Methods for treating multiple myeloma with immunomodulatory compounds in combination with antibodies

Description

1. FIELD OF THE INVENTION

[0001] This invention relates to compounds for use in methods of treating multiple myeloma in a patient, by the administration of such compounds in combination with a monoclonal anti-CS1 antibody. The invention also relates to pharmaceutical compositions for such use and dosing regimens applied in such methods.2. BACKGROUND OF THE INVENTION 2.1 PATHOBIOLOGY OF CANCER

[0002] Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

[0003] There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the lung, colon, rectum, prostate, breast, brain, and intestine. The incidence of cancer continues to climb as the general population ages, as new cancers develop, and as susceptible populations (e.g., people infected with AIDS or excessively exposed to sunlight) grow. A tremendous demand therefore exists for new methods and compositions that can be used to treat patients with cancer.

[0004] Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor (a,b-FGF), angiogenin, vascular endothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., b-FGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-α, bFGF).

[0005] A variety of other diseases and disorders are also associated with, or characterized by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, choroidal neovascular diseases, retina neovascular diseases, rubeosis (neovascularization of the angle), viral diseases, genetic diseases, inflammatory diseases, allergic diseases, fibrosis, arthritis and autoimmune diseases. Examples of such diseases and conditions include, but are not limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; and proliferative vitreoretinopathy.

[0006] Accordingly, compounds that can control and / or inhibit unwanted angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful in the treatment and prevention of various diseases and conditions.

[0007] Multiple myeloma is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common hematological malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin. M-protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by the myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.

[0008] Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast stimulating factors (including IL-1, IL-6 and TNF) which cause calcium to be leached from bones causing lytic lesions; hypercalcemia is another symptom. The osteoclast stimulating factors, also referred to as cytokines, may prevent apoptosis, or death of myeloma cells. Fifty percent of patients have radiologically detectable myeloma-related skeletal lesions at diagnosis. Other common clinical symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.

[0009] Bone marrow stromal cells are well known to support multiple myeloma disease progression and resistance to chemotherapy. Disrupting the interactions between multiple myeloma cells and stromal cells is an additional target of multiple myeloma chemotherapy.

[0010] In the last decade, novel therapeutic agents, in particular immunomodulatory drugs such as lenalidomide and pomalidomide, significantly increased the response rates and prolonged progression free survival (PFS) and overall survival (OS) in multiple myeloma patients. However, persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, protein electrophoresis with immunofixation, and light chain quantitation exists in many patients with multiple myeloma, even after these patients have achieved complete response (CR), and will eventually cause relapse of the disease. Minimal residual disease (MRD) in myeloma is an independent predictor of progression-free survival (PFS) and is under consideration as a surrogate trial endpoint to improve the identification of effective treatments, particularly for frontline trials, which now require 5 to 10 years of follow-up to identify survival differences. Monitoring minimal residual disease (MRD) in patients with multiple myeloma thus provides prognostic value in predicting PFS and OS and making treatment decisions. The detection of minimal residual disease (MRD) in myeloma can use a 0.01% threshold (10 -4< ) after treatment, i.e., having 10 -4< cells or fewer is considered MRD-negative, and having 10 -4< cells or higher MRD-positive. The 10 -4< MRD threshold was originally based on technical capability, but quantitative MRD detection is now possible at 10 -5< by flow cytometry and 10 -6< by high-throughput sequencing. Rawstron et al., Blood. 2015;125(12):1932-1935 (2015). Methods for measuring MRD include polymerase chain reaction (PCR) and multiparameter flow cytometry (MPF). Assays for MRD, e.g., based on clonotype profile measurement are also described in US Patent No. 8,628,927, to Faham et al.2.2 METHODS OF TREATING CANCER

[0011] Current cancer therapy may involve surgery, chemotherapy, hormonal therapy and / or radiation treatment to eradicate neoplastic cells in a patient (see, for example, Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV). Recently, cancer therapy could also involve biological therapy or immunotherapy. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic tissue. Radiation therapy is only effective when the neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue. Radiation therapy can also often elicit serious side effects. Hormonal therapy is rarely given as a single agent. Although hormonal therapy can be effective, it is often used to prevent or delay recurrence of cancer after other treatments have removed the majority of cancer cells. Biological therapies and immunotherapies are limited in number and may produce side effects such as rashes or swellings, flu-like symptoms, including fever, chills and fatigue, digestive tract problems or allergic reactions.

[0012] With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of cancer. A majority of cancer chemotherapeutics act by inhibiting DNA synthesis, either directly, or indirectly by inhibiting the biosynthesis of deoxyribonucleotide triphosphate precursors, to prevent DNA replication and concomitant cell division. Gilman et al., Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York).

[0013] Despite availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous side effects including severe nausea, bone marrow depression, and immunosuppression. Additionally, even with administration of combinations of chemotherapeutic agents, many tumor cells are resistant or develop resistance to the chemotherapeutic agents. In fact, those cells resistant to the particular chemotherapeutic agents used in the treatment protocol often prove to be resistant to other drugs, even if those agents act by different mechanism from those of the drugs used in the specific treatment. This phenomenon is referred to as pleiotropic drug or multidrug resistance. Because of the drug resistance, many cancers prove refractory to standard chemotherapeutic treatment protocols.

[0014] Other diseases or conditions associated with, or characterized by, undesired angiogenesis are also difficult to treat. However, some compounds such as protamine, hepain and steroids have been proposed to be useful in the treatment of certain specific diseases. Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. 5,001,116 and 4,994,443. Thalidomide and certain derivatives of it have also been proposed for the treatment of such diseases and conditions. U.S. patent nos. 5,593,990, 5,629,327, 5,712,291, 6,071,948 and 6,114,355 to D' Amato.

[0015] Still, there is a significant need for safe and effective methods of treating, preventing and managing cancer (e.g., multiple myeloma) and other diseases and conditions associated with, or characterized by, undesired angiogenesis, while reducing or avoiding the toxicities and / or side effects associated with the conventional therapies.2.3 IMMUNOMODULATORY DRUG(S)

[0016] A number of studies have been conducted with the aim of providing compounds that can safely and effectively be used to treat diseases associated with abnormal production of TNF-α. See, e.g., Marriott, J.B., et al., Expert Opin. Biol. Ther. 1(4):1-8 (2001); G.W. Muller, et al., Journal of Medicinal Chemistry 39(17): 3238-3240 (1996); and G.W. Muller, et al., Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998). Some studies have focused on a group of compounds selected for their capacity to potently inhibit TNF-α production by LPS stimulated PBMC. L.G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These compounds, which are referred to as immunomodulatory drug(s) (Celgene Corporation), show not only potent inhibition of TNF-α but also marked inhibition of LPS induced monocyte IL1ß and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, albeit partially. These compounds are potent stimulators of LPS induced IL10. Id. Particular examples of immunomodulatory drug(s) include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in United States Patent Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al.

[0017] Compounds for the methods provided herein include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described in U.S. Patent Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al. Still other specific compounds disclosed herein belong to a class of isoindole-imides disclosed in U.S. Patent Nos. 6,395,754, 6,555,554, 7,091,353, U.S. Publication No. 2004 / 0029832, and International Publication No. WO 98 / 54170.

[0018] Thalidomide and immunomodulatory drugs such as lenalidomide and pomalidomide have shown remarkable responses in patients with multiple myeloma, lymphoma and other hematological diseases such as myelodysplastic syndrome. See Galustian C, et al., Expert Opin Pharmacother., 2009, 10:125-133. These drugs display a broad spectrum of activity, including anti-angiogenic properties, modulation of pro-inflammatory cytokines, co-stimulation of T cells, increased NK cell toxicity, direct antitumor effects and modulation of stem cell differentiation.

[0019] For example, thalidomide, lenalidomide and pomalidomide have emerged as important options for the treatment of multiple myeloma in newly diagnosed patients, in patients with advanced disease who have failed chemotherapy or transplantation, and in patients with relapsed or refractory multiple myeloma. Lenalidomide in combination with dexamethasone has been approved for the treatment of patients with multiple myeloma who have received at least one prior therapy. Pomalidomide has also been approved for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Phase 3 clinical trials have confirmed the efficacy of pomalidomide in combination with dexamethasone to treat relapsed and / or refractory multiple myeloma after prior therapy. U.S. Patent No. 7,968,569 and 8,198,262, disclose the treatment of multiple myeloma.

[0020] Dimopoulos et al. (European Journal of Haematology, vol. 86, no. 1, pages 1-15) and WO 2008 / 019378 A1 disclose the combination of lemalidomide and elotuzumab for the treatment of multiple myeloma.3. SUMMARY OF THE INVENTION

[0021] The invention is set out in the appended set of claims. One aspect of the invention encompasses a compound for use in a method of treating multiple myeloma in a patient, wherein the compound is a compound of the formula (i.e., pomalidomide), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound is administered in combination with a therapeutically effective amount of a monoclonal anti-CS1 antibody. In some embodiments, the compound is the free base. In other embodiments, the compound is a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate. In a preferred embodiment, the compound is the free base.

[0022] In certain embodiments, the multiple myeloma is newly diagnosed multiple myeloma. In other embodiments, the multiple myeloma is relapsed, refractory, or relapsed and refractory multiple myeloma.

[0023] In certain embodiments, the method comprises cyclic administration of the compound. In a preferred embodiment, the compound is administered for 21 days followed by seven days of rest in a 28 day cycle.

[0024] In certain embodiments, the compound is administered in an amount of from 1 to about 50 mg per day. In certain embodiments, the compound is administered in an amount of from 1 to about 50 mg per day, in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In some embodiments, the compound is administered in an amount of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg per day. In some embodiments, the compound is administered in an amount of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg per day, in combination with with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In a preferred embodiment, the compound is administered in an amount of about 25 mg per day. In a preferred embodiment, the compound is administered in an amount of about 25 mg per day, in combination with the antibody, preferably with elotuzumab. In a preferred embodiment, the compound is administered in an amount of about 20 mg per day. In a preferred embodiment, the compound is administered in an amount of about 20 mg per day, in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In a preferred embodiment, the compound is administered in an amount of about 15 mg per day. In a preferred embodiment, the compound is administered in an amount of about 15 mg per day, in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In another preferred embodiment, the compound is administered in an amount of about 10 mg per day. In another preferred embodiment, the compound is administered in an amount of about 10 mg per day; in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In a preferred embodiment, the compound is administered in an amount of about 5 mg per day. In a preferred embodiment, the compound is administered in an amount of about 5 mg per day, in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab. In a preferred embodiment, the compound is administered in an amount of about 2.5 mg per day. In a preferred embodiment, the compound is administered in an amount of about 2.5 mg per day, in combination with the monoclonal anti-CS1 antibody, preferably with elotuzumab.

[0025] In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered orally, whereas the monoclonal anti-CS1 antibody during combination therapy is not administered orally. In some embodiments, the compound is administered in the form of a capsule or tablet. The capsule may comprise about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg of the compound. The tablet may comprise about 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg or 25 mg of the compound. The capsule may comprise about 2.5 mg of the compound. The tablet may comprise about 2.5 mg of the compound. The capsule may comprise about 5 mg. The tablet may comprise about 5 mg of the compound. The capsule may comprise about 10 mg of the compound. The tablet may comprise about 10 mg of the compound. The capsule may comprise about 15 mg of the compound. The tablet may comprise about 15 mg of the compound. The capsule may comprise about 20 mg of the compound. The tablet may comprise about 20 mg of the compound. The capsule may comprise about 25 mg of the compound. The tablet may comprise about 25 mg of the compound. In certain embodiments, the capsule comprises lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and magnesium stearate in addition to the compound.

[0026] The antibody administered with the compound is an monoclonal anti-CS1 antibody. In some embodiments, the anti-CS antibody is a humanized monoclonal antibody. In a preferred embodiment, the anti-CS1 antibody is elotuzumab

[0027] In certain embodiments, the monoclonal anti-CS1 antibody is administered intravenously in an amount of from about 1 to about 1000 mg weekly or every other week. In a preferred embodiment, elotuzumab is administered as a 10 mg / kg IV solution. In another preferred embodiment, elotuzumab is administered weekly on days 1, 8, 15, 22 in a 28-day cycle (cycles 1 & 2), and days 1 and 15 in a 28-day cycle (cycles 3-onward).

[0028] In certain embodiments, the patient has received stem cell transplantation, wherein the stem cell transplantation is autologous stem cell transplantation. In other embodiments, the stem cell transplantation is hematopoietic stem cell transplantation or peripheral blood stem cell transplantation. In other embodiments, the stem cell transplantation is hematopoietic stem cell transplantation. In other embodiments, the stem cell transplantation is peripheral blood stem cell transplantation.

[0029] In certain embodiments, the patient has received treatment with the compound, and optionally a proteasome inhibitor, prior to receiving the stem cell transplantation. In a specific embodiment, the proteasome inhibitor is bortezomib or carfilzomib. In a specific embodiment, the proteasome inhibitor is bortezomib. In a specific embodiment, the proteasome inhibitor is carfilzomib.

[0030] In certain embodiments, the patient is identified as minimal residual disease positive (MRD(+)) prior to administering the compound. In other embodiments, the patient is identified as MRD negative (MRD(-)) prior to administering the compound.

[0031] In yet other embodiments, the immunomodulatory compound is administered in further combination with a second active agent or therapy conventionally used to treat, prevent or manage cancer. Examples of such second active agents are described in section 4.2. Specific examples include, but are not limited to, proteasome inhibitors such as ixazomib and marizomib, immunomodulators such as cyclophosphamide, vaccines such as Prevnar, checkpoint inhibitors such as PD-L1 inhibitors, and epigenetic modifiers such as azacitidine. Examples of such conventional therapies include, but are not limited to, surgery, chemotherapy, radiation therapy, hormonal therapy, biological therapy and immunotherapy. Specific examples include, but are not limited to, cell therapy such as CAR T-cell immunotherapy.

[0032] Another aspect of this invention encompasses pharmaceutical compositions, single unit dosage forms, and dosing regimens for use of the invention which comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an antibody.4. DETAILED DESCRIPTION OF THE INVENTION

[0033] References to methods of treatment by therapy in this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in thos methods.

