Favorable therapy of disorders mediated by ikaros or aiolos

Abstract

Provided are novel methods of treatment of Ikaros and / or Aiolos mediated disorders, comprising administering an effective amount of a hydrolipoxygenase binding agent that degrades Ikaros or Aiolos via the ubiquitin proteasome pathway.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 063,011, filed August 7, 2020; U.S. Provisional Application No. 63 / 173,160, filed April 9, 2021; and U.S. Provisional Application No. 63 / 212,463, filed June 18, 2021. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0003] The present invention provides therapeutic compositions, combinations and uses thereof for treating conditions mediated by the transcriptional proteins Ikaros (IKZF1) and / or Aiolos (IKZF3), said treatment being carried out by degradation of these proteins via the ubiquitin-proteasome pathway. Background Technology

[0004] The Ikaros family is a series of zinc finger protein transcription factors that are important for certain physiological processes, particularly the development of hematopoietic cells and lymphocytes (see Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521). Ikaros (IKZF1) was first discovered in 1992 (see Georgopoulos, K. et al., “Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment” Science, 1992, 258:802-812), and four other homologs have been identified in the following two decades: Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), and Pegasus (IKZF5) (see John, LB, and Ward, AC, “The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity” Mol Immunol, 2011, 48:1272-1278). The distribution of the various members of the Ikaros protein family in vivo varies significantly.

[0005] Ikaros, Helios, and Aiolos are primarily found in lymphoid cells and their corresponding progenitor cells. Ikaros have also been detected in the brain, and Ikaros and Helios have been detected in erythrocytes. Eos and Pegasus are widely distributed and found in skeletal muscle, liver, brain, and heart (see 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; Schmitt, C. et al. "Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation" Apoptosis, 2002, 7: 277-284; Yoshida, T. and Georgopoulos, K. "Ikaros fingers on lymphocyte differentiation" Int J Hematol, 2014, 100: 220-229).

[0006] Ikaros are important for proper lymphocyte development. Deletion of the first three exons encoding the N-terminal zinc finger results in a lack of T cells, B cells, natural killer (NK) cells, and their progenitor cells in mice. Genetic alterations in Ikaros are associated with poor outcomes from treatment of acute lymphoblastic leukemia (ALL). Ikaros and Aiolos are involved in the proliferation of multiple myeloma cells and lymphoma cells.

[0007] Multiple myeloma (MM) is a malignant tumor of plasma cells characterized by abnormal production of monoclonal immunoglobulins, bone marrow involvement, renal dysfunction, immune dysfunction, and bone damage. In the United States, MM accounts for nearly 1.8% of all new cancers. Although outcomes for patients with MM have improved significantly over the past few decades, the disease remains incurable, with a current predicted 5-year relative survival rate of 53.9%. Because the available treatments are not curative, almost all patients eventually experience progression.

[0008] Historically, treatment for MM has included chemotherapy, including alkylating agents and corticosteroids. In the 1980s, autologous stem cell transplantation further advanced treatment. In the 1990s, thalidomide (a pioneering immunomodulatory imide) was discovered. Its efficacy in myeloma has led to a significant shift in treatment options and improved patient outcomes. [Approved] Follow-on drugs, lenalidomide and pomalidomide, are now widely used to treat MM, similar to the first-in-class drug thalidomide. These agents bind to E3 ligase substrates that recognize the adaptor protein cereblon (CRBN) and promote the degradation of Ikaros (IKZF1) and Aiolos (IKZF3), leading to antitumor effects; they also influence the tumor microenvironment and immune regulation, resulting in T-cell priming and antitumor activity. Many patients with MM are treated with multiple regimens containing one of these IMiDs. Combinations of these drugs with agents including dexamethasone, anti-differentiation cluster 38 (CD38) antibodies, and proteasome inhibitors (such as bortezomib) are now considered standard of care in multi-line therapy for MM. Although these agents have successfully prolonged progression-free survival in MM patients, relapse is common, with shorter progression-free survival after each relapse. Recent studies of the new drugs belemmatab and selinexor have shown improved outcomes in several types of refractory myeloma, leading to recent accelerated approval by the FDA; however, low response rates (26-31%) and short progression-free survival (3.7-4.9 months) highlight the ongoing unmet medical needs in these patients.

[0009] Non-Hodgkin's lymphoma (NHL) is a heterogeneous group of lymphoid malignancies originating from T, B, or NK cells. It 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 the most common, while T-cell lymphoma is less frequent. In newly diagnosed patients with aggressive NHL, chemotherapy-based regimens including cyclophosphamide, vincristine, prednisone, and daunorubicin (called CHOP) remain the primary treatment. In B-cell aggressive lymphoma, rituximab in combination with CHOP is the main therapy given to newly diagnosed patients. In some patients, particularly those with T-cell NHL, autologous stem cell rescue is performed after initial chemotherapy. In the relapsed / refractory population, various targeted therapies have been developed, thus improving treatment options for multiple subtypes of NHL; however, these options are often not curative. Furthermore, the biological heterogeneity of NHL subtypes limits the broad applicability of therapeutic agents for various indications.

[0010] In newly diagnosed patients with aggressive lymphoma, initial treatment is often intensive and administered with a cure-oriented approach. Aside from the addition of rituximab to the CHOP in B-cell NHL treatment and bentuximab to the CHOP in anaplastic large cell lymphoma (ALCL), no other new targeted therapies have shown improved survival, and therefore no other drugs have been approved for treatment-naïve patients. Recent advances in the treatment of relapsed NHL include Bruton's tyrosine kinase (BTK) inhibitors, particularly for mantle cell lymphoma (MCL) and more indolent forms of NHL, chimeric antigen receptor T-cell (CAR-T) therapy already approved for diffuse large B-cell lymphoma (DBLCL) and MCL, and novel antibody-drug conjugates such as polotuzumab, belantatumab, or tafasitamab already approved for DLBCL. Recently approved drugs for T-cell NHL include romidesin, belituxa, and bentuximab. Lenalidomide has demonstrated clinical activity in B-cell and T-cell NHL, including MCL, DLBCL, and peripheral T-cell lymphoma (PTCL), relevant to the NHL population studied in this protocol. Lenalidomide was investigated in the relapsed / refractory (r / r) MCL population and received FDA approval in June 2013 based on results from the Phase II EMERGE study, which examined the efficacy and safety of lenalidomide in r / r MCL subjects who had received bortezomib (overall response rate [ORR] 28%; median duration of response [DOR] 16.6 months). Lenalidomide is also active in DLBCL and PTCL. While lenalidomide and other new targeted therapies have modest to good response rates, the durability of response tends to be short in most NHL subtypes. The median duration of response tends to be low once patients relapse after 1–2 treatment regimens and depends on whether the patient has sufficient performance status and organ function to tolerate these therapies. Therefore, there remains an unmet medical need among patients with r / r NHL.

[0011] Protein degradation is a fundamental and highly tunable process for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) enables the selective identification and removal of damaged, misfolded, or excess proteins. The UPP is central to the regulation of almost all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, neural and muscle degeneration, neural network morphogenesis, regulation of cell surface receptors, ion channels and secretion pathways, responses to stress and extracellular regulators, ribosome biogenesis, and viral infection. Proteins for proteasome degradation are labeled by covalently linking multiple ubiquitin molecules to terminal lysine residues via E3 ubiquitin ligases. These proteins are digested into small peptides and ultimately into their constituent amino acids, which serve as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0012] Patent applications describing certain protein degrading agents include WO2020 / 210630, WO2020 / 006262, WO2020 / 010227 and WO2020 / 010177.

[0013] Patent applications filed by C4 Pharmaceuticals describing compounds capable of binding to E3 ubiquitin ligases and target proteins for degradation include: WO / 2021 / 127561, entitled "Isoindolinone and Indazole Compounds For The Degradation Of EGFR"; WO / 2021 / 086785, entitled "Bifunctional Compounds"; WO / 2021 / 083949, entitled "Bifunctional Compounds for the Treatment of Cancer"; WO / 2020 / 210630, entitled "Tricyclic Degraders of Ikaros and Aiolos"; WO / 2020 / 181232, entitled "Heterocyclic Compounds for Medical Treatment"; WO / 2020 / 132561, entitled "Targeted Protein Degradation"; and WO / 2019 / 236483, entitled "Spirocyclic WO2020 / 051235, titled "Compounds for the degradation of BRD9 or MTH1"; WO / 2019 / 191112, titled "Cereblon binders for the Degradation of Ikaros"; WO / 2019 / 204354, titled "Spirocyclic Compounds"; WO / 2019 / 099868, titled "Degraders and Degrons for Targeted Protein Degradation"; WO / 2018 / 237026, titled "N / O-Linked Degrons and Degronimers for Protein Degradation"; WO 2017 / 197051, titled "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation"; WO 2017 / 197055, titled "Heterocyclic Degronimers for Target Protein Degradation".WO 2017 / 197036, titled "Spirocyclic Degronimers for Target Protein Degradation"; WO 2017 / 197046, titled "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and WO 2017 / 197056, titled "Bromodomain Targeting Degronimers for Target Protein Degradation".

[0014] The object of this invention is to provide new compositions of substances, combinations thereof, formulations and uses thereof, and methods for preparing compounds for treating medical conditions mediated by Ikaros or Aiolos. Summary of the Invention

[0015] Compound 1 is a small-molecule anticancer agent that binds to a high-affinity hydroxycerebroside E3 ligase, thereby creating a novel surface on the hydroxycerebroside that interacts with IKZF1 and IKZF3 (see WO2020 / 210630). As a result, IKZF1 and IKZF3 are efficiently ubiquitinated by the hydroxycerebroside E3 ligase and degraded by the proteasome. The high hydroxycerebroside binding affinity of Compound 1 enables rapid, deep, and persistent degradation of IKZF1 / 3, thereby producing potent activity in cancer cells, including but not limited to hematopoietic cancers such as multiple myeloma and various types of non-Hodgkin's lymphoma.

[0016]

[0017] It has been found that Compound 1 and other compounds described herein can be administered in a high-efficiency treatment regimen at low doses, once or twice daily, optionally with a drug holiday, to treat conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3). For example, it has been found that anticancer therapy can be effective in patients when one of the compounds described herein is used at doses not exceeding about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or even 100, 75, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 microgram (μg) once daily (QD) or twice daily (BID). In some implementations, the patient is an adult (typically at least 100 pounds or more, sometimes even 125 or 150 pounds (e.g., 70 kg or more and typically at least 18 years of age or older). In another implementation, the patient is a child (may be less than 100, 125, or 150 pounds and typically less than 18 years of age). Not only has Compound 1 been found to be effective as a low-dose therapy, but it can also have a drug holiday that is beneficial to the patient. For example, Compound 1 can be administered once or twice daily for 21 days, followed by a 7-day break before delivery. Alternative dosing regimens are also useful, such as those that increase or decrease the drug holiday by 1, 2, 3, 4, 5, 6, or 7 days.

[0018] In some implementations, 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 crucial for anticancer therapy.

[0019] In non-limiting embodiments, compound 1 or another compound described herein may be administered daily or intermittently with dexamethasone. In some embodiments, dexamethasone or another corticosteroid or another immunosuppressant or anti-inflammatory agent is administered daily over a 28-day cycle without a drug holiday. In other embodiments, dexamethasone or another corticosteroid or another immunosuppressant or anti-inflammatory agent is administered with a drug holiday, which may be the same as or different from the drug holiday of compound 1 or another compound described herein.

[0020] In one aspect of the 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 for hydroxycerebroside (dissociation constant K). d=0.9 nM). Compound 1 promoted the degradation of >75% steady-state IKZF1 in multiple myeloma cells within 1.5 hours at 0.3 nM. The high binding affinity and degradation catalysis of compound 1 resulted in 96% maximum growth inhibition in the previously untreated NCIH929 multiple myeloma cell line (mean half-maximal inhibitory concentration IC50). 50 The maximum growth inhibition was 0.071 nM in NCIH929 cells resistant to lenalidomide and pomalidomide (70% maximum growth inhibition, mean IC50). 50 This makes it possible to achieve effective cell growth inhibition at 2.3 nM.

[0022] The compounds described herein can be used to treat cancer cells that are resistant, refractory, or unresponsive to standard care therapies for IKZF1 or IKZF3-mediated cancers (including IMiD, including pomalidomide or any of those described in the background or specific embodiments).

[0023] As shown in Example 12, compound 1 exhibited strong anticancer activity in a group of multiple myeloma cell lines (8 out of 12 showed a response, with an average IC50 in the responding cell lines). 50 (0.3 nM). The anticancer activity of compound 1 was also demonstrated in several cell line models of various non-Hodgkin lymphoma subtypes, including mantle cell lymphoma (MCL) (four of the six cell lines tested showed a response, with an average IC50 in the responding cell lines). 50 (13 nM), diffuse large B-cell lymphoma (DLBCL) (six of the eleven germinal center B-cell-like DLBCLs and three of the six activated B-cell DLBCL cell lines were responsive, with an average IC50 in the responsive cell lines). 50 The values ​​were 12 nM and 1.6 nM respectively. Anaplastic large cell lymphoma (ALCL) (four of the six cell lines were responsive, and the average IC50 of the responsive cell lines was 12 nM and 1.6 nM respectively). 50 (1.7 nM) and cutaneous T-cell lymphoma (CTCL) (three of the four cell lines tested were responsive, with an average IC50 in the responsive cell lines). 50 (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 tested, daily administration of compound 1 at doses from 30 μg / kg / day to 100 μg / kg / day resulted in durable tumor regression. Figure 45A , Figure 45B , Figure 45C , Figure 52 As shown in other figures, compound 1 was more than 100 times more potent than pomalidomide in a variety of cancer assays.

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

[0025] Due to the significant efficacy of compound 1 and the other compounds described herein, novel and advantageous treatments for conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) have been discovered. In a non-limiting embodiment of the invention, the Ikaros (IKZF1) and / or Aiolos (IKZF3) degradation compounds described herein may be used in the following non-limiting examples:

[0026] 1. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein said compounds are administered in low doses. For example, doses not exceeding about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 microgram (μg), once daily (QD) or twice daily (BID), optionally with a pharmaceutical holiday.

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

[0028] 3. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a blood or tissue sample is first collected from the patient and the concentration of one or more biomarkers is determined, such as 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 lysed caspase-1, caspase-3, caspase-7, PARP, BIM, or survival protein, or combinations thereof); or zinc finger proteins (e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or combinations thereof), and wherein if the patient has statistically different biomarker concentrations, including but not limited to those differing from healthy individuals by approximately 5%, 10%, 15%, or 20%, then the patient is administered compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound.

[0029] 4. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a blood or tissue sample is first collected from the patient and the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2 and / or IFN-γ, is determined, and wherein if the patient has a statistically lower concentration of a biomarker than that of a healthy person, including but not limited to being up to about 5%, 10%, 15% or 20% lower, the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound.

[0030] 5. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a blood or tissue sample is first collected from the patient, and the concentration of one or more biomarkers is measured, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4, etc.

[0031] BLIMP1 and / or MYC, and wherein if the patient has a statistically significant higher concentration of biomarkers than healthy individuals, including but not limited to up to about 5%, 10%, 15%, or 20% higher, then the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound.

[0032] 6. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the patient is administered compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound, and then a blood or tissue sample is collected from the patient, and the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2, and / or IFN-γ, is determined, wherein if the concentration of the biomarker does not increase significantly, for example, by at least about 1.25,

[0033] The dosage of the compound is increased if the concentration is 1.5, 1.75, or 2 times higher. For treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), the patient is administered compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound, and then a blood or tissue sample is collected from the patient, and the concentration of one or more biomarkers, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC, is determined. If the concentration of the biomarker does not decrease significantly, for example, by approximately 1.25, 1.5, 1.75, or 2 times higher, the dosage of the compound is increased.

[0034] 7. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3) wherein the patient is administered compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound, and then a blood or tissue sample is collected from the patient and the concentration of one or more biomarkers is determined, such as 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 combinations thereof); apoptosis markers (e.g., total and / or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM or survival protein, or combinations thereof); or zinc finger proteins (e.g., IKZF1, IKZF3, ZFP91, WIZ or SALL4, or combinations thereof), wherein if the concentration of the biomarker does not change significantly, e.g., by at least about 1.25, 1.5, 1.75 or 2-fold, the dose of the compound is increased.

[0035] 8. Treat activated diffuse large B-cell lymphoma, germinal center diffuse large B-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma with an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0036] 9. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein said compounds are administered in low doses. For example, doses not exceeding about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125 or even 100, 75, 50 or 25 micrograms (μg), once daily (QD) or twice daily (BID), optionally with a pharmaceutical holiday.

[0037] 10. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with a BTK inhibitor, such as acalatinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

[0038] 11. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with CD38 antibodies, such as CD38 antibodies selected from fuzetumab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mizetumab.

[0039] 12. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with a proteasome inhibitor, such as a proteasome inhibitor selected from bortezomib, carfilzomib, esazomib citrate, opzomib, delanzomib, lactocinol, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602 and KZR-616.

[0040] 13. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with IMiDs, such as IMiDs selected from thalidomide, pomalidomide, lenalidomide, ibedomide, CC-92480, CC-90009 and CC-99282.

[0041] 14. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with HDAC inhibitors, such as those selected from trapoxin B, sodium chlorate, acetyldenalin, moxitetstat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydocin, depudecin, panobinostat, ricolinostat, vorinostat, and CUDC-101.

[0042] 15. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the compounds described herein are used in combination with other compounds, such as those selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0043] 16. Treatment of cancer mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), including administration of an effective amount of compound 1 to activate T cell proliferation.

[0044] These new treatments offer advantages over currently approved cancer therapies. 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)-related cancers, such as CNS-associated lymphoma; can treat cancers that have relapsed or are refractory to standard of care (including first-generation IMiDs); ​​and / or can provide patients with longer progression-free survival than with first-generation IMiDs (such as thalidomide, pomalidomide, and lenalidomide). In some embodiments, the compounds described herein are approximately 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 some embodiments, the compounds described herein cause persistent degradation of IKZF1 and / or IKZF3 (e.g., IKZF1 and / or IKZF3 levels require 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, or longer to recover to pre-treatment levels). This persistent degradation is a result of high in vivo potency, metabolic stability, and / or selectivity.

[0045] In one respect, the compounds used in the treatments described herein are selected from:

[0046]

[0047]

[0048]

[0049] Or its pharmaceutically acceptable salt.

[0050] The compounds described herein modulate immune system activity, such as activating IFN-α, IFN-β, or IFN-γ. By activating the immune system, these compounds can treat cancer more effectively. This immunomodulatory activity enhances the efficacy of the compounds described herein with another anticancer agent, such as daratumumab.

[0051] In some implementations, the degradation of IKZF1 and IKZF3 from malignant B or T cells leads to tumor cell death, and their depletion from the tumor microenvironment leads to T cell activation.

[0052] The compound may be provided, for example, for oral, parenteral, or topical delivery. In some embodiments, the compound is provided in a solid, gel, or liquid dosage form for oral delivery, or may be administered intravenously. In some embodiments, the selected compound is provided as a soft-shell capsule or a solid dosage form tablet for oral administration. In some embodiments, the dosage strength of the pharmaceutical composition is about 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. In a non-limiting respect, it may be administered once daily (QD) or twice daily (BID) on days 1–21 of a 28-day treatment cycle.

[0053] The compound may be provided, for example, for oral or parenteral delivery. In some embodiments, the compound is provided in a solid, gel, or liquid dosage form for oral delivery, or may be administered intravenously. In some embodiments, the selected compound is provided as a soft-shell capsule or tablet for oral administration. In some embodiments, the dose strength of the solid or gel dosage form is 25 μg, 50 μg, 100 μg, 200 μg, 300 μg, or 400 μg, and in a non-limiting aspect, it may be administered once daily (QD) on days 1-21 of a 28-day cycle.

[0054] In one key aspect, the compound used for the treatment described herein is compound 1 or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, any of the compounds described herein has at least one desired atomic isotopic substitution in an amount approximately equal to the natural abundance of the isotope, i.e., enriched. In some embodiments, the compound contains one or more deuterium atoms.

[0056] Other features and advantages of the present invention will become apparent from the following detailed description and claims. Attached Figure Description

[0057] Figure 1A This is a dose-response curve describing the effect of compound 1 on H929 cell viability compared to pomalidomide, as described in Example 9. The x-axis represents the concentration (nM) of compound 1 or pomalidomide, and the y-axis represents the % H929 cell viability after 96 hours.

[0058] Figure 1B This is a dose-response curve describing the effect of compound 1 on the degradation of IKZF1 compared to pomalidomide, as described in Example 9. The x-axis is the concentration (nM) of compound 1 or pomalidomide, and the y-axis is the remaining IKZF1% after 1.5 hours.

[0059] Figure 2A This is a scatter plot of data from tumor lysates obtained by multiplex quantitative proteomics analysis in mice treated with compound 1 for 4 hours. The scatter plot depicts the fold change in relative abundance between compound 1 treatment and the DMSO control, using multiplex quantitative proteomics analysis of tumor lysates. The x-axis shows the Log2 fold change, and the y-axis shows the negative Log10 adjusted p-value. Horizontal dashed lines indicate statistical significance (adjusted p ≤ 0.01), and vertical lines indicate fold changes ≥ 2. IKZF1 and IKZF3 were the only proteins with significantly downregulated fold changes of 5.5 and 4.1, respectively. The data shown are biological replicates measured in a single 10-plex TMT experiment, quantifying a total of 7903 proteins. P-values ​​are derived from modified t-statistics and corrected for multiple hypothesis testing using the Benjamini–Hochberg method. Experimental procedures are provided in Example 10.

[0060] Figure 2B This is a scatter plot of data from tumor lysates obtained by multiplex quantitative proteomics analysis in mice treated with compound 1 for 24 hours. The scatter plot depicts the fold change in relative abundance between compound 1 treatment and the DMSO control, using multiplex quantitative proteomics analysis of tumor lysates. The x-axis shows the Log2 fold change, and the y-axis shows the negative Log10 adjusted p-value. Horizontal dashed lines indicate statistical significance (adjusted p ≤ 0.01), and vertical lines indicate a fold change ≥ 2. The experimental procedures are provided in Example 10.

[0061] Figure 3 This is a dose-response curve describing the effect of compound 1 with and without bortezomib (a proteasome inhibitor) or MLN-4924 (a neddylation inhibitor) on Ikaros degradation. 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, 3, and 6 hours of compound 1, and at 6 hours of the combination of compound 1 and 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 as a percentage relative to DMSO.

[0062] Figure 4 This is a graph illustrating 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 with pomalidomide. The x-axis represents the time of measurement in days, and the y-axis represents the time in mm. 3 The measured NCI-H929 tumor volume is expressed in units of measurement.

[0063] Figure 5 This is a graph illustrating 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 with pomalidomide. The x-axis represents the time of measurement in days, and the y-axis represents the time in mm. 3 The RPMI-8226 tumor volume is measured in units of 1.

[0064] Figure 6 These are images of mice subjected to a comparison of compound 1 and the solvent. As described in Example 14, mice were imaged using IVISLumina II.

[0065] Figure 7 This is a graph of bioluminescence signals in mice that were orally administered (PO) daily (QD) with Compound 1 or its solvent and imaged with IVISLumina II, as described in Example 14. The x-axis represents the time of measurement in days, and the y-axis represents the time in photons / 10 6 The total bioluminescence signal (BLI) of the MM1S-Luc system is measured in units.

[0066] Figure 8 This is a graph showing the tumor volume in mice that were injected with NCI-H929 pomalidomide-resistant cells and orally administered compound 1 (100 μg / kg) or pomalidomide (3000 μg / kg) daily (QD) (PO), as described in Example 15. The x-axis is measured in days, and the y-axis is measured in mm. 3 These tumor volumes were measured in units of [unit].

[0067] Figure 9 This is a graph showing the tumor volume in mice injected with the refractory multiple myeloma cell line RPMI-8226. As described in Example 15, mice were injected with RPMI-8226 tumors, allowing the tumors to grow to 109-158 mm. 3 The volume (28 days post-implantation). Solvent-treated animals continued treatment until the tumor reached 2211 mm.3 MTV (mean tumor volume). Animals treated with pomalidomide were crossed with compound 1 (100 μg / kg / day) on day 17 for another 21 days. The x-axis is measured in days, and the y-axis is measured in mm. 3 These tumor volumes were measured in units of [unit].

[0068] Figure 10 This is a graph showing the tumor volume in mice injected with REC1 lymphoma mantle cells and administered either 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, and 100 μg / kg), and pomalidomide was administered at a dose of 3000 μg / kg. Both agents were administered orally (PO) daily (QD). The x-axis represents the time of measurement in days, and the y-axis represents the time in mm. 3 These tumor volumes were measured in units of [unit].

