Morphic forms of CFT7455 and methods for their manufacture

Abstract

An advantageous morphic form of compound (1), also known as CFT7455, is (S)-3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione, and methods for preparing compound 1 for therapeutic use are provided. The present invention also provides new dosing regimens for administering compound (1).

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of China Provisional Patent Application No. 202210119643.2, filed February 9, 2022, U.S. Provisional Patent Application No. 63 / 308,883, filed February 10, 2022, U.S. Provisional Patent Application No. 63 / 328,659, filed April 7, 2022, and U.S. Provisional Patent Application No. 63 / 437,718, filed January 8, 2023, each of which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention provides advantageous isolated morphic forms of Compound 1, also known as CFT7455 or (S)-3-(6-(4-(morpholinomethyl)benzyl)-2-oxobenzo[cd]indol-1(2H)-yl)piperidine-2,6-dione, and methods of preparing Compound 1 for therapeutic use as further described herein. The present invention also provides new dosing regimens for administering Compound 1. [Background technology]

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

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

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

[0006] Multiple myeloma (MM) is a plasma cell malignancy typically characterized by abnormal production of monoclonal immunoglobulins, bone marrow involvement, renal dysfunction, immune dysfunction, and skeletal damage. In the United States, MM accounts for approximately 1.8% of all new cancers. Although outcomes for subjects with MM have improved considerably over the past few decades, it remains incurable, with a current predicted 5-year relative survival rate of 53.9%. Available therapies are not curative, and almost all patients eventually progress.

[0007] Historically, management of MM included chemotherapy with corticosteroids and alkylating agents. In the 1980s, further advances in treatment with autologous stem cell transplantation were made. In the 1990s, the discovery of the efficacy of thalidomide (a first-in-class immunomodulatory imid drug ("IID"), also called IMiD™ or IMiDs™) in myeloma significantly changed treatment regimens and improved patient outcomes. Subsequent approved IIDs, lenalidomide and pomalidomide, are now widely used to treat MM, as is the first-in-class agent, thalidomide. This class of agents binds to the E3 ligase substrate recognition adaptor protein cereblon (CRBN) and promotes degradation of Ikaros (IKZF1) and Aiolos (IKZF3), resulting in antitumor effects, effects on the tumor microenvironment, and immune modulation leading to T-cell priming and antitumor activity. Many patients with MM are treated with multiple regimens that include one of these IIDs. Currently, these drugs, in combination with agents including dexamethasone, cluster of differentiation 38 (CD38) antibodies, and proteasome inhibitors such as bortezomib, are considered the standard of care for the treatment of MM in many types of therapy. Although these agents have been successful in extending progression-free survival in patients with MM, patients commonly relapse and progression-free survival after each relapse shortens. Recent studies with the novel agents belantamab and selinexor have shown improved outcomes in multiclass refractory myeloma, leading to their recent accelerated FDA approval, but the low response rates (26%-31%) and short progression-free survival (3.7-4.9 months) highlight the continuing unmet medical need in these patients.

[0008] Non-Hodgkin's lymphoma (NHL) is a heterogeneous group of lymphoid malignancies derived from T cells, B cells, or NK cells. NHL includes diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt's 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.

[0009] B-cell NHL predominates, whereas T-cell lymphomas are less common. Among patients newly diagnosed with aggressive NHL, chemotherapy-based regimens including cyclophosphamide, vincristine, prednisone, and daunorubicin (referred to as CHOP) remain the mainstay of treatment. In B-cell aggressive lymphomas, a combination of rituximab and CHOP is the primary treatment administered to newly diagnosed patients. In some patients, particularly those with T-cell NHL, initial chemotherapy is followed by autologous stem cell rescue. In the relapsed and refractory population, various targeted agents have been developed, improving treatment options in multiple subtypes of NHL, although these treatment options tend not to be curative. Furthermore, NHL subtypes are biologically heterogeneous, limiting the development of therapeutic agents across a broad range of indications.

[0010] In patients newly diagnosed with aggressive lymphomas, initial treatment is often intensive and administered with curative intent. Other than the addition of rituximab to CHOP in B-cell NHL and brentuximab to CHOP in anaplastic large cell lymphoma (ALCL), other novel targeted agents have not shown improved survival, and therefore no other agents have been approved for the treatment of treatment-naive patients. Recent advances in treatment in relapsed NHL include Bruton's tyrosine kinase (BTK) inhibitors, especially for mantle cell lymphoma (MCL) and more indolent forms of NHL, chimeric antigen receptor T-cell (CAR-T) therapy approved for diffuse large B-cell lymphoma (DLBCL) and MCL, and novel antibody-drug conjugates such as polatuzumab, belantamab, or tafasitamab approved for DLBCL. Recently approved drugs for T-cell NHL include romidepsin, belinostat, and brentuximab. Relevant to the NHL population studied in this protocol, lenalidomide has demonstrated clinical activity in both B-cell and T-cell NHL, including MCL, DLBCL, and peripheral T-cell lymphoma (PTCL). Lenalidomide has been studied in the relapsed / refractory (r / r) MCL population and was approved by the US Food and Drug Administration (FDA) in June 2013 following the results of the Phase II EMERGE trial, which investigated the efficacy and safety of lenalidomide in r / r subjects with MCL following bortezomib (overall response rate [ORR] 28%, median duration of response [DOR] 16.6 months). Lenalidomide also shows activity in DLBCL and PTCL. Lenalidomide and other novel targeted therapies have moderate to good response rates, although the durability of responses tends to be short in most NHL subtypes. Once patients relapse after one or two treatment regimens, the median duration of response tends to be low and depends on the patient having sufficient performance status and organ function to tolerate these treatments. Thus, there remains an unmet medical need for patients with r / rNHL.

[0011] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). 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 response and inflammation, neuronal and muscular degradation, morphogenesis of neural networks, regulation of cell surface receptors, ion channels, and secretory pathways, response to stress and extracellular modulators, ribosome biogenesis, and viral infection. Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases marks the protein for proteasomal degradation, where it is digested into small peptides and ultimately into constituent amino acids that serve as building blocks for new proteins. Defects in proteasomal degradation have been associated with a variety of clinical disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophies, cardiovascular disease, and cancer, among others.

[0012] Patent applications describing certain protein degrading agents include U.S. Patent Nos. 5,393, 6,433, 6,571, 6,671, 6,713, 6,891, 7,943, 7,133, 7,146, 7,192, 7,171, 7,213, 7,227, 7,376, 7,281, and 5,363, 6,471.

[0013] Patent applications filed by C4 Therapeutics, Inc. describing compounds capable of binding to E3 ubiquitin ligases and targeting proteins for degradation include the following: U.S. Patent No. 5,399,433 entitled "Compounds for Targeted Degradation of RET"; U.S. Patent No. 5,399,433 entitled "Compounds for Targeting the Degradation of Bruton's Tyrosine Kinase"; U.S. Patent No. 5,399,433 entitled "EGFR Degraders for Treating Cancer Metastasis to the Brain or CNS"; U.S. Patent No. 5,399,433 entitled "Therapeutic Agents for Degrading Mutant BRAF"; U.S. Patent No. 5,399,433 entitled "Isoindolinone and Indoazole Compounds for Degradation of EGFR"; U.S. Patent No. 5,399,433 entitled "Bifunctional Compounds"; U.S. Patent No. 5,399,433 entitled "Bifunctional Compounds for the Treatment of Cancer"; U.S. Patent No. 5,399,433 entitled "Ikaros and Aiolos Tricyclic Degradation Inducers"; U.S. Patent No. 5,399,433 entitled "Heterocyclic Compounds for Medical Treatment"; U.S. Patent No. 5,399,433 entitled "Targeted Protein Degradation Inducers for the Treatment of Cancer"; US Patent No. 5,399,663 entitled "Cereblon Binding Agents for the Degradation of Ikaros"; US Patent No. 5,399,663 entitled "Spirocyclic Compounds"; US Patent No. 5,399,663 entitled "Compounds for the Degradation of BRD9 or MTH1"; US Patent No. 5,399,663 entitled "Cereblon Binding Agents for the Degradation of Ikaros"; US Patent No. 5,399,663 entitled "Spirocyclic Compounds"; US Patent No. 5,399,663 entitled "Degraders and Degrons for Targeted Protein Degradation"; US Patent No. 5,399,663 entitled "N / O-Linked Degrons and Degronimers for Protein Degradation"; US Patent No. 5,399,663 entitled "Amine-Linked C3-Glutarimide Degronimers for Target Protein Degradation";US Patent No. 24, entitled "Heterocyclic Degronimers for Target Protein Degradation"; US Patent No. 25, entitled "Spirocyclic Degronimers for Target Protein Degradation"; US Patent No. 26, entitled "C3-Carbon Linked Glutarimide Degronimers for Target Protein Degradation"; and US Patent No. 27, entitled "Bromodomain Targeting Degronimers for Target Protein Degradation".

[0014] Despite these efforts, there remains a need for new therapeutics, including compounds that bind to cereblon and degrade Ikaros (IKZF1) or Aiolos (IKZF3), for use in treating abnormal cell proliferation. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. 2022 / 081928 [Patent Document 2] International Publication No. 2022 / 081927 [Patent Document 3] International Publication No. 2022 / 081925 [Patent Document 4] International Publication No. 2020 / 210630 [Patent Document 5] International Publication No. 2020 / 006262 [Patent Document 6] International Publication No. 2020 / 010227 [Patent Document 7] International Publication No. 2020 / 010177 [Patent Document 8] International Publication No. 2022 / 032026 [Patent Document 9] International Publication No. 2022 / 235945 [Patent Document 10] International Publication No. 2022 / 251539 [Patent Document 11] International Publication No. 2022 / 261250 [Patent Document 12] International Publication No. 2021 / 127561 [Patent Document 13] International Publication No. 2021 / 086785 [Patent Document 14] International Publication No. 2021 / 083949 [Patent Document 15] International Publication No. 2020 / 181232 [Patent Document 16] International Publication No. 2020 / 132561 [Patent Document 17] International Publication No. 2019 / 236483 [Patent Document 18] International Publication No. 2020 / 051235 [Patent Document 19] International Publication No. 2019 / 191112 [Patent Document 20] International Publication No. 2019 / 204354 [Patent Document 21] International Publication No. 2019 / 099868 [Patent Document 22] International Publication No. 2018 / 237026 [Patent Document 23] International Publication No. 2017 / 197051 [Patent Document 24] International Publication No. 2017 / 197055 [Patent Document 25] International Publication No. 2017 / 197036 [Patent Document 26] International Publication No. 2017 / 197046

Patent document 27

Non-licensed literature

[0016] [Non-licensed document 1] Fan, Y. and Lu, D. "The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B, 2016, 6:513-521 [Non-licensed document 2] Georgopoulos, K. et al. "Ikaros, an early lymphoid-specific transcription factor and a putative mediator for T cell commitment" Science, 1992, 258:802-812 [Non-licensed document 3] John, LB, and Ward, AC "The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity" Mol Immunol, 2011, 48:1272-1278

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

[0017] A highly stable crystalline morphic form of Compound 1 has been discovered. This morphic form (Form I) is superior to other morphic forms of Compound 1 due to its high stability, scalability, and reproducibility. For example, when Compound 1 Form I is tested in solvents with high water content, including, for example, acetone / water, DMSO / water, or pure water, there is no significant change in the morphic form (see Example 9). The stability of Compound 1 Form I in high water content systems is a useful property that allows Compound 1 Form I to have an extended shelf life and to have improved purity and reproducibility in manufacturing scale preparations. This property can also be used to modulate the delivery rate of Compound 1 for improved therapeutic efficacy. A method for manufacturing scale production of Compound 1 Form I has also been discovered (see Example 1). [ka]

[0018] Compound 1 (also known as CFT7455) is a small molecule anticancer drug that binds with high affinity to cereblon E3 ligase, thereby creating a new surface on cereblon that interacts with IKZF1 and IKZF3 (see Patent Document 4). As a result, IKZF1 and IKZF3 are efficiently ubiquitinated by cereblon E3 ligase and degraded by the proteasome. The high cereblon binding affinity of Compound 1 allows for rapid, deep, and sustained degradation of IKZF1 / 3, resulting in potent activity in cancer cells, including, but not limited to, hematopoietic cancers such as multiple myeloma and multiple non-Hodgkin's lymphoma.

[0019] Compound 1 is in clinical trials for oral low-dose treatment of multiple myeloma and non-Hodgkin's lymphoma. Compound 1 can be administered at microgram doses of, for example, about 100 micrograms (μg), 95 μg, 90 μg, 85 μg, 80 μg, 75 μg, 70 μg, 62.5 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 37.5 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 12.5 μg, 10 μg, 5 μg, or 1 μg or less to treat cancer and / or certain IKZF1 / 3-sensitive hematological cancers. The present invention provides advantageous stable crystalline morphic forms of Compound 1 for use in therapeutic applications, such as low-dose treatment of cancer, and also provides additional morphic forms for desired uses.

[0020] In one embodiment, Compound 1 Form I is administered to a patient in need thereof, for example as part of a pharmaceutical composition, to treat an Ikaros and / or Aiolos-mediated disorder. In another embodiment, Compound 1 Form I is used in the production of a pharmaceutical composition for administration to a patient in need thereof to treat an Ikaros and / or Aiolos-mediated disorder. For example, Compound 1 Form I can be dissolved in a suitable excipient and then loaded into a gel capsule. Non-limiting examples of excipients that can be used in gel capsules include polyethylene glycol, surfactants such as polysorbates, alcohols such as ethanol, and glycerin. In certain embodiments, Compound 1 Form I is dissolved in PEG-400 and loaded into a gel capsule.

[0021] Also described herein are other morphic forms of Compound 1, including methanol solvate Form II, and hydrate Forms III and IV. In certain embodiments, Compound 1 Form I can be selectively prepared by adding the antisolvents ethanol or 2-propanol to DMSO.

[0022] A morphic form of racemic compound 5 was also discovered. Compound 5 can be separated by chiral chromatography to prepare compound 1. The present invention provides a morphic form of compound 5 with high stability and purity for the preparation of compound 1. Four crystalline forms of compound 5, designated Form V, Form VI, Form VII, and Form VIII, were identified as polymorphs or pseudopolymorphs. Of these four crystalline forms, Form VI can be a hydrate with favorable solubility, chemical stability, and physical stability. Form V is also very stable and can be obtained by equilibration from all solvent systems tested (see Example 14) and by rapid evaporation from benzyl alcohol and THF (see Example 15). [ka]

[0023] In another aspect, a manufacturing-scale method for producing Compound 1 and Compound 5 is provided. The method includes a reactor-scale cross-coupling reaction (Step 1), a nucleophilic substitution (Step 2), a preparative chiral high performance liquid chromatography (HPLC) separation (Step 3), and selective crystallization (Step 4). [ka]

[0024] Compound 1 Form I or pharmaceutical compositions prepared from Compound 1 Form I can be used for oral or parenteral delivery. In certain embodiments, Compound 1 Form I or pharmaceutical compositions prepared from Compound 1 Form I are used for oral delivery. In certain embodiments, pharmaceutical compositions prepared from or including Compound 1 Form I are provided in a solid, gel, or liquid dosage form for oral delivery. In certain embodiments, the solid dosage form is a tablet. In certain embodiments, the dose size of the pharmaceutical composition is at least about 1 μg, 5 μg, 10 μg, 12.5 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 37.5 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 62.5 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 87.5 μg, 90 μg, 95 μg, 100 μg, 125 μg, 150 μg, 17 μg, 20 μg, 25 μg, 26 μg, 27 μg, 28 ... In one non-limiting embodiment, treatment occurs on days 1-14 or days 1-21 of a 28 day treatment cycle and may be given once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or once daily (QD). In certain embodiments, the dosage size of a pharmaceutical composition prepared from or including Compound 1 or Compound 5 is at least about 1 μg, 5 μg, 10 μg, 12.5 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 37.5 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 62.5 μg, 70 μg, 75 μg, 80 μg, 85 μg, 87.5 μg, 90 μg, 95 μg, 100 μg, 120 μg, 140 μg, 160 μg, 170 μg, 180 μg, 190 μg, 200 μg, 210 μg, 220 μg, 230 μg, 240 μg, 250 μg, 260 μg, 270 μg, 280 μg, 290 μg, 300 μg, 310 μg, 320 μg, 330 μg, 340 μg, 350 μg, 360 μg, 370 μg, 380 μg, 390 μg, 400 μg, 410 μg, 420 μg, 430 μg, 440 μg, 450 μg, 460 μg, 470 μg, 480 μg, 490 μg, 500 μg, 510 μg, 520 μg, 530 μg, 540 μg, 550 μg, 550 μg, 560 μg, 570 μg, 580 μg, 590 μg In one non-limiting aspect, treatment occurs on days 1-14 or days 1-21 of a 28 day treatment cycle and may be given once weekly, twice weekly, three times weekly, four times weekly, five times weekly, six times weekly, or once daily (QD).

[0025] The compound may be provided, for example, for oral or parenteral delivery. In certain embodiments, the compound may be provided in a solid, gel, or liquid dosage form for oral delivery, or may be provided intravenously or otherwise systemically. In some embodiments, compound 1 Form 1 is provided as a soft shell capsule or tablet for oral administration. In certain embodiments, the dose size of the solid or gel dosage form is about 1 μg, 5 μg, 10 μg, 12.5 μg, 15 μg, 20 μg, 25 μg, 37.5 μg, 50 μg, 62.5 μg, 75 μg, 87.5 μg, or 100 μg, and in one non-limiting aspect, may be given once daily (QD) on days 1 to 14 of a 28-day cycle, QD on Mondays, Wednesdays, and Fridays for the first two weeks of a 28-day cycle, QD on days 1 to 7 of a 21-day cycle, or QD on days 1 to 21 of a 28-day cycle.

[0026] In certain aspects, the selected dosage form of Compound 1, Compound 1 Form I, or pharmaceutical composition comprising Compound 1 is determined by monitoring blood sampling to confirm neutrophil status, and the dose can then be adjusted as necessary to avoid unacceptable neutropenia or other reduction in blood cell levels. The resulting dosage may be administered for less than 21 days in a cycle, for example, for a total of 28 or 21 days, followed by a cycle of several days of administration followed by several days of rest, for example, 1, 2, 3, 4, 5, or 6 days per week, repeated for 1, 2, 3, or 4 weeks. In other embodiments, Compound 1 is administered for several days over 1, 2, or 3 weeks in a treatment cycle, followed by several days of rest, followed by a 1, 2, or 3 week rest period. In certain embodiments, Compound 1 is administered every other day. In certain embodiments, Compound 1 is administered at very low doses, for example, less than about 87.5 μg, 75 μg, 62.5 μg, 50 μg, 37.5 μg, 25 μg, 20 μg, 15 μg, 12.5 μg, 10 μg, 5 μg, and 1 μg, every day of a treatment cycle.

[0027] In certain aspects, a new dosing regimen for the treatment of cancer is provided, which comprises administering Compound 1 or a pharma- ceutically acceptable salt thereof, Compound 1 Form I, or a pharmaceutical composition comprising Compound 1 to a patient in need thereof (a) once daily for 14 consecutive days followed by a 14-day dosing period in a 28-day treatment cycle, (b) once daily for 14 days on selected three days per week, e.g., Monday, Wednesday, and Friday, followed by a 14-day dosing period in a 28-day treatment cycle, or (c) once daily for 7 consecutive days followed by a 14-day dosing period in a 21-day treatment cycle. In certain embodiments, the treatment cycle is repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more times. In certain embodiments, Compound 1 is provided in a dose of about 1 μg, 5 μg, 10 μg, 12.5 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 37.5 μg, 40 μg, 45 μg, 50 μg, 62.5 μg, 75 μg, 87.5 μg, or 100 μg. In certain embodiments, Compound 1 is provided in a dose of at least about 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 75 μg, 87.5 μg, or 100 μg. In certain embodiments, Compound 1 is provided in a dose of less than about 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 75 μg, 87.5 μg, or 100 μg. In certain embodiments, Compound 1 is provided in a dose of about 50 μg, 62.5 μg, or 75 μg.

[0028] In certain embodiments, Compound 1 is used to modulate the activity of the immune system, for example to activate IFN-alpha, IFN-beta, or IFN-gamma. By activating the immune system, the compound can more effectively treat cancer. This immunomodulatory activity may enhance the effectiveness of Compound 1 in combination with another anti-cancer drug, such as daratumumab.

[0029] In certain embodiments, Compound 1 is used to cause degradation of IKZF1 and IKZF3 from malignant B or T cells, resulting in tumor cell death, potentially resulting in depletion of IKZF1 and IKZF3 from the tumor microenvironment and activating T cells.

[0030] The dosing regimen of Compound 1 described herein can be used to treat cancer. Non-limiting examples of cancer include multiple myeloma, non-Hodgkin's lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma. In certain embodiments, Compound 1 is administered as a monotherapy. In other embodiments, Compound 1 is administered as part of a two-drug or three-drug combination.

[0031] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

[0032] Thus, the present invention includes at least the following features: (a) a morphic form of Compound 1 or Compound 5 described herein; (b) Compound 1 Form I; (c) Compound 5 Form V; (d) Compound 5 Form VI; (e) a pharmaceutical composition comprising a compound according to any one of embodiments (a)-(d); (f) a pharmaceutical composition prepared from a compound of any one of embodiments (a)-(d), e.g., a composition comprising a liquid excipient in which Compound 1 Form I is dissolved in the excipient; (g) A method for treating a disorder mediated by Ikaros or Aiolos comprising administering an effective amount of a compound or pharmaceutical composition of any one of embodiments (a)-(f). (h) the method of (g), wherein the compound or pharmaceutical composition of any one of embodiments (a)-(f) is administered once daily for 21 days, followed by a 7-day treatment rest period, in a (a) 28-day treatment cycle; (i) A method for treating a disorder mediated by Ikaros or Aiolos comprising administering an effective amount of Compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f), wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, in a 28-day treatment cycle, followed by administration of an effective amount of the compound or pharmaceutical composition in ... (b) once daily on selected 3 days per week, e.g., Monday, Wednesday and Friday, for 14 days followed by a 14-day dosing rest period in a 28-day treatment cycle; (c) once daily for 7 consecutive days followed by a 14-day dosing rest period in a 21-day treatment cycle; or (d) once daily on Monday, Wednesday and Friday followed by a 14-day dosing rest period in a 28-day treatment cycle; (j) The method of (i), wherein compound 1 is administered at a dose of about 10 μg to about 75 μg. (k) The method of (i), wherein compound 1 is administered at a dose of about 25 μg to about 75 μg. (l) The method of (i), wherein compound 1 is administered at a dose of about 50 μg to about 75 μg. (m) The method of (i), wherein compound 1 is administered at a dose of about 50 μg to about 100 μg. (n) a compound or pharmaceutical composition according to any one of embodiments (a)-(f) for use in the treatment of a disorder mediated by Ikaros or Aiolos; (o) Compound 1 or the compound or pharmaceutical composition of any one of embodiments (a)-(f) for use in the treatment of a disorder mediated by Ikaros or Aiolos, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, in a 28-day treatment cycle, followed by a 14-day dosing period. (b) administered once daily on selected three days per week, e.g., Monday, Wednesday, and Friday, for 14 days, followed by a 14-day dosing period in a 28-day treatment cycle, (c) administered once daily for 7 consecutive days, followed by a 14-day dosing period in a 21-day treatment cycle, or (d) administered once daily on Monday, Wednesday, and Friday, followed by a 14-day dosing period in a 28-day treatment cycle; (p) use of a compound or pharmaceutical composition according to any one of embodiments (a) to (f) for the treatment of a disorder mediated by Ikaros or Aiolos; (q) use of a compound or pharmaceutical composition according to any one of embodiments (a)-(f) in the manufacture of a medicament for the treatment of a disorder mediated by Ikaros or Aiolos; (r) Use of compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f) for the treatment of a disorder mediated by Ikaros or Aiolos, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days at a dose of about 12.5 μg to about 100 μg, for example about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, in a 28-day treatment cycle, followed by a 14-day treatment holiday. (b) once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days, followed by a 14-day dosing period, in a 28-day treatment cycle; (c) once daily for 7 consecutive days, followed by a 14-day dosing period, in a 21-day treatment cycle; or (d) once daily on Monday, Wednesday, and Friday, followed by a 14-day dosing period, in a 28-day treatment cycle; (s) Use of Compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f) in the manufacture of a medicament for the treatment of a disorder mediated by Ikaros or Aiolos, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days at a dose of about 12.5 μg to about 100 μg, for example about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, in a 28-day treatment cycle, followed by administration of the compound or pharmaceutical composition ... (b) once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days, followed by a 14-day dosing period in a 28-day treatment cycle; (c) once daily for 7 consecutive days, followed by a 14-day dosing period in a 21-day treatment cycle; or (d) once daily on Monday, Wednesday, and Friday, followed by a 14-day dosing period in a 28-day treatment cycle; (t) a method for treating cancer comprising administering an effective amount of a compound or pharmaceutical composition of any one of embodiments (a)-(f); (u) the method of (t), wherein the compound or pharmaceutical composition of any one of embodiments (a)-(f) is administered (a) once daily for 14 consecutive days in a 28 day treatment cycle, followed by a 14 day dosing period, or (b) once daily for 21 days in a 28 day treatment cycle, followed by a 7 day dosing period; (v) a compound or pharmaceutical composition according to any one of embodiments (a)-(f) for use in the treatment of cancer; (w) Use of a compound or pharmaceutical composition according to any one of embodiments (a) to (f) for the treatment of cancer: (x) use of a compound or pharmaceutical composition of any one of embodiments (a)-(f) in the manufacture of a medicament for the treatment of cancer; (y) a method for treating cancer comprising administering an effective amount of Compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f), wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days in a 28 day treatment cycle at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, followed by a 14 day treatment rest period; (b) administered once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days in a 28 day treatment cycle, followed by a 14 day treatment rest period; (c) administered once daily for 7 consecutive days in a 21 day treatment cycle, followed by a 14 day treatment rest period, or (d) administered once daily on Monday, Wednesday, and Friday, followed by a 14 day treatment rest period in a 28 day treatment cycle; (z) Compound 1 or the compound or pharmaceutical composition of any one of embodiments (a)-(f) for use in the treatment of cancer, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days in a 28 day treatment cycle at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, followed by a 14 day dosing period; (b) administered once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days in a 28 day treatment cycle, followed by a 14 day dosing period; (c) administered once daily for 7 consecutive days in a 21 day treatment cycle, followed by a 14 day dosing period; or (d) administered once daily on Monday, Wednesday, and Friday in a 28 day treatment cycle, followed by a 14 day dosing period; (aa) use of compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f) for the treatment of cancer, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days in a 28 day treatment cycle at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, followed by a 14 day dosing period; (b) administered once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days in a 28 day treatment cycle, followed by a 14 day dosing period; (c) administered once daily for 7 consecutive days in a 21 day treatment cycle, followed by a 14 day dosing period; or (d) administered once daily on Monday, Wednesday, and Friday, followed by a 14 day dosing period, in a 28 day treatment cycle; (bb) use of Compound 1 or a compound or pharmaceutical composition of any one of embodiments (a)-(f) in the manufacture of a medicament for the treatment of cancer, wherein the compound or pharmaceutical composition is (a) administered once daily for 14 consecutive days in a 28 day treatment cycle at a dose of about 12.5 μg to about 100 μg, e.g., about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg, followed by a 14 day dosing period; (b) administered once daily on selected 3 days per week, e.g., Monday, Wednesday, and Friday, for 14 days in a 28 day treatment cycle, followed by a 14 day dosing period; (c) administered once daily for 7 consecutive days in a 21 day treatment cycle, followed by a 14 day dosing period, or (d) administered once daily on Monday, Wednesday, and Friday, followed by a 14 day dosing period, in a 28 day treatment cycle; (cc) a method for treating hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma, comprising administering an effective amount of a compound or pharmaceutical composition according to any one of embodiments (a)-(f); (dd) a compound or pharmaceutical composition of any one of embodiments (a)-(f) for use in the treatment of a hematological malignancy, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma; (ee) use of a compound or pharmaceutical composition according to any one of embodiments (a)-(f) for the treatment of hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma; (ff) use of a compound or pharmaceutical composition according to any one of embodiments (a) to (f) in the manufacture of a medicament for the treatment of hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma; and (gg) A method for preparing compound 1 Form I described herein. [Brief description of the drawings]