[0034] An embodiment of the invention encompasses a compound for use in a method of treating multiple myeloma in a patient, wherein the compound is a compound of the formula or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is administered in combination with a therapeutically effective amount of a monoclonal anti-CS1 antibody. The term "in combination with" or "administered with" within the meaning of the invention includes administration as a mixture, simultaneous administration using separate formulations, and consecutive administration in any order.

[0035] The antibody is a monoclonal anti-CS1 antibody, and, more preferably, a humanized monoclonal anti-CS1 antibody. In a particular embodiment, the anti-CS1 antibody is elotuzumab.

[0036] In particular methods encompassed by this embodiment, the immunomodulatory compound is administered in combination with elotuzumab in patients having multiple myeloma who have received autologous stem cell transplantation. In more particular methods, the patients have received treatment with the immunomodulatory compound, a proteasome inhibitor (e.g., bortezomib or carfilzomib), or both in induction therapy prior to the autologous stem cell transplantation.

[0037] Methods encompassed by the present invention may comprise administering a therapeutically or prophylactically effective amount of one or more additional active agents (i.e., second active agent) or other method of treating, managing, or preventing multiple myeloma. Second active agents include small molecules and large molecules (e.g., proteins), examples of which are provided herein, as well as stem cells. Methods or therapies that can be used in combination with the administration of the immunomodulatory compound and the antibody include, but are not limited to, surgery, blood transfusions, immunotherapy, biological therapy, radiation therapy, and other non-drug based therapies presently used to treat, prevent or manage cancer or disease and conditions associated with, or characterized by, undesired angiogenesis.

[0038] The invention also encompasses pharmaceutical compositions (e.g., single unit dosage forms) for use according to the appended claims. Particular pharmaceutical compositions comprise an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and an antibody.4.1 IMMUNOMODULATORY COMPOUNDS

[0039] Compounds used in the invention include immunomodulatory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, or stereoisomers thereof. Preferred compounds used in the invention are small organic molecules having a molecular weight less than about 1,000 g / mol, and are not proteins, peptides, oligonucleotides, oligosaccharides or other macromolecules.

[0040] As used herein, the terms "immunomodulatory compounds" (Celgene Corporation) encompass pomalidomide. The immunomodulatory compound according to the claimed invention is pomalidomide. Other immunomodulatory compounds disclosed herein are not according to the claimed invention.

[0041] TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for a diverse range of signaling events within cells. TNF-α may play a pathological role in cancer. Without being limited by theory, one of the biological effects exerted by the immunomodulatory compounds of the invention is the reduction of synthesis of TNF-α. Immunomodulatory compounds of the invention enhance the degradation of TNF-α mRNA.

[0042] Further, without being limited by theory, immunomodulatory compounds used in the invention may also be potent co-stimulators of T cells and increase cell proliferation dramatically in a dose dependent manner. Immunomodulatory compounds of the invention may also have a greater co-stimulatory effect on the CD8+ T cell subset than on the CD4+ T cell subset. In addition, the compounds preferably have anti-inflammatory properties, and efficiently co-stimulate T cells.

[0043] Examples of immunomodulatory compounds not part of the invention, include, but are not limited to, cyano and carboxy derivatives of substituted styrenes such as those disclosed in U.S. Patent No. 5,929,117; 1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Patent No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines described in U.S. Patent No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of thalidomide and EM-12), including, but not limited to, those disclosed in U.S. Patent No. 5,635,517; and a class of non-polypeptide cyclic amides disclosed in U.S. patent nos. 5,698,579 and 5,877,200; analogs and derivatives of thalidomide, including hydrolysis products, metabolites, derivatives and precursors of thalidomide, such as those described in U.S. patent nos. 5,593,990, 5,629,327, and 6,071,948 to D'Amato; aminothalidomide, as well as analogs, hydrolysis products, metabolites, derivatives and precursors of aminothalidomide, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described in U.S. patent nos. 6,281,230 and 6,316,471; isoindole-imide compounds such as those described in U.S. patent application no. 09 / 972,487 filed on October 5, 2001, U.S. patent application no. 10 / 032,286 filed on December 21, 2001, and International Application No. PCT / US01 / 50401 (International Publication No. WO 02 / 059106). Immunomodulatory compounds of the invention do not include thalidomide.

[0044] Other specific immunomodulatory compounds not part of the invention include 1-oxo-and 1,3 dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Patent No. 5,635,517. These compounds have the structure I: in which one of X and Y is C=O, the other of X and Y is C=O or CH 2 , and R 2< is hydrogen or lower alkyl, in particular methyl. Specific immunomodulatory compounds include, but are not limited to: 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-6-aminoisoindoline; 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.

[0045] Other specific immunomodulatory compounds not part of the invention belong to a class of substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those described in U.S. patent nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT / US97 / 13375 (International Publication No. WO 98 / 03502). Compounds representative of this class are of the formulas: wherein R 1< is hydrogen or methyl.

[0046] Still other specific immunomodulatory compounds not part of the invention belong to a class of isoindole-imides disclosed in U.S. patent application nos. 10 / 032,286 and 09 / 972,487, and International Application No. PCT / US01 / 50401 (International Publication No. WO 02 / 059106). Representative compounds are of formula II: and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein: one of X and Y is C=O and the other is CH 2 or C=O; R 1< is H, (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3< , C(S)R 3< , C(O)OR 4< , (C 1 -C 8 )alkyl-N(R 6< ) 2 , (C 1 -C 8 )alkyl-OR 5< , (C 1 -C 8 )alkyl-C(O)OR 5< C(O)NHR 3< , C(S)NHR 3< , C(O)NR 3< R 3'< , C(S)NR 3< R 3'< or (C 1 -C 8 )alkyl-O(CO)R 5< ; R 2< is H, F, benzyl, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl; R 3< and R 3'< are independently (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 0 -C 8 )alkyl-N(R 6< ) 2 , (C 1 -C 8 )alkyl-OR 5< , (C 1 -C 8 )alkyl-C(O)OR 5< , (C 1 -C 8 )alkyl-O(CO)R 5< , or C(O)OR 5< ; R 4< is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkyl-OR 5< , benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, or (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl; R 5< is (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, or (C 2 -C 5 )heteroaryl; each occurrence of R 6< is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 2 -C 5 )heteroaryl, or (C 0 -C 8 )alkyl-C(O)O-R 5< or the R 6< groups can join to form a heterocycloalkyl group; n is 0 or 1; and * represents a chiral-carbon center.

[0047] In specific examples of formula II, when n is 0 then R 1< is (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, C(O)R 3< , C(O)OR 4< , (C 1 -C 8 )alkyl-N(R 6< ) 2 , (C 1 -C 8 )alkyl-OR 5< , (C 1 -C 8 )alkyl-C(O)OR 5< , C(S)NHR 3< , or (C 1 -C 8 )alkyl-O(CO)R 5< ; R 2< is H or (C 1 -C 8 )alkyl; and R 3< is (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, benzyl, aryl, (C 0 -C 4 )alkyl-(C 1 -C 6 )heterocycloalkyl, (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 5 -C 8 )alkyl-N(R 6< ) 2 , (C 0 -C 8 )alkyl-NH-C(O)O-R 5< ; (C 1 -C 8 )alkyl-OR 5< , (C 1 -C 8 )alkyl-C(O)OR 5< , (C 1 -C 8 )alkyl-O(CO)R 5< , or C(O)OR 5< ; and the other variables have the same definitions.

[0048] In other specific compounds of formula II, R 2< is H or (C 1 -C 4 )alkyl.

[0049] In other specific compounds of formula II, R 1< is (C 1 -C 8 )alkyl or benzyl.

[0050] In other specific compounds of formula II, R 1< is H, (C 1 -C 8 )alkyl, benzyl, CH 2 OCH 3 , CH 2 CH 2 OCH 3 , or

[0051] In another example of the compounds of formula II, R 1< is wherein Q is O or S, and each occurrence of R 7< is independently H, (C 1 -C 8 )alkyl, benzyl, CH 2 OCH 3 , or CH 2 CH 2 OCH 3 .

[0052] In other specific compounds of formula II, R 1< is C(O)R 3< .

[0053] In other specific compounds of formula II, R 3< is (C 0 -C 4 )alkyl-(C 2 -C 5 )heteroaryl, (C 1 -C 8 )alkyl, aryl, or (C 0 -C 4 )alkyl-OR 5< .

[0054] In other specific compounds of formula II, heteroaryl is pyridyl, furyl, or thienyl.

[0055] In other specific compounds of formula II, R 1< is C(O)OR 4< .

[0056] In other specific compounds of formula II, the H of C(O)NHC(O) can be replaced with (C 1 -C 4 )alkyl, aryl, or benzyl.

[0057] Still other specific immunomodulatory compounds not part of the invention belong to a class of isoindole-imides disclosed in U.S. patent application no. 09 / 781,179, International Publication No. WO 98 / 54170, and U.S. Patent No. 6,395,754. Representative compounds are of formula III: and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mixtures of stereoisomers thereof, wherein: one of X and Y is C=O and the other is CH 2 or C=O; R is H or CH 2 OCOR'; (i) each of R 1< , R 2< , R 3< , or R 4< , independently of the others, is halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms or (ii) one of R 1< , R 2< , R 3< , or R 4< is nitro or -NHR 5< and the remaining of R 1< , R 2< , R 3< , or R 4< are hydrogen; R 5< is hydrogen or alkyl of 1 to 8 carbons; R 6< hydrogen, alkyl of 1 to 8 carbon atoms, benzo, chloro, or fluoro; R' is R 7< -CHR 10< -N(R 8< R 9< ); R 7< is m-phenylene or p-phenylene or -(C n H 2n )- in which n has a value of 0 to 4; each of R 8< and R 9< taken independently of the other is hydrogen or alkyl of 1 to 8 carbon atoms, or R 8< and R 9< taken together are tetramethylene, pentamethylene, hexamethylene, or -CH 2 CH 2 [X]X 1 CH 2 CH 2 - in which [X]X 1 is -O-, -S-, or -NH-; R 10< is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and * represents a chiral-carbon center.

[0058] Specific 5-Substituted Quinazolinone Compounds not part of the invention and described herein include compounds such as those described in U.S. Patent No. 7,635,700 and U.S. Patent Publication No. 2012 / 0230983, published September 13, 2012. In one example, representative 5-Substituted Quinazolinone Compounds are of the formula (I): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 1< is: hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or -(CH 2 ) n NHR a< , wherein R a< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR b< R c< , wherein R b< and R c< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 2< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 3< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0059] In one example, representative 5-Substituted Quinazolinone Compounds are of the formula (II): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 4< is: hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; R 5< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 6< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0060] In one example, R 4< is hydrogen. In another example, R 4< is halo. In another example, R 4< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 4< is -(CH 2 ) n OH or hydroxyl. In another example, R 4< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0061] In one example, R 5< is hydrogen. In another example, R 5< is -(CH 2 ) n OH or hydroxyl. In another example, R 5< is phenyl. In another example, R 5< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 5< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0062] In one example, R 6< is hydrogen. In another example, R 6< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0063] In one example, n is 0. In another embodiment, n is 1. In another example, n is 2.

[0064] Compounds described herein encompass any of the combinations of R 4< , R 5< , R 6< and n described above.

[0065] In one specific example, R 4< is methyl. In another example, R 4< is methoxy. In another example, R 4< is -CF3. In another example, R 4< is F or Cl.

[0066] In another specific example, R 5< is methyl. In another example, R 5< is -CF3.

[0067] Specific examples of 5-Substituted Quinazolinone Compounds include those from Table A:

[0068] In another example, representative 5-Substituted Quinazolinone Compounds are of the formula (III): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 1< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); C(O)-(CH 2 ) n -NR e< R f< , wherein R e< and R f< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl. R 7< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 8< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0069] In one example, R d< is hydrogen. In another example, R d< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R d< is -C(O)-(C 1 -C 8 )alkyl. In another example, R d< is -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl). In another example, R d< is - C(O)-(CH 2 ) n -NR e< R f< , wherein R e< and R f< are as described herein above. In another example, R d< is -C(O)-(CH 2 ) n -O-(CH 2 ) n -(C 1 -C 6 )alkyl.

[0070] In one example, R 7< is hydrogen. In another example, R 7< is -(CH 2 ) n OH or hydroxyl. In another example, R 7< is phenyl. In another example, R 7< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 7< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0071] In one example, R 8< is hydrogen. In another example, R 8< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0072] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0073] 5-Substituted Quinazolinone Compounds describedv herein encompass any of the combinations of R d< , R 7< , R 8< and n described above.

[0074] In one specific example, R 7< is methyl. In another example, R d< is -C(O)-(C 1 -C 6 )alkyl. In another example, R d< is NH 2 . In another example, R d< is -C(O)-CH 2 -O-(C 1 -C 6 )alkyl.

[0075] Specific examples of 5-Substituted Quinazolinone Compounds include those from Table B:

[0076] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0077] In one example, the 5-Substituted Quinazolinone Compound is 3-(5-Amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-piperidine-2,6-dione hydrochloride.

[0078] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0079] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0080] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0081] In another example, representative 5-Substituted Quinazolinone Compounds are of the formula (IV): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R g< is: -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -NHR h< , wherein R h< is: 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 9< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 10< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0082] In one example, R g< is -(CH 2 ) n -(6 to 10 membered aryl). In another example, R g< is -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted as described above. In another example, R g< is -C(O)-(CH 2 ) n -NHR h< , wherein R h< is 6 to 10 membered aryl, optionally substituted as described above. In another example, R g< is -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl).

[0083] In one example, R 9< is hydrogen. In another example, R 9< is -(CH 2 ) n OH or hydroxyl. In another example, R 9< is phenyl. In another example, R 9< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 9< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0084] In one example, R 10< is hydrogen. In another example, R 10< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0085] In one example, n is 0. In another example, n is 1. In another embodiment, n is 2.

[0086] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R g< , R 9< , R 10< and n described above.

[0087] In one specific example, R 9< is methyl. In another example, R g< is -C(O)-phenyl or -C(O)-CH 2 -phenyl, wherein the phenyl is optionally substituted with methyl, -CF 3 , and / or halo. In another example, R g< is -C(O)-NH-phenyl, wherein the phenyl is optionally substituted with methyl, -CF 3 , and / or halo.

