounds of the present invention are present in amounts of at least about 1000 μg, 950 μg, 900 μg, 850 μg, 800 μg, 750 μg, 700 μg, 650 μg, 600 μg, 550 μg, 500 μg, 475 μg, 450 μg, 425 μg, 400 μg, 375 μg, 350 μg, 325 μg, 300 μg, and 275 μg. It is administered in doses of μg, 250μg, 225μg, 200μg, 175μg, 150μg, 125μg, 100μg, 90μg, 80μg, 75μg, 70μg, 65μg, 60μg, 55μg, 50μg, 45μg, 40μg, 35μg, 30μg, 25μg, 20μg, 15μg, 10μg, 5μg, or less than 1μg.

[0292] Disorders mediated by Ikaros and / or Aiolos In one aspect of the present invention, a disorder mediated by Ikaros or Aiolos is treated with compound 1, or a pharmaceutically acceptable salt thereof, or another compound described herein. In certain embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a lymphoma, leukemia, or myeloma. In certain embodiments, the cancer is a non-Hodgkin lymphoma or Hodgkin lymphoma.

[0293] In certain embodiments, the compounds of the present invention are administered to patients in need in an amount effective for the treatment of diffuse large B-cell lymphoma. In certain embodiments, diffuse large B-cell lymphoma is activated B-cell lymphoma or germinal center B-cell lymphoma. In certain embodiments, diffuse large B-cell lymphoma is cancer with BCL2 / 6 translocation. In certain embodiments, diffuse large B-cell lymphoma is double-hit bearing cancer. In certain embodiments, diffuse large B-cell lymphoma is BCL2 / 6 MYC wild-type cancer.

[0294] In certain embodiments, the compounds of the present invention increase the concentrations of caspase-3 and / or caspase-7. In certain embodiments, this increase in the concentrations of caspase-3 and / or caspase-7 induces cancer cell death, for example, in the treatment of diffuse large B-cell lymphoma.

[0295] In certain embodiments, the compound of the present invention is administered to a patient in need of treatment for anaplastic large cell lymphoma in an amount effective for the treatment of the disease.

[0296] In certain embodiments, the compound of the present invention is administered to a patient in need in an amount effective for treating cutaneous T-cell lymphoma.

[0297] In certain embodiments, the compound of the present invention is administered to a patient in need in an amount effective for treating mantle cell lymphoma.

[0298] In certain embodiments, the compound of the present invention is administered to a patient in need in an amount effective for treating multiple myeloma.

[0299] In certain embodiments, the compounds of the present invention are administered to patients in need in an effective amount to treat disorders that are resistant to treatment with other cereblon ligands. In certain embodiments, the compounds of the present invention are used to treat refractory IMiD disorders.

[0300] In certain embodiments, compound 1 is administered to a patient in need in an amount effective for treating diffuse large B-cell lymphoma. In certain embodiments, diffuse large B-cell lymphoma is activated B-cell lymphoma or germinal center B-cell lymphoma. In certain embodiments, diffuse large B-cell lymphoma is a cancer with BCL2 / 6 translocation. In certain embodiments, diffuse large B-cell lymphoma is a cancer with double hits. In certain embodiments, diffuse large B-cell lymphoma is a BCL2 / 6 MYC wild-type cancer.

[0301] In a particular embodiment, compound 1 is administered to a patient in need in an amount effective for treating anaplastic large cell lymphoma.

[0302] In a particular embodiment, compound 1 is administered to a patient in need in an amount effective for treating cutaneous T-cell lymphoma.

[0303] In a particular embodiment, compound 1 is administered to a patient in need in an amount effective for treating mantle cell lymphoma.

[0304] In a particular embodiment, compound 1 is administered to a patient in need in an amount effective for treating multiple myeloma.

[0305] In certain embodiments, compound 1 is administered to a patient in need of it in an amount effective for treating a disorder that is resistant to treatment with other cereblon ligands. In certain embodiments, compound 1 is administered to a patient in need of it in an amount effective for treating refractory IMiD disorder.

[0306] In one embodiment, an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, is administered to a patient to treat cancers involving the central nervous system (CNS), such as lymphoma in the CNS. In certain embodiments, patients with cancers involving the CNS, such as lymphoma in the CNS, are also administered one or more additional therapeutic agents, such as ibrutinib or rituximab. In certain embodiments, the compounds described herein are used to treat peripheral central nervous system lymphoma.

[0307] In certain embodiments, compound 1 is administered for the treatment of PTCL-NOS (i.e., unspecified PTCL). In other embodiments, compound 1 is administered for the treatment of PTCL having a specific subtype, such as anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), intestinal disease-type T-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma.

[0308] In certain embodiments, the disorder treated by the compounds of the present invention is an immunomodulatory disorder. In certain embodiments, the disorder treated by the compounds of the present invention is mediated by angiogenesis. In certain embodiments, the disorder treated by the compounds of the present invention is related to the lymphatic system.

[0309] In certain embodiments, the compounds of the present invention or their pharmaceutical salts in a pharmaceutical composition as optionally described herein are administered in effective amounts to patients who require them to degrade Ikaros or Aiolos, which are mediators of disorders affecting patients such as humans. The control of protein levels achieved by any of the compounds of the present invention results in the treatment of disease conditions or pathologies modulated by Ikaros or Aiolos by reducing the level of that protein in cells, for example, in a patient's cells, or by reducing the level of downstream proteins within the cells. In certain embodiments, the treatment involves administering an effective amount of the compounds described herein, optionally including pharmaceutically acceptable excipients, carriers, and adjuvants (i.e., a pharmaceutically acceptable composition), in combination with or alternately with another bioactive agent or combination of bioactive agents.

[0310] In certain embodiments, the compounds of the present invention are administered to patients in need in amounts effective for treating disorders including, but not limited to, benign growths, neoplasms, tumors, cancer, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid protein disorders, protein disorders, or fibrous disorders.

[0311] The terms “disease state” or “pathological condition,” when used in relation to any compound, are intended to refer to any disease state or pathological condition mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or pathological condition mediated by downstream proteins of Ikaros or Aiolos, the degradation of such proteins in a patient may provide beneficial therapy or symptom relief to the patient in need. In some cases, the disease state or pathological condition may be cured.

[0312] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be administered in effective doses to treat a host, such as a human, having lymphoma or lymphocytic or myeloid proliferative disorders or abnormalities. For example, the compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may include, but is not limited to, AIDS-associated lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-incisional nuclear cell lymphoma); small incisional nuclear cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia; small lymphocytic lymphoma; non-Hodgkin lymphoma (NOS); cutaneous T-cell lymphoma; diffuse large B-cell lymphoma. Enteropathy-type T-cell lymphoma; Follicular lymphoma; Hepatosplenic γ-δ T-cell lymphoma; Lymphoblastic lymphoma; Mantle cell lymphoma; Marginal zone lymphoma; Nasal T-cell lymphoma; Childhood lymphoma; Peripheral lymphoma, peripheral T-cell lymphoma; Primary central nervous system lymphoma; T-cell leukemia; Transformed lymphoma; Treatment-associated T-cell lymphoma; Non-Hodgkin lymphoma such as Langerhans cell histiocytosis or Waldenström macroglobulinemia may also be present.

[0313] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, can be administered in effective doses to a host, such as a human, having Hodgkin lymphoma, including but not limited to tuberous sclerosis classical Hodgkin lymphoma (CHL), mixed cell type CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-dominant Hodgkin lymphoma, or nodular lymphocyte-dominant HL.

[0314] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, may be administered in effective doses to treat a host having an immunomodulatory condition, such as a human. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes mellitus, alopecia areata, vasculitis, and temporal arteritis.

[0315] In certain embodiments, the conditions treated with the compounds of the present invention are disorders associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0316] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a wide range of diseases, including cancer, proliferative disorders, and inflammatory / immune diseases. Treating a host suffering from any of these disorders, such as a human, with an effective amount of the compounds described herein can reduce (palliative) the symptoms. It can achieve either a reduction in underlying disease (disease modifying agent).

[0317] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; Nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; hairy cell leukemia; unclassifiable splenic lymphoma / leukemia; diffuse red pulp small B-cell lymphoma; hairy cell leukemia - subtype; lymphoplasmacytic lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; form It can be administered in effective doses to treat specific B-cell lymphomas or proliferative disorders in hosts, such as humans, including plasmacytomyeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma occurring in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0318] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, are not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous progressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous γ-δ T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); bud It can be administered in an effective dose to treat a host, such as a human, who has a T-cell or NK-cell lymphoma, including conditions such as: cytoplasmic NK-cell lymphoma; enteropathy-type T-cell lymphoma; hepatosplenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-associated T-cell lymphoma; lymphoma occurring after, for example, solid organ or bone marrow transplantation; pre-T-cell lymphocytic leukemia; T-cell macrogranular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK-cell leukemia; systemic EBV+ T-cell lymphoproliferative disorder in children (associated with chronic active EBV infection); vaccinia-like varicella-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatosplenic T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0319] In certain embodiments, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, may be administered to treat a host having leukemia, such as a human. For example, the host may have, but is not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); macrogranular lymphocytic leukemia; or acute or chronic leukemia of lymphocyte or myeloid origin, such as adult T-cell chronic leukemia. In certain embodiments, the patient suffers from acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or subtype M3 (M3V)); myelomonocytic leukemia (M4 or subtype M4 with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0320] Numerous skin disorders are associated with cell overgrowth. For example, psoriasis is a benign disease of human skin generally characterized by plaques covered with thickened scales. This disease is caused by an increase in the proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with marked epidermal overgrowth. Other diseases caused by excessive proliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0321] Other hyperproliferative cell disorders include vascular disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancers.

[0322] Vascular proliferative disorders include neovascularization and vascular disorders. The proliferation of smooth muscle cells during plaque formation in vascular tissue leads to conditions such as restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0323] Fibrotic disorders are often caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cytotoxicity. Cirrhosis is characterized by an increase in extracellular matrix components that lead to the formation of liver scars. Cirrhosis can lead to diseases such as liver cirrhosis. The increase in extracellular matrix that leads to liver scars may also be due to viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0324] Mesangial disorders are caused by the abnormal proliferation of mesangial cells. Mesangial hyperproliferative cytotoxicity includes various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection, and glomerulopathy.

[0325] Another disease caused by proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered an autoimmune disease associated with the activity of autoreactive T cells and caused by autoantibodies produced against collagen and IgE.

[0326] Other disorders that may contain abnormal cell proliferation components include Behçet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipid histiocytosis, septic shock, and general inflammation.

[0327] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be administered in effective doses to treat hosts, such as humans, who have proliferative conditions including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelometaplastic myelopathy with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilic syndrome (HES), and systemic mastocytosis (SMCD). In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[0328] In certain embodiments, the compounds described herein, or their pharmaceutically acceptable salts, isotopic analogs, or prodrugs, can be administered in effective doses to treat hosts, such as humans, who have myelodysplastic syndromes (MDS), including but not limited to refractory cytopenia with monocytic lineage dysplasia, refractory anemia with ring sideroblasts (RARS), refractory anemia-thrombocytosis with ring sideroblasts (RARS-t), refractory cytopenia with polycytic lineage dysplasia (RCMD), including RCMD-RS, refractory anemia I (RAEB-I) and II (RAEB-II), 5q syndrome, and childhood refractory cytopenia.

[0329] In certain embodiments, the compounds of the present invention can exert a therapeutic effect by directly degrading Ikaros or Aiolos, which can alter the transcriptional regulation of downstream proteins of Ikaros or Aiolos.

[0330] The terms “neoplasia” or “cancer” are used to refer to the pathological process that results in the formation and growth of malignant or cancerous neoplasms, which are abnormal tissues that grow more rapidly than normal through cell proliferation and continue to grow even after the stimulus that initiated the new growth has ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissue, most invade surrounding tissues, metastasize to several sites, and may recur even after attempts to remove them, leading to patient death if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease conditions and includes or encompasses pathological processes associated with malignant hematological malignancies, ascites tumors, and solid tumors. Exemplary cancers that can be treated with this compound alone or in combination with at least one additional anticancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma; cancers of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovaries, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's positivity. Sarcomas including sarcomas, liposarcomas, myosarcomas, peripheral neuroepitheliomas, synovial sarcomas, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, and Schwann cell tumors; intestinal cancers, breast cancers, prostate cancers, cervical cancers, uterine cancers, lung cancers, ovarian cancers, testicular cancers, thyroid cancers, astrocytomas, esophageal cancers, pancreatic cancers, gastric cancers, liver cancers, colon cancers, melanomas; carcinosarcomas, Hodgkin's disease, Wilms' tumors, and teratomas. Additional cancers that can be treated with the compounds according to the present invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, and Philadelphia chromosome-positive CML.