[0033] [Figure 1] 1 shows the XRPD pattern of Compound 1 Form I. The XRPD pattern of Form I exhibits sharp peaks, indicating that the sample is composed of crystalline material. [Diagram 2] FIG. 2 shows the XRPD pattern of Compound 1 Form II. [Diagram 3] FIG. 2 shows the XRPD pattern of Compound 1 Form III. [Figure 4] FIG. 2 shows the XRPD pattern of Compound 1 Form IV. [Diagram 5] FIG. 2 shows the XRPD pattern of compound 5 form V. [Figure 6] FIG. 2 shows the XRPD pattern of Compound 5 Form VI. [Figure 7] FIG. 2 shows the XRPD pattern of compound 5 form VII. [Figure 8] FIG. 2 shows the XRPD pattern of compound 5 Form VIII. [Figure 9] FIG. 1 shows XRPD overlay patterns of Form V, Form VI, Form VII, and Form VIII of Compound 5. [Figure 10] FIG. 1 shows the treatment regimen used to orally dose five patients with Compound 1 and the observed responses. Patients were treated as described in Example 24. Responses (SD=stable disease, and PD=progressive disease) were determined using the International Myeloma Working Group (IMWG) Unified Response Criteria. The x-axis is time in weeks. [Figure 11] FIG. 1 shows neutrophil concentrations in five patients treated with Compound 1. Patients were treated as described in Example 24. The x-axis is time in days and the y-axis is concentration in 109 / L. [Figure 12] Figure 1 shows the concentrations of Compound 1 in five patients treated with Compound 1. Patients were treated as described in Example 24. The x-axis is time in hours and the y-axis is concentration in ng / mL. [Figure 13]Figure 1 shows concentrations of Ikaros and Aiolos in patient 2. The patient was treated as described in Example 24. The y-axis is degradation in % compared to baseline and the x-axis is time measured in days. [Figure 14] Figure 1 shows concentrations of Ikaros and Aiolos in patient 4. The patient was treated as described in Example 24. The y-axis is resolution in % compared to baseline and the x-axis is time measured in days. [Figure 15] Figure 1 shows concentrations of Ikaros and Aiolos in patient 5. The patient was treated as described in Example 24. The y-axis is degradation in % compared to baseline and the x-axis is time measured in days. [Figure 16] FIG. 2 shows the percent change in dFLC as defined in Example 25 for patients treated with Compound 1 (see Example 24). The y-axis is the percent change in dFLC and the x-axis is the concentration of Compound 1 as measured by area under the curve (AUC) at day 15 measured in time x ng / mL. [Figure 17] FIG. 1 shows the concentrations of Compound 1 and CC-92480 in tumor or plasma in a xenograft study when dosed as described in Example 26. The y-axis is concentration in ng / mL (plasma) and ng / g (tumor) and the x-axis is time measured in hours. [Figure 18] FIG. 1 shows the concentration of IKZF3 remaining after administration of Compound 1, CC-92480, or pomalidomide in the xenograft study described in Example 26. The y-axis is the concentration of IKZF3 remaining measured in percent and the x-axis is time measured in hours. [Figure 19] FIG. 1 shows tumor volume in mice following administration of Compound 1, CC-92480, or pomalidomide in the xenograft study described in Example 26. The y-axis is tumor volume measured in mm3 and the x-axis is time measured in days. [Figure 20]Figure 1 shows the change in body weight after administration of test substances to female CB17 SCID mice bearing OCI-LY10 intracranial xenografts. Data points represent the mean body weight of the group. Error bars represent the standard error of the mean (SEM). Experimental procedures are described in Example 27. [Figure 21] Figure 1 shows the percent body weight (BW) change in an efficacy study. BW change was calculated based on the animal's weight on the first day of grouping. Data points represent group mean percent change in BW. Error bars represent standard error of the mean (SEM). Experimental procedures are described in Example 27. [Figure 22] Figure 1 shows Kaplan-Meier survival curves of mice treated with vehicle, compound 1 at a dose of 10 mg / kg QD, ibrutinib at a dose of 25 mg / kg QD, or a combination of compound 1 at 10 mg / kg QD and ibrutinib at 25 mg / kg QD. The experimental procedure is described in Example 27. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Compound 1 (also known as CFT7455) is a small molecule anticancer drug that binds with high affinity to cereblon E3 ligase, thereby creating a new surface on cereblon that interacts with IKZF1 and IKZF3 (see Patent Document 4). As a result, IKZF1 and IKZF3 are efficiently ubiquitinated by cereblon E3 ligase and degraded by the proteasome. The high cereblon binding affinity of Compound 1 allows for rapid, deep, and sustained degradation of IKZF1 / 3, resulting in potent activity in cancer cells, including, but not limited to, hematopoietic cancers such as multiple myeloma and multiple non-Hodgkin's lymphoma.

[0035] Compound 1 is in clinical trials for oral low-dose treatment of multiple myeloma and non-Hodgkin's lymphoma. Compound 1 can be administered in microgram doses, for example, about 100 micrograms (μg), 95 μg, 90 μg, 85 μg, 80 μg, 75 μg, 70 μg, 67.5 μg, 65 μg, 60 μg, 55 μg, 50 μg, 45 μg, 40 μg, 37.5 μg, 35 μg, 30 μg, 25 μg, 20 μg, 15 μg, 10 μg, 12.5 μg, 5 μg, or 1 μg or less, to treat cancer. The present invention provides stable crystalline morphic forms of Compound 1 for use in therapeutic applications, for example, in low-dose treatment of cancer. [ka]

[0036] Compound 5 is a racemic mixture that is separated to prepare compound 1. The present invention provides a morphic form of compound 5 with high stability and purity for the preparation of compound 1. [ka]

[0037] Compound 1 morphic form Compound 1 as the free base was investigated under a variety of crystallization conditions. Unless otherwise specified, the starting material in each experiment was Form I. Conditions tested included equilibration at 25° C. and 50° C., precipitation by addition of antisolvent, slow evaporation, and crystallization by heating and cooling.

[0038] Four crystalline morphic forms have been identified, including one anhydrate designated Form I, two hydrates designated Form III and Form IV, and one methanol solvate designated Form II.

[0039] Compound 1 Form I Form I is a highly crystalline anhydrate. In certain embodiments, Form I is characterized by an XRPD pattern having one or more peaks within ±0.4° 2-theta of the peaks listed in Peak List No. 1 (see XRPD Method 1 in Example 23).

[0040] TIFF2025505687000007.tif251170TIFF2025505687000008.tif139170

[0041] 1. In certain embodiments, Compound 1 Form I is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, 31.3±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form I is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form I is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 4.8±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 16.4±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 19.2±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 22.9±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 13.5±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 19.6±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 23.2±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 17.8±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 26.5±0.2 degrees 2-theta. 20. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 21.5±0.2 degrees 2-theta.

[0042] In certain embodiments, Form I is characterized by an onset of melting of about 235° C. on a DSC thermogram and / or a melting enthalpy of about 115 J / g. In certain embodiments, Form I is characterized by a weight loss of about 2% at about 225° C. as measured by TGA.

[0043] In certain embodiments, Form I is characterized by a solubility of at least about 50 mg / mL in DMSO when solubilized at about 25° C., as described in Example 2.

[0044] When tested by DSC (see Example 8), Form I had an onset of melting at 233.9° C. and a melting enthalpy of 114 J / g. When tested by TGA (see Example 8), Form I exhibited a weight loss of 2.0% at 225° C. The XRPD of Form I is shown in FIG.

[0045] Precipitation of Compound 1 Form I by Addition of Antisolvent Compound 1 Form I was prepared by anti-solvent crystallization of Compound 1 in DMSO (see Examples 5 and 12) when methanol, water, ethanol, or 2-propanol (IPA) were used as anti-solvents. In certain embodiments, Compound 1 Form I is prepared by anti-solvent addition of ethanol or 2-propanol to DMSO.

[0046] Water activity studies at 25°C The water activity study described in Example 9 was performed to evaluate the stability of Form I in the presence of water. In this study, only Form I was obtained in acetone / water, DMSO / water systems, and pure water, indicating that Form I is stable under high water activity conditions.

[0047] Compound 1 Form II Form II is a crystalline methanol solvate, which was obtained after slow evaporation from MeOH / DCM (vol:vol=1:1) system. 1About 1.0 equivalent of methanol was detected by H-NMR. When tested by DSC (see Example 8), Form II had an onset of desolvation at 103.1° C. When tested by TGA (see Example 8), Form II showed a weight loss of about 7.1% at 125° C. After desolvation, Form I was obtained. The XRPD of Form II is shown in FIG. 2. Form II is characterized by an XRPD pattern (XRPD Method 1 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 2.

[0048] TIFF2025505687000009.tif179170

[0049] 1. In certain embodiments, Compound 1 Form II is characterized by an XRPD pattern having at least three peaks selected from 4.5, 17.9, 27.0, and 31.6±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form II is characterized by an XRPD pattern having at least three peaks selected from 4.5, 17.9, 27.0, and 31.6±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form II is characterized by an XRPD pattern having at least three peaks selected from 4.5, 17.9, 27.0, and 31.6±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein the XRPD comprises a peak at 4.5±0.2 degrees 2-theta. 5. The morphic form of any one of embodiments 1-4, wherein the XRPD comprises a peak at 17.9±0.2 degrees 2-theta. 6. The morphic form of any one of embodiments 1-5, wherein the XRPD comprises a peak at 31.6±0.2 degrees 2-theta. 7. The morphic form of any one of embodiments 1-6, wherein the XRPD comprises a peak at 27.0±0.2 degrees 2-theta.

[0050] In certain embodiments, Form II is characterized by desolvation of methanol on a DSC thermogram at about 105° C. In certain embodiments, Form II is characterized by a weight loss of about 7% at about 125° C. as measured by TGA.

[0051] Compound 1 Form III Form III is a crystalline hydrate, which was obtained after slow evaporation of THF / water (vol:vol=95:5). 1 No residual solvent was detected by H-NMR. When tested by DSC (see Example 8), Form III showed a dehydration peak before melting. When tested by TGA (see Example 8), Form III had a weight loss of about 5.8% (0.4 equivalents of water) at 150° C. No change in form was observed after heating to 150° C. to evaporate water. In some cases, repeated conditions yielded Form IV rather than Form III. For example, Form IV was obtained even though seeds of Form III were added during repeated evaporation experiments. This suggests that Form III may be a metastable form compared to Form IV. The XRPD of Form III is shown in FIG. 3. Form III is characterized by an XRPD pattern (XRPD Method 1 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in peak list number 3.

[0052] TIFF2025505687000010.tif248170TIFF2025505687000011.tif29170

[0053] 1. In certain embodiments, Compound 1 Form III is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.3, 16.1, 16.4, 17.6, 18.1, 18.5, 19.1, 19.5, 19.9, 21.8, 23.1, 25.6, and 27.4±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form III is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.3, 16.1, 16.4, 17.6, 18.1, 18.5, 19.1, 19.5, 19.9, 21.8, 23.1, 25.6, and 27.4±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form III is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.3, 16.1, 16.4, 17.6, 18.1, 18.5, 19.1, 19.5, 19.9, 21.8, 23.1, 25.6, and 27.4±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 4.8±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 23.1±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 19.1±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 16.1±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 13.3±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 18.1±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 16.4±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 17.6±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 18.5±0.2 degrees 2-theta.

[0054] In certain embodiments, Form III is characterized on a DSC thermogram by dehydration before melting, hi certain embodiments, Form III is characterized by a weight loss of about 6% at about 120° C. as measured by TGA.

[0055] Compound 1 Form IV Form IV is a crystalline hydrate. 1 No residual solvent was detected by H-NMR. Form IV showed dehydration peaks before melting by DSC (see Example 8) and a weight loss of about 1.3% (0.4 equivalents of water) at 105° C. by TGA (see Example 8). After dehydration (heating to 150° C.), no change in morphology was observed. The XRPD of Form IV is shown in FIG. 4. Form IV is characterized by an XRPD pattern (XRPD Method 1 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 4.

[0056] TIFF2025505687000012.tif251170TIFF2025505687000013.tif57170

[0057] 1. In certain embodiments, Compound 1 Form IV is characterized by an XRPD pattern having at least three peaks selected from 4.7, 12.3, 13.2, 16.3, 17.8, 18.1, 18.5, 19.9, 21.4, 23.0, 24.3, 25.3, 29.2, and 32.6±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form IV is characterized by an XRPD pattern having at least three peaks selected from 4.7, 12.3, 13.2, 16.3, 17.8, 18.1, 18.5, 19.9, 21.4, 23.0, 24.3, 25.3, 29.2, and 32.6±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form IV is characterized by an XRPD pattern having at least three peaks selected from 4.7, 12.3, 13.2, 16.3, 17.8, 18.1, 18.5, 19.9, 21.4, 23.0, 24.3, 25.3, 29.2, and 32.6±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 4.7±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 18.5±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 16.3±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 18.1±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 19.9±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 13.2±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 17.8±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 23.0±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 12.3±0.2 degrees 2-theta. 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 29.2±0.2 degrees 2-theta.

[0058] In certain embodiments, Form IV is characterized on a DSC thermogram by dehydration before melting, hi certain embodiments, Form IV is characterized by a weight loss of about 1% at about 105° C. as measured by TGA.

[0059] Competitive equilibrium experiments Competitive equilibrium experiments of Form I and Form IV were carried out in THF / water and DMSO / water systems with different water activities to study the interconversion relationship between the hydrate and anhydrous forms (see Example 10). In THF / water systems, Form IV (hydrate) was obtained when the water activity (aw) was 0.6 or higher, and Form I (anhydrous) was obtained when the aw was 0.3 or lower. In DMSO / water systems, all selected water activity mixtures yielded physical mixtures of Form I and Form IV, with Form I predominating in the solid mixtures. It is noteworthy that both hydrate forms were obtained only by recrystallization in THF / water systems, while the anhydrous Form I was very stable alone in water. Thus, the formation of Form IV is solvent and water activity dependent. Form IV is stable in THF / water systems at high water activity.

[0060] Based on the above results, THF plays an important role in the formation of Form IV and the transformation between Form I and Form IV. The dehydration temperature of Form IV was relatively low, below 30 °C. The crystallinity of Form IV decreased after dehydration, even though the hydration-dehydration process was reversible. Form I was stable in equilibrium experiments even in pure water.

[0061] Compound 5 morphic form Compound 5 was investigated under various crystallization conditions to identify potential polymorphs and pseudopolymorphs and to select the metastable polymorph in terms of solubility and stability for chiral separation. Unless otherwise stated, the starting material in each experiment was Form V. Conditions tested included equilibration at 25° C., rapid cooling, rapid evaporation, and addition of antisolvent.

[0062] Four crystalline forms of compound 5 were identified as polymorphs or pseudopolymorphs. They are designated Form V, Form VI, Form VII, and Form VIII. An amorphous form was also obtained by rapid evaporation from chloroform.

[0063] Compound 5 Form V Form V is a potential hydrate. It was obtained by equilibration from all solvent systems tested (see Example 14) and by flash evaporation from benzyl alcohol and THF (see Example 15). Form V is crystalline. DSC (see Example 21) showed a dehydration peak at 38.5° C. and an endothermic peak at 220.0° C. TGA (see Example 21) showed a weight loss of about 5.1% at about 140° C. The XRPD of Form V is shown in FIG. 5. In certain embodiments, Form V is characterized by an XRPD pattern (XRPD Method 2 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 5.

[0064] TIFF2025505687000014.tif192170

[0065] 1. In certain embodiments, Compound 1 Form V is characterized by an XRPD pattern having at least three peaks selected from 4.7, 9.4, 12.3, 14.3, 16.2, 16.4, 17.6, 18.0, 18.7, 19.6, 20.3, 21.5, 22.6, 22.9, 24.8, 25.6, 26.2, 26.9, 28.0, 28.9, 29.2, 29.8, 31.8, 32.5, 33.0, and 33.2±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form V is characterized by an XRPD pattern having at least three peaks selected from 4.7, 9.4, 12.3, 14.3, 16.2, 16.4, 17.6, 18.0, 18.7, 19.6, 20.3, 21.5, 22.6, 22.9, 24.8, 25.6, 26.2, 26.9, 28.0, 28.9, 29.2, 29.8, 31.8, 32.5, 33.0, and 33.2±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form V is characterized by an XRPD pattern having at least three peaks selected from 4.7, 9.4, 12.3, 14.3, 16.2, 16.4, 17.6, 18.0, 18.7, 19.6, 20.3, 21.5, 22.6, 22.9, 24.8, 25.6, 26.2, 26.9, 28.0, 28.9, 29.2, 29.8, 31.8, 32.5, 33.0, and 33.2±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 22.9±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 26.2±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 17.6±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 18.7±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 22.6±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 19.6±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 21.5±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 18.0±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 24.8±0.2 degrees 2-theta. 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 16.2±0.2 degrees 2-theta. 21. The morphic form of any one of embodiments 1-20, wherein the XRPD comprises a peak at 16.4±0.2 degrees 2-theta. 22. The morphic form of any one of embodiments 1-21, wherein the XRPD comprises a peak at 25.6±0.2 degrees 2-theta. 23. The morphic form of any one of embodiments 1-22, wherein the XRPD comprises a peak at 20.3±0.2 degrees 2-theta. 24. The morphic form of any one of embodiments 1-23, wherein the XRPD comprises a peak at 12.3±0.2 degrees 2-theta. 25. The morphic form of any one of embodiments 1-24, wherein the XRPD comprises a peak at 29.2±0.2 degrees 2-theta. 26. The morphic form of any one of embodiments 1-25, wherein the XRPD comprises a peak at 32.5±0.2 degrees 2-theta. 27. The morphic form of any one of embodiments 1-26, wherein the XRPD comprises a peak at 31.8±0.2 degrees 2-theta. 28. The morphic form of any one of embodiments 1-27, wherein the XRPD comprises a peak at 14.3±0.2 degrees 2-theta. 29. The morphic form of any one of embodiments 1-28, wherein the XRPD comprises a peak at 28.9±0.2 degrees 2-theta. 30. The morphic form of any one of embodiments 1-29, wherein the XRPD comprises a peak at 4.7±0.2 degrees 2-theta.

[0066] In certain embodiments, Form V is characterized on a DSC thermogram by an onset of dehydration at about 40° C. and / or an onset of an endotherm at about 220° C. In certain embodiments, Form V is characterized by a weight loss of about 5% at about 140° C. as measured by TGA.

[0067] In certain embodiments, Form V is characterized by a solubility of at least about 50 mg / mL in DMSO and / or 1-methyl-2-pyrrolidinone when solubilized at about 25° C., as described in Example 13.

[0068] Compound 5 Form VI Form VI is a potential hydrate. It was obtained by equilibration from THF / IPA, THF / heptane mixtures and by fast evaporation from DMSO. Form VI is crystalline. When tested by DSC (see Example 21), Form VI exhibited a dehydration peak at 5.9° C. and an evaporation peak with an onset at about 154° C. Form VI also exhibited a melting onset of 226.4° C. and a melting enthalpy of 35 J / g. When tested by TGA (see Example 21), Form VI exhibited a weight loss of about 1.4% at about 85° C., a weight loss of about 8.3% from about 85° C. to 215° C., and a weight loss of about 1.4% from about 215° C. to 250° C. The XRPD of Form VI is shown in FIG. 6. Form VI is characterized by an XRPD pattern (XRPD Method 2 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 6.

[0069] TIFF2025505687000015.tif180170

[0070] 1. In certain embodiments, Compound 1 Form VI is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.1, 13.4, 16.2, 16.9, 17.4, 17.9, 19.0, 19.3, 19.6, 20.9, 21.5, 21.7, 22.9, 23.0, 24.9, 25.4, 25.9, 26.4, 27.1, 29.2, 31.3, and 33.3±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form VI is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.1, 13.4, 16.2, 16.9, 17.4, 17.9, 19.0, 19.3, 19.6, 20.9, 21.5, 21.7, 22.9, 23.0, 24.9, 25.4, 25.9, 26.4, 27.1, 29.2, 31.3, and 33.3±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form VI is characterized by an XRPD pattern having at least three peaks selected from 4.8, 13.1, 13.4, 16.2, 16.9, 17.4, 17.9, 19.0, 19.3, 19.6, 20.9, 21.5, 21.7, 22.9, 23.0, 24.9, 25.4, 25.9, 26.4, 27.1, 29.2, 31.3, and 33.3±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 22.9±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 16.2±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 17.9±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 23.0±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 13.4±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 21.5±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 26.4±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 19.3±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 19.6±0.2 degrees 2-theta. 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 21.7±0.2 degrees 2-theta. 21. The morphic form of any one of embodiments 1-20, wherein the XRPD comprises a peak at 19.0±0.2 degrees 2-theta. 22. The morphic form of any one of embodiments 1-21, wherein the XRPD comprises a peak at 20.9±0.2 degrees 2-theta. 23. The morphic form of any one of embodiments 1-22, wherein the XRPD comprises a peak at 17.4±0.2 degrees 2-theta. 24. The morphic form of any one of embodiments 1-23, wherein the XRPD comprises a peak at 24.9±0.2 degrees 2-theta. 25. The morphic form of any one of embodiments 1-24, wherein the XRPD comprises a peak at 27.1±0.2 degrees 2-theta. 26. The morphic form of any one of embodiments 1-25, wherein the XRPD comprises a peak at 25.9±0.2 degrees 2-theta. 27. The morphic form of any one of embodiments 1-26, wherein the XRPD comprises a peak at 4.8±0.2 degrees 2-theta. 28. The morphic form of any one of embodiments 1-27, wherein the XRPD comprises a peak at 16.9±0.2 degrees 2-theta.

[0071] In certain embodiments, Form VI is characterized on a DSC thermogram by an onset of dehydration at about 6° C. and / or an onset of evaporation at about 155° C. and / or an onset of melting at about 225° C. and / or a melting enthalpy of about 35 J / g. In certain embodiments, Form VI is characterized by a weight loss of about 1.5% at about 85° C., a weight loss of about 8% from about 85° C. to 215° C., and a weight loss of about 1.5% from about 215° C. to 250° C., as measured by TGA.

[0072] In certain embodiments, Form VI is characterized by a solubility of about 30 mg / mL in MeOH / DCM (vol:vol=1:2) and / or a solubility of 27 mg / mL in EtOH / DCM (vol:vol=1:4) when solubilized at about 25° C. as described in Example 20.

[0073] Compound 5 Form VII Form VII is a latent NMP solvate. It was obtained by fast evaporation from NMP. Form VII is crystalline. 1H-NMR indicates about 25.2 wt% (1.6 equivalents) NMP residual. The XRPD of Form VII is shown in Figure 7. Form VII is characterized by an XRPD pattern (XRPD Method 2 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 7.

[0074] TIFF2025505687000016.tif246170TIFF2025505687000017.tif36170

[0075] 1. In certain embodiments, Compound 1 Form VII is characterized by an XRPD pattern having at least three peaks selected from 3.9, 7.7, 11.5, 15.7, 16.2, 16.7, 17.8, 18.0, 18.4, 18.9, 19.2, 19.7, 20.0, 20.4, 21.1, 21.5, 22.2, 22.7, 23.3, 24.2, 25.1, 25.3, 25.8, and 26.3±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form VII is characterized by an XRPD pattern having at least three peaks selected from 3.9, 7.7, 11.5, 15.7, 16.2, 16.7, 17.8, 18.0, 18.4, 18.9, 19.2, 19.7, 20.0, 20.4, 21.1, 21.5, 22.2, 22.7, 23.3, 24.2, 25.1, 25.3, 25.8, and 26.3±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form VII is characterized by an XRPD pattern having at least three peaks selected from 3.9, 7.7, 11.5, 15.7, 16.2, 16.7, 17.8, 18.0, 18.4, 18.9, 19.2, 19.7, 20.0, 20.4, 21.1, 21.5, 22.2, 22.7, 23.3, 24.2, 25.1, 25.3, 25.8, and 26.3±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 3.9±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 19.2±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 22.7±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 15.7±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 18.0±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 21.1±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 17.8±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 18.4±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 20.4±0.2 degrees 2-theta.

[0076] Compound 5 Form VIII Form VIII is a potential hydrate. It was obtained from a DMF / H2O solvent mixture by the addition of antisolvent. Form VIII is crystalline. When tested by DSC (see Example 21), Form VIII showed a dehydration and evaporation peak at about 8°C, a melting onset of 231.4°C, and an enthalpy of about 105 J / g. When tested by TGA (see Example 21), Form VIII showed a weight loss of about 4.7% at about 200°C. 1 H-NMR indicates approximately 1.6% by weight (0.1 equivalents) of DMF remaining. The XRPD of Form VIII is shown in Figure 8. Form VIII is characterized by an XRPD pattern (XRPD Method 2 in Example 23) with peaks at ±0.4° 2-theta of the peaks listed in Peak List No. 8.