[0088] Specific 5-Substituted Quinazolinone Compounds include those from Table C:

[0089] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0090] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0091] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0092] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0093] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0094] Specific 5-Substituted Quinazolinone Compounds described herein include, but are not limited to, 6-, 7-, or 8-substituted quinazolinone compounds such as those described in U.S. Patent Application Publication No. US 2009 / 0093504. In one example, representative 5-Substituted Quinazolinone Compounds are of the formula (V): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 1< is hydrogen; each of R 2< , R 3< , and R 4< is independently: hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or -(CH 2 ) n NHR a< , wherein R a< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or - C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, said alkyl itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, said alkoxy itself optionally substituted with one or more halo;-C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo;-C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR b< R c< , wherein R b< and R c< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or-C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); or two of R 1< -R 4< together can form a 5 or 6 membered ring, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; R 5< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 6< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0095] In another example, representative 5-Substituted Quinazolinone Compounds are of formula (VI): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 7< is : hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or -(CH 2 ) n NHR d< , wherein R d< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR e< R f< , wherein R e< and R f< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 8< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 9< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0096] In another example, representative 5-Substituted Quinazolinone Compounds are of formula (VII): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 10< is: hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; R 11< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 12< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0097] In one example, R 10< is hydrogen. In another example, R 10< is halo. In another example, R 10< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 10< is -(CH 2 ) n OH or hydroxyl. In another example, R 10< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0098] In one example, R 11< is hydrogen. In another example, R 11< is -(CH 2 ) n OH or hydroxyl. In another example, R 11< is phenyl. In another example, R 11< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 11< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0099] In one example, R 12< is hydrogen. In another example, R 12< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0100] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0101] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R 10< , R 11< , R 12< and n described above.

[0102] In one specific example, R 10< is halo. In another example, R 10< is hydroxyl. In another example, R 10< is methyl.

[0103] In another specific example, R 11< is hydrogen. In another example, R 11< is methyl.

[0104] In another specific example, R 12< is hydrogen. In another example, R 12< is methyl.

[0105] Specific 5-Substituted Quinazolinone Compounds include those from Table D:

[0106] In another example, described herein are 5-Substituted Quinazolinone Compounds of formula (VIII): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R g< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR h< R i< , wherein R h< and R i< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 13< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 14< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0107] In one example, R g< is hydrogen. In another example, R g< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R g< is -(CH 2 ) n -(6 to 10 membered aryl). In another example, R g< is -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted as described above. In another example, R g< is -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo. In another example, R g< is -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl). In another example, R g< is -C(O)-(CH 2 ) n -NR h< R i< , wherein R h< and R i< are as described above. In another example, R g< is -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl. In another example, R g< is -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl).

[0108] In one example, R 13< is hydrogen. In another example, R 13< is -(CH 2 ) n OH or hydroxyl. In another example, R 13< is phenyl. In another example, R 13< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 13< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0109] In one example, R 14< is hydrogen. In another example, R 14< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0110] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0111] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R 8< , R 13< , R 14< and n described above.

[0112] In one specific example, R g< is hydrogen, and n is 0 or 1. In another example, R g< is -C(O)-(C 1 -C 6 )alkyl. In another example, R g< is -C(O)-phenyl, optionally substituted with one or more methyl, halo, and / or (C 1 -C 6 )alkoxy.

[0113] In another specific example, R 13< is methyl. In another example, R 14< is hydrogen.

[0114] Specific 5-Substituted Quinazolinone Compounds include those from Table E:

[0115] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0116] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0117] In another example, representative 5-Substituted Quinazolinone Compounds are of formula (IX): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 15< is : hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or -(CH 2 ) n NHR i< , wherein R i< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR k< Rl, wherein R k< and R l< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 16< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 17< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0118] In one example, R 15< is hydrogen. In another example, R 15< is halo. In another example, R 15< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 15< is -(CH 2 ) n OH or hydroxyl. In another example, R 15< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0119] In one example, R 15< is -(CH 2 ) n NHR i< . In one example, wherein R 15< is - (CH 2 ) n NHR i< , R i< is hydrogen. In another example, R i< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R j< is -(CH 2 ) n -(6 to 10 membered aryl). In another example, R j< is -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted as described above. In another example, R j< is -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo. In another example, R j< is -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl). In another example, R j< is -C(O)-(CH 2 ) n -NR k< R l< , wherein R k< and R l< are as described above. In another example, R j< is -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl. In another example, R j< is -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl).

[0120] In one example, R 16< is hydrogen. In another example, R 16< is -(CH 2 ) n OH or hydroxyl. In another example, R 16< is phenyl. In another example, R 16< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 16< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0121] In one example, R 17< is hydrogen. In another example, R 17< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0122] In one example, n is 0. In another example, n is 1. In another embodiment, n is 2.

[0123] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R 15< , R 16< , R 17< and n described above.

[0124] In one specific example, R 15< is methyl. In another example, R 15< is halo. In another example, R 15< is -CF 3 . In another example, R 15< is -(CH 2 ) n NHR j< .

[0125] In one specific examplewherein R 15< is -(CH 2 ) n NHR i< , R i< is hydrogen, and n is 0 or 1. In another examplewherein R 15< is -(CH 2 )-NHR j< , R j< is -C(O)-(O)-(C 1 -C 6 )alkyl.

[0126] In one specific example, R 16< is hydrogen. In another example, R 16< is methyl. In another specific example, R 17< is hydrogen or methyl.

[0127] Specific 5-Substituted Quinazolinone Compounds include those from Table F:

[0128] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0129] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0130] In another example, representative 5-Substituted Quinazolinone Compounds are of formula (X): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 18< is : hydrogen; halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or -(CH 2 ) n NHR m< , wherein R m< is: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; -(CH 2 ) n -(6 to 10 membered aryl); -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one or more of: halo; -SCF 3 ; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo; -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl); -C(O)-(CH 2 ) n -NR n< R o< , wherein R n< and R o< are each independently: hydrogen; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or 6 to 10 membered aryl, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halo; or (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halo; -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl; or -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl); R 19< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 20< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0131] In one example, R 18< is hydrogen. In another example, R 18< is halo. In another example, R 18< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 18< is -(CH 2 ) n OH or hydroxyl. In another example, R 18< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0132] In one example, R 18< is -(CH 2 ) n NHR m< . In one example, wherein R 28< is - (CH 2 ) n NHR s< , R s< is hydrogen. In another example, R m< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R m< is -(CH 2 ) n -(6 to 10 membered aryl). In another example, R m< is -C(O)-(CH 2 ) n -(6 to 10 membered aryl) or -C(O)-(CH 2 ) n -(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is optionally substituted as described above. In another example, R s< is -C(O)-(C 1 -C 8 )alkyl, wherein the alkyl is optionally substituted with one or more halo. In another example, R m< is -C(O)-(CH 2 ) n -(C 3 -C 10 -cycloalkyl). In another example, R m< is -C(O)-(CH 2 ) n -NR n< R o< , wherein R n< and R o< are as described above. In another example, R m< is -C(O)-(CH 2 ) n -O-(C 1 -C 6 )alkyl. In another example, R m< is -C(O)-(CH 2 ) n -O-(CH 2 ) n -(6 to 10 membered aryl).

[0133] In one example, R 19< is hydrogen. In another example, R 19< is -(CH 2 ) n OH or hydroxyl. In another example, R 19< is phenyl. In another example, R 19< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 19< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0134] In one example, R 20< is hydrogen. In another example, R 20< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0135] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0136] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R 18< , R 19< , R 20< and n described above.

[0137] In one specific example, R 18< is methyl. In another example, R 18< is halo. In another example, R 18< is hydroxyl. In another example, R 18< is -CF 3 .

[0138] In one specific example, R 19< is hydrogen. In another example, R 19< is methyl. In another specific example, R 20< is hydrogen.

[0139] Specific 5-Substituted Quinazolinone Compounds include those from Table G:

[0140] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0141] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0142] In another example, representative 5-Substituted Quinazolinone Compounds are of formula (XI): and pharmaceutically acceptable salts, solvates, and stereoisomers thereof, wherein: R 21< is hydrogen; R 22< , R 23< , and R 24< are each independently: halo; -(CH 2 ) n OH; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; or two of R 21< -R 24< together form a 5 to 6 membered ring, optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and (C 1 -C 6 )alkoxy, optionally substituted with one or more halo; R 25< is: hydrogen; -(CH 2 ) n OH; phenyl; -O-(C 1 -C 6 )alkyl; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; R 26< is: hydrogen; or (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and n is 0, 1, or 2.

[0143] In one example, two of R 22< -R 24< are halo. In another example, two of R 22< -R 24< are (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, two of R 22< -R 24< are (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0144] In another example, one of R 22< -R 24< are is halo, and another one of R 22< -R 24< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, one of R 22< -R 24< is halo, and another one of R 22< -R 24< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo. In another example, one of R 22< -R 24< is (C 1 -C 6 )alkoxy, optionally substituted with one or more halo, and another one of R 22< -R 24< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0145] In another example, two of R 22< -R 24< together form a 5 to 6 membered ring. In one specific example, R 22< and R 23< together form a 5 to 6 membered ring. In one specific example, R 22< and R 23< together form phenyl ring. In another example, the ring formed by R 22< and R 23< is optionally substituted with one or more of: halo; (C 1 -C 6 )alkyl, optionally substituted with one or more halo; and (C 1 -C 6 )alkoxy, optionally substituted with one or more halo.

[0146] In one example, R 25< is hydrogen. In another example, R 25< is -(CH 2 ) n OH or hydroxyl. In another example, R 25< is phenyl. In another example, R 25< is -O-(C 1 -C 6 )alkyl, optionally substituted with one or more halo. In another example, R 25< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0147] In one example, R 26< is hydrogen. In another example, R 26< is (C 1 -C 6 )alkyl, optionally substituted with one or more halo.

[0148] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0149] 5-Substituted Quinazolinone Compounds described herein encompass any of the combinations of R 21< , R 22< , R 23< , R 24< , R 25< , R 26< , and n described above.

[0150] Specific 5-Substituted Quinazolinone Compounds include:

[0151] In one example, the 5-Substituted Quinazolinone Compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0152] All of the 5-Substituted Quinazolinone Compounds described can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure 5-Substituted Quinazolinone Compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.

[0153] Still other specific immunomodulatory drugs described herein belong to a class of 5-substituted isoindole compounds disclosed in U.S. Patent Application Publication No. US 2009 / 0142297. Representative compounds are of formula XI: and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, wherein: n is 0 or 1; X is CH 2 , C=O, or C=S; R 1< is: a) -(CH 2 ) m R 3< or -CO(CH 2 ) m R 3< , wherein m is 0, 1, 2, or 3; and R 3< is 5-10 membered aryl or heteroaryl, optionally substituted with one or more halogen; b) -C=YR 4< , wherein Y is O or S; and R 4< is: (C 1 -C 10 )alkyl; (C 1 -C 10 )alkoxy; (C 0 -C 10 )alkyl-(5 to 10 membered heteroaryl or heterocycle), said heteroaryl or heterocycle optionally substituted with one or more of (C 1 -C 6 )alkyl, halogen, oxo, (C 1 -C 6 )alkoxy, or -Z-(C 1 -C 6 )alkyl, wherein Z is S or SO 2 , and wherein said (C 1 -C 6 )alkyl may be optionally substituted with one or more halogen; (C 0 -C 10 )alkyl-(5 to 10 membered aryl), said aryl optionally substituted with one or more of: halogen; (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; or -Z-(C 1 -C 6 )alkyl, wherein Z is S or SO 2 , and wherein said (C 1 -C 6 )alkyl may be optionally substituted with one or more halogen; or (C 1 -C 6 )alkyl-CO-O-R 12< , wherein R 12< is H or (C 1 -C 6 )alkyl; or c) -C=ZNHR 6< , wherein Z is O or S; and R 6< is: (C 1 -C 10 )alkyl; (C 1 -C 10 )alkoxy; 5 to 10 membered aryl or heteroaryl, optionally substituted with one or more of: halogen; cyano; (C 1 -C 6 )alkylenedioxy; (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; or (C 1 -C 6 )alkylthio, itself optionally substituted with one or more halogen; and R 2< is H or (C 1 -C 6 )alkyl.

[0154] Representative compounds are of formula: and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, wherein: n is 0 or 1; X is CH 2 or C=O; R 7< is -(CH 2 ) m R 9< , wherein m is 0, 1, 2, or 3, and R 9< is 5-10 membered aryl or heteroaryl, optionally substituted with one or more halogen; and R 8< is H or (C 1 -C 6 )alkyl.

[0155] In one example, X is C=O. In another example, X is CH 2 .

[0156] In one example, n is 0. In another example, n is 1.

[0157] In one example, m is 0. In another example, m is 1. In another example, m is 2. In another example, m is 3.

[0158] In one example, R 9< is 5-10 membered aryl. In certain specific example, R 9< is phenyl, optionally substituted with one or more halogen.

[0159] In one example, R 9< is 5-10 membered heteroaryl. In certain specific example, R9 is furyl or benzofuryl.

[0160] In one example, R 8< is H. In another example, R 8< is (C 1 -C 6 )alkyl. In certain specific example, R 8< is methyl.

[0161] All of the combinations of the above examples are not part of this invention.

[0162] Examples include those listed below, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug or stereoisomer thereof:

[0163] Other representative compounds are of formula: and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, wherein: X is CH 2 or C=O; Y is O or S; R 10< is: (C 1 -C 10 )alkyl; (C 1 -C 10 )alkoxy; (C 0 -C 10 )alkyl-(5 to 10 membered heteroaryl or heterocycle), said heteroaryl or heterocycle optionally substituted with one or more of: (C 1 -C 6 )alkyl, itself substituted with one or more halogen; halogen; oxo; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; or -Z-(C 1 -C 6 )alkyl, wherein Z is S or SO 2 , and wherein said (C 1 -C 6 )alkyl may be optionally substituted with one or more halogen; (C 0 -C 10 )alkyl-(5 to 10 membered aryl), said aryl optionally substituted with one or more of: halogen; (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; or -Z-(C 1 -C 6 )alkyl, wherein Z is S or SO 2 , and wherein said (C 1 -C 6 )alkyl may be optionally substituted with one or more halogen; or (C 1 -C 6 )alkyl-CO-O-R 12< , wherein R 12< is H or (C 1 -C 6 )alkyl; and R 11< is H or (C 1 -C 6 )alkyl.

[0164] In one example, X is CH 2 . In another example, X is C=O.

[0165] In one example, Y is O. In another example, Y is S.