[0331] Additional cancers that can be treated with the compounds disclosed according to the present invention include, for example, acute granulocytic leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone, and HER-2) (negative for both progesterone and HER-2), single-negative (negative for one of estrogen, progesterone, and HER-2), estrogen receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, Ewing's sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tubes Cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasion Lobular carcinoma (ILC), inflammatory breast cancer (IBC), colon cancer, intrahepatic cholangiocarcinoma, invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leukemia, lip cancer, liposarcoma, liver cancer, non-invasive lobular carcinoma, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal mesothelioma, metastatic breast cancer, metastatic melanoma, metastatic squamous cell carcinoma of the neck, mixed glioma, monodermal teratoma, mouth cancerCancer), mucinous carcinoma, mucosal melanoma, multiple bone marrow abscess, fungal polyposis, osteomyelopathy syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-homologous lymphadenopathy, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, intraocular melanoma, follicular colloid tumor, oral cancer, oral cavity cancer, oral and pharyngeal cancer, osteosarcoma, osteosarcoma, ovarian carcinoma, epithelial ovarian carcinoma, ovarian germ cell tumor, ovarian Primary peritoneal carcinoma, ovarian cord-stromal tumor, pethopathy, lipoma, papillary carcinoma, paranasal cavity carcinoma, parathyroid carcinoma, pelvic carcinoma, penile cancer, peripheral nerve carcinoma, peritoneal carcinoma, pharyngeal carcinoma, brown cell tumor, trichomeal stellate tumor, pineal gland tumor, pineal bud, pituitary carcinoma, primary central nervous system (CNS) lipoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma. Sarcoma, sarcoma, paranasal cavity cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal cord cancer, spinal marrow cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell leukemia, seminal vesicle cancer, pharyngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, cancer of unknown diagnosis, ureteral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute leukemia (T-ALL), T-cell leukemia (T-LL), peripheral T-cell leukemia, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (a subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prelymphocytic leukemia; Unclassifiable splenic lymphoma / leukemia, Diffuse red pulp small B-cell lymphoma; Lymphoid Plasma cell lymphoma; heavy chain disease, e.g., α-heavy chain disease, γ-heavy chain disease, μ-heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicular lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL lower extremity type; ALK + large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma; or unclassifiable B-cell lymphoma with intermediate characteristics between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In certain embodiments, the lesion is adenoid cystic carcinoma. In certain embodiments, the lesion is NUT midline carcinoma.

[0332] In another embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotopic derivatives, or prodrugs, may be used in effective amounts to treat a host with an autoimmune disorder, such as a human. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid antibody syndrome; antisynthetic enzyme syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; polyglandular autoimmune syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorder; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; and Barlow's disease. (disease) / Barrow concentric sclerosis; Behçet's disease; Berger's disease; Bickerstaff's encephalitis; Blau syndrome; bullous pemphigoid; cancer; Castleman disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing polymyelitis; Churg-Strauss syndrome; scarring pemphigoid; Cogan syndrome; cold agglutinin disease; complement component 2 deficiency; contact dermatitis; cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; cutaneous leukocytoclastic vasculitis; Degos disease; Darkham's disease; herpetiform dermatitis; dermatomyositis; type 1 diabetes; diffuse dermatitis Systemic sclerosis of the skin; discoid lupus erythematosus; Dressler syndrome; drug-induced lupus; eczema; endometriosis; enthesitis-associated arthritis; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; acquired epidermolysis bullosa; erythema nodosum; erythroblastosis fetus; essential mixed cryoglobulinemia; Evans syndrome; exogenous and endogenous reactive airway disease (asthma); fibrodysplasia ossificans progressive; fibrous alveolitis (or idiopathic pulmonary fibrosis); gastritis; pemphigoid gastroenteritis; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's disease; hemolytic anemia; Henoch-Schönlein purpura;Herpes zoster of pregnancy (bullous pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stovin syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating disease; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; IgA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonia; inclusion body myositis; inflammatory bowel disease; interstitial cystitis; juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis; Kawasaki disease; Lambert-Eaton myasthenic syndrome; leukocytoclastic vasculitis; lichen planus; lichen sclerosing; linear IgA disease (LAD); Lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Magid's syndrome; microscopic polyangiitis; Miller-Fischer syndrome; mixed connective tissue disease; focal scleroderma; Mucher-Habermann disease, also known as acute pityriasis lichenoides; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ocular pemphigoid; opsoclonus myoclonus syndrome; Ord's thyroiditis Thyroiditis; Recurrent rheumatoid arthritis; PANDAS (Pediatric autoimmune streptococcal neuropsychiatric disorder); Paraneoplastic cerebellar degeneration; Paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; Slamic mange; Personage-Turner syndrome; Pemphigus vulgaris; Perivenous encephalomyelitis; Pernicious anemia; POEMS syndrome; Polyarteritis nodosa; Polymyalgia rheumatica; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; Pure red cell aplasia; Pyoderma gangrenosum; Rasmussen's encephalitis; Raynaud's phenomenon; Reiter's syndrome; Relapsing polychondritis; Restless legs syndrome Retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoidosis; schizophrenia; Schmidt syndrome; Schnitzler syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; Sjögren's syndrome; spondyloarthritis; stiff person syndrome; Still's disease; subacute bacterial endocarditis (SBE); Suzak syndrome; Sweet's syndrome; Sydenham's chorea; sympathetic ophthalmitis; systemic lupus erythematosus; Takayasu's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; undifferentiated spondyloarthritis; urticarial vasculitis; vasculitis; vitiligo;Examples include, but are not limited to, viral diseases such as Epstein-Barr virus (EBV), hepatitis B, hepatitis C, HIV, HTLV-1, varicella-zoster virus (VZV), and human papillomavirus (HPV); or Wegener's granulomatosis. In some embodiments, autoimmune diseases are allergic conditions, including asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0333] Skin contact hypersensitivity and asthma are just two examples of immune responses that may have a significant prevalence. Other examples include atopic dermatitis, eczema, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions. These conditions may present with one or more of the following symptoms or signs: itching, swelling, redness, blistering, crusting, ulceration, pain, desquamation, cracking, hair loss, scarring, or exudation of fluid from the skin, eyes, or mucous membranes.

[0334] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly mononuclear cells, lymphocytes, neutrophils, and eosinophils) generally plays a significant role in the development of these diseases. Chronic eczema is also associated with marked epidermal hyperplasia. Immune-mediated leukocyte infiltration can occur in areas other than the skin, such as the airways in asthma and the tear-producing glands in keratoconjunctivitis sicca.

[0335] The compounds described herein, or their pharmaceutically acceptable salts, isotopic variants, or prodrugs, can be administered in effective doses to a host, such as a human, having skin disorders such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, skin rashes, skin irritations, or skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, may cause skin sensitization when applied topically. In some embodiments, skin disorders are treated by topical administration of compounds known in the art in combination with the compounds disclosed herein. In one non-limiting embodiment, the compounds of the present invention are used as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, Sjögren's syndrome including keratoconjunctivitis sicca secondary to Sjögren's syndrome, alopecia areata, allergic reactions due to arthropod bites, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.

[0336] Diseases or conditions that can be treated with the compounds according to the present invention include, for example, autoimmune diseases such as asthma and multiple sclerosis, various cancers, ciliary diseases, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, intellectual disability, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot-Marie-Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease 1 (PKD1) or 2 (PKD2), Prader-Willi syndrome, sickle cell anemia, Tay-Sachs disease, and Turner syndrome.

[0337] Further disease conditions or pathological states that can be treated with the compounds according to the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barré syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, Parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, Tourette syndrome, and vasculitis.

[0338] Further additional disease conditions or pathologies that can be treated with the compounds according to the present invention include, in particular, aceruloplasminemia, achondroplasia type II, chondrodysplasia, acrocephaly, Gaucher disease type II, acute intermittent porphyria, Canavan disease, adenomatous polyposis of the colon, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric tissue browning, α1-antitrypsin deficiency, α-1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, amelodysplasia, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, and diffuse endokeratosis. Candidoma, retinal hemangioma (von Hippel-Lindau disease), Apert syndrome, arachnoid finger (Marfan syndrome), Stickler syndrome, congenital polyarthralgia (Ehlers-Danlos syndrome #polyarthralgia type), telangiectasia ataxia, Rett syndrome, primary pulmonary hypertension, Sandhoff disease, neurofibromatosis type II, Behle-Stevenson gyrus syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral acoustic neurofibromatosis (neurofibromatosis type II), factor V Leiden embolism, Bloch-Salzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnewi-Ulrich syndrome (Turner syndrome), Brunneville disease (tubular sclerosis), prion disease, Birt-Hogg-Duvet syndrome, osteoporosis (osteogenesis imperfecta), broad thumb-toe syndrome (Broad Thumb-Hallux syndrome (Rubinstein-Taybe syndrome), Bronzed Cirrhosis (hemochromatosis), Spinal and bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency), CGD (chronic granulomatous disease), flexor limb dysplasia, biotinidase deficiency, cardiomyopathy (Noonan syndrome), cat-meow syndrome, CAVD (congenital absence of the vas deferens), Keiler's cardiac face syndrome (CBAVD), CEP (congenital erythroblastic porphyria), cystic fibrosis, congenital hypothyroidism, chondrodysplasia (chondrodysplasia), megaepiphysis of the otospinal dysplasia, Lesch-Nyhan syndrome,Galactosemia, Ehlers-Danlos syndrome, fatal dysplasia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), congenital erythroblastic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, chondrodysplasia, X-linked sideroblastic anemia, connective tissue disease, conotibial stump anomalous facies syndrome, Cooley's anemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease Menkes disease, hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Kruschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyroscal syndrome, primary hyperoxaluria, spondyloeiophygeous dysplasia (Stradwick type), Duchenne and Becker syndromes. Degenerative neurological disorders including DBMD, Usher syndrome, de Grouchy syndrome and Degerin-Sottas syndrome, developmental disorders, distal spinal muscular atrophy type V, androgen insensitivity syndrome, diffuse globoid body sclerosis (Krabbe disease), DiGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, myeloid protoporphyria, erythroblastic type 5-aminolevulinate synthase deficiency Porphyria, myeloid protoporphyria, erythropoiesis-producing uroporphyria, Friedreich's ataxia - familial paroxysmal polyserositis, latent cutaneous disease, familial pressure-sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cyst, fragile X syndrome, galactosemia, hereditary brain disorder, giant cell hepatitis (neonatal hemochromatosis), Glenblatt-Strandbury syndrome (pseudoxanthoma elasticum), Günther's disease (congenital erythroblastic porphyria) Phosphorus, hemochromatosis, Hargren's syndrome, sickle cell anemia, hemophilia, hepatic myeloid porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenosis, achondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome,Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniist dysplasia, mottled dementia, Langer-Sardino achondroplasia, telangiectatic ataxia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniist dysplasia, Marfan syndrome, motor disorders, Mowat-Wilson syndrome, cystic fibrosis, Muwenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney achondroplasia, Niemann-Pick disease, Noak syndrome (Pfeiffer syndrome), Osler-Weber-Lange disease, Peutz-Jegers syndrome, polycystic kidney disease, polyosteid fibrous dysplasia (McKune-Albright syndrome), Peutz-Jegers syndrome, Prader-Raaphardt-Willi syndrome Group, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), chronic hereditary progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PX E (pseudoxanthoma elasticum), Rb (retinoblastoma), neurofibromatosis type 1, relapsing polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Licker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe chondrodysplasia with developmental delay and acanthosis nigricans (SADDAN), Lie-Fraumeni syndrome, sarcoma, mammary gland, leukemia and adrenal gland (sarcoma, Breast, leukemia, and adrenal gland (SBLA) syndrome, tuberous sclerosis (sclerosis tuberose (tuberous sclerosis)), SDAT, congenital SED (congenital spondyloepiphysis dysplasia), Stradwick type SED (Stradwick type spondyloepiphysis dysplasia), SEDc (congenital spondyloepiphysis dysplasia), Stradwick type SEMD (Stradwick type spondyloepiphysis dysplasia), Sprinzen syndrome, cutaneous pigmentation disorder, Smith-Lemle-Opitz syndrome, South African hereditary porphyria (atypical porphyria),These include infant-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disorders, sausage-like neuropathy (hereditary pressure-fragility neuropathy), Treacher Collins syndrome, triplo-X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Floric disease, Waardenburg syndrome, Warburg-Schöf-Frederius syndrome, Wolf-Hirschhorn syndrome, Wolf's periodic disorder, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0339] In a particular embodiment, a treatment for multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition. In another embodiment, a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, is used in a treatment for multiple myeloma, comprising administering the compound to a patient.