[0077] TIFF2025505687000018.tif194170

[0078] 1. In certain embodiments, Compound 1 Form VIII is characterized by an XRPD pattern having at least three peaks selected from 4.5, 12.1, 14.4, 16.1, 16.2, 17.5, 17.9, 18.4, 19.5, 20.0, 20.9, 22.0, 22.4, 22.8, 24.3, 24.7, 25.4, 26.1, 26.5, 26.9, 27.4, 28.0, 28.8, 29.2, 29.5, and 31.8±0.4 degrees two-theta. 2. The morphic form of embodiment 1, wherein Compound 1 Form VIII is characterized by an XRPD pattern having at least three peaks selected from 4.5, 12.1, 14.4, 16.1, 16.2, 17.5, 17.9, 18.4, 19.5, 20.0, 20.9, 22.0, 22.4, 22.8, 24.3, 24.7, 25.4, 26.1, 26.5, 26.9, 27.4, 28.0, 28.8, 29.2, 29.5, and 31.8±0.3 degrees two-theta. 3. The morphic form of embodiment 1, wherein Compound 1 Form VIII is characterized by an XRPD pattern having at least three peaks selected from 4.5, 12.1, 14.4, 16.1, 16.2, 17.5, 17.9, 18.4, 19.5, 20.0, 20.9, 22.0, 22.4, 22.8, 24.3, 24.7, 25.4, 26.1, 26.5, 26.9, 27.4, 28.0, 28.8, 29.2, 29.5, and 31.8±0.2 degrees two-theta. 4. The morphic form of any one of embodiments 1-3, wherein at least four peaks selected from the recited peaks are present. 5. The morphic form of any one of embodiments 1-3, wherein at least five peaks selected from the recited peaks are present. 6. The morphic form of any one of embodiments 1-3, wherein at least six peaks selected from the recited peaks are present. 7. The morphic form of any one of embodiments 1-3, wherein at least seven peaks selected from the recited peaks are present. 8. The morphic form of any one of embodiments 1-3, wherein at least eight peaks selected from the recited peaks are present. 9. The morphic form of any one of embodiments 1-3, wherein at least nine peaks selected from the recited peaks are present. 10. The morphic form of any one of embodiments 1-3, wherein at least 10 peaks selected from the recited peaks are present. 11. The morphic form of any one of embodiments 1-10, wherein the XRPD comprises a peak at 18.4±0.2 degrees 2-theta. 12. The morphic form of any one of embodiments 1-11, wherein the XRPD comprises a peak at 22.8±0.2 degrees 2-theta. 13. The morphic form of any one of embodiments 1-12, wherein the XRPD comprises a peak at 26.1±0.2 degrees 2-theta. 14. The morphic form of any one of embodiments 1-13, wherein the XRPD comprises a peak at 19.5±0.2 degrees 2-theta. 15. The morphic form of any one of embodiments 1-14, wherein the XRPD comprises a peak at 12.1±0.2 degrees 2-theta. 16. The morphic form of any one of embodiments 1-15, wherein the XRPD comprises a peak at 22.4±0.2 degrees 2-theta. 17. The morphic form of any one of embodiments 1-16, wherein the XRPD comprises a peak at 17.9±0.2 degrees 2-theta. 18. The morphic form of any one of embodiments 1-17, wherein the XRPD comprises a peak at 17.5±0.2 degrees 2-theta. 19. The morphic form of any one of embodiments 1-18, wherein the XRPD comprises a peak at 25.4±0.2 degrees 2-theta. 20. The morphic form of any one of embodiments 1-19, wherein the XRPD comprises a peak at 16.2±0.2 degrees 2-theta. 21. The morphic form of any one of embodiments 1-20, wherein the XRPD comprises a peak at 4.5±0.2 degrees 2-theta. 22. The morphic form of any one of embodiments 1-21, wherein the XRPD comprises a peak at 20.0±0.2 degrees 2-theta. 23. The morphic form of any one of embodiments 1-22, wherein the XRPD comprises a peak at 31.8±0.2 degrees 2-theta. 24. The morphic form of any one of embodiments 1-23, wherein the XRPD comprises a peak at 20.9±0.2 degrees 2-theta. 25. The morphic form of any one of embodiments 1-24, wherein the XRPD comprises a peak at 24.3±0.2 degrees 2-theta. 26. The morphic form of any one of embodiments 1-25, wherein the XRPD comprises a peak at 24.7±0.2 degrees 2-theta. 27. The morphic form of any one of embodiments 1-26, wherein the XRPD comprises a peak at 14.4±0.2 degrees 2-theta. 28. The morphic form of any one of embodiments 1-27, wherein the XRPD comprises a peak at 22.0±0.2 degrees 2-theta. 29. The morphic form of any one of embodiments 1-28, wherein the XRPD comprises a peak at 28.0±0.2 degrees 2-theta.

[0079] In certain embodiments, Form VIII is characterized on a DSC thermogram by an onset of dehydration and evaporation at about 8° C., and / or an onset of melting at about 230° C., and / or an enthalpy of melting of about 105 J / g. In certain embodiments, Form VIII is characterized by a weight loss of about 5% at about 200° C. as measured by TGA.

[0080] In certain embodiments, Form VIII is characterized by a solubility of about 30 mg / mL in MeOH / DCM (vol:volume=1:2) and / or a solubility of 39 mg / mL in EtOH / DCM (vol:volume=1:4) when solubilized at about 25° C. as described in Example 20.

[0081] Approximate solubility Four polymorphs of Compound 5, Form V, Form VI, Form VII, and Form VIII, were tested in EtOH:DCM (volume:volume=1:4) for approximate solubility in Example 18. By visual observation, Form VI and Form VIII showed higher solubility in EtOH:DCM (volume:volume=1:4) than Form V and Form VII.

[0082] solubility In Example 20, the solubility of Forms VI and VIII of Compound 5 was investigated in MeOH:DCM (v:v=1:2), EtOH:DCM (v:v=1:4), THF:2-propanol (v:v=1:2), THF:heptane (v:v=1:2), and THF:water (v:v=1:2.5) at 25° C. for 24 hours. Both Form VI (ca. 30 mg / mL) and Form VIII (ca. 30 mg / mL-40 mg / mL) showed high solubility in MeOH:DCM (v:v=1:2) and EtOH:DCM (v:v=1:4), but low solubility (ca. 1 mg / mL) in THF:IPA (v:v=1:2), THF:heptane (v:v=1:2), and THF:heptane (v:v=1:2.5).

[0083] After solubility testing, Form VI was converted to a nearly amorphous form in MeOH:DCM (vol:vol=1:2) and EtOH:DCM (vol:vol=1:4), but no change in form was observed in THF:2-propanol (vol:vol=1:2), THF:heptane (vol:vol=1:2), and THF:water (vol:vol=1:2.5).

[0084] After solubility studies, Form VIII was converted to Form V in MeOH:DCM (vol:vol=1:2) and THF:water (vol:vol=1:2.5) and to Form VI in THF:2-propanol (vol:vol=1:2) and THF:heptane (vol:vol=1:2). A physical mixture of Forms V and VI was obtained in EtOH:DCM (vol:vol=1:4).

[0085] Bulk Stability The bulk stability of Forms VI and VIII of Compound 5 was evaluated over a one week period at 25° C. / 60% RH in an open container as described in Example 19. Forms VI and VIII of Compound 5 are chemically stable under these conditions. Form VI also showed excellent physical stability. Form VIII was converted to Form V upon exposure to 25° C. / 60% RH for one week.

[0086] In certain embodiments, Compound 5 Form VI is used to prepare Compound 1, such as Compound 1 Form I.

[0087] New dosing regimen for Compound 1 In another aspect of the present invention, a new dosing regimen for the treatment of cancer is provided, which comprises administering Compound 1 or a pharma- ceutically acceptable salt thereof, Compound 1 Form II, or a pharmaceutical composition comprising Compound 1 to a patient in need thereof (a) once daily for 3 selected days per week for 14 days in a 28-day treatment cycle, followed by a 14-day dosing rest period, or (b) once daily for 7 consecutive days in a 21-day treatment cycle, followed by a 14-day dosing rest period. In certain embodiments, the treatment cycle is repeated 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or more times. In certain embodiments, Compound 1 is provided in a dose of about 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 37.5 μg, 50 μg, 62.5 μg, 75 μg, 87.5 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, or 400 μg. In certain embodiments, Compound 1 is provided in a dose of at least about 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 37.5 μg, 50 μg, 75 μg, 87.5 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, or 400 μg. In certain embodiments, Compound 1 is provided in a dose of less than about 1 μg, 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 37.5 μg, 50 μg, 75 μg, 87.5 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, or 400 μg.

[0088] In certain embodiments, Compound 1 is administered at a dose of less than about 50 μg. In certain embodiments, treatment is administered at a dose of less than about 25 μg.

[0089] In certain embodiments, the treatment is administered at a dose of about 50 μg.

[0090] In certain embodiments, the treatment is administered at a dose of about 45 μg.

[0091] In certain embodiments, the treatment is administered at a dose of about 40 μg.

[0092] In certain embodiments, the treatment is administered at a dose of about 35 μg.

[0093] In certain embodiments, the treatment is administered at a dose of about 30 μg.

[0094] In certain embodiments, the treatment is administered at a dose of about 25 μg.

[0095] In certain embodiments, the treatment is administered at a dose of about 20 μg.

[0096] In certain embodiments, the treatment is administered at a dose of about 15 μg.

[0097] In certain embodiments, the treatment is administered at a dose of about 10 μg.

[0098] In certain embodiments, the treatment is administered at a dose of about 5 μg.

[0099] In certain embodiments, the treatment is administered at a dose of about 1 μg.

[0100] In certain embodiments, the therapy is administered at a dose of less than about 800 μg. In certain embodiments, the therapy is administered at a dose of less than about 600 μg. In certain embodiments, the therapy is administered at a dose of less than about 400 μg. In certain embodiments, the therapy is administered at a dose of less than about 300 μg. In certain embodiments, the therapy is administered at a dose of less than about 200 μg. In certain embodiments, the therapy is administered at a dose of less than about 100 μg.

[0101] In certain embodiments, Compound 1 is administered at a concentration of about 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg, 475 μg, 500 μg, The drug is administered in a dose of up to 1000μg, 525μg, 550μg, 575μg, 600μg, 625μg, 650μg, 675μg, 700μg, 725μg, 750μg, 775μg, 800μg, 825μg, 850μg, 875μg, 900μg, 925μg, 950μg, 975μg or 1000μg.

[0102] Treatment of disorders mediated by Ikaros and / or Aiolos Advantageous treatments of Ikaros- and / or Aiolos-mediated disorders are provided, which comprise administering Compound 1 Form I, a pharmaceutical composition comprising Compound 1 Form I, a pharmaceutical composition prepared from Compound 1 Form I (e.g., a liquid dosage form or gel capsule comprising Compound 1 that was in Form I prior to being dissolved), or Compound 1 as part of the new dosing regimens described herein. In certain embodiments, the methods of treatment use a low effective dose of Compound 1. For example, the dose of Compound 1 is about 500 micrograms (μg), 450 μg, 400 μg, 350 μg, 325 μg, 300 μg, 275 μg, 250 μg, 225 μg, 200 μg, 175 μg, 150 μg, 125 μg, 100 μg, 75 μg, 62.5 μg, 50 μg, 37.5 μg, 25 μg, 20 μg, 15 μg, 10 μg, 5 μg, or 1 μg or less once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or once a day (QD), optionally with a rest period. For example, a regimen in which treatment is administered on days 1 to 14 or days 1 to 21 of a 28-day treatment cycle. In some embodiments, the patient is an adult (a human usually weighing at least 100 pounds, and usually over 18 years of age). In other embodiments, the patient is a child (may be under 100 pounds, and typically under 18 years of age).

[0103] Compound 1 can be administered as a monotherapy or can be combined with standard treatments for target tumors or cancers, including but not limited to any of those described in the background of the present invention, or with proteasome inhibitors and / or anti-CD38 monoclonal antibodies (mAbs), etc. In MCL, compound 1 can be used in combination with, for example, Bruton's tyrosine kinase (BTK) inhibitors or anti-CD20 monoclonal antibodies. In PTCL, particularly ALCL, compound 1 can be administered in combination with, for example, anti-CD30 or anti-CD38 monoclonal antibodies.

[0104] In certain embodiments, Compound 1 is used to treat disorders mediated by Ikaros or Aiolos in accordance with the treatment regimens described herein.

[0105] In certain embodiments, compound 1 is used to treat cancer that has metastasized. In certain embodiments, compound 1 is used to treat cancer that has metastasized to the brain. In certain embodiments, compound 1 is used to treat multiple myeloma that has metastasized to the brain. In certain embodiments, compound 1 is used to treat non-Hodgkin's lymphoma that has metastasized to the brain. In certain embodiments, compound 1 is used to treat diffuse large B-cell lymphoma that has metastasized to the brain.

[0106] Treatment cycle In certain embodiments, the treatment includes a drug holiday.A drug holiday is a period during which the patient is not administered with the active compound.For example, during a 28-day cycle, the patient is administered the pharmaceutical composition for 14 or 21 consecutive days, and the chemotherapy drug is not administered for 14 or 7 days, and then the regimen is optionally repeated once, several times, or more.

[0107] In certain embodiments, treatment cycles are provided to allow for recovery of blood cell levels, and in non-limiting embodiments, to allow for a drop in neutrophil counts. The provider can monitor blood cell levels during treatment and allow the patient to take a drug holiday for a period during the 28-day treatment cycle. Alternatively, the provider can reduce the dose administered until the dropped blood cell counts are adequately restored. If desired, these two approaches can be used in combination.

[0108] In certain embodiments, Compound 1 is administered once daily for 14 consecutive days of a 28-day treatment cycle. In certain embodiments, Compound 1 is administered three times a week, for example, on Mondays, Wednesdays, and Fridays, and then Compound 1 is not administered for 7 or 14 consecutive days of a 28-day treatment cycle.

[0109] In certain embodiments, Compound 1 is administered once daily for one day in a seven day treatment cycle.

[0110] In certain embodiments, Compound 1 is administered once daily for two days in a seven day treatment cycle.

[0111] In certain embodiments, Compound 1 is administered once daily for three days in a seven day treatment cycle.

[0112] In certain embodiments, Compound 1 is administered once daily for 4 days in a 7-day treatment cycle.

[0113] In certain embodiments, Compound 1 is administered once daily for 5 days in a 7-day treatment cycle.

[0114] In certain embodiments, Compound 1 is administered once daily for 6 days in a 7-day treatment cycle.

[0115] In certain embodiments, Compound 1 is administered once daily for seven days in a seven-day treatment cycle.

[0116] In certain embodiments, Compound 1 is administered once daily, one day per week, in a 14-day treatment cycle.

[0117] In certain embodiments, Compound 1 is administered once daily, two days per week, in a 14-day treatment cycle.

[0118] In certain embodiments, Compound 1 is administered once daily, three days per week, in a 14-day treatment cycle.

[0119] In certain embodiments, Compound 1 is administered once daily, four days per week, in a 14-day treatment cycle.

[0120] In certain embodiments, Compound 1 is administered once daily, five days per week, in a 14-day treatment cycle.

[0121] In certain embodiments, Compound 1 is administered once daily, six days per week, in a 14-day treatment cycle.

[0122] In certain embodiments, Compound 1 is administered once daily, one day per week, in a 21 day treatment cycle.

[0123] In certain embodiments, Compound 1 is administered once daily, two days per week, in a 21-day treatment cycle.

[0124] In certain embodiments, Compound 1 is administered once daily, three days per week, in a 21-day treatment cycle.

[0125] In certain embodiments, Compound 1 is administered once daily, four days per week, in a 21-day treatment cycle.

[0126] In certain embodiments, Compound 1 is administered once daily, five days per week, in a 21-day treatment cycle.

[0127] In certain embodiments, Compound 1 is administered once daily, six days per week, in a 21-day treatment cycle.

[0128] In certain embodiments, Compound 1 is administered once daily, one day per week, in a 28 day treatment cycle.

[0129] In certain embodiments, Compound 1 is administered once daily, two days per week, in a 28-day treatment cycle.

[0130] In certain embodiments, Compound 1 is administered once daily, three days per week, in a 28-day treatment cycle.

[0131] In certain embodiments, Compound 1 is administered once daily, four days per week, in a 28-day treatment cycle.

[0132] In certain embodiments, Compound 1 is administered once daily, five days per week, in a 28-day treatment cycle.

[0133] In certain embodiments, Compound 1 is administered once daily, six days per week, in a 28-day treatment cycle.

[0134] In certain embodiments, Compound 1 is administered once daily, 7 days per week for a week, in a 28 day treatment cycle.

[0135] In certain embodiments, Compound 1 is administered once daily, 7 days per week for 2 weeks, in a 28 day treatment cycle.

[0136] In certain embodiments, the above treatment schedule is modified to include a one-week rest period, e.g., Compound 1 is administered once daily, five days per week, in a 28-day treatment cycle, with Compound 1 being administered only during the first three weeks of the 28-day treatment cycle.

[0137] In certain embodiments, the above treatment schedule is modified to include a two-week rest, e.g., Compound 1 is administered once daily, five days per week, in a 28-day treatment cycle, with Compound 1 being administered only during the first two weeks of the 28-day treatment cycle.

[0138] In certain embodiments, the three days selected for treatment are Monday, Wednesday, and Friday. In certain embodiments, the three days selected for treatment are Tuesday, Thursday, and Saturday. In certain embodiments, the three days selected for treatment are Wednesday, Friday, and Sunday.

[0139] In certain embodiments, Compound 1 is administered orally. In certain embodiments, Compound 1 is administered as a gel capsule or tablet. In certain embodiments, Compound 1 is administered as a tablet. For example, in certain embodiments, Compound 1 is administered in a tablet made in a spray-dried dispersion.

[0140] dosage In certain embodiments, compound 1 is administered at a dose of about 75 μg or less. In certain embodiments, the therapy (i.e., compound 1 form I, or a pharmaceutical composition comprising or prepared from compound 1 form I, or compound 1 as part of the new dosing regimen described herein) is administered at a dose of 75 μg or less. In certain embodiments, the therapy (i.e., compound 1 form I, or a pharmaceutical composition comprising or prepared from compound 1 form I, or compound 1 as part of the new dosing regimen described herein) is administered at a dose of about 50 μg or less. In certain embodiments, the therapy (i.e., compound 1 form I, or a pharmaceutical composition comprising or prepared from compound 1 form I, or compound 1 as part of the new dosing regimen described herein) is administered at a dose of about 25 μg or less.

[0141] In certain embodiments, the treatment is administered at a dose of about 75 μg.

[0142] In certain embodiments, the treatment is administered at a dose of about 62.5 μg.

[0143] In certain embodiments, the treatment is administered at a dose of about 50 μg.

[0144] In certain embodiments, the treatment is administered at a dose of about 45 μg.

[0145] In certain embodiments, the treatment is administered at a dose of about 40 μg.

[0146] In certain embodiments, the treatment is administered at a dose of about 37.5 μg.

[0147] In certain embodiments, the treatment is administered at a dose of about 35 μg.

[0148] In certain embodiments, the treatment is administered at a dose of about 30 μg.

[0149] In certain embodiments, the treatment is administered at a dose of about 25 μg.

[0150] In certain embodiments, the treatment is administered at a dose of about 20 μg.

[0151] In certain embodiments, the treatment is administered at a dose of about 15 μg.

[0152] In certain embodiments, the treatment is administered at a dose of about 12.5 μg.

[0153] In certain embodiments, the treatment is administered at a dose of about 10 μg.

[0154] In certain embodiments, the treatment is administered at a dose of about 5 μg.

[0155] In certain embodiments, the treatment is administered at a dose of about 1 μg.

[0156] In certain embodiments, the treatment is administered at a dose of less than about 800 μg. In certain embodiments, the treatment is administered at a dose of less than about 600 μg. In certain embodiments, the treatment is administered at a dose of less than about 400 μg. In certain embodiments, the treatment is administered at a dose of less than about 300 μg. In certain embodiments, the treatment is administered at a dose of less than about 200 μg. In certain embodiments, the treatment is administered at a dose of less than about 100 μg, 75 μg, 50 μg, or 25 μg.

[0157] In certain embodiments, Compound 1 is administered in an amount of at least about 10 μg, 12.5 μg, 25 μg, 37.5 μg, 50 μg, 62.5 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 225 μg, 250 μg, 275 μg, 300 μg, 325 μg, 350 μg, 375 μg, 400 μg, 425 μg, 450 μg , 475 μg, 500 μg, 525 μg, 550 μg, 575 μg, 600 μg, 625 μg, 650 μg, 675 μg, 700 μg, 725 μg, 750 μg, 775 μg, 800 μg, 825 μg, 850 μg, 875 μg, 900 μg, 925 μg, 950 μg, 975 μg or 1000 μg, or any dose in between.

[0158] In certain aspects, compound 1 is administered at a dose of 50 μg once daily for 14 days in a 28-day treatment cycle, followed by a 14-day treatment rest period. In certain embodiments, compound 1 is administered at a dose of 62.5 μg once daily for 14 days in a 28-day treatment cycle, followed by a 14-day treatment rest period. In certain embodiments, compound 1 is administered at a dose of 75 μg once daily for 14 days in a 28-day treatment cycle, followed by a 14-day treatment rest period.

[0159] In certain aspects, compound 1 is administered at a dose of 50 μg once a day, 3 days a week, for the first 2 weeks of a 14-day treatment break in a 28-day treatment cycle. In certain embodiments, compound 1 is administered at a dose of 62.5 μg once a day, 3 days a week, for the first 2 weeks of a 14-day treatment break in a 28-day treatment cycle. In certain embodiments, compound 1 is administered at a dose of 75 μg once a day, 3 days a week, for the first 2 weeks of a 14-day treatment break in a 28-day treatment cycle.

[0160] In certain aspects, compound 1 is administered at a dose of 50 μg once daily on Mondays, Wednesdays, and Fridays during the first two weeks of a 14-day treatment break in a 28-day treatment cycle. In certain embodiments, compound 1 is administered at a dose of 62.5 μg once daily on Mondays, Wednesdays, and Fridays during the first two weeks of a 14-day treatment break in a 28-day treatment cycle. In certain embodiments, compound 1 is administered at a dose of 75 μg once daily on Mondays, Wednesdays, and Fridays during the first two weeks of a 14-day treatment break in a 28-day treatment cycle.

[0161] In certain aspects, compound 1 is administered at a dose of 50 μg once daily for 7 days in a 21-day treatment cycle, followed by a 14-day treatment rest period. In certain embodiments, compound 1 is administered at a dose of 62.5 μg once daily for 7 days in a 21-day treatment cycle, followed by a 14-day treatment rest period. In certain embodiments, compound 1 is administered at a dose of 75 μg once daily for 7 days in a 21-day treatment cycle, followed by a 14-day treatment rest period.

[0162] Disorders mediated by Ikaros and / or Aiolos In one aspect of the present invention, disorders mediated by Ikaros or Aiolos are treated with Compound 1. In certain embodiments, the cancer is a hematopoietic cancer. In some embodiments, the cancer is a lymphoma, leukemia, or myeloma. In certain aspects, the cancer is multiple myeloma. In certain aspects, the cancer is non-Hodgkin's lymphoma or Hodgkin's lymphoma.

[0163] In certain embodiments, the cancer is diffuse large B cell lymphoma. In certain embodiments, the diffuse large B cell lymphoma is an activated B cell lymphoma or a germinal center B cell lymphoma. In certain embodiments, the diffuse large B cell lymphoma is a cancer with a BCL2 / 6 translocation. In certain embodiments, the diffuse large B cell lymphoma is a double hit bearing cancer. In certain embodiments, the diffuse large B cell lymphoma is a BCL2 / 6 MYC wild type cancer.

[0164] In certain embodiments, Compound 1 increases the concentration of caspase-3 and / or caspase-7. In certain embodiments, this increase in the concentration of caspase-3 and / or caspase-7 causes cancer cell death, for example, mediating treatment of diffuse large B-cell lymphoma.

[0165] In certain embodiments, the cancer is anaplastic large cell lymphoma.

[0166] In certain embodiments, the cancer is cutaneous T-cell lymphoma.

[0167] In certain embodiments, the cancer is mantle cell lymphoma.

[0168] In certain embodiments, the cancer is multiple myeloma.

[0169] In certain embodiments, the patient has extramedullary disease.

[0170] In certain embodiments, the patient has multiple myeloma and extramedullary disease. Extramedullary disease can occur when cancer cells form tumors outside the bone marrow, for example in soft tissues or organs of the body. In certain embodiments, the extramedullary disease occurs in the CNS, skull, orbit, vertebrae, breast, thyroid, soft tissue of the neck, lung, spleen, heart, liver, pancreas, gastrointestinal tract, peritoneal omentum, testes, skin, subcutaneous tissue, lymph nodes, muscle, female reproductive system, or adrenal glands. In certain embodiments, the extramedullary disease is selected from multiple plasmacytomas, lytic bone lesions, or a combination of plasmacytomas and bone lesions.

[0171] In certain embodiments, the patient has multiple myeloma and multiple plasmacytoma.

[0172] In certain embodiments, the patient has multiple myeloma and lytic bone lesions.

[0173] In certain embodiments, the patient has multiple myeloma, plasmacytoma, and bone lesions.

[0174] In certain embodiments, the patient undergoes surgical therapy either before, during, or after treatment with Compound 1.

[0175] In certain embodiments, Compound 1 is administered to a patient in need thereof in an amount effective to treat a disorder resistant to treatment with other cereblon ligands. In certain embodiments, Compound 1 is used to treat an immunomodulatory imid drug refractory disorder or an IID refractory disorder. In certain embodiments, Compound 1 is used to treat relapsed or refractory multiple myeloma. In certain embodiments, Compound 1 is used to treat relapsed or refractory non-Hodgkin's lymphoma.

[0176] In one aspect, the patient has a cancer involving the CNS, such as lymphoma in the CNS.In certain embodiments, the patient with a cancer involving the CNS, such as lymphoma in the CNS, is also administered one or more additional therapeutic agents, such as ibrutinib or rituximab.In certain embodiments, the compounds described herein are used to treat peripheral central nervous system lymphoma.

[0177] In certain embodiments, the cancer is PTCL-NOS (i.e., PTCL not otherwise specified). In other embodiments, the cancer is a PTCL having a specific subtype, such as anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy T-cell lymphoma, extranodal natural killer (NK)-cell lymphoma, or extranodal T-cell lymphoma.

[0178] In certain embodiments, the disorder is an immunomodulatory disorder. In certain embodiments, the disorder treated as described herein is mediated by angiogenesis. In certain embodiments, the disorder is associated with the lymphatic system.

[0179] In certain embodiments, the disorder is selected from a benign growth, a neoplasm, a tumor, a cancer, an abnormal cell proliferation, an immune disorder, an inflammatory disorder, a graft-versus-host rejection, a viral infection, a bacterial infection, an amyloidotic proteinopathy, a proteinopathy, or a fibrotic disorder.

[0180] In certain embodiments, the term "disease state" or "pathology" as used herein is intended to refer to any disease state or pathology mediated by Ikaros or Aiolos, such as cell proliferation, or any disease state or pathology mediated by a downstream protein of Ikaros or Aiolos, where degradation of such a protein in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof. In some cases, the disease state or pathology may be cured.

[0181] For example, Compound 1 can be administered to a host suffering from Hodgkin's lymphoma or non-Hodgkin's lymphoma, including, but not limited to, AIDS-related lymphoma; anaplastic large cell lymphoma; angioimmunoblastic lymphoma; blastic NK cell lymphoma; Burkitt's lymphoma; Burkitt-like lymphoma (small non-cleaved cell lymphoma); small cleaved cell diffuse lymphoma (DSCCL); chronic lymphocytic leukemia; small lymphocytic lymphoma; non-Hodgkin's lymphoma (NOS), cutaneous T-cell lymphoma; diffuse large B-cell lymphoma; The patient may be suffering from enteropathic T-cell lymphoma; follicular lymphoma; hepatosplenic gamma-delta T-cell lymphoma; lymphoblastic lymphoma; mantle cell lymphoma; marginal zone lymphoma; nasal T-cell lymphoma; childhood lymphoma; peripheral lymphoma, peripheral T-cell lymphoma; primary central nervous system lymphoma; T-cell leukemia; transformed lymphoma; therapy-related T-cell lymphoma; non-Hodgkin's lymphoma such as Langerhans cell histiocytosis or Waldenstrom's macroglobulinemia.

[0182] In certain embodiments, the disorder is Hodgkin lymphoma, such as, but not limited to, nodular sclerosing classical Hodgkin lymphoma (CHL), mixed cellularity CHL, lymphopenic CHL, lymphocyte-rich CHL, lymphocyte-predominant Hodgkin lymphoma, or nodular lymphocyte-predominant HL.

[0183] In certain embodiments, the disorder is an immunomodulatory condition. Non-limiting examples of immunomodulatory conditions include arthritis, lupus, celiac disease, inflammatory bowel disease, ulcerative colitis, Sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.

[0184] In certain embodiments, the condition to be treated as described herein is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferation, can result from a wide range of factors, including genetic mutations, infections, exposure to toxins, autoimmune disorders, and the induction of benign or malignant tumors.

[0185] Abnormal proliferation of B cells, T cells and / or NK cells can result in a wide variety of diseases, such as cancer, proliferative disorders and inflammatory / immune diseases. A host, e.g., a human, afflicted with any of these disorders can be treated with an effective amount of a compound described herein to reduce (palliate) symptoms. Therapeutic agents can achieve a reduction in the severity of the disease (disease modifying agent) or a reduction in the underlying disease (disease modifying agent).