[0166] In one example, R 10< is (C 1 -C 10 )alkyl. In certain specific examples, R 10< is (C 5 -C 10 )alkyl. In certain specific examples, R 10< is pentyl or hexyl.

[0167] In one example, R 10< is (C 1 -C 10 )alkoxy. In certain specific examples, R 10< is (C 5 -C 10 )alkoxy. In certain specific examples, R 10< is pentyloxy or hexyloxy.

[0168] In one example, R 10< is 5 to 10 membered heteroaryl. In certain specific examples, R 10< is thiopheneyl or furyl.

[0169] In one example, R 10< is 5 to 10 membered aryl, optionally substituted with one or more halogen. In certain specific examples, R 10< is phenyl, optionally substituted with one or more halogen.

[0170] In one example, R 10< is 5 to 10 membered aryl or heteroaryl, optionally substituted with (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy, themselves optionally substituted with one or more halogen. In certain specific examples, R 10< is phenyl substituted with (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy, substituted with one or more halogen. In certain specific examples, R 10< is phenyl substituted with methyl or methoxy, substituted with 1, 2, or 3 halogens.

[0171] In one example, R 10< is aryl or heteroaryl substituted with -S-(C 1 -C 6 )alkyl, wherein said alkyl itself optionally substituted with one or more halogen. In another example, R 10< is aryl or heteroaryl substituted with -SO 2 -(C 1 -C 6 )alkyl, wherein said alkyl itself optionally substituted with one or more halogen.

[0172] In one example, R 10< is (C 1 -C 6 )alkyl-CO-O-R 12< , and R 12< is (C 1 -C 6 )alkyl. In one specific example, R 10< is butyl-CO-O-tBu.

[0173] In one example, R 10< is (C 1 -C 6 )alkyl-CO-O-R 12< , and R 12< is H. In one specific example, R 10< is butyl-COOH.

[0174] In one example, R 11< is H. In another example, R 11< is (C 1 -C 6 )alkyl. In certain specific examples, R 11< is methyl.

[0175] Examples include those listed in Table J, below, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), or stereoisomer thereof:

[0176] Other examples include those listed in Table K, below, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), or stereoisomer thereof:

[0177] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0178] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0179] Still other representative compounds of formula: and pharmaceutically acceptable salts, solvates, stereoisomers, and prodrugs thereof, wherein: X is CH 2 or C=O; Y is O or S; R 13< is: (C 1 -C 10 )alkyl; (C 1 -C 10 )alkoxy; 5 to 10 membered aryl or heteroaryl, optionally substituted with one or more of: halogen; cyano; (C 1 -C 6 )alkylenedioxy; (C 1 -C 6 )alkoxy, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; or (C 1 -C 6 )alkylthio, itself optionally substituted with one or more halogen; and R 14< is H or (C 1 -C 6 )alkyl.

[0180] In one example, X is CH 2 . In another example, X is C=O.

[0181] In one example, Y is O. In another example, Y is S.

[0182] In one example, R 13< is (C 1 -C 10 )alkyl. In certain specific examples, R 13< is (C 1 -C 6 )alkyl. In certain specific examples, R 13< is propyl, butyl, pentyl, or hexyl.

[0183] In one example, R 13< is (C 1 -C 10 )alkoxy.

[0184] In one example, R 13< is 5 to 10 membered aryl or heteroaryl, optionally substituted with cyano. In certain specific examples, R 13< is phenyl, optionally substituted with cyano.

[0185] In one example, R 13< is 5 to 10 membered aryl or heteroaryl, optionally substituted with (C 1 -C 6 )alkylenedioxy. In certain specific examples, R 13< is phenyl, optionally substituted with methylenedioxy.

[0186] In one example, R 13< is 5 to 10 membered aryl or heteroaryl, optionally substituted with one or more halogen. In certain specific examples, R 13< is phenyl, optionally substituted with one or more halogen.

[0187] In another example, R 13< is 5 to 10 membered aryl or heteroaryl, optionally substituted with (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy, themselves optionally substituted with one or more halogens. In certain specific examples, R 13< is phenyl, optionally substituted with methyl or methoxy, themselves optionally substituted with 1, 2, or 3 halogens.

[0188] In another example, R 13< is 5 to 10 membered aryl or heteroaryl, optionally substituted with (C 1 -C 6 )alkylthio, itself optionally substituted with one or more halogens.

[0189] In another example, R 14< is H. In another example, R 14< is (C 1 -C 6 )alkyl. In certain specific examples, R 14< is methyl.

[0190] Examples include listed in Table L, below, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug or stereoisomer thereof:

[0191] Other examples include those listed in Table M, below, or a pharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug or stereoisomer thereof:

[0192] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0193] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0194] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0195] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0196] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0197] Still other specific immunomodulatory drugs described herein belong to a class of isoindoline compounds disclosed in U.S. Patent No. 8,129,375. Representative compounds are of formula XIII: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is C(=O) or CH 2 ; Y is O, cyanamido (N-≡N), or amido (NH); m is an integer of 0, 1, 2, or 3; R 1< is hydrogen or C 1-6 alkyl; R 2< is hydrogen, -NO 2 , C 1-10 alkyl, C 0-6 alkyl-(5 to 10 membered heteroaryl), C 0-6 alkyl-(5 to 6 membered heterocyclyl), C 0-6 alkyl-OH, C 0-4 alkyl-NH 2 , -NHCO-C 1-6 alkyl, -OR 21< , or -(CH 2 -Z) 0-2 -(5 to 10 membered heteroaryl), where each heteroaryl and heterocyclyl is optionally substituted with one or more C 1-6 alkyl; R 3< is hydrogen, halogen, -NO 2 , C 0-6 alkyl-(5 to 10 membered heteroaryl), C 0-6 alkyl-(5 to 6 membered heterocyclyl), C 0-6 alkyl-OH, C 0-4 alkyl-NH 2 , -NHCO-C 1-6 alkyl, - OR 21< , or -(CH 2 -Z) 0-2 -(5 to 10 membered heteroaryl), where each heteroaryl and heterocyclyl is optionally substituted with one or more C 1-6 alkyl; R 21< is C 6-10 aryl, 5 to 10 membered heteroaryl, 5 to 6 membered heterocyclyl, or -CO(CH 2 ) 0-2 R 22< , wherein the aryl, heteroaryl, and heterocyclyl are each optionally substituted with one or more C 1-6 alkyl; R 22< is -NH 2 or 5 to 6 membered heterocyclyl; and Z is CH 2 , NH, or O; with the proviso that when R 1< is hydrogen, then R 2< is not hydrogen or C 1-10 alkyl; with the proviso that when Y is O, then R 3< is not halogen; and with the proviso that when Y is O and R 3< is halogen, then R 2< is C 0-6 alkyl-(5-6 membered heterocyclyl).

[0198] In certain examples, X is CH 2 . In certain examples, X is C(=O).

[0199] In certain examples, Y is O. In certain examples, Y is cyanamido. In certain examples, Y is amido.

[0200] In certain examples, Z is CH 2 . In certain examples, Z is NH. In certain examples, Z is O.

[0201] In certain examples, m is 0. In certain examples, m is 1. In certain examples, m is 2. In certain examples, m is 3.

[0202] In certain examples, R 1< is hydrogen. In certain examples, R 1< is C 1-6 alkyl, optionally substituted with one, two, or three substituents Q as described herein. In certain examples, R 1< is methyl.

[0203] In certain examples, R 2< is hydrogen. In certain examples, R 2< is halogen. In certain examples, R 2< is nitro. In certain examples, R 2< is C 1-10 alkyl. In certain examples, R 2< is C 0-6 alkyl-(5 to 10 membered heteroaryl), where the heteroaryl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 2< is C 0-6 alkyl-(5 to 6 membered heterocyclyl), where the heterocyclyl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 2< is C 0-6 alkyl-OH. In certain examples, R 2< is C 0-4 alkyl-NH 2 . In certain examples, R 2< is -NHCO-C 1-6 alkyl. In certain examples, R 2< is -OR 21< , wherein R 21< is as described herein. In certain examples, R 2< is or -(CH 2 -Y) 0-2 -(5 to 10 membered heteroaryl), where the heteroaryl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 2< is hydrogen, amino, acetamido, hydroxy, nitro, aminomethyl, hydroxymethyl, 2-methyl-1H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 2-methylthiazol-4-yl, 4-methyl-4H-1,2,4-triazol-3-yl, morpholinomethyl, (pyridin-4-yl)methyl, (pyridin-4-yloxy)methyl, pheoxy, pyridin-2-yloxy, piperidin-4-yloxy, 2-aminoacetoxy, or 2-piperazin-1-ylacetoxy.

[0204] In certain examples, R 3< is hydrogen. In certain examples, R 3< is nitro. In certain examples, R 3< is C 0-6 alkyl-(5 to 10 membered heteroaryl), where the heteroaryl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 3< is C 0-6 alkyl-(5 to 6 membered heterocyclyl), where the heterocyclyl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 3< is C 0-6 alkyl-OH. In certain examples, R 3< is C 0-4 alkyl-NH 2 . In certain examples, R 3< is -NHCO-C 1-6 alkyl. In certain examples, R 3< is -OR 21< , wherein R 21< is as described herein. In certain examples, R 3< is or -(CH 2 -Y) 0-2 -(5 to 10 membered heteroaryl), where the heteroaryl is optionally substituted with one or more C 1-6 alkyl. In certain examples, R 3< is hydrogen, amino, acetamido, hydroxy, nitro, methyl, aminomethyl, hydroxymethyl, 2-methyl-1H-imidazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 4-methylpiperazin-1-yl)methyl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-1H-pyrazol-3-yl, 2-methylthiazol-4-yl, 4-methyl-4H-1,2,4-triazol-3-yl, morpholinomethyl, (pyridin-4-yl)methyl, (pyridin-4-yloxy)methyl, pheoxy, pyridin-2-yloxy, piperidin-4-yloxy, 2-aminoacetoxy, or 2-piperazin-1-ylacetoxy.

[0205] In one example, the compound is from those listed in Table Q, below: or a pharmaceutically acceptable salt, solvate, prodrug, and stereoisomer thereof.

[0206] In another example, representative compounds are of Formula XIV: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is C(=O) or CH 2 ; m is an integer of 0, 1, 2, or 3; R 4< is C 3-10 cycloalkyl, 5 to 10 membered heterocyclyl, 5 to 10 membered heteroaryl, or C 0-4 alkyl-NR 41< R 42< ; wherein the cycloalkyl, heterocyclyl, and heteroaryl are each optionally substituted with one or more halogen, C 1-6 alkyl, -CO-NR 43< R 44< , -COOR 45< , or C 0-4 alkyl-C 6-10 aryl, wherein the aryl itself may be optionally substituted with one or more halogen; and R 41< , R 42< , R 43< , R 44< , and R 45< are each independently hydrogen or C 1-6 alkyl.

[0207] In certain examples, X is CH 2 . In certain examples, X is C(=O).

[0208] In certain examples, m is 0. In certain examples, m is 1. In certain examples, m is 2. In certain examples, m is 3.

[0209] In certain examples, R 4< is C 3-10 cycloalkyl, optionally substituted with one or more (C 1-6 ) alkyl or C 0-4 alkyl-C 6-10 aryl. In certain examples, R 4< is 5 to 6 membered heterocyclyl, optionally substituted with one or more (C 1-6 ) alkyl or C 0-4 alkyl-C 6-10 aryl. In certain examples, R 4< is C 0-4 alkyl-NR 41< R 42< , wherein R 41< and R 42< are each described herein.

[0210] In certain examples, R 4< is 3-(N,N-diethylamino)propyl, 4-acetamidophenyl, 3-(2-aminoacetoxy)-4-methylphenyl, 3-aminomethyl-4-methylphenyl, 2-aminomethyl-5-methylphenyl, 3-aminophenyl, 3-amino-4-methylphenyl, 3-chloro-4-methylphenyl, 4-hydroxymethylphenyl, 3-hydroxy-4-methylphenyl, 3-(2-methyl-1H-imidazol-1-yl)phenyl, 4-methyl-3-nitrophenyl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl, 4-methyl-3-(2-piperazin-1-ylacetoxy)-phenyl, 3-((4-methylpiperazin-1-yl)methyl)phenyl, 3-(1-methyl-1H-pyrazol-3-yl)phenyl, 3-(2-methyl-2H-pyrazol-3-yl)phenyl, 3-(2-methylthiazol-4-yl)phenyl, 4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl, 3-(morpholinomethyl)phenyl, 4-(morpholinomethyl)phenyl, 4-nitrophenyl, phenyl, 3-(piperidin-4-yloxy)phenyl, 4-(pyridin-4-yl)methylphenyl, 4-((pyridin-4-yloxy)methyl)phenyl, 3-(pyridin-2-yloxy)phenyl, 3-phenoxyphenyl, 4-tert-butylcyclohexyl, cis-4-tert-butylcyclohexyl, trans-4-tert-butylcyclohexyl, 4-methylcyclohexyl, cis-4-methylcyclohexyl, trans-4-methylcyclohexyl, 1-benzylpiperidin-4-yl, 4-methyltetrahydro-2H-pyran-4-yl, piperidin-4-yl, 4-phenylcyclohexyl, cis-4-phenylcyclohexyl, or trans-4-phenylcyclohexyl.

[0211] In one example, the compound is from those listed in Table R, below: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0212] In yet another example, representative compounds are of Formula XV: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is C(=O) or CH 2 ; m is an integer of 0, 1, 2, or 3; R 5< and R 6< are each independently: hydrogen, halo, C 1-6 alkyl, oxo, -NOz, C 1-6 alkoxy, -Z-C 1-6 alkyl, C 0-6 alkyl-(5 to 10 membered heteroaryl), C 0-6 alkyl-(5 to 6 membered heterocyclyl), C 0-6 alkyl-OH, C 0-4 alkyl-NH 2 , -NHCO-C 1-6 alkyl, -OR 21< , or - (CH 2 -Y) 0-2 -(5 to 10 membered heteroaryl), wherein Z is S or SO 2 ; wherein R 21< is as defined above; wherein each heteroaryl and heterocyclyl above is optionally substituted with one or more C 1-6 alkyl; and wherein the alkyl or alkoxy above may be optionally substituted with one or more: halogen; cyano; nitro; amino; C 1-6 alkylidenedioxy; C 1-6 alkoxy, itself optionally substituted with one or more halogens; or C 1-6 alkylthio, itself optionally substituted with one or more halogens; R 7< is -COR 71< or -PO(OR 72< )(OR 73< ); R 71< is C 1-10 alkyl, C 6-10 aryl, or 5 to 6 membered heterocyclyl; wherein the alkyl, aryl, heterocyclyl may be optionally substituted with one or more amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, or -COOR 74< ; and R 72< , R 73< , and R 74< are each independently hydrogen or C 1-10 alkyl.