[0340] In a particular embodiment, a treatment for managing the progression of multiple myeloma is provided, comprising administering to a patient an effective dose of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition. In another embodiment, a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, is used in a treatment for managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0341] In addition to patients who have not previously received treatment, treatment will also be provided for patients who have previously received treatment for multiple myeloma but have not responded to standard therapy. In addition to patients who have not undergone surgery, supplementary treatment will be provided for patients who have undergone surgery to treat multiple myeloma. In addition to patients who have not received transplant therapy, treatment will also be provided for patients who have previously received transplant therapy.

[0342] In certain embodiments, the disorder treated by the present invention is wild-type cancer, where “wild-type” refers to cancer that has not developed resistance to previously effective treatments (i.e., recurrent cancer) and does not have mutations that confer resistance (i.e., refractory cancer). In certain embodiments, the disorder treated by the present invention is recurrent cancer. In certain embodiments, the disorder treated by the present invention is refractory cancer. In certain embodiments, the disorder treated by the present invention is recurrent, refractory cancer.

[0343] The compounds described herein, for example, Compound 1 or a pharmaceutically acceptable salt thereof, can be administered for the treatment or management of relapsed, refractory, or resistant multiple myeloma or non-Hodgkin lymphoma. In some embodiments, the disorder is primary, secondary, or has relapsed three, four, or five times. In certain embodiments, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0344] The types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to, monoclonal hypergammaglobulinemia of unspecified significance (MGUS), low-risk, intermediate-risk, or high-risk multiple myeloma, newly diagnosed multiple myeloma (including newly diagnosed low-risk, intermediate-risk, or high-risk multiple myeloma), transplant-eligible and non-transplant-eligible multiple myeloma, smoldering (painless) multiple myeloma (including low-risk, intermediate-risk, or high-risk smoldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma.

[0345] In a particular embodiment, a treatment for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, as induction therapy.

[0346] In a particular embodiment, a treatment for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, as a consolidation therapy.

[0347] In a particular embodiment, a method for treating or managing multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, as maintenance therapy.

[0348] In certain embodiments, multiple myeloma is a plasma cell leukemia.

[0349] In certain embodiments, multiple myeloma is high-risk multiple myeloma. In some embodiments, high-risk multiple myeloma is relapsing or refractory. In certain embodiments, high-risk multiple myeloma relapses within 12 months of initial treatment. In other embodiments, high-risk multiple myeloma is characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, high-risk multiple myeloma is relapsing or refractory to one, two, or three prior treatments.

[0350] In some embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is suitable for transplantation. In other embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is not suitable for transplantation.

[0351] In some embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) after autologous stem cell transplantation. In yet another embodiment, multiple myeloma is refractory to lenalidomide. In yet another embodiment, multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In yet another embodiment, multiple myeloma is relapsed or refractory to three or more treatments and is exposed to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), or is double refractory to proteasome inhibitors and immunomodulatory compounds. In yet another embodiment, multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, CD38 monoclonal antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide or avadomide), or is double refractory to proteasome inhibitors or immunomodulatory compounds and CD38 mAbs. In further embodiments, multiple myeloma is triple-refractory, for example, to proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdomide, or avadomide), and another activator described herein.

[0352] In a particular embodiment, a treatment is provided for treating or managing relapsed or refractory multiple myeloma in a patient having renal impairment or symptoms thereof, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0353] In another embodiment, a treatment is provided for managing relapsed or refractory multiple myeloma in a frail patient, comprising administering to the patient an effective dose of a compound described herein, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug, in a pharmaceutically acceptable carrier for optionally forming a composition, wherein the frail patient is characterized by being unsuitable for induction therapy or intolerant to dexamethasone treatment. In another embodiment, the frail patient is elderly, for example, over 65 years of age.

[0354] In another embodiment, a fourth-line treatment for managing relapsed or refractory multiple myeloma is provided, comprising administering to a patient an effective dose of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0355] In another embodiment, a treatment for managing newly diagnosed, transplant-unsuitable multiple myeloma is provided, comprising administering to a patient an effective dose of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0356] In another embodiment, a treatment for managing newly diagnosed, transplant-unsuitable multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition, as an alternative therapy or post-transplant maintenance therapy.

[0357] In another embodiment, a treatment is provided for managing high-risk multiple myeloma that has relapsed or refractory to one, two, or three prior treatments, comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0358] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory non-Hodgkin lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed non-Hodgkin lymphoma. In certain embodiments, the disorder treated by the present invention is refractory non-Hodgkin lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory non-Hodgkin lymphoma.

[0359] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is relapsed multiple myeloma. In certain embodiments, the disorder treated by the present invention is refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is relapsed refractory multiple myeloma.

[0360] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory peripheral T-cell lymphoma.

[0361] In certain embodiments, compound 1 is administered for the treatment of PTCL-NOS (i.e., unspecified PTCL). In other embodiments, compound 1 is administered for the treatment of PTCL having specific subtypes, such as anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), intestinal disease-type T-cell lymphoma, and extranodal natural killer (NK) cell / T-cell lymphoma.

[0362] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK). + ) In certain embodiments, the disorder treated by the present invention is relapsed systemic anaplastic large cell lymphoma (ALK). + In certain embodiments, the disorder treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK). + In certain embodiments, the disorder treated by the present invention is relapsed, refractory systemic anaplastic large cell lymphoma (ALK). + )

[0363] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK). - ) In certain embodiments, the disorder treated by the present invention is relapsed systemic anaplastic large cell lymphoma (ALK). - In certain embodiments, the disorder treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK). - In certain embodiments, the disorder treated by the present invention is relapsed, refractory systemic anaplastic large cell lymphoma (ALK). - )

[0364] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory angioimmunoblastic T-cell lymphoma.

[0365] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory anaplastic large cell lymphoma.

[0366] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory mantle cell lymphoma.

[0367] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed follicular lymphoma. In certain embodiments, the disorder treated by the present invention is refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory follicular lymphoma.

[0368] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory follicular T-cell lymphoma.

[0369] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory peripheral T-cell lymphoma.

[0370] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed refractory diffuse large B-cell lymphoma.

[0371] In certain embodiments, compound 1 is administered to a patient who requires it in an effective amount for the treatment of follicular T-cell lymphoma. In certain embodiments, compound 1 is administered to a patient who requires it in an effective amount for the treatment of angioimmunoblastic T-cell lymphoma. In certain embodiments, compound 1 is administered to a patient who requires it in an effective amount for the treatment of systemic anaplastic large cell lymphoma (ALK). - It is administered to patients who require it in an effective amount to treat systemic anaplastic large cell lymphoma (ALK). In certain embodiments, compound 1 is used to treat systemic anaplastic large cell lymphoma (ALK). + It is administered to patients who need it in an effective amount to treat )

[0372] Additional examples of non-Hodgkin lymphomas that can be treated with the compounds described herein include double-hit lymphoma, triple-hit lymphoma, extranodal marginal zone B-cell lymphoma of MALT, extranodal NK / T-cell lymphoma, and myeloid lymphoma.

[0373] Pharmacodynamic dose adjustment and biomarkers In certain embodiments, the compounds of the present invention are administered in an effective amount to treat a patient having a cereblon-mediated disorder, the treatment comprising administering an effective amount of the compound to the patient and monitoring the concentration of a biomarker selected from IRF-1, caspase-1, caspase-3, caspase-7, cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, MYC, IL-2, T cell activation and / or proliferation, BCMA, M protein, PARP, BIM, Survivin, IKZF1, IKZF3, ZFP91, WIZ and / or IFN-γ or a combination thereof.

[0374] In certain embodiments, treatment of a patient with the compounds described herein increases the concentrations of IRF-1 and / or caspase 3. The magnitude of this increase can be used to determine whether the dose of the compounds described herein should be increased, decreased, or maintained at the same level. For example, if the concentrations of IRF-1 and / or caspase 3 increase by less than 1.25, 1.5, 1.75, or 2 times, a physician may increase the dose of compound 1 administered to a patient being treated for lymphoma.

[0375] In certain embodiments, treatment of a patient with the compounds described herein results in a decrease in the concentrations of cyclin D and / or E2F1. The magnitude of this decrease can be used to determine whether the dose of the compounds described herein should be increased, decreased, or maintained. For example, if the concentrations of cyclin D and E2F1 decrease by less than 1.25, 1.5, 1.75, or 2 times, a physician may increase the dose of compound 1 administered to a patient being treated for lymphoma.

[0376] In certain embodiments, the concentrations of cyclin D, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC are reduced when treating a patient with the compounds described herein. In certain embodiments, the patient has lymphoma. The magnitude of the reduction can be used to determine whether the dose of the compounds described herein should be increased, decreased, or maintained at the same level.

[0377] In certain embodiments, treatment of a patient with the compounds described herein increases the concentration of IL-2 and / or IFN-γ. In certain embodiments, the patient has myeloma. The magnitude of the increase can be used to determine whether the dose of the compounds described herein should be increased, decreased, or maintained at the same level.

[0378] In certain embodiments, the concentration of a biomarker increases by approximately 3, 4, 5, 6, 7, or 8 times upon delivery of an effective dose of a compound described herein, for example, compound 1. For example, as shown in Figure 51, treatment with compound 1 increases the activity levels of caspase-3 and caspase-7 by more than 800%. In certain embodiments, the caspase 3 / 7 activity levels are measured, and if they are less than approximately 2, 3, 4, 5, 6, 7, or 8 times, the dose of compound 1 is increased.

[0379] In a particular embodiment, the biomarker is STAT3.

[0380] In a particular embodiment, the biomarker is Ki67.

[0381] In certain embodiments, the concentration of the biomarker decreases by approximately 3, 4, 5, 6, 7, or 8 times upon delivery of an effective dose of the compounds described herein, for example, compound 1.

[0382] In certain embodiments, patients treated with compounds selected from compound 1, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, and compound 13 are selected based on the concentration of a biomarker. For example, patients treated with compound 1 may be selected based on the concentration of a biomarker.

[0383] In a particular embodiment, the biomarker is selected from IKZF1, IKZF3, MYC, il2, INFy, TNFa, sFLC, and sBCMA.

[0384] In certain embodiments, the biomarker is selected from IRF-1, caspase-3, cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, MYC, IL-2, and / or IFN-γ.

[0385] In certain embodiments, the biomarker is a tumor immune marker (e.g., cytokines, tumor-infiltrating lymphocytes, T cell activation and / or proliferation, and B cell markers such as BCMA or M protein, or a combination thereof).

[0386] In certain embodiments, the biomarker is an apoptosis marker (e.g., whole and / or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM, or survivin, or a combination thereof).

[0387] In certain embodiments, the biomarker is a zinc finger protein (e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof).

[0388] Therapeutic benefits In one aspect of the present invention, the treatment described herein has one or more advantages over currently approved cancer treatments, such as the treatment of multiple myeloma or non-Hodgkin lymphoma. For example, compound 1 or a pharmaceutically acceptable salt thereof administered using the treatment described herein has better outcomes in one or more of the following measurements than currently approved treatments, such as thalidomide, pomalidomide, or lenalidomide (see Examples 9, 12, 13, 15-19, 26-31, and 35, which demonstrate the superior efficacy of compound 1 in models of multiple myeloma and non-Hodgkin lymphoma).