[0186] In certain embodiments, the compounds described herein, or their corresponding pharma- ceutically acceptable salts, isotopic derivatives, or prodrugs thereof, are useful in treating, but not limited to, multiple myeloma; diffuse large B-cell lymphoma; follicular lymphoma; mucosa-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphoma; diffuse poorly differentiated lymphocytic lymphoma; mediastinal large B-cell lymphoma; Nodal marginal zone B-cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; hairy cell leukemia; splenic lymphoma / leukemia unclassifiable; diffuse red pulp small B-cell lymphoma; hairy cell leukemia-subtype; lymphoplasmacytic lymphoma; heavy chain disease, e.g. alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasmacytoid The compositions may be administered in an effective amount to treat a host, e.g., a human, having a particular B-cell lymphoma or proliferative disorder, such as follicular myeloma; isolated plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma; T-cell / histiocyte-rich large B-cell lymphoma; DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma; primary cutaneous DLBCL leg type; ALK+ large B-cell lymphoma; plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease; unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma; or unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma.

[0187] In certain embodiments, the compounds described herein, or their corresponding pharma- ceutically acceptable salts, isotopic derivatives, or prodrugs thereof, are useful in treating a variety of conditions, including, but not limited to, anaplastic lymphoma kinase (ALK)-positive, ALK-negative anaplastic large cell lymphoma or primary cutaneous anaplastic large cell lymphoma; angioimmunoblastic lymphoma; cutaneous T-cell lymphomas, such as mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferative disorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primary cutaneous small / medium cell CD4+ T-cell lymphoma and lymphomatoid papulosis; adult T-cell leukemia / lymphoma (ATLL). and / or subcutaneous panniculitis-like T cell lymphoma, such as blastic NK cell lymphoma; enteropathy-type T cell lymphoma; hepatosplenic gamma-delta T cell lymphoma; lymphoblastic lymphoma; nasal NK / T cell lymphoma; therapy-related T cell lymphoma; lymphomas arising, for example, after solid organ or bone marrow transplantation; T cell prolymphocytic leukemia; T cell large granular lymphocytic leukemia; chronic lymphoproliferative disorder of NK cells; rapidly progressive NK cell leukemia; systemic EBV+ T cell lymphoproliferative disease of children (associated with chronic active EBV infection); vaccinia bullosa-like lymphoma; adult T cell leukemia / lymphoma; enteropathy-associated T cell lymphoma; hepatosplenic T cell lymphoma; or subcutaneous panniculitis-like T cell lymphoma.

[0188] In certain embodiments, the compounds described herein, or their corresponding pharma- ceutically acceptable salts, isotopic derivatives, or prodrugs, can be administered to treat a host, such as a human, with leukemia. For example, the host may suffer from acute or chronic leukemia of lymphocytic or myeloid origin, such as, but not limited to, acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); chronic lymphocytic leukemia (CLL); chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (a subtype of AML); large granular lymphocytic leukemia; or adult T-cell chronic leukemia. In certain embodiments, the patient suffers from acute myeloid leukemia, e.g., anaplastic AML (M0); myeloblastic leukemia (M1; with / without minimal cellular maturation); myeloblastic leukemia (M2; with cellular maturation); promyelocytic leukemia (M3 or M3 subtype (M3V)); myelomonocytic leukemia (M4 or M4 subtype with eosinophilia (M4E)); monocytic leukemia (M5); erythroleukemia (M6); or megakaryoblastic leukemia (M7).

[0189] There are many skin disorders associated with cell hyperproliferation. For example, psoriasis is a benign disease of human skin that is generally characterized by plaques covered with thickened scales. This disease is caused by increased proliferation of epidermal cells with unknown causes. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.

[0190] Other hyperproliferative cell disorders include blood vessel proliferative disorders, fibrotic disorders, autoimmune disorders, graft-versus-host rejection, tumors and cancer.

[0191] Vascular proliferative disorders include neovascular and angiogenic disorders. The proliferation of smooth muscle cells during the development of plaques in vascular tissues leads to, for example, restenosis, retinopathy, and atherosclerosis. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.

[0192] Fibrotic disorders are often caused by abnormal formation of extracellular matrix. Examples of fibrotic disorders include liver cirrhosis and mesangial proliferative cell disorder. Liver cirrhosis is characterized by an increase in extracellular matrix components that leads to the formation of liver scars. Liver cirrhosis can lead to diseases such as cirrhosis of the liver. The increase in extracellular matrix that leads to liver scars can also be caused by viral infections such as hepatitis. Lipid cells appear to play an important role in liver cirrhosis.

[0193] Mesangial disorders are caused by abnormal proliferation of mesangial cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, graft rejection and glomerulopathy.

[0194] Another disease with a proliferative component is rheumatoid arthritis, which is generally considered an autoimmune disease associated with the activity of autoreactive T cells and thought to result from autoantibodies produced against collagen and IgE.

[0195] Other disorders that may involve an abnormal cell proliferative component include Behcet's syndrome, acute respiratory distress syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immune deficiency syndrome, vasculitis, lipidic histiocytosis, septic shock, and inflammation in general.

[0196] The compounds described herein, or pharma- ceutically acceptable salts, isotopic analogs, or prodrugs thereof, can be administered in an effective amount to treat a host, e.g., a human, having a proliferative condition, such as myeloproliferative disorder (MPD), polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), and the like. In another embodiment, the compounds provided herein are useful for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, and secondary acute myeloid leukemia.

[0197] In certain embodiments, the compounds described herein, or pharma- ceutically acceptable salts, isotopic analogs, or prodrugs thereof, can be administered in an effective amount to treat a host, e.g., a human, having a myelodysplastic syndrome (MDS), such as, but not limited to, refractory cytopenia with single lineage dysplasia, refractory anemia with ringed sideroblasts (RARS), refractory anemia-thrombocytosis with ringed sideroblasts (RARS-t), refractory cytopenia with multilineage dysplasia (RCMD), including RCMD with multilineage dysplasia and ringed sideroblasts (RCMD-RS), refractory anemia with excess blasts I (RAEB-I) and II (RAEB-II), 5q-syndrome, refractory cytopenia of childhood.

[0198] The term "neoplasia" or "cancer" is used to refer to a pathological process that results in the formation and growth of cancerous or malignant neoplasms, i.e., abnormal tissues that grow by cellular proliferation more rapidly than normal and continue to grow after the stimuli that initiated the new growth have ceased. Malignant neoplasms exhibit a partial or complete lack of structural organization and functional coordination with normal tissues, most invade surrounding tissues, metastasize to several sites, may recur after attempted removal, and cause the death of the patient if not properly treated. As used herein, the term neoplasia is used to describe all cancerous disease states and includes or encompasses the pathological processes associated with malignant hematogenous tumors, ascites tumors, and solid tumors. Exemplary cancers that may be treated by the present compounds alone or in combination with at least one additional anti-cancer agent include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma, cancer of the bladder, intestine, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemia; benign and malignant lymphomas, particularly Burkitt's lymphoma and non-Hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative disorders; Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, and other cancers. Sarcomas including sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma and Schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, hepatic cancer, colon cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinoma. Additional cancers that may be treated using the compounds according to the invention include, for example, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-B ALL, Pre-B lymphoma, large B-cell lymphoma, Burkitt's lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.

[0199] Additional cancers that can be treated using the compounds disclosed herein include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adenocarcinoma, adenosarcoma, adrenal gland cancer, adrenal cortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, basal cell carcinoma, B-cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, intestinal cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (estrogen, progesterone and HER-2) negative breast cancer, and HER-2 positive breast cancer. Single negative (negative for two of estrogen, progesterone and HER-2), single negative (negative for one of estrogen, progesterone and HER-2), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2 negative breast cancer, HER2 positive or negative breast cancer, progesterone receptor negative breast cancer, progesterone receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (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's sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer , fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumor (GIST), germ cell tumor, glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin's lymphoma, hypopharyngeal cancer, invasive ductal carcinoma (IDC), invasive Lobular carcinoma (ILC), Inflammatory Breast Cancer (IBC), Intestinal Cancer, Intrahepatic Cholangiocarcinoma, Invasive / Invasive Breast Cancer, Islet Cell Carcinoma, Jaw Cancer, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Leiomyosarcoma, Leptomeningeal Metastasis, Leukemia, Lip Cancer, Liposarcoma, Hepatoma, 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, Mesenchymous Mesothelioma, Metastatic Breast Cancer, Metastatic Melanoma, Metastatic Squamous Neck Cancer, Mixed Glioma, Monodermal Teratoma, Mouth Cancercancer), mucinous carcinoma, mucosal melanoma, multiple myeloma, fungating polyposis, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oat cell carcinoma, eye cancer, intraocular melanoma, anaplastic glioma, oral cavity cancer, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, primary peritoneal cancer of the ovary, ovarian sex cord-stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal gland tumor, pineoblastoma, 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, bone sarcoma, sarcoma, paranasal sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, vertebral cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsillar cancer, transitional cell carcinoma, fallopian tube cancer, tubular carcinoma, cancer of undetermined diagnosis, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, Pre-BALL, Pre-B lymphoma, Large B-cell lymphoma, Burkitt lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, Juvenile myelomonocytic leukemia (JMML), Acute promyelocytic leukemia (subtype of AML), Large granular lymphocytic leukemia, Adult T-cell chronic leukemia, Diffuse large B-cell lymphoma, Follicular lymphoma; Mucosa-associated lymphoid tissue lymphoma (MALT), Small cell lymphocytic lymphoma, Mediastinal large B-cell lymphoma, Nodal marginal zone B-cell lymphoma (NMZL); Splenic marginal zone lymphoma (SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma; or Lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; Splenic lymphoma / leukemia unclassifiable; Diffuse red pulp small B-cell lymphoma; Lymphoplasmic cell lymphoma; heavy chain diseases such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, isolated plasmacytoma of bone; extraskeletal plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histiocyte-rich large B cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL in the elderly; primary mediastinal (thymic) large B cell lymphoma, primary cutaneous DLBCL leg type, ALK+ large B cell lymphoma, plasmablastic lymphoma; large B cell lymphoma arising in HHV8-associated multicentric Castleman disease; unclassifiable B cell lymphoma with features intermediate to diffuse large B cell lymphoma or unclassifiable B cell lymphoma with features intermediate between diffuse large B cell lymphoma and classical Hodgkin lymphoma. In certain embodiments, the disorder is adenoid cystic carcinoma.In certain embodiments, the disorder is NUT midline carcinoma.

[0200] In another embodiment, the compounds described herein, or a pharma- ceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, having an autoimmune disorder. Examples include acute disseminated encephalomyelitis (ADEM); Addison's disease; agammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as Lou Gehrig's disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; antisynthetase syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune enteropathy; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; autoimmune polyglandular syndrome; autoimmune progesterone dermatitis; autoimmune thrombocytopenic purpura; autoimmune thyroid disorders; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; Balo's disease disease) / Barrow concentric sclerosis;Behcet's disease;Berger's disease;Bickerstaff encephalitis;Blau syndrome;Bullous pemphigoid;Cancer;Castleman's disease;Celiac disease;Chagas disease;Chronic inflammatory demyelinating polyneuropathy;Chronic inflammatory demyelinating polyneuropathy;Chronic obstructive pulmonary disease;Chronic relapsing multifocal osteomyelitis;Churg-Strauss syndrome;Cicatricial pemphigoid;Cogan syndrome;Cold agglutinin disease;Complement component 2 deficiency;Contact dermatitis;Cranial arteritis;CREST syndrome;Crohn's disease;Cushing's syndrome;Cutaneous leukocytoclastic vasculitis;Degos disease;Dercum's disease;Dermatitis herpetiformis;Dermatomyositis;Type 1 diabetes;Diffuse dermatologic Cutaneous systemic sclerosis;Disciform lupus erythematosus;Dresler's syndrome;Drug-induced lupus;Eczema;Endometriosis;Enthesitis-associated arthritis;Eosinophilic fasciitis;Eosinophilic gastroenteritis;Eosinophilic pneumonia;Epidermolysis bullosa acquisita;Erythema nodosum;Erythroblastosis fetalis;Essential mixed cryoglobulinemia;Evans syndrome;Extrinsic and intrinsic reactive airway disease (asthma);Fibrodysplasia ossificans progressiva;Fibrosing alveolitis (or idiopathic pulmonary fibrosis);Gastritis;Gastrointestinal pemphigoid;Glomerulonephritis;Goodpasture's syndrome;Graves' disease;Guillain-Barré syndrome (GBS);Hashimoto's encephalopathy;Hashimoto's disease;Hemolytic anemia;Henoch-Schönlein purpura;Herpes gestationis (pemphigoid of gestationis);hidradenitis suppurativa;Hughes-Stovin syndrome;hypogammaglobulinemia;idiopathic inflammatory demyelinating disease;idiopathic pulmonary fibrosis;idiopathic thrombocytopenic purpura;IgA nephropathy;immune glomerulonephritis;immune nephritis;immune pneumonia;inclusion body myositis;inflammatory bowel disease;interstitial cystitis;juvenile idiopathic arthritis, also known as juvenile rheumatoid arthritis;Kawasaki disease;Lambert-Eaton myasthenic syndrome;leukocytoclastic vasculitis;Lichen planus;Lichen sclerosus;Linear IgA disease (LAD); Lupoid hepatitis, also known as autoimmune hepatitis; lupus erythematosus; Majeed syndrome; microscopic polyangiitis; Miller-Fisher syndrome; mixed connective tissue disease; localized scleroderma; Much-Habermann disease, also known as acute pityriasis lichenoidis; multiple sclerosis; myasthenia gravis; myositis; Meniere's disease; narcolepsy; neuromyelitis optica (also known as Devic's disease); neuromyotonia; ophthalmic cicatricial pemphigoid; opsoclonus-myoclonus syndrome; Ord's thyroiditis thyroiditis);relapsing rheumatism;PANDAS (pediatric autoimmune streptococcal neuropsychiatric disorders);paraneoplastic cerebellar degeneration;paroxysmal nocturnal hemoglobinuria (PNH);Parry-Romberg syndrome;parsplanitis;Parsonage-Turner syndrome;pemphigus vulgaris;perivenous encephalomyelitis;pernicious anemia;POEMS syndrome;polyarteritis nodosa;polymyalgia rheumatica;polymyositis;primary biliary cirrhosis;primary sclerosing cholangitis;progressive inflammatory neuropathy;psoriasis;psoriatic arthritis;purpuric red cell aplasia;pyoderma gangrenosum;Rasmussen encephalitis;Raynaud's phenomenon;Reiter's syndrome;relapsing polychondritis;restless legs syndrome ;retroperitoneal fibrosis;rheumatic fever;rheumatoid arthritis;sarcoidosis;schizophrenia;Schmidt syndrome;Schnitzler syndrome;scleritis;scleroderma;sclerosing cholangitis;serum sickness;Sjögren's syndrome;spondyloarthropathy;stiff-person syndrome;Still's disease;subacute bacterial endocarditis (SBE);Suzac syndrome;Sweet syndrome;Sydenham chorea;sympathetic ophthalmia;systemic lupus erythematosus;Takayasu arteritis;temporal arteritis (also known as "giant cell arteritis");thrombocytopenia;Tolosa-Hunt syndrome;transverse myelitis;ulcerative colitis;undifferentiated connective tissue disease;undifferentiated spondyloarthropathy;urticarial vasculitis;vasculitis;vitiligo;In some embodiments, the autoimmune disease includes, but is not limited to, viral diseases such as Epstein-Barr virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster virus (VZV) and Human Papillomavirus (HPV); or Wegener's granulomatosis. In some embodiments, the autoimmune disease is an allergic condition, including those caused by asthma, food allergies, atopic dermatitis, chronic pain and rhinitis.

[0201] Skin contact hypersensitivity and asthma are just two examples of immune responses that may be associated with significant morbidity. Others include atopic dermatitis, eczema, Sjogren's syndrome, including dry keratoconjunctivitis secondary to Sjogren's syndrome, alopecia areata, allergic reactions due to arthropod sting reactions, 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 exudation of fluids on the skin, eyes, or mucous membranes.

[0202] In atopic dermatitis and eczema, immune-mediated leukocyte infiltration into the skin (particularly monocytes, lymphocytes, neutrophils and eosinophils) generally plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with marked hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways in asthma and the tear producing glands of the eye in keratoconjunctivitis sicca.

[0203] The compounds described herein, or pharma- ceutically acceptable salts, isotopic variants, or prodrugs thereof, can be administered in an effective amount to treat a host, e.g., a human, having a skin disorder, such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceutical agents, can cause skin sensitization when applied topically. In some embodiments, the skin disorder is treated by topical administration of a compound known in the art in combination with a compound disclosed herein. In one non-limiting embodiment, the disorder of the invention is selected from contact dermatitis, atopic dermatitis, eczematoid dermatitis, psoriasis, Sjogren's syndrome including dry keratoconjunctivitis secondary to Sjogren's syndrome, alopecia areata, allergic responses due to arthropod bite reactions, Crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis, and drug rash.

[0204] Disease states or conditions that can be treated by the present invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, cilia-related disorders, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, 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.

[0205] Further disease states or conditions that can be treated by the present invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety disorders, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, Guillain-Barre 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's syndrome, vasculitis.

[0206] Further disease states or conditions that can be treated by the present invention include, inter alia, aceruloplasminemia, achondroplasia type II, achondroplasia, acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, adenomatous polyposis coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, alkaptonuria, Alexander disease, alkaptonuric histopathology, alpha 1-antitrypsin deficiency, alpha-1 proteinase inhibitor deficiency, emphysema, amyotrophic lateral sclerosis, Alström syndrome, Alexander disease, ameloplasia imperfecta, ALA dehydratase deficiency, Anderson-Fabry disease, androgen insensitivity syndrome, anemia, angiokeratoma corporis diffuse, Retinal angiomatosis (von Hippel-Lindau disease), Apert syndrome, Arachnodactyly (Marfan syndrome), Stickler syndrome, Congenital multiple joint laxity (Ehlers-Danlos syndrome #multiple joint laxity type), Ataxia-telangiectasia, Rett syndrome, Primary pulmonary hypertension, Sandhoff disease, Neurofibromatosis type II, Behre-Stevenson gyriform scalp syndrome, Familial Mediterranean fever, Benjamin syndrome, β-thalassemia, Bilateral acoustic neurofibromatosis (neurofibromatosis type II), Factor V Leiden thrombophilia, Bloch-Sulzberger syndrome (incontinentia pigmenti), Bloom syndrome, X-linked sideroblastic anemia, Bonnevie-Ullrich syndrome (Turner syndrome), Bourneville disease (tuberous sclerosis), Prion disease, Birt-Hogg-Dubé syndrome, Osteoporosis (osteogenesis imperfecta), Broad hallux syndrome (Broad Thumb-Hallux syndrome (Rubinstein-Taybi syndrome), Bronze diabetes mellitus / Bronze cirrhosis (hemochromatosis), Spinal-bulbar muscular atrophy (Kennedy disease), Bürger-Grütz syndrome (lipoprotein lipase deficiency), Chronic Granulomatous Disease (CGD), Bengal dysplasia, Biotinidase deficiency, Cardiomyopathy (Noonan syndrome), Crimson-Cry syndrome, Congenital absence of the vas deferens (CAVD), Keyler cardio-facial syndrome (CBAVD), Congenital erythroblastic porphyria (CEP), Cystic fibrosis, Congenital hypothyroidism, Chondrodysplasia syndrome (achondroplasia), Otospondylomegaly epiphyseal dysplasia, Lesch-Nyhan syndrome,Galactosemia, Ehlers-Danlos syndrome, Thalassemia, Coffin-Lowry syndrome, Cockayne syndrome (familial adenomatous polyposis), Congenital erythroblastic porphyria, Congenital heart disease, Methemoglobinemia, Chondrodysplasia, X-linked sideroblastic anemia, Connective tissue disease, Conotruncal dysfacies syndrome, Cooley anemia (β-thalassemia), Copper storage disease (Wilson's disease), Copper transport disease Menkes disease, hereditary coproporphyria, Cowden syndrome, craniofacial joint abnormalities (Crouzon syndrome), Creutzfeldt-Jakob disease (prion disease), Cockayne syndrome, Cowden syndrome, Curschmann-Batten-Steinert syndrome (myotonic dystrophy), Behle-Stevenson gyriform scalp syndrome, primary hyperoxaluria, spondyloepiphyseal dysplasia (Strudwick type), Duchenne and Becker Degenerative neurological disorders including DBMD, Usher syndrome, de Grouchy syndrome and Dejerine-Sottas syndrome, Developmental disorders, Distal spinal muscular atrophy type V, Androgen insensitivity syndrome, Diffuse globoid sclerosis (Krabbe disease), DiGeorge syndrome, Dihydrotestosterone receptor deficiency, Androgen insensitivity syndrome, Down syndrome, Dwarfism, Erythropoietic protoporphyria, Erythroid 5-aminolevulinic acid synthase deficiency, Erythroblastic Porphyria, erythropoietic protoporphyria, erythropoietic uroporphyria, Friedreich's ataxia-familial paroxysmal polyserositis, late-onset dermatosis, familial pressure sensitive neuropathy, primary pulmonary hypertension (PPH), pancreatic fibrous cysts, fragile X syndrome, galactosemia, hereditary encephalopathy, giant cell hepatitis (neonatal hemochromatosis), Glenn-Blood-Strandberry syndrome (pseudoxanthoma elasticum), Gunther's disease (congenital erythroblastic porphyria) erythropoietinosis), hemochromatosis, Hallgren's syndrome, sickle cell anemia, hemophilia, hepatic erythropoietic porphyria (HEP), Hippel-Lindau disease (von Hippel-Lindau disease), Huntington's disease, Hutchinson-Gilford progeria syndrome (progeria), hyperandrogenism, hypochondroplasia, hypochromic anemia, immune system disorders including X-linked severe combined immunodeficiency, Insley-Astley syndrome, Jackson-Weiss syndrome, Joubert syndrome,Lesch-Nyhan syndrome, Jackson-Weiss syndrome, renal disease including hyperoxaluria, Klinefelter syndrome, Kniest dysplasia, patchy dementia, Langer-Sardino achondroplasia, ataxia-telangiectasia, Lynch syndrome, lysyl hydroxylase deficiency, Machado-Joseph disease, metabolic disorders including Kniest dysplasia, Marfan syndrome, movement disorders, Mowat-Wilson syndrome, cystic fibrosis, Muenke syndrome, multiple neurofibromatosis, Nance-Insley syndrome, Nance-Sweeney chondrodysplasia, Niemann-Pick disease, Noack syndrome (Pfeiffer syndrome), Osler-Weber-Lange disease, Peutz-Jeghers syndrome, polycystic kidney disease, polyostotic fibrous dysplasia (McCune-Albright syndrome), Peutz-Jeghers syndrome, Prader-Larbhardt-Willi syndrome group, hemochromatosis, primary hyperuricemia (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary senile degenerative dementia, prion disease, progeria (Hutchinson-Gilford progeria syndrome), chronic hereditary progressive chorea (Huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acidemia, protoporphyria, proximal myotonic dystrophy, pulmonary arterial hypertension, PX E (pseudoxanthoma elasticum), Rb (retinoblastoma), Recklinghausen's disease (neurofibromatosis type I), recurrent polyserositis, retinal disorders, retinoblastoma, Rett syndrome, RFALS type 3, Ricker syndrome, Riley-Day syndrome, Lucy-Lewy syndrome, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Li-Fraumeni syndrome, sarcoma, breast, leukemia and adrenal gland (sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, tuberous sclerosis (sclerosis tuberose (tuberous sclerosis)), SDAT, congenital SED (spondyloepiphyseal dysplasia congenita), Strudwick type SED (spondyloepiphyseal dysplasia congenita), SEDc (spondyloepiphyseal dysplasia congenita), Strudwick type SEMD (spondyloepiphyseal dysplasia congenita), Shprintzen syndrome, skin pigmentation disorder, Smith-Lemli-Opitz syndrome, South African hereditary porphyria (variant porphyria),Infantile-onset ascending hereditary spastic paralysis, speech and communication disorders, sphingolipidosis, Tay-Sachs disease, spinocerebellar ataxia, Stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, sausage neuropathy (hereditary neuropathy with liability to pressure palsies), Treacher Collins syndrome, Triplo X syndrome (triple X syndrome), trisomy 21 (Down syndrome), trisomy X, VHL syndrome (von Hippel-Lindau disease), visual impairment and blindness (Alström syndrome), Frolik's disease, Waardenburg syndrome, Warburg-Shaw-Frederius syndrome, Wolf-Hirschhorn syndrome, Wolff periodic disorder, Weissenbacher-Zweimüller syndrome, and xeroderma pigmentosum.

[0207] In certain embodiments, a method for treating multiple myeloma is provided, comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition. In another embodiment, a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition, is used in a method for treating multiple myeloma, comprising administering the compound to a patient.

[0208] In certain embodiments, a treatment is provided for managing the progression of multiple myeloma, comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition. In another embodiment, a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition, is used in a treatment for managing the progression of multiple myeloma, comprising administering the compound to a patient.

[0209] Treatment is provided for previously untreated patients as well as patients who have been previously treated for multiple myeloma but have not responded to standard therapy. Treatment is provided for patients who have not undergone surgery as well as adjunctive treatment for patients who have undergone surgery to treat multiple myeloma. Treatment is provided for patients who have not undergone transplant therapy as well as patients who have previously undergone transplant therapy.

[0210] In certain embodiments, the disorder treated by the present invention is a wild-type cancer, the term "wild-type" referring to a cancer that has not developed resistance to a previously effective treatment (i.e., a recurrent cancer), that does not have a mutation that confers resistance (i.e., a refractory cancer). In certain embodiments, the disorder treated by the present invention is a recurrent cancer. In certain embodiments, the disorder treated by the present invention is a refractory cancer. In certain embodiments, the disorder treated by the present invention is a relapsed, refractory cancer.

[0211] In certain embodiments, the cancer is unresectable. In other embodiments, the cancer is resectable. If the cancer is resectable, the methods described herein can be performed with or without surgery to remove the cancer. In certain embodiments, the cancer patient has histologically and / or cytologically confirmed cancer, such as histologically or cytologically confirmed non-Hodgkin's lymphoma or multiple myeloma.

[0212] The compounds described herein, for example, Compound 1 or a pharma- ceutically acceptable salt thereof, can be administered to treat or manage relapsed, refractory, or resistant multiple myeloma or non-Hodgkin's lymphoma. In some embodiments, the disorder is primary, secondary, 3rd, 4th, or 5th relapse. In certain embodiments, the compounds described herein can be used to reduce, maintain, or eliminate minimal residual disease (MRD).

[0213] The types of multiple myeloma that can be treated with Compound 1 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 newly diagnosed multiple myeloma of low-risk, intermediate-risk or high-risk), transplant eligible and non-transplant eligible multiple myeloma, smoldering (indolent) multiple myeloma (including smoldering multiple myeloma of low-risk, intermediate-risk or high-risk), active multiple myeloma, solitary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma. Other types of multiple myeloma that can be treated with Compound 1 include immunoglobulin A myeloma, immunoglobulin M myeloma, and immunoglobulin G myeloma.

[0214] In certain embodiments, a therapy for treating or managing multiple myeloma is provided that comprises administering to a patient, as induction therapy, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition.

[0215] In certain embodiments, a therapy is provided for treating or managing multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition, as consolidation therapy.

[0216] In certain embodiments, methods are provided for treating or managing multiple myeloma, comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition, as a maintenance therapy.

[0217] In certain embodiments, the multiple myeloma is plasma cell leukemia.