[0069] Figure 11 This is a graph showing the tumor volume in mice treated with TMD8 DLBCL lymphoma via injection and daily (QD) oral (PO) administration of compound 1 (100 μg / kg) or pomalidomide (3000 μg / kg), as described in Example 16. The x-axis represents time measured in days, and the y-axis represents time measured in mm. 3 These tumor volumes were measured in units of [unit].

[0070] Figure 12 This is a graph showing the tumor volume in mice injected with KI-JK ALCL and administered 30 μg / kg or 100 μg / kg PO QD (orally daily) of compound 1, pomalidomide (3000 μg / kg, QD PO), or CC-92480 (1000 μg / kg, QD PO) as described in Example 17. Mice were administered the medication for 21 days. The x-axis is the measurement in days, and the y-axis is in mm. 3 These tumor volumes were measured in units of [unit].

[0071] Figure 13A This is a bar graph showing IKZF1 protein expression in mice injected with KI-JK ALCL tumor-associated with either compound 1 or pomalidomide, as described in Example 17. Mice were sacrificed and tumors were collected at 6 and 24 hours after a single dose. The x-axis is labeled with the time post-dose in the sacrificed animals, and the y-axis is the percentage of IKZF1 protein normalized to GAPDH compared to the solvent control.

[0072] Figure 13BThis is a bar graph showing IRF4 protein expression in mice injected with KI-JK ALCL tumor-associated with either compound 1 or pomalidomide, as described in Example 17. Mice were sacrificed and tumors were collected at 6 and 24 hours after a single dose. The x-axis is labeled with the time post-dose at which the animals were sacrificed, and the y-axis is the percentage of IRF4 protein normalized relative to GAPDH compared to the solvent control.

[0073] Figure 14 This is a graph showing tumor volume in mice injected with DL-40ALCL and administered with Compound 1, pomalidomide, or CC-92480, as described in Example 18. Compound 1 was administered orally (PO) daily (QD) at three different concentrations (10 μg / kg, 30 μg / kg, or 100 μg / kg). Pomalidomide was administered orally daily at a dose of 3000 μg / kg. CC-92480 was administered orally daily at a dose of 300 μg / kg. The x-axis represents time measured in days, and the y-axis represents time measured in mm. 3 These tumor volumes were measured in units of [unit].

[0074] Figure 15A This is a graph showing IKZF1 protein expression in mice injected with DL-40ALCL tumor cells and administered compound 1 or pomalidomide, as described in Example 18. Mice were sacrificed and tumors were collected at 1, 4, and 24 hours after a single dose. The x-axis is labeled with the time after administration for euthanizing the animals, and the y-axis is the percentage of IKZF1 protein normalized to GAPDH compared to the solvent control.

[0075] Figure 15B As described in Example 18, Western blot analysis was performed to measure the concentrations of IKZF1 and IKZF3 in mice injected with DL-40ALCL tumors and administered either compound 1 or pomalidomide. Concentrations were determined when mice were sacrificed at 1, 4, and 24 hours after a single administration. DL-40ALCL tumor

[0076] Figure 16 This is a graph showing the tumor volume in mice injected with DL-40ALCL and administered either 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 the measurement in days, and the y-axis represents the measurement in mm. 3 These tumor volumes were measured in units of [unit].

[0077] Figure 17This is a graph showing the tumor volume in mice injected with DL-40ALCL 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 the time measured in days, and the y-axis represents the percentage change in body weight.

[0078] Figure 18 This is a graph showing the tumor volume in mice injected with KI-JK ALCL and administered compound 1 (100 μg / kg, orally once daily (QD)) as described in Example 20. The x-axis is measured in days, and the y-axis is measured in mm. 3 These tumor volumes were measured in units of [unit].

[0079] Figure 19 This is a graph showing the expression of IKZF1, IKZF3, IRF-4, caspase-3, and IRF-1 proteins in mice injected with KI-JK ALCL tumor-associated with compound 1, as described in Example 20. The x-axis is labeled with the time after administration to euthanize the animals, and the y-axis is the percentage of protein normalized to GAPDH compared to the solvent control.

[0080] Figure 20 This is a graph comparing the effects of compound 1, ibrutinib, and the 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 individual doses of each drug. The x-axis represents the measurement time in days, and the y-axis represents the measurement time in mm. 3 These tumor volumes were measured in units of [unit].

[0081] Figure 21 This is a graph showing the survival percentage of mice carrying TMD8 DLBCL after administration of 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 individual doses of each drug. The x-axis represents the number of days after administration, and the y-axis represents the survival percentage.

[0082] Figure 22This is a graph comparing the effects of compound 1, dexamethasone, and the combination of compound 1 and dexamethasone on tumor volume of RPMI-8226 multiple myeloma in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) at a dose of 5 mg / kg weekly (QW), and compound 1 was administered orally at a dose of 10 μg / kg daily. Compound 1 and dexamethasone were administered in combination at their respective dose levels and schedules. The x-axis represents the time of measurement in days, and the y-axis represents the time in mm. 3 These tumor volumes were measured in units of [unit].

[0083] Figure 23 This is a graph showing the survival percentage of mice carrying RPMI-8226 multiple myeloma tumors after administration of Compound 1, dexamethasone, and a combination of Compound 1 and dexamethasone, as described in Example 22. Dexamethasone was administered intravenously (IV) at a dose of 5 mg / kg weekly (QW), and Compound 1 was administered orally at a dose of 10 μg / kg daily. Compound 1 and dexamethasone were administered in combination at their respective dose levels and schedules. The x-axis represents the number of days after administration, and the y-axis represents the survival percentage.

[0084] Figure 24 This is a graph showing the concentrations of IKZF1 and IKZF3 in a monkey administered compound 1. As described in Example 23, compound 1 was administered to a monkey, and blood was collected at 0, 4, and 24 hours post-administration to determine the concentrations of IKZF1 and IKZF3. The x-axis represents the measurement time in hours post-administration, and the y-axis represents the average fluorescence intensity of IKZF1 and IKZF3.

[0085] Figure 25A This is a graph showing the plasma concentrations of compound 1 or compound 14 measured after administration of compound 1 (60 μg / kg or 100 μg / kg) to monkeys PO, as described in Example 24. The x-axis represents the measurement time in hours, and the y-axis represents the measured plasma concentration in ng / mL.

[0086] Figure 25B This is a graph showing the plasma concentrations of compound 1 or compound 14 measured after administration of compound 1 (30 mg / kg) to rats at PO, as described in Example 24. The x-axis represents the measurement time in hours, and the y-axis represents the measured plasma concentration in ng / mL.

[0087] Figure 26A This is a graph depicting the effect of compound 1 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0088] Figure 26B This is a graph depicting the effect of compound 2 (100 μg / kg, QD PO) on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0089] Figure 26C This is a graph depicting the effect of compound 3 (100 μg / kg, QD PO) on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0090] Figure 26D This is a graph depicting the effect of compound 4 (100 μg / kg, QD PO) on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0091] Figure 26E This is a graph depicting the effect of compound 5 (100 μg / kg, QD PO) on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0092] Figure 26F This is a graph depicting the effect of compound 6 (100 μg / kg, QD PO) on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0093] Figure 26G This is a graph depicting the effect of compound 7 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0094] Figure 26HThis is a graph depicting the effect of compound 8 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0095] Figure 26I This is a graph depicting the effect of compound 9 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0096] Figure 26J This is a graph depicting the effect of compound 10 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the time measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0097] Figure 26K This is a graph depicting the effect of compound 11 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0098] Figure 26L This is a graph depicting the effect of compound 12 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with DL-40ALCL, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the time measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0099] Figure 26M This is a graph depicting the effect of compound 13 (100 μg / kg, QD PO) compared to the solvent on tumor volume in mice injected with H929 tumor cells, as described in Example 25. The x-axis represents the treatment duration measured in days, and the y-axis represents the treatment duration measured in mm. 3 The volume of the H929 tumor is measured in units of [unit].

[0100] Figure 27This graph shows the in vitro binding of compound 1 to purified hydroxycerebroside-DDB1 measured by fluorescence polarization experiments. Compound 1 (circled) or the reference compound (pomalidomide) competes with an Alexa-647-based fluorescent probe for binding to hydroxycerebroside-DDB1. Probe displacement results in a decrease in fluorescence polarization level, which is used to calculate the fraction of bound probes using signals from positive and negative controls. Error bars represent standard deviation (SD). The measured Kd values ​​are as follows: Compound 1: K d =0.9±0.5nM; Pomalidomide K d =712±140 nM. Fluorescence polarization experiments are described in Example 26.

[0101] Figure 28 This describes the dose-response curves depicting the substitution of the cerebroside-NanoLuc fusion complex with compound 1 or pomalidomide for the cerebroside-binding tracer molecule in 293T cells expressing the cerebroside-NanoLuc fusion complex, as described in Example 27. The x-axis represents the concentration (nM) of compound 1 or pomalidomide, and the y-axis represents the %NanoBRET signal relative to cells treated with only the cerebroside-binding tracer (100%) or without any tracer (0%). 50% of the tracer was replaced by compound 1 at an IC50 concentration. 50 =0.4 nM and pomalidomide at IC50 50 =644nM permutation.

[0102] Figure 29 This is a dose-response curve describing the effect of compound 1 on the degradation of IKZF1 compared to pomalidomide, as described in Example 9. The x-axis is the concentration (nM) of compound 1 or pomalidomide, and the y-axis is the remaining IKZF1% after treatment with compound 1 or pomalidomide for 1 or 2 hours.

[0103] Figure 30 This is a Western blot showing the dose-response levels of Aiolos and Ikaros in H929 cells after treatment with compound 1 or pomalidomide for 4 hours. The method of this experiment is described in Example 28.

[0104] Figure 31 This is a dose-response curve describing 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 (nM) of compound 1 or pomalidomide, and the y-axis represents the luminescence signal (RLU) measured after the addition of the caspase 3 / 7 substrate reagent. The method of this experiment is described in Example 29.

[0105] Figure 32This is a graph showing 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 (in nM, IC50) at which compound 1 or pomalidomide inhibits cell growth by 50% at 96 hours. 50 The y-axis represents the cell line being tested.

[0106] Figure 33 This graph shows the in vivo efficacy of compound 1 and pomalidomide in treating female NOD SCID mice with NCI-H929 multiple myeloma xenograft tumors. Mice were treated for 21 days with either solvent control, dose-response mice (3, 10, 30, and 100 μg / kg / day) of compound 1 or 3000 μg / kg / day of pomalidomide. All compounds were administered orally (PO) daily (QD). Tumor regrowth was monitored after 21 days of administration. Arrows indicate rechallenge with compound 1 at 30 μg / kg / day starting from day 40. The x-axis is time measured in days, and the y-axis is in mm. 3 The NCI-H929 tumor volume was measured in units of [unit]. This measurement is described in Example 31.

[0107] Figure 34 This is a graph of bioluminescence signals in mice that were orally administered (PO) daily (QD) with Compound 1 or its solvent and imaged with IVISLumina II, as described in Example 14. The x-axis represents the time of measurement in days, and the y-axis represents the time in photons / 10 6 The total bioluminescence signal (BLI) of the MM1S-Luc system is measured in units.

[0108] Figure 35 The in vivo efficacy of compound 1 and pomalidomide in treating female CB17 SCID mice carrying RPM-8226 multiple myeloma xenograft tumors is shown. Mice were treated for 21 days with solvent control, (3, 10, 30, and 100 μg / kg / day) doses of compound 1, or 3000 μg / kg / day of pomalidomide. All compounds were administered orally (PO) daily (QD). Tumors are plotted individually and expressed as a percentage of their original volume, as shown on the y-axis.

[0109] Figure 36 This is a graph showing IKZF3 protein expression in mice that received RPMI-8226 tumor injection and were administered dose-responsive compound 1, as described in Example 32. The x-axis is labeled with the time after administration to euthanize the animals, and the y-axis is the percentage of protein normalized to GAPDH compared to the solvent control.

[0110] Figure 37This is a graph showing the expression of tumor proteins IKZF1, IKZF3, and IRF-4 in mice injected with RPMI-8226MM tumor cells and administered compound 1, as described in Example 32. The x-axis is labeled with the time after administration when the animals were euthanized, and the y-axis is the percentage of protein normalized to GAPDH compared to the solvent control.

[0111] Figure 38 This study evaluated the levels of hydroxycerebroside, IKZF1, and IKZF3 in untreated (parental) H929 cells, and cells treated with DMSO (LTC; long-term culture), lenalidomide, or pomalidomide for 4 months using Western blotting. Focal adhesion proteins were used as a loading control. Western blotting was performed using the method described in Example 33.

[0112] Figure 39 The effect of compound 1 on the growth of IMiD-resistant NCIH929 multiple myeloma cells compared to pomalidomide is described, as described in Example 34. The x-axis represents the concentration (nM) of compound 1 or pomalidomide, and the y-axis represents the % cell viability of IMiD-resistant NCIH929 cells relative to untreated cells after 96 hours.

[0113] Figure 40 This is a figure showing the tumor volume in mice injected with the refractory multiple myeloma cell line RPMI-8226. Except for the pomalidomide group, mice were orally administered solvent control, pomalidomide (3000 μg / kg / day), or compound 1 (100 μg / kg / day) daily for 35 days. In this group, pomalidomide administration was discontinued on day 17 and replaced with compound 1 (100 μg / kg / day) for the remainder of the study. This experiment is described in more detail in Example 15.

[0114] Figure 41 This is a graph comparing the effects of compound 1, dexamethasone, and the combination of compound 1 and dexamethasone on tumor volume of RPMI-8226 multiple myeloma in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) at a dose of 5 mg / kg weekly (QW), and compound 1 was administered orally at a dose of 10 μg / kg or 100 μg / kg daily. Compound 1 at 10 μg / kg was combined with dexamethasone at their respective dose levels and schedules. The x-axis represents the measurement time in days, and the y-axis represents the measurement time in mm. 3 These tumor volumes were measured in units of [unit].

[0115] Figure 42This is a graph comparing the effects of compound 1, dexamethasone, and the combination of compound 1 and dexamethasone on tumor volume of RPMI-8226 multiple myeloma in mice, as described in Example 22. Dexamethasone was administered intravenously (IV) at a dose of 5 mg / kg weekly (QW), and compound 1 was administered orally at a dose of 10 μg / kg daily. Compound 1 and dexamethasone were administered in combination at their respective dose levels and schedules. Once the tumor volume reached 1000 mm², 3 Animals were removed from the study and recorded as dead. The y-axis represents the probability of an animal surviving a particular treatment, and the x-axis represents the number of days an animal survived.

[0116] Figure 43 This is a graph showing the expression of tumor proteins 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 the time after administration when the animals were euthanized, and the y-axis is the percentage of protein normalized to GAPDH compared to the solvent control.

[0117] Figure 44 This is a graph showing the protein expression of E2F1 and cyclin D1 in mice injected with REC1 MCL tumors and administered compound 1, as described in Example 35. The x-axis is labeled with the time after administration to euthanize the animals, and the y-axis is the percentage of protein normalized to GAPDH compared to the solvent control.

[0118] Figure 45A , Figure 45B and Figure 45C This is a bar graph depicting 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 (in nM, IC50) of compound 1 or pomalidomide that inhibits cell growth by 50% at 96 hours. 50 The y-axis represents the cell line being tested. Hollow symbols indicate that growth was inhibited by no more than 50% at the highest tested concentrations (100 nM or 10 μM for compound 1, 10 μM for pomalidomide, and 10 μM for CC-92480), and therefore the IC50 was not determined. 50 .

[0119] Figure 46 Western blots were taken from mice carrying established KI-JK xenografts, which were administered a single dose of compound 1 (100 μg / kg) or five daily doses. Tumors were collected at 4 and 24 hours after the single dose and at 24 hours after the five daily doses. The levels of IKZF1 and IRF-4 in the tumors were analyzed by Western blot. The experimental procedure is described in Example 38.

[0120] Figure 47This is a line graph showing changes in tumor volume in mice carrying Mino xenograft tumors, treated with compound 1 (100 μg / kg) orally once daily, rituximab IV once weekly (10 mg / kg), or a combination of both at their respective doses. Data are presented as mean tumor volume ± SEM values. The experimental procedure is described in Example 39.

[0121] Figure 48 This is a line graph showing the concentration changes over time after treatment of 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 at 1, 4, 24, and 48 hours after a single dose and analyzed by LC-MS / MS. Data are expressed as total compound concentration ± SEM values. Experimental procedures are provided in Example 40.

[0122] Figure 49 This is a line graph showing the concentration changes over time after treatment of 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 at 1, 4, 24, and 48 hours after a single administration, and IKZF3 levels were analyzed by Western blotting. Data are presented as a percentage of residual IKZF3 compared to the solvent control and relative to GAPDH normalized ± SEM values. Experimental procedures are provided in Example 40.

[0123] Figure 50 This is a line graph showing the change in tumor volume over time after mice carrying established NCI-H929 xenograft tumors were treated orally with compound 1 (100 μg / kg), CC-92480 (1000 μg / kg), or pomalidomide (3000 μg / kg) daily for 18 consecutive days. Tumor volume and body weight were measured twice weekly. Data are expressed as mean tumor volume ± SEM value. The experimental procedures are provided in Example 40.

[0124] Figure 51 This is a dose-response curve describing 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 is the concentration (nM) of compound 1 or pomalidomide, and the y-axis is the luminescence signal (RLU) measured relative to the DMSO-treated control after the addition of the caspase 3 / 7 substrate reagent.

[0125] Figure 52This is a dose-response curve describing 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 (nM) of compound 1 or pomalidomide, and the y-axis represents the percentage cell viability relative to the DMSO-treated control after the addition of CellTiter Glo reagent.

[0126] Figure 53 This is a line graph demonstrating 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 compound 1 at a dose of 30 μg / kg / day, ibrutinib at a dose of 25 mg / kg, combinations of ibrutinib and compound 1 at individual dose levels, or a solvent control, daily for 34 days. The x-axis represents time in days, and the y-axis represents time in mm. 3 These tumor volumes were measured in units of [unit missing]. Statistical analysis was performed using paired t-tests in GraphPad Prism software. Experimental procedures are provided in Example 44.

[0127] Figure 54 This is a line graph demonstrating the effects of compound 1, CC-92480, pomalidomide, or solvent control on 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 19 days. The x-axis represents time measured in days, and the y-axis represents time measured in mm. 3 These tumor volumes were measured in units of [unit missing]. Statistical analysis was performed using paired t-tests in GraphPad Prism software. Experimental procedures are provided in Example 45.

[0128] Figure 55 This is a line graph demonstrating the effect of compound 1, CC-92480, pomalidomide, or the solvent 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 for 7 days. Tumors were sampled at 4 hours and 24 hours after a single dose, and at 24 hours after 3, 5, and 7 daily doses. Data are presented as the percentage of the target present in the solvent control and normalized relative to total protein. Error bars represent ± SEM values. The experimental procedure is provided in Example 45.

[0129] Figure 56This is a line graph demonstrating the effects of compound 1, bortezomib, and the combination of compound 1 and bortezomib in NCI-H929 xenografts. Mice carrying established NCI-H929 xenografts were administered compound 1 (10 μg / kg), bortezomib (0.5 mg / kg), the combination of compound 1 and bortezomib, or a solvent control for 14 days. Compound 1 was administered orally daily, while bortezomib was administered intravenously every other week. Statistical analysis was performed using two-way ANOVA on day 14, with all animals in the study on the last day, using GraphPad Prism software. Data are presented as mean tumor volume ± SEM.

[0130] Figure 57 This is a line graph illustrating the effects of compound 1, bortezomib, and the combination of compound 1 and bortezomib in NCI-H929 xenografts. Mice carrying established NCI-H929 xenografts were administered compound 1 (10 μg / kg), bortezomib (0.25 mg / kg), the combination of compound 1 and bortezomib, or a solvent control for 14 days. Compound 1 was administered orally daily, while bortezomib was administered intravenously twice weekly. Statistical analysis was performed using two-way ANOVA on day 14, with all animals in the study on the last day, using GraphPad Prism software. Data are presented as mean tumor volume ± SEM.

[0131] Figure 58 This is a line graph showing the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL2 secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0132] Figure 59 This is a line graph showing the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IFNg secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0133] Figure 60 This is a line graph showing the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL21 secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0134] Figure 61This is a line graph showing the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL9 secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0135] Figure 62 This is a line graph showing the effects of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL4 secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0136] Figure 63 This is a line graph showing the effects of compounds 1, 2, 15, CC-92480, or pomalidomide on the concentration of TNF-α secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46.

[0137] Figure 64 This is a line graph showing the effect of compound 1, compound 2, compound 15, CC-92480, or pomalidomide on the concentration of IL17A secreted by anti-CD3 stimulated T cells after 6 days of incubation. The x-axis represents the compound concentration in nM, and the y-axis represents the fold change relative to the DMSO-treated control wells. The experimental procedure is provided in Example 46. Detailed Implementation

[0138] The novel treatments described herein, such as low-dose regimens, are based on the discovery that the described compounds are exceptionally potent degraders of Ikaros and Aiolos. Compound 1 is considered to be the most potent IKZF1 / 3 degrader disclosed to date. Data described herein and obtained otherwise confirm that the combination of compound 1 and dexamethasone significantly improves antitumor activity. The compounds described herein, particularly compound 1, are significantly more potent than pomalidomide in in vitro and in vivo NHL models, including PTCL and MCL. Therefore, these compounds are preferred over thalidomide, lenalidomide, and pomalidomide for NHL subtypes in which classic IMiDs have shown clinical activity but are not widely adopted as standard of care (MCL, DLBCL, PTCL, etc.).

[0139] It has been found that the compounds described herein can be administered in a highly effective therapeutic manner, in a low-dose regimen once or twice daily, optionally with a pharmacological holiday, to treat conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3). For example, treatment has been found to be effective in patients when using one of the compounds described herein at doses not exceeding about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or even 100, 75, 50, or 25 micrograms (μg) once daily (QD) or twice daily (BID). In some embodiments, the patient is an adult (typically at least 100 pounds or heavier, sometimes even 125 or 150 pounds (e.g., 70 kg or heavier and typically at least 18 years of age or older). In another embodiment, the patient is a child (may be less than 100, 125, or 150 pounds and typically less than 18 years of age).

[0140] In some embodiments, the dosage includes a pharmacological holiday. A pharmacological holiday is a period during which the active compound is not administered to the patient. For the purposes of this disclosure, treatment cycles are typically based on a 28-day cycle. For example, the active compound or a pharmaceutically acceptable salt thereof may be administered to the patient for 21 consecutive days in a 28-day cycle, without chemotherapy for 7 consecutive days, and then optionally the regimen may be repeated one or more times. In some instances, 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 days, and then enter the pharmacological holiday 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 pharmacological holiday until the end of the 28-day cycle. In yet another embodiment, the drug is administered daily during the dosing regimen without holidays to achieve continuous dosing. The dosing regimen period can be 1, 2, 3, or 4 weeks, or even 1, 2, 3, 4, 5, or 6 or more consecutive or cyclical months. In another embodiment, the use of the compounds described herein eliminates the need for off-cycle periods, drug holidays, or reduces the concentration of antitumor compounds co-administered during treatment. In yet another embodiment, the cycle is greater than 28 days, for example greater than 30 or 35 days, and the appropriate on-cycle and off-cycle regimens are determined by the patient's healthcare professional.

[0141] In some 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 can be used in combination with the degrading agents described herein include:

[0142] 1. BTK inhibitors selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

[0143] 2. CD38 antibodies selected from fuzumab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mizanumab.

[0144] 3. Proteasome inhibitors selected from esazolidinium citrate, opzomib, delanzomib, lactosomalin, bortezomib, carfilzomib, VLX1570, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0145] 4. IMiD selected from pomalidomide, lenalidomide, thalidomide, iberdomide, CC-92480, CC-90009 and CC-99282.

[0146] 5. HDAC inhibitors selected from trapoxin B, sodium phenylbutyrate, acetyldenalin, moxitistat, BRD73954, BG45, domastartar, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0147] 6. Compounds selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0148] I. Definition

[0149] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. In this specification, the singular form also includes the plural unless the context clearly indicates otherwise. Although methods and materials similar to or equivalent to those described herein may be used in the practice and testing of this application, suitable methods and materials are described below. All published materials, patent applications, patents, and other references mentioned herein are incorporated herein by reference. References cited herein are not an admission that they are prior art to the claimed application. In the event of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not restrictive.

[0150] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0151] In some embodiments, unless explicitly excluded by the context, each compound described herein may be in the form of a racemic mixture, an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, an N-oxide, or an isomer such as a rotational isomer, as each is specifically described.