[0389] In certain embodiments, the advantage of compound 1 over currently known treatments is a reduced tendency to develop resistance. For example, mice that showed resistance to treatment with pomalidomide still responded rapidly to treatment with compound 1 (see Figure 40). Furthermore, even when treatment was discontinued for a sufficient period for the mouse tumors to regrow and compound 1 was re-administered, the tumor size rapidly decreased (see Figure 33).

[0390] In other embodiments, a significant advantage over currently approved therapies is the ability to treat refractory tumors. For example, in mice, a low dose of 30 μg / kg of compound 1 was effective in treating NCI-H929 tumors that did not respond to 3000 μg / kg (see Figure 33). Furthermore, across a panel of cell lines, compound 1 was consistently 2-3 magnitude potent than pomalidomide, demonstrating efficacy even against cells refractory to pomalidomide (see Figure 32). This effect was also demonstrated by tracking biomarker concentrations such as caspase 3 (see Figure 31).

[0391] In other embodiments, an advantage over currently approved therapies is that IKZF1 and IKZF3 are broken down more quickly, and therefore cancer can be treated more rapidly. For example, compound 1, when administered at the same concentration, breaks down more IKZF1 in one hour than pomalidomide, which breaks down in two hours (see Figure 29).

[0392] In certain embodiments, a treatment is provided for inducing a therapeutic response in a patient with multiple myeloma, as assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in Durie BG M; et al. "International uniform response criteria for multiple myeloma. Leukemia 2006, 10(10):1-7"), comprising administering to a patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0393] In another embodiment, a treatment is provided for achieving a severe complete response, complete response, or very good partial response as assessed by the IURC for multiple myeloma in a patient with multiple myeloma, comprising administering to the patient an effective amount of a compound described herein, or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, in a pharmaceutically acceptable carrier for optionally forming a composition.

[0394] In another embodiment, a treatment is provided for patients with multiple myeloma to achieve an increase in overall survival, progression-free survival, relapse-free survival, time to process, or disease-free survival, optionally comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, isotope analog, or prodrug, in a pharmaceutically acceptable carrier for forming a composition (see Examples 21 and 22, which demonstrate a dose-dependent increase in overall survival in animal models).

[0395] The benefits of compound 1 can be further enhanced by administering additional bioactive agents in combination therapy. For example, in a mouse study, administering compound 1 in a treatment regimen that included dexamethasone weekly was far more effective than administering the same dose of compound 1 or dexamethasone alone (see Figure 41).

[0396] Treatment of IKZF1 / IKZF3-mediated cancers with significant mutations In certain embodiments, the compounds described herein are administered in an effective amount to treat cancer mediated by a protein having one or more mutations, such as multiple myeloma mediated by a protein having one or more mutations.

[0397] In some embodiments, the compounds described herein can be administered in effective doses for the treatment or management of multiple myeloma characterized by genetic abnormalities, such as, but not limited to, cyclin D translocations (e.g., t(11;14)(q13;q32), t(6;14)(p21;32), t(12;14)(p13;q32), or t(6;20)), MMSET translocations (e.g., t(4;14)(p16;q32)), MAF translocations (e.g., t(14;16)(q32;a32), t(20;22), t(16;22)(q11;q13), or t(14;20)(q32;q11)), or other chromosomal factors (e.g., 17p13 or deletion of chromosome 13, del(17 / 17p), non-hyperdiploidy, and (1q) amplification).

[0398] In certain embodiments, multiple myeloma has a p53 mutation. In certain embodiments, the p53 mutation is a Q331 mutation. In certain embodiments, the p53 mutation is an R273H mutation. In certain embodiments, the p53 mutation is a K132 mutation. In certain embodiments, the p53 mutation is a K132N mutation. In certain embodiments, the p53 mutation is an R337 mutation. In certain embodiments, the p53 mutation is an R337L mutation. In certain embodiments, the p53 mutation is a W146 mutation. In certain embodiments, the p53 mutation is an S261 mutation. In certain embodiments, the p53 mutation is an S261T mutation. In certain embodiments, the p53 mutation is an E286 mutation. In certain embodiments, the p53 mutation is an E286K mutation. In certain embodiments, the p53 mutation is an R175 mutation. In certain embodiments, the p53 mutation is the R175H mutation. In certain embodiments, the p53 mutation is the E258 mutation. In certain embodiments, the p53 mutation is the E258K mutation. In certain embodiments, the p53 mutation is the A161 mutation. In certain embodiments, the p53 mutation is the A161T mutation.

[0399] In certain embodiments, multiple myeloma has a homozygous deletion of p53. In certain embodiments, multiple myeloma has a homozygous deletion of wild-type p53. In certain embodiments, multiple myeloma has wild-type p53.

[0400] In certain embodiments, multiple myeloma exhibits activation of one or more oncogenic drivers. In certain embodiments, one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In certain embodiments, multiple myeloma exhibits activation of C-MAF. In certain embodiments, multiple myeloma exhibits activation of MAFB. In certain embodiments, multiple myeloma exhibits activation of FGFR3 and MMset. In certain embodiments, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In certain embodiments, multiple myeloma exhibits activation of cyclin D1. In certain embodiments, multiple myeloma exhibits activation of MAFB and cyclin D1. In certain embodiments, multiple myeloma exhibits activation of cyclin D.

[0401] In certain embodiments, multiple myeloma has one or more chromosomal translocations. In certain embodiments, the chromosomal translocation is t(14;16). In certain embodiments, the chromosomal translocation is t(14;20). In certain embodiments, the chromosomal translocation is t(4;14). In certain embodiments, the chromosomal translocations are t(4;14) and t(14;16). In certain embodiments, the chromosomal translocation is t(11;14). In certain embodiments, the chromosomal translocation is t(6;20). In certain embodiments, the chromosomal translocation is t(20;22). In certain embodiments, the chromosomal translocations are t(6;20) and t(20;22). In certain embodiments, the chromosomal translocation is t(16;22). In certain embodiments, the chromosomal translocations are t(14;16) and t(16;22). In a particular embodiment, the chromosomal translocations are t(14;20) and t(11;14).

[0402] In certain embodiments, multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In certain embodiments, multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t(4;14) and t(14;16). In certain embodiments, multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In certain embodiments, multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In certain embodiments, multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocations at t(14;20) and t(11;14).In a particular embodiment, multiple myeloma has an A161T p53 mutation, cyclin D activation, and a chromosomal translocation at t(11;14).

[0403] Patient Selection In certain embodiments, patients treated with the compounds described herein may have previously received treatment with an IMiD, such as thalidomide, lenalidomide, or pomalidomide.

[0404] In certain embodiments, patients treated with the compounds described herein have previously received treatment with CD20 antibodies, such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab, tocitumomab, or ubrituximab.

[0405] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with a CD38 antibody, such as daratumumab or isatuximab.

[0406] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with a CD30 antibody, such as brentuximab.

[0407] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with BTK inhibitors, such as ibrutinib, acalabrutinib, or zanubrutinib.

[0408] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with alkylating agents, such as cyclophosphomide, melphan, melphalanflufenamide, or bendamustine.

[0409] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with proteasome inhibitors, such as bortezomib, carfilzomib, or ixazomib.

[0410] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with glucocorticoids, such as dexamethasone, predinisone, or methylprednisolone.

[0411] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with bone-modifying agents, such as denosumab, zoledronic acid, or pamidronate.

[0412] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with an HDAC inhibitor, such as panobinostat.

[0413] In certain embodiments, patients treated with the compounds described herein may have previously received treatment with a nuclear transport inhibitor, such as selinexol.

[0414] In certain embodiments, a patient treated for multiple myeloma has previously received at least one, two, three, or four anti-myeloma or lymphoma regimens, such as lenalidomide, pomalidomide, proteasome inhibitors, glucocorticoids, or anti-CD38 antibodies. For example, the patient has previously received at least three anti-myeloma regimens, each comprising at least two consecutive cycles of administration of lenalidomide, pomalidomide, proteasome inhibitors, glucocorticoids, or anti-CD38 antibodies.

[0415] In certain embodiments, patients treated for multiple myeloma have an M protein level of approximately 0.5 g / dL or higher by serum protein electrophoresis (sPEP), an M protein level of 200 mg / L or higher in a 24-hour urine sample by urinary protein electrophoresis (uPEP), a serum free light chain (FLC) level of more than 100 mg / L of the light chain involved, an abnormal kappa / lambda (κ / λ) ratio in subjects without measurable serum or urine M protein, and / or a serum IgA level of 0.50 g / dL or higher.

[0416] In certain embodiments, the treated patient has peripheral T-cell lymphoma and has previously received at least one alkylating agent-based chemotherapy treatment.

[0417] In certain embodiments, the treated patient has anaplastic large cell lymphoma (ALCL), has previously received at least one alkylating agent-based chemotherapy regimen, and has also received CD30 antibody therapy.

[0418] In a particular embodiment, the treated patient has mantle cell lymphoma and has previously received at least two lines of treatment, including a CD20 antibody and alkylating agent chemotherapy line and a Bruton's tyrosine kinase inhibitor.

[0419] In a particular embodiment, the treated patient has follicular lymphoma and has previously received at least two lines of treatment, including a CD20 antibody and alkylating agent chemotherapy line.

[0420] In certain embodiments, the treated patient has diffuse large B-cell lymphoma, has previously received at least two lines of treatment including CD20 antibody therapy, and has previously undergone (or is not eligible for) an autologous bone marrow transplant.

[0421] In a particular embodiment, a patient treated for non-Hodgkin lymphoma has a lesion measurable in at least two dimensions by PET-CT, for example, a lesion with a minimum measurement of at least about 15 mm in longest diameter.

[0422] In some embodiments, patients targeted for treatment with one of the compounds described herein have not been treated with multiple myeloma therapy prior to administration. In some embodiments, patients targeted for treatment with one of the compounds described herein have been treated with multiple myeloma therapy prior to administration. In some embodiments, patients targeted for treatment with one of the compounds described herein have developed drug resistance to multiple myeloma therapy. In some embodiments, patients targeted for treatment with one of the compounds described herein have developed resistance to one, two, or three multiple myeloma therapies, therapies selected from CD38 antibodies (CD38 mAbs, e.g., daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib or marizomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iverdamide or avadomide).

[0423] The compounds described herein can be administered in doses effective for the treatment of patients regardless of the patient's age. In some embodiments, the patient is 18 years of age or older. In other embodiments, the patient is 18, 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years of age. In other embodiments, the patient is under 65 years of age. In other embodiments, the patient is over 65 years of age. In certain embodiments, the patient is an elderly multiple myeloma patient, for example, over 65 years of age. In certain embodiments, the patient is an elderly multiple myeloma patient, for example, over 75 years of age.

[0424] V. Combination Therapy Any of the compounds described herein may be administered alone or in combination in an effective amount to treat a host, such as a human, having one of the disorders described herein. In certain embodiments, the compounds described herein are administered together with additional bioactive agents.

[0425] The term "bioactive agent" is used to describe active substances other than the compounds of the present invention that can be administered in combination with or alternately with the compounds of the present invention to achieve a desired therapeutic outcome. In certain embodiments, the compounds of the present invention and the bioactive agent are administered such that they have overlapping periods during which they are active in vivo, for example, Cmax, Tmax, AUC, or other pharmacokinetic parameters. In other embodiments, the compounds of the present invention and the bioactive agent are administered to a host in need, where they do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0426] As used herein, when a compound is administered in combination with another compound, the combination may be administered as one dosage form or as multiple dosage forms simultaneously or at different times. Furthermore, the compounds administered in combination may be administered on different dosing schedules. For example, the combination of compound 1 and dexamethasone may include a treatment regimen in which compound 1 is administered once daily for 21 consecutive days over a 28-day treatment cycle, and dexamethasone is administered once weekly during the same treatment cycle.

[0427] In certain embodiments, compound 1 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0428] In certain embodiments, compound 2 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0429] In certain embodiments, compound 3 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0430] In certain embodiments, compound 4 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0431] In certain embodiments, compound 5 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0432] In certain embodiments, compound 6 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0433] In certain embodiments, compound 7 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0434] In certain embodiments, compound 8 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0435] In certain embodiments, compound 9 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0436] In certain embodiments, compound 10 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0437] In certain embodiments, compound 11 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0438] In certain embodiments, compound 12 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0439] In certain embodiments, compound 13 is administered to a patient in need in an effective dose, in combination with one or more additional therapeutic agents described herein.