[0213] In certain examples, X is CH2. In certain examples, X is C(=O).

[0214] In certain examples, m is 0. In certain examples, m is 1. In certain examples, m is 2. In certain examples, m is 3.

[0215] In certain examples, R 5< is hydrogen. In certain examples, R5 is halo. In certain examples, R 5< is fluoro or chloro.

[0216] In certain examples, R 6< is hydrogen. In certain examples, R6 is halo. In certain examples, R 6< is fluoro or chloro.

[0217] In certain examples, R 7< is -COR 41< , wherein R 41< is as described herein. In certain examples, R7 is -PO(OR 42< ))(OR 43< ), wherein R 42< and R 43< are each as described herein.

[0218] In one example, the compound is from those listed in Table S, below: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein R 5< and R 6< are as defined above.

[0219] In yet another example, representative compounds are of Formula XVI: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is C(=O) or CH 2 ; n is an integer of 0 or 1; R 8< is hydrogen or halo; and R 9< is hydrogen, amino, or 5 to 10 membered heteroaryl or heterocyclyl; with the proviso that when m is 0, R 9< is not hydrogen.

[0220] In certain examples, X is CH 2 . In certain examples, X is C(=O).

[0221] In certain examples, n is 0. In certain examples, n is 1.

[0222] In certain examples, R 8< is hydrogen. In certain examples, R 8< is halo. In certain examples, R 8< is fluoro or chloro.

[0223] In certain examples, R 9< is hydrogen. In certain examples, R 9< is amino. In certain examples, R 9< is 5 to 10 membered heteroaryl. In certain examples, R 9< is 5 to 10 membered heterocyclyl.

[0224] In one example, the compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0225] In yet another example, representative compounds are of Formula XVII: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is C(=O) or CH 2 ; m is an integer of 0, 1, 2, or 3; R 10< and R 11< are each independently hydrogen, halo, C 1-6 alkyl, or C 6-10 aryloxy, wherein the alkyl and aryl are each optionally substituted with one or more halo.

[0226] In certain examples, X is CH 2 . In certain examples, X is C(=O).

[0227] In certain examples, m is 0. In certain examples, m is 1. In certain examples, m is 2. In certain examples, m is 3.

[0228] In certain examples, R 10< is hydrogen. In certain examples, R 10< is halo. In certain examples, R 10< is fluoro or chloro. In certain examples, R 10< is C 1-6 alkyl, optionally substituted with one or more halo. In certain examples, R 10< is C 6-10 aryloxy, optionally substituted with one or more halo.

[0229] In certain examples, R 11< is hydrogen. In certain examples, R 11< is halo. In certain examples, R 11< is fluoro or chloro. In certain examples, R 11< is C 1-6 alkyl, optionally substituted with one or more halo. In certain examples, R 11< is C 6-10 aryloxy, optionally substituted with one or more halo.

[0230] In one example, the compound is selected from those listed in Table T, below: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0231] In yet another example, representative compounds are of Formula XVIII: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof, wherein: X is CH 2 or C=O m and n are each independently 0 or 1; p is 0, 1, 2, or 3; R 81< is 5 to 6 membered heterocyclyl, optionally substituted with C 1-6 alkyl; and R 82< is hydrogen or halogen.

[0232] In one example, X is CH 2 . In another example, X is C=O.

[0233] In one example, m is 0. In another example, m is 1. In another example, n is 0. In another example, n is 1.

[0234] In one example, p is 0. In another example, p is 1. In another example, p is 2. In another example, p is 3.

[0235] In one example, R 81< is 5 membered heterocycle. In another example, the 5 membered heterocycle is substituted with C 1-6 alkyl. In another example, R 81< is 6 membered heterocycle. In another example, the 6 membered heterocycle is substituted with C 1-6 alkyl.

[0236] In one example, R 82< is hydrogen. In another example, R 82< is halogen.

[0237] In one example, the compound is from those listed in Table U, below: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0238] In yet another example, representative compounds are of the following formula in Table V, below: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0239] Still other specific immunomodulatory drugs described herein and outside the scope of the invention belong to a class of 4'-arylmethoxy isoindoline compounds disclosed in U.S. Patent Application Publication No. US 2011 / 0196150. Representative compounds are of formula XIX: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is C=O or CH 2 ; R 1< is -Y-R 3< ; R 2< is H or (C 1 -C 6 )alkyl; Y is: 6 to 10 membered aryl, heteroaryl or heterocycle, each of which may be optionally substituted with one or more halogen; or a bond; R 3< is: -(CH 2 ) n -aryl, -O-(CH 2 ) n -aryl or -(CH 2 ) n -O-aryl, wherein the aryl is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen; -(CH 2 ) n -heterocycle, -O-(CH 2 ) n -heterocycle or -(CH 2 ) n -O-heterocycle, wherein the heterocycle is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen; or -(CH 2 ) n -heteroaryl, -O-(CH 2 ) n -heteroaryl or -(CH 2 ) n -O-heteroaryl, wherein the heteroaryl is optionally substituted with one or more: (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen; (C 1 -C 6 )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; deuterium; 6 to 10 membered aryl or heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen; -CONH 2 ; or -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen; and n is 0, 1, 2 or 3.

[0240] In one example, X is C=O. In another example, C is CH 2 .

[0241] In one example, R 2< is H. In another example, R 2< is (C 1 -C 6 )alkyl.

[0242] In one example, Y is aryl. In another example, Y is heteroaryl. In another example, Y is heterocycle. In another example, Y is a bond.

[0243] In one example, R 3< is unsubstituted -(CH 2 ) n -aryl. In another example, R 3< is - (CH 2 ) n -aryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more oxo. In another example, R 3< is -(CH 2 ) n - aryl substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more carboxyl. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n - aryl substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -aryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0244] In one example, R 3< is unsubstituted -O-(CH 2 ) n -aryl. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more oxo. In another example, R 3< is -O-(CH 2 ) n - aryl substituted with one or more amino. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more carboxyl. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more cyano. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more hydroxyl. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more deuterium. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more -CONH 2 . In another example, R 3< is -O-(CH 2 ) n -aryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0245] In one example, R 3< is unsubstituted -(CH 2 ) n -O-aryl. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is - (CH 2 ) n -O-aryl substituted with one or more oxo. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more carboxyl. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -O-aryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0246] In one example, R 3< is unsubstituted -(CH 2 ) n -heterocycle. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more oxo. In another emexamplebodiment, R 3< is -(CH 2 ) n -heterocycle substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more carboxyl. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -heterocycle substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0247] In one example, R 3< is unsubstituted -O-(CH 2 ) n -heterocycle. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more oxo. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more amino. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more carboxyl. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more cyano. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more hydroxyl. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more deuterium. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more -CONH 2 . In another example, R 3< is -O-(CH 2 ) n -heterocycle substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0248] In one example, R 3< is unsubstituted -(CH 2 ) n -O-heterocycle. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more oxo. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more carboxyl. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -O-heterocycle substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0249] In one example, R 3< is unsubstituted -(CH 2 ) n -heteroaryl. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more oxo. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more carboxyl. In another example, R 3< is - (CH 2 ) n -heteroaryl substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -heteroaryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0250] In one example, R 3< is unsubstituted -O-(CH 2 ) n -heteroaryl. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more oxo. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more amino. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more carboxyl. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more cyano. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more hydroxyl. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more halogen. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more deuterium. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more -CONH 2 . In another example, R 3< is -O-(CH 2 ) n -heteroaryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0251] In one example, R 3< is unsubstituted -(CH 2 ) n -O-heteroaryl. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more (C 1 -C 6 )alkyl, itself optionally substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more (C 1 -C 6 )alkoxy, itself substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more oxo. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more amino. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more carboxyl. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more cyano. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more hydroxyl. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more halogen. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more deuterium. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more 6 to 10 membered aryl, optionally substituted with one or more (C 1 -C 6 )alkyl. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more 6 to 10 membered heteroaryl, optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or halogen. In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more -CONH 2 . In another example, R 3< is -(CH 2 ) n -O-heteroaryl substituted with one or more -COO-(C 1 -C 6 )alkyl, wherein the alkyl may be optionally substituted with one or more halogen.

[0252] In one example, n is 0. In another example, n is 1. In another example, n is 2.

[0253] All of the specific combinations that can result from the definition described herein for X, R 1< , R 2< , Y, R 3< and n are encompassed.

[0254] In one example, X is CH 2 .

[0255] In one example, Y is aryl. In another example, Y is phenyl.

[0256] In another examplewherein Y is phenyl, R 3< is -(CH 2 ) n -heterocycle. In one example, the heterocycle is morpholinyl, piperidinyl or pyrrolidinyl.

[0257] In one example, Y is a heteroaryl. In another example, Y is a 10 membered hetero aryl. In another example, Y is benzo[d]thiazole. In another example, Y is benzofuran. In another example, Y is quinoline.

[0258] In another examplewhere Y is heteroaryl, R 3< is -(CH 2 ) n -heterocycle. In one example, the heterocycle is morpholinyl, piperidinyl or pyrrolidinyl.

[0259] In one example, Y is a bond. In another examplewhere Y is a bond, R 3< is - (CH 2 ) n -heterocycle or -(CH 2 ) n -heteroaryl.

[0260] In one example, examples include those listed in Table W, below: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0261] In another example, representative compounds are of formula (XX): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: R 4< is unsubstituted 9 to 10 membered bicyclic ring is benzothiazole, quinoline, isoquinoline, naphthalene, 2,3-dihydro-1H-indene, benzo[d][1,2,3]triazole, imidazo[1,2-a]pyridine, benzofuran, 2,3-dihydrobenzofuran, benzothiophene, benzo[d]oxazole isoindoline or chroman; with the proviso that if the bicyclic ring is benzofuran or benzothiophene, then the ring is not connected to the isoindole ring through the 2-position.

[0262] In one example, R 4< is benzothiazole. In another example, R 4< is quinoline. In another example, R 4< is isoquinoline. In another example, R 4< is naphthalene. In another example, R 4< is 2,3-dihydro-1H-indene. In another example, R 4< is benzo[d][1,2,3]triazole. In another example, R 4< is imidazo[1,2-a]pyridine. In another example, R 4< is benzofuran. In another example, R 4< is 2,3-dihydrobenzofuran. In another example, R 4< is benzothiophene. In another example, R 4< is benzo[d]oxazole isoindoline. In another example, R 4< is chroman.

[0263] In one example, specific examples include those listed in Table X, below: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0264] In another example, representative compounds are of formula (XXI): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is CH 2 or C=O; R 5< , R 6< and R 7< are each independently hydrogen, halogen, nitro, carbamoyl, amino, -SO 2 R 8< , - CONR 9< R 10< , -(C 1 -C 6 )alkyl or -(C 1 -C 6 )alkoxy, said alkyl or alkoxy may be optionally substituted with one or more halogen, amino, hydroxyl, or NR 9< R 10< ; R 8< is: (C 1 -C 6 )alkyl, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; amino, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; or 6 to 10 membered heterocycle, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl; R 9< and R 10< are each independently hydrogen, 6 to 10 membered aryl, -COO-(C 1 -C 6 )alkyl, - (C 0 -C 6 )alkyl- CHO, -(C 0 -C 6 )alkyl-COOH, -(C 0 -C 6 )alkyl-NR 9'< R 10'< , -(C 0 -C 6 )alkyl-(5 to 10 membered heterocycle), -(C 1 -C 6 )alkyl-OH, -(C 1 -C 6 )alkyl-O-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, or (C 3 - C 6 )cycloalkyl; or R 9< and R 10< together may form an optionally substituted 5 to 6 membered ring containing one or more heteroatoms; and R 9'< and R 10'< are each independently hydrogen or (C 1 -C 6 )alkyl; with the proviso that all of R 5< -R 7< cannot be hydrogen; and with the proviso that if one of R 5< -R 7< is hydrogen and the remaining two of R 5< -R 7< are both chloride, then the two chloride atoms cannot be on 3 and 4 position of the phenyl ring.

[0265] In one example, R 5< is hydrogen. In another example, R 5< is halogen. In another example, R 5< is nitro. In another example, R 5< is carbamoyl. In another example, R 5< is amino. In another example, R 5< is -SO 2 R 8< . In another example, R 5< is -CONR 9< R 10< . In another example, R 5< is -(C 1 -C 6 )alkyl, optionally substituted with one or more halogen, amino, hydroxyl, or NR 9< R 10< . In another example, R 5< is -(C 1 -C 6 )alkoxy, optionally substituted with one or more halogen, amino, hydroxyl or NR 9< R 10< .

[0266] In one example, R 6< is hydrogen. In another example, R 6< is halogen. In another example, R 6< is nitro. In another example, R 6< is carbamoyl. In another example, R 6< is amino. In another example, R 6< is -SO 2 R 8< . In another example, R 6< is -CONR 9< R 10< . In another example, R 6< is -(C 1 -C 6 )alkyl, optionally substituted with one or more halogen, amino, hydroxyl, or NR 9< R 10< . In another example, R 6< is -(C 1 -C 6 )alkoxy, optionally substituted with one or more halogen, amino, hydroxyl or NR 9< R 10< .

[0267] In one example, R 7< is hydrogen. In another example, R 7< is halogen. In another example, R 7< is nitro. In another example, R 7< is carbamoyl. In another example, R 7< is amino. In another example, R 7< is -SO 2 R 8< . In another example, R 7< is -CONR 9< R 10< . In another example, R 7< is -(C 1 -C 6 )alkyl, optionally substituted with one or more halogen, amino, hydroxyl, or NR 9< R 10< . In another example, R 7< is -(C 1 -C 6 )alkoxy, optionally substituted with one or more halogen, amino, hydroxyl or NR 9< R 10< .

[0268] In one example, R 8< is (C 1 -C 6 )alkyl, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl. In another example, R 8< is amino, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl. In another example, R 8< is 6 to 10 membered heterocycle, optionally substituted with (C 1 -C 6 )alkyl or (C 6 -C 10 )aryl.