[0218] In certain embodiments, the multiple myeloma is high-risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is relapsed or refractory. In certain embodiments, the high-risk multiple myeloma has relapsed within 12 months of the first treatment. In another embodiment, the high-risk multiple myeloma is characterized by one or more genetic abnormalities, such as del(17 / 17p) and t(14;16)(q32;q32). In some embodiments, the high-risk multiple myeloma is relapsed or refractory to one, two, or three previous treatments.

[0219] In some embodiments, the multiple myeloma is transplant-eligible newly diagnosed multiple myeloma. In other embodiments, the multiple myeloma is transplant-ineligible newly diagnosed multiple myeloma.

[0220] In some embodiments, the multiple myeloma shows early progression (e.g., less than 12 months) after initial treatment. In other embodiments, the multiple myeloma shows early progression (e.g., less than 12 months) after autologous stem cell transplant. In another embodiment, the multiple myeloma is refractory to lenalidomide. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, the multiple myeloma is relapsed or refractory to three or more lines of therapy and has been exposed to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide, or avadomide), or is dual refractory to a proteasome inhibitor and an immunomodulatory compound. In yet other embodiments, the multiple myeloma is relapsed or refractory to three or more prior therapies including, for example, a CD38 monoclonal antibody (CD38 mAb, e.g., daratumumab or isatuximab), a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdimide, or avadomide), or is dual refractory to a proteasome inhibitor or an immunomodulatory compound and a CD38 mAb. In yet other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib), an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, iverdomib, or avadomide), and another active agent described herein.

[0221] In another aspect, the cancer has downregulated cereblon levels. In certain embodiments, the cancer has downregulated cereblon concentrations after prior treatment with lenalidomide. In certain embodiments, the cancer has downregulated cereblon concentrations after prior treatment with pomalidomide.

[0222] In another aspect, the multiple myeloma has downregulated cereblon levels. In certain embodiments, the multiple myeloma has downregulated cereblon concentrations after prior treatment with lenalidomide. In certain embodiments, the multiple myeloma has downregulated cereblon concentrations after prior treatment with pomalidomide.

[0223] In another aspect, the non-Hodgkin's lymphoma has downregulated cereblon levels. In certain embodiments, the non-Hodgkin's lymphoma has downregulated cereblon concentrations after prior treatment with lenalidomide. In certain embodiments, the non-Hodgkin's lymphoma has downregulated cereblon concentrations after prior treatment with pomalidomide.

[0224] In certain embodiments, there is provided a therapy for treating or managing relapsed or refractory multiple myeloma in a patient with renal impairment or symptoms thereof, comprising administering to the patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition.

[0225] In another embodiment, a treatment is provided for managing relapsed or refractory multiple myeloma in a frail patient, comprising administering to the patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition, wherein the frail patient is characterized by non-compliance with induction therapy or intolerance to dexamethasone treatment. In another embodiment, the frail patient is elderly, e.g., over 65 years of age.

[0226] In another embodiment, there is provided a treatment for managing fourth line relapsed or refractory multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition.

[0227] In another embodiment, there is provided a treatment for managing newly diagnosed transplant-ineligible multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition.

[0228] In another embodiment, there is provided a treatment for managing newly diagnosed transplant-ineligible multiple myeloma comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutical acceptable salt, isotopic analog or prodrug thereof, optionally in a pharma- ceutical acceptable carrier to form a composition, as an alternative therapy or post-transplant maintenance therapy.

[0229] In another embodiment, there is provided a treatment for managing high-risk multiple myeloma that is relapsed or refractory to one, two, or three prior treatments, comprising administering to a patient an effective amount of a compound described herein, or a pharma- ceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharma- ceutically acceptable carrier to form a composition.

[0230] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is refractory non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory non-Hodgkin's lymphoma.

[0231] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is relapsed multiple myeloma. In certain embodiments, the disorder treated by the present invention is refractory multiple myeloma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory multiple myeloma.

[0232] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is refractory non-Hodgkin's lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory non-Hodgkin's lymphoma.

[0233] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory peripheral T-cell lymphoma.

[0234] In certain embodiments, Compound 1 is administered to treat PTCL-NOS (i.e., PTCL not otherwise specified). In other embodiments, Compound 1 is administered to treat PTCL having a specific subtype, such as, for example, anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy T-cell lymphoma, and extranodal natural killer (NK) cell / T-cell lymphoma.

[0235] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK +In certain embodiments, the disorder treated by the present invention is recurrent systemic anaplastic large cell lymphoma (ALK + In certain embodiments, the disorder treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK + In certain embodiments, the disorder treated by the present invention is relapsed and refractory systemic anaplastic large cell lymphoma (ALK + ).

[0236] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory systemic anaplastic large cell lymphoma (ALK - In certain embodiments, the disorder treated by the present invention is recurrent systemic anaplastic large cell lymphoma (ALK - In certain embodiments, the disorder treated by the present invention is refractory systemic anaplastic large cell lymphoma (ALK - In certain embodiments, the disorder treated by the present invention is relapsed and refractory systemic anaplastic large cell lymphoma (ALK - ).

[0237] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory angioimmunoblastic T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory angioimmunoblastic T-cell lymphoma.

[0238] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory anaplastic large cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory anaplastic large cell lymphoma.

[0239] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory mantle cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory mantle cell lymphoma.

[0240] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed follicular lymphoma. In certain embodiments, the disorder treated by the present invention is refractory follicular lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory follicular lymphoma.

[0241] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory follicular T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory follicular T-cell lymphoma.

[0242] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory peripheral T-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory peripheral T-cell lymphoma.

[0243] In certain embodiments, the disorder treated by the present invention is relapsed and / or refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is refractory diffuse large B-cell lymphoma. In certain embodiments, the disorder treated by the present invention is relapsed and refractory diffuse large B-cell lymphoma.

[0244] In certain embodiments, Compound 1 is administered to a patient in need thereof in an amount effective to treat follicular T-cell lymphoma. In certain embodiments, Compound 1 is administered to a patient in need thereof in an amount effective to treat angioimmunoblastic T-cell lymphoma. In certain embodiments, Compound 1 is administered to a patient in need thereof in an amount effective to treat systemic anaplastic large cell lymphoma (ALK - In certain embodiments, Compound 1 is administered to a patient in need thereof in an amount effective to treat systemic anaplastic large cell lymphoma (ALK). + ) is administered to a patient in need thereof in an amount effective to treat the condition.

[0245] Additional examples of non-Hodgkin's lymphomas that may be treated with the compounds described herein include double-hit lymphoma, triple-hit lymphoma, extranodal marginal zone B-cell lymphoma of MALT, extranodal NK / T-cell lymphoma, and myeloid lineage lymphoma.

[0246] Treatment of IKZF1 / IKZF3-mediated cancers with prominent mutations In certain embodiments, compound 1 is administered in an amount effective to treat a cancer mediated by a protein having one or more mutations, such as multiple myeloma mediated by a protein having one or more mutations.

[0247] In some embodiments, the compounds described herein can be administered in an effective amount 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., 17p13 or chromosome 13 deletions, del(17 / 17p), non-hyperdiploidy, and (1q) amplification).

[0248] In certain embodiments, the multiple myeloma has a p53 mutation. In certain embodiments, the p53 mutation is a Q331 mutation. In certain embodiments, the p53 mutation is a R273H mutation. In certain embodiments, the p53 mutation is a K132 mutation. In certain embodiments, the p53 mutation is a K132N mutation. In certain embodiments, the p53 mutation is a R337 mutation. In certain embodiments, the p53 mutation is a R337L mutation. In certain embodiments, the p53 mutation is a W146 mutation. In certain embodiments, the p53 mutation is a S261 mutation. In certain embodiments, the p53 mutation is a S261T mutation. In certain embodiments, the p53 mutation is an E286 mutation. In certain embodiments, the p53 mutation is an E286K mutation. In certain embodiments, the p53 mutation is a R175 mutation. In certain embodiments, the p53 mutation is an R175H mutation. In certain embodiments, the p53 mutation is an E258 mutation. In certain embodiments, the p53 mutation is an E258K mutation. In certain embodiments, the p53 mutation is an A161 mutation. In certain embodiments, the p53 mutation is an A161T mutation.

[0249] In certain embodiments, the multiple myeloma has a homozygous deletion of p53. In certain embodiments, the multiple myeloma has a homozygous deletion of wild-type p53. In certain embodiments, the multiple myeloma has wild-type p53.

[0250] In certain embodiments, the multiple myeloma shows activation of one or more oncogenic drivers. In certain embodiments, the one or more oncogenic drivers are selected from the group consisting of C-MAF, MAFB, FGFR3, MMset, cyclin D1 and cyclin D. In certain embodiments, the multiple myeloma shows activation of C-MAF. In certain embodiments, the multiple myeloma shows activation of MAFB. In certain embodiments, the multiple myeloma shows activation of FGFR3 and MMset. In certain embodiments, the multiple myeloma shows activation of C-MAF, FGFR3 and MMset. In certain embodiments, the multiple myeloma shows activation of cyclin D1. In certain embodiments, the multiple myeloma shows activation of MAFB and cyclin D1. In certain embodiments, the multiple myeloma shows activation of cyclin D.

[0251] In certain embodiments, the multiple myeloma has one or more chromosomal translocations. In certain embodiments, the chromosomal translocation is t(14;16). In certain embodiments, the chromosomal translocation is t(14;20). In certain embodiments, the chromosomal translocation is t(4;14). In certain embodiments, the chromosomal translocation is t(4;14) and t(14;16). In certain embodiments, the chromosomal translocation is t(11;14). In certain embodiments, the chromosomal translocation is t(6;20). In certain embodiments, the chromosomal translocation is t(20;22). In certain embodiments, the chromosomal translocation is t(6;20) and t(20;22). In certain embodiments, the chromosomal translocation is t(16;22). In certain embodiments, the chromosomal translocation is t(14;16) and t(16;22). In certain embodiments, the chromosomal translocations are t(14;20) and t(11;14).

[0252] In certain embodiments, the multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, the multiple myeloma has a homozygous deletion of p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, the multiple myeloma has a K132N p53 mutation, activation of MAFB, and a chromosomal translocation at t(14;20). In certain embodiments, the multiple myeloma has wild-type p53, activation of FGFR3 and MMset, and a chromosomal translocation at t(4;14). In certain embodiments, the multiple myeloma has wild-type p53, activation of C-MAF, and a chromosomal translocation at t(14;16). In certain embodiments, the multiple myeloma has homozygous deletion of p53, activation of FGFR3, MMset and C-MAF, and chromosomal translocation at t(4;14) and t(14;16). In certain embodiments, the multiple myeloma has homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, the multiple myeloma has R337L p53 mutation, activation of cyclin D1, and chromosomal translocation at t(11;14). In certain embodiments, the multiple myeloma has W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In certain embodiments, the multiple myeloma has S261T p53 mutation, activation of MAFB, and chromosomal translocation at t(6;20) and t(20;22). In certain embodiments, the multiple myeloma has E286K p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In certain embodiments, the multiple myeloma has R175H p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t(4;14). In certain embodiments, the multiple myeloma has E258K p53 mutation, activation of C-MAF, and chromosomal translocation at t(14;16) and t(16;22). In certain embodiments, the multiple myeloma has wild-type p53, activation of MAFB and cyclin D1, and chromosomal translocation at t(14;20) and t(11;14).In certain embodiments, the multiple myeloma has an A161T p53 mutation, activated cyclin D, and a chromosomal translocation at t(11;14).

[0253] Combination therapy Compound 1 Form I or pharmaceutical compositions comprising or prepared from Compound 1 Form I, or Compound 1 as part of the new dosing regimens described herein, may be administered alone or in combination in effective amounts to treat a host, e.g., a human, having a disorder described herein. In certain embodiments, the compounds described herein are administered with an additional bioactive agent.

[0254] The term "bioactive agent" is used to describe an agent other than the compound according to the present invention that can be administered in combination or alternation with the compound of the present invention to achieve the desired outcome of therapy. In certain embodiments, the morphic form or pharmaceutical composition of the present invention and the bioactive agent are administered such that they are active in vivo during the overlapping period, e.g., Cmax, Tmax, AUC or other pharmacokinetic parameters overlapping. In another embodiment, the morphic form or pharmaceutical composition of the present invention and the bioactive agent are administered to a host in need thereof that do not have overlapping pharmacokinetic parameters, but one has a therapeutic effect on the therapeutic efficacy of the other.

[0255] As used herein, when a compound is administered in combination with another compound, the combination may be administered in one dosage form or in multiple dosage forms at the same time or at different times. In addition, the compounds administered in combination may be administered in different dosing schedules. For example, the combination of compound 1 and dexamethasone may be achieved by a treatment regimen in which compound 1 is administered once a day for 21 consecutive days in a 28-day treatment cycle and dexamethasone is administered once a week during the treatment cycle. Alternative dosing schedules include compound 1 is administered once a day for 14 consecutive days in a 28-day treatment cycle and dexamethasone is administered once a week during the treatment cycle, or compound 1 is administered three times a week, two weeks or three consecutive days in a 28-day treatment cycle and dexamethasone is administered once a week during the treatment cycle.

[0256] Corticosteroids In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with a corticosteroid, hi certain embodiments, the corticosteroid is dexamethasone.

[0257] TIFF2025505687000019.tif64170

[0258] In certain aspects, compound 1 is administered QD in combination with another bioactive agent (e.g., dexamethasone administered once a week) on a 14 / 14 or 21 / 7 dosing schedule every 28 days. In certain embodiments, the dose of dexamethasone for adults 75 years of age or younger is 40 mg QW on days 1, 8, 15, and 22 of a 28 day cycle. In certain embodiments, the dose of dexamethasone for adults over 75 years of age is 20 mg QW on days 1, 8, 15, and 22 of a 28 day cycle. In certain aspects, compound 1 is administered QD in combination with another bioactive agent (e.g., dexamethasone administered once a week) on a 7 / 14 dosing schedule every 21 days. In certain embodiments, the dose of dexamethasone for adults 75 years of age or younger is 40 mg QW on days 1, 8, and 15 of a 21 day cycle. In certain embodiments, the dose of dexamethasone for adults over 75 years of age is 20 mg QW on days 1, 8, and 15 of a 21 day cycle.

[0259] In certain embodiments, the morphic forms or pharmaceutical compositions described herein are administered in combination with a corticosteroid, non-limiting examples of which include dexamethasone, prednisone, fludrocortisone, hydrocortisone, cortisone, betamethasone, and methylprednisolone.

[0260] In certain embodiments, the corticosteroid is dexamethasone.

[0261] Further non-limiting examples of corticosteroids include corticosterone, aldosterone, prednisolone, triamcinolone, budesonide, deflazacort, flugestone, fluorometholone, medrysone, prebedilone acetate, chloroprednisone, cloprednol, difluprednate, fluocinolone, fluperolone, fluperolone acetate, fluprednisolone, loteprednol, prednicarbate, tixocortol. acetaminophen, alclometasone, alclometasone dipropionate, beclomethasone, clobetasol, clobetasone, clocortolone, desoximetasone, diflorasone, diflorasone diacetate, difluocortolone, difluocortolone valerate, fluprednidene, fluprednidene acetate, fluticasone, fluticasone furoate, halometasone, meprednisone, mometasone, mometasone furoate, paramethasone, prednilidene , rimexolone, urobetasol, amcinonide, ciclesonide, desonide, formocortal, fluclorone, fluclorone acetonide, fludroxycortide, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, halcinonide, triamcinolone, triamcinolone acetonide, cortivazol, RU-28362, dexamethasone aceflate, dexamethasone acetate, dexamethasone cepephate sylate, dexamethasone diethylaminoacetate, dexamethasone dipropionate, dexamethasone isonicotinate, dexamethasone linoleate, dexamethasone metasulfobenzoate, dexamethasone palmitate, dexamethasone phosphate, dexamethasone pivalate, dexamethasone succinate, dexamethasone sulfate, dexamethasone tebutate, dexamethasone troxundate, and dexamethasone valerate.

[0262] Kinase inhibitors In certain embodiments, the bioactive agent is a kinase inhibitor, such as a Bruton's tyrosine kinase (BTK) inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton's tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.

[0263] In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with a BTK inhibitor. In certain embodiments, the BTK inhibitor is ibrutinib. In certain embodiments, the BTK inhibitor is acalabrutinib. In certain embodiments, compound 1 is administered in combination with a BTK inhibitor. In certain embodiments, the BTK inhibitor is zanubrutinib. In certain embodiments, compound 1 is administered in combination with ibrutinib. In certain embodiments, compound 1 is administered in combination with zanubrutinib. In certain embodiments, compound 1 is administered in combination with acalabrutinib.

[0264] In certain embodiments, compound 1 is administered to a patient with cancer that has metastasized to the brain. In certain embodiments, compound 1 is administered in combination with ibrutinib to treat cancer that has metastasized to the brain. In certain embodiments, compound 1 is administered in combination with rituximab to treat cancer that has metastasized to the brain.

[0265] Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine 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 U.S. Patent Application Publication No. 2011 / 0117073, which is incorporated by reference in its entirety), dasatinib ([N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide]), LFM-A13 (α-cyano-β -hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide), GDC-0834 ([RN-(3-(6-(4-(1,4-dimethyl-3-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-(morpholine-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-methylpicolinamide), CTA056 (7-benzyl-1-(3-(piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), 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-acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyl quinolin-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-isoquinolin-1-one), as well as other molecules capable of inhibiting BTK activity, such as the BTK inhibitors disclosed in Akinleye et al., Journal of Hematology & Oncology, 2013, 6:59, which is incorporated herein by reference in its entirety.

[0266] In certain embodiments, the BTK inhibitor is selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib. In certain embodiments, compound 1 is administered in combination with a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, and fenebrutinib.

[0267] Examples of PI3 kinase inhibitors include wortmannin, demethoxyviridin, perifosine, idelalisib, pictilisib, Palomid 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]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-phenoxy-2-butanyl hydrogen ( or methyl(oxo){[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium), BYL-719 ((2S)-N1-[4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide), d) (omipalisib), TGX-221 ((±)-7-methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9 -yl)ethyl)amino)benzoic acid), TGR-1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl ]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl) -8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholin-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecane-18-oate), PF-05212384 (N-[4-[[4-(dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-( 4,6-di-4-morpholinyl-1,3,5-triazin-2-yl]phenyl]urea) (gedatorisib), 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}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide) and GSK1059615 (5-[[4-(4-pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidinedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl) ethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate (also known as sonolisib), LY294002, AZD8186, PF-4989216, piraralisib, 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 structures described in WO 2014 / 071109.

[0268] Syk inhibitors include, for example, celduratinib (4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6-({5-fluoro-2-[(3,4,5-trimethoxyphenyl)amino ]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (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), BAY 61-3606 (2-(7-(3,4-dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)-nicotinamide HCl), RO9021 (6-[(1R,2S)-2-amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), Imatinib (Gleevac; 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide), Staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro -2H-pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-d]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-diyl)bis(azanediyl))diphenol), 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]oxazin-3(4H)-one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643), Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), Compound D (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), PRT060318 (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), luteolin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55,3614-3643, which is incorporated herein by reference in its entirety), apigenin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), quercetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), fisetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643, which is incorporated herein by reference in its entirety), 3614-3643 (incorporated herein in its entirety by reference), myricetin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein in its entirety by reference), and morin (Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 (incorporated herein in its entirety by reference).

[0269] Proteasome inhibitors In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with a proteasome inhibitor. In certain embodiments, the proteasome inhibitor is bortezomib. In certain embodiments, the proteasome inhibitor is ixazomib. In certain embodiments, the proteasome inhibitor is carfilzomib. In certain embodiments, compound 1 is administered in combination with a proteasome inhibitor. In certain embodiments, compound 1 is administered in combination with bortezomib. In certain embodiments, compound 1 is administered in combination with ixazomib. In certain embodiments, compound 1 is administered in combination with carfilzomib. In certain embodiments, compound 1 is administered in combination with carfilzomib and daratumumab.

[0270] Further examples of proteasome inhibitors include ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616. In certain embodiments, compound 1 is administered in combination with a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, VLX1570, and KZR-616.

[0271] HDAC inhibitors In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with an HDAC inhibitor. In certain embodiments, the HDAC inhibitor is vorinostat. In certain embodiments, the HDAC inhibitor is romidepsin. In certain embodiments, the HDAC inhibitor is panobinostat. In certain embodiments, the HDAC inhibitor is belinostat. In certain embodiments, compound 1 is administered in combination with an HDAC inhibitor. In certain embodiments, compound 1 is administered in combination with vorinostat. In certain embodiments, compound 1 is administered in combination with romidepsin. In certain embodiments, compound 1 is administered in combination with panobinostat. In certain embodiments, compound 1 is administered in combination with belinostat.

[0272] In certain embodiments, the HDAC inhibitor is selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzamate A, splitomycin, LMK-235, sodium butyrate, pivaloyloxymethylbutyrate, piroxamide, abexinostat, resminostat, divinostat, xinostat, psammaprin A, KD5170, 1-alanine chlamydocin, depudecin, and CUDC-101. In certain embodiments, compound 1 is administered in combination with an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzamate A, splitomycin, LMK-235, sodium butyrate, pivaloyloxymethylbutyrate, piroxamide, abexinostat, resminostat, divinostat, xinostat, psammaprin A, KD5170, 1-alanine chlamydocin, depudecin, and CUDC-101.

[0273] Immunomodulatory imide drugs In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with an immunomodulatory imide drug (IID), also referred to as IMiD™. In certain embodiments, the IID is thalidomide. In certain embodiments, the IID is lenalidomide. In certain embodiments, the IID is pomalidomide. In certain embodiments, compound 1 is administered in combination with thalidomide. In certain embodiments, compound 1 is administered in combination with lenalidomide. In certain embodiments, compound 1 is administered in combination with pomalidomide.

[0274] In certain embodiments, the IID is CC-90009. In certain embodiments, the IID is CC-99282. In certain embodiments, the IID is mezigdomide, also known as CC-92480. In certain embodiments, compound 1 is administered in combination with CC-90009. In certain embodiments, compound 1 is administered in combination with CC-99282. In certain embodiments, compound 1 is administered in combination with CC-92480. In certain embodiments, compound 1 is administered in combination with iverdimide, also known as CC-220.

[0275] In certain embodiments, the IID is selected from CC-90009, CC-99282, mezigdomide (CC-92480), and iberdomide (CC-220).

[0276] antibody In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with an antibody that targets CD20, CD30, or CD38. In certain embodiments, the targeting antibody is rituximab. In certain embodiments, the targeting antibody is daratumumab. In certain embodiments, the targeting antibody is elotuzumab. In certain embodiments, the targeting antibody is isatuximab. In certain embodiments, compound 1 is administered in combination with an antibody that targets CD20, CD30, or CD38. In certain embodiments, compound 1 is administered in combination with rituximab. In certain embodiments, compound 1 is administered in combination with daratumumab. In certain embodiments, compound 1 is administered in combination with elotuzumab. In certain embodiments, compound 1 is administered in combination with isatuximab.

[0277] In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with an antibody-drug conjugate. In certain embodiments, the antibody-drug conjugate is brentuximab vedotin. In certain embodiments, the antibody-drug conjugate is ibritumomab tiuxetan. In certain embodiments, the antibody-drug conjugate is mogamulizumab. In certain embodiments, the antibody-drug conjugate is obinutuzumab. In certain embodiments, the antibody-drug conjugate is polatuzumab vedotin. In certain embodiments, the antibody-drug conjugate is belantamab mafodotin (GSK2857916). In certain embodiments, the antibody-drug conjugate is MEDI2228. In certain embodiments, the antibody-drug conjugate is CC-99712. In certain embodiments, compound 1 is administered in combination with an antibody-drug conjugate. In certain embodiments, compound 1 is administered in combination with brentuximab vedotin. In certain embodiments, compound 1 is administered in combination with ibritumomab tiuxetan. In certain embodiments, compound 1 is administered in combination with mogamulizumab. In certain embodiments, compound 1 is administered in combination with obinutuzumab. In certain embodiments, compound 1 is administered in combination with polatuzumab vedotin. In certain embodiments, compound 1 is administered in combination with belantamab mafodotin (GSK2857916). In certain embodiments, compound 1 is administered in combination with MEDI2228. In certain embodiments, compound 1 is administered in combination with CC-99712. In certain embodiments, compound 1 is administered in combination with tafasitamab.

[0278] In certain embodiments, the morphic form or pharmaceutical composition of the present invention is administered in combination with a bispecific antibody. In certain embodiments, the bispecific antibody is PF-06863135. In certain embodiments, the bispecific antibody is TNB-383B. In certain embodiments, the bispecific antibody is REGN5458. In certain embodiments, the bispecific antibody is JNJ-64007957. In certain embodiments, compound 1 is administered in combination with a bispecific antibody. In certain embodiments, compound 1 is administered in combination with PF-06863135. In certain embodiments, compound 1 is administered in combination with TNB-383B. In certain embodiments, compound 1 is administered in combination with REGN5458. In certain embodiments, compound 1 is administered in combination with JNJ-64007957.

[0279] In certain embodiments, the bispecific antibody is selected from PF-06863135, TNB-383B, REGN5458, and JNJ-64007957.

[0280] In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with a naked monoclonal antibody (mAb). In certain embodiments, the naked mAb is SEA-BCMA. In certain embodiments, Compound 1 is administered in combination with a naked mAb. In certain embodiments, Compound 1 is administered in combination with SEA-BCMA.

[0281] Additional non-limiting examples of CD38 antibodies include felzalutamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, and mezagitamab. In certain embodiments, compound 1 is administered in combination with a CD38 antibody selected from felzalutamab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab.

[0282] CAR T cell therapy Chimeric antigen receptor T cells (CAR-T) are T lymphocytes genetically engineered to express synthetic CAR molecules on their surface. CAR molecules confer the T lymphocyte the ability to recognize cell surface target antigens of interest and mediate exclusive cytotoxicity against cells expressing these antigens (S. Kozani et al. "Nanobody-based CAR-T cells for cancer immunotherapy". Biomarker Research (2022) 10:24). CAR targets include B-cell maturation antigen (BCMA), SLAMF7 (also known as CS1), CD19, CD38, CD138, and GPRC5D. CD38 is highly expressed on MM cells. BCMA is primarily expressed in plasma cells and plasmacytoid dendritic cells, but not in other normal cells, and is therefore thought to be a target for CAR-T cells in the treatment of r / r MM (M. Kleber et al., "BCMA in Multiple Myeloma - A Promising Key to Therapy". J. Clin. Med. 2021, 10, 4088, Nobari et al. "B-cell maturation antigen targeting strategies in multiple myeloma treatment, advantages and disadvantages" J. Transl. Med. (2022) 20:82).Recently, bispecific BCMA-CD38 CAR-T cells containing a BCMA targeting domain and a CD38 targeting domain have been reported (H. Mei et al. "A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma". J. Hematol. Oncol. (2021) 14:161, Y. Tang et al. "High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma". J. Exp. Clin. Cancer Res. (2022) 41:2). BCMA / CS1 bispecific CAR-T cells have also been shown to be effective in targeting MM cells expressing BCMA or CS1 (Zah, E., et al. "Systematically optimized BCMA / CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma". Nat. Commun. (2020), 11, 2283; V. Golubovskaya et al. "Novel CS1 CAR-T Cells and Bispecific CS1-BCMA CAR-T Cells Effectively Target Multiple Myeloma". Biomedicines. 2021 Oct; 9(10): 1422).Bispecific BCMA-CD19 and BCMA-GPRC5D CAR-T have also been described recently (G. Roex et al., "Two for one: targeting BCMA and CD19 in B-cell malignancies with off-the-shelf dual-CAR NK-92 cells". J. Transl. Med. (2022) 20:124; CF de Larrea et al., "Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent BCMA Escape-Driven Relapse in Multiple Myeloma". Blood Cancer Discov. 2020 Sep; 1(2):146-154).