[0440] corticosteroids In certain embodiments, the compounds of the present invention are administered in combination with a corticosteroid. In certain embodiments, the corticosteroid is dexamethasone. In certain embodiments, compound 1 is administered together with a corticosteroid. In certain embodiments, compound 1 is administered together with dexamethasone, for example, in the following administration regimen.

[0441] [Table 1]

[0442] In certain embodiments, compound 1 is administered in combination with another bioactive agent (e.g., dexamethasone once a week) in a 21 / 7 dosing schedule every 28-day cycle in QD. In certain embodiments, the dose of dexamethasone for adults under 75 years of age is 40 mg QW on days 1, 8, 15, and 22 of the 28-day cycle. In certain embodiments, the dose of dexamethasone for adults over 75 years of age is 20 mg QW on days 1, 8, 15, and 22 of the 28-day cycle.

[0443] In certain embodiments, the compounds described herein are administered in combination with a corticosteroid. Non-limiting examples of corticosteroids include dexamethasone, prednisone, fludrocortisone, hydrocortisone, cortisone, betamethasone, and methylprednisolone.

[0444] In certain embodiments, compound 1 is administered in combination with a corticosteroid. In certain embodiments, compound 2 is administered in combination with a corticosteroid. In certain embodiments, compound 3 is administered in combination with a corticosteroid. In certain embodiments, compound 4 is administered in combination with a corticosteroid. In certain embodiments, compound 5 is administered in combination with a corticosteroid. In certain embodiments, compound 6 is administered in combination with a corticosteroid. In certain embodiments, compound 7 is administered in combination with a corticosteroid. In certain embodiments, compound 8 is administered in combination with a corticosteroid. In certain embodiments, compound 9 is administered in combination with a corticosteroid. In certain embodiments, compound 10 is administered in combination with a corticosteroid. In certain embodiments, compound 11 is administered in combination with a corticosteroid. In certain embodiments, compound 12 is administered in combination with a corticosteroid. In certain embodiments, compound 13 is administered in combination with a corticosteroid. In certain embodiments, the corticosteroid is dexamethasone.

[0445] Further non-exclusive examples of corticosteroids include corticosterone, aldosterone, prednisolone, triamcinolone, budesonide, deflazacort, flugestone, fluorometholone, medrizone, prepediolon acetate, chloroprednisone, cloprednol, difluprednate, fluocinolone, fluperolone, fluperolone acetate, fluprednisolone, loteprednol, prednicarbate, and thixocort. Alclomethasone, Alclomethasone dipropionate, Beclomethasone, Clobetasol, Clobetasol, Crocoltrone, Desoxymethasone, Diflorasone, Diflorasone diacetate, Difluocortrone, Difluocortrone valerate, Flupredniden, Flupredniden acetate, Fluticasone, Fluticasone furoate, Halomethasone, Meprednisone, Mometasone, Mometasone furoate, Paramethasone, Prednilide Rimexolone, urobetasol, amcinonide, ciclesonide, desonide, formocortal, fluchlorolone, fluchlorolone acetonide, fludroxycortide, flunisolid, fluocinolone, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone, triamcinolone acetonide, cortibazole, RU-28362, dexamethasone acephrate, dexamethasone acetate, dexamethasone cephate Examples include silate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulfobenzoate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone pivalate, dexamethasone succinate, dexamethasone sulfate, dexamethasone tebutate, dexamethasone troxinate, and dexamethasone valerate.

[0446] Kinase inhibitors In certain embodiments, the bioactive agent is a kinase inhibitor, such as a Bruton's tyrosine kinase (BTK) inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[0447] In certain embodiments, the compound of the present invention is administered in combination with a BTK inhibitor. In certain embodiments, the BTK inhibitor is ibrutinib. In certain embodiments, the BTK inhibitor is acalabrutinib. In certain embodiments, compound 1 is administered in combination with a BTK inhibitor. In certain embodiments, compound 1 is administered in combination with a BTK inhibitor, which is zanubrutinib. In certain embodiments, it is administered with ibrutinib. In certain embodiments, compound 1 is administered in combination with zanubrutinib. In certain embodiments, compound 1 is administered in combination with acalabrutinib.

[0448] In certain embodiments, compound 2 is administered in combination with a BTK inhibitor. In certain embodiments, compound 3 is administered in combination with a BTK inhibitor. In certain embodiments, compound 4 is administered in combination with a BTK inhibitor. In certain embodiments, compound 5 is administered in combination with a BTK inhibitor. In certain embodiments, compound 6 is administered in combination with a BTK inhibitor. In certain embodiments, compound 7 is administered in combination with a BTK inhibitor. In certain embodiments, compound 8 is administered in combination with a BTK inhibitor. In certain embodiments, compound 9 is administered in combination with a BTK inhibitor. In certain embodiments, compound 10 is administered in combination with a BTK inhibitor. In certain embodiments, compound 11 is administered in combination with a BTK inhibitor. In certain embodiments, compound 12 is administered in combination with a BTK inhibitor. In certain embodiments, compound 13 is administered in combination with a BTK inhibitor. In certain embodiments, the BTK inhibitor is selected from ibrutinib, zanubrutinib, and acalabrutinib.

[0449] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica®) (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine-1-yl]piperidine-1-yl]propa-2-en-1-one), dianilinopyrimidine inhibitors, such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidine-4-yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see U.S. Patent Application Publication No. 2011 / 0117073, which in whole forms part of this specification), dasatinib (N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidine-4-ylamino)thiazole-5-carboxamide), LFM-A13 (α-cyano-β -Hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834(RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), CGI-560 4-(tert-butyl)-N-(3-(8-(phenylamino)imidazo[1,2-a]pyrazine-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazine-2-yl)phenyl)benzamide), CNX-774(4-(4- ((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidine-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056(7-benzyl-1-(3-(piperidine-1-yl)propyl)-2-(4-(pyridine-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline-6(5H)-one), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazine-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazine-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059(Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindorin-6-yl)-9-(1-methyl-1H-pyrazole-4-yl)benzo[h][1,6]naphthili Examples include dzin-2(1H)-one) and RN486(6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridine-2-ylamino]-6-oxo-1,6-dihydropyridine-3-yl}phenyl)-2H-isoquinoline-1-one), as well as other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59 (which in whole constitutes part of this specification by reference).

[0450] In certain embodiments, the BTK inhibitor is selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib. In certain embodiments, compound 1 is administered in combination with a BTK inhibitor selected from acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.

[0451] Examples of PI3 kinase inhibitors include wartmannin, demethoxypyridine, perifosine, idelalisib, pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (tasericib), (2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazole-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-9-yl]pyrazole-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( S)-methylphosphonate; or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458(2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (Omiparisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidine-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylate dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidine-9 -yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-mohydroxypropane(mohydroxypropan)-1-one), GS-1101(5-fluoro-3-phenyl-2-([S])-1-[9H-purine-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-Dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424(5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidin-2,4-dione), CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridin-3-sulfonamide), Buparlicib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941(2-(1H-indazole-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidine-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazine-2-yl)phenyl]urea) (dactolisib), LY3023414, BEZ235 (2-methyl-2-{4-[3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinoline-1-yl]phenyl}propannitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-Dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(propa-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethylene) (Chill)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpericib, IC-87114, TGI100713, CH5132799, PKI-402, copanlicib (BAY 80-6946), XL Examples include, but are not limited to, structures described in International Publication No. 2014 / 071109, 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitricib (GDC-0980; RG7422), and International Publication No. 2014 / 071109.

[0452] Syk inhibitors include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazine-1-yl)phenyl)aminopyrimidine-5-carboxamide), entospletinib (6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazine-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyf [( 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidine-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridine-2-ylamino)-pyridazine-3-carboxylic acid amide), Imatinib (Gleevac; 4-[(4-methylpiperazine-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridine-3-yl)pyrimidine-2-yl]amino}phenyl)benzamide), Staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine), PRT-060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazole-2-yl)phenyl)amino)-2-(((1R,R112(3,3'-((5-fluoropyrimidine-2,4-diyl)bis(azandiyl))diphenol), R348(3-ethyl-4-methylpyridine), R406(6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), piceatannol(3-hydroxyresveratrol), YM193306(Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, See 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (the entire text is incorporated herein by reference)), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, See 3614-3643 (the entirety of which constitutes part of this specification by reference), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,See 3614-3643 (which in whole form constitutes part of this specification by reference), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (which in whole form constitutes part of this specification by reference)), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, Examples include 3614-3643 (see references thereto, which in whole form form part of this specification), myricetin (see references Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (see references thereto, which in whole form form part of this specification)), and morin (see references Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (see references thereto, which in whole form form part of this specification)).

[0453] Proteasome inhibitors In certain embodiments, the compound of the present invention is administered in combination with a proteasome inhibitor. In certain embodiments, the proteasome inhibitor is bortezomib. In certain embodiments, the proteasome inhibitor is ixazomib. In certain embodiments, the proteasome inhibitor is carfilzomib. In certain embodiments, compound 1 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 1 is administered in combination with bortezomib. In certain embodiments, compound 1 is administered in combination with ixazomib. In certain embodiments, compound 1 is administered in combination with carfilzomib. In certain embodiments, compound 1 is administered in combination with carfilzomib and daratumumab.

[0454] In certain embodiments, compound 2 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 3 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 4 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 5 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 6 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 7 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 8 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 9 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 10 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 11 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 12 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 13 is administered in combination with a proteasome inhibitor. In certain embodiments, the proteasome inhibitor is selected from bortezomib, ixazomib, VLX1570, and carfilzomib.

[0455] Further examples of proteasome inhibitors include ixazomib citrate, oprozomib, delanzomib, lactacystine, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616. In certain embodiments, compound 1 is administered in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystine, epixomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, VLX1570, and KZR-616.

[0456] HDAC inhibitors In certain embodiments, the compound of the present invention is administered in combination with an HDAC inhibitor. In certain embodiments, the HDAC inhibitor is vorinostat. In certain embodiments, the HDAC inhibitor is romidepsin. In certain embodiments, the HDAC inhibitor is panobinostat. In certain embodiments, the HDAC inhibitor is belinostat. In certain embodiments, compound 1 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 1 is administered in combination with vorinostat. In certain embodiments, compound 1 is administered in combination with romidepsin. In certain embodiments, compound 1 is administered in combination with panobinostat. In certain embodiments, compound 1 is administered in combination with belinostat.

[0457] In certain embodiments, compound 2 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 3 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 4 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 5 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 6 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 7 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 8 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 9 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 10 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 11 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 12 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 13 is administered in combination with an HDAC inhibitor. In certain embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, and verinostat.

[0458] In certain embodiments, the HDAC inhibitor is selected from trapoxin B, sodium phenylbutyrate, tasedinarin, mosetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzamate A, spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, avexinostat, resminostat, zivinostat, xinostat, psammaprin A, KD5170, 1-alanine clamidosin, depdesin, and CUDC-101. In certain embodiments, compound 1 is administered in combination with an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tasedinarin, mosetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzamate A, spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, pyroxamide, avexinostat, resminostat, zivinostat, xinostat, psammaprin A, KD5170, 1-alanine clamidosin, depdesin, and CUDC-101.

[0459] IMiD In certain embodiments, the compound of the present invention is administered in combination with IMiD. In certain embodiments, IMiD is thalidomide. In certain embodiments, IMiD is lenalidomide. In certain embodiments, IMiD is pomalidomide. In certain embodiments, compound 1 is administered in combination with thalidomide. In certain embodiments, compound 1 is administered in combination with lenalidomide. In certain embodiments, compound 1 is administered in combination with pomalidomide.

[0460] In certain embodiments, compound 2 is administered in combination with IMiD. In certain embodiments, compound 3 is administered in combination with IMiD. In certain embodiments, compound 4 is administered in combination with IMiD. In certain embodiments, compound 5 is administered in combination with IMiD. In certain embodiments, compound 6 is administered in combination with IMiD. In certain embodiments, compound 7 is administered in combination with IMiD. In certain embodiments, compound 8 is administered in combination with IMiD. In certain embodiments, compound 9 is administered in combination with IMiD. In certain embodiments, compound 10 is administered in combination with IMiD. In certain embodiments, compound 11 is administered in combination with IMiD. In certain embodiments, compound 12 is administered in combination with IMiD. In certain embodiments, compound 13 is administered in combination with IMiD. In certain embodiments, IMiD is selected from pomalidomide, thalidomide, and lenalidomide.