[0269] In one example, R 9< is hydrogen. In another example, R 9< is 6 to 10 membered aryl. In another example, R 9< is -COO-(C 1 -C 6 )alkyl. In another example, R 9< is -(C 0 -C 6 )alkyl-CHO. In another embodiment, R 9< is -(C 0 -C 6 )alkyl-COOH. In another example, R 9< is -(C 0 -C 6 )alkyl-NR 9'< R 10'< . In another example, R 9< is -(C 0 -C 6 )alkyl-(5 to 10 membered heterocycle). In another example, R 9< is -(C 1 -C 6 )alkyl-OH. In another example, R 9< is -(C 1 -C 6 )alkyl-O-(C 1 -C 6 )alkyl. In another example, R 9< is (C 1 -C 6 )alkyl. In another example, R 9< is (C 3 -C 6 )cycloalkyl.

[0270] In one example, R 10< is hydrogen. In another example, R 10< is 6 to 10 membered aryl. In another example, R 10< is -COO-(C 1 -C 6 )alkyl. In another example, R 10< is - (C 0 -C 6 )alkyl-CHO. In another example, R 10< is -(C 0 -C 6 )alkyl-COOH. In another example, R 10< is -(C 0 -C 6 )alkyl-NR 9'< R 10'< . In another example, R 10< is -(C 0 -C 6 )alkyl-(5 to 10 membered heterocycle). In another example, R 10< is -(C 1 -C 6 )alkyl-OH. In another example, R 10< is -(C 1 -C 6 )alkyl-O-(C 1 -C 6 )alkyl. In another example, R 10< is (C 1 -C 6 )alkyl. In another , R 10< is (C 3 -C 6 )cycloalkyl.

[0271] In one example, R 9< and R 10< together form a 5 to 6 membered ring. In one example, the ring contains one or more heteroatoms. In one example, the heteroatoms are selected from the group consisting of N, S and O.

[0272] In one example, R 9'< is hydrogen. In another example, R 9'< is (C 1 -C 6 )alkyl.

[0273] In one example, R 10'< is hydrogen. In another example, R 10'< is (C 1 -C 6 )alkyl.

[0274] In certain example, provided herein are compounds that result from any combination of R 5< -R 10< and R 9'< -R 10'< .

[0275] In one example, one of R 5< -R 7< is hydrogen and the remaining two of R 5< -R 7< are halogen. In one example, one of R 5< -R 7< is hydrogen and the remaining two of R 5< -R 7< are (C 1 -C 6 )alkoxy. In one example, one of R 5< -R 7< is hydrogen and the remaining two of R 5< -R 7< are (C 1 -C 6 )alkyl. In one example, R 5< is hydrogen, R 6< is halogen, and R 7< is (C 1 -C 6 )alkoxy.

[0276] In one example, two of R 5< -R 7< are hydrogen and the remaining one of R 5< -R 7< is halogen. In one example, two of R 5< -R 7< are hydrogen and the remaining one of R 5< -R 7< is (C 1 -C 6 )alkoxy. In one example, two of R 5< -R 7< are hydrogen and the remaining one of R 5< -R 7< is (C 1 -C 6 )alkyl.

[0277] In one example, specific examples include those listed in Table Y, below: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0278] In another example, representative compounds are of formula (XXII): or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein: X is N or C; Y is CH 2 or C=O; R 11< and R 12< are each independently hydrogen, -(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl-(C 3 -C 6 )cycloalkyl, -(C 1 -C 6 )alkoxy, -(C 6 -C 10 )aryl, -CO(C 1 -C 6 )alkyl, -CO(C 3 -C 6 )cycloalkyl, -CO(C 6 -C 10 )aryl, -COO(C 1 -C 6 )alkyl, halogen, hydroxyl, oxo, 3 to 10 membered heterocycle, 6 to 10 membered heteroaryl, -NHCO(C 1 -C 6 )alkyl, -(CH 2 ) n -phenyl, -SO 2 (C 1 -C 6 )alkyl, -SO 2 (C 3 -C 6 )cycloalkyl, -SO 2 (C 6 -C 10 )aryl or -NR 14< R 15< , wherein the alkyl, aryl or heteroaryl portion of each of the groups may be optionally substituted with one or more halogen, hydroxyl or -(C 1 -C 6 )alkoxy; R 13< is hydrogen or -(C 1 -C 6 )alkyl; R 14< and R 15< are each independently hydrogen or -(C 1 -C 6 )alkyl; and n is 0, 1, 2 or 3.

[0279] In one example, X is N. In another example, X is C.

[0280] In one example, Y is CH 2 . In another example, Y is C=O.

[0281] In one example, R 11< is hydrogen. In another example, R 11< is -(C 1 -C 6 )alkyl. In another example, R 11< is -(C 1 -C 6 )alkyl-(C 3 -C 6 )cycloalkyl. In another example, R 11< is -(C 1 -C 6 )alkoxy. In another example, R 11< is -(C6-C10)aryl. In another example, R 11< is -CO(C 1 -C 6 )alkyl. In another example, R 11< is -CO(C 3 -C 6 )cycloalkyl. In another example, R 11< is - CO(C 6 -C 10 )aryl. In another example, R 11< is -COO(C 1 -C 6 )alkyl. In another example, R 11< is halogen. In another example, R 11< is hydroxyl. In another example, R 11< is oxo. In another example, R 11< is 3 to 10 membered heterocycle. In another example, R 11< is 6 to 10 membered heteroaryl. In another example, R 11< is -NHCO(C 1 -C 6 )alkyl. In another example, R 11< is - (CH 2 ) n -phenyl. In another embodiment, R 11< is -SO 2< (C 1 -C 6 )alkyl. In another example, R 11< is - SO 2< (C 3 -C 6 )cycloalkyl. In another example, R 11< is -SO 2 (C 6 -C 10 )aryl. In another example, R 11< is -NR 14< R 15< . In another example, is the alkyl, aryl or heteroaryl portion of R 11< is substituted with one or more halogen, hydroxyl and / or -(C1-C6)alkoxy.

[0282] In one example, R 12< is hydrogen. In another example, R 12< is -(C 1 -C 6 )alkyl. In another example, R 12< is -(C 1 -C 6 )alkyl-(C 3 -C 6 )cycloalkyl. In another example, R 12< is -(C 1 -C 6 )alkoxy. In another example, R 12< is -(C6-C10)aryl. In another example, R 12< is -CO(C 1 -C 6 )alkyl. In another example, R 12< is -CO(C 3 -C 6 )cycloalkyl. In another example, R 12< is - CO(C 6 -C 10 )aryl. In another example, R 12< is -COO(C 1 -C 6 )alkyl. In another example, R 12< is halogen. In another example, R 12< is hydroxyl. In another example, R 12< is oxo. In another example, R 12< is 3 to 10 membered heterocycle. In another example, R 12< is 6 to 10 membered heteroaryl. In another example, R 12< is -NHCO(C 1 -C 6 )alkyl. In another example, R 12< is - (CH 2 ) n -phenyl. In another example, R 12< is -SO2(C 1 -C 6 )alkyl. In another example, R 12< is - SO 2 (C 3 -C 6 )cycloalkyl. In another example, R 12< is -SO 2 (C 6 -C 10 )aryl. In another embodiment, R 12< is -NR14R15. In another example, is the alkyl, aryl or heteroaryl portion of R 12< is substituted with one or more halogen, hydroxyl and / or -(C 1 -C 6 )alkoxy.

[0283] In one example, R 13< is hydrogen. In another example, R 13< is -(C 1 -C 6 )alkyl.

[0284] In one example, R 14< is hydrogen. In another example, R 14< is -(C 1 -C 6 )alkyl.

[0285] In one example, R 15< is hydrogen. In another example, R 15< is -(C 1 -C 6 )alkyl.

[0286] In one example, n is 0. In another example, n is 1. In another example, n is 2. In another example, n is 3.

[0287] In one example, described herein are compounds that result from any combination of X, Y, R 11< -R 15< and n as defined above.

[0288] In one example, specific examples include to those listed in Table Z, below: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0289] In another example, representative compounds are those listed in Table AA, below: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0290] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0291] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0292] In one example, the immunomodulatory compound is: or a pharmaceutically acceptable salt, solvate, prodrug, or stereoisomer thereof.

[0293] Other immunomodulatory compounds not part of the invention are 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. The compounds can be obtained via standard, synthetic methods (see e.g., U.S. Patent No. 5,635,517). The compounds are available from Celgene Corporation, Warren, NJ. 4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) has the following chemical structure:

[0294] The compound 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (lenalidomide) has the following chemical structure:

[0295] Compounds for use of the invention can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral columns as well as other standard synthetic organic chemistry techniques.

[0296] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" encompasses non-toxic acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases know in the art, which include, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, and the like.

[0297] Compounds that are acidic in nature are capable of forming salts with various pharmaceutically acceptable bases. The bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.

[0298] Immunomodulatory compounds for use of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers or mixtures of diastereomers. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular immunomodulatory compounds for use of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0299] As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. A stereomerically pure compound for use according to the invention comprises greater than about 80% by weight of one stereoisomer of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one chiral center. Similarly, the term "stereomerically enriched" means a stereomerically enriched composition of a compound having one chiral center.

[0300] Also provided herein are isotopically enriched analogs of the compounds for use provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics ("PK"), pharmacodynamics ("PD"), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. Al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. Al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. Al., Mutation Res. 308: 33 (1994); Gordon et. Al., Drug Metab. Dispos., 15: 589 (1987); Zello et. Al., Metabolism, 43: 487 (1994); Gately et. Al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

[0301] Without being limited by any particular theory, isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and / or (6) decrease the production of deleterious metabolites in specific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[0302] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect ("KIE"). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect ("DKIE"). (See, e.g, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0303] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0304] Tritium ("T") is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T 2 O. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium ("T") for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects.

[0305] Similarly, substitution of isotopes for other elements, including, but not limited to, 13< C or 14< C for carbon, 33< S, 34< S, or 36< S for sulfur, 15< N for nitrogen, and 17< O or 18< O for oxygen, will provide a similar kinetic isotope effects.

[0306] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes ("CYPs"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. As a result, these drugs often require the administration of multiple or high daily doses.

[0307] Isotopic enrichment at certain positions of a compound for use provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and / or toxicological profiles of a compound for use provided herein in comparison with a similar compound having a natural isotopic composition. In one embodiment, the deuterium enrichment is performed on the site of C-H bond cleavage during metabolism.

[0308] It should be noted that if there is a discrepancy between a depicted structure and a name given that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.4.2 COMBINATION THERAPY

[0309] Antibodies that can be used in combination with the immunomodulatory compound are monoclonal anti-CS1 antibodies, and, more preferably, humanized monoclonal anti-CS1 antibodies. In a particular embodiment, the anti-CS1 antibody is elotuzumab.

[0310] The immunomodulatory compounds and monoclonal anti-CS1 antibodies can be administered in further combination with other pharmacologically active compounds ("second active agents") for use in methods and compositions of the invention. It is believed that certain combinations work synergistically in the treatment of particular types of cancer and certain diseases and conditions associated with, or characterized by, undesired angiogenesis. Immunomodulatory compounds can also work to alleviate adverse effects associated with certain second active agents, and some second active agents can be used to alleviate adverse effects associated with immunomodulatory compounds.

[0311] One or more second active ingredients or agents can be used in the methods and compositions for use of the invention together with an immunomodulatory compound and a monoclonal anti-CS1 antibody. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[0312] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors and cytokines. Typical large molecule active agents are biological molecules, such as naturally occurring or artificially made proteins. Proteins that are particularly useful in this invention include proteins that stimulate the survival and / or proliferation of hematopoietic precursor cells and immunologically active poietic cells in vitro or in vivo. Others stimulate the division and differentiation of committed erythroid progenitors in cells in vitro or in vivo. Particular proteins include, but are not limited to: interleukins, such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF; and EPO.

[0313] Particular proteins that can be used in the methods and compositions for use of the invention include, but are not limited to: filgrastim, which is sold in the United States under the trade name Neupogen ®< (Amgen, Thousand Oaks, CA); sargramostim, which is sold in the United States under the trade name Leukine ®< (Immunex, Seattle, WA); and recombinant EPO, which is sold in the United States under the trade name Epogen ®< (Amgen, Thousand Oaks, CA).

[0314] Recombinant and mutated forms of GM-CSF can be prepared as described in U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496. Recombinant and mutated forms of G-CSF can be prepared as described in U.S. Patent Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755.

[0315] This invention further encompasses the use of native, naturally occurring, and recombinant proteins. The invention further encompasses the use mutants and derivatives (e.g., modified forms) of naturally occurring proteins that exhibit, in vivo, at least some of the pharmacological activity of the proteins upon which they are based. Examples of mutants include, but are not limited to, proteins that have one or more amino acid residues that differ from the corresponding residues in the naturally occurring forms of the proteins. Also encompassed by the term "mutants" are proteins that lack carbohydrate moieties normally present in their naturally occurring forms (e.g., nonglycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M.L. and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001).

[0316] Large molecule active agents may be administered in the form of anti-cancer vaccines. For example, vaccines that secrete, or cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF can be used in the methods, and pharmaceutical compositions for use of the invention. See, e.g., Emens, L.A., et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001). Other vaccines include anti-infection vaccines such as Prevnar.

[0317] In one embodiment of the invention, the large molecule active agent reduces, eliminates, or prevents an adverse effect associated with the administration of an immunomodulatory compound. Depending on the particular immunomodulatory compound and the disease or disorder begin treated, adverse effects can include, but are not limited to, drowsiness and somnolence, dizziness and orthostatic hypotension, neutropenia, infections that result from neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxic epidermal necrolysis, and seizures (e.g., grand mal convulsions). A specific adverse effect is neutropenia.

[0318] Second active agents that are small molecules can also be used to alleviate adverse effects associated with the administration of an immunomodulatory compound. However, like some large molecules, many are believed to be capable of providing a synergistic effect when administered with (e.g., before, after or simultaneously) an immunomodulatory compound. Examples of small molecule second active agents include, but are not limited to, anti-cancer agents, antibiotics, immunosuppressive agents, and steroids.