[0152] The terms “an” and “a” do not indicate a limitation of quantity, but rather the presence of at least one referenced item. The term “or” means “and / or”. Unless otherwise stated herein, the listing of numerical ranges is intended only as a shorthand method for individually referencing each individual value falling within the range, and each individual value is incorporated into the specification as if it were listed separately herein. The endpoints of all ranges are included within the range and can be combined independently. All methods and treatments / treatments described herein can be performed in a suitable order unless otherwise indicated herein or otherwise obviously contradicted by the context. The use of examples or exemplary language (e.g., “as”) is intended only to better illustrate the invention and does not constitute a limitation on the scope of the invention unless otherwise required.

[0153] This invention comprises compounds described herein that have at least one desired isotope substitution of atoms in amounts higher than the natural abundance of the isotope, i.e., enriched. An isotope is an atom having the same atomic number but different mass numbers, i.e., atoms with the same number of protons but different numbers of neutrons. If isotope substitution is used, the usual substitution is at least one deuterium-substituted hydrogen atom.

[0154] 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, for example, respectively. 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O, and 18 F. In one non-limiting example, the isotope-labeled compound can be used for metabolic studies (e.g., using...) 14 C) Reaction kinetic studies (e.g., using...) 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in patient radiotherapy. Additionally, any hydrogen atoms present in the compounds of this invention can be... 18 F atom substitution, 18The F atom is a substituent that may be particularly desirable in PET or SPECT studies. The isotopically labeled compounds and their prodrugs of the present invention can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents, through the reaction schemes or examples and preparation procedures disclosed below.

[0155] As a general example and not a limitation, isotopes of hydrogen, such as deuterium (… 2 H) and tritium ( 3 H) can be used anywhere in the described structure to achieve the desired result. Alternatively, carbon isotopes, such as... 13 C and 14 C.

[0156] Isotopic substitution, such as deuterium substitution, can be partial or complete. Partial deuterium substitution means that at least one hydrogen atom is substituted with deuterium. In some embodiments, the isotope is an isotope enriched at 90%, 95%, or 99% or more at any site of interest. In a non-limiting embodiment, deuterium is enriched at 90%, 95%, or 99% at the desired site.

[0157] In a non-limiting embodiment, hydrogen atoms may be substituted with deuterium atoms in any of the compounds described herein. For example, when any group is methyl or ethyl, the alkyl residue may be deuterated (in a non-limiting embodiment, CDH2, CD2H, CD3, CH2CD3, CD2CD3, CHDCH2D, CH2CD3, CHDCHD2, etc.).

[0158] The compounds of the present invention can form solvates with solvents, including water. Therefore, in a non-limiting embodiment, the present invention includes the solvated form of the compounds 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 are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the present invention and water. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent can be substituted with an isotope, such as D₂O, d₆-acetone, d₆-DMSO. Solvates can be in liquid or solid form.

[0159] "Dosage form" refers to the unit of administration of the active ingredient. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, sublingual tablets, topical preparations, gels, and mucosal preparations. "Dosage form" can also include implants, such as optical implants.

[0160] As used herein, “endogenous” means any material that originates from or is produced within an organism, cell, tissue, or system.

[0161] As used herein, the term “exogenous” means any material introduced from or produced outside of an organism, cell, tissue, or system.

[0162] As used herein, the term "modulation" refers to mediating a detectable increase or decrease in response levels in a patient compared to response levels in patients without treatment or compounds, and / or compared to response levels in other, equally untreated patients. This term includes interfering with and / or influencing natural signals or responses, thereby mediating a patient's, preferably, beneficial therapeutic response.

[0163] "Parenteral" administration of compounds includes techniques such as subcutaneous (sc), intravenous (iv), intramuscular (im), intrasternal injection, or infusion.

[0164] As used herein, a “pharmaceutical composition” is a composition comprising at least one active agent (such as the selected active compound described herein) and at least one other substance (such as a carrier). A “pharmaceutical combination” is a combination of at least two active agents that may be provided together in a single dosage form or in separate dosage forms, with instructions to use these active agents together to treat any of the disorders described herein.

[0165] As used herein, a "pharmaceutically acceptable salt" is a derivative of the disclosed compound wherein the parent compound is modified by preparing a biologically acceptable (non-toxic) inorganic or organic acid or base addition salt. Salts of the compounds of the present invention can be synthesized by conventional chemical methods from a parent compound containing a basic or acidic moiety. Typically, such salts are prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (e.g., hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Typically, where feasible, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical. Salts of the compounds of the present invention also include the compound and a solvate of the compound salt.

[0166] Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include, for example, 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, aminosulfonic acid, phosphoric acid, nitric acid, etc.; and those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pyric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, ethanesulfonic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, mesylic acid, ethanedisulfonic acid, oxalic acid, hydroxyethylsulfonic acid, HOOC-(CH2) n -COOH (where n is 0-4), etc., or salts prepared using different acids that produce the same counterion. Examples of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).

[0167] The term "carrier" refers to a diluent, excipient, or solvent in which an active agent is used or delivered.

[0168] "Pharmaceutically acceptable excipients" refers to excipients that can be used to prepare pharmaceutical compositions / combinations, are generally safe, and are not biologically or otherwise unsuitable for administration to a host (typically a human). In some embodiments, the excipients used are veterinarily acceptable.

[0169] "Patient" or "host" refers to a person or non-person who needs treatment for any condition as specifically described in this article. Usually, "host" refers to a person. Alternatively, "host" can also refer to, for example, mammals, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.

[0170] The "therapeutic effective amount" of the pharmaceutical composition / combination of the present invention refers to the effective amount that provides therapeutic benefits, such as relieving symptoms or reducing or decreasing the disease itself, when administered to a host.

[0171] I1. The compounds of the present invention

[0172] In some embodiments, the compound used in this invention is

[0173]

[0174] Or its pharmaceutically acceptable salt.

[0175] In some embodiments, the compound used in this invention is

[0176]

[0177] Or its pharmaceutically acceptable salt.

[0178] In some embodiments, the compound used in this invention is

[0179] Or its pharmaceutically acceptable salt.

[0180] In some embodiments, the compound used in this invention is

[0181]

[0182] Or its pharmaceutically acceptable salt.

[0183] In some embodiments, the compound used in this invention is

[0184]

[0185] Or its pharmaceutically acceptable salt.

[0186] In some embodiments, the compound used in this invention is

[0187]

[0188] Or its pharmaceutically acceptable salt.

[0189] In some embodiments, the compound used in this invention is

[0190]

[0191] Or its pharmaceutically acceptable salt.

[0192] In some embodiments, the compound used in this invention is

[0193]

[0194] Or its pharmaceutically acceptable salt.

[0195] In some embodiments, the compound used in this invention is

[0196]

[0197] Or its pharmaceutically acceptable salt.

[0198] In some embodiments, the compound used in this invention is

[0199]

[0200] Or its pharmaceutically acceptable salt.

[0201] In some embodiments, the compound used in this invention is

[0202]

[0203] Or its pharmaceutically acceptable salt.

[0204] In some embodiments, the compound used in this invention is

[0205]

[0206] Or its pharmaceutically acceptable salt.

[0207] In some embodiments, the compound used in this invention is

[0208]

[0209] Or its pharmaceutically acceptable salt.

[0210] III. Embodiments of the Invention

[0211] 1. In some embodiments, the present invention provides treatment for Ikaros or Aiolos-mediated conditions, including administration of low-dose treatment regimens to a host in need, including once-daily (QD) or twice-daily (BID) doses not exceeding about 500, 450, 400, etc.

[0212] 350, 300, 250, 200, 150 or even 100 micrograms (μg) 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 or compound 13 or a pharmaceutically acceptable salt thereof.

[0213] 2. The treatment as described in implementation scheme 1, wherein the treatment scheme includes a drug vacation.

[0214] 3. The treatment as described in embodiment 2, wherein the drug holiday is achieved by administering the drug 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, and then entering the drug holiday until the next 28-day cycle.

[0215] 4. Treatment as described in Implementation Scheme 3, wherein the therapy is administered once or twice daily for 21 days, followed by a 7-day medication break.

[0216] 5. The treatment as described in any one of embodiments 1-4, wherein the dose is less than about 400 μg.

[0217] 6. The treatment as described in any one of embodiments 1-4, wherein the dose is less than about 300 μg.

[0218] 7. The treatment as described in any one of embodiments 1-4, wherein the dose is less than about 200 μg.

[0219] 8. The treatment as described in any one of embodiments 1-4, wherein the dose is less than about 100 μg.

[0220] 9. The treatment as described in any one of embodiments 1-4, wherein the dose is less than about 50 or 25 μg.

[0221] 10. The treatment as described in any one of embodiments 1-9, wherein the Ikaros or Aiolos-mediated condition is diffuse large B-cell lymphoma.

[0222] 11. The treatment as described in embodiment 10, wherein the diffuse large B-cell lymphoma is an activated B-cell lymphoma.

[0223] 12. The treatment as described in embodiment 10, wherein the diffuse large B-cell lymphoma is a germinal center B-cell lymphoma.

[0224] 13. The treatment as described in embodiments 1-9, wherein the Ikaros or Aiolos-mediated condition is anaplastic large cell lymphoma.

[0225] 14. The treatment as described in any one of embodiments 1-9, wherein the Ikaros or Aiolos-mediated condition is cutaneous T-cell lymphoma.

[0226] 15. The treatment as described in any one of embodiments 1-9, wherein the Ikaros or Aiolos-mediated condition is mantle cell lymphoma.

[0227] 16. The treatment as described in any one of embodiments 1-9, wherein the Ikaros or Aiolos-mediated condition is multiple myeloma.

[0228] 17. The treatment as described in any one of embodiments 1-16, wherein the condition is resistant to treatment with a first-generation IMiD drug.

[0229] 18. The treatment as described in embodiment 17, wherein the condition is resistant to thalidomide treatment.

[0230] 19. The treatment as described in embodiment 17, wherein the condition is resistant to pomalidomide treatment.

[0231] 20. The treatment as described in embodiment 17, wherein the condition is resistant to lenalidomide treatment.

[0232] 21. The treatment as described in embodiment 17, wherein the condition is resistant to iberlidomide treatment.

[0233] 22. Treatment of a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a blood or tissue sample is first collected from the patient and the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2, and / or IFN-γ, is determined, wherein if the patient has a statistically lower concentration of the biomarker than a healthy person, including but not limited to, at most about 5%, 10%, 15%, or 20%, then the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound.

[0234] 23. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein blood or tissue samples are collected from the patient and the concentrations of one or more biomarkers are measured, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4,

[0235] BLIMP1 and / or MYC, wherein if the patient has a statistically higher concentration of biomarkers than healthy individuals, including but not limited to up to about 5%, 10%, 15%, or 20% higher, then the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound.

[0236] 24. Treatment of a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound, and then a blood or tissue sample is collected from the patient and the concentration of one or more biomarkers, such as IRF-1, caspase-3, IL-2 and / or IFN-γ, wherein if the concentration of the biomarker does not increase significantly, for example, by at least about 1.25, 1.5, 1.75 or 2 times, the dose of the compound is increased.

[0237] 25. Treatment of a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein the patient is given compound 1 described herein or a pharmaceutically acceptable salt thereof or another compound, and then a blood or tissue sample is collected from the patient and the concentration of one or more biomarkers, such as cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1 and / or MYC, wherein if the concentration of the biomarker is not significantly reduced, for example, reduced by at least about 1.25, 1.5, 1.75 or 2 times, the dose of the compound is increased.

[0238] 26. The treatment as described in any one of embodiments 22-25, wherein if the concentration of the biomarker is less than 150%, the dose is increased.

[0239] 27. The treatment as described in any one of embodiments 22-25, wherein if the concentration of the biomarker is less than 160%, the dose is increased.

[0240] 28. The treatment as described in any one of embodiments 22-25, wherein if the concentration of the biomarker is less than 170%, the dose is increased.

[0241] 29. The treatment as described in any one of embodiments 22-25, wherein if the concentration of the biomarker is less than 180%, the dose is increased.

[0242] 30. Treatment of Ikaros or Aiolos-mediated disease, comprising administering to a patient in need 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 Ikaros or Aiolos-mediated disease is activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.

[0243] 31. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination 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, and a compound selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and BTK inhibitors of fenebrutinib.

[0244] 32. Treatment of a disease mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination of 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 or pharmaceutically acceptable salts thereof are used with a CD38 antibody selected from felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0245] 33. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination of 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, or pharmaceutically acceptable salts thereof, is used with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0246] 34. Treatment of a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination of 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, or pharmaceutically acceptable salts thereof, is used with an IMiD selected from CC-92480, CC-90009, and CC-99282.

[0247] 35. Treatment of a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination of 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, or pharmaceutically acceptable salts thereof, is used with a mixture selected from trapoxin B, sodium chlorate, acetyldinarin, moxiceptistat,

[0248] BRD73954, BG45, Domastamine, cay10603, HPOB, TMP269

[0249] nexturastat A, Santacruzamate A, Splitomicin, LMK-235, Sodium Butyrate, Neopentyloxymethyl Butyrate, Pyroxamide, Abexinostat, Resminost

[0250] HDAC inhibitors of givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0251] 36. Treatment of conditions mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a combination 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 is used with a compound selected from: selinexor, oxaphenamide, belantamabmafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilimumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0252] 37. The treatment as described in any one of embodiments 1-36, wherein said compound is

[0253]

[0254] Or its pharmaceutically acceptable salt.

[0255] 38. The treatment according to any one of embodiments 1-36, wherein said compound is

[0256]

[0257] Or its pharmaceutically acceptable salt.

[0258] 39. The treatment as described in any one of embodiments 1-36, wherein said compound is

[0259]

[0260] Or its pharmaceutically acceptable salt.

[0261] 40. The treatment according to any one of embodiments 1-36, wherein said compound is

[0262]

[0263] Or its pharmaceutically acceptable salt.

[0264] 41. The treatment according to any one of embodiments 1-36, wherein said compound is

[0265]

[0266] Or its pharmaceutically acceptable salt.

[0267] 42. The treatment according to any one of embodiments 1-36, wherein said compound is

[0268]

[0269] Or its pharmaceutically acceptable salt.

[0270] 43. The treatment according to any one of embodiments 1-36, wherein said compound is

[0271]

[0272] Or its pharmaceutically acceptable salt.

[0273] 44. The treatment as described in any one of embodiments 1-36, wherein said compound is

[0274]

[0275] Or its pharmaceutically acceptable salt.

[0276] 45. The treatment according to any one of embodiments 1-36, wherein said compound is

[0277]

[0278] Or its pharmaceutically acceptable salt.

[0279] 46. ​​The treatment according to any one of embodiments 1-36, wherein said compound is

[0280]

[0281] Or its pharmaceutically acceptable salt.

[0282] 47. The treatment according to any one of embodiments 1-36, wherein said compound is

[0283]

[0284] Or its pharmaceutically acceptable salt.

[0285] 48. The treatment according to any one of embodiments 1-36, wherein said compound is

[0286]

[0287] Or its pharmaceutically acceptable salt.

[0288] 49. The treatment as described in any one of embodiments 1-36, wherein said compound is

[0289]

[0290] Or its pharmaceutically acceptable salt.

[0291] 50. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with a Bruton's tyrosine kinase inhibitor.

[0292] 51. The treatment as described in embodiment 50, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

[0293] 52. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with a corticosteroid.

[0294] 53. The treatment as described in embodiment 52, wherein the corticosteroid is dexamethasone.

[0295] 54. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with CAR T-cell therapy.

[0296] 55. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with an antibody-drug conjugate.

[0297] 56. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with BiTE therapy.

[0298] 57. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with the bispecific antibody.

[0299] 58. The treatment as described in any one of embodiments 1-49, wherein the compound is administered in combination with a monoclonal antibody.

[0300] 59. The treatment according to any one of embodiments 1-49, wherein said compound is administered in combination with acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and a BTK inhibitor of fenebrutinib.

[0301] 60. The treatment according to any one of embodiments 1-49, wherein said compound is combined with a compound selected from phenzetumab, daratumumab, GBR 1342, TAK-573, CID-103,

[0302] The combination of OKT10, STI-6129, SGX301, TAK-079, and the CD38 antibody Myzotuzumab was administered.

[0303] 61. The treatment according to any one of embodiments 1-49, wherein said compound is combined with esazolidinium citrate, opzomib, delanzomib, lactocytocin, bortezomib, carfilzomib, VLX1570, cyclooxygenase, MG132, MG-262, CEP-18770,

[0304] The proteasome inhibitors NEOSH101, TQB3602, and KZR-616 were administered in combination.

[0305] 62. The treatment according to any one of embodiments 1-49, wherein the compound is administered in combination with an IMiD selected from pomalidomide, lenalidomide, thalidomide, iberlidomide, CC-92480, CC-90009 and CC-99282.

[0306] 63. The treatment according to any one of embodiments 1-49, wherein said compound is administered in combination with an HDAC inhibitor selected from trapoxin B, sodium chlorate, acetyldenalin, moxitetstat, BRD73954, BG45, domaststat, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0307] 64. The treatment according to any one of embodiments 1-49, wherein said compound is administered in combination with a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0308] In some implementations, the treatment described above is provided, wherein the dose of compound 1 is less than or equal to about 5 μg.

[0309] In some implementations, the treatment described above is provided, wherein the dose of compound 1 is less than or equal to about 10 μg.

[0310] Other implementation plans

[0311] 1. In some embodiments, a method of treating conditions mediated by Ikaros and / or Aiolos is provided, comprising administering a non-daily (QD) or twice-daily (BID) dose of...

[0312] Compounds selected from the following groups are used in doses exceeding approximately 500 micrograms (μg):

[0313]

[0314]

[0315]

[0316] Or its pharmaceutically acceptable salt.

[0317] 2. The method of embodiment 1, wherein the compound is administered at a dose between about 500 micrograms and 1 microgram.

[0318] 3. The method as described in embodiment 1 or embodiment 2, wherein the compound is administered for multiple days with a drug holiday between subsequent treatment cycles.

[0319] 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, and then enters the drug holiday until the next 28-day cycle.

[0320] 5. The method as described in embodiment 3, wherein the compound is administered once or twice daily for 21 days, followed by a 7-day drug holiday.

[0321] 6. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 400 μg.

[0322] 7. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 300 μg.

[0323] 8. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 200 μg.

[0324] 9. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 100 μg.

[0325] 10. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 50 μg.

[0326] 11. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 25 μg.

[0327] 12. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 10 μg.

[0328] 13. The method as described in any one of embodiments 1-5, wherein the dose is less than or equal to about 5 μg.

[0329] 14. The method as described in any one of embodiments 1-5, wherein the dose is about 50 μg.

[0330] 15. The method as described in any one of embodiments 1-5, wherein the dose is about 25 μg.

[0331] 16. The method as described in any one of embodiments 1-5, wherein the dose is about 10 μg.

[0332] 17. The method as described in any one of embodiments 1-5, wherein the dose is about 5 μg.

[0333] 18. The method as described in any one of embodiments 1-17, wherein the disease is diffuse large B-cell lymphoma.

[0334] 19. The method of embodiment 18, wherein the diffuse large B-cell lymphoma is an activated B-cell lymphoma.

[0335] 20. The method of embodiment 18, wherein the diffuse large B-cell lymphoma is a germinal center B-cell lymphoma.

[0336] 21. The method as described in any one of embodiments 1-17, wherein the disease is anaplastic large cell lymphoma.

[0337] 22. The method as described in any one of embodiments 1-17, wherein the condition is cutaneous T-cell lymphoma.

[0338] 23. The method as described in any one of embodiments 1-17, wherein the disease is mantle cell lymphoma.

[0339] 24. The method as described in any one of embodiments 1-17, wherein the disease is multiple myeloma.

[0340] 25. The method of any one of embodiments 1-24, wherein the condition is resistant to treatment with a first-generation IMiD drug.

[0341] 26. The method as described in embodiment 25, wherein the condition is resistant to thalidomide treatment.

[0342] 27. The method of embodiment 25, wherein the condition is resistant to pomalidomide treatment.

[0343] 28. The method of embodiment 25, wherein the condition is resistant to lenalidomide treatment.

[0344] 29. The method of embodiment 25, wherein the condition is resistant to iberlidomide treatment.

[0345] 30. In some embodiments, a treatment is provided consisting of Ikaros (IKZF1) and / or...

[0346] A method for treating conditions mediated by Aiolos (IKZF3), wherein a blood or tissue sample is collected from a patient and the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN-γ is determined, wherein if the patient has a statistically lower concentration of the biomarker compared to a healthy person, 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, is administered to the patient.

[0347] 31. The method of embodiment 30, wherein the statistically low concentration of the biomarker is 5% lower than the average concentration in healthy patients.

[0348] 32. The method of embodiment 30, wherein the statistically low concentration of the biomarker is 20% lower than the average concentration in healthy patients.

[0349] 33. A method for treating a condition mediated by Ikaros (IKZF1) and / or Aiolos (IKZF3), wherein a blood or tissue sample is collected from a patient and the concentration of one or more biomarkers selected from cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and MYC is determined, wherein if the patient has a statistically higher concentration of the biomarker than a healthy person, 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, is administered to the patient.

[0350] 34. The method of embodiment 33, wherein the statistically higher concentration of the biomarker is 5% higher than the average concentration of healthy patients.

[0351] 35. The method of embodiment 33, wherein the statistically higher concentration of the biomarker is 20% higher than the average concentration of healthy patients.

[0352] 36. In some embodiments, a treatment is provided consisting of Ikaros (IKZF1) and / or...

[0353] A method for treating conditions mediated by Aiolos (IKZF3) involves 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, followed by collection of a blood or tissue sample from the patient and determination of the concentration of one or more biomarkers selected from IRF-1, caspase-3, IL-2, and IFN-γ, wherein if the concentration of the biomarker does not increase significantly, the dose of the compound is increased.

[0354] 37. The method of embodiment 36, wherein if the concentration of the biomarker does not increase by at least about 25%, the dose of the compound is increased.

[0355] 38. The method of embodiment 36, wherein if the concentration of the biomarker does not increase by at least about 100%, the dose of the compound is increased.

[0356] 39. The method of embodiment 36, wherein if the concentration of the biomarker does not increase by at least about 200%, the dose of the compound is increased.

[0357] 40. In some embodiments, a treatment is provided consisting of Ikaros (IKZF1) and / or...

[0358] A method for treating conditions mediated by Aiolos (IKZF3) involves 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, followed by collection of blood or tissue samples from the patient and determination of cyclin D1, E2F1, ZFP91, etc.

[0359] The concentration of one or more biomarkers of SALL4, IRF-4, BLIMP1, and MYC, wherein if the concentration of the biomarker does not decrease significantly, the dose of the compound is increased.

[0360] 41. The method of embodiment 40, wherein if the concentration of the biomarker does not decrease by at least about 10%, the dose of the compound is increased.

[0361] 42. The method of embodiment 40, wherein if the concentration of the biomarker does not decrease by at least about 25%, the dose of the compound is increased.

[0362] 43. The method of embodiment 40, wherein if the concentration of the biomarker does not decrease by at least about 50%, the dose of the compound is increased.

[0363] 44. In some embodiments, a method of treating Ikaros and / or Aiolos-mediated disease is provided, comprising administering to a patient in need 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 Ikaros or Aiolos-mediated disease is activated diffuse large B-cell lymphoma or germinal center large B-cell lymphoma.

[0364] 45. In some embodiments, a method of treating Ikaros and / or Aiolos-mediated conditions is provided, 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 compound selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, tolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and BTK inhibitors of fenebrutinib.

[0365] 46. ​​In some embodiments, a method of treating a condition mediated by Ikaros and / or Aiolos is provided, 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 felzartamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0366] 47. In some embodiments, a method of treating a condition mediated by Ikaros and / or Aiolos is provided, 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, lactacystin, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0367] 48. In some embodiments, a method of treating a condition mediated by Ikaros and / or Aiolos is provided, comprising administering to a patient in need 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 an IMiD selected from CC-92480, CC-90009, and CC-99282.

[0368] 49. In some embodiments, a method of treating a condition mediated by Ikaros and / or Aiolos is provided, comprising administering to a patient in need 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 compound selected from trapoxin B, sodium chlorate, acetyldenaline, moxiceptistat,

[0369] BRD73954, BG45, Domastamine, cay10603, HPOB, TMP269

[0370] nexturastat A, Santacruzamate A, Splitomicin, LMK-235, Sodium Butyrate, Neopentyloxymethyl Butyrate, Pyroxamide, Abexinostat, Resminost

[0371] HDAC inhibitors of givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0372] 50. In some embodiments, a method of treating conditions mediated by Ikaros and / or Aiolos is provided, comprising administering to a patient in need 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 said patient also receives a compound selected from: selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilimumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0373] 51. The method according to any one of embodiments 1-50, wherein said compound is

[0374]

[0375] Or its pharmaceutically acceptable salt.