[0461] In certain embodiments, IMiD is CC-90009. In certain embodiments, IMiD is CC-99282. In certain embodiments, IMiD is CC-92480. In certain embodiments, compound 1 is administered in combination with CC-90009. In certain embodiments, compound 1 is administered in combination with CC-99282. In certain embodiments, compound 1 is administered in combination with CC-92480.

[0462] In certain embodiments, compound 2, compound 3, compound 4, compound 5, compound 6, compound 7, compound 8, compound 9, compound 10, compound 11, compound 12, or compound 13 is administered in combination with IMiD. In certain embodiments, IMiD is selected from CC-90009, CC-99282, and CC-92480.

[0463] antibody In certain embodiments, the compound of the present invention is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, the targeted antibody is rituximab. In certain embodiments, the targeted antibody is daratumumab. In certain embodiments, the targeted antibody is elotuzumab. In certain embodiments, the targeted antibody is isatuximab. In certain embodiments, compound 1 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 1 is administered in combination with rituximab. In certain embodiments, compound 1 is administered in combination with daratumumab. In certain embodiments, compound 1 is administered in combination with elotuzumab. In certain embodiments, compound 1 is administered in combination with isatuximab.

[0464] In certain embodiments, compound 2 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 3 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 4 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 5 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 6 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 7 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 8 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 9 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 10 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 11 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 12 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, compound 13 is administered in combination with an antibody targeting CD20, CD30, or CD38. In certain embodiments, the targeted antibody is selected from rituximab, daratumumab, elotuzumab, and isatuximab.

[0465] In certain embodiments, the compound of the present invention is administered in combination with an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is brentuximab vedotin. In certain embodiments, the antibody-drug conjugate is ibritumomab tiuxetan. In certain embodiments, the antibody-drug conjugate is mogamulizumab. In certain embodiments, the antibody-drug conjugate is obinutuzumab. In certain embodiments, the antibody-drug conjugate is polatuzumab vedotin. In certain embodiments, the antibody-drug conjugate is verantamab mahodotin (GSK2857916). In certain embodiments, the antibody-drug conjugate is MEDI2228. In certain embodiments, the antibody-drug conjugate is CC-99712. In certain embodiments, compound 1 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 1 is administered in combination with brentuximab vedotin. In certain embodiments, compound 1 is administered in combination with ibritumomab tiuxetan. In certain embodiments, compound 1 is administered in combination with mogamulizumab. In certain embodiments, compound 1 is administered in combination with obinutuzumab. In certain embodiments, compound 1 is administered in combination with polatuzumab vedotin. In certain embodiments, compound 1 is administered in combination with verantamab mahodotin (GSK2857916). In certain embodiments, compound 1 is administered in combination with MEDI2228. In certain embodiments, compound 1 is administered in combination with CC-99712. In certain embodiments, compound 1 is administered in combination with tafacitamab.

[0466] In certain embodiments, compound 2 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 3 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 4 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 5 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 6 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 7 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 8 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 9 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 10 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 11 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 12 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 13 is administered in combination with an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is selected from brentuximab vedotin, ibritumomab tiuxetan, mogamulizumab, obinutuzumab, polatuzumab vedotin, verantamab mahodotin (GSK2857916), MEDI2228, and CC-99712.

[0467] In certain embodiments, the compound of the present invention is administered in combination with a bispecific antibody. In certain embodiments, the bispecific antibody is PF-06863135. In certain embodiments, the bispecific antibody is TNB-383B. In certain embodiments, the bispecific antibody is REGN5458. In certain embodiments, the bispecific antibody is JNJ-64007957. In certain embodiments, compound 1 is administered in combination with a bispecific antibody. In certain embodiments, compound 1 is administered in combination with PF-06863135. In certain embodiments, compound 1 is administered in combination with TNB-383B. In certain embodiments, compound 1 is administered in combination with REGN5458. In certain embodiments, compound 1 is administered in combination with JNJ-64007957.

[0468] In certain embodiments, compound 2 is administered in combination with a bispecific antibody. In certain embodiments, compound 3 is administered in combination with a bispecific antibody. In certain embodiments, compound 4 is administered in combination with a bispecific antibody. In certain embodiments, compound 5 is administered in combination with a bispecific antibody. In certain embodiments, compound 6 is administered in combination with a bispecific antibody. In certain embodiments, compound 7 is administered in combination with a bispecific antibody. In certain embodiments, compound 8 is administered in combination with a bispecific antibody. In certain embodiments, compound 9 is administered in combination with a bispecific antibody. In certain embodiments, compound 10 is administered in combination with a bispecific antibody. In certain embodiments, compound 11 is administered in combination with a bispecific antibody. In certain embodiments, compound 12 is administered in combination with a bispecific antibody. In certain embodiments, compound 13 is administered in combination with a bispecific antibody. In certain embodiments, the bispecific antibody is selected from PF-06863135, TNB-383B, REGN5458, and JNJ-64007957.

[0469] In certain embodiments, the compounds of the present invention are administered in combination with a naked monoclonal antibody (mAb). In certain embodiments, the naked mAb is SEA-BCMA. In certain embodiments, compound 1 is administered in combination with a naked mAb. In certain embodiments, compound 1 is administered in combination with SEA-BCMA.

[0470] In certain embodiments, compound 2 is administered in combination with a naked mAb. In certain embodiments, compound 3 is administered in combination with a naked mAb. In certain embodiments, compound 4 is administered in combination with a naked mAb. In certain embodiments, compound 5 is administered in combination with a naked mAb. In certain embodiments, compound 6 is administered in combination with a naked mAb. In certain embodiments, compound 7 is administered in combination with a naked mAb. In certain embodiments, compound 8 is administered in combination with a naked mAb. In certain embodiments, compound 9 is administered in combination with a naked mAb. In certain embodiments, compound 10 is administered in combination with a naked mAb. In certain embodiments, compound 11 is administered in combination with a naked mAb. In certain embodiments, compound 12 is administered in combination with a naked mAb. In certain embodiments, compound 13 is administered in combination with a naked mAb. In certain embodiments, the naked mAb is SEA-BCMA.

[0471] Other non-limiting examples of CD38 antibodies include ferzaltamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, and mezagitamab. In certain embodiments, compound 1 is administered in combination with a CD38 antibody selected from ferzaltamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0472] CAR T cell therapy In certain embodiments, the compounds of the present invention are administered in combination with CAR T-cell therapy. In certain embodiments, the CAR T-cell therapy is axicabtagene ciloleucel. In certain embodiments, the CAR T-cell therapy is tisagenlecleucel. In certain embodiments, the CAR T-cell therapy is idecabutagene vicleucel (ide-cel; bb2121). In certain embodiments, the CAR T-cell therapy is LCAR-B38M (JNJ-4528; JNJ-68284528). In certain embodiments, the CAR T-cell therapy is P-BCMA-101. In certain embodiments, the CAR T-cell therapy is PBCAR269A. In certain embodiments, the CAR T-cell therapy is bb21217. In certain embodiments, the CAR T cell therapy is JCARK125 (orva-cel; orvacabtagene autoleucel). In certain embodiments, the CAR T cell therapy is ALLO-715. In certain embodiments, the CAR T cell therapy is Descartes-08. In certain embodiments, the CAR T cell therapy is FCARH143. In certain embodiments, the CAR T cell therapy is CT053.

[0473] In certain embodiments, compound 1 is administered in combination with CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with axicaptagene silolucel. In certain embodiments, compound 1 is administered in combination with tisagenecleucel. In certain embodiments, compound 1 is administered in combination with idekabutagene bicleucel (ide-cel; bb2121). In certain embodiments, compound 1 is administered in combination with LCAR-B38M (JNJ-4528; JNJ-68284528). In certain embodiments, compound 1 is administered in combination with P-BCMA-101. In certain embodiments, compound 1 is administered in combination with PBCAR269A. In certain embodiments, compound 1 is administered in combination with bb21217. In certain embodiments, compound 1 is administered in combination with JCARK125 (orva-cel; orbabutagene ordolucel). In certain embodiments, compound 1 is administered in combination with ALLO-715. In certain embodiments, compound 1 is administered in combination with Descartes-08. In certain embodiments, compound 1 is administered in combination with FCARH143. In certain embodiments, compound 1 is administered in combination with CT053.

[0474] In certain embodiments, compound 2 is administered in combination with CAR T cell therapy. In certain embodiments, compound 3 is administered in combination with CAR T cell therapy. In certain embodiments, compound 4 is administered in combination with CAR T cell therapy. In certain embodiments, compound 5 is administered in combination with CAR T cell therapy. In certain embodiments, compound 6 is administered in combination with CAR T cell therapy. In certain embodiments, compound 7 is administered in combination with CAR T cell therapy. In certain embodiments, compound 8 is administered in combination with CAR T cell therapy. In certain embodiments, compound 9 is administered in combination with CAR T cell therapy. In certain embodiments, compound 10 is administered in combination with CAR T cell therapy. In certain embodiments, compound 11 is administered in combination with CAR T cell therapy. In certain embodiments, compound 12 is administered in combination with CAR T cell therapy. In certain embodiments, compound 13 is administered in combination with CAR T cell therapy. In certain embodiments, the CAR T cell therapy is selected from axicaptagene silolucel, tisagenlecleucel, idekabutagene bicleucel (ide-cel; bb2121), LCAR-B38M (JNJ-4528; JNJ-68284528), and P-BCMA-101. In certain embodiments, the CAR T cell therapy is selected from PBCAR269A, bb21217, JCARK125 (orva-cel; orbabutagene ortreucel), ALLO-715, Descartes-08, FCARH143, and CT053.

[0475] In certain embodiments, CAR T cell therapy is selected from ALLO-715, bb21217, BCMA CAR-T, CD138 CAR-T, CD19 CAR-T, ciltacabtagene autoleucel, CS1(SLAMF7)CAR-T, CT053, Descartes-11, idekabutagene villeucel, NKG2D CAR-T, orbabubutagene autoleucel, P-BCMA-101, and UCARTCS1.

[0476] cell therapy In certain embodiments, the compounds of the present invention are administered in combination with cell therapy. In certain embodiments, compound 1 is used in combination with cell therapy.

[0477] Non-limited examples of cell therapy include allo-HSCT, allo-NKT, auto-HSCT, and auto-NKT.

[0478] T cell engager In certain embodiments, the compound of the present invention is administered in combination with a bispecific T cell engager (BiTE). In certain embodiments, the BiTE is blinatumomab. In certain embodiments, the BiTE is CC-93268. In certain embodiments, the BiTE is AMG 420. In certain embodiments, the BiTE is AMG 701. In certain embodiments, compound 1 is administered in combination with a bispecific T cell engager (BiTE). In certain embodiments, compound 1 is administered in combination with blinatumomab. In certain embodiments, compound 1 is administered in combination with AMG 420. In certain embodiments, compound 1 is administered in combination with CC-93269. In certain embodiments, compound 1 is administered in combination with AMG 701.

[0479] In certain embodiments, compound 2 is administered in combination with BiTE. In certain embodiments, compound 3 is administered in combination with BiTE. In certain embodiments, compound 4 is administered in combination with BiTE. In certain embodiments, compound 5 is administered in combination with BiTE. In certain embodiments, compound 6 is administered in combination with BiTE. In certain embodiments, compound 7 is administered in combination with BiTE. In certain embodiments, compound 8 is administered in combination with BiTE. In certain embodiments, compound 9 is administered in combination with BiTE. In certain embodiments, compound 10 is administered in combination with BiTE. In certain embodiments, compound 11 is administered in combination with BiTE. In certain embodiments, compound 12 is administered in combination with BiTE. In certain embodiments, compound 13 is administered in combination with BiTE. In certain embodiments, BiTE is selected from blinatumomab, AMG 420, CC-93269, and AMG 4701.

[0480] In certain embodiments, compound 1 is used in combination with a bispecific antibody selected from AMG 420, AMG 701, BFCR4350A, blinatumomab, CC-93269, erranatamab, EM801, REGN5458, talketamab, tecristamab, and TNB-383B.