[0319] Examples of anti-cancer agents include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0320] Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec ®< ), imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim;Erbitux, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense ®< ); O 6< -benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[0321] Specific second active agents include, but are not limited to, oblimersen (Genasense ®< ), remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron ®< ), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, Arisa ®< , taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine, doxorubicin (Doxil ®< ), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emcyt ®< ), sulindac, and etoposide.

[0322] Further specific second active agents include, but are not limited to, proteasome inhibitors such as ixazomib and marizomib, immunomodulators such as cyclophosphamide, checkpoint inhibitors such as PD-L1 inhibitors, and epigenetic modifiers such as azacitidine.4.3 METHODS OF TREATMENTS AND PREVENTION

[0323] Methods of this invention encompass methods of treating multiple myeloma. As used herein, unless otherwise specified, the term "treating" refers to the administration of an immunomodulatory compound described herein and a monoclonal anti-CS1 antibody, and, optionally, other additional active agent after the onset of symptoms of multiple myeloma. As used herein, unless otherwise specified, the term "preventing" refers to the administration prior to the onset of symptoms, particularly to patients at risk of multiple myeloma. The term "prevention" includes the inhibition of a symptom of multiple myeloma. Patients with familial history of multiple myeloma are preferred candidates for preventive regimens. As used herein and unless otherwise indicated, the term "managing" encompasses preventing the recurrence of multiple myeloma in a patient who had suffered from it, and / or lengthening the time a patient who had suffered from multiple myeloma remains in remission.

[0324] This invention encompasses methods of treating patients who have been previously treated for multiple myeloma, but are non-responsive to standard therapies, as well as those who have not previously been treated. The invention also encompasses methods of treating patients regardless of patient's age, although multiple myeloma is more common in certain age groups. The invention further encompasses methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with multiple myeloma have heterogenous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his / her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with multiple myeloma.

[0325] Methods encompassed by this invention comprise administering one or more immunomodulatory compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with one or more monoclonal anti-CS1 antibodies to a patient (e.g., a human) suffering, or likely to suffer, from multiple myeloma.

[0326] In one embodiment of the invention, an immunomodulatory compound of the invention can be administered orally and in single or divided daily doses in an amount of from about 0.10 to about 150 mg / day. In a particular embodiment, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) may be administered in an amount of from about 0.1 to about 5 mg per day.

[0327] In a specific embodiment, 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) may be administered daily and continuously at an initial dose of 0.1 to 5 mg / day with dose escalation (every week) by 1 to 10 mg / day to a maximum dose of 50 mg / day for as long as therapy is tolerated. In a particular embodiment, pomalidomide can be administered in an amount of about 1, 2, 3, 4 or 5 mg per day to patients with relapsed multiple myeloma. The escalating dosing regimen can be used to overcome adverse effects.

[0328] In one embodiment, a monoclonal anti-CS1 antibody can be administered intravenously or subcutaneously, in an amount of from about 1 to about 1000 mg weekly or every other week. In a specific embodiment, a monoclonal anti-CS1 antibody (e.g., elotuzumab) is administered intravenously in an amount of about 10 mg / kg weekly or every other week.4.3.1 COMBINATION THERAPY WITH A SECOND ACTIVE AGENT

[0329] Specific methods of the invention comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a monoclonal anti-CS1 antibody (e.g., elotuzumab) further in combination with one or more second active agents, and / or in combination with radiation therapy, blood transfusions, or surgery. Specific methods of the invention comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a monoclonal anti-CS1antibody (e.g., elotuzumab) further in combination with one or more second active agents, or in combination with radiation therapy, blood transfusions, or surgery. Specific methods of the invention comprise administering an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a monoclonal anti-CS1 antibody (e.g., elotuzumab) further in combination with one or more second active agents, and in combination with radiation therapy, blood transfusions, or surgery. Examples of immunomodulatory compounds of the invention are disclosed herein (see, e.g., section 4.1). Examples of second active agents are also disclosed herein (see, e.g., section 4.2).

[0330] Administration of the immunomodulatory compounds, the monoclonal anti-CS1 antibodies, and the second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease being treated. A preferred route of administration for an immunomodulatory compound is orally. A preferred route of administration for a monoclonal anti-CS1 antibody (e.g., elotuzumab) is intravenous infusion. Preferred routes of administration for the second active agents or ingredients of the invention are known to those of ordinary skill in the art. See, e.g., Physicians' Desk Reference, 1755-1760 (56th ed., 2002).

[0331] The second active agent can be administered orally, intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount(s) of immunomodulatory compounds of the invention and any optional additional active agents concurrently administered to the patient. In a particular embodiment, the second active agent is oblimersen (Genasense ®< ), GM-CSF, G-CSF, EPO, taxotere, irinotecan, dacarbazine, transretinoic acid, topotecan, pentoxifylline, ciprofloxacin, dexamethasone, vincristine, doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, ixazomib, marizomib, cyclophosphamide, Prevnar, an PD-L1 inhibitor, azacitidine, or a combination thereof.

[0332] In a particular embodiment, GM-CSF, G-CSF or EPO is administered subcutaneously during about five days in a four or six week cycle in an amount of from about 1 to about 750 mg / m 2< / day, preferably in an amount of from about 25 to about 500 mg / m 2< / day, more preferably in an amount of from about 50 to about 250 mg / m 2< / day, and most preferably in an amount of from about 50 to about 200 mg / m 2< / day. In a certain embodiment, GM-CSF may be administered in an amount of from about 60 to about 500 mcg / m 2< intravenously over 2 hours, or from about 5 to about 12 mcg / m 2< / day subcutaneously. In a specific embodiment, G-CSF may be administered subcutaneously in an amount of about 1 mcg / kg / day initially and can be adjusted depending on rise of total granulocyte counts. The maintenance dose of G-CSF may be administered in an amount of about 300 (in smaller patients) or 480 mcg subcutaneously. In a certain embodiment, EPO may be administered subcutaneously in an amount of 10,000 Unit 3 times per week.

[0333] In one embodiment, the second active agents that can be administered to patients with various types or stages of multiple myeloma in combination with an immunomodulatory compound and a monoclonal anti-CS1 antibody include, but are not limited to, dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, ixazomib, marizomib, Prevnar, an PD-L1 inhibitor, azacitidine, or a combination thereof.

[0334] In another embodiment, the second active agents that can be administered to patients with relapsed or refractory multiple myeloma in combination with an immunomodulatory compound and a monoclonal anti-CS1 antibody is doxorubicin (Doxil ®< ), vincristine and / or dexamethasone (Decadron ®< ).

[0335] In one embodiment, an immunomodulatory compound can be administered orally and daily in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg prior to, during, or after the occurrence of the adverse effect associated with the administration of an anti-cancer drug to a patient. In a particular embodiment, an immunomodulatory compound of the invention is administered further in combination with specific agents such as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects that are associated with anti-cancer drugs such as but not limited to neutropenia or thrombocytopenia.

[0336] In one embodiment, an immunomodulatory compound can be administered to patients with multiple myeloma further in combination with additional active ingredients including but not limited to anti-cancer drugs, anti-inflammatories, antihistamines, antibiotics, and steroids.

[0337] In another embodiment, this invention encompasses a method of treating multiple myeloma, which comprises administering the immunomodulatory compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with a monoclonal anti-CS1 antibody, further in conjunction with (e.g. before, during, or after) conventional therapy including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug based therapy presently used to treat, prevent or manage cancer. Such therapies also include cell therapy such as CAR T-cell immunotherapy. The combined use of the immunomodulatory compound, monoclonal anti-CS1 antibody and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in certain patients. Without being limited by theory, it is believed that immunomodulatory compounds and / or monoclonal anti-CS1 antibodies may provide additive or synergistic effects when given concurrently with conventional therapy.

[0338] In one embodiment, the immunomodulatory compound can be administered in an amount of from about 0.1 to about 150 mg, and preferably from about 1 to about 50 mg, more preferably from about 2 to about 25 mg orally and daily, prior to, during, or after the use of conventional therapy.4.3.2 USE WITH TRANSPLANTATION THERAPY

[0339] As those of ordinary skill in the art are aware, the treatment of cancer is often based on the stages and mechanism of the disease. For example, as inevitable leukemic transformation develops in certain stages of cancer, transplantation of peripheral blood stem cells, hematopoietic stem cell preparation or bone marrow may be necessary. The combined use of the immunomodulatory compound, monoclonal anti-CS1 antibody and transplantation therapy provides a unique and unexpected synergism. In particular, an immunomodulatory compound exhibits immunomodulatory activity that may provide additive or synergistic effects when given concurrently with transplantation therapy in patients with cancer.

[0340] This invention encompasses a method of treating multiple myeloma which comprises administering to a patient (e.g., a human) the immunomodulatory compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof in combination with a monoclonal anti-CS1 antibody, before, during, or after the transplantation of umbilical cord blood, placental blood, peripheral blood stem cell, hematopoietic stem cell preparation or bone marrow. Examples of stem cells suitable for use in the methods of the invention are disclosed in U.S. Patent No. 7,498,171 by R. Hariri et al..

[0341] In one embodiment of this method, an immunomodulatory compound is administered in combination with a monoclonal anti-CS1 antibody to patients with multiple myeloma before, during, or after the transplantation of autologous peripheral blood progenitor cell.

[0342] In another embodiment, an immunomodulatory compound is administered in combination with a monoclonal anti-CS1 antibody to patients with relapsing multiple myeloma after the stem cell transplantation.

[0343] In another embodiment, an immunomodulatory compound, a monoclonal anti-CS1 antibody and prednisone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous stem cell.

[0344] In another embodiment, an immunomodulatory compound, a monoclonal anti-CS1 antibody and dexamethasone are administered as salvage therapy for low risk post transplantation to patients with multiple myeloma.

[0345] In another embodiment, an immunomodulatory compound, a monoclonal anti-CS1 antibody and dexamethasone are administered as maintenance therapy to patients with multiple myeloma following the transplantation of autologous bone marrow.

[0346] In another embodiment, an immunomodulatory compound and a monoclonal anti-CS1 antibody are administered following the administration of high dose of melphalan and the transplantation of autologous stem cell to patients with chemotherapy responsive multiple myeloma.

[0347] In another embodiment, an immunomodulatory compound, a monoclonal anti-CS1 antibody and PEG INTRO-A are administered to patients with multiple myeloma following the transplantation of autologous CD34-selected peripheral stem cell.

[0348] In another embodiment, an immunomodulatory compound and a monoclonal anti-CS1 antibody are administered with post transplant consolidation chemotherapy to patients with newly diagnosed multiple myeloma to evaluate anti-angiogenesis.

[0349] In another embodiment, an immunomodulatory compound, a monoclonal anti-CS1 antibody and dexamethasone are administered as maintenance therapy after DCEP consolidation, following the treatment with high dose of melphalan and the transplantation of peripheral blood stem cell to 65 years of age or older patients with multiple myeloma.

[0350] In a preferred embodiment, an immunomodulatory compound (e.g., lenalidomide) and a monoclonal anti-CS1 antibody (e.g., elotuzumab) are administered to patients with minimal residual disease after autologous stem cell transplantation. In a more particular embodiment, the patient has received treatment with an immunomodulatory compound (e.g., lenalidomide), a proteasome inhibitor (e.g., bortezomib or carfilzomib), or both, as induction therapy for newly diagnosed multiple myeloma. In another preferred embodiment, an immunomodulatory compound (e.g., lenalidomide) is administered in combination with an anti-CS1 antibody (e.g., elotuzumab) and dexamethasone.4.3.3 CYCLING THERAPY

[0351] In certain embodiments, the therapeutic agents for use of the invention are cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improves the efficacy of the treatment.

[0352] Consequently, in one specific embodiment of the invention, an immunomodulatory compound is administered daily in a single or divided doses in a four to six week cycle with a rest period of about a week or two weeks. The invention further allows the frequency, number, and length of dosing cycles to be increased. Thus, another specific embodiment of the invention encompasses the administration of an immunomodulatory compound of the invention for more cycles than are typical when it is administered alone. In yet another specific embodiment of the invention, an immunomodulatory compound of the invention is administered for a greater number of cycles that would typically cause dose-limiting toxicity in a patient to whom a second active ingredient is not also being administered.

[0353] In one embodiment, an immunomodulatory compound described herein is administered daily and continuously for three or four weeks at a dose of from about 0.1 to about 150 mg / day followed by a break of one or two weeks. In a particular embodiment, pomalidomide is administered in an amount of about 1, 2, 3, 4 and 5 mg / day for three to four weeks, followed by one week or two weeks of rest in a four or six week cycle.

[0354] In one embodiment of the invention, an immunomodulatory compound and a second active ingredient are administered orally, with administration of an immunomodulatory compound of the invention occurring 30 to 60 minutes prior to a second active ingredient, during a cycle of four to six weeks. In another embodiment of the invention, the combination of an immunomodulatory compound and a second active ingredient is administered by intravenous infusion over about 90 minutes every cycleIn another specific embodiment, each cycle comprises the administration of from about 1 to about 10 mg / day of pomalidomide and from about 50 to about 200 mg / m 2< / day of a second active ingredient for 3 to 4 weeks followed by one or two weeks of rest. Typically, the number of cycles during which the combinatorial treatment is administered to a patient will be from about one to about 24 cycles, more typically from about two to about 16 cycles, and even more typically from about four to about three cycles.

[0355] Monoclonal anti-CS1 antibodies in the methods of the present invention can also be administered cyclically to patients with multiple myeloma. A monoclonal anti-CS1 antibody (e.g., elotuzumab) is preferably administered weekly or every other week. In a specific embodiment, the anti-CS1 antibody is administered on days 1, 8, 15 and 22 in the first two 28-day cycles, and then on days 1 and 15 in the following 28-day cycles.4.4 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[0356] Pharmaceutical compositions can be used in the preparation of individual, single unit dosage forms. Pharmaceutical compositions and dosage forms for use of the invention comprise an immunomodulatory compound of the invention, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Pharmaceutical compositions and dosage forms for use of the invention can further comprise one or more excipients.

[0357] Pharmaceutical compositions and dosage forms for use of the invention also comprise one (or more) monoclonal anti-CS1 antibodies, and, optionally, additional active ingredients. Consequently, pharmaceutical compositions and dosage forms for use of the invention comprise the active ingredients disclosed herein (e.g., an immunomodulatory compound and an antibody). Examples of optional second, or additional, active ingredients are disclosed herein (see, e.g., section 5.2).