[0283] In certain embodiments, the morphic forms or pharmaceutical compositions of the invention are administered in combination with CAR T cell therapy. In certain embodiments, the CAR T cell therapy is Axicabtagene ciloleucel. In certain embodiments, the CAR T cell therapy is ALLO-715. In certain embodiments, the CAR T cell therapy is bb21217. In certain embodiments, the CAR T cell therapy is BCMA CAR-T. In certain embodiments, the CAR T cell therapy is CD138 CAR-T. In certain embodiments, the CAR T cell therapy is CD19 CAR-T. In certain embodiments, the CAR T cell therapy is Tisagenlecleucel. In certain embodiments, the CAR T cell therapy is Idecabtagene vicleucel (ide-cel; bb2121; ABECMA™ (Celgene)). In certain embodiments, the CAR T cell therapy is LCAR-B38M (JNJ-4528; JNJ-68284528). In certain embodiments, the CAR T cell therapy is P-BCMA-101. In certain embodiments, the CAR T cell therapy is PBCAR269A. In certain embodiments, the CAR T cell therapy is bb21217. In certain embodiments, the CAR T cell therapy is JCARK125 (orva-cel; orvacabtagene autoleucel). In certain embodiments, the CAR T cell therapy is ALLO-715. In certain embodiments, the CAR T cell therapy is Descartes-08. In certain embodiments, the CAR T cell therapy is FCARH143. In certain embodiments, the CAR T cell therapy is CT053.

[0284] In certain embodiments, compound 1 is administered in combination with axicabtagene siloleucel. In certain embodiments, compound 1 is administered in combination with tisagenlecleucel. In certain embodiments, compound 1 is administered in combination with idecabutagen viculeucel (ide-cel; bb2121). In certain embodiments, compound 1 is administered in combination with LCAR-B38M (JNJ-4528; JNJ-68284528). In certain embodiments, compound 1 is administered in combination with P-BCMA-101. In certain embodiments, compound 1 is administered in combination with PBCAR269A. In certain embodiments, compound 1 is administered in combination with bb21217. In certain embodiments, compound 1 is administered in combination with JCARK125 (orva-cel; orvacabutagen viculeucel). In certain embodiments, compound 1 is administered in combination with ALLO-715. In certain embodiments, Compound 1 is administered in combination with Descartes-08. In certain embodiments, Compound 1 is administered in combination with FCARH143. In certain embodiments, Compound 1 is administered in combination with CT053.

[0285] In certain embodiments, the CAR T cell therapy is selected from axicabtagene ciloreucel, tisagenlecleucel, idecbutagen vicelucel (ide-cel; bb2121), LCAR-B38M (JNJ-4528; JNJ-68284528), and P-BCMA-101. In certain embodiments, the CAR T cell therapy is selected from PBCAR269A, bb21217, JCARK125 (orva-cel; orva-celo), ALLO-715, Descartes-08, FCARH143, and CT053.

[0286] In certain embodiments, the CAR T cell therapy is selected from ALLO-715, bb21217, BCMA CAR-T, CD138 CAR-T, CD19 CAR-T, ciltacabtagene autoleucel, CS1 (SLAMF7) CAR-T, CT053, Descartes-11, idecabtagene autoleucel, NKG2D CAR-T, orbacabutagen autoleucel, P-BCMA-101, and UCARTCS1.

[0287] In certain embodiments, the CAR T cell therapy is idecbutagen vecricel, e.g., ABECMA (trademark).

[0288] In certain embodiments, the CAR T cell therapy is lisocabtagene maraleucel, e.g., BREYANZI (trademark).

[0289] In certain embodiments, Compound 1 is administered in combination with lysocbutagen maraleucel, such as BREYANZI (trademark).

[0290] In certain embodiments, the CAR T cell therapy is siltacavtagene autorucel, e.g., CARVYKTI (trademark).

[0291] In certain embodiments, the CAR T cell therapy is tisagenelecleucel, e.g., KYMRIAH™.

[0292] In certain embodiments, the CAR T cell therapy is brexucabtagene autoleucel, e.g., TECARTUS™.

[0293] In certain embodiments, Compound 1 is administered in combination with brexcavtagene autolucel, such as TECARTUS (trademark).

[0294] In certain embodiments, the CAR T cell therapy is axicabtagene silol-eucel, e.g., YESCARTA (trademark).

[0295] In certain embodiments, the CAR T cell therapy is a bispecific CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a BCMA-CD38 CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a BCMA-CS1 CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a BCMA-CD19 CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a BCMA-GPRC5D CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a C19-C20 CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a CD138-CD38 CAR T cell therapy. In certain embodiments, the bispecific CAR T cell therapy is a CD19-CD138 CAR T cell therapy.

[0296] In certain embodiments, compound 1 is administered in combination with bispecific CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with BCMA-CD38 CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with BCMA-CS1 CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with BCMA-CD19 CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with BCMA-GPRC5D CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with C19-C20 CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with CD138-CD38 CAR T cell therapy. In certain embodiments, compound 1 is administered in combination with CD19-CD138 CAR T cell therapy.

[0297] cell therapy In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with cell therapy. In certain embodiments, Compound 1 is used in combination with cell therapy.

[0298] Non-limiting examples of cell therapy include allo-HSCT, allo-NKT, auto-HSCT, and auto-NKT.

[0299] T Cell Engager In certain embodiments, the morphic forms or pharmaceutical compositions of the present invention are administered in combination with a bispecific T cell engager (BiTE). In certain embodiments, the BiTE is blinatumomab. In certain embodiments, the BiTE is CC-93268. In certain embodiments, the BiTE is AMG 420. In certain embodiments, the BiTE is AMG 701. In certain embodiments, Compound 1 is administered in combination with a bispecific T cell engager (BiTE). In certain embodiments, Compound 1 is administered in combination with blinatumomab. In certain embodiments, Compound 1 is administered in combination with AMG 420. In certain embodiments, Compound 1 is administered in combination with CC-93269. In certain embodiments, Compound 1 is administered in combination with AMG 701.

[0300] In certain embodiments, the BiTE is selected from blinatumomab, AMG 420, CC-93269, and AMG 4701. In certain embodiments, the BiTE is BCMA-CD38.

[0301] In certain embodiments, compound 1 is used in combination with a bispecific antibody selected from AMG 420, AMG 701, BFCR4350A, blinatumomab, CC-93269, erlanatamab, EM801, REGN5458, talquetamab, teclistamab, and TNB-383B.

[0302] Immune Modulators Checkpoint Inhibitors In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with a checkpoint inhibitor. In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with a PD-1 checkpoint inhibitor. In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, the morphic form or pharmaceutical composition of the invention is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is nivolumab. In certain embodiments, the checkpoint inhibitor is pembrolizumab. In certain embodiments, the checkpoint inhibitor is interferon alpha-2b. In certain embodiments, compound 1 is administered in combination with a checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with a PD-1 checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with a PD-L1 checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with an IFNAR checkpoint inhibitor. In certain embodiments, compound 1 is administered in combination with nivolumab. In certain embodiments, Compound 1 is administered in combination with pembrolizumab. In certain embodiments, Compound 1 is administered in combination with interferon alpha-2b.

[0303] Examples of PD-1 inhibitors that block the interaction between PD-1 and PD-L1 by binding to the PD-1 receptor and inhibit immunosuppression include nivolumab (OPDIVO™ (Bristol-Myers Squibb)), pembrolizumab (KEYTRUDA™ (Merck & Co)), 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 Inc.) and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). Examples of PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor and inhibit immunosuppression include atezolizumab (TECENTRIQ™ (Genentech)), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab Oncology) and BMS-936559 (Bristol-Myers Squibb). Examples of CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (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).

[0304] In certain embodiments, the checkpoint inhibitor is selected from nivolumab / OPDIVO™; pembrolizumab / KEYTRUDA™; and pidilizumab / CT-011, MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559, PDL2 / Ig fusion proteins such as AMP 224, or inhibitors of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof.

[0305] In certain embodiments, the PD-1 inhibitor is BGB-A317. In certain embodiments, the PD-L1 inhibitor is MED14736. In certain embodiments, the PD-L2 inhibitor is rHIgM12B7A.

[0306] In certain embodiments, the checkpoint inhibitor is a B7 inhibitor, such as a B7-H3 inhibitor or a B7-H4 inhibitor. In certain embodiments, the B7-H3 inhibitor is MGA271.

[0307] In certain embodiments, the checkpoint inhibitor is an OX40 agonist. In certain embodiments, the checkpoint inhibitor is an anti-OX40 antibody, such as anti-OX-40 or MEDI6469.

[0308] In certain embodiments, the checkpoint inhibitor is a GITR agonist. In certain embodiments, the GITR agonist is an anti-GITR antibody, such as TRX518.

[0309] In certain embodiments, the checkpoint inhibitor is a CD137 agonist. In certain embodiments, the CD137 agonist is an anti-CD137 antibody, such as PF-05082566.

[0310] In certain embodiments, the checkpoint inhibitor is a CD40 agonist. In certain embodiments, the CD40 agonist is an anti-CD40 antibody, such as CF-870,893.

[0311] In certain embodiments, the checkpoint inhibitor is an IDO inhibitor, such as INCB24360 or indoximod.

[0312] In certain embodiments, the checkpoint inhibitor is selected from atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab.

[0313] Additional Bioactive Agents In another embodiment, the active compounds described herein can be administered in effective amounts in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist, for the treatment of abnormal tissues of the male reproductive system, such as prostate or testicular cancer. In certain embodiments, the prostate or testicular cancer is androgen resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and U.S. Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti-androgen compounds include enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topirutamide, abiraterone acetate, and cimetidine.

[0314] In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, alectinib, ceritinib, TAE684 (NVP-TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101) and AP26113.

[0315] In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (TARCEVA™ (Genentech)), gefitinib (IRESSA™ (AstraZeneca)), afatinib (GILOTRIF™ (Boehringer Ingelheim)), rociletinib (CO-1686), osimertinib (TAGRISSO™ (AstraZeneca)), olmutinib (OLITA™ (Hanmi Pharm)), and rituximab (TARCEVA™ (Hanmi Pharm)). Co.), nacotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer).

[0316] In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab.

[0317] In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, ofatumumab, ibritumomab, tositumomab, and ocrelizumab.

[0318] In certain embodiments, the bioactive agent is a JAK3 inhibitor. An example of a JAK3 inhibitor is tasocitinib.

[0319] In certain embodiments, the bioactive agent is a JAK inhibitor, such as ruxolitinib.

[0320] In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-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), ABT-737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl), and venetoclax (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl). navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3((trimethylamino)-2-pyridyl)-1,2-dihydro-3,4,5,6-tetra ... Fluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (Obatoclax mesylate, (2Z)-2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid)), 2-Methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9-dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), Pogosine, Ethyl 2- amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, nilotinib-d3, TW-37 (N-[4-[[2-(1,1-dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1-methylethyl)phenyl]methyl]benzamide), apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid or G3139 (oblimersen).

[0321] In certain embodiments, the bioactive agent is venetoclax.

[0322] In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are known, such as trametinib / GSK1120212 (N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY8697 66 / RDEA119 (N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide), PD-0325901 (N-[(2R)-2,3-dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide), TAK73 3((R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxylate R05126766 (3-[[3-fluoro-2-(methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide) or AZD8330 (2-((2-fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX02189, BIX02188, binimetinib, SL-327, TAK-733, PD318088.

[0323] In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known, such as vemurafenib (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-methylpyridine-2-carboxamide; 4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4-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-(trifluoro methyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2-bromoardisine (2-bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf kinase inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-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, AZ628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120 and GX818 (encorafenib).

[0324] In certain embodiments, the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, perifosine (KRX-0401), GDC-0068, triciribine, AZD5363, honokiol, PF-04691502, and miltefosine, an FLT-3 inhibitor, including but not limited to, P406, dovitinib, quizartinib (AC220), amuvatinib (MP-470), tanzutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof.

[0325] In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and its analogs, everolimus (AFINITOR™ (Novartis)), temsirolimus, ridaforolimus, sirolimus, and deforolimus.

[0326] In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, Reolysin and siG12D LODER.

[0327] In certain embodiments, the bioactive agent is an HSP inhibitor, including, but not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), and radicicol.

[0328] In certain embodiments, the bioactive agent is a biphosphonate. Examples of biphosphonates include, but are not limited to, clodronate, pamidronate, and zoledronic acid.

[0329] Additional biologically active 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, enzastaurin, 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, VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1KRX-0402, lucanton, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, Talampanel, Atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, 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]benzoyl]-, 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-(Methylsulfonylpiperazinemethyl)-indolyl-quinolone, Vatalanib, AG-013736, AVE-0005, Goserelin Acetate, Leuprolide Acetate, Triptorelin Pamoate, Medroxyprogesterone Acetate, Hydroxyprogesterone Caproate, Megestrol Acetate raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, canertinib, ABX-EGF antibody, Erbitux, EKB-569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid acid), valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, Gleevec, gemcitabine, hydramnios Roxiurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine,Altretamine, floxuridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxine, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfen e), spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezomib, paclitaxel, paclitaxel without cremophor, docetaxel, epothilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alpha-2a, interferon alpha-2a, pegylated interferon alpha-2b, interferon alpha-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immunoglobulin, nitrogen mustard, methylprednisolone,ibritumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, etidronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa, and mixtures thereof.

[0330] In certain embodiments, the bioactive agent is imatinib mesylate (GLEEVAC™), dasatinib (SPRYCEL™), nilotinib (TASIGNA™), bosutinib (BOSULIF™), trastuzumab (HERCEPTIN™), trastuzumab-DM1, pertuzumab (PERJETA™), lapatinib (TYKERB™), gefitinib (IRESSA™), erlotinib (TARCEVA™), cetuximab (ERBITUX™), panitumumab (VECTIBIX™), vandetanib (CAPRELSA™), vemurafenib (ZELBORAF™), vorinostat (ZOLIN™), or a combination of these. and / or ZA™), romidepsin (ISTODAX™), bexarotene (TAGRETIN™), alitretinoin (PANRETIN™), tretinoin (VESANOID™), carfilzomib (KYPROLIS™), pralatrexate (FOLOTYN™), bevacizumab (AVASTIN™), Ziv-aflibercept (ZALTRAP™), sorafenib (NEXAVAR™), sunitinib (SUTENT™), pazopanib (VOTRIENT™), regorafenib (STIVARGA™), and cabozantinib (COMETRIQ™).

[0331] In certain embodiments, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic agent, an additional therapeutic agent, or an immunosuppressant agent.

[0332] Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic drugs, any agent detrimental to cell viability, and liposomes or other vesicles containing chemotherapeutic compounds. Common anti-cancer drugs include vincristine (ONCOVIN™) or liposomal vincristine (MARQIBO™), daunorubicin (daunomycin or CERUBIDINE™) or doxorubicin (ADRIAMYCIN™), cytarabine (cytosine arabinoside, ara-C or CYTOSAR™), L-asparaginase (ELSPAR™) or PEG-L-asparaginase (pegaspargase or ONCASPAR™), These include etoposide (VP-16), teniposide (VUMON™), 6-mercaptopurine (6-MP or PURINETHOL™), methotrexate, cyclophosphamide (CYTOXAN™), prednisone, dexamethasone (Decadron), imatinib (GLEEVEC™), dasatinib (SPRYCEL™), nilotinib (TASIGNA™), bosutinib (BOSULIF™), and ponatinib (ICLUSIG™). Examples of additional suitable chemotherapeutic agents include 1-dehydrotestosterone, 5-fluorouracil, dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), antimitotic agents, cis-dichlorodiamineplatinum(II) (DDP) (cisplatin), diaminodichloroplatinum, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG bacteria (BCGlive (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyclothosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin, dactinomycin (formerly actinomycin), daunorubicin HCL, daunorubicin citrate, denileukin diftitox, dexrazoxane, dibromomannitol, dihydroxy anthracin dione dione), docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, Escherichia coli (E.coli) L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine sodium phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide, citrovorum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoids, Mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, disodium pamidronate, pentostatin, pilocarpine HCL, primycin, porphyromonas sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil chlorambucil), thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0333] In some embodiments, the morphic forms or pharmaceutical compositions of the present invention are administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or another chemical compound useful in the treatment of cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodopyrotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, adrenocortical steroids, 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; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatasin and bullatasinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); Cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatins; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as the enediyne antibiotics (e.g., the calicheamicins, especially calicheamicin gamma-mol and calicheamicin omegal) (see, e.g., Agnew, Chem. Inti. Ed Engl. 33:183-186 (1994)); the dynemicins, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoproteins (enediyne, antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo -5-oxo-L-norleucine, ADRIAMYCIN™ (doxorubicins including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potofilomycin, puromycin, keramycin, rodorubicin, streptonigrin, phosphodiesterase, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; metabolic antagonists such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxacin, Pyrimidine analogues such as lysine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as floric acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diazicon; elfomitine; elliptinium acetate; epothilone;Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Maytansinoids such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidamol; Nitraerin; Pentostatin; Phenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine; PSK™ Polysaccharide Complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids such as TAXOL™ (paclitaxel, Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE™, Cremophor Free, an albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumburg, IL), and TAXOTERE™ docetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR™ gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE™ vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (e.g., CPT-11); topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents can be used in cocktails to be administered in combination with the morphic forms or pharmaceutical compositions of the present invention. Suitable dosing regimens for combination chemotherapy are widely 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).

[0334] Additional therapeutic agents that may be administered in combination with the compounds disclosed herein include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, and the like. Mab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiplimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nervium mesylate Finavir, indinavir sulfate, belinstat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene Examples of other anti-cancer drugs include AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), abemaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B).

[0335] In certain embodiments, the 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 cancer cell surface and trigger its 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 the development of tumor blood vessels. When VEGF binds to bevacizumab, it cannot interact with its cell receptor, preventing signaling that leads to the growth of new blood vessels. 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 receptor from sending normal growth-promoting signals. They can also induce apoptosis and activate the immune system to destroy tumor cells.

[0336] In one embodiment of the invention, the bioactive agent is an immunosuppressant. Immunosuppressants include calcineurin inhibitors such as cyclosporine or ascomycin, e.g., cyclosporine A (NEORAL™), FK506 (tacrolimus), pimecrolimus, mTOR inhibitors such as rapamycin or derivatives thereof, e.g., sirolimus (RAPAMUNE™), everolimus (CERTICAN™), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalogs such as ridaforolimus, azathioprine, campath 1H, S1P receptor modulators such as fingolimod or analogs thereof, anti-IL-8 antibodies, mycophenolic acid or a salt thereof, e.g., the sodium salt or a prodrug thereof, e.g., mycophenolate mofetil (CELLCEPT™), OKT3 (ORTHOCLONE™), and the like. OKT3™), prednisone, ATGAM™, THYMOGLOBULIN™, brequinar sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, leflunomide (ARAVA™), CTLAI-Ig, anti-CD25, anti-IL2R, basiliximab (SIMULECT™), daclizumab (ZENAPAX™), mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, ELIDEL™), CTLA4Ig (abatacept), belatacept, LFA3Ig, etanercept (sold as ENBREL™ by Immunex), adalimumab (HUMIRA™), infliximab (REMICADE™), anti-LFA-1 antibody, natalizumab (ANTEGREN™), enlimomab, gavilimomab, anti-thymocyte immunoglobulin, siplizumab, alefacept, efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

[0337] In some embodiments, the bioactive agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in cancer treatment. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumab (AVASTIN™). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragments thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to the cancer.Such agents include, but are not limited to, RITUXAN™ (rituximab); ZENAPAX™ (daclizumab); SIMULECT™ (basiliximab); SYNAGIS™ (palivizumab); REMICADE™ (infliximab); HERCEPTIN™ (trastuzumab); MYLOTARG™ (gemtuzumab ozogamicin); CAMPATH™ (alemtuzumab). ;ZEVALIN(TM) (Ibritumomab Tiuxetan);HUMIRA(TM) (Adalimumab);XOLAIR(TM) (Omalizumab);BEXXAR(TM) (Tositumomab-I-131);RAPTIVA(TM) (Efalizumab);ERBITUX(TM) (Cetuximab);AVASTIN(TM) (Bevacizumab);TYSABRI(TM) (Natalizumab);ACTEMRA(TM) (Tosi tsirolimumab;VECTIBIX(TM) (panitumumab);LUCENTIS(TM) (ranibizumab);SOURIS(TM) (eculizumab);CIMZIA(TM) (certolizumab pegol);SIMPONI(TM) (golimumab);ILARIS(TM) (canakinumab);STELARA(TM) (ustikinumab);ARZERRA(TM) (ofatumumab);PROLIA(TM) (denosumab ); NUMAX™ (motavizumab); ABTHRAX™ (raxibacumab); BENLYSTA™ (belimumab); YERVOY™ (ipilimumab); ADCETRIS™ (brentuximab vedotin), PERJETA™ (pertuzumab), KADCYLA™ (ado-trastuzumab emtansine); and GAZYVA™ (obinutuzumab). Antibody-drug conjugates are also included.

[0338] In certain embodiments, the additional therapy is bendamustine. In certain embodiments, the additional therapy is obinutuzumab. In certain embodiments, the additional therapy is a proteasome inhibitor, such as ixazomib or oprozomib. In certain embodiments, the additional therapy is a histone deacetylase inhibitor, such as ACY241. In certain embodiments, the additional therapy is a BET inhibitor, such as GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610, INCB54329, BAY1238097, FT-1101, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one, EP11313, and EP11336. In certain embodiments, the additional therapy is an MCL-1 inhibitor, such as AZD5991, AMG176, MIK665, S64315, or S63845. In certain embodiments, the additional therapy is an LSD-1 inhibitor, such as ORY-1001, ORY-2001, INCB-59872, IMG-7289, TAK-418, GSK-2879552, 4-[2-(4-amino-piperidin-1-yl)-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]-2-fluoro-benzonitrile or a salt thereof. In certain embodiments, the additional therapy is a CS1 antibody, such as elotuzumab. In certain embodiments, the additional therapy is a CD38 antibody, such as daratumumab or isatuximab. In certain embodiments, the additional therapy is a BCMA antibody or antibody-conjugate, such as GSK2857916 or BI 836909.

[0339] In certain embodiments, the bioactive agent is selinexor. In certain embodiments, Compound 1 is administered in combination with selinexor. In certain embodiments, Compound 1 is administered in combination with aspirin.

[0340] In other embodiments, a compound described herein is administered in combination with an agent selected from selinexor, oxafenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricorinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, urocuprumab, and urelumab.

[0341] In certain embodiments, Compound 1 is used in combination with a chemokine receptor antagonist, such as plerixafor.

[0342] In certain embodiments, Compound 1 is used in combination with a vaccine, such as PVX-410.

[0343] In certain embodiments, Compound 1 is used in combination with a chemotherapeutic agent, such as bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.

[0344] In certain embodiments, compound 1 is used in combination with a conjugated antibody, such as belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.

[0345] In certain embodiments, compound 1 is used in combination with a phospholipid-drug conjugate, such as CLR 131.

[0346] In certain embodiments, the compounds described herein are used in combination with a chemokine receptor antagonist, such as plerixafor.

[0347] In certain embodiments, the compounds described herein are used in combination with a vaccine, such as PVX-410.

[0348] In certain embodiments, the compounds described herein are used in combination with a chemotherapeutic agent such as bendamustine, busulfan, carmustine, cyclophosphamide, doxorubicin, etoposide, fludarabine, melphalan, or vincristine.

[0349] In certain embodiments, the compounds described herein are used in combination with a conjugated antibody, such as belantamab mafodotin, CC-99712, HDP-101, or MEDI2228.

[0350] In certain embodiments, the compounds described herein are used in combination with a phospholipid-drug conjugate, such as CLR 131.

[0351] In certain embodiments, the compound described herein is used in combination with CHOP regimen (cyclophosphamide, vincristine, prednisone, and daunorubicin).In certain embodiments, compound 1 is used in combination with CHOP regimen (cyclophosphamide, vincristine, prednisone, and daunorubicin).In certain embodiments, compound 1, rituximab, and CHOP are administered in combination.

[0352] In certain embodiments, the compounds described herein are used in combination with CVP regimen (cyclophosphamide, vincristine, and prednisone). In certain embodiments, compound 1 is used in combination with CVP regimen (cyclophosphamide, vincristine, and prednisone). In certain embodiments, compound 1, rituximab, and CVP are administered in combination.

[0353] In certain embodiments, the compounds described herein are used in combination with romidepsin, belinstat, or brentuximab to treat cancer, such as T-NHL. In certain embodiments, compound 1 is used in combination with romidepsin, belinstat, or brentuximab to treat cancer, such as T-NHL.

[0354] In certain embodiments, the compounds described herein are used in combination with polatuzumab, tafasitamab, CAR-T, BTK inhibitors, or PI3 kinase inhibitors to treat cancer, such as B-NHL. In certain embodiments, compound 1 is used in combination with polatuzumab, tafastamab, CAR-T, BTK inhibitors, or PI3 kinase inhibitors to treat cancer, such as B-NHL.

[0355] In certain embodiments, compound 1 is used to treat relapsed and / or refractory mantle cell leukemia. In certain embodiments, compound 1 and rituximab are used to treat relapsed and / or refractory mantle cell leukemia. In certain embodiments, compound 1, rituximab, and bendamustine are used to treat relapsed and / or refractory mantle cell leukemia. In certain embodiments, compound 1, rituximab, and ibrutinib are used to treat relapsed and / or refractory mantle cell leukemia.

[0356] In certain embodiments, the cancer is primary central nervous system lymphoma (PCNSL).

[0357] In certain embodiments, Compound 1 is used to treat relapsed and / or refractory marginal zone leukemia. In certain embodiments, Compound 1 and rituximab are used to treat relapsed and / or refractory marginal zone leukemia. In certain embodiments, Compound 1, rituximab, and dexamethasone are used to treat relapsed and / or refractory marginal zone leukemia.

[0358] In certain embodiments, compound 1 is used in combination with rituximab and DHAP (dexamethasone, cytarabine, and cisplatin). In certain embodiments, compound 1 is used in combination with DHAP (dexamethasone, cytarabine, and cisplatin). In certain embodiments, compound 1 is used in combination with rituximab and ICE (ifosfamide, carboplatin, and etoposide). In certain embodiments, compound 1 is used in combination with ICE (ifosfamide, carboplatin, and etoposide). In certain embodiments, compound 1 is used in combination with rituximab and GemOx (gemcitabine and oxaliplatin). In certain embodiments, compound 1 is used in combination with GemOx (gemcitabine and oxaliplatin). In certain embodiments, compound 1 is used in combination with polatuzumab and brentuximab. In certain embodiments, compound 1 is used in combination with polatuzumab. In certain embodiments, compound 1 is used in combination with tafasitamab. In certain embodiments, compound 1 is used in combination with tafasitamab and lenalidomide. In certain embodiments, compound 1 is used in combination with rituximab and lenalidomide. In certain embodiments, compound 1 is used in combination with anti-CD19 CART (e.g., axicabtagene, lysocabtagene, tisagenlecleucel, loncastuximab, or tesirin). In certain embodiments, one of the above combinations is used to treat DLBCL or B-NHL.