[0481] Immunomodulator checkpoint inhibitors In certain embodiments, the compound of the present invention is administered in combination with a checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with a PD-1 checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, the compound of the present invention is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is nivolumab. In certain embodiments, the checkpoint inhibitor is pembrolizumab. In certain embodiments, the checkpoint inhibitor is interferon alpha-2b. In certain embodiments, compound 1 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with a PD-1 checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with nivolumab. In certain embodiments, compound 1 is administered in combination with pembrolizumab. In a particular embodiment, compound 1 is administered in combination with interferon alpha-2b.

[0482] In certain embodiments, compound 2 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 3 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 4 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 5 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 6 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 7 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 8 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 9 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 10 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 11 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 12 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 13 is administered in combination with a checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is a PD-1 checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is a PD-L1 checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is an IFNAR checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is selected from nivolumab, pembrolizumab, and interferon alpha-2b.

[0483] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and thereby inhibit immunosuppression include nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Examples of PD-L1 inhibitors that inhibit immunosuppression by blocking the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor include atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that inhibit immunosuppression by binding to CTLA-4 include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). Examples of LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the PD-1 and LAG-3 dual inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0484] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO®; pembrolizumab / KEYTRUDA®; and PDL2 / Ig fusion proteins such as pizilizumab / CT-011, MPDL3280A / RG7446;MEDI4736;MSB0010718C;BMS936559, AMP224, or B7-H3 inhibitors (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0485] In certain embodiments, the PD-1 inhibitor is BGB-A317. In certain embodiments, the PD-L1 inhibitor is MED14736. In certain embodiments, the PD-L2 inhibitor is rHIgM12B7A.

[0486] In certain embodiments, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. In certain embodiments, the B7-H3 inhibitor is MGA271.

[0487] In certain embodiments, the checkpoint inhibitor is an OX40 agonist. In certain embodiments, the checkpoint inhibitor is an anti-OX40 antibody, such as anti-OX-40 or MEDI6469.

[0488] In certain embodiments, the checkpoint inhibitor is a GITR agonist. In certain embodiments, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0489] In certain embodiments, the checkpoint inhibitor is a CD137 agonist. In certain embodiments, the CD137 agonist is an anti-CD137 antibody, for example, PF-05082566.

[0490] In certain embodiments, the checkpoint inhibitor is a CD40 agonist. In certain embodiments, the CD40 agonist is an anti-CD40 antibody, such as CF-870, 893.

[0491] In certain embodiments, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0492] In certain embodiments, the checkpoint inhibitor is selected from atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

[0493] Additional bioactive agents In another embodiment, the active compounds described herein may be administered in combination with or alternately in effective amounts of an androgen (e.g., testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, selective androgen receptor degrader, complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. In certain embodiments, prostate or testicular cancer is androgen-resistant. Non-limiting examples of antiandrogen compounds are presented in International Publication No. 2011 / 156518 and U.S. Patents No. 8,455,534 and 8,299,112. Additional non-limiting examples of antiandrogen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0494] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113.

[0495] In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rosiletinib (CO-1686), osimertinib (Tagrisso), olmutinib (Olita), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272;PB272); abitinib (a Examples include vitinib (AC0010), EAI045, tarloxotinib (TH-4000;PR-610), PF-06459988 (Pfizer), tesevatinib (XL647;EXEL-7647;KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804;Pfizer).

[0496] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0497] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tocitumomab, and ocrelizumab.

[0498] In certain embodiments, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0499] In certain embodiments, the bioactive agent is a JAK inhibitor, such as ruxolitinib.

[0500] In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexa-1-en-1-yl]methyl]piperazine-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]aminophenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridine-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]pi [Perazin-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylsulfanylbutan-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((tri Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrole-2-yl)methylidene]-4-methoxypyrrole-2-ylidene]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazole-2-ylamino)-phenyl ester), pogosin, ethyl 2- Examples include amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossiporone (ApoG2), HA14-1, AT101, sabutoclax, gumbognate, or G3139 (oblimersene).

[0501] In certain embodiments, the bioactive agent is venetoclax.

[0502] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, for example, trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H)-yl}phenyl)acetamide), selmetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimacertib / AS703026 / MSC 1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol), refametinib / BAY8697 66 / RDEA119(N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK73 3((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6- Ruboxamide), R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,Examples include 2-oxazinan-2yl(methyl)benzamide) or AZD8330(2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352(CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, vinimetinib, SL-327, TAK-733, and PD318088.

[0503] In certain embodiments, the bioactive agent is a Raf inhibitor. Known Raf inhibitors include, for example, vemurafenib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylamino)phenyl)benzamide), NVP-BHG712(4-methyl-3-(1-methyl-6-(pyridine-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265(1-methyl-5-[2-[5-(trifluoro Methyl)-1H-imidazole-2-yl]pyridine-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazole-2-amine), 2-bromoardicine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazole-4-yl)phenol), sorafenib N-oxide ( Examples include 4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0504] In certain embodiments, the bioactive agent is, but is not limited to, an AKT inhibitor comprising MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, trisirivine, AZD5363, honokiol, PF-04691502, and miltefosine; or, but is not limited to, an FLT-3 inhibitor comprising P406, dovitinib, quizartinib (AC220), amvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449; or a combination thereof.

[0505] In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridafololimus, sirolimus, and defololimus. Examples of MEK inhibitors include trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H-yl}phenyl)acetamide) and selumetinib (6-(4-bromo-2-chloroanilino)-7 -Fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimacertib / AS703026 / MSC1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(1-({3,4-difluoro-2-[(2-fluoro (-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidine-2-yl]azetidine-3-ol) (cobimetinib), refametinib / BAY869766 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfone) N-amide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733 ((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162(5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766(3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidine-2-yloxychromen-2-one), WX-554, R04987655 / C Examples include, but are not limited to, H4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxadinan-2-yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide).

[0506] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0507] In certain embodiments, the bioactive agent is an HSP inhibitor. Examples of HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG) and radicicol.

[0508] In certain embodiments, the bioactive agent is a biphosphonate. Examples of biphosphonates include, but are not limited to, clodronate, pamidronate, and zoledronic acid.

[0509] Additional bioactive compounds include, for example, everolimus, trabectedin, Abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, and AZD 1152, Enzastaurin, Vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, Aurora kinase inhibitor, PIK-1 modulator, HDAC inhibitor, c-MET inhibitor, PARP inhibitor, Cdk inhibitor, IGFR-TK inhibitor, Anti-HGF antibody, Focal adhesion plaque kinase inhibitor, Map kinase (mek) inhibitor, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, olegobomab, Lep-etu, noratexide, azd2171, batabulin, ofatumumab, zanorimumab, edtecalin, tetrandrin, lubitecan, tesmilifene, oblimersen, tisilimmab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, sirengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, rucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, Taranpanel, Atracentane, Xr 311, Romidepsin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposomal Doxorubicin, 5'-Deoxy-5-Fluorouridine, Vincristine, Temozolomide, ZK-304709, Sericiclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoyl]-, Disodium Salt Heptahydrate, Camptothecin, PEG-labeled Irinotecan, Tamoxifen, Toremifene Citrate, Anastrazole, Exemestane, Letrozole,DES (Diethylstilbestrol), Estradiol, Estrogen, Conjugated Estrogen, Bevacizumab, IMC-1C11, CHIR-258); 3-[5-(Methylsulfonylpiperazine methyl)-Indolyl-Quinolone, Batalanib, AG-013736, AVE-0005, Goserelin Acetate, Leuprolide Acetate, Triptorelin Pamoate, Medroxyprogesterone Acetate, Hydroxyprogesterone Caproate, Megestrol Acetate Raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, ronafarnib, BMS-214662, tipifarnib; amifostin, NVP-LAQ824, suberoyl analide hydroxamic acid (acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrin, anagrelide, L-asparaginase, Calmette-Guéran bacillus (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hidol Roxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprolide, Levamisole, Lomustine, Mechloretamine, Melphalan, 6-Mercaptopurine, Mesna, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Niltamide, Octreotide, Oxaliplatin, Pamidronate, Pentostatin, Plicamycin, Porfimer, Procarbazine, Larcitrexed, Rituximab, Streptozocin, Teniposide, Testosterone, Thalidomide, Thioguanine, Thiotepa, Tretinoin, Vindesine, 13-Cis-Retinoic Acid, Phenylalanine Mustard, Uracil Mustard, Estramustine,Altretamine, phloxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, barrubicin, mitramycin, vinblastine, vinorelbine, topotecan, razoxin, marimast, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifen, idoxyfen e) Spironolactone, finasteride, cimitidine, trastuzumab, denileukin difutitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremofol, docetaxel, epotilon B, BMS-247550, BMS-310705, droloxifen, 4-hydroxytamoxifen, pipendoxifen, ERA-923, alzoxifen, fulvestrant, acorbifen, rasofoxifen, idoxifen, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, Temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wartmannin, ZM336372, L-779,450, PEG-filgrastim, Darbepoetin, Erythropoetin, Granulocyte colony-stimulating factor, Zoledronate, Prednisone, Cetuximab, Granulocyte macrophages Dicolony-stimulating factor, histrelin, pegylated interferon α-2a, interferon α-2a, pegylated interferon α-2b, interferon α-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone,Examples include ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tocitumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium-89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, drasetron, tropisetron, pegfilgrastim, erytropoetin, epoetin α, darbepoetin α, and mixtures thereof.

[0510] In certain embodiments, the bioactive agents include imatinib mesylate (Gleevac®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), trastuzumab (Herceptin®), trastuzumab-DM1, pertuzumab (Perjeta®), lapatinib (Tykerb®), gefitinib (Iressa®), erlotinib (Tarceva®), cetuximab (Erbitux®), panitumumab (Vectibix®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), and vorinostat (Zolin). Selected from, but not limited to, za(trademark), romidepsin (Istodax(trademark)), bexarotene (Tagretin(trademark)), alitretinoin (Panretin(trademark)), tretinoin (Vesanoid(trademark)), carfilzomib (Kyprolis(trademark)), pralatrexate (Folotyn(trademark)), bevacizumab (Avastin(trademark)), Ziv-aflibercept (Zaltrap(trademark)), sorafenib (Nexavar(trademark)), sunitinib (Sutent(trademark)), pazopanib (Votrient(trademark)), regorafenib (Stivarga(trademark)), and cabozantinib (Cometriq(trademark)).

[0511] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant.

[0512] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, cytotoxins, or toxins also known as cytotoxic agents, as well as any active substance harmful to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer drugs include vincristine (Oncovin®) or liposomal vincristine (Marqibo®), daunorubicin (Daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), cytarabine (cytosine arabinoside, ara-C or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (Pegasparagase or Oncaspar®), et Examples include poside (VP-16), teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), methotrexate, cyclophosphamide (Cytoxan®), prednisone, dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig®). Examples of suitable additional chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altoretamine, amiphostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamine platinum(II) (DDP) (cisplatin), diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, and BCG bacteria (BCG).(live) (in bladder), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogen, cyclophosphamide, cyclotosphamide, cytarabine, cytarabine, cytochalasin B, cytoxane, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCl, daunorubicin citrate, denileukin difutitox, dexrazoxane, dibromomannitol, dihydroxyanthracine dione dione), docetaxel, drasetron mesylate, doxorubicin HCl, dronabinol, Escherichia coli (E. coli)coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estramustine sodium phosphate, ethidium bromide, ethinylestradiol, etidronate, etoposide, citroborum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCl, glucocorticoid, goserelin acetate, gramicidin D, granisetron HCl, hydroxyurea, idarubicin HCl, ifosfamide, interferon α-2b, irinotecan HCl, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCl, lidocaine, lomustine, maytansinoid, Mechloretamine HCl, medroxyprogesterone acetate, megestrol acetate, melphalan HCl, mercaptopurine, mesna, methotrexate, methyltestosterone, mitramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCl, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCl, primycin, polyfeprozan 20 carmustine implant, porfimer sodium, procaine, procarbazine HCl, propranolol, rituximab, salglamostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testactone, tetracaine, thioepachlorambucil Examples include, but are not limited to, chlorambucil, thioguanine, thiotepa, topotecan HCl, toremifene citrate, trastuzumab, tretinoin, barrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0513] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other chemical compounds useful for treating cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracendione-substituted ureas, methylhydrazine derivatives, corticosteroids, progestins, estrogens, antiestrogens, androgens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-exclusive examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocon, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analog topotecan); briostatin; calistatin; and CC-1065 (including its synthetic analogs adzeresin, karzeresin, and bizeresin). Cryptophycin (especially cryptophycin 1 and cryptophycin 8); dorastatin; duocalmycin (including synthetic analogues, KW-2189 and CB1-TM1); eleuterobin; pancratistatin; sarcodictiin; spongistatin; chlorambucil, chlornafadin, chlorophosphamide, estramustine, ifosfamide, mechloretamine, mechloretamine oxide hydrochloride, melphalan, nobenbitin, fenestrine, prednimustine, trophosphamide, uracil mustard, and other nitrogen mustards; nitroureas such as carmustine, chlorozotosine, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as enegyoin antibiotics (e.g., calicheamicin, especially calicheamicin gammol and calicheamicin omegar) (see, for example, Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); dynemycin including dynemycin A; bisphosphonates such as clodronate; esperamycin; and neocardinostatin chromophore and related pigment proteins (endiynes, antibiotic chromophore), acrasinomycin, actinomycin, ausramycin, azaserin, bleomycin, kakutinomycin, carabicin, kaminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detrubicin, 6-diazo -5-oxo-L-norleucine, ADRIAMYCIN (trademark) (including doxorubicin containing morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin such as mitomycin C, mycophenolic acid, nogaramycin, olibomycin, peplomycin, potophyllomycin, puromycin, keramycin, rhodorubicin, streptonig Phosphorus, streptozocin, tubercidine, ubenimex, dinostatin, zolubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimethrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamipurine, and thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxu Pyrimidine analogs such as lysine; androgens such as carsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testactone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as floric acid; acegraton; aldofamide glycosides; aminolevulinic acid; enyluracil; amsacrin; bestrabusil; bisantren; edatraxate; defofamine; demecolsin; diazicon; elfomitin; eriptinium acetate; epotilon;Etoglucid; gallium nitrate; hydroxyurea; lentinan; ronidamine; meitansinoids such as maytansine and anthamitosine; ...