[0376] 52. The method according to any one of embodiments 1-50, wherein said compound is

[0377]

[0378] Or its pharmaceutically acceptable salt.

[0379] 53. The method according to any one of embodiments 1-50, wherein said compound is

[0380]

[0381] Or its pharmaceutically acceptable salt.

[0382] 54. The method according to any one of embodiments 1-50, wherein said compound is

[0383]

[0384] Or its pharmaceutically acceptable salt.

[0385] 55. The method according to any one of embodiments 1-50, wherein said compound is

[0386]

[0387] Or its pharmaceutically acceptable salt.

[0388] 56. The method according to any one of embodiments 1-50, wherein said compound is

[0389]

[0390] Or its pharmaceutically acceptable salt.

[0391] 57. The method according to any one of embodiments 1-50, wherein said compound is

[0392]

[0393] Or its pharmaceutically acceptable salt.

[0394] 58. The method according to any one of embodiments 1-50, wherein said compound is

[0395]

[0396] Or its pharmaceutically acceptable salt.

[0397] 59. The method according to any one of embodiments 1-50, wherein the compound is

[0398]

[0399] Or its pharmaceutically acceptable salt.

[0400] 60. The method according to any one of embodiments 1-50, wherein said compound is

[0401]

[0402] Or its pharmaceutically acceptable salt.

[0403] 61. The method according to any one of embodiments 1-50, wherein said compound is

[0404]

[0405] Or its pharmaceutically acceptable salt.

[0406] 62. The method according to any one of embodiments 1-50, wherein the compound is

[0407]

[0408] Or its pharmaceutically acceptable salt.

[0409] 63. The method according to any one of embodiments 1-50, wherein the compound is

[0410]

[0411] Or its pharmaceutically acceptable salt.

[0412] 64. The method as described in any one of embodiments 1-63, wherein the patient is further administered a Bruton's tyrosine kinase inhibitor.

[0413] 65. The method of embodiment 64, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

[0414] 66. The method as described in any one of embodiments 1-65, wherein a corticosteroid is also administered to the patient.

[0415] 67. The method of embodiment 66, wherein the corticosteroid is dexamethasone.

[0416] 68. The method as described in any one of embodiments 1-67, wherein the patient is further administered CAR T-cell therapy.

[0417] 69. The method as described in any one of embodiments 1-67, wherein the antibody-drug conjugate is further administered to the patient.

[0418] 70. The method as described in any one of embodiments 1-67, wherein the patient is further given BiTE therapy.

[0419] 71. The method as described in any one of embodiments 1-67, wherein the bispecific antibody is further administered to the patient.

[0420] 72. The method as described in any one of embodiments 1-67, wherein the monoclonal antibody is further administered to the patient.

[0421] 73. The method as described in any one of embodiments 1-67, wherein the patient is further administered a product selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, and evobrutinib.

[0422] TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-

[0423] A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and BTK inhibitors of fenebrutinib.

[0424] 74. The method as described in any one of embodiments 1-67, wherein the patient is further administered a drug selected from ferruginumab, daratumumab, GBR 1342, TAK-573, CID-103,

[0425] OKT10, STI-6129, SGX301, TAK-079, and CD38 antibodies of Myzotuzumab.

[0426] 75. The method as described in any one of embodiments 1-67, wherein the patient is further administered a proteasome inhibitor selected from esazomib citrate, opzomib, delanzomib, lactosomalin, bortezomib, carfilzomib, VLX1570, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

[0427] 76. The method of any one of embodiments 1-67, wherein the patient is further administered an IMiD selected from pomalidomide, lenalidomide, thalidomide, iberlidomide, CC-92480, CC-90009 and CC-99282.

[0428] 77. The method as described in any one of embodiments 1-67, wherein the patient is further administered an HDAC inhibitor selected from trapoxin B, sodium chlorate, acetyldenalin, moxitetstat, BRD73954, BG45, domaststat, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0429] 78. The method of any one of embodiments 1-67, wherein the patient is further administered a compound selected from selinexor, oxaphenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumab, palbociclib, ricolinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, ulocuplumab, and urelumab.

[0430] 79. The method as described in any one of embodiments 1-78, wherein the 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, is administered once daily.

[0431] 80. The method of any one of embodiments 1-78, wherein the 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 is administered twice daily.

[0432] 81. The method as described in any one of embodiments 1-80, wherein the disease is non-Hodgkin's lymphoma.

[0433] 82. The method as described in any one of embodiments 1-80, wherein the disease is multiple myeloma.

[0434] 83. The method as described in any one of embodiments 1-82, wherein the condition is recurrent.

[0435] 84. The method as described in any one of embodiments 1-82, wherein the condition is refractory.

[0436] 85. The method as described in any one of embodiments 1-82, wherein the condition is recurrent and refractory.

[0437] IV. Treatment of Ikaros and / or Aiolos-mediated conditions

[0438] This provides a favorable treatment for symptoms mediated by Ikaros and / or Aiolos. In some embodiments, the treatment comprises administering a low-dose form once or twice daily, optionally with a therapeutic holiday, which is a highly effective form of treatment. For example, it has been found that treatment is effective for patients when used at doses not exceeding about 500, 450, 400, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, or even 100, 75, 50, or 25 micrograms (μg) once daily (QD) or twice daily (BID), optionally with a therapeutic holiday. In some embodiments, the patient is an adult (typically weighing at least 100 pounds or more and typically 18 years of age or older). In another embodiment, the patient is a child (may be less than 100 pounds and typically less than 18 years of age).

[0439] The selected compound (e.g., compound 1) may be administered as a monotherapy or in combination with standard care therapies for the target tumor or cancer, including but not limited to any of those described in the background of this invention, or such as proteasome inhibitors and / or anti-CD38 monoclonal antibodies (mAbs). In MCL, the selected compound may be used, for example, in combination with Bruton's tyrosine kinase (BTK) inhibitors or anti-CD20 monoclonal antibodies. In PTCL, particularly ALCL, the selected compound may be administered, for example, in combination with anti-CD30 or anti-CD38 monoclonal antibodies.

[0440] In some implementations, according to the treatment regimen described herein, compound 1 is used to treat conditions mediated by Ikaros or Aiolos.

[0441] In some implementations, according to the treatment regimen described herein, compound 2 is used to treat conditions mediated by Ikaros or Aiolos.

[0442] In some implementations, according to the treatment regimens described herein, compound 3 is used to treat conditions mediated by Ikaros or Aiolos.

[0443] In some implementations, according to the treatment regimens described herein, compound 4 is used to treat conditions mediated by Ikaros or Aiolos.

[0444] In some implementations, according to the treatment regimens described herein, compound 5 is used to treat conditions mediated by Ikaros or Aiolos.

[0445] In some implementations, according to the treatment regimens described herein, compound 6 is used to treat conditions mediated by Ikaros or Aiolos.

[0446] In some implementations, according to the treatment regimens described herein, compound 7 is used to treat conditions mediated by Ikaros or Aiolos.

[0447] In some implementations, according to the treatment regimens described herein, compound 8 is used to treat conditions mediated by Ikaros or Aiolos.

[0448] In some implementations, according to the treatment regimen described herein, compound 9 is used to treat conditions mediated by Ikaros or Aiolos.

[0449] In some implementations, according to the treatment regimen described herein, compound 10 is used to treat conditions mediated by Ikaros or Aiolos.

[0450] In some implementations, according to the treatment regimen described herein, compound 11 is used to treat conditions mediated by Ikaros or Aiolos.

[0451] In some implementations, according to the treatment regimen described herein, compound 12 is used to treat conditions mediated by Ikaros or Aiolos.

[0452] In some implementations, according to the treatment regimen described herein, compound 13 is used to treat conditions mediated by Ikaros or Aiolos.

[0453] In some embodiments, the compounds described herein, such as compound 1, are used to treat metastatic cancer. In some embodiments, the compounds described herein, such as compound 1, are used to treat cancer that has metastasized to the brain.

[0454] Treatment cycle In some embodiments, the dosage includes a pharmacological holiday. A pharmacological holiday is a period during which the active compound is not administered to the patient. For example, the active compound or a pharmaceutically acceptable salt thereof may be administered to the patient for 21 consecutive days in a 28-day cycle, without chemotherapy for 7 consecutive days, and then optionally the regimen may be repeated once or several times or more. In some instances, 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 days, and then enter a pharmacological holiday 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, and then a pharmacological holiday until the end of the 28-day cycle. In yet another embodiment, the drug is administered daily without a holiday during the dosing regimen to achieve continuous dosing, the dosing regimen period may be 2, 3, or 4 weeks, or even 1, 2, 3, 4, 5, 6, or 1 or more consecutive months. In another embodiment, the use of the compounds described herein eliminates the need for out-of-cycle periods, drug holidays, or reduces the concentration of antitumor compounds co-administered during treatment. In another embodiment, the cycle is longer than 28 days, for example, longer than 30 or 35 days.

[0455] In some 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 some embodiments, the compound of the present invention is administered continuously for 14 days, followed by a 14-day dose holiday. In some embodiments, the compound of the present invention is administered continuously for 21 days, followed by a 7-day dose holiday.

[0456] In some 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 some embodiments, the compound of the present invention is administered daily for 14 consecutive days, followed by a 14-day dose holiday. In some embodiments, the compound of the present invention is administered daily for 21 consecutive days, followed by a 7-day dose holiday.

[0457] In some 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 some embodiments, the compound of the present invention is administered twice daily for 14 consecutive days, followed by a 14-day dose holiday. In some embodiments, the compound of the present invention is administered twice daily for 21 consecutive days, followed by a 7-day dose holiday.

[0458] In some implementations, compound 1 is administered orally daily for 21 days within each 28-day treatment cycle, followed by a 7-day break.

[0459] dose

[0460] In some alternative embodiments, the compound of the present invention is administered at a dose of about 800 μg. In some embodiments, the compound of the present invention is administered at a dose of less than about 600 μg. In some embodiments, the compound of the present invention is administered at a dose of less than about 400 μg. In some embodiments, the compound of the present invention is administered at a dose of less than about 300 μg. In some embodiments, the compound of the present invention is administered at a dose of less than about 200 μg. In some embodiments, the compound of the present invention is administered at a dose of less than about 100 μg.

[0461] In some embodiments, the compounds of the present invention are administered at a dose of less than about 50 μg.

[0462] In some embodiments, the compounds of the present invention are administered at a dose of less than about 25 μg.

[0463] In some embodiments, the compounds of the present invention are administered at a dose of about 50 μg.

[0464] In some embodiments, the compounds of the present invention are administered at a dose of about 45 μg.

[0465] In some embodiments, the compounds of the present invention are administered at a dose of about 40 μg.

[0466] In some embodiments, the compounds of the present invention are administered at a dose of about 35 μg.

[0467] In some embodiments, the compounds of the present invention are administered at a dose of about 30 μg.

[0468] In some embodiments, the compounds of the present invention are administered at a dose of about 25 μg.

[0469] In some embodiments, the compounds of the present invention are administered at a dose of about 20 μg.

[0470] In some embodiments, the compounds of the present invention are administered at a dose of about 15 μg.

[0471] In some embodiments, the compounds of the present invention are administered at a dose of about 10 μg.

[0472] In some embodiments, the compound of the present invention is administered at a dose of about 5 μg.

[0473] In some embodiments, the compound of the present invention is administered at a dose of about 1 μg.

[0474] In some embodiments, compound 1 is administered at a dose of less than about 800 μg. In some embodiments, compound 1 is administered at a dose of less than about 600 μg. In some embodiments, compound 1 is administered at a dose of less than about 400 μg. In some embodiments, compound 1 is administered at a dose of less than about 300 μg. In some embodiments, compound 1 is administered at a dose of less than about 200 μg. In some embodiments, compound 1 is administered at a dose of less than about 100 μg.

[0475] In some embodiments, compound 1 is administered at a dose of about 800 μg. In some embodiments, compound 1 is administered at a dose of about 600 μg. In some embodiments, compound 1 is administered at a dose of about 400 μg. In some embodiments, compound 1 is administered at a dose of about 300 μg. In some embodiments, compound 1 is administered at a dose of about 200 μg. In some embodiments, compound 1 is administered at a dose of about 100 μg.

[0476] In some embodiments, compound 1 is administered at a dose of at least about 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 μg or a range thereof.

[0477] In some embodiments, compound 1 is administered at a dose of about 25 μg. In some embodiments, compound 1 is administered at a dose of about 50 or 75 μg. In some embodiments, compound 1 is administered at a dose of about 100 or 150 μg. In some embodiments, compound 1 is administered at a dose of about 175 or 200 μg. In some embodiments, compound 1 is administered at a dose of about 225 or 250 μg. In some embodiments, compound 1 is administered at a dose of about 275, 300, 325, or 350 μg. In some embodiments, compound 1 is administered at a dose of about 400 or 450 μg. In some embodiments, compound 1 is administered at a dose of about 550 μg. In some embodiments, compound 1 is administered at a dose of about 650 μg. In some embodiments, compound 1 is administered at a dose of about 725 μg. In some embodiments, compound 1 is administered at a dose of about 800 μg.

[0478] This invention includes at least the following low-dose features:

[0479] (a) Low-dose treatment regimens for Ikaros or Aiolos-mediated conditions in the host, comprising administering, once daily (QD) or twice daily (BID) doses of up to about 500, 450, 400, 350, 300, 250, 200, 150 or even 100 micrograms (μg) of compounds selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13 to patients in need.

[0480] (b) The treatment as described in (a), wherein the treatment regimen includes a drug vacation;

[0481] (c) The treatment as described in (b), wherein the drug holiday is achieved by administering the drug 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, and then entering the drug holiday until the next 28-day cycle.

[0482] (d) The treatment as described in (c), wherein the therapy is administered once or twice daily for 21 days, followed by a 7-day medication break;

[0483] (e) The treatment as described in (a)-(d), wherein a single dose does not exceed 400 micrograms;

[0484] (f) The treatment as described in (a)-(d), wherein a single dose does not exceed 300, 200 or 100 micrograms;

[0485] (g) The treatment as described in (a)-(d), wherein a single dose does not exceed 25, 50 or 75 micrograms;

[0486] (h) The treatment as described in (b) may last for 2, 3, 4, 5 or 6 weeks, or even 1, 2, 3, 4, 5 or 6 or more months, with staggered holidays;

[0487] (i) The treatment as described in (a), excluding holiday periods;

[0488] (j) The treatment as described in (a) wherein the period is longer than 28 days, for example longer than 30 or 35 days, and includes a pharmacological holiday;

[0489] (k) The treatment as described in (a)-(j), wherein the condition is selected from diffuse large B-cell lymphoma, anaplastic large cell lymphoma, cutaneous T-cell lymphoma, mantle cell lymphoma and multiple myeloma, wherein the treatment comprises administering to a patient in need 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;

[0490] (l) The treatment as described in (a)-(j), wherein the condition is resistant to treatment with other hydroxycerebroside ligands, the treatment as described in (a)-(j) comprising administering to a patient in need 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.

[0491] (m) The treatment as described in (a)-(j), wherein the patient has a hydroxycerebroside-mediated condition, the treatment comprising monitoring the concentration of one or more biomarkers selected from IRF-1 and caspase-3;

[0492] (n) The treatments described in (a)-(j), wherein combination therapy for patients with hydroxycerebroside-mediated disease comprises administering, in combination or alternating, effective amounts 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 patients in need in combination or alternating with Bruton's tyrosine kinase inhibitors, corticosteroids, CAR T-cell therapy, antibody-drug conjugates, BiTE therapy, bispecific antibodies, or monoclonal antibodies;

[0493] (o) Low-dose pharmaceutical compositions of the compounds described herein or their pharmaceutically acceptable salts, isotope derivatives (including deuterated derivatives) or prodrugs in a pharmaceutically acceptable carrier;

[0494] (p) Treatment of any condition described herein as described in (a)-(j) includes 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.

[0495] (q) The compounds described herein or their pharmaceutically acceptable salts, isotopic derivatives or prodrugs are used to treat conditions mediated by Ikaros or Aiolos as described in (a)-(j);

[0496] (r) Use of an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof in the treatment of patients (generally human) suffering from any of the conditions described herein (including those mediated by Ikaros or Aiolos) as described in (a)-(j).

[0497] (s) A method of manufacturing a low-dose medicament for treating a disease described herein in a host, characterized in that the compound described herein is used in the manufacturing process at a low dose specified herein;

[0498] (t) The use of the compounds described herein or their pharmaceutically acceptable salts, isotope derivatives or prodrugs for the manufacture of a medicament for the treatment of cancers as described in (a)-(j), including any cancers described herein;

[0499] (u) A method of manufacturing a medicament for treating cancers as described in (a)-(j) in a host, including any cancers described herein, characterized in that the preparation uses compounds described herein;

[0500] (v) The compounds described herein or their pharmaceutically acceptable salts, isotope derivatives or prodrugs, for the treatment of tumors in a host as described in (a)-(j), including any tumors described herein;

[0501] (w) The use of the compounds described herein or their pharmaceutically acceptable salts, isotope derivatives or prodrugs for the manufacture of a medicament for the treatment of tumors as described in (a)-(j), including any tumors described herein;

[0502] (x) A method of manufacturing a medicament for treating tumors as described in (a)-(j) in a host, including any tumors described herein, characterized in that the preparation uses compounds described herein;

[0503] (y) The compounds described herein or their pharmaceutically acceptable salts, isotopic derivatives or prodrugs, for the treatment of immune, autoimmune or inflammatory diseases in the host as described in (a)-(j);

[0504] (z) Use of the compounds described herein or pharmaceutically acceptable salts, isotope derivatives or prodrugs thereof for the manufacture of medicaments for the treatment of immune, autoimmune or inflammatory diseases as described in (a)-(j);

[0505] (aa) A method for manufacturing a medicament for treating immune, autoimmune, or inflammatory diseases as described in (a)-(j) in a host, characterized in that the preparation uses compounds described herein;

[0506] (bb) The compounds described herein or their pharmaceutically acceptable salts, isotope derivatives or prodrugs are used to treat hematologic malignancies as described in (a)-(j), such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0507] (cc) Use of the compounds described herein or their pharmaceutically acceptable salts, isotope derivatives or prodrugs in the manufacture of medicines for the treatment of hematologic malignancies as described in (a)-(j), such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma.

[0508] (dd) A method of manufacturing a medicament for treating a hematologic malignancy as described in (a)-(j) in a host, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, characterized in that the preparation uses compounds described herein;

[0509] (ee) A pharmaceutical composition comprising a host-therapeutic amount of the compound described herein as described in (a)-(j) or a pharmaceutically acceptable salt, isotope derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;

[0510] (ff) The treatments as described in (a)-(j), wherein the compounds described herein are mixtures of enantiomers or diastereomers (as related), including racemates;

[0511] (gg) the treatments as described in (a)-(j), wherein the compounds described herein are enriched forms of enantiomers or diastereomers (as relevant), including isolated enantiomers or diastereomers (i.e., greater than 85%, 90%, 95%, 97%, or 99% purity); and

[0512] (hh) A method for preparing a therapeutic product containing a low effective amount of the compound described herein.

[0513] In some alternative embodiments, the compound of the present invention is administered at a dose of less than about 800 mg. In some embodiments, the compound of the present invention is administered at a dose of less than about 600 mg. In some embodiments, the compound of the present invention is administered at a dose of less than about 400 mg. In some embodiments, the compound of the present invention is administered at a dose of less than about 300 mg. In some embodiments, the compound of the present invention is administered at a dose of less than about 200 mg. In some embodiments, the compound of the present invention is administered at a dose of less than about 100 mg.

[0514] In some embodiments, the compounds of the present invention are administered in doses of about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 mg.

[0515] In some embodiments, the compounds of the present invention are administered at doses of about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 μg.

[0516] In some embodiments, the compounds of the present invention are administered at doses of at least about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 μg.

[0517] In some embodiments, the compounds of the present invention are administered in doses of less than or equal to about 1,000, 950, 900, 850, 800, 750, 700, 650, 600, 550, 500, 475, 450, 425, 400, 375, 350, 325, 300, 275, 250, 225, 200, 175, 150, 125, 100, 90, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 μg.

[0518] Ikaros and / or Aiolos-mediated symptoms

[0519] In one aspect of the invention, a condition mediated by Ikaros or Aiolos is treated by compound 1 or a pharmaceutically acceptable salt thereof or another compound described herein. In some embodiments, the cancer is a hematopoietic system cancer. In some embodiments, the cancer is lymphoma, leukemia, or myeloma. In some aspects, the cancer is non-Hodgkin lymphoma or Hodgkin lymphoma.

[0520] In some embodiments, the compound of the invention is administered to a patient in need in an effective amount for treating diffuse large B-cell lymphoma. In some embodiments, diffuse large B-cell lymphoma is activated B-cell lymphoma or germinal center B-cell lymphoma. In some embodiments, diffuse large B-cell lymphoma is cancer carrying BCL2 / 6 translocation. In some embodiments, diffuse large B-cell lymphoma is cancer carrying double hit. In some embodiments, diffuse large B-cell lymphoma is BCL2 / 6MYC wild-type cancer.

[0521] In some embodiments, the compounds of the present invention increase the concentration of caspase-3 and / or caspase-7. In some embodiments, this increased concentration of caspase-3 and / or caspase-7 drives cancer cell death, for example, mediating the treatment of diffuse large B-cell lymphoma.

[0522] In some embodiments, the compounds of the present invention are administered to patients in need in an effective amount for treating anaplastic large cell lymphoma.

[0523] In some embodiments, the compounds of the present invention are administered to patients in need in an effective amount for treating cutaneous T-cell lymphoma.

[0524] In some embodiments, the compound of the invention is administered to a patient in need in an effective amount for treating mantle cell lymphoma.

[0525] In some embodiments, the compounds of the present invention are administered to patients in need in an effective amount for treating multiple myeloma.

[0526] In some embodiments, the compounds of the present invention are administered to patients in need in an effective amount for treating conditions resistant to treatments of other hydroxycerebroside ligands. In some embodiments, the compounds of the present invention are used to treat IMiD-refractory conditions.

[0527] In some embodiments, compound 1 is administered to a patient in need in an effective amount for treating diffuse large B-cell lymphoma. In some embodiments, diffuse large B-cell lymphoma is activated B-cell lymphoma or germinal center B-cell lymphoma. In some embodiments, diffuse large B-cell lymphoma is cancer carrying BCL2 / 6 translocation. In some embodiments, diffuse large B-cell lymphoma is cancer carrying double-hit disease. In some embodiments, diffuse large B-cell lymphoma is BCL2 / 6MYC wild-type cancer.

[0528] In some implementations, compound 1 is administered to patients in need at an effective dose for treating anaplastic large cell lymphoma.

[0529] In some implementations, compound 1 is administered to patients in need in an effective amount for treating cutaneous T-cell lymphoma.

[0530] In some implementations, compound 1 is administered to patients in need in an effective amount for treating mantle cell lymphoma.

[0531] In some implementations, compound 1 is administered to patients in need at an effective dose for treating multiple myeloma.

[0532] In some embodiments, compound 1 is administered to a patient in need in an effective amount for treating conditions resistant to other hydroxycerebroside ligands. In some embodiments, compound 1 is administered to a patient in need in an effective amount for treating IMiD-refractory conditions.

[0533] In one aspect, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is administered to a patient to treat CNS-related cancers, such as lymphoma in the CNS. In some embodiments, one or more additional therapeutic agents, such as ibrutinib or rituximab, are also administered to a patient with a CNS-related cancer (e.g., lymphoma in the CNS). In some embodiments, the compound described herein is used to treat peripheral central nervous system lymphoma.

[0534] In some embodiments, compound 1 is administered for the treatment of PTCL-NOS (i.e., PTCL not otherwise specified). In other embodiments, compound 1 is administered for the treatment of PTCL with a specific subtype, such as anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathic T-cell lymphoma, extranodal natural killer (NK) cell lymphoma, or extranodal T-cell lymphoma.

[0535] In some embodiments, the condition treated by the compounds of the present invention is an immunomodulatory condition. In some embodiments, the condition treated by the compounds of the present invention is mediated by angiogenesis. In some embodiments, the condition treated by the compounds of the present invention is related to the lymphatic system.