[0359] In certain embodiments, compound 1 is used in combination with praltrexate. In certain embodiments, compound 1 is used in combination with bendamustine. In certain embodiments, compound 1 is used in combination with brexcavtagene. In certain embodiments, compound 1 is used in combination with bortezomib and rituximab. In certain embodiments, compound 1 is used in combination with bendamustine and rituximab. In certain embodiments, compound 1 is used in combination with VR-CAP (rituximab, cyclophosphamide, doxorubicin, prednisone, and bortezomib).

[0360] In certain embodiments, compound 1 is used in combination with carfilzomib and daratumumab.

[0361] In certain embodiments, compound 1 is used in combination with avecuma. In certain embodiments, compound 1 is used in combination with melflufen. In certain embodiments, compound 1 is used in combination with siltacabtagene autorucel.

[0362] Non-limiting examples of combination or monotherapies comprising Compound 1 Form I, pharma- ceutically acceptable compositions prepared from Compound 1 Form I, or novel dosing regimens of Compound 1 for specific cancers are described below.

[0363] TIFF2025505687000020.tif225170

[0364] Additional non-limiting examples of combination or monotherapy treatments involving Compound 1 Form I, pharma- ceutically acceptable compositions prepared from Compound 1 Form I, or novel dosing regimens of Compound 1 for specific cancers are described below.

[0365] TIFF2025505687000021.tif150170

[0366] In certain embodiments, the combinations described above are used to treat different cancers. In certain embodiments, the cancers are doubly refractory, triply refractory, quad refractory, or penta refractory, such as penta refractory multiple myeloma.

[0367] In certain embodiments, the monotherapy or combination described herein further comprises administering one or more additional therapeutic agents to reduce the side effects of the treatment. For example, in certain embodiments, Compound 1 or a combination comprising Compound 1 is administered simultaneously with, before, or after administration of an antineutropenic drug, an antiemetic drug, an antihistamine, and / or an antipain drug. Non-limiting examples of antineutropenic drugs include growth factors, such as granulocyte colony stimulating factor (G-CSF). In certain embodiments, the treatments in the above table are administered in combination with G-CSF. G-CSF (or other active agent) can be given before Compound 1, after Compound 1, or on a different day than Compound 1.

[0368] Non-limiting examples of granulocyte colony stimulating factors include filgrastim (neupogen, zarxio, nivestim, or other forms), CG-10639, and PEGF.

[0369] In certain embodiments, the granulocyte colony stimulating factor is pegfilgrastim. In certain embodiments, the granulocyte colony stimulating factor is Neulasta. In certain embodiments, the granulocyte colony stimulating factor is selected from Ristempa, Tezmota, Fulphila, Pelgraz, Udenyca, Udenyca, Pelmeg, Ziextenzo, Grasustek, Ziextenzo, Lapelga, Neutropeg, Cegfila, Nyvepria, and Stimufend.

[0370] In certain embodiments, the therapeutic methods described herein further comprise an antiemetic drug, non-limiting examples of which include aprepitant, dolasetron, granisetron, ondansetron, palonosetron, prochlorperazine, promethazine, netupitant-palonosetron, rolapitant, lorazepam, metoclopramide, famotidine, dexamethasone, and ranitidine.

[0371] In certain embodiments, the methods of treatment described herein further comprise an antihistamine, non-limiting examples of which include benadryl, cetirizine, loratadine, and fexofenadine.

[0372] In certain embodiments, the therapeutic methods described herein further comprise an analgesic, non-limiting examples of which include tramadol, hydromorphone, methadone, morphine, oxycodone, hydrocodone, oxymorphone, fentanyl, and tapentadol.

[0373] Pharmaceutical Compositions In certain embodiments, a pharmaceutical composition is provided that includes an effective amount of Compound 1 Form I and one or more pharma- ceutically acceptable excipients. In other embodiments, a pharmaceutical composition is prepared from Compound 1 Form I. For example, Compound 1 Form I can be dissolved or suspended in an excipient, and the mixture can then be used to fill gel capsules, or can be used as a liquid dosage form, such as a pharmaceutical composition for intravenous administration. In other embodiments, Compound 1 Form I is dissolved in a solvent, optionally mixed with one or more excipients, and then dried or spray-dried to form a solid. In other embodiments, Compound 1 is used in a pharmaceutical composition for use in the new dosing regimen described herein. The pharmaceutical composition may contain the compound or salt as the only active agent, or in alternative embodiments, the compound and at least one additional active agent.

[0374] In certain embodiments, the pharmaceutical composition is in a dosage form containing about 1 μg to about 2000 μg, about 10 μg to about 1000 μg, about 50 μg to about 600 μg, or about 100 μg to about 400 μg of active compound. In other embodiments, the pharmaceutical composition is in a dosage form containing about 1 μg to about 400 μg, about 5 μg to about 400 μg, about 10 mg to about 250 μg, or about 25 μg to about 250 μg of active compound. Examples include, at least or in some embodiments, dosage forms that contain up to 0.1 μg, 1 μg, 5 μg, 10 μg, 12.5 μg, 25 μg, 37.5 μg, 50 μg, 62.5 μg, 75 μg, 100 μg, 200 μg, 250 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, or 750 μg of active compound or a salt thereof.

[0375] The pharmaceutical composition may also contain a molar ratio of the active compound and the additional bioactive agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.0005:1, about 0.001:1, about 0.01:1, about 0.05:1, or about 0.1:1 of the active compound to the anti-inflammatory or immunosuppressant agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1 of the active compound to the anti-inflammatory or immunosuppressant agent. The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by implants, including ocular implants, transdermally, by buccal administration, rectally, as eye drops, injections, including intraocular injections, intravenously, intra-aortal, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingual or rectal, or by other means in dosage unit formulations containing conventional pharma- ceutically acceptable carriers. For intraocular delivery, the compounds can be administered, for example, by intravitreal, intrastromal, intracameral, sub-Tenon, subretinal, retrobulbar, peribulbar, suprachoroidal, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, pericornal or lacrimal injection, or in immediate or controlled release mode via mucus, mucin or mucosal barriers, or by intraocular devices, as desired.

[0376] The pharmaceutical compositions can be formulated as any pharma- ceutical useful form, such as an aerosol, cream, gel, pill, injection or infusion solution, capsule, tablet, syrup, transdermal patch, subcutaneous patch, dry powder, inhalation formulation within a medical device, suppository, buccal or sublingual formulation, parenteral formulation, or eye drops. Some dosage forms, such as tablets and capsules, are divided into suitably sized unit doses containing an appropriate amount of the active ingredient, e.g., an effective amount to achieve a desired purpose.

[0377] In certain embodiments, the pharmaceutical composition is a tablet suitable for oral administration.

[0378] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. Carriers may be inert or may have their own medicinal properties. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0379] Types of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, for example, vegetable oils can be used as lubricants in some formulations and as diluents in others. A pharmaceutically acceptable carrier is one that does not cause any significant adverse reactions in the human body when administered in the amounts used in the corresponding pharmaceutical composition. Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Any active agent that does not substantially interfere with the activity of the morphic form or pharmaceutical composition of the present invention may be included in the pharmaceutical composition.

[0380] Formulations suitable for rectal administration are usually presented as unit-dose suppositories, which may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0381] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0382] Formulations suitable for transdermal administration can be provided as individual patches adapted to remain in intimate contact with the epidermis of the recipient for an extended period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)), and typically take the form of an aqueous solution of active compound, optionally buffered. In certain embodiments, microneedle patches or devices are provided for the delivery of drugs across or into biological tissue, particularly the skin. Microneedle patches or devices allow drug delivery across or into the skin or other tissue barrier at clinically relevant rates with little or no damage, pain or irritation to the tissue.

[0383] Formulations suitable for pulmonary administration can be delivered by a wide range of passive respiratory and active powered single / multiple dose dry powder inhalers (DPIs).The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers and dry powder inhalers.Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers and vibrating mesh nebulizers.The selection of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action and the pathophysiology of the lungs.

[0384] In certain embodiments, the compounds described herein, such as Compound 1, are formulated as described in Table A.

[0385] The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example, 0.1% by weight (wt.%) to 99% by weight (wt.%) of the compound, usually at least about 5% by weight of the compound. Some embodiments contain about 25% by weight to about 50% by weight, or about 5% by weight to about 75% by weight of the compound.

[0386] In certain embodiments, the pharmaceutical composition is a tablet comprising 12.5 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0387] In certain embodiments, the pharmaceutical composition is a tablet comprising 25 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0388] In certain embodiments, the pharmaceutical composition is a tablet comprising 37.5 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0389] In certain embodiments, the pharmaceutical composition is a tablet comprising 50 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0390] In certain embodiments, the pharmaceutical composition is a tablet comprising 62.5 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0391] In certain embodiments, the pharmaceutical composition is a tablet comprising 75 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0392] In certain embodiments, the pharmaceutical composition is a tablet comprising 87.5 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0393] In certain embodiments, the pharmaceutical composition is a tablet comprising 100 μg of Compound 1 or a pharma- ceutically acceptable salt thereof.

[0394] Liquid-filled capsules and gel capsules In certain embodiments, a liquid-filled or gel-filled capsule (as used herein, gel capsule refers to either liquid-filled or gel-filled capsule) is provided that contains an effective amount of Compound 1 Form I as a suspension and one or more pharma- ceutically acceptable excipients. In other embodiments, the gel capsule is prepared from Compound 1 Form I. In certain embodiments, the gel capsule contains Compound 1 Form I as a suspension or Compound 1 as a solution and a liquid excipient. Non-limiting examples of liquid excipients include polyethylene glycol, aqueous surfactants such as polysorbates, alcohols such as ethanol, and glycerin.

[0395] In certain embodiments, the gel capsule is a hydrogel capsule. Hydrogels provide unique morphology including swelling and elasticity. The rate of swelling of the hydrogel can be adjusted to change the release rate of the drug, and the elasticity of the system can be adjusted to change the stability and slow the release. The hydrogel capsule can provide both spatial and temporal control over the release of Compound 1 Form I or Compound 1. In other embodiments, Compound 1 Form I or Compound 1 is administered as a hydrogel outside the capsule, for example, as a liquid solution or suspension that forms a hydrogel when administered into the body. Non-limiting examples of hydrogels include various macroscopic hydrogels, such as in situ gelling hydrogels (e.g., liquid solutions that form a gel after injection into the body), shear thinning hydrogels (e.g., hydrogels that can be injected into the body via shear stress), and microporous hydrogels (hydrogels with large interconnected pores that can recover after being crushed by mechanical forces). Alternatively, non-macroscopic hydrogels, such as microgels or nanogels, can be used.

[0396] In certain embodiments, Compound 1 Form I is a solid suspended in a hydrogel.

[0397] TIFF2025505687000022.tif37170

[0398] In certain embodiments, the concentration of Compound 1 of Table A is instead about 0.20 mg / capsule, 0.15 mg / capsule, 0.10 mg / capsule, 0.05 mg / capsule, or 0.01 mg / capsule, and the concentration of PEG 400 is adjusted to maintain a total volume of 1200 mg / capsule, 300 mg / capsule, or 250 mg / capsule.

[0399] In certain embodiments, the present invention provides a pharmaceutical composition comprising Compound 1, a non-aqueous solvent, a preservative, and / or a pH controlling agent.

[0400] In certain embodiments, a compound described herein, such as Compound 1, is formulated as described herein, for example, as described in Table B or Table C.

[0401] Non-limiting examples of preservatives include alcohol (e.g., ethanol, benzyl alcohol), aluminum acetate, benzalkonium chloride, benzethonium chloride, benzoic acid and its salts (e.g., potassium benzoate, sodium benzoate), boric acid and its salts (e.g., sodium borate), bronopol, butylene glycol, butylated hydroxyanisole, calcium acetate, calcium chloride, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, citric acid monohydrate, cresol, dimethyl ether, edetic acid and its salts, gelatin, glycerin, hexetidine, imidurea, lactic acid and its salts (e.g. ... For example, calcium lactate, sodium lactate), monothioglycerol, parabens (e.g., butylparaben, ethylparaben, methylparaben, propylparaben, sodium propylparaben), pentetic acid and its salts, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, propyl gallate, potassium metabisulfite, sorbic acid and its salts (e.g., potassium sorbate), propionic acid and its salts (e.g., sodium propionate), propylene glycol, sodium acetate, sodium sulfite, sulfur dioxide, thimerosal, and xylitol.

[0402] The term pH control agent may be used interchangeably with pH adjusters, pH regulators, and / or buffers. Non-limiting examples of pH control agents include acetic acid, glacial acetic acid, adipic acid, strong ammonia solution and its salts (e.g., ammonium carbonate, ammonium chloride, ammonium phosphate), arginine, boric acid and its salts (e.g., sodium borate), calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate tribasic, citric acid (anhydrous or monohydrate) and its salts (e.g., potassium citrate, sodium citrate), diethanolamine, fumaric acid and its salts, glycine, gluconic acid, hydrochloric acid, dilute hydrochloric acid, alpha-lactalbumin, lactic acid and its salts (e.g., sodium lactate, sodium solution), lysine hydrochloride, maleic acid, malic acid, methionine, monoethanolamine, monosodium glutamate, meglumine, nitric acid, phosphoric acid and its salts (e.g., sodium phosphate dibasic, sodium phosphate monobasic, potassium phosphate, potassium hydrogen phosphate, potassium phosphate dibasic), dilute phosphoric acid, potassium bicarbonate, potassium hydroxide, potassium metaphosphate monobasic, propionic acid, racemethionine, sodium acetate, sodium bicarbonate, sodium carbonate, sodium hydroxide, succinic acid, sulfuric acid, tartaric acid, trolamine, hydroxides, amines, and their salts.

[0403] Non-limiting examples of buffering agents include, but are not limited to, adipic acid, ammoniacal solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, citric acid, sodium phosphate, diethanolamine, maleic acid, malic acid, methionine, monoethanolamine, sodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide, sodium lactate, and triethanolamine.

[0404] In certain embodiments, the buffering agent is selected from carbonate, citrate, gluconate, lactate, phosphate, tartrate, potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and dihydrate.

[0405] In certain embodiments, the pharmaceutical composition comprises water.

[0406] In certain embodiments, the pharmaceutical composition comprises a non-aqueous or anhydrous solvent.

[0407] Non-limiting examples of non-aqueous solvents include alcohols (e.g., ethanol), PEG 300, PEG 400, propylene glycol, cremophor, caplex 355, Capryol™ 90, Lauroglycol™ 90, Transcutol HP, butylated hydroxytoluene, benzyl alcohol, citric acid, triacetin, propylene glycol, lipids and oils.

[0408] TIFF2025505687000023.tif40170

[0409] TIFF2025505687000024.tif41170

[0410] In certain embodiments, the concentration of Compound 1 of Table A is instead about 0.20 mg / capsule, 0.15 mg / capsule, 0.10 mg / capsule, 0.05 mg / capsule, or 0.01 mg / capsule, and the concentrations of other excipients are adjusted to maintain or achieve a total volume of 1200 mg / capsule, 300 mg / capsule, or 250 mg / capsule.

[0411] 1. In certain embodiments, Compound 1 is provided in a liquid-filled capsule containing a solvent, a preservative, and a pH control agent, and Compound 1 was Compound 1 Form I described herein before being dissolved. 2. The capsule comprises about 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.033%, 0.035%, 0.04%, 0.045%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0. ...9%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 0.9%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, 0.5%, 0.5%, 0.6%, 0 The pharmaceutical composition of embodiment 1, wherein the pharmaceutical composition is filled with a solution comprising 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of Compound 1. 3. The capsule comprises at least about 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.033%, 0.035%, 0.04%, 0.045%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3% by weight , 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of Compound 1. 4. The pharmaceutical composition of any one of embodiments 1 to 3, wherein the solvent is not aqueous. 5. The pharmaceutical composition of embodiment 4, wherein the solvent is PEG. 6. The pharmaceutical composition of embodiment 5, wherein the solvent is PEG 400. 7. The pharmaceutical composition of any one of embodiments 1-6, wherein the capsule is filled with a solution comprising about 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.75%, 98.8%, 98.85%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, or 99.5% by weight of the solvent. 8. The pharmaceutical composition of any one of embodiments 1-6, wherein the capsule is filled with a solution comprising at least about 85%, 90%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.75%, 98.8%, 98.85%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, or 99.5% by weight of the solvent. 9. The pharmaceutical composition of any one of embodiments 1-8, wherein the preservative is butylated hydroxytoluene. 10. The pharmaceutical composition of any one of embodiments 1-9, wherein the capsule is filled with a solution comprising at least about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, or 1% by weight of a preservative. 11. The pharmaceutical composition of any one of embodiments 1-9, wherein the capsule is filled with a solution comprising about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, or 1% by weight of a preservative. 12. The pharmaceutical composition of any one of embodiments 1-11, wherein the pH control agent is citric acid. 13. The pharmaceutical composition of any one of embodiments 1-11, wherein the pH control agent is anhydrous citric acid. 14. The pharmaceutical composition of any one of embodiments 1-13, wherein the capsule is filled with a solution comprising at least about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.25%, 2.5%, 2.75%, or 3% by weight of the pH control agent. 15. The pharmaceutical composition of any one of embodiments 1-13, wherein the capsule is filled with a solution comprising about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.25%, 2.5%, 2.75%, or 3% by weight of the pH control agent. 16. The pharmaceutical composition of any one of embodiments 1-15, comprising about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg of compound 1. 17. The pharmaceutical composition of any one of embodiments 1 to 15, comprising about 12.5 μg of compound 1. 18. The pharmaceutical composition of any one of embodiments 1 to 15, comprising about 25 μg of compound 1. 19. The pharmaceutical composition of any one of embodiments 1 to 15, comprising about 37.5 μg of compound 1. 20. A pharmaceutical composition of any one of embodiments 1 to 15, comprising about 50 μg of compound 1. 21. The pharmaceutical composition of any one of embodiments 1 to 15, comprising about 62.5 μg of compound 1. 22. The pharmaceutical composition of any one of embodiments 1 to 15, comprising about 75 μg of compound 1.

[0412] In other embodiments, compound 1 is provided as a tablet containing one or more pharma- ceutically acceptable excipients. In certain embodiments, compound 1. In certain embodiments, the tablet contains about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg of compound 1. In certain embodiments, the tablet contains about 12.5 μg of compound 1. In certain embodiments, the tablet contains about 25 μg of compound 1. In certain embodiments, the tablet contains about 37.5 μg of compound 1. In certain embodiments, the tablet contains about 50 μg of compound 1. In certain embodiments, the tablet contains about 62.5 μg of compound 1. In certain embodiments, the tablet contains about 75 μg of compound 1. In certain embodiments, the tablet contains about 87.5 μg of compound 1. In certain embodiments, the tablet contains about 100 μg of Compound 1.

[0413] Additional excipients In certain embodiments, the compounds described herein are administered as a pharmaceutical composition comprising one or more excipients from the Handbook of Pharmaceutical Excipients, 9th Edition (or any earlier edition).

[0414] In certain embodiments, the compounds described herein are dissolved or dispersed in an oil component, which upon oral administration forms a microemulsion in the digestive system, allowing the compounds to be absorbed more quickly in the body.

[0415] In certain embodiments, the oil is an edible oil, a medicinal oil, a pharma- ceutically acceptable oil or fat, or a food acceptable oil or fat, for example, a pharma- ceutically acceptable oil or fat, including, but not limited to, a vegetable oil, an animal oil, a fish oil, or a mineral oil.

[0416] In certain embodiments, the edible oil is selected from the group consisting of medium chain triglycerides, amaranth oil, apricot oil, apple oil, argan oil, artichoke oil, avocado oil, almond oil, acai berry extract, peanut oil, buffalo pumpkin oil, borage seed oil, borage oil, babassu oil, coconut oil, corn oil, cottonseed oil (cotton seed oil), cashew oil, carob oil, coriander oil, camellia oil (Camellia oil), cauliflower oil, chestnut oil, blackcurrant oil, deer oil, evening primrose oil, grape syrup oil, hibiscus oil, grapeseed oil, gourd oil, hazelnut oil, hemp oil, kapok oil, krill oil, linseed oil, macadamia nut oil, Mongolian oil, moringa oil, marula oil, meadowfoam oil, mustard oil, niger seed oil, olive oil, okrao oil, palm oil, palm kernel oil, peanut oil, pecan oil, pine oil, pistachio oil, pumpkin oil, papaya oil, perilla oil, poppy seed oil, prune oil, saw palmetto oil, quinoa oil, rapeseed oil, rice germ oil, rice bran oil, rice oil, lalermantia oil, safflower oil oil), soybean oil, sesame oil, sunflower oil, thistle oil, tomato oil, wheat germ oil, walnut oil, watermelon oil, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and any combination thereof.

[0417] In certain embodiments, fat-soluble oils, including but not limited to vitamin A oil, vitamin D oil, vitamin E oil, vitamin K oil and derivatives thereof, and glycerophospholipids such as lecithin, and any combination thereof, may also be used as fats and oils in the present invention.

[0418] In certain embodiments, the oils in the present invention may be liquid (such as fats and oils) or solid (such as fats) at room temperature. In certain embodiments, the oils in the present invention are liquid at in vivo temperatures (particularly stomach temperature, about 37° C.). In certain embodiments, the fats contain many saturated fatty acids (e.g., palmitic acid, stearic acid) and / or the fatty oils contain many unsaturated fatty acids (e.g., oleic acid, linoleic acid, linolenic acid), and these fatty acids and oils may be esterified.

[0419] In certain embodiments, fatty acids having 2 to 4 carbon atoms are referred to as short chain fatty acids (lower fatty acids), fatty acids having 5 to 12 carbon atoms are referred to as medium chain fatty acids, and fatty acids having 12 or more carbon atoms are referred to as long chain fatty acids (higher fatty acids). Fatty acids generally have higher hydrophilicity when they have fewer carbon atoms, so oils of the present invention include medium chain fatty acids (e.g., medium chain fatty acid triglycerides such as tri(caprylic / capric)glycerol and glyceryl tricaprylate) and long chain fatty acids.

[0420] In certain embodiments, fatty acids are used in combination with saturated polyglycolized glycerides obtained by polysaccharide degradation of hydrogenated vegetable oils with polyethylene glycols, mono-, di- or triglycerides, and mono- or di-fatty acid esters of polyethylene glycol.

[0421] In certain embodiments, the pharmaceutical composition comprises a diluent.Non-limiting examples of diluents used in capsules include, but are not limited to, calcium carbonate, calcium phosphate dibasic or tribasic, kaolin, lactose, lactitol, mannitol, microcrystalline cellulose, powdered cellulose, cellulose acetate, sorbitol, starch, calcium sulfate, dextrates, dextrin, dextrose, maltodextrin, erythritol, glyceryl palmitostearate, isomalt, magnesium carbonate, magnesium oxide, mannitol, sodium chloride, sucrose, sulfobutyl ether b-cyclodextrin, talc, and xylitol.

[0422] Dosage Form Pack In certain embodiments, the pharmaceutical compositions described herein are administered as part of a dosage form pack or kit, for example as part of a blister pack. For example, a blister pack containing daily doses of a therapeutic agent as individual tablets or pills, and optionally a blister pack containing non-therapeutic tablets or pills for drug holiday days. In certain embodiments, the therapeutic tablets or pills are of a different color, shape, or size than the non-therapeutic tablets or pills.

[0423] In certain embodiments, the other therapeutic agent is included within the blister pack, either as a separate tablet, pill, or capsule, or as a component of the same tablet, pill, or capsule as Compound 1. For example, a blister pack may provide a weekly dose of dexamethasone as part of the same tablet, pill, or capsule as Compound 1, or as part of a different tablet, pill, or capsule. In other embodiments, multiple blister packs containing different pharmaceutical compositions are used. For example, a blister pack containing a tablet of Compound 1 and another blister pack containing tablets or capsules of one or more additional therapeutic agents.

[0424] In certain embodiments, the pharmaceutical compositions described herein are administered as minitablets, such as tablets less than about 9 millimeters, 8 millimeters, 7 millimeters, 6 millimeters, 5 millimeters, 4 millimeters, 3 millimeters, 2 millimeters, or 1 millimeter in diameter. In certain embodiments, the minitablets are formulated for delayed release, immediate release, or pulsed release.