Claims

1. A pharmaceutical composition for the treatment of Ikaros and / or Aiolos-mediated hematological malignancies in patients, comprising a dosage formula of about 1 microgram to about 300 micrograms: 【Chemistry 1】 A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, further characterized by being administered once daily (QD) or twice daily (BID).

2. The pharmaceutical composition according to claim 1, further characterized in that the pharmaceutical composition is administered for several days with a drug-free period during a subsequent treatment cycle.

3. The pharmaceutical composition according to claim 2, further characterized in that the pharmaceutical composition is administered once or twice a day for 14 consecutive days, followed by a drug-free period until the next 28-day cycle.

4. The pharmaceutical composition according to claim 2, further characterized in that the pharmaceutical composition is administered once or twice a day for 21 days, followed by a 7-day drug-free period.

5. The pharmaceutical composition according to claim 1, wherein the dose is approximately 200 μg or less.

6. The pharmaceutical composition according to claim 1, wherein the dose is approximately 100 μg or less.

7. The pharmaceutical composition according to claim 1, wherein the dose is approximately 75 μg or less.

8. The pharmaceutical composition according to claim 1, wherein the dose is approximately 50 μg or less.

9. The pharmaceutical composition according to claim 1, wherein the dose is approximately 25 μg or less.

10. The pharmaceutical composition according to claim 1, wherein the dose is approximately 10 μg or less.

11. The pharmaceutical composition according to claim 1, wherein the dose is approximately 5 μg or less.

12. The pharmaceutical composition according to claim 1, wherein the aforementioned dose is approximately 100 μg.

13. The pharmaceutical composition according to claim 1, wherein the aforementioned dose is approximately 75 μg.

14. The pharmaceutical composition according to claim 1, wherein the aforementioned dose is approximately 50 μg.

15. The pharmaceutical composition according to claim 1, wherein the dose is approximately 25 μg.

16. The pharmaceutical composition according to claim 1, wherein the aforementioned dose is approximately 10 μg.

17. The pharmaceutical composition according to claim 1, wherein the aforementioned dose is approximately 5 μg.

18. The pharmaceutical composition according to claim 1, further characterized in that a corticosteroid is also administered to the patient.

19. The pharmaceutical composition according to claim 18, wherein the corticosteroid is dexamethasone.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is a B-cell lymphoma.

21. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is diffuse large B-cell lymphoma.

22. The pharmaceutical composition according to claim 21, wherein the diffuse large B-cell lymphoma is activated B-cell lymphoma.

23. The pharmaceutical composition according to claim 21, wherein the diffuse large B-cell lymphoma is germinal center B-cell lymphoma.

24. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is an undifferentiated large cell lymphoma.

25. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is cutaneous T-cell lymphoma.

26. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is mantle cell lymphoma.

27. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is multiple myeloma.

28. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is non-Hodgkin lymphoma.

29. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is peripheral T-cell lymphoma.

30. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is adult T-cell leukemia.

31. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is angioimmunoblastic T-cell lymphoma.

32. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is marginal zone lymphoma.

33. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is plasmablastic lymphoma.

34. The pharmaceutical composition according to any one of claims 1 to 19, wherein the hematological malignancy is resistant to treatment with a first-generation IMiD drug, and the first-generation IMiD drug is selected from the group consisting of thalidomide, pomalidomide, lenalidomide, and iverdamide.

35. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) in patients, comprising the formula: 【Chemistry 2】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that, after a blood sample or tissue sample is taken from the patient, the concentration of one or more biomarkers selected from the group consisting of IRF-1, caspase-3, IL-2, and IFN-γ is measured to be statistically lower in the patient than the concentration of the one or more biomarkers in an average healthy patient, and the pharmaceutical composition is administered to the patient.

36. The pharmaceutical composition according to claim 35, wherein the statistically low concentration of the biomarker is 5% lower than that of the average healthy patient.

37. The pharmaceutical composition according to claim 35, wherein the statistically low concentration of the biomarker is 20% lower than that of the average healthy patient.

38. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) in patients, comprising the formula: 【Transformation 3】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that, after a blood or tissue sample is taken from the patient, the concentration of one or more biomarkers selected from the group consisting of cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and MYC is measured to be statistically higher in the patient than the concentration of the one or more biomarkers in an average healthy patient, and the pharmaceutical composition is administered to the patient.

39. The pharmaceutical composition according to claim 38, wherein the statistically high concentration of the biomarker is 5% higher than that of the average healthy patient.

40. The pharmaceutical composition according to claim 38, wherein the statistically high concentration of the biomarker is 20% higher than that of the average healthy patient.

41. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) in patients, comprising the formula: 【Chemistry 4】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized by being administered to the patient, then collecting a blood or tissue sample from the patient, measuring the concentration of one or more biomarkers selected from the group consisting of IRF-1, caspase-3, IL-2, and IFN-γ, and increasing the dose of the compound if the concentration of the one or more biomarkers has not significantly increased.

42. The pharmaceutical composition according to claim 41, wherein if the concentration of the biomarker has not increased by at least about 25%, the dose of the compound is increased.

43. The pharmaceutical composition according to claim 41, wherein if the concentration of the biomarker has not increased by at least about 100%, the dose of the compound is increased.

44. The pharmaceutical composition according to claim 41, wherein if the concentration of the biomarker has not increased by at least about 200%, the dose of the compound is increased.

45. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) in patients, comprising the formula: 【Transformation 5】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized by being administered to the patient, then collecting a blood or tissue sample from the patient, measuring the concentration of one or more biomarkers selected from the group consisting of cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and MYC, and increasing the dose of the compound if the concentration of the biomarker has not decreased significantly.

46. The pharmaceutical composition according to claim 45, further characterized in that the dose of the compound is increased if the concentration of the biomarker has not decreased by at least about 10%.

47. The pharmaceutical composition according to claim 45, further characterized in that the dose of the compound is increased if the concentration of the biomarker has not decreased by at least about 25%.

48. The pharmaceutical composition according to claim 45, further characterized in that the dose of the compound is increased if the concentration of the biomarker has not decreased by at least about 50%.

49. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Transformation 6】 A pharmaceutical composition comprising a compound of or a pharmaceutically acceptable salt thereof, wherein the Ikaros or Aiolos-mediated hematological malignancy is activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.

50. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Transformation 7】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that a BTK inhibitor selected from the group consisting of acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib is also administered to the patient.

51. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Transformation 8】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that a CD38 antibody selected from the group consisting of ferzaltamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient.

52. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Chemistry 9】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that a proteasome inhibitor selected from the group consisting of ixazomib citrate, oprozomib, delanzomib, lactacystine, epixomicin, MG132, MG262, CEP-18770, NEOSH101, TQB3602, and KZR-616 is also administered to the patient.

53. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Chemistry 10】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that an IMiD selected from the group consisting of CC-92480, CC-90009, and CC-99282 is also administered to the patient.

54. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Chemistry 11】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that the patient is also administered an HDAC inhibitor selected from the group consisting of Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinostat, Cay10603, HPOB, TMP269, Nextulastat A, Santacruzmato A, Spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, Pyroxamide, Abexinostat, Resminostat, Divinostat, Xynostat, Psammaprin A, KD5170, 1-Alanine Clamidosin, Depdesin, and CUDC-101.

55. A pharmaceutical composition for the treatment of hematological malignancies mediated by Ikaros and / or Aiolos in patients, comprising an effective amount of formula: 【Chemistry 12】 The compound comprises, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition further characterized in that a compound selected from the group consisting of selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuplumab, and urerumab is also administered to the patient.

56. The pharmaceutical composition according to any one of claims 35 to 55, further characterized in that a corticosteroid is also administered to the patient.

57. The pharmaceutical composition according to claim 56, wherein the corticosteroid is dexamethasone.

58. The pharmaceutical composition according to any one of claims 1 to 19, 35 to 49, and 51 to 55, further characterized in that a Bruton's tyrosine kinase inhibitor is also administered to the patient.

59. The pharmaceutical composition according to claim 58, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

60. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that CAR T cell therapy is also administered to the patient.

61. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that an antibody-drug conjugate is also administered to the patient.

62. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that BiTE therapy is also administered to the patient.

63. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a bispecific antibody is also administered to the patient.

64. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a monoclonal antibody is also administered to the patient.

65. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a BTK inhibitor selected from the group consisting of acalabrutinib, spebralutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, olerabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib is also administered to the patient.

66. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a CD38 antibody selected from the group consisting of ferzaltamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient.

67. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a proteasome inhibitor selected from the group consisting of ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epixomycin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616 is also administered to the patient.

68. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that an IMiD selected from the group consisting of pomalidomide, lenalidomide, thalidomide, iverdamide, CC-92480, CC-90009, and CC-99282 is also administered to the patient.

69. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that an HDAC inhibitor selected from the group consisting of Trapoxin B, sodium phenylbutyrate, Tasejinarin, Mosetinostat, BRD73954, BG45, Domatinostat, Cay10603, HPOB, TMP269, Nextulastat A, Santacruzmato A, Spritomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, Pyroxamide, Abexinostat, Resminostat, Divinostat, Xynostat, Psammaprin A, KD5170, 1-Alanine Chlamydosin, Depdesin, and CUDC-101 is also administered to the patient.

70. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that a compound selected from the group consisting of selinexol, oxafenamide, verantamab mahodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, licorinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, macitinib, sonidedib, sotatercept, urocuplumab, and urerumab is also administered to the patient.

71. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that the pharmaceutical composition is administered once a day.

72. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that the pharmaceutical composition is administered twice a day.

73. The pharmaceutical composition according to any one of claims 35 to 48 and 50 to 55, wherein the hematological malignancy is non-Hodgkin lymphoma.

74. The pharmaceutical composition according to any one of claims 35 to 48 and 50 to 55, wherein the hematological malignancy is multiple myeloma.

75. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, wherein the hematological malignancy is recurrent.

76. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, wherein the hematological malignancy is refractory.

77. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, wherein the hematological malignancy is recurrent and / or refractory.

78. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that blinatumomab is also administered to the patient.

79. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that erlanatamab is also administered to the patient.

80. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that talketamab is also administered to the patient.

81. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that teclistamag is also administered to the patient.

82. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that BFCR4350A is also administered to the patient.

83. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that CC-93269 is also administered to the patient.

84. The pharmaceutical composition according to any one of claims 1 to 19 and 35 to 55, further characterized in that REGN5458 is also administered to the patient.

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