[0536] In some embodiments, optionally, a compound of the present invention or a pharmaceutically acceptable salt thereof in a pharmaceutical composition as described herein is administered to a patient in need in an effective amount that degrades Ikaros or Aiolos, which are mediators of a patient's (e.g., a human) condition. Control of protein levels provided by any compound of the present invention provides treatment for a disease state or condition that is modulated by reducing protein levels in cells (e.g., a patient's cells) or by reducing downstream protein levels in cells via Ikaros or Aiolos. In some embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including pharmaceutically acceptable excipients, carriers, adjuvants (i.e., pharmaceutically acceptable compositions), optionally in combination with or alternating with other therapeutically active agents or pharmaceutical agents.

[0537] In some embodiments, the compounds of the present invention are administered to patients in need in an effective amount for treating conditions including, but not limited to, benign growths, vegetations, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft-versus-host rejection, viral infections, bacterial infections, amyloid-based proteases, proteases, or fibrotic disorders.

[0538] When used in conjunction with any compound, the term "disease state" or "symptom" refers to any disease state or symptom mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or symptom mediated by proteins downstream of Ikaros or Aiolos, wherein the degradation of such proteins in a patient can provide beneficial treatment or symptom relief to a patient in need. In some cases, the disease state or symptom can be cured.

[0539] In some embodiments, compounds such as those described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be administered in effective amounts to treat a host, such as a human, suffering from lymphoma or a lymphocyte or myeloid cell proliferation disorder or abnormality. For example, compounds described herein can be administered to a host suffering from Hodgkin lymphoma or non-Hodgkin lymphoma. For example, the host may have non-Hodgkin lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK-cell lymphoma; Burkitt lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma). Lymphoma; Diffuse small cleavage cell 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; Hepatocellular γ-δ T-cell lymphoma; Lymphoblastic lymphoma; Mantle cell lymphoma; Marginal zone lymphoma; Nasal T-cell lymphoma; Pediatric lymphoma; Peripheral lymphoma, Peripheral T-cell lymphoma; Primary central nervous system lymphoma; T-cell leukemia; Transformed lymphoma; Treatment-related T-cell lymphoma; Langerhans cell histiocytosis; or Waldenström macroglobulinemia.

[0540] In another embodiment, the compounds described herein or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs may be administered in an effective amount to treat a host (e.g., a human) suffering from Hodgkin lymphoma, such as, but not limited to: tuberous sclerosis classical Hodgkin lymphoma (CHL); mixed cellularity CHL; lymphocyte-depleted CHL; lymphocyte-rich CHL; lymphocyte-predominant Hodgkin lymphoma; or nodular lymphocyte-predominant HL.

[0541] In another embodiment, the compounds described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, may be administered in an effective amount to treat a host (e.g., a human) suffering from an immunomodulatory disorder. Non-limiting examples of immunomodulatory disorders include: arthritis, lupus, celiac disease, Sjögren's syndrome, polymyalgia rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[0542] In some embodiments, the symptoms treated with the compounds of the present invention are conditions associated with abnormal cell proliferation. Abnormal cell proliferation, particularly excessive proliferation, can be the result of a variety of factors, including gene mutations, infections, exposure to toxins, autoimmune disorders, and induction by benign or malignant tumors.

[0543] Abnormal proliferation of B cells, T cells, and / or NK cells can lead to a variety of diseases, such as cancer, proliferative disorders, and inflammatory / immune diseases. Hosts, such as humans, suffering from any of these conditions can be treated with effective amounts of the compounds described herein to achieve symptom relief (palliative agents) or reduction of the underlying disease (disease modulators).

[0544] In some embodiments, compounds as described herein, or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs, can be administered in effective amounts to treat a host, such as a human, suffering from a specific B-cell lymphoma or proliferative condition, such as, but not limited to: multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphoma; diffuse poorly differentiated lymphoma; mediastinal large B-cell lymphoma; marginal zone lymphoma of the lymph nodes (NMZL); marginal zone lymphoma of the spleen (SMZL); intravascular large B-cell lymphoma; primary exudative lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia, unclassifiable; diffuse red pulp small B-cell lymphoma of the spleen. Lymphoma; hairy cell leukemia variant; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease; plasma cell myeloma; solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma; large B-cell lymphoma rich in T cells / histocytes; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV) + DLBCL in the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL, leg type; ALK + large B-cell lymphoma; plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma; Kassman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma; or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma.

[0545] In some embodiments, compounds such as those described herein, or their corresponding pharmaceutical salts, isotope derivatives, or prodrugs, may be administered in an effective amount for the treatment of a host, such as a human, with T-cell or NK-cell lymphomas, including, but not limited to: anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphomas or primary cutaneous anaplastic large cell lymphomas; angioimmunoblastic lymphomas; cutaneous T-cell lymphomas, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphomas, primary cutaneous CD30+ T-cell lymphoproliferative disorders; primary cutaneous invasive epidermal CD8+ cytotoxic T-cell lymphomas; and primary cutaneous anaplastic large cell lymphomas. γ-δ T-cell lymphoma; primary cutaneous small / medium CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL); blastoblastic NK-cell lymphoma; enteropathy-type T-cell lymphoma; blood-splenic γ-δ T-cell lymphoma; lymphoblastic lymphoma; nasal NK / T-cell lymphoma; treatment-related T-cell lymphoma; lymphoma following solid organ or bone marrow transplantation; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; NK-cell chronic lymphoproliferative disorder; aggressive NK-cell leukemia; childhood systemic EBV+ T-cell lymphoproliferative disorder (associated with chronic active EBV infection); varicella-like lymphoma (Hydroa) vacciniforme-like lymphoma; adult T-cell leukemia / lymphoma; enteropathy-associated T-cell lymphoma; hepatocellular T-cell lymphoma; or subcutaneous panniculitis-like T-cell lymphoma.

[0546] In some implementations, the compounds described herein or their corresponding pharmaceutically acceptable salts, isotope derivatives, or prodrugs may be administered to treat a host (e.g., a human) suffering from leukemia. For example, the host may have acute or chronic leukemia of lymphocytic or bone marrow origin, such as, but 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); large granular lymphoblastic leukemia; or adult T-cell chronic leukemia. In some implementations, the patient has acute myeloid leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with / without minimum cell maturation); myeloblastic leukemia (M2; cell maturation); promyelocytic leukemia (M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); or megakaryocytic leukemia (M7).

[0547] Several skin disorders are associated with excessive cell proliferation. For example, psoriasis is a benign skin condition typically characterized by plaques covered with thickened scales. This disease is caused by an unexplained increase in the proliferation of epidermal cells. Chronic eczema is also associated with significant excessive proliferation of the epidermis. Other diseases caused by excessive skin cell proliferation include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma.

[0548] Other disorders of excessive cell proliferation include angiogenesis disorders, fibrosis disorders, autoimmune disorders, graft-versus-host rejection, tumors, and cancer.

[0549] Angiogenesis disorders include angiogenesis and vasogenic disorders. Smooth muscle cell proliferation during plaque development 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.

[0550] Fibrotic disorders are typically caused by abnormal formation of the extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disorder. Cirrhosis is characterized by an increase in extracellular matrix components leading to liver scarring. Cirrhosis can cause diseases such as liver hardening. The increased extracellular matrix leading to liver scarring can also be caused by viral infections, such as hepatitis. Adipocytes appear to play a major role in cirrhosis.

[0551] Mesangial diseases are caused by the abnormal proliferation of mesangial cells. Disorders of excessive mesangial cell proliferation include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection, and glomerulonephropathy.

[0552] Another disease with a proliferative component 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.

[0553] Other diseases that may include abnormal cell proliferation components include Bechet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, postdialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipohistiocytosis, septic shock, and general inflammation.

[0554] The compounds described herein, or their pharmaceutically acceptable salts, isotope analogs, or prodrugs, can be administered in effective amounts to treat hosts with proliferative disorders, such as humans, including myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myelomecosis with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilia (HES), systemic mast cell disease (SMCD), etc. In another embodiment, the compounds provided herein can be used to treat essential myelofibrosis, post-polycythemia vera myelofibrosis, post-esophagectomy myelofibrosis, and secondary acute myeloid leukemia.

[0555] In some embodiments, compounds such as those described herein, or pharmaceutically acceptable salts, isotope analogs, or prodrugs thereof, may be administered in an effective amount for the treatment of a host (e.g., a human) suffering from myelodysplastic syndromes (MDS), such as, but not limited to: refractory cytopenia with single lineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia with ringed sideroblasts-thrombocytosis (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory anemia with excess embryonal cells I (RAEB-I) and II (RAEB-II), 5q- syndrome, refractory cytopenia in children, etc.

[0556] In some embodiments, the compounds of the present invention can provide therapeutic effects by directly degrading Ikaros or Aiolos, the degradation of which can alter the transcriptional regulation of proteins downstream of Ikaros or Aiolos.

[0557] The terms “tumor formation” or “cancer” are used to refer to the pathological process leading to the formation and growth of cancerous or malignant tumors, i.e., abnormal tissue that grows through cell proliferation, typically faster than normal tissue and continues to grow after the stimuli that initiated new growth cease. Malignant tumors exhibit partial or complete lack of structural organization and functional coordination with normal tissue, and largely invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted resection, leading to patient death unless adequate treatment is administered. As used herein, the term tumor formation is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous, ascites, and solid tumors. Exemplary cancers that can be treated by the compounds of the present invention, alone or in combination with at least one other anticancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer and stomach cancer; leukemia; benign and malignant lymphomas, particularly Burkitt lymphoma and non-Hodgkin lymphoma; benign and malignant melanomas; myeloproliferative disorders; sarcomas, including Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and lipomas. Liposarcoma, myoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioglioma, ganglioblastoma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma; colorectal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratoma. Other cancers that can be treated with the compounds according to the invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphocytic 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.

[0558] Other cancers that can be treated with the compounds disclosed in this invention include, for example, acute myeloid leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendiceal cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, colorectal cancer, brain cancer, brainstem glioma, breast cancer, triple (estrogen, progesterone, and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone, and HER-2 are negative), single negative breast cancer (one of estrogen, progesterone, and HER-2 is negative), and estrogen receptor-positive HER2-negative breast cancer. Estrogen receptor-negative breast cancer, estrogen receptor-positive breast cancer, metastatic breast cancer, luminal type A breast cancer, luminal type 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, chondrocyte carcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), 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 sarcoma, extrahepatic bile duct cancer, ocular cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer. Gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), inflammatory breast cancer (IBC), colorectal cancer, intrahepatic cholangiocarcinoma, invasive / invasive breast cancer, islet cell carcinoma, jaw cancer, Kaposi's sarcoma, renal cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymal tissue, mesothelial cell carcinoma. Metastatic breast cancer, metastatic melanoma, metastatic squamous neck cancer, mixed glioma, monoblastic teratoma, oral mucinous carcinoma, mucosal melanoma, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal carcinoma, neck cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteosarcoma, osteosarcoma, ovarian cancer, ovarian epithelial carcinoma, ovarian germ cell tumor, primary ovarian peritoneal cancer, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid carcinoma, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer.Pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pinealoblastoma, pituitary cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T cell carcinoma. T-cell lymphoma, testicular cancer, laryngeal cancer, thymic / thymic cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubal cancer, undiagnosed cancer, ureteral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphocytic 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, 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, Marginal zone lymphoma of lymph nodes (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary exudative lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Splenic lymphoma / leukemia, unclassifiable, Diffuse red pulp small B-cell lymphoma of the spleen Lymphoma; lymphoplasmacytic lymphoma; heavy chain disease, such as alpha heavy chain disease, gamma heavy chain disease, Mu heavy chain disease, plasmacytic myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicular center lymphoma, T-cell / histiocytic 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, leg type, ALK + large B-cell lymphoma, plasmablastic lymphoma; HHV8-associated multicentric large B-cell lymphoma, Kassman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In some embodiments, the condition is adenoid cystic carcinoma. In some embodiments, the condition is NUT midline carcinoma. ,

[0559] In another embodiment, the compounds described herein, or their pharmaceutically acceptable salts, isotope derivatives, or prodrugs, may be used in an effective amount to treat a host (e.g., a human) suffering from an autoimmune disease. Examples include, but are not limited to: acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also called Luger's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynergistic 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; and so on. Immune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyendocrine syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo disease / Balo concentric sclerosis; Behçet's disease; Bergey's disease; Bickerstaff encephalitis; Blau syndrome; bullous pemphigoid; cancer; Kassman's disease; celiac disease; Chagas disease; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic relapsing multifocal osteomyelitis; Churg-Strauss disease. Syndrome; Cicatricial pemphigoid; Cogan syndrome; Cold agglutinin disease; Supplement 2 deficiency; Contact dermatitis; Cranial arteritis; CREST syndrome; Crohn's disease; Cushing's syndrome; Cutaneous leukocytoclastic vasculitis; Dego's disease; Dercum's disease; Herpetic dermatitis; Dermatomyositis; Type 1 diabetes; Diffuse systemic sclerosis of the cutaneous region; Discoid lupus erythematosus; Dereskir syndrome; Drug-induced lupus; Eczema; Endometriosis; Enthes-associated arthritis; Eosinophilic fasciitis; Eosinophilic gastroenteritis; Eosinophilic pneumonia; Epidermolysis bullosa; Erythema nodosum; Erythroblastosis; Basic mixed cryoglobulinemia; Evan's syndrome; External and internal reactivity Airway diseases (asthma); progressive fibrosis; fibrotic alveolitis (or idiopathic pulmonary fibrosis); gastritis; gastrointestinal pemphigoid; glomerulonephritis; Goodpasture syndrome; Graves' disease; Guillain-Barré syndrome (GBS); Hashimoto's encephalopathy; Hashimoto's thyroiditis; hemolytic anemia; allergic purpura; herpes gestationis (pemphigoid of pregnancy); hidradenitis suppurativa; Hughes-Stoven 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 sclerosis; linear IgA disease (LAD); lupus hepatitis, also known as autoimmune hepatitis; systemic lupus erythematosus; Majid syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; morphea; Mucha-Habermann disease, also known as acute pustular lichenoid pityriasis; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Dweck's disease); neuromuscular rigidity; ocular cicatricial pemphigoid; ocular myoclonus syndrome; Auder's thyroiditis; palindromic rheumatism; PANDAS (a streptococcal-associated pediatric autoimmune neuropsychiatric disorder); paraneoplastic cerebellar degeneration; paroxysmal nocturnal hemoglobinuria (PNH); Parry-Romberg syndrome; tonsillitis; Clerk-Turner syndrome; pemphigus vulgaris; peripheral encephalomyelitis; pernicious anemia; POEMS syndrome; polyarteritis nodosa; polymyalgia rheumatica Pain; Polymyositis; Primary biliary cirrhosis; Primary sclerosing cholangitis; Progressive inflammatory neuropathy; Psoriasis; Psoriatic arthritis; Pure red cell aplasia; Pyoderma gangrenosa; Rasmussen encephalitis; Raynaud's phenomenon; Ritter syndrome; Relapsing polychondritis; Restless legs syndrome; Retroperitoneal fibrosis; Rheumatic fever; Rheumatoid arthritis; Sarcoidosis; Schmidt syndrome; Schnitzler syndrome; Scleritis; Scleroderma; Sclerosing cholangitis; Serum sickness; Sjögren's syndrome; Spondyloarthropathy; Stiff-person syndrome; Still's disease; Sub Acute bacterial endocarditis (SBE); Sussac syndrome; Sweet syndrome; Sidnam's chorea; sympathetic ophthalmia; systemic lupus erythematosus; Goran's arteritis; temporal arteritis (also known as "giant cell arteritis"); thrombocytopenia; Tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; indiscriminate spondyloarthritis; urticarial vasculitis; vasculitis; vitiligo; 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 implementations, autoimmune diseases are allergic diseases, including those arising from asthma, food allergies, atopic dermatitis, chronic pain, and rhinitis.

[0560] Skin contact hypersensitivity and asthma are just two examples of immune responses that may be associated with a significant incidence rate. Others 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 cause any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulceration, pain, scaling, cracking, hair loss, scarring, or fluid exudation involving the skin, eyes, or mucous membranes.

[0561] In atopic dermatitis and generalized eczema, immune-mediated leukocyte infiltration (particularly monocytes, lymphocytes, neutrophils, and eosinophils) into the skin is a significant factor in the pathogenesis of these diseases. Chronic eczema is also associated with significant epidermal hyperplasia. Immune-mediated leukocyte infiltration also occurs in sites outside the skin, such as the airways of asthmatic patients and the lacrimal glands in the eyes of patients with dry keratoconjunctivitis.

[0562] A host, such as a human, suffering from a skin disorder can be treated by applying an effective amount of the compounds described herein or their pharmaceutically acceptable salts, isotope variants, or prodrugs, such as psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rashes, skin irritation, or skin allergies (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances (including certain drugs) can cause skin allergies when applied topically. In some embodiments, skin disorders are treated by topical application of compounds known in the art in combination with those disclosed herein. In a non-limiting embodiment, the degrading agent of the present invention is used as a topical agent for treating contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, 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, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug eruptions.

[0563] Disease conditions that can be treated with the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia, 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 disease, Tay-Sachs disease, and Turner syndrome.

[0564] Other disease states or conditions that can be treated with the compounds of this invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorder, 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, Gurney-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.

[0565] Other disease states or conditions that can be treated with the compounds of this invention include ceruloplasminemia, type II chondrodysplasia, chondrodysplasia, cranial malformations, type 2 Gaucher disease, acute intermittent porphyria, Canavan disease, adenomatous polyposis, ALA dehydratase deficiency, adenosine lyase deficiency, adrenogenous syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaline aciduria, Alexander disease, alkaline acidosis, α1-antitrypsin deficiency, α-1 protease inhibitors, emphysema, amyotrophic lateral sclerosis (ALS), Alexander disease with ALA dehydratase deficiency, Anderson-Fabry disease, and androgen insensitivity. Syndrome, anemic body angiokeratoma, von Hippel-Lindau disease, Apert syndrome, arachnoidosis (Marfan syndrome), Stickler syndrome, Ehlers-Danlos syndrome (joint laxity type), ataxia-telangiectasia, Rett syndrome, primary pulmonary hypertension, Sandhoff's disease, neurofibromatosis type II, Beare-Stevenson gyrate scalp syndrome, familial Mediterranean fever, Benjamin syndrome, β-thalassemia, bilateral auditory neurofibromatosis (neurofibromatosis type II), factor VLeiden's tendency to thrombosis, Bloch-Sulzberger syndrome (incontinence of pigmentation), Bloom syndrome, X-linked siderocytic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), prions, Birt-Hogg-Dubé syndrome, osteogenesis imperfecta, Rubinstein-Taybi syndrome, bronze diabetes / bronze cirrhosis (hemochromatosis), bulbospinal muscular atrophy. Kennedy's disease, Berg-Grutz syndrome (lipoprotein lipase deficiency), chronic granulomatous granulomatosis (CGD), Campomelic dysplasia, biotinylate deficiency, cardiomyopathy (Noonan syndrome), cat-like crying, CAVD (congenital absence of vas deferens), Caylor's cardiofacial syndrome (CBAVD), CEP (congenital erythropoietic porphyria), cystic fibrosis, congenital hypothyroidism, achondroplasia syndrome (chondrodysplasia), auricular hypertrophy and epiphyseal dysplasia, Lesch-Nyhan syndrome, galactosemia Ehlers-Danlos syndrome, lethal osteodystrophy, Coffin-Lowry syndrome, Cockayne syndrome, familial adenomatous polyposis, congenital erythropoietic porphyria, congenital heart disease, methemoglobinemia / congenital methemoglobinemia, achondroplasia, X-linked sideroblastic anemia, connective tissue disease, nasal condyle, facial anemia, thalassemia (β-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes disease), hereditary coprophytic porphyria, Cowden syndrome Comorbidities, craniofacial joint disorders (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myocardial dystrophy), Beare-Stevenson gyrate scalp syndrome, primary hyperoxaluria, Strudwick type vertebral metaphysema, muscular dystrophy, Duchenne and Becker type (DBMD), Arthur syndrome, degenerative neurological diseases (including dementia)Grouchy syndrome and Dejerine-Sottas syndrome), developmental disorders, distal spinal muscular atrophy, type V, androgen insensitivity syndrome, diffuse spheroid sclerosis (Krabbe disease), DeGeorge syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, Down syndrome, dwarfism, erythropoietic protoporphyria, erythropoietic 5-aminolevulinic acid synthase deficiency, erythropoietic porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Felidech ataxia-familial sudden onset polyserositis, delayed-onset cutaneous porphyria, familial barosensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic cystic fibrosis. Fragile X syndrome, galactosemia, hereditary brain disorders, giant cell hepatitis (neonatal hemochromatosis), Gronblad-Strandberg syndrome (pseudoxanthomas elastica), Gunther's disease (congenital erythropoietic porphyria), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatoretrophoblastic porphyria (HEP), Hippel-Lindau disease, Huntington's disease, Hutchinson-Gilford progeria, hyperandrogenemia, hypochondroitinemia, immune system disorders, including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackso... n-Weiss syndrome, Joubert syndrome, Lesch-Nyhan syndrome, Jackson-Weiss syndrome, kidney diseases including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, lacunar dementia, Langer-Saldino chondrodysplasia, ataxia-telangiectasia, Lynch syndrome, lysylhydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, neurofibromatosis, Nance-Insl. Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Rendu disease, Peutz-Jeghers syndrome, polycystic kidney disease, McCune-Albright syndrome, Peutz-Jeghers syndrome, Prader-Labhart-Willi syndrome, hemochromatosis, Lesch-Nyhan syndrome, primary pulmonary hypertension, primary Alzheimer's disease, prion diseases, premature aging (Hutchinson's disease)Gilford's progeria syndrome, progressive chorea, chronic hereditary (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthomas elastica), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), relapsing polyserositis, retinal diseases, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Roussy-Levy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast cancer, leukemia and adrenal gland (SBLA) syndrome, tuberous sclerosis, SDAT, SED congenital (congenital vertebral epiphyseal dysplasia), SED Strudwick (vertebral epiphyseal dysplasia, Strudwick type), SEDc (congenital vertebral epiphyseal dysplasia), SEMD, Strudwick type (vertebral diaphysis dysplasia, Strudwick type), Shprintzen syndrome, hyperpigmentation, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (porphyria variegata), infantile ascending spastic paralysis, speech and communication disorders, sphingolipidosis, Ty-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, β-thalassemia, thyroid disease, giant spot disease (hereditary neuropathy with pressure paralysis), Treacher Collins syndrome, Triplo X syndrome, Down syndrome, Trisomy 21, Trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness. (Syndromes), Vrolik disease, Waardenburg syndrome, Warburg-Sjo-Fledelius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disease, Weissenbacher-Zweymüller syndrome, and xeroderma pigmentosum, etc.

[0566] In some embodiments, a method for treating 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, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof is optionally in a pharmaceutically acceptable carrier to form a composition for treating multiple myeloma, wherein the method comprises administering the compound to a patient.

[0567] In some embodiments, a method for managing the progression of 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, optionally in a pharmaceutically acceptable carrier to form a composition. In another embodiment, a compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof is optionally in a pharmaceutically acceptable carrier to form a composition for managing the progression of multiple myeloma, wherein the method comprises administering the compound to a patient.

[0568] In addition to previously untreated patients, treatment is provided for patients who have previously received multiple myeloma treatment but have not responded to standard therapy. In addition to patients who have not undergone surgery, additional treatment is provided for patients who have undergone surgery in an attempt to treat multiple myeloma. In addition to those who have not received transplantation, treatment is provided for those who have previously received transplantation.

[0569] In some embodiments, the condition treated by the present invention is wild-type cancer, wherein the term "wild-type" refers to cancer that has not developed resistance to previously effective treatments (i.e., recurrent cancer) and cancer that does not have any resistance-conferring mutations (i.e., refractory cancer). In some embodiments, the condition treated by the present invention is recurrent cancer. In some embodiments, the condition treated by the present invention is refractory cancer. In some embodiments, the condition treated by the present invention is both recurrent and refractory cancer.

[0570] The compounds described herein, such as compound 1 or a pharmaceutically acceptable salt thereof, may be administered in the treatment or management of multiple myeloma or non-Hodgkin lymphoma that is relapsed, refractory, or resistant. In some embodiments, the condition is primary, secondary, third, fourth, or fifth relapse. In some embodiments, the compounds described herein may be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0571] Types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to: monoclonal gammopathy of undetermined significance (MGUS); low-risk, intermediate-risk, or high-risk multiple myeloma; newly diagnosed multiple myeloma, including low-risk, intermediate-risk, or high-risk new-diagnosed multiple myeloma; transplantable and non-transplantable multiple myeloma; slowly progressive (indolent) 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-secreting myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma.

[0572] In some embodiments, methods for managing multiple myeloma are provided, including administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.

[0573] In some embodiments, methods for treating or managing multiple myeloma are provided, including administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.