[0358] Single unit dosage forms for use of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal or transcutaneous administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient.

[0359] The composition, shape, and type of dosage forms for use of the invention will typically vary depending on their use. For example, a dosage form used in the acute treatment of a disease may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the chronic treatment of the same disease. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease. These and other ways in which specific dosage forms for use this invention will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0360] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients may be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms for use that contain little, if any, lactose mono- or di-saccharides. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient.

[0361] Lactose-free compositions for use of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions comprise active ingredients, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.

[0362] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms for use of the invention comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and / or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[0363] Anhydrous pharmaceutical compositions and dosage forms for use of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[0364] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0365] The invention further encompasses pharmaceutical compositions and dosage forms for use that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0366] Like the amounts and types of excipients, the amounts and specific types of active ingredients in a dosage form may differ depending on factors such as, but not limited to, the route by which it is to be administered to patients. However, typical dosage forms for use of the invention comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of from about 0.10 to about 150 mg. Typical dosage forms comprise an immunomodulatory compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof in an amount of about 0.1, 1, 2, 2.5, 3, 4, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular embodiment, a preferred dosage form for use comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) in an amount of about 1, 2, 3, 4, 5, 10, 25 or 50 mg. In a specific embodiment, a preferred dosage form for use comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) in an amount of about 1 mg. In a specific embodiment, a preferred dosage form for use comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) in an amount of about 2 mg. In a specific embodiment, a preferred dosage form for use comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) in an amount of about 3 mg. In a specific embodiment, a preferred dosage form for use comprises 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (pomalidomide) in an amount of about 4 mg.

[0367] Typical dosage forms for use comprise the monoclonal anti-CS1 antibody in an amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. In a specific embodiment, elotuzumab is in a 10 mg / kg IV solution. Of course, the specific amount of the antibody or second, additional anticancer drug will depend on the specific agent used, the type of cancer being treated or managed, and the amount(s) of an immunomodulatory compound and any optional additional active agents concurrently administered to the patient.4.4.1 ORAL DOSAGE FORMS

[0368] Pharmaceutical compositions for use of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990).

[0369] Typical oral dosage forms for use of the invention are prepared by combining the active ingredients in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[0370] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[0371] For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0372] Examples of excipients that can be used in oral dosage forms for use of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0373] Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. An specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103 ™< and Starch 1500 LM.

[0374] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions for use of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[0375] Disintegrants are used in the compositions for use of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms for use of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.

[0376] Disintegrants that can be used in pharmaceutical compositions and dosage forms for use of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[0377] Lubricants that can be used in pharmaceutical compositions and dosage forms for use of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

[0378] A preferred solid oral dosage form for use of the invention comprises an immunomodulatory compound described herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin. In a specific embodiment, the solid oral dosage form is a capsule comprising an immunomodulatory compound, lactose anhydrous, microcrystalline cellulose, croscarmellose sodium and magnesium stearate.4.4.2 DELAYED RELEASE DOSAGE FORMS

[0379] Active ingredients for use of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients for use of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.

[0380] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[0381] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.4.4.3 PARENTERAL DOSAGE FORMS

[0382] Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions, suspensions ready for injection, and emulsions.

[0383] Suitable vehicles that can be used to provide parenteral dosage forms for use of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0384] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms for use of the invention. For example, cyclodextrin and its derivatives can be used to increase the solubility of an immunomodulatory compound for use of the invention and its derivatives. See, e.g., U.S. Patent No. 5,134,127.4.4.4 TOPICAL AND MUCOSAL DOSAGE FORMS

[0385] Topical and mucosal dosage forms for use of the invention include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops or other ophthalmic preparations, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels.

[0386] Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide topical and mucosal dosage forms for use of this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form solutions, emulsions or gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton PA (1980 & 1990).

[0387] The pH of a pharmaceutical composition or dosage form may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.4.4.5 KITS

[0388] Typically, active ingredients for use of the invention are preferably not administered to a patient at the same time or by the same route of administration. Described herein are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a patient.

[0389] A typical kit comprises a dosage form of an immunomodulatory compound, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Kits can further comprise an antibody (e.g., elotuzumab) for administration in with the immunomodulatory compound. The kits can further comprise additional active ingredients such as oblimersen (Genasense ®< ), melphalan, G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutant or derivative thereof, or a combination thereof. Examples of the additional active ingredients include, but are not limited to, those disclosed herein (see, e.g., section 4.2).

[0390] Kits can further comprise devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, drip bags, patches, and inhalers.

[0391] Kits can further comprise cells or blood for transplantation as well as pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.5. EXAMPLES

[0392] Certain embodiments of the invention are illustrated by the following nonlimiting examples.5.1 CYCLING THERAPY IN PATIENTS

[0393] In a specific embodiment, an immunomodulatory compound, e.g., lenalidomide (not according to the claimed invention), is cyclically administered to patients with multiple myeloma. Cycling therapy involves the administration of a first agent for a period of time, followed by a rest for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improves the efficacy of the treatment.

[0394] In a specific embodiment, prophylactic or therapeutic agents are administered in a cycle of about 4 to 6 weeks, about once or twice every day. One cycle can comprise the administration of a therapeutic on prophylactic agent for three to four weeks and at least a week or two weeks of rest. The number of cycles administered is from about one to about 24 cycles, more typically from about two to about 16 cycles, and more typically from about four to about eight cycles.

[0395] For example, in a cycle of four weeks, on day 1, the administration of 10 mg / day of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is started. On day 22, the administration of the compound is stopped for a week of rest. On day 29, the administration of 10 mg / day 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is resumed.

[0396] An anti-CS1 antibody, e.g., elotuzumab, can also be cyclically administered to patients with multiple myeloma. For example, in a cycle of four weeks, elotuzumab is administered intravenously in 10 mg / kg IV solution on days 1, 8, 15 and 22, but not on the other days in the four week cycle. After the initial two cycles, elotuzumab is administered intravenously in 10 mg / kg IV solution on days 1 and 15, but not on the other days in the four week cycle.5.2 CLINICAL STUDIES IN PATIENTS

[0397] Clinical studies of patients who have received stem cell transplantation for treating multiple myeloma is conducted to assess the ability of lenalidomide in combination with elotuzumab to treat multiple myeloma.5.2.1. MRD (+) Study (CC-5013-MM-029)

[0398] MRD(+) (MRD positive) is defined as having 10 -5< cells or greater as determined by Sequenta.

[0399] Patients eighteen years of age or older can participate in this study after signing informed consent. The patients must have newly diagnosed multiple myeloma with symptomatic multiple myeloma and have undergone induction lenalidomide in combination with bortezomib / carfilzomib and dexamethasone (triplet) or bortezomib / carfilzomib in combination with dexamethasone (doublet) therapy and, subsequently, stem cell transplantation. Prior to induction the following criteria must have been met: i. All 3 criteria MM diagnostic criteria and at least one of the CRAB criteria must be met prior to induction ii. Monoclonal plasma cells in the bone marrow ≥ 10% and / or presence of a biopsy-proven plasmacytoma iii. Monoclonal protein in the serum and / or urine iv. Myeloma-related organ dysfunction (at least one of the following*): a) [C] Calcium elevation in the blood (Serum Calcemia ≥ upper limit of normal [ULN]) b) [R] Renal insufficiency (serum creatinine > 2 mg / dL) c) [A] Anemia (hemoglobin < 10 g / dL or 2 g < laboratory normal) d) [B] Lytic bone lesions or osteoporosis.

[0400] Patients must have minimum residue disease (MRD) determination by Sequenta, LDH, cytogenetics, B2M and serum albumin (ISS stage) from their initial diagnosis at screening. No prior anti-myeloma chemotherapy except for induction regimen prior to autologous stem cell transplantation. Complete response (CR), very good partial response (VGPR), partial response (PR), or stable disease (SD) must be documented according to International Myeloma Working Group (IMWG) criteria prior to randomization.

[0401] Prior to the autologous stem cell transplantation, the patients must have received in induction a proteasome inhibitor- or lenalidomide-based therapy. At 100 days after the stem cell transplantation, the patients who achieve at least stable disease are randomized to lenalidomide plus elotuzumab cohort and lenalidomide plus placebo cohort. The stratification at randomization is based on cytogenetics (high risk vs standard risk), types of induction therapy prior to stem cell transplantation (doublet vs triplet regimen), and minimization. In the lenalidomide plus elotuzumab cohort, lenalidomide is administered orally in an amount of 10 mg per day on days 1-21 of 28-day cycles. Elotuzumab is administered as a 10 mg / kg IV solution weekly on days 1, 8, 15, 22 in 28-day cycles (cycles 1 & 2); and on days 1 & 15 in 28-day cycles (cycle 3 and onward). In both cohorts the treatments continue until progressive disease (PD) or unacceptable toxicity.

[0402] Prior to the lenalidomide- or proteasome inhibitor-based induction therapy, the MRD status is evaluated by bone marrow aspirate (BMA) and Sequenta. Baseline evaluation of cytogenetics is also conducted. The MRD status is also monitored at randomization (BMA), every 12 months (BMA), every 2 cycles (BMA), and at discontinuation (peripheral blood). Once MRD (-) status is obtained, the status is confirmed with BMA.

[0403] The primary endpoint of the study is progression-free survival (PFS). The second endpoints for all patient subjects include the following: progression-free survival 2 (PFS2); overall survival (OS); overall response rate (ORR); duration of response (DoR); MRD(-) conversion rate; time from randomization to MRD(-) conversion; safety; duration of MRD(-) status; MRD levels over time (Exploratory); correlation of MRD status change with outcomes (PFS, OS) (Exploratory); and quality of life (QoL). The second end points for patient subjects achieving MRD(-) conversion include the following: time to MRD(+) recurrence (Exploratory); and time from MRD(+) recurrence to IMWG-defined progression (Exploratory). An interim analysis will be performed to assess MRD(-) conversion rates.5.2.2. MRD (-) Study (Phase II)

[0404] MRD(-) (MRD negative)is defined as having 10 -4< cells or fewer as determined by Sequenta. Prior to the autologous stem cell transplantation, the patients must have received in induction a proteasome inhibitor- or lenalidomide-based therapy. At 100 days after the stem cell transplantation, the patients who achieve at least stable disease are randomized to lenalidomide plus elotuzumab cohort and lenalidomide plus placebo cohort. The stratification at randomization is based on cytogenetics (high risk vs standard risk), and types of induction therapy prior to stem cell transplantation (doublet vs triplet regimen). In the lenalidomide plus elotuzumab cohort, lenalidomide is administered orally in an amount of 10 mg per day on days 1-21 of 28-day cycles. Elotuzumab is administered as a 10 mg / kg IV solution weekly on days 1, 8, 15, 22 in 28-day cycles (cycles 1 & 2); and on days 1 & 15 in 28-day cycles (cycle 3 and onward). In both cohorts the treatments continue until progressive disease (PD) or unacceptable toxicity.

[0405] Prior to the lenalidomide- or proteasome inhibitor-based induction therapy, the MRD status is evaluated by bone marrow aspirate (BMA) and Sequenta. Baseline evaluation of cytogenetics is also conducted. The MRD status is also monitored at randomization (BMA), every 12 months (BMA), every 2 cycles (BMA), and at discontinuation (peripheral blood). Once MRD (+) status is obtained, the status is confirmed with peripheral blood.

[0406] The primary endpoint of the study is progression-free survival (PFS) Rate at 24 months. The second endpoints for all patient subjects include the following: PFS; PFS2; PFS at interim analysis; OS; OS at interim analysis; ORR; DoR; rate of loss of MRD(-); comparison of High Risk patients vs. Standard Risk patients for loss of MRD(-) status; MRD(+) conversion at 12 and 18 months; time from MRD(+) conversion to IMWG-defined progression; time to MRD(+) conversion; duration of MRD(-) status; MRD levels over time (Exploratory); correlation of MRD status change with outcomes (PFS, OS) (Exploratory); QoL; and safety.

Claims

1. A compound for use in a method of treating multiple myeloma in a patient, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; wherein the compound is administered in combination with a therapeutically effective amount of a monoclonal anti-CS1 antibody.

2. The compound for use of claim 1, wherein the multiple myeloma is relapsed, refractory, or relapsed and refractory multiple myeloma.

3. The compound for use of claim 1 or 2, wherein the patient has received prior stem cell transplantation.

4. The compound for use of claim 3, wherein the patient has minimal residual disease after autologous stem cell transplantation.

5. The compound for use of claim 4, wherein the minimal residual disease is characterized by 10-4 or higher cells, 10-5 or higher cells when determined by flow cytometry or 10-6 or higher cells when determined by high-throughput sequencing.

6. The compound for use of claim 4 or 5, wherein the patient has received treatment with an immunomodulatory compound, a proteasome inhibitor or both, as induction therapy for newly diagnosed multiple myeloma.

7. The compound for use of claim 6, wherein the patient has received induction therapy with the immunomodulatory compound lenalidomide, and / or wherein the patient has received induction therapy with the proteasome inhibitor bortezomib or carfilzomib.

8. The compound for use of any one of claims 1 to 7, wherein the compound is administered further in combination with dexamethasone.

9. The compound for use of any one of claims 1 to 8, wherein the compound is administered cyclically, optionally wherein the compound is administered for 21 days followed by seven days of rest in a 28 day cycle.

10. The compound for use of any one of claims claim 1 to 9, wherein the compound is administered in an amount of from 1 to 50 mg per day, optionally wherein the compound is administered in an amount of 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg per day.

11. The compound for use of any one of claims 1 to 10, wherein the compound is administered orally.

12. The compound for use of claim 11, wherein the compound is administered in the form of a capsule or tablet; optionally wherein the capsule comprises the compound, lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

13. The compound for use of any one of claims 1 to 12, wherein the monoclonal anti-CS1 antibody is elotuzumab.

14. The compound for use of any one of claims 1 to 13, wherein the monoclonal anti-CS1 antibody is administered intravenously in an amount of from 1 to 1000 mg weekly or every other week, optionally wherein the monoclonal anti-CS1 antibody is administered in an amount of 10 mg / kg weekly or every other week.

15. A pharmaceutical composition for use in a method of treating multiple myeloma in a patient, wherein the pharmaceutical composition comprises a compound of the formula: or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more excipients; wherein the pharmaceutical composition is administered in combination with a therapeutically effective amount of a monoclonal anti-CS1 antibody.