[0425] Additional embodiments of the present invention 1. In certain embodiments, the structure: [ka] The crystalline compound is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 2. The crystalline compound of embodiment 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least four 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 3. The crystalline compound of embodiment 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 4. The crystalline compound of embodiment 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 5. The crystalline compound of embodiment 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 6. The crystalline compound of embodiment 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta. 7. The crystalline compound of any one of embodiments 1-6, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.3 degrees 2-theta. 8. The crystalline compound of any one of embodiments 1-6, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.2 degrees 2-theta. 9. The crystalline compound of any one of embodiments 1-8, wherein the XRPD comprises a peak at 4.8±0.4 degrees 2-theta. 10. The crystalline compound of any one of embodiments 1-9, wherein the XRPD comprises a peak at 16.4±0.2 degrees 2-theta. 11. The crystalline compound of any one of embodiments 1-10, wherein the XRPD comprises a peak at 19.2±0.2 degrees 2-theta. 12. The crystalline compound of any one of embodiments 1-11, wherein the XRPD comprises a peak at 22.9±0.2 degrees 2-theta. 13. The crystalline compound of any one of embodiments 1-12, wherein the XRPD comprises a peak at 13.5±0.2 degrees 2-theta. 14. The crystalline compound of any one of embodiments 1-13, wherein the XRPD comprises a peak at 19.6±0.2 degrees 2-theta. 15. The crystalline compound of any one of embodiments 1-14, wherein the XRPD comprises a peak at 23.2±0.2 degrees 2-theta. 16. The crystalline compound of any one of embodiments 1-15, wherein the XRPD comprises a peak at 17.8±0.2 degrees 2-theta. 17. The crystalline compound of any one of embodiments 1-16, wherein the XRPD comprises a peak at 26.5±0.2 degrees 2-theta. 18. The crystalline compound of any one of embodiments 1-17, wherein the XRPD comprises a peak at 21.5±0.2 degrees 2-theta. 19. In certain embodiments, a pharmaceutical composition is provided comprising a crystalline compound of any one of embodiments 1-18 and one or more pharma- ceutically acceptable excipients. 20. In certain embodiments, there is provided a pharmaceutical composition prepared from a crystalline compound of any one of embodiments 1-18 and one or more pharma- ceutically acceptable excipients. 21. The pharmaceutical composition of embodiment 19 or 20, which is a solid dosage form. 22. The pharmaceutical composition of embodiment 21, which is a capsule or tablet. 23. The pharmaceutical composition of embodiment 19 or 20, which is in a liquid dosage form. 24. The pharmaceutical composition of embodiment 23, which is a gel- or liquid-filled capsule. 25. The pharmaceutical composition of embodiment 20, wherein the crystalline compound is dissolved in polyethylene glycol. 26. The pharmaceutical composition of embodiment 25, wherein the crystalline compound is dissolved in PEG-400. 27. The pharmaceutical composition of any one of embodiments 19-26, comprising about 1 microgram of compound 1. 28. The pharmaceutical composition of any one of embodiments 19-26, comprising about 5 micrograms of compound 1. 29. The pharmaceutical composition of any one of embodiments 19-26, comprising about 10 micrograms of compound 1. 30. The pharmaceutical composition of any one of embodiments 19-26, comprising about 15 micrograms of compound 1. 31. The pharmaceutical composition of any one of embodiments 19-26, comprising about 20 micrograms of compound 1. 32. The pharmaceutical composition of any one of embodiments 19-26, comprising about 25 micrograms of compound 1. 33. The pharmaceutical composition of any one of embodiments 19-26, comprising about 30 micrograms of compound 1. 34. The pharmaceutical composition of any one of embodiments 19-26, comprising about 35 micrograms of compound 1. 35. The pharmaceutical composition of any one of embodiments 19-26, comprising about 40 micrograms of compound 1. 36. The pharmaceutical composition of any one of embodiments 19-26, comprising about 45 micrograms of compound 1. 37. The pharmaceutical composition of any one of embodiments 19-26, comprising about 50 micrograms of compound 1. 38. In certain embodiments, a pharmaceutical composition is provided, the pharmaceutical composition being a liquid-filled capsule comprising a solvent, a preservative, and a pH controlling agent, and compound 1 being compound 1 form I herein prior to dissolution. 39. The capsule comprises about 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.033%, 0.035%, 0.04%, 0.045%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0. The pharmaceutical composition of embodiment 38, wherein the pharmaceutical composition is filled with a solution comprising 35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5% by weight of Compound 1. 40. The pharmaceutical composition of embodiment 38 or 39, wherein the solvent is not aqueous. 41. The pharmaceutical composition of embodiment 40, wherein the solvent is PEG. 42. The pharmaceutical composition of embodiment 41, wherein the solvent is PEG 400. 43. The pharmaceutical composition of any one of embodiments 38-42, wherein the capsule is filled with a solution comprising about 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.65%, 98.7%, 98.75%, 98.8%, 98.85%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, or 99.5% by weight of the solvent. 44. The pharmaceutical composition of any one of embodiments 38-43, wherein the preservative is butylated hydroxytoluene. 45. The pharmaceutical composition of any one of embodiments 38-44, wherein the capsule is filled with a solution comprising at least about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, or 1% by weight of a preservative. 46. ​​The pharmaceutical composition of any one of embodiments 38-45, wherein the pH control agent is citric acid. 47. The pharmaceutical composition of any one of embodiments 38-45, wherein the pH control agent is anhydrous citric acid. 48. The pharmaceutical composition of any one of embodiments 38-47, wherein the capsule is filled with a solution comprising at least about 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.25%, 2.5%, 2.75%, or 3% by weight of the pH control agent. 49. In certain embodiments, a method of treating cancer is provided, the method comprising administering to a patient in need thereof an effective amount of a crystalline compound or pharmaceutical composition of any one of embodiments 1-48. 50. In certain embodiments, a method of treating cancer is provided comprising administering to a patient in need thereof an effective amount of Compound 1 or a pharma- ceutically acceptable salt or pharmaceutical composition thereof, or a crystalline compound or pharmaceutical composition of any one of embodiments 1-48 (a) once daily for 3 selected days per week for 14 days in a 28 day treatment cycle, followed by a 14 day treatment rest period, or (b) once daily for 7 consecutive days, followed by a 14 day treatment rest period, in a 21 day treatment cycle. 51. The method of embodiment 50, wherein the compound is administered once daily on Mondays, Wednesdays, and Fridays for 14 days, followed by a 14-day dosing rest period, in a 28-day treatment cycle. 52. The method of embodiment 49, wherein the compound is administered for several days with drug holidays between subsequent treatment cycles. 53. The method of embodiment 52, wherein the compound is administered once or twice daily for at least 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 consecutive days, followed by a drug holiday until the next 28-day cycle. 54. The method of embodiment 52, wherein the compound is administered once or twice daily for 21 days, followed by a 7-day rest period. 55. The method of any one of embodiments 49-54, wherein the dosage is about 400 μg or less. 56. The method of any one of embodiments 49-54, wherein the dosage is about 300 μg or less. 57. The method of any one of embodiments 49-54, wherein the dosage is about 200 μg or less. 58. The method of any one of embodiments 49-54, wherein the dosage is about 100 μg or less. 59. The method of any one of embodiments 49-54, wherein the dosage is about 50 μg or less. 60. The method of any one of embodiments 49-54, wherein the dosage is about 25 μg or less. 61. The method of any one of embodiments 49-54, wherein the dosage is about 10 μg or less. 62. The method of any one of embodiments 49-54, wherein the dosage is about 5 μg or less. 63. The method of any one of embodiments 49-54, wherein the dosage is about 1 μg or less. 64. The method of any one of embodiments 49-54, wherein the dose is about 50 μg. 65. The method of any one of embodiments 49-54, wherein the dose is about 25 μg. 66. The method of any one of embodiments 49-54, wherein the dose is about 10 μg. 67. The method of any one of embodiments 49-54, wherein the dose is about 5 μg. 68. The method of any one of embodiments 49-54, wherein the dose is about 1 μg. 69. The method of any one of embodiments 49-68, wherein the disorder is diffuse large B-cell lymphoma. 70. The method of embodiment 69, wherein the diffuse large B-cell lymphoma is an activated B-cell lymphoma. 71. The method of embodiment 69, wherein the diffuse large B-cell lymphoma is germinal center B-cell lymphoma. 72. The method of any one of embodiments 49-68, wherein the disorder is anaplastic large cell lymphoma. 73. The method of any one of embodiments 49-68, wherein the disorder is cutaneous T-cell lymphoma. 74. The method of any one of embodiments 49-68, wherein the disorder is mantle cell lymphoma. 75. The method of any one of embodiments 49-68, wherein the disorder is multiple myeloma. 76. The method of any one of embodiments 49-75, wherein the disorder is resistant to treatment with a first generation immunomodulatory imide drug. 77. The method of embodiment 76, wherein the disorder is resistant to treatment with thalidomide. 78. The method of embodiment 76, wherein the disorder is resistant to treatment with pomalidomide. 79. The method of embodiment 76, wherein the disorder is resistant to treatment with lenalidomide. 80. The method of embodiment 76, wherein the disorder is resistant to treatment with iverdamide. 81. The method of any one of embodiments 49-80, wherein a Bruton's tyrosine kinase inhibitor is also administered to the patient. 82. The method of embodiment 81, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib. 83. The method of any one of embodiments 49-81, wherein a corticosteroid is also administered to the patient. 84. The method of embodiment 83, wherein the corticosteroid is dexamethasone. 85. The method of any one of embodiments 49-84, wherein CAR T cell therapy is also administered to the patient. 86. The method of embodiment 85, wherein the CAR T cell therapy is idecbutagen-vicel. 87. The method of embodiment 85, wherein the CAR T cell therapy is lysocabtagene maraleucel. 88. The method of embodiment 85, wherein the CAR T cell therapy is siltacavtagene autorucel. 89. The method of embodiment 85, wherein the CAR T cell therapy is tisagenlecleucel. 90. The method of embodiment 85, wherein the CAR T cell therapy is brexucabtagene autorucel. 91. The method of embodiment 85, wherein the CAR T cell therapy is axicabtagene ciloreucel. 92. The method of embodiment 85, wherein the CAR T cell therapy is a bispecific CAR T cell therapy. 93. The method of embodiment 92, wherein the CAR T cell therapy is BCMA-CD38 CAR T cell therapy. 94. The method of any one of embodiments 49-93, wherein an antibody-drug conjugate is also administered to the patient. 95. The method of any one of embodiments 49-94, wherein BiTE therapy is also administered to the patient. 96. The method of any one of embodiments 49-95, wherein a bispecific antibody is also administered to the patient. 97. The method of any one of embodiments 49-96, wherein a monoclonal antibody is also administered to the patient. 98. The method of any one of embodiments 49-97, wherein the patient is also administered a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib. 99. The method of any one of embodiments 49-98, wherein a CD38 antibody selected from felzalutamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient. 100. The method of any one of embodiments 49-99, wherein the patient is also administered a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616. 101. The method of any one of embodiments 49-100, wherein the patient is also administered an immunomodulatory imide drug selected from pomalidomide, lenalidomide, thalidomide, iverdimide, CC-92480, CC-90009, and CC-99282. 102. The method of any one of embodiments 49-101, wherein the patient is also administered an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzmate A, splitomycin, LMK-235, sodium butyrate, pivaloyloxymethylbutyrate, piroxamide, abexinostat, resminostat, divinostat, xinostat, psammaprin A, KD5170, 1-alanine chlamydocin, depudecin, and CUDC-101. 103. The method of any one of embodiments 49-102, wherein the patient is also administered a compound selected from selinexor, oxafenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricorinostat, afuresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, urocuprumab, and urelumab. 104. The method of any one of embodiments 49-103, wherein the disorder is non-Hodgkin's lymphoma. 105. The method of any one of embodiments 49-103, wherein the disorder is multiple myeloma. 106. The method of any one of embodiments 49-105, wherein the disorder is recurrent. 107. The method of any one of embodiments 49-106, wherein the disorder is refractory. 108. The method of any one of embodiments 49-107, wherein the cancer is mediated by Ikaros and / or Aiolos. 109. The method of any one of embodiments 49-108, comprising administering the compound once daily on Mondays, Wednesdays, and Fridays for 14 days, followed by a 14-day dosing rest period, in a 28-day treatment cycle. 110. The method of any one of embodiments 49-109, comprising administering the compound once daily for 7 consecutive days, followed by a 14-day dosing rest period, in a 21-day treatment cycle. 111. In certain embodiments, there is provided the use of a compound or pharmaceutical composition of any one of embodiments 1-48 in the manufacture of a medicament for treating cancer in a patient in need thereof. 112. In certain embodiments, there is provided a compound or pharmaceutical composition of any one of embodiments 1-48 for use in treating cancer in a patient in need thereof. 113. In certain embodiments, the formula: [ka] A process for preparing a compound of formula (I) is provided, the process comprising: (i) reacting a compound of the formula: [ka] or a salt thereof; formula: [ka] with intermediate 2 of the formula: [ka] and obtaining intermediate 3 of the formula: (ii) reacting intermediate 3 of step (i) with a compound of formula: [ka] with intermediate 4 to obtain a compound; Includes. 114. The process of embodiment 113, additionally comprising a step (iii) of chiral separation by isocratic chiral preparative high pressure liquid chromatography to obtain the compound as the S-enantiomer. 115. In step (i), The base is cesium carbonate, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex or tris(dibenzylideneacetone)-dipalladium(0); 115. The process of embodiment 113 or 114, wherein the solvent is 1,4-dioxane, water, ethanol, toluene, benzene, isopropyl alcohol, N,N-dimethylacetamide, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, 4-dimethylaminopyridine, acetic acid, acetone, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyme, dimethoxyethane, dimethylsulfoxide, ethyl acetate, ethylene glycol, glycerin, heptane, methanol, methyl tertiary butyl ether, n-methyl-2-pyrrolidone, pentane, pyridine, toluene, triethylamine, or a mixture thereof. 116. In step (i), The base is cesium carbonate, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex; The process of any one of embodiments 113 to 115, wherein the solvent is a mixture of 1,4-dioxane and water. 117. In step (ii), The base is lithium tert-butoxide; 117. The process of any one of embodiments 113-116, wherein the solvent is tetrahydrofuran, 1,4-dioxane, water, ethanol, toluene, benzene, isopropyl alcohol, N,N-dimethylacetamide, dichloromethane, N,N-dimethylformamide, acetonitrile, 4-dimethylaminopyridine, acetic acid, acetone, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyme, dimethoxyethane, dimethylsulfoxide, ethyl acetate, ethylene glycol, glycerin, heptane, methanol, methyl tertiary butyl ether, n-methyl-2-pyrrolidone, pentane, pyridine, toluene, or a mixture thereof. 118. In step (ii), The base is lithium tert-butoxide; The process of any one of embodiments 113 to 117, wherein the solvent is tetrahydrofuran. 119. In step (iii), The process of any one of embodiments 113-118, wherein the isocratic chiral preparative high pressure liquid chromatography is carried out using an eluent selected from a mixture of methanol and dichloromethane, a mixture of ethanol and dichloromethane, and a mixture of isopropanol and dichloromethane. 120. In step (iii), 120. The process of any one of embodiments 113-119, wherein the eluent is about 20% ethanol and about 80% dichloromethane, or about 20% methanol and about 80% dichloromethane. EXAMPLES

[0426] Example 1: Manufacturing Process Step 1: [ka]

[0427] Starting materials 1-1 and 1-2 are coupled with a palladium catalyst (e.g., Pd(dppf)Cl2·CH2Cl2) and a base (e.g., cesium carbonate) in a solvent or mixture of solvents (e.g., 1,4-dioxane and water) at elevated temperature (e.g., 90°C-100°C) to produce intermediate 1-3. After the reaction is complete, residual palladium is removed using a palladium scavenger (e.g., trithiocyanuric acid (TMT)). The crude intermediate 1-3 is then purified by salt formation with an acid (e.g., 1N HCl) followed by slurrying in EtOH. After filtration, subsequent destruction of the salt can be performed using a base (e.g., aqueous Na2CO3) in an extractive solvent or solvent mixture (e.g., THF / EtOAc).

[0428] In certain embodiments, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2). In other embodiments, the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0).

[0429] In certain embodiments, at least about 0.01 equivalents, 0.02 equivalents, 0.03 equivalents, 0.04 equivalents, 0.05 equivalents, 0.06 equivalents, 0.07 equivalents, 0.08 equivalents, 0.09 equivalents, or 0.1 equivalents of palladium catalyst are used in step 1.

[0430] In certain embodiments, about 0.06 equivalents of catalyst are used in step 1.

[0431] In certain embodiments, the palladium scavenger is TMT. In other embodiments, the palladium scavenger is X SiliaMets Thiol, activated carbon, Si-TMT, Na-TMT, or silica gel. In certain embodiments, at least about 0.3 equivalents, 0.4 equivalents, 0.5 equivalents, 0.6 equivalents, 0.7 equivalents, or 0.8 equivalents of Pd scavenger are used. In certain embodiments, about 0.6 equivalents of Pd scavenger are used.

[0432] In certain embodiments, the reaction solvent is selected from 1,4-dioxane, water, ethanol, toluene, benzene, isopropyl alcohol, N,N-dimethylacetamide, dichloromethane, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, 4-dimethylaminopyridine, acetic acid, acetone, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyme, dimethoxyethane, dimethylsulfoxide, ethyl acetate, ethylene glycol, glycerin, heptane, methanol, methyl tertiary butyl ether, n-methyl-2-pyrrolidone, pentane, pyridine, toluene, and triethylamine, or a mixture of solvents selected therefrom.

[0433] In certain embodiments, the extraction solvent is selected from tetrahydrofuran, ethyl acetate, 1,4-dioxane, water, ethanol, toluene, benzene, isopropyl alcohol, N,N-dimethylacetamide, dichloromethane, N,N-dimethylformamide, acetonitrile, 4-dimethylaminopyridine, acetic acid, acetone, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyme, dimethoxyethane, dimethylsulfoxide, ethylene glycol, glycerin, heptane, methanol, methyl tertiary butyl ether, n-methyl-2-pyrrolidone, pentane, pyridine, toluene, and triethylamine, or a mixture of solvents selected therefrom.

[0434] Step 1 can be carried out on a manufacturing scale to prepare large quantities of 1-3 for use in preparing compound 1. A non-limiting example of this scaled-up reaction is provided below, where the reaction sequence was carried out on a 100 gram scale. [ka]

[0435] A non-limiting example of this scaled-up reaction and raw material inputs is provided below.

[0436] TIFF2025505687000033.tif106170

[0437] TIFF2025505687000034.tif249170TIFF2025505687000035.tif103170

[0438] Step 2: [ka]

[0439] Intermediate 1-3 was treated with a base (e.g., lithium tert-butoxide (t-BuOLi)) followed by heating (e.g., 55° C.-65° C.) of bromoglutarimide (1-4) in a solvent or mixture of solvents (e.g., THF) to produce racemic compound 5. After the reaction was complete, the reaction was quenched with an acid (e.g., 1N aqueous hydrochloric acid), neutralized with aqueous sodium bicarbonate, and filtered to give compound 5.

[0440] In certain embodiments, intermediate 1-3 is stirred with lithium tert-butoxide for deprotonation at elevated temperature before adding intermediate 1-4. In certain embodiments, the temperature of deprotonation is about 30° C. to about 70° C. In certain embodiments, the temperature of deprotonation is about 55° C. to 65° C. In certain embodiments, the temperature of deprotonation is about 25° C. to 35° C. In certain embodiments, the temperature of deprotonation is about 60° C. to 70° C. In certain embodiments, the temperature of providing 1-4 is 55° C. to 65° C. or 40° C. to 45° C. In a preferred embodiment, the temperature of deprotonation and providing 1-4 is about 55° C. to 65° C.

[0441] In certain embodiments, at least about 4.5, 5.5, 7, or 10 equivalents of t-BuOLi are used. In certain embodiments, at least about 4, 4.5, or 5 equivalents of 1-4 are used. In preferred embodiments, about 5 equivalents of 1-4 and about 10 equivalents of t-BuOLi are used.

[0442] In certain embodiments, the reaction solvent is selected from tetrahydrofuran, 1,4-dioxane, water, ethanol, toluene, benzene, isopropyl alcohol, N,N-dimethylacetamide, dichloromethane, N,N-dimethylformamide, acetonitrile, 4-dimethylaminopyridine, acetic acid, acetone, benzene, 1-butanol, 2-butanol, tert-butyl alcohol, carbon tetrachloride, chloroform, cyclohexane, hexane, diethyl ether, diglyme, dimethoxyethane, dimethylsulfoxide, ethyl acetate, ethylene glycol, glycerin, heptane, methanol, methyl tertiary butyl ether, n-methyl-2-pyrrolidone, pentane, pyridine, and toluene, or a mixture of these solvents.

[0443] Step 2 can be carried out on a manufacturing scale to prepare large quantities of compound 5 for use in preparing compound 1. A non-limiting example of this scaled-up reaction on a 100 gram scale is shown below. [ka]

[0444] A non-limiting example of this scaled-up reaction and raw material inputs is provided below.

[0445] TIFF2025505687000038.tif113170

[0446] TIFF2025505687000039.tif246170

[0447] Step 3: [ka]

[0448] Isocratic, chiral, preparative high pressure liquid chromatography (HPLC) separation using a chiral column (e.g., CHIRALPAK™ IC stationary phase) and solvent (e.g., methanol / dichloromethane or ethanol / dichloromethane mobile phase) was performed to separate compound 1 (S enantiomer) from the R enantiomer. After concentration of the solvent, compound 1 was collected by filtration and dried.

[0449] In certain embodiments, the eluent for the preparative HPLC is IPA / DCM in a ratio of about 1 / 1. In certain embodiments, the eluent for the preparative HPLC is EtOH / DCM in a ratio of about 1 / 4. The 1 / 4 EtOH / DCM ratio avoids high column pressure, and the separation is completed within 30 minutes per injection, compared to about 60 minutes per injection for a 1 / 1 IPA / DCM ratio. In certain embodiments, the eluent is MeOH / DCM in a ratio of about 1 / 4.

[0450] Step 3 can be carried out on a manufacturing scale to prepare large quantities of Compound 1 for use in preparing the drug substance...

Claims

1. structure: 【Chemistry 1】 1. A crystalline compound of formula (I) characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta.

2. 10. The crystalline compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least six 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta.

3. 10. The crystalline compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least seven 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta.

4. 10. The crystalline compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.4 degrees 2-theta.

5. 10. The crystalline compound of claim 1, characterized by an X-ray powder diffraction (XRPD) pattern comprising at least five 2-theta values ​​selected from 4.8, 13.5, 16.0, 16.4, 17.8, 17.9, 19.2, 19.6, 20.9, 21.5, 21.8, 22.9, 23.2, 24.8, 26.5, and 31.3±0.2 degrees 2-theta.

6. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 4.8±0.2 degrees 2-theta.

7. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 16.4±0.2 degrees two-theta.

8. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 19.2±0.2 degrees two-theta.

9. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 22.9±0.2 degrees two-theta.

10. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 13.5±0.2 degrees two-theta.

11. 10. The crystalline compound of claim 1, wherein the XRPD comprises a peak at 19.6±0.2 degrees two-theta.

12. 10. A pharmaceutical composition comprising the crystalline compound of claim 1 and one or more pharmaceutically acceptable excipients.

13. 10. A pharmaceutical composition prepared from the crystalline compound of claim 1 and one or more pharmaceutically acceptable excipients.

14. 13. The pharmaceutical composition of claim 12, which is in a solid dosage form.

15. 15. The pharmaceutical composition of claim 14, which is a capsule or tablet.

16. 14. The pharmaceutical composition of claim 13, in liquid dosage form.

17. 17. The pharmaceutical composition of claim 16, which is a gel or liquid filled capsule.

18. 13. The pharmaceutical composition of claim 12, comprising about 50 micrograms of Compound 1.

19. 13. The pharmaceutical composition of claim 12, comprising about 62.5 micrograms of Compound 1.

20. 13. The pharmaceutical composition of claim 12, comprising about 75 micrograms of Compound 1.

21. A pharmaceutical composition for treating cancer in a human patient, comprising an effective amount of Compound 1 or a pharmaceutically acceptable salt thereof, or prepared from or comprising the crystalline compound of claim 1 and one or more pharmaceutically acceptable excipients; the patient is administered (a) once daily for 14 days selected for 3 days per week, followed by a 14-day treatment rest period, in a 28-day treatment cycle; (b) once daily for 14 consecutive days in a 28-day treatment cycle at a dose of about 12.5 μg, about 25 μg, about 37.5 μg, about 50 μg, about 62.5 μg, or about 75 μg of Compound 1, followed by a 14-day treatment rest period; or (c) once daily for 7 consecutive days in a 21-day treatment cycle, followed by a 14-day treatment rest period. Pharmaceutical compositions.

22. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered once daily on Mondays, Wednesdays, and Fridays for 14 days, followed by a 14-day dosing rest period, in a 28-day treatment cycle.

23. 22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered for several days with drug holidays between subsequent treatment cycles.

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

25. 24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition is administered once or twice daily for 21 days, followed by a 7-day rest period.

26. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is about 100 μg or less.

27. ​​The pharmaceutical composition of claim 21, wherein the dose of compound 1 is about 75 μg or less.

28. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is about 62.5 μg or less.

29. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is about 100 μg.

30. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is approximately 87.5 μg.

31. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is approximately 75 μg.

32. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is approximately 62.5 μg.

33. The pharmaceutical composition of claim 21, wherein the dose of compound 1 is about 50 μg.

34. The pharmaceutical composition described in claim 21, wherein the cancer is diffuse large B-cell lymphoma.

35. 35. The pharmaceutical composition of claim 34, wherein the diffuse large B-cell lymphoma is an activated B-cell lymphoma.

36. 35. The pharmaceutical composition of claim 34, wherein the diffuse large B-cell lymphoma is germinal center B-cell lymphoma.

37. The pharmaceutical composition described in claim 21, wherein the cancer is anaplastic large cell lymphoma.

38. The pharmaceutical composition described in claim 21, wherein the cancer is cutaneous T-cell lymphoma.

39. The pharmaceutical composition described in claim 21, wherein the cancer is mantle cell lymphoma.

40. The pharmaceutical composition described in claim 21, wherein the cancer is multiple myeloma.

41. 22. The pharmaceutical composition of claim 21, wherein the cancer is resistant to treatment with a first generation immunomodulatory imidazole drug.

42. 42. The pharmaceutical composition of claim 41, wherein the cancer is resistant to treatment with thalidomide, pomalidomide, lenalidomide, or iveldomide.

43. 22. The pharmaceutical composition of claim 21, wherein a Bruton's tyrosine kinase inhibitor is also administered to the patient.

44. 44. The pharmaceutical composition of claim 43, wherein the Bruton's tyrosine kinase inhibitor is ibrutinib.

45. 22. The pharmaceutical composition of claim 21, wherein a corticosteroid is also administered to the patient.

46. 46. ​​The pharmaceutical composition of claim 45, wherein the corticosteroid is dexamethasone.

47. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered a CAR T-cell therapy.

48. 48. The pharmaceutical composition of claim 47, wherein the CAR T cell therapy is idecabutagen viclucel.

49. 48. The pharmaceutical composition of claim 47, wherein the CAR T cell therapy is lisocabtagene malaleucel, siltacabtagene autrucel, tisagenlecleucel, brexcabtagene autrucel, or axicabtagene ciloreucel.

50. 48. The pharmaceutical composition of claim 47, wherein the CAR T-cell therapy is a bispecific CAR T-cell therapy.

51. 51. The pharmaceutical composition of claim 50, wherein the CAR T-cell therapy is a BCMA-CD38 CAR T-cell therapy.

52. 22. The pharmaceutical composition of claim 21, wherein an antibody-drug conjugate is also administered to the patient.

53. 22. The pharmaceutical composition of claim 21, wherein BiTE therapy is also administered to the patient.

54. 22. The pharmaceutical composition of claim 21, wherein a bispecific antibody is also administered to the patient.

55. 22. The pharmaceutical composition of claim 21, wherein a monoclonal antibody is also administered to the patient.

56. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered a BTK inhibitor selected from acalabrutinib, spebrutinib, zanubrutinib, LOXO-305, evobrutinib, TG-1701, trebrutinib, BIIB091, DZD-9008, HZ-A-018, orelabrutinib, AC0058TA, SN1011, rilzabrutinib, ARQ 531, DTRMWXHS-12, JNJ-64264681, branebrutinib, ibrutinib, and fenebrutinib.

57. 22. The pharmaceutical composition of claim 21, wherein a CD38 antibody selected from felzalutamab, daratumumab, GBR 1342, TAK-573, CID-103, OKT10, STI-6129, SGX301, TAK-079, and mezagitamab is also administered to the patient.

58. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered a proteasome inhibitor selected from ixazomib citrate, oprozomib, delanzomib, lactacystin, bortezomib, carfilzomib, VLX1570, epoxomicin, MG132, MG-262, CEP-18770, NEOSH101, TQB3602, and KZR-616.

59. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered an immunomodulatory imidazole selected from pomalidomide, lenalidomide, thalidomide, iveldomide, CC-92480, CC-90009, and CC-99282.

60. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered an HDAC inhibitor selected from trapoxin B, sodium phenylbutyrate, tacedinaline, mocetinostat, BRD73954, BG45, domatinostat, cay10603, HPOB, TMP269, nextulastat A, santacruzmate A, splitomycin, LMK-235, sodium butyrate, pivaloyloxymethyl butyrate, piroxamide, abexinostat, resminostat, divinostat, xinostat, psammaplin A, KD5170, l-alanine chlamydocin, depudecin, and CUDC-101.

61. 22. The pharmaceutical composition of claim 21, wherein the patient is also administered a pharmaceutical composition selected from selinexor, oxafenamide, belantamab mafodotin, denosumab, zoledronic acid, plerixafor, eltrombopag, ipilumumab, palbociclib, ricolinostat, afresertib, dinaciclib, filanesib, indatuximab ravtansine, masitinib, sonidegib, sotatercept, urocuplumab, and urelumab.

62. 22. The pharmaceutical composition of claim 21, wherein the cancer is non-Hodgkin's lymphoma.

63. 22. The pharmaceutical composition of claim 21, wherein the cancer is recurrent.

64. 22. The pharmaceutical composition of claim 21, wherein the cancer is refractory.

65. 22. The pharmaceutical composition of claim 21, wherein the cancer is mediated by Ikaros and / or Aiolos.

66. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered once daily for 7 consecutive days, followed by a 14-day treatment rest period, in a 21-day treatment cycle.

67. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition is administered once daily for 14 consecutive days at a dose of about 50 μg, about 62.5 μg, or about 75 μg of compound 1 in a 28-day treatment cycle, followed by a 14-day treatment rest period.

68. 68. Use of a crystalline pharmaceutical composition according to any one of claims 1 to 11 or a pharmaceutical composition according to any one of claims 12 to 67 in the manufacture of a medicament for treating cancer in a human patient in need thereof.

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