[0574] In some embodiments, methods for treating or managing multiple myeloma are provided, including administering to a patient as maintenance therapy an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0575] In some implementations, multiple myeloma is plasma cell leukemia.

[0576] In some embodiments, the multiple myeloma is high-risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is relapsed or refractory. In some embodiments, the high-risk multiple myeloma relapses within 12 months of the first treatment. In another embodiment, the high-risk multiple myeloma is characterized by a genetic abnormality, such as one or more of del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two, or three prior treatments.

[0577] In some implementations, multiple myeloma is a newly diagnosed multiple myeloma that meets the transplant criteria. In other implementations, multiple myeloma is a newly diagnosed multiple myeloma that does not meet the transplant criteria.

[0578] In some embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplantation. In another embodiment, multiple myeloma is lenalidomide-resistant. In yet another embodiment, multiple myeloma is pomalidomide-resistant. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, multiple myeloma is relapsed or refractory to three or more treatments and has been exposed to proteasome inhibitors (e.g., bortezomib, carfilzomib, esazomib, opzomib, or marizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, iberdomide, or avadomide); or is doubly refractory to both proteasome inhibitors and immunomodulatory compounds. In other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies, including, for example, CD38 monoclonal antibodies (CD38 mAbs, such as daratumumab or isatuximab), proteasome inhibitors (such as bortezomib, carfilzomib, esazolidinyl, or marizumab), and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, ipridomide, or avalidomide); or is doubly refractory to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (such as bortezomib, carfilzomib, esazolidinyl, opzomib, or marizumab), an immunomodulatory compound (such as thalidomide, lenalidomide, pomalidomide, ipridomide, or avalidomide), and one other active agent, as described herein.

[0579] In some embodiments, a method is provided for managing relapsed or refractory multiple myeloma in patients with impaired renal function or symptoms thereof, comprising administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0580] In another embodiment, a method for managing relapsed or refractory multiple myeloma in a frail patient is provided, comprising administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the frail patient is characterized as being unsuitable for induction therapy or intolerant of dexamethasone treatment. In other embodiments, the frail patient is an elderly person, for example, older than 65 years.

[0581] In another embodiment, a method for managing fourth-line relapsed or refractory multiple myeloma is provided, comprising administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0582] In another embodiment, a method for managing a newly diagnosed multiple myeloma that is ineligible for transplantation is provided, comprising administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0583] In another embodiment, a method for managing newly diagnosed multiple myeloma that is ineligible for transplantation is provided, comprising administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition as an alternative therapy or maintenance therapy after transplantation.

[0584] In another embodiment, a method for managing high-risk multiple myeloma that has relapsed or is refractory to one, two, or three prior treatments is provided, comprising administering to a patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0585] In some embodiments, the condition treated by the present invention is relapsed and / or refractory non-Hodgkin's lymphoma. In some embodiments, the condition treated by the present invention is relapsed non-Hodgkin's lymphoma. In some embodiments, the condition treated by the present invention is refractory non-Hodgkin's lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory non-Hodgkin's lymphoma.

[0586] In some embodiments, the condition treated by the present invention is relapsed and / or refractory multiple myeloma. In some embodiments, the condition treated by the present invention is relapsed multiple myeloma. In some embodiments, the condition treated by the present invention is refractory multiple myeloma. In some embodiments, the condition treated by the present invention is both relapsed and refractory multiple myeloma.

[0587] In some embodiments, the condition treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is refractory peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory peripheral T-cell lymphoma.

[0588] In some embodiments, compound 1 is administered for the treatment of PTCL-NOS (i.e., PTCL not otherwise specified). In other embodiments, compound 1 is administered for the treatment of PTCL with a specific subtype, such as anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathic T-cell lymphoma, or extranodal natural killer (NK) cell / T-cell lymphoma.

[0589] In some embodiments, the condition treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK). + In some embodiments, the condition treated by the present invention is relapsed systemic anaplastic large cell lymphoma (ALK). + In some embodiments, the condition treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK). + In some embodiments, the condition treated by the present invention is relapsed and refractory systemic anaplastic large cell lymphoma (ALK). + ).

[0590] In some embodiments, the condition treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK). - In some embodiments, the condition treated by the present invention is relapsed systemic anaplastic large cell lymphoma (ALK). - In some embodiments, the condition treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK). - In some embodiments, the condition treated by the present invention is relapsed and refractory systemic anaplastic large cell lymphoma (ALK-).

[0591] In some embodiments, the condition treated by the present invention is relapsed and / or refractory angioimmunoblastic T-cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed angioimmunoblastic T-cell lymphoma. In some embodiments, the condition treated by the present invention is refractory angioimmunoblastic T-cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory angioimmunoblastic T-cell lymphoma.

[0592] In some embodiments, the condition treated by the present invention is relapsed and / or refractory anaplastic large cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed anaplastic large cell lymphoma. In some embodiments, the condition treated by the present invention is refractory anaplastic large cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory anaplastic large cell lymphoma.

[0593] In some embodiments, the condition treated by the present invention is relapsed and / or refractory mantle cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed mantle cell lymphoma. In some embodiments, the condition treated by the present invention is refractory mantle cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory mantle cell lymphoma.

[0594] In some embodiments, the condition treated by the present invention is relapsed and / or refractory follicular lymphoma. In some embodiments, the condition treated by the present invention is relapsed follicular lymphoma. In some embodiments, the condition treated by the present invention is refractory follicular lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory follicular lymphoma.

[0595] In some embodiments, the condition treated by the present invention is relapsed and / or refractory follicular T-cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed follicular T-cell lymphoma. In some embodiments, the condition treated by the present invention is refractory follicular T-cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory follicular T-cell lymphoma.

[0596] In some embodiments, the condition treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is relapsed peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is refractory peripheral T-cell lymphoma. In some embodiments, the condition treated by the present invention is both relapsed and refractory peripheral T-cell lymphoma.

[0597] In some embodiments, the condition treated by the present invention is relapsed and / or refractory diffuse large B-cell lymphoma. (This text is repeated four times in the original.)

[0598] In some embodiments, compound 1 is administered to a patient in need at an effective amount for treating follicular T-cell lymphoma. In some embodiments, compound 1 is administered to a patient in need at an effective amount for treating angioimmunoblastic T-cell lymphoma. In some embodiments, compound 1 is administered to a patient in need at an effective amount for treating systemic anaplastic large cell lymphoma (ALK). - Compound 1 is administered to patients in need in an effective dose. In some embodiments, it is used to treat systemic anaplastic large cell lymphoma (ALK). + The effective amount of compound 1 is administered to patients in need.

[0599] Other examples of non-Hodgkin lymphomas that can be treated with the compounds described in this article include double-hit lymphoma, triple-hit lymphoma, MALT extranodal marginal zone B-cell lymphoma, extranodal NK / T-cell lymphoma, and myeloid lymphoma.

[0600] Pharmacodynamic dosage modification and biomarkers

[0601] In some embodiments, the compounds of the present invention are administered in an effective amount to treat a patient suffering from a hydroxycerebroside-mediated condition, including administering an effective amount of the compound to the patient and monitoring the concentration of biomarkers 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, survival protein, IKZF1, IKZF3, ZFP91, WIZ and / or IFN-γ, or combinations thereof.

[0602] In some embodiments, the concentrations of IRF-1 and / or caspase 3 increase after a patient has been treated with the compounds described herein. The magnitude of the increase can be used to determine whether the dose of the compounds described herein should be increased, decreased, or remained unchanged. 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, the physician may increase the dose of compound 1 administered to a patient being treated for lymphoma.

[0603] In some implementations, the concentrations of cyclin D and / or E2F1 decrease after a patient has been treated with the compounds described herein. The magnitude of the decrease can be used to determine whether the dose of the compounds described herein should be increased, decreased, or left unchanged. For example, if the concentrations of cyclin D and E2F1 decrease by less than 1.25, 1.5, 1.75, or 2 times, the physician may increase the dose of compound 1 administered to a patient being treated for lymphoma.

[0604] In some embodiments, the concentrations of cyclin D, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, and / or MYC decrease after treatment of the patient with the compounds described herein. In some embodiments, the patient has lymphoma. The magnitude of the decrease can be used to determine whether the dose of the compounds described herein should be increased, decreased, or remained unchanged.

[0605] In some embodiments, the concentrations of IL-2 and / or IFN-γ increase after treatment of a patient with the compounds described herein. In some embodiments, the patient has multiple myeloma. The magnitude of the increase can be used to determine whether the dose of the compounds described herein should be increased, decreased, or remained unchanged.

[0606] In some embodiments, the concentration of the biomarker increases by about 3, 4, 5, 6, 7, or 8 times after delivery of an effective dose of a compound described herein, such as compound 1. For example, as... Figure 51 As shown, when treated with compound 1, the activity levels of caspase-3 and caspase-7 increased by more than 800%. In some embodiments, the level of caspase 3 / 7 activity was determined, and if the increase was less than about 2, 3, 4, 5, 6, 7, or 8 times, the dose of compound 1 was increased.

[0607] In some implementations, the biomarker is STAT3.

[0608] In some implementations, the biomarker is Ki67.

[0609] In some implementations, the concentration of the biomarker decreases by about 3, 4, 5, 6, 7 or 8 times after delivery of an effective dose of a compound described herein, such as compound 1.

[0610] In some implementations, the selection of patients treated with compounds selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 13 is based on the concentration of a biomarker. For example, patients treated with compound 1 may be selected based on the concentration of a biomarker.

[0611] In some implementations, the biomarkers are selected from IKZF1, IKZF3, MYC, IL2, INFy, TNFα, sFLC, and sBCMA.

[0612] In some embodiments, the biomarkers are selected from IRF-1, caspase-3, cyclin D1, E2F1, ZFP91, SALL4, IRF-4, BLIMP1, MYC, IL-2 and / or IFN-γ.

[0613] In some implementations, the biomarker is a tumor immune marker (e.g., cytokines, tumor-infiltrating lymphocytes, T cell activation and / or proliferation, or B cell markers such as BCMA or M protein, or a combination thereof).

[0614] In some implementations, the biomarker is an apoptosis marker (e.g., intact and / or cleaved caspase-1, caspase-3, caspase-7, PARP, BIM, or a survival protein, or a combination thereof).

[0615] In some implementations, the biomarker is a zinc finger protein (e.g., IKZF1, IKZF3, ZFP91, WIZ, or SALL4, or a combination thereof).

[0616] Treatment advantages

[0617] In one aspect of the invention, the treatment described herein has one or more advantages compared to currently approved cancer treatments (e.g., treatments for multiple myeloma or non-Hodgkin's lymphoma). For example, the use of the treatment described herein with compound 1 or a pharmaceutically acceptable salt thereof yields better results in one or more measurements below compared to 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's lymphoma).

[0618] In some implementations, the advantage of compound 1 over currently known treatments is a reduced tendency to develop resistance. For example, mice that have developed resistance to pomalidomide still respond rapidly to treatment with compound 1 (see [link to relevant documentation]). Figure 40 Additionally, when the treatment was withdrawn from the mice for a sufficiently long period to allow their tumors to regrow and then rechallenged with compound 1, the tumor size still decreased rapidly (see [link to article]). Figure 33 ).

[0619] In other implementations, an advantage over currently approved therapies is the ability to treat refractory tumors. For example, in mice, doses of compound 1 as low as 30 μg / kg were effective in treating NCI-H929 tumors that did not respond to doses of 3,000 μg / kg (see [link to previous instructions]). Figure 33 Furthermore, in a group of cell lines, compound 1 was consistently 2-3 orders of magnitude more potent than pomalidomide, and even demonstrated efficacy against pomalidomide-refractory cells (see [link]). Figure 32 This effect has also been demonstrated by tracking the concentration of biomarkers such as caspase-3 (see [link]). Figure 31 ).

[0620] In other implementations, the advantage over currently approved therapies is the faster degradation of IKZF1 and IKZF3, and therefore faster treatment of the cancer. For example, when administered at the same concentration, compound 1 degrades more IKZF1 in 1 hour than pomalidomide in 2 hours (see [link to relevant documentation]). Figure 29 ).

[0621] In some embodiments, a treatment is provided to induce a therapeutic response in patients with multiple myeloma, the therapeutic response being assessed by the International Uniform Response Criteria for Multiple Myeloma (IURC) (described in “International uniform response criteria for multiple myeloma” by Durie BGM et al., Leukemia 2006, 10(10):1-7), comprising administering to the patient an effective amount of a compound of the form described herein or a pharmaceutically acceptable salt, isotope analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0622] In another embodiment, a treatment is provided to achieve a strict complete response, complete response, or very good partial response to multiple myeloma as assessed by IURC in a patient with multiple myeloma, comprising administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.

[0623] In another embodiment, a treatment is provided to achieve an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in patients with multiple myeloma, comprising administering to the patient an effective amount of the compound described herein or a pharmaceutically acceptable salt, isotope analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition (see Examples 21 and 22, which demonstrate a dose-dependent increase in overall survival in animal models).

[0624] The benefits of compound 1 can be further enhanced by administering additional bioactive agents in combination therapy. For example, in mouse studies, compound 1 was significantly more effective when administered as a treatment regimen including weekly dexamethasone than the same dose of compound 1 or dexamethasone alone (see [link to study]). Figure 41 ).

[0625] Treatment of IKZF1 / IKZF3-mediated cancers with significant mutations

[0626] In some embodiments, the compounds described herein can be administered in an effective amount to treat cancers mediated by proteins having one or more mutations, such as multiple myeloma mediated by proteins having one or more mutations.

[0627] In some embodiments, the compounds described herein can be administered in effective amounts to treat or manage 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., deletion of 17p13 or chromosome 13; del(17 / 17p), non-hyperdiploidy, and gain(1q)).

[0628] In some embodiments, multiple myeloma has a p53 mutation. In some embodiments, the p53 mutation is a Q331 mutation. In some embodiments, the p53 mutation is an R273H mutation. In some embodiments, the p53 mutation is a K132 mutation. In some embodiments, the p53 mutation is a K132N mutation. In some embodiments, the p53 mutation is an R337 mutation. In some embodiments, the p53 mutation is an R337L mutation. In some embodiments, the p53 mutation is a W146 mutation. In some embodiments, the p53 mutation is an S261 mutation. In some embodiments, the p53 mutation is an S261T mutation. In some embodiments, the p53 mutation is an E286 mutation. In some embodiments, the p53 mutation is an E286K mutation. In some embodiments, the p53 mutation is an R175 mutation. In some embodiments, the p53 mutation is an R175H mutation. In some embodiments, the p53 mutation is an E258 mutation. In some implementations, the p53 mutation is the E258K mutation. In some implementations, the p53 mutation is the A161 mutation. In some implementations, the p53 mutation is the A161T mutation.

[0629] In some embodiments, the multiple myeloma has a homozygous deletion of p53. In some embodiments, the multiple myeloma has a homozygous deletion of wild-type p53. In some embodiments, the multiple myeloma has wild-type p53.

[0630] In some embodiments, multiple myeloma exhibits activation of one or more oncogenic drivers. In some embodiments, the one or more oncogenic drivers are selected from C-MAF, MAFB, FGFR3, MMset, cyclin D1, and cyclin D. In some embodiments, multiple myeloma exhibits activation of C-MAF. In some embodiments, multiple myeloma exhibits activation of MAFB. In some embodiments, multiple myeloma exhibits activation of FGFR3 and MMset. In some embodiments, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In some embodiments, multiple myeloma exhibits activation of cyclin D1. In some embodiments, multiple myeloma exhibits activation of MAFB and cyclin D1. In some embodiments, multiple myeloma exhibits activation of cyclin D.

[0631] In some embodiments, multiple myeloma has one or more chromosomal translocations. In some embodiments, the chromosomal translocation is t(14;16). In some embodiments, the chromosomal translocation is t(14;20). In some embodiments, the chromosomal translocation is t(4;14). In some embodiments, the chromosomal translocation is t(4;14) and t(14;16). In some embodiments, the chromosomal translocation is t(11;14). In some embodiments, the chromosomal translocation is t(6;20). In some embodiments, the chromosomal translocation is t(20;22). In some embodiments, the chromosomal translocation is t(6;20) and t(20;22). In some embodiments, the chromosomal translocation is t(16;22). In some embodiments, the chromosomal translocation is t(14;16) and t(16;22). In some embodiments, the chromosomal translocation is t(14;20) and t(11;14).

[0632] In some embodiments, the multiple myeloma has a Q331 p53 mutation, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the multiple myeloma has a homozygous deletion of p53, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the multiple myeloma has a K132N p53 mutation, MAFB activation, and a chromosomal translocation at t(14;20). In some embodiments, the multiple myeloma has wild-type p53, FGFR3, and MMset activation, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has wild-type p53, C-MAF activation, and a chromosomal translocation at t(14;16). In some embodiments, the 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 some embodiments, the multiple myeloma has a homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In some embodiments, the multiple myeloma has an R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In some embodiments, the multiple myeloma has a W146p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an S261T p53 mutation, activation of MAFB, and chromosomal translocations at t(6;20) and t(20;22). In some embodiments, the multiple myeloma has an E286K p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an R175H p53 mutation, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In some embodiments, the multiple myeloma has an E258K p53 mutation, activation of C-MAF, and chromosomal translocations at t(14;16) and t(16;22). In some embodiments, the multiple myeloma has wild-type p53, MAFB, and cyclin D1 activation, and chromosomal translocations at t(14;20) and t(11;14). In some embodiments, the multiple myeloma has an A161T p53 mutation, activation of cyclin D, and a chromosomal translocation at t(11;14).

[0633] Patient selection

[0634] In some implementations, patients treated with the compounds described herein have received prior treatment with IMiDs such as thalidomide, lenalidomide, or pomalidomide.

[0635] In some implementations, patients treated with the compounds described herein have received prior treatment with CD20 antibodies such as rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab, tositumomab, or ublituximab.

[0636] In some implementations, patients treated with the compounds described herein have received prior treatment with CD38 antibodies such as daratumumab or ixartuximab.

[0637] In some implementations, patients treated with the compounds described herein have received prior treatment with CD30 antibodies such as bentuximab.

[0638] In some implementations, patients treated with the compounds described herein have received prior treatment with BTK inhibitors such as ibrutinib, acalatinib, or zanubrutinib.

[0639] In some implementations, patients treated with the compounds described herein have received prior treatment with alkylating agents such as cyclophosphamide, melphan, melphalan flufenamide, or bendamustine.

[0640] In some implementations, patients treated with the compounds described herein have received prior treatment with proteasome inhibitors such as bortezomib, carfilzomib, or esazomib.

[0641] In some implementations, patients treated with the compounds described herein have received prior treatment with glucocorticoids such as dexamethasone, prednisone, or methylprednisolone.

[0642] In some implementations, patients treated with the compounds described herein have received prior treatment with bone modulators such as denosumab, zoledronic acid, or pamidronate.

[0643] In some implementations, patients treated with the compounds described herein have received prior treatment with an HDAC inhibitor such as pabisostat.

[0644] In some implementations, patients treated with the compounds described herein have received prior treatment with nuclear export inhibitors such as cyclophosphamide.

[0645] In some implementations, patients treating multiple myeloma have received at least one, two, three, or four prior antimyeloma or lymphoma regimens, such as lenalidomide, pomalidomide, a proteasome inhibitor, glucocorticoids, or anti-CD38 antibodies. For example, a patient who has received at least three prior antimyeloma regimens, including at least two consecutive cycles of lenalidomide, pomalidomide, a proteasome inhibitor, glucocorticoids, or anti-CD38 antibodies.

[0646] In some implementations, patients treated with multiple myeloma have M-protein levels ≥ about 0.5 g / dL as measured by serum protein electrophoresis (sPEP), urine collection ≥ 200 mg / 24 hours as measured by urine protein electrophoresis (uPEP), serum free light chain (FLC) levels > 100 mg / L (involving light chains and abnormal kappa / lambda (κ / λ) ratios) in subjects without measurable serum or urine M-protein, and / or serum IgA levels ≥ 0.50 g / dL.

[0647] In some implementations, the treated patient has peripheral T-cell lymphoma and has previously received at least one alkylating agent-based chemotherapy treatment.

[0648] In some implementations, the treated patient has anaplastic large cell lymphoma (ALCL) and has previously received at least one alkylating agent-based chemotherapy treatment and has also received CD30 antibody treatment.

[0649] In some implementations, the treated patient has mantle cell lymphoma and has received at least two prior lines of treatment, including CD20 antibody and alkylating agent chemotherapy, as well as Bruton's tyrosine kinase inhibitors.

[0650] In some implementations, the treated patient has follicular lymphoma and has received at least two prior lines of treatment, including CD20 antibody and alkylating agent chemotherapy.

[0651] In some implementations, the treated patient has diffuse large B-cell lymphoma and has received at least two prior lines of treatment, including CD20 antibody therapy, and has previously received autologous bone marrow transplantation (or is not suitable for bone marrow transplantation).

[0652] In some implementations, patients treated for non-Hodgkin's lymphoma have lesions that can be measured in at least two dimensions using PET-CT, such as lesions with a minimum measurement of at least about 15 mm in the longest diameter.

[0653] In some embodiments, the patient to be treated with one of the compounds described herein has not been treated with multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has received multiple myeloma therapy prior to administration. In some embodiments, the patient to be treated with one of the compounds described herein has developed resistance to multiple myeloma therapy. In some embodiments, the patient to be treated with one of the compounds described herein has developed resistance to one, two, or three multiple myeloma therapies selected from CD38 antibodies (CD38 mAb, such as daratumumab or ixartuximab), proteasome inhibitors (such as bortezomib, carfilzomib, esazomib, or marizomib), and immunomodulatory compounds (such as thalidomide, lenalidomide, pomalidomide, iberlidomide, or avaduromide).

[0654] The compounds described herein can be administered in a therapeutically effective amount, regardless of the patient's age. In some embodiments, the patient is 18 years of age or older. In other embodiments, the patient is older than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years of age. In other embodiments, the patient is younger than 65 years of age. In other embodiments, the patient is older than 65 years of age. In some embodiments, the patient is an elderly patient with multiple myeloma, such as a patient over 65 years of age. In some embodiments, the patient is an elderly patient with multiple myeloma, such as a patient over 75 years of age.

[0655] V. Combination Therapy

[0656] Any of the compounds described herein may be administered alone or in combination in effective amounts to treat a host, such as a human, suffering from the condition described herein. In some embodiments, the compounds described herein are administered together with additional bioactive agents.

[0657] The term "bioactive agent" is used to describe pharmaceutical agents, other than those according to the invention, that can be used in combination with or alternately with the compounds of the invention to achieve a desired therapeutic outcome. In some embodiments, the compounds and bioactive agents of the invention are administered in such a way that they are active in vivo over overlapping time periods, for example, having overlapping Cmax, Tmax, AUC, or other pharmacokinetic parameters. In another embodiment, the compounds and bioactive agents of the invention are administered to a host in need, which do not have overlapping pharmacokinetic parameters; however, one of them has a therapeutic effect on the efficacy of the others.

[0658] As used herein, when a compound is administered in combination with another compound, the combination may be one or more dosage forms administered at the same or different times. Additionally, the compounds administered in combination may be administered using different dosing regimens. For example, the combination of compound 1 and dexamethasone includes a treatment regimen in which compound 1 is administered once daily for 21 consecutive days during a 28-day treatment cycle, and dexamethasone is administered once weekly during the treatment cycle.

[0659] In some embodiments, compound 1 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0660] In some embodiments, compound 2 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0661] In some embodiments, compound 3 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0662] In some embodiments, compound 4 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0663] In some embodiments, compound 5 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0664] In some embodiments, compound 6 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0665] In some embodiments, compound 7 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0666] In some embodiments, compound 8 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0667] In some embodiments, compound 9 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0668] In some embodiments, compound 10 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0669] In some embodiments, compound 11 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0670] In some embodiments, compound 12 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0671] In some embodiments, compound 13 is administered in an effective amount in combination with one or more other therapeutic agents described herein to patients in need.

[0672] Corticosteroids

[0673] In some embodiments, the compounds of the present invention are administered in combination with a corticosteroid. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, compound 1 is administered together with a corticosteroid. In some embodiments, compound 1 is administered together with dexamethasone, for example, according to the following dosing regimen:

[0674]

[0675] In some embodiments, compound 1 is combined with another bioactive agent and administered via a 21 / 7 dosing schedule every 28 days, for example, dexamethasone once weekly. In some embodiments, the dose of dexamethasone for adults ≤75 years of age is 40 mg QW on days 1, 8, 15, and 22 of a 28-day cycle. In some embodiments, the dose of dexamethasone for adults >75 years of age is 20 mg QW on days 1, 8, 15, and 22 of a 28-day cycle.

[0676] In some embodiments, the compounds described herein are administered in combination with corticosteroids. Non-limiting examples of corticosteroids include dexamethasone, prednisone, fludrocortisone, hydrocortisone, cortisone, betamethasone, and methylprednisolone.

[0677] In some embodiments, compound 1 is administered in combination with a corticosteroid. In some embodiments, compound 2 is administered in combination with a corticosteroid. In some embodiments, compound 3 is administered in combination with a corticosteroid. In some embodiments, compound 4 is administered in combination with a corticosteroid. In some embodiments, compound 5 is administered in combination with a corticosteroid. In some embodiments, compound 6 is administered in combination with a corticosteroid. In some embodiments, compound 7 is administered in combination with a corticosteroid. In some embodiments, compound 8 is administered in combination with a corticosteroid. In some embodiments, compound 9 is administered in combination with a corticosteroid. In some embodiments, compound 10 is administered in combination with a corticosteroid. In some embodiments, compound 11 is administered in combination with a corticosteroid. In some embodiments, compound 12 is administered in combination with a corticosteroid. In some embodiments, compound 13 is administered in combination with a corticosteroid. In some embodiments, the corticosteroid is dexamethasone.

[0678] Other non-limiting examples of corticosteroids include corticosterone, aldosterone, prednisolone, triamcinolone, budesonide, defcodone, fluprogesterone, flumethrin, methylprednisolone, prednisolone acetate, cloprednisolone, cloprednisolone alcohol, difluprednisolone ester, fluocinolone, floperidone, floperidone acetate, fluprednisolone, clotipronol, prenicardium, tecortisone, aclomethasone, aclomethasone dipropionate, beclomethasone, clobetasol, clobetasol, clobetasol, clocoroxone, desoxymethasone, difluralasone, difluralasone diacetate, diflucoroxone, diflucoroxone valerate, fluprednididine, fluprednididine acetate, fluticasone, fluticasone furoate, halometasone, methylprednisolone, mometasone, mometasone furoate, peramisone, prednisolone, limexone. Ubetasol, Ancinonide, Cyclosonede, Desonide, Formococcus, Fluchlordone, Fluchlordone Acetone, Fluhydrocopeptide, Flunisolone, Fluocinolone Acetonide, Fluocinolone Acetate, Fluocinolone Acetonide, Halcinonide, Triamcinolone Acetonide, Cortivastatin, RU-28362, Ethiophanate-methyl Dexamethasone, Dexamethasone Acetate, Dexamethasone Diethylaminoacetate, Dexamethasone Dipropionate, Isonicotinic Acid Dexamethasone, Linoleic Acid Dexamethasone, Dexamethasone m-Sulfobenzoate, Dexamethasone Palmitate, Dexamethasone Phosphate, Dexamethasone Neopentanoate, Dexamethasone Succinate Tert-butyl Acetate, Dexamethasone Sulfate, Dexamethasone Tert-butyl Acetate, Dexamethasone Troxundate, and Dexamethasone Valerate.

[0679] kinase inhibitors In some embodiments, the bioactive agent is a kinase inhibitor, such as a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, the kinase inhibitor is selected from phosphoinositol 3-kinase (PI3K) inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, or spleen tyrosine kinase (Syk) inhibitors, or combinations thereof.

[0680] In some embodiments, the compounds of the present invention are administered in combination with a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the BTK inhibitor of the embodiment is acalabrutinib. In some embodiments, compound 1 is administered in combination with a BTK inhibitor. In some embodiments, compound 1 is administered in combination with the BTK inhibitor zanubrutinib. In some embodiments, ibrutinib is used. In some embodiments, compound 1 is administered in combination with zanubrutinib. In some embodiments, compound 1 is administered in combination with acalabrutinib.

[0681] In some embodiments, compound 2 is administered in combination with a BTK inhibitor. In some embodiments, compound 3 is administered in combination with a BTK inhibitor. In some embodiments, compound 4 is administered in combination with a BTK inhibitor. In some embodiments, compound 5 is administered in combination with a BTK inhibitor. In some embodiments, compound 6 is administered in combination with a BTK inhibitor. In some embodiments, compound 7 is administered in combination with a BTK inhibitor. In some embodiments, compound 8 is administered in combination with a BTK inhibitor. In some embodiments, compound 9 is administered in combination with a BTK inhibitor. In some embodiments, compound 10 is administered in combination with a BTK inhibitor. In some embodiments, compound 11 is administered in combination with a BTK inhibitor. In some embodiments, compound 12 is administered in combination with a BTK inhibitor. In some embodiments, compound 13 is administered in combination with a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, zanubrutinib, or acalabrutinib.

[0682] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica) TM(1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), diphenylamine pyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292(N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide)(Avila Therapeutics (see patent publication US2011 / 0117073, which is incorporated herein by reference in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazolyl-5-carboxamide], LFM-A13 (α-cyano-β-hydroxy-β-methyl-N-(2,5-bromophenyl)acrylamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-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]pyrazin-6-yl)phenyl)benzamide, CGI-1746(4-(tert-butyl)-N-(2-methyl-3-(4-methyl-6-((4-(morpholin-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)benzamide), CNX-774(4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpyridinamide), CTA056(7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxaline-6-( 5H)-ketone), GDC-0834((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide), GDC-0837((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-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-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1-acryloylindol-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthidin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinoline-1-one), and other molecules capable of inhibiting BTK activity, such as those BTK inhibitors disclosed below: Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which are incorporated herein by reference in their entirety.

[0683] In some implementations, the BTK inhibitor is selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib. In some embodiments, compound 1 is administered in combination with a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.

[0684] Examples of PI3 kinase inhibitors include, but are not limited to, womanpem, demethoxyvirine, piperafosine, idelalisib, Pictilisib, Palomida 529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib)(2-[4-[2-(2-isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazine). -9-yl]pyrazol-1-yl]-2-methylpropionamide), MLN-1117 ((2R)-1-phenoxy-2-butylhydro(S)-methylphosphonate; or methyl(oxo){[(2R)-l-phenoxy-2-butyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]]-1,2-pyrrolidinedicarboxamide), GSK212645 8(2,4-difluoro-N-{2-(methoxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)(omipalisib), TGX-221((±)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2-a]pyrimidin-4-one), GSK2636771(2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholin-lH-benzo[d]imidazolium -4-carboxylic acid dihydrochloride), KIN-193((R)-2-((l-(7-methyl-2-morpholin-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-hydroxypropane-1-one), GS-1101(5-fluoro-3-phenyl-2-([S)]-1-[9H-purine) [N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)aminesulfonyl)phenyl)-3-methoxy-4-methylbenzamide], BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2-c]quinoxalin], AS 252424 (5-[l-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-methylene-(Z)-yl]-thiazolidin-2,4-dione], CZ 24832(5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib(5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinylamine), GDC-0941(2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)-l-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinylthieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-l-yl)-2-hydroxyprop-l-one (also known as RG7422)), SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-onthium)-2-oxo (7,10,13,16-tetraazaoctadecane-18-acid), PF-05212384(N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholino-1,3,5-triazin-2-yl)phenyl]urea)(gedatolisib), LY3023414, BEZ235(2-methyl-2-{4- [3-Methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propionitrile)(dactolisib), XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxolin-2-yl)aminosulfonyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615(5 -[[4-(4-pyridyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindene[4,[5h] isobenzopyran-10-yl]acetic acid (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, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422), and the structures described in WO2014 / 071109.

[0685] Syk inhibitors include, for example, cerdulatinib (4-(cyclopropylamino)-2-((4-(4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazole-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), and fostamatinib ([6-({5-fluoro-2-[(3,4-yl)-[4-yl]-[4-yl]-[4-yl]-[4-yl]-[5 ... ,5-trimethoxyphenyl)amino]-4-pyrimidinyl)amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl phosphate dihydrogen ester), fotentinib disodium salt ((6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate sodium salt), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide hydrochloride), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylate), imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N- (4-Methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), staphylococcin, GSK143(2-(((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidin-5-carboxamide), PP2(1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT -060318(2-(((1R,2S)-2-aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607(4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), R112(3,3'-((5-fluoropyrimidine-2,4-) R348 (3-ethyl-4-methylpyridine), R406 (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one), piperazine (3-hydroxyresveratrol), YM193306 (see Singh et al.).The compounds mentioned include: 7-azaindole, leucine, ER-27319 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety), compound D (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety), and PRT060318 (see Singh et al., Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety). Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference), quercetin ... Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference), spleen tyrosine (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference), myricetin (see Singh et al.).Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference. (See Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, cited in its entirety and incorporated herein by reference).

[0686] Proteasome inhibitors In some embodiments, the compounds of the present invention are administered in combination with a proteasome inhibitor. In some embodiments, the proteasome inhibitor is bortezomib. In some embodiments, the proteasome inhibitor is esazomib. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, compound 1 is administered in combination with a proteasome inhibitor. In some embodiments, compound 1 is administered in combination with bortezomib. In some embodiments, compound 1 is administered in combination with esazomib. In some embodiments, compound 1 is administered in combination with carfilzomib. In some embodiments, compound 1 is administered in combination with carfilzomib and daratumumab.

[0687] In some embodiments, compound 2 is administered in combination with a proteasome inhibitor. In some embodiments, compound 3 is administered in combination with a proteasome inhibitor. In some embodiments, compound 4 is administered in combination with a proteasome inhibitor. In some embodiments, compound 5 is administered in combination with a proteasome inhibitor. In some embodiments, compound 6 is administered in combination with a proteasome inhibitor. In some embodiments, compound 7 is administered in combination with a proteasome inhibitor. In some embodiments, compound 8 is administered in combination with a proteasome inhibitor. In some embodiments, compound 9 is administered in combination with a proteasome inhibitor. In some embodiments, compound 10 is administered in combination with a proteasome inhibitor. In some embodiments, compound 11 is administered in combination with a proteasome inhibitor. In some embodiments, compound 12 is administered in combination with a proteasome inhibitor. In some embodiments, compound 13 is administered in combination with a proteasome inhibitor. In some embodiments, the proteasome inhibitor is selected from bortezomib, esazomib, VLX1570, and carfilzomib.

[0688] Other examples of proteasome inhibitors include those selected from esazolidinium citrate, opzomib, delanzomib, lactoscin, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616. In some embodiments, compound 1 is administered in combination with a proteasome inhibitor selected from esazolidinium citrate, opzomib, delanzomib, lactoscin, cyclooxygenase, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, VLX1570, and KZR-616.

[0689] HDAC inhibitors

[0690] In some embodiments, the compounds of the present invention are administered in combination with an HDAC inhibitor. In some embodiments, the HDAC inhibitor is volinistat. In some embodiments, the HDAC inhibitor is romidesin. In some embodiments, the HDAC inhibitor is pabilistat. In some embodiments, the HDAC inhibitor is belistat. In some embodiments, compound 1 is administered in combination with an HDAC inhibitor. In some embodiments, compound 1 is administered in combination with volinistat. In some embodiments, compound 1 is administered in combination with romidesin. In some embodiments, compound 1 is administered in combination with pabilistat. In some embodiments, compound 1 is administered in combination with belistat.

[0691] In some embodiments, compound 2 is administered in combination with an HDAC inhibitor. In some embodiments, compound 3 is administered in combination with an HDAC inhibitor. In some embodiments, compound 4 is administered in combination with an HDAC inhibitor. In some embodiments, compound 5 is administered in combination with an HDAC inhibitor. In some embodiments, compound 6 is administered in combination with an HDAC inhibitor. In some embodiments, compound 7 is administered in combination with an HDAC inhibitor. In some embodiments, compound 8 is administered in combination with an HDAC inhibitor. In some embodiments, compound 9 is administered in combination with an HDAC inhibitor. In some embodiments, compound 10 is administered in combination with an HDAC inhibitor. In some embodiments, compound 11 is administered in combination with an HDAC inhibitor. In some embodiments, compound 12 is administered in combination with an HDAC inhibitor. In some embodiments, compound 13 is administered in combination with an HDAC inhibitor. In some embodiments, the HDAC inhibitor is selected from vorinstat, romidesin, pabistal, and belinostat.

[0692] In some implementations, the HDAC inhibitor is selected from trapoxin B, sodium chlorate, acetyldenalin, moxitistat, BRD73954, BG45, domastartar, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101. In some embodiments, compound 1 is administered in combination with an HDAC inhibitor selected from trapoxin B, sodium chlorate, acetyldenalin, moxitistat, BRD73954, BG45, domastartar, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

[0693] IMiD

[0694] In some embodiments, the compounds of the present invention are administered in combination with IMiD. In some embodiments, IMiD is thalidomide. In some embodiments, IMiD is lenalidomide. In some embodiments, IMiD is pomalidomide. In some embodiments, compound 1 is administered in combination with thalidomide. In some embodiments, compound 1 is administered in combination with lenalidomide. In some embodiments, compound 1 is administered in combination with pomalidomide.

[0695] In some embodiments, compound 2 is administered in combination with IMiD. In some embodiments, compound 3 is administered in combination with IMiD. In some embodiments, compound 4 is administered in combination with IMiD. In some embodiments, compound 5 is administered in combination with IMiD. In some embodiments, compound 6 is administered in combination with IMiD. In some embodiments, compound 7 is administered in combination with IMiD. In some embodiments, compound 8 is administered in combination with IMiD. In some embodiments, compound 9 is administered in combination with IMiD. In some embodiments, compound 10 is administered in combination with IMiD. In some embodiments, compound 11 is administered in combination with IMiD. In some embodiments, compound 12 is administered in combination with IMiD. In some embodiments, compound 13 is administered in combination with IMiD. In some embodiments, IMiD is selected from pomalidomide, thalidomide, and lenalidomide.

[0696] In some embodiments, IMiD is CC-90009. In some embodiments, IMiD is CC-99282. In some embodiments, IMiD is CC-92480. In some embodiments, compound 1 is administered in combination with CC-90009. In some embodiments, compound 1 is administered in combination with CC-99282. In some embodiments, compound 1 is administered in combination with CC-92480.

[0697] In some 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 are administered in combination with IMiD. In some embodiments, IMiD is selected from CC-90009, CC-99282, and CC-92480.

[0698] Anti-rest

[0699] In some embodiments, the compounds of the present invention are administered in combination with antibodies targeting CD20, CD30, or CD38. In some embodiments, the targeting antibody is rituximab. In some embodiments, the targeting antibody is daratumumab. In some embodiments, the targeting antibody is elotuzumab. In some embodiments, the targeting antibody is ixartuximab. In some embodiments, compound 1 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 1 is administered in combination with rituximab. In some embodiments, compound 1 is administered in combination with daratumumab. In some embodiments, compound 1 is administered in combination with elotuzumab. In some embodiments, compound 1 is administered in combination with ixartuximab.

[0700] In some embodiments, compound 2 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 3 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 4 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 5 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 6 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 7 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 8 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 9 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 10 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 11 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 12 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, compound 13 is administered in combination with an antibody targeting CD20, CD30, or CD38. In some embodiments, the targeting antibody is selected from rituximab, daratumumab, elozumab, and ixartuximab.

[0701] In some embodiments, the compounds of the present invention are administered in combination with an antibody-drug conjugate. In some embodiments, the antibody-drug conjugate is brentuximab vedotin. In some embodiments, the antibody-drug conjugate is ilimetuzumab tiuxetan. In some embodiments, the antibody-drug conjugate is mogamulizumab. In some embodiments, the antibody-drug conjugate is oxalimetuzumab. In some embodiments, the antibody-drug conjugate is vepolatuzumab vedotin. In some embodiments, the antibody-drug conjugate is berenmodorin (GSK2857916). In some embodiments, the antibody-drug conjugate is MEDI2228. In some embodiments, the antibody-drug conjugate is CC-99712. In some embodiments, compound 1 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 1 is administered in combination with brentuximab. In some embodiments, compound 1 is administered in combination with teimomab. In some embodiments, compound 1 is administered in combination with mojazumab. In some embodiments, compound 1 is administered in combination with oxantuzumab. In some embodiments, compound 1 is administered in combination with vepotuzumab. In some embodiments, compound 1 is administered in combination with berenmodorin (GSK2857916). In some embodiments, compound 1 is administered in combination with MEDI2228. In some embodiments, compound 1 is administered in combination with CC-99712. In some embodiments, compound 1 is administered in combination with tafacitinib.

[0702] In some embodiments, compound 2 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 3 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 4 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 5 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 6 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 7 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 8 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 9 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 10 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 11 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 12 is administered in combination with an antibody-drug conjugate. In some embodiments, compound 13 is administered in combination with an antibody-drug conjugate. In some implementations, the antibody-drug conjugate is selected from entuximab, tiimomab, mojazumab, oxantuximab, veportozumab, berenmodorin (GSK2857916), MEDI2228, and CC-99712.

[0703] In some embodiments, the compounds of the present invention are administered in combination with a bispecific antibody. In some embodiments, the bispecific antibody is PF-06863135. In some embodiments, the bispecific antibody is TNB-383B. In some embodiments, the bispecific antibody is REGN5458. In some embodiments, the bispecific antibody is JNJ-64007957. In some embodiments, compound 1 is administered in combination with a bispecific antibody. In some embodiments, compound 1 is administered in combination with PF-06863135. In some embodiments, compound 1 is administered in combination with TNB-383B. In some embodiments, compound 1 is administered in combination with REGN5458. In some embodiments, compound 1 is administered in combination with JNJ-64007957.

[0704] In some embodiments, compound 2 is administered in combination with a bispecific antibody. In some embodiments, compound 3 is administered in combination with a bispecific antibody. In some embodiments, compound 4 is administered in combination with a bispecific antibody. In some embodiments, compound 5 is administered in combination with a bispecific antibody. In some embodiments, compound 6 is administered in combination with a bispecific antibody. In some embodiments, compound 7 is administered in combination with a bispecific antibody. In some embodiments, compound 8 is administered in combination with a bispecific antibody. In some embodiments, compound 9 is administered in combination with a bispecific antibody. In some embodiments, compound 10 is administered in combination with a bispecific antibody. In some embodiments, compound 11 is administered in combination with a bispecific antibody. In some embodiments, compound 12 is administered in combination with a bispecific antibody. In some embodiments, compound 13 is administered in combination with a bispecific antibody. In some embodiments, the bispecific antibody is selected from PF-06863135, TNB-383B, REGN5458, and JNJ-64007957.

[0705] In some embodiments, the compounds of the present invention are administered in combination with a naked monoclonal antibody (mAb). In some embodiments, the naked mAb is SEA-BCMA. In some embodiments, compound 1 is administered in combination with a naked mAb. In some embodiments, compound 1 is administered in combination with SEA-BCMA.

[0706] In some embodiments, compound 2 is administered in combination with a naked mAb. In some embodiments, compound 3 is administered in combination with a naked mAb. In some embodiments, compound 4 is administered in combination with a naked mAb. In some embodiments, compound 5 is administered in combination with a naked mAb. In some embodiments, compound 6 is administered in combination with a naked mAb. In some embodiments, compound 7 is administered in combination with a naked mAb. In some embodiments, compound 8 is administered in combination with a naked mAb. In some embodiments, compound 9 is administered in combination with a naked mAb. In some embodiments, compound 10 is administered in combination with a naked mAb. In some embodiments, compound 11 is administered in combination with a naked mAb. In some embodiments, compound 12 is administered in combination with a naked mAb. In some embodiments, compound 13 is administered in combination with a naked mAb. In some embodiments, the naked mAb is SEA-BCMA.

[0707] Other non-limiting examples of CD38 antibodies include phenzalozymec, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, and mizalozymec. In some embodiments, compound 1 is administered in combination with a CD38 antibody selected from phenzalozymec, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mizalozymec.

[0708] CAR T-cell therapy

[0709] In some embodiments, the compounds of the present invention are administered in combination with CAR T-cell therapy. In some embodiments, the CAR T-cell therapy is Axicabtagene ciloleucel. In some embodiments, the CAR T-cell therapy is Tisagenlecleucel. In some embodiments, the CAR T-cell therapy is Idecabtagene vicleucel (ide-cel; bb2121). In some embodiments, the CAR T-cell therapy is LCAR-B38M (JNJ-4528; JNJ-68284528). In some embodiments, the CAR T-cell therapy is P-BCMA-101. In some embodiments, the CAR T-cell therapy is PBCAR269A. In some embodiments, the CAR T-cell therapy is bb21217. In some embodiments, the CAR T-cell therapy is JCARK125 (orva-cel; orvacabtagene autoleucel). In some embodiments, the CAR T-cell therapy is ALLO-715. In some embodiments, the CAR T-cell therapy is Descartes-08. In some implementations, the CAR T-cell therapy is FCARH143. In some implementations, the CAR T-cell therapy is CT053.

[0710] In some embodiments, compound 1 is administered in combination with CAR T-cell therapy. In some embodiments, compound 1 is administered in combination with Axicabtagene ciloleucel. In some embodiments, compound 1 is administered in combination with Tisagenlecleucel. In some embodiments, compound 1 is administered in combination with Idecabtagene vicleucel (ide-cel; bb2121). In some embodiments, compound 1 is administered in combination with LCAR-B38M (JNJ-4528; JNJ-68284528). In some embodiments, compound 1 is administered in combination with P-BCMA-101. In some embodiments, compound 1 is administered in combination with PBCAR269A. In some embodiments, compound 1 is administered in combination with bb21217. In some embodiments, compound 1 is administered in combination with JCARK125 (orva-cel; orvacabtagene autoleucel). In some embodiments, compound 1 is administered in combination with ALLO-715. In some embodiments, compound 1 is administered in combination with Descartes-08. In some embodiments, compound 1 is administered in combination with FCARH143. In some embodiments, compound 1 is administered in combination with CT053.

[0711] In some embodiments, compound 2 is administered in combination with CAR T-cell therapy. In some embodiments, compound 3 is administered in combination with CAR T-cell therapy. In some embodiments, compound 4 is administered in combination with CAR T-cell therapy. In some embodiments, compound 5 is administered in combination with CAR T-cell therapy. In some embodiments, compound 6 is administered in combination with CAR T-cell therapy. In some embodiments, compound 7 is administered in combination with CAR T-cell therapy. In some embodiments, compound 8 is administered in combination with CAR T-cell therapy. In some embodiments, compound 9 is administered in combination with CAR T-cell therapy. In some embodiments, compound 10 is administered in combination with CAR T-cell therapy. In some embodiments, compound 11 is administered in combination with CAR T-cell therapy. In some embodiments, compound 12 is administered in combination with CAR T-cell therapy. In some embodiments, compound 13 is administered in combination with CAR T-cell therapy. In some embodiments, the CAR T-cell therapy is selected from Axicabtagene ciloleucel, Tisagenlecleucel, Idecabtagene vicleucel (ide-cel; bb2121), LCAR-B38M (JNJ-4528; JNJ-68284528), and P-BCMA-101. In some embodiments, the CAR T-cell therapy is selected from PBCAR269A, bb21217, JCARK125 (orva-cel; orvacabtagene autoleucel), ALLO-715, Descartes-08, FCARH143, and CT053.

[0712] In some implementations, the CAR T-cell therapy is selected from ALLO-715, bb21217, BCMA CAR-T, CD138CAR-T, CD19 CAR-T, ciltacabtagene autoleucel, CS1(SLAMF7)CAR-T, CT053, Descartes-11, idecabtagene vicleucel, NKG2D CAR-T, orvacabtagene autoleucel, P-BCMA-101, and UCARTCS1.

[0713] Cell therapy

[0714] In some embodiments, the compounds of the present invention are administered in combination with cell therapy. In some embodiments, compound 1 is administered in combination with cell therapy.

[0715] Non-limiting examples of cell therapies include allo-HSCT, allo-NKT, auto-HSCT, and auto-NKT.

[0716] T cell engagement protein

[0717] In some embodiments, the compounds of the present invention are administered in combination with a bispecific T-cell conjugating protein (BiTE). In some embodiments, BiTE is bonnetumab. In some embodiments, BiTE is CC-93268. In some embodiments, BiTE is AMG 420. In some embodiments, BiTE is AMG 701. In some embodiments, compound 1 is administered in combination with a bispecific T-cell conjugating protein (BiTE). In some embodiments, compound 1 is administered in combination with bonnetumab. In some embodiments, compound 1 is administered in combination with AMG 420. In some embodiments, compound 1 is administered in combination with CC-93269. In some embodiments, compound 1 is administered in combination with AMG 701.

[0718] In some embodiments, compound 2 is administered in combination with BiTE. In some embodiments, compound 3 is administered in combination with BiTE. In some embodiments, compound 4 is administered in combination with BiTE. In some embodiments, compound 5 is administered in combination with BiTE. In some embodiments, compound 6 is administered in combination with BiTE. In some embodiments, compound 7 is administered in combination with BiTE. In some embodiments, compound 8 is administered in combination with BiTE. In some embodiments, compound 9 is administered in combination with BiTE. In some embodiments, compound 10 is administered in combination with BiTE. In some embodiments, compound 11 is administered in combination with BiTE. In some embodiments, compound 12 is administered in combination with BiTE. In some embodiments, compound 13 is administered in combination with BiTE. In some embodiments, BiTE is selected from bonnetumab, AMG 420, CC-93269, and AMG 4701.

[0719] In some embodiments, compound 1 is used in combination with a bispecific antibody selected from AMG 420, AMG 701, BFCR4350A, bonatumab, CC-93269, elranatamab, EM801, REGN5458, talquetamab, teclistamab, and TNB-383B.

[0720] Immunomodulators and checkpoint inhibitors

[0721] In some embodiments, the compounds of the present invention are administered in combination with a checkpoint inhibitor. In some embodiments, the compounds of the present invention are administered in combination with a PD-1 checkpoint inhibitor. In some embodiments, the compounds of the present invention are administered in combination with a PD-L1 checkpoint inhibitor. In some embodiments, the compounds of the present invention are administered in combination with an IFNAR inhibitor. In some embodiments, the checkpoint inhibitor is nivolumab. In some embodiments, the checkpoint inhibitor is pembrolizumab. In some embodiments, the checkpoint inhibitor is interferon α-2b. In some embodiments, compound 1 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 1 is administered in combination with a PD-1 checkpoint inhibitor. In some embodiments, compound 1 is administered in combination with a PD-L1 checkpoint inhibitor. In some embodiments, compound 1 is administered in combination with an IFNAR checkpoint inhibitor. In some embodiments, compound 1 is administered in combination with nivolumab. In some embodiments, compound 1 is administered in combination with pembrolizumab. In some embodiments, compound 1 is administered in combination with interferon α-2b.

[0722] In some embodiments, compound 2 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 3 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 4 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 5 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 6 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 7 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 8 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 9 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 10 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 11 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 12 is administered in combination with a checkpoint inhibitor. In some embodiments, compound 13 is administered in combination with a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a PD-1 checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is a PD-L1 checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an IFNAR checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is selected from nivolumab, pembrolizumab, and interferon α-2b.

[0723] PD-1 inhibitors that block the interaction between PD-1 and PD-L1 and thus inhibit immunosuppression by binding to the PD-1 receptor include, for example, 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.). PD-L1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-L1 receptor and thereby inhibiting immunosuppression include, for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, trimemumab (AstraZeneca and MedImmune), AGEN1884, and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[0724] In some implementations, the checkpoint inhibitor is selected from nivolumab / Pembrolizumab / Inhibitors of pildizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS 936559, PDL2 / lg fusion proteins such as AMP 224 or B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0725] In some embodiments, the PD-1 inhibitor is BGB-A317. In some embodiments, the PD-L1 inhibitor is MED14736. In some embodiments, the PD-L2 inhibitor is rHIgM12B7A.

[0726] In some embodiments, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. In some embodiments, the B7-H3 inhibitor is MGA271.

[0727] In some embodiments, the checkpoint inhibitor is an OX40 agonist. In some embodiments, the checkpoint inhibitor is an anti-OX40 antibody, such as anti-OX-40 or MEDI6469.

[0728] In some implementations, the checkpoint inhibitor is a GITR agonist. In some implementations, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0729] In some embodiments, the checkpoint inhibitor is a CD137 agonist. In some embodiments, the CD137 agonist is an anti-CD137 antibody, such as PF-05082566.

[0730] In some implementations, the checkpoint inhibitor is a CD40 agonist. In some implementations, the CD40 agonist is an anti-CD40 antibody, such as CF-870,893.

[0731] In some implementations, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0732] In some implementations, the checkpoint inhibitor is selected from atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

[0733] Other bioactive agents

[0734] In another embodiment, the active compound described herein may be administered in combination with or alternately with an effective amount of an androgen (e.g., testosterone) inhibitor for the treatment of abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer. The androgen inhibitor includes, but is not limited to, another form of selective androgen receptor modulators, selective androgen receptor degraders, complete androgen receptor degraders, or partial or complete androgen antagonists. In some embodiments, the prostate cancer or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and US 8,455,534 and US 8,299,112. Further non-limiting examples of anti-androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine.

[0735] In some implementations, 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.

[0736] In some implementations, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), roxitinib (CO-1686), osimertinib (Tagrisso), omamotinib (Olita), naquotinib (ASP8273), nazatinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), and neratinib (HKI-272; P B272); Avitinib (AC0010), EAI045, Tasotinib (TH-4000; PR-610), PF-06459988 (Pfizer), Tesevatinib (XL647; EXEL-7647; KD-019), Transtinib, WZ-3146, WZ8040, CNX-2006, and Dacomitinib (PF-00299804; Pfizer).

[0737] In some implementations, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0738] In some implementations, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include olibutuzumab, rituximab, tiimomab, tosimomumab, and olibutuzumab.

[0739] In some implementations, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib.

[0740] In some implementations, the bioactive agent is a JAK inhibitor, such as ruxolitinib.

[0741] In some 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-dimethylcyclohexyl-1-en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), and ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]benzamide). [azine-1-yl]-N-[4-[[(2R)-4-(dimethylamino)-1-phenylthioalkylbut-2-yl]amino]-3-nitrophenyl]sulfonylbenzamide)(navitoclax), ABT-263((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]-2-yl)methyl)piperazine-1-yl)-N-((4-((4-morpholin-1-(phenylthio)but-2-yl)amino)-3((tri) Fluoromethyl(sulfonyl)phenyl(sulfonyl)benzamide), GX15-070 (Obaclamamide, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrolo-2-yl)methylene]-4-methoxypyrrolo-2-yl]indole; methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazolyl-2-ylamino)phenyl ester), pogosin, 2-amino-6-bromo- 4-(1-Cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylic acid ethyl ester, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogospermone (ApoG2), HA14-1, AT101, sabutoclax, gambogeylic acid, or G3139 (Oblimersen).

[0742] In some implementations, the bioactive agent is venetotok.

[0743] In some implementations, the bioactive agent is a MEK inhibitor.MEK inhibitors are well known and include, for example, trametinib / GSKl120212(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]pyrimidin-l(2H-yl}phenyl)acetamide), sumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), and pimastetinib / AS703026 / MSC. 1935369((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutane-3-ol), Refatinib / BAY869766 / RDEAl 19(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), TAK733((R)-3-(2,3-dihydroxypropoxy)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)-1-sulfonamide), PD-0325901(N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK733((R)-3-(2,3-dihydroxypropyl)-1-sulfonamide)-1 ... Hydroxypropyl)-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-carboxamide), R05126766 (3-[[3 -Fluoro-2-(methylaminesulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinyl)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, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, PD318088.

[0744] In some embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridin-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropane-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)). 4-(1-methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3-(trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazo-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]aza) -4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazo-4-yl)phenol), sorafenib N-oxide (4-[4-[[[[4-chloro-3(trifluoromethyl)phenyl]amino]carbonyl]amino]phenoxy]-N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (encorafenib).

[0745] In some embodiments, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, perifoxine, (KRX-0401), GDC-0068, tricerebroside, AZD5363, honokiol, PF-04691502, and mitefoxine; and an FLT-3 inhibitor, including but not limited to P406, dovatinib, quezatinib (AC220), amuvatinib (MP-470), tandutinib (MLN518), ENMD-2076, and KW-2449, or combinations thereof.

[0746] In some embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogues, everolimus (Afinitor), tansirolimus, ridaforolimus, sirolimus, and deforolimus. Examples of MEK inhibitors include, but are not limited to, trametinib / GSKl120212(N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyridino[4,3-d]pyrimidin-1(2H-yl}phenyl)acetamide), sumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimastetinib / AS703026 / MSC1935369((S)-N-(2,3-dihydroxypropyl) )-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973(l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azacyclobutane-3-ol)(cobitinib), refatinib / BAY869766 / RDEAl19(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), TAK733((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-carboxamide), R05126766(3-[[3- Fluoro-2-(methylaminosulfonylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromene-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazin-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).

[0747] In some implementations, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0748] In some embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldmycin or 17-N-allylamino-17-demethoxygeldmycin (17AAG) and rhizocarpine.

[0749] In some embodiments, the bioactive agent is a bisphosphonate. Examples of bisphosphonates include, but are not limited to, chlorophosphonate, pamidronate, and zoledronic acid.

[0750] Other 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, AZD 1152, enzatolin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitors, VEGFR inhibitors, aurora kinase inhibitors, PIK-1 modulators, HDAC inhibitors, c-MET inhibitors, PARP inhibitors, CdK inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, Map kinase (mek) inhibitors, and VEGF. Traps, Pemetrexed, Panitumumab, Amrubicin, Ogovovomab, Lep-etu, Noratrexed, Azd2171, Batabulin, Ofatumumab, Zanolimumab, Edotecarin, Tetrandrine, Rubibacin, Tesmilifene, Oblimersen, Ticilimumab, Ipilimumab, Gossypol, Bio111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, Cimenitoline, Gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX-0402, Methionine, LY317615, Neuradiab, Vitespan, Rta 744, Sdx 102, Talenpanel, Atrasentan, Xr 311, Romidesin, ADS-100380, Sunitinib, 5-Fluorouracil, Vorinostat, Etoposide, Gemcitabine, Doxorubicin, Liposome Doxorubicin, 5′-Deoxy-5-Fluorouracil, Vincristine, Temozolomide, ZK-304709, Seliciclib; PD0325901, AZD-6244, Capecitabine, L-Glutamic Acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzyl] [Acyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5-(methylsulfonylpiperidinylmethyl)-indolyl-quinolone, valtarani, AG-013736, AVE-0005, goserelin acetate, leuprorelin acetate, triptorelin dihydroxynaphthyl acetate, medroxyprogesterone acetateHydroxyprogesterone caproate, medroxyprogesterone acetate, raloxifene, bicalutamide, flutamide, nilumethoxazole, medroxyprogesterone acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canenatinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662, tepifenabine; amifostine, NVP-LAQ824, succinyl aniline isohydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib Nitroglycerin, KRN951, Aminoglutamine, Arnsacrine, Anagrelide, L-Asparaginase, BCG, Doxorubicin, Bleomycin, Busereline, Busulfan, Carboplatin, Carmustine, Chlorbutazone, Cisplatin, Cladribine, Clodronate, Cyproterone Acid, Cytarabine, Dacarbazine, Actinomycin D, Daunorubicin, Diethylstilbestrol, Epirubicin, Fludarabine, Fludrocortisone, Flumethasone, Flutamide, Gleevec, Gemcitabine, Hydroxyurea, Idarubicin, Ifosfamide, Imatinib, Leuprorelin, Levamisole, Cyclohexanonitrosourea, Nitrogen Mustard, Melphalan, 6 -Mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilumethicone, octreotide, oxaliplatin, pamidronate, pentostatin, procainamide, porphyrin sodium, procarbazine, raltitrexed, rituximab, streptozotocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vinblastine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estradiol, hexamethylmelamine, fluorouracil, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxymyotrophic lateral tincture, calcitriol, pentorubicin, photomycin, vincristine Vinorelbine, Topotecan, Rivaroxin, Marimastat, COL-3, Neovastatin, BMS-275291, Squalamine, Endostatin, SU5416, SU6668, EMD121974, Interleukin-12, IM862, Angiostatin, Vitaxin, Droloxifen, Idoxyfene, Spironolactone, Finasteride, Cimetidine, Trastuzumab, Dernixetine, Gefitinib, Bortezimib, Paclitaxel, Clemotaxel, Docetaxel, Epithilone B) BMS-247550, BMS-310705, Droxifen, 4-Hydroxytamoxifen, Piperoxifen, ERA-923, Azoxifen, Fulvestrant, Acobifen, Lasoxifen, Edocifen, TSE-424, HMR-3339, ZK186619, Topotecan, PTK787 / ZK 222584, VX-745, PD 184352, Rapamycin, 40-O-(2-Hydroxyethyl)-Rapamycin, Tansirolimus, AP-23573, RAD001, ABT-578BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, Wolman penicillin, ZM336372, L-779,450, PEG-filgrastim, dabepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histamine relin Pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, medroxyprogesterone acetate, immunoglobulin, nitrogen mustard, methylprednisolone, ibritgumomab Tiuxetan), androgens, decitabine, hexamethyl melamine, bexarotin, tocetolimab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Erwinia asparaginase, strontium-89, caspitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, fluphenazine, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, alfabepoline, alfadabepoline, and mixtures thereof.

[0751] In some embodiments, the bioactive agent is selected from, but is not limited to, imatinib mesylate. Dasatinib Nilotinib Bosutinib Trastuzumab Trastuzumab-DM1, Pertuzumab (Perjeta™), Lapatinib Gefitinib Erlotinib cetuximab Panitumumab Van der Thani Verofenib Vorinostat Romidesin Besarodine Alivenic acid Retinoic acid Carfilizomib (Kyprolis™), Pratroxa bevacizumab Ziv-Abersipu Sorafenib Sunitinib Pazopanib Regorafenib And cabozantinib (Cometriq™).

[0752] In some respects, bioactive agents are anti-inflammatory agents, chemotherapeutic agents, radiotherapy agents, other therapeutic agents, or immunosuppressants.

[0753] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxic agents, which include any agent harmful to cell viability), and liposomes or other vesicles containing chemotherapeutic compounds. Common anticancer agents include: vincristine. Or liposomal vincristine Daunorubicin (daunorubicin or) Or Dorothy Star Cytarabine (cytosine arabinoside, ara-C or...) L-asparaginase Or PEG-L-asparaginase (pegaspargase or Etoposide (VP-16), Teniposide 6-Mercaptopurine (6-MP or Methotrexate, cyclophosphamide Prednisone, Dexamethasone (Decadron), Imatinib Dasatinib Nilotinib Bosutinib and punatinib (Iclusig) TMOther suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aldehyde-interleukin, alkylating agents, allopurinol sodium, hexamethylmelamine, amifostine, anastrozole, amiodarone (AMC), antimitotic agents, cis-dichlorodiamineplatin(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracycline, antimetabolites, asparaginase, live BCG (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucovorin. Leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogen, cyclophosphamide, cyclothosphamide, cytarabine, cytarabine, cytochalasin B, cytoxan, dacarbazine, cytosine, actinomycin D (original) (Cytoxin), daunorubicin hydrochloride, daunorubicin citrate, dinitroleukin, dexrazoxane, dibromomannitol, dihydroxyanthradinone, docetaxel, dolasetron methanesulfonate, doxorubicin hydrochloride, drocannabinol, Escherichia coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogen, estradiol, estradiol sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, etoposide tetrahydrofolate (citrororum) Factor), etoposide phosphate, filgrastim, fluorouridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, leucovorin, gemcitabine hydrochloride, glucocorticoids, goserelin acetate, bacitracin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alpha-2b, irinotecan hydrochloride, letrozole, calcium leucovorin, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansine, nitrogen mustard hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methylphenidate Aminoplastin, methyltestosterone, photomycin, mitomycin C, mitotane, mitoxantrone, nilumethicone, octreotide acetate, ondansetron hydrochloride, paclitaxel, disodium pamidronate, pentostatin, pilocarpine hydrochloride, priloin, carmustine polyphenylpropionate 20 implant, porphyrin sodium, procaine, procarbazine hydrochloride, propranolol, rituximab, saxaglastine, streptozotocin, tamoxifen, paclitaxel, tenoposide, tenoposide, testosterone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan hydrochloride, toremifene citrate, trastuzumab, retinoic acid, pentorubicin, vincristine sulfate, vinorelbine sulfate, and vinorelbine tartrate.

[0754] In some embodiments, the compounds of the present invention are administered in combination with chemotherapeutic agents (e.g., cytotoxic agents or other chemical compounds that can be used to treat cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxin, antibiotics, L-asparaginase, topoisomerase inhibitors, interferon, platinum coordination complexes, anthrone-substituted ureas, methylhydrazine derivatives, adrenocorticosteroids, adrenocorticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel, and docetaxel.Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piperazine; aziridines such as phenyldopa, carboquinone, metoprolol, and uradopa; ethyleneimine and methylmelamine, including hexamethylmelamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide, and tris(hydroxymethylmelamine); acetogenins (especially bratacin and bratacinone); camptothecin (including its synthetic analogue topotecan); lichenin; callystatin; CC-1065 (including its synthetic analogues adolexin, calcexin, and bizexin); nostocin ( Especially nostocin 1 and nostocin 8); dolalastatin; pyruvic oxytocin (including synthetic analogs, KW-2189 and CB1-TM1); eleutheroside; silicodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthylambucil, chlorphosphamide, estradiol, ifosfamide, methyl chloroethylamine, methyl chloroethylamine hydrochloride oxide, melphalan, neo-embezzin, benzethonol, prednimustine, trazophos, uramustine; nitroureides such as carmustine, chlorzoxazone, flumustine, lomustine, nimustine, and ranistine; antibiotics such as enediyne antibiotics (e.g., galicarmycin, especially galicarmycin γ11 and galicarmycin ω11 (see, e.g., Agnew, Chem. Inti. Ed.) Engl. 33:183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clophosphonate; esperamicin; and neocarzinostatin chromophore and related chromogenic chromophores of ethynylene antibiotics), aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine. (Doxorubicin, including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrololino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin (e.g., mitomycin C), mycophenolic acid Drugs containing citric acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); and folic acid analogues, such as folate (deoxyfolic acid). Pterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine; and androgens such as calusterone and dromostanolone. Propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergic agents, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as frolinic acid; aceglatone; aldophosphamide glycoside;Aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate); epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; Polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid acid); triaziquone; 2,2',2”-trichlorotriethylamine; trichothecene (especially T-2 toxin, verrucarin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, such as (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ) Cremophor-free, albumin-engineered paclitaxel nanoparticle formulations (American Pharmaceutical Partners, Schaumberg, IL) and Docetaxel (Rhone-Poulenc Rorer, Antony, France); Chlorobutyrate; Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vincristine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Vinorelbine; Novantoron; Teniposide; Idatroxa; Donomycin; Aminopterin; Xeloda; Ibandronic acid; Irinotecan (e.g., CPT-11); topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoic acid such as retinoic acid; Capecitabine; and any pharmaceutically acceptable salts, acids, or derivatives of the foregoing agents. Two or more chemotherapeutic agents may be used in mixtures administered in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al., Proc. Am. Soc. Clin. Oncol. 18:233a (1999) and Douillard et al., Lancet 355 (9209):1041-1047 (2000).

[0755] Other therapeutic agents that can be administered in combination with the compounds disclosed herein may include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vataranib, vandetanib, aflibercept, volociximab, irapizumab (MEDI-522), silengimetide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, ataseptiprazole, rituximab, alemtuzumab, and aldine. Anti-aldesleukine, atelizumab, tocilizumab, tansirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atipremod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate sulfate), belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifofoxine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, barbiturates Doxofenadine, AZD4547, rilotumab, oxaliplatin, PD0332991, ribociclib (LEE011), amicacilib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0756] In some implementations, an additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to antibodies naturally produced by B cells, these MAbs can “coat” the surface of cancer cells, thereby triggering their destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes tumor angiogenesis. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, thus blocking the signaling that leads to new blood vessel growth. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They can also trigger apoptosis and activate the immune system to destroy tumor cells.

[0757] In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, such as cyclosporine or ascomycin, such as cyclosporine A. FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or its derivatives such as sirolimus Everolimus Tansirolimus, Zotalolimus, Biolimus-7, Biolimus-9, rapalog (e.g., ridaforolimus), azathioprine, Campasz1H, S1P receptor modulators (e.g., fingolimod or its analogues), anti-IL-8 antibodies, mycophenolic acid or its salts (e.g., sodium salt), or their prodrugs (e.g., mycophenolate mofetil). OKT3 (ORTHOCLONE) ),prednisone, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyguanidin, tropelimide, leflunomide CTLAI-Ig, anti-CD25, anti-IL2R, balithiba Daklizumab mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecris), ), CTLA4l...

Claims

1. A pharmaceutical composition comprising not more than 500 micrograms (μg) of an effective low-dose compound for the treatment of multiple myeloma or lymphoma mediated by Ikaros and / or Aiolos, wherein said compound is: ， Or a pharmaceutically acceptable salt thereof, and said pharmaceutical composition is formulated for administration once daily (QD) or twice daily (BID).

2. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 400 µg.

3. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 300 µg.

4. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 200 µg.

5. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 100 µg.

6. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 50 µg.

7. The pharmaceutical composition of claim 1, wherein the dosage of the compound is not more than 25 µg.

8. The pharmaceutical composition of claim 1, wherein the dosage is no more than 75 µg of the compound.

9. A pharmaceutical composition comprising not more than 500 micrograms (μg) of an effective low-dose compound for the treatment of multiple myeloma or lymphoma mediated by Ikaros and / or Aiolos, wherein said compound is: ， Or a pharmaceutically acceptable salt thereof, and said pharmaceutical composition is formulated for administration once daily (QD) or twice daily (BID).

10. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition is for the treatment of diffuse large B-cell lymphoma.

11. The pharmaceutical composition of claim 10, wherein the diffuse large B-cell lymphoma is an activated B-cell lymphoma.

12. The pharmaceutical composition of claim 10, wherein the diffuse large B-cell lymphoma is a germinal center B-cell lymphoma.

13. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is for the treatment of anaplastic large cell lymphoma.

14. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition is for the treatment of cutaneous T-cell lymphoma.

15. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is for treating mantle cell lymphoma.

16. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition is for the treatment of multiple myeloma.

17. The pharmaceutical composition of claim 1, wherein the multiple myeloma or lymphoma is resistant to treatment with a first-generation IMiD drug.

18. The pharmaceutical composition of claim 17, wherein the multiple myeloma or lymphoma is resistant to thalidomide treatment.

19. The pharmaceutical composition of claim 17, wherein the multiple myeloma or lymphoma is resistant to pomalidomide treatment.

20. The pharmaceutical composition of claim 17, wherein the multiple myeloma or lymphoma is resistant to lenalidomide treatment.

21. The pharmaceutical composition of claim 17, wherein the multiple myeloma or lymphoma is resistant to iberdomide treatment.

22. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or is co-administered with, a Bruton's tyrosine kinase inhibitor.

23. The pharmaceutical composition of claim 22, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

24. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or is co-administered with, a corticosteroid.

25. The pharmaceutical composition of claim 24, wherein the corticosteroid is dexamethasone.

26. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or is co-administered with, CAR T-cell therapy.

27. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises an antibody-drug conjugate, or is co-administered therewith.

28. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administers with, BiTE (bispecific T-cell conjugate protein) therapy.

29. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition is co-administered with bonatetumab.

30. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is co-administered with CC-93269.

31. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises a bispecific antibody, or is co-administered therewith.

32. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises a monoclonal antibody, or is co-administered therewith.

33. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administered with, a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, toolebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

34. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administered with, a CD38 antibody selected from phenzartuzumab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129 and mizartuzumab.

35. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administered with, a proteasome inhibitor selected from esazolidin citrate, opzomib, delanzomib, lactosomalin, bortezomib, carfilzomib, VLX1570, cyclooxygenase, MG132, MG-262, NEOSH101, TQB3602, and KZR-616.

36. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or is co-administered with, pomalidomide, lenalidomide, thalidomide, iberlidomide, CC-92480, CC-90009 and CC-99282.

37. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administered with, an HDAC inhibitor selected from trapoxin B, sodium chlorate, acetyldenalin, moxitistat, BRD73954, BG45, domastartar, cay10603, HPOB, TMP269, nexturastat A, Santacruzamate A, splitomicin, LMK-235, sodium butyrate, neopentyloxymethyl butyrate, pyroxamide, abexinostat, resminost, givinostat, quisinostat, Psammaplin A, KD5170, 1-alanine chlamydin, depudecin, and CUDC-101.

38. The pharmaceutical composition of any one of claims 1-9, wherein the pharmaceutical composition further comprises, or co-administered 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, ulocuplumab, and urelumab.

39. The pharmaceutical composition according to any one of claims 1-9, wherein the lymphoma is non-Hodgkin lymphoma.

40. The pharmaceutical composition of any one of claims 1-9, wherein the multiple myeloma or lymphoma is recurrent.

41. The pharmaceutical composition according to any one of claims 1-9, wherein the multiple myeloma or lymphoma is refractory.

42. The pharmaceutical composition according to any one of claims 1-9, wherein the multiple myeloma or lymphoma is relapsed and refractory